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Heller, Jason E., Benjamin F. Cummings e Jason Martin. "Distribution channel effects on advisor managed investment performance". Financial Services Review 30, n. 2 (30 giugno 2022): 145–64. http://dx.doi.org/10.61190/fsr.v30i2.3479.
Abstract (sommario):
This study focuses on the effects that business models have on advisor managed portfolio per- formance by attempting to determine if advisors at Registered Investment Advisory (RIA) firms pro- duce higher net investment results compared with advisors employed at dually registered Independent Broker/Dealer (IBD) firms. Using data from one of the largest investment advisory plat- forms in the United States, we found qualified supporting evidence that advisors at RIAs outper- formed advisors at IBDs in higher-risk portfolios through the use of Turnkey Asset Management Programs and Unified Managed Accounts.
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Hall-Yannessa, Stacey L., e Scott Forrester. "Impact of Advisor Interaction on the Development of Leadership Skills in Club Sports Officers". Recreational Sports Journal 29, n. 1 (maggio 2005): 9–21. http://dx.doi.org/10.1123/rsj.29.1.9.
Abstract (sommario):
Club sports are an important component of a comprehensive recreational sports program. Participation in club sports and student organizations has been of particular interest to student services professionals who relate this type of involvement to increased skills development and other dimensions of personal growth. For years, club sports programs have required an advisor for each club sport. While there is a growing body of knowledge on the personal growth and development that students experience from faculty and staff academic advising, there is little, if any, empirical research examining the impact of club sports advisors on the development of club sports officers. This study attempts to identify differences in leadership-skills development of club sport officers based on the number of hours the officers spend consulting with their advisor. The researchers surveyed 94 officers using the Student Leadership Skills Inventory eight months after their leadership role had begun. Analysis of the self-reported data reveals a positive correlation between leadership-skills development, and the amount of time spent with the advisor. Suggestions for future research are made in the context of the limitations of the study.
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P. Bramnik, Robert, e Mauro M. Wolfe. "SEC targets investment adviser community". Journal of Investment Compliance 15, n. 1 (27 febbraio 2014): 45–47. http://dx.doi.org/10.1108/joic-01-2014-0004.
Abstract (sommario):
Purpose – To draw attention to the US Securities and Exchange Commission's (SEC) disciplinary focus on the investment adviser community Design/methodology/approach – Describes six recent enforcement cases for disclosure, custody, supervisory, procedural, and other rule violations and compliance failures; explains changes in registered investment adviser (RIA) exemptions following enactment of the Dodd-Frank Act; discusses recent SEC announcements concerning inspections and examinations of RIAs. Findings – The SEC's recent announcements and enforcement actions signal that all advisers (both registered investment advisers and exempt reporting advisers) may want to pay particular attention to their compliance programs and supervisory procedures. Originality/value – Practical advice from experienced financial services lawyers.
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Gaspar, Raquel M., e Madalena Oliveira. "Robo Advising and Investor Profiling". FinTech 3, n. 1 (3 febbraio 2024): 102–15. http://dx.doi.org/10.3390/fintech3010007.
Abstract (sommario):
The rise of digital technology and artificial intelligence has led to a significant change in the way financial services are delivered. One such development is the emergence of robo advising, which is an automated investment advisory service that utilizes algorithms to provide investment advice and portfolio management to investors. Robo advisors gather information about clients’ preferences, financial situations, and future goals through questionnaires. Subsequently, they recommend ETF-based portfolios tailored to match the investor’s risk profile. However, these questionnaires often appear vague, and robo advisors seldom disclose the methodologies employed for investor profiling or asset allocation. This study aims to contribute by introducing an investor profiling method relying solely on investors’ relative risk aversion (RRA), which, in addition, allows for the determination of optimal allocations. We also show that, for the period under analysis and using the same ETF universe, our RRA portfolios consistently outperform those recommended by the Riskalyze platform, which may suffer from ultraconservadorism in terms of the proposed volatility.
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Daar, Eric, Edwin DeJesus, Peter Ruane, Gordon Crofoot, Godson Oguchi, Catherine Creticos, Jurgen K. Rockstroh et al. "Phase 3 Randomized, Controlled Trial of Switching to Fixed-dose Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) from Boosted Protease Inhibitor-based Regimens in Virologically Suppressed Adults: Week 48 Results". Open Forum Infectious Diseases 4, suppl_1 (2017): S735. http://dx.doi.org/10.1093/ofid/ofx180.003.
Abstract (sommario):
Abstract Background Boosted protease inhibitor regimens (bPIs) are effective and often used in HIV-infected individuals with difficulties with adherence, but they can have drug–drug interactions and GI adverse effects. Bictegravir (B), a novel, potent integrase strand transfer inhibitor with a high barrier to resistance and low potential for drug–drug interactions, was coformulated with the recommended nucleoside reverse transcriptase inhibitor backbone emtricitabine (FTC)/tenofovir alafenamide (F/TAF) and demonstrated high efficacy and tolerability in randomized studies in treatment-naïve adults. This randomized Phase 3 study assesses efficacy and safety of switching to B/F/TAF from a multi-tablet regimen containing a bPI. Methods HIV-infected adults suppressed on regimens of boosted atazanavir (ATV) or darunavir (DRV) + abacavir/lamivudine (ABC/3TC) or FTC/tenofovir disoproxil fumarate (TDF) were randomized 1:1 to continue their current bPI regimen or switch to open-label coformulated B/F/TAF (50/200/25 mg) once daily. Primary endpoint was proportion with HIV-1 RNA ≥50 copies/mL (c/mL) at W48 (FDA snapshot). Noninferiority was assessed through 95.002% confidence intervals (CI) using a margin of 4%. Secondary endpoints included proportion with HIV-1 RNA <50 c/mL and safety measures at W48. Results A total of 577 participants were randomized and treated with B/F/TAF (n = 290) or current bPI regimens (n = 287): 17% women, 26% Black, median age 48 years. Most were receiving a bPI with FTC/TDF (85%) at screening. At W48, switching to B/F/TAF was noninferior to continuing bPI with 1.7% in each group having HIV-1 RNA ≥50 c/mL (difference −0.0%; 95.002% CI −2.5% to 2.5%, P = 1.00); the proportion with HIV-1 RNA <50 c/mL was 92.1% in B/F/TAF vs. 88.9% in bPI. No participant on B/F/TAF developed resistance to study drugs. One participant on DRV/ritonavir + ABC/3TC developed a treatment-emergent L74V mutation. Incidence of grade 3 or 4 AEs was similar (B/F/TAF 4%, bPI regimens 6%). No renal discontinuations or tubulopathy cases occurred with B/F/TAF. Conclusion Adults switching to B/F/TAF from a boosted PI maintained high rates of virologic suppression without resistance. B/F/TAF was safe and well tolerated. Disclosures E. Daar, Bristol-Myers Squibb: Consultant, Consulting fee. Gilead Sciences, Inc.: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Janssen: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Teva Pharmaceuticals: Consultant and Scientific Advisor, Consulting fee. ViiV: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. E. DeJesus, Abbott Laboratories; Achillion Pharmaceuticals, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann LaRoche, Idenix, Janssen, Merck, Pfizer, Sangamo, Taimed, Tobira, and Vertex: Grant Investigator, Research grant. Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Vertex: Scientific Advisor, Consulting fee. P. Ruane, Gilead: Investigator, Scientific Advisor and Shareholder, Consulting fee and Research support. Merck: Speaker’s Bureau, Speaker honorarium. Boehringer: Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. Janssen: Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. Abbott: Investigator, Scientific Advisor and Speaker’s Bureau, Research support and Speaker honorarium. Idenix: Investigator, Research support. ViiV: Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium. BMS: Consultant, Investigator and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. G. Crofoot, Gilead: Investigator and Scientific Advisor, Advisory honorarium and Research grant. ViiV: Investigator and Scientific Advisor, Advisory honorarium, Research grant and Research support. C. Creticos, Thera Technologies and ViiV Healthcare: Scientific Advisor, Consulting fee. Gilead sciences, Merck, and ViiV Healthcare: Investigator, Research support. Pfizer: Speaker’s Bureau, Speaker honorarium. J. K. Rockstroh, Abbvie: Consultant and Investigator, Consulting fee and Speaker honorarium. Gilead: Consultant, Investigator and Scientific Advisor, Consulting fee and Speaker honorarium. ViiV: Scientific Advisor, Consulting fee. Janssen: Investigator and Speaker at educational event, Speaker honorarium. J. M. Molina, Gilead, ViiV, Merck, Janssen, BMS and TEVA: Scientific Advisor, Speaker honorarium. Y. P. Liu, Gilead: Employee and Shareholder, Salary and Shareholder. K. Andreatta, Gilead: Employee and Shareholder, Salary and Shareholder. H. Graham, Gilead Sciences: Employee and Shareholder, Salary. A. Cheng, Gilead: Employee and Shareholder, Salary. H. Martin, Gilead Sciences: Employee, Salary. E. Quirk, Gilead: Employee and Shareholder, Salary
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Largeaud, Laetitia, Sarah Bertoli, Emilie Berard, Suzanne Tavitian, Muriel Picard, Stephanie Dufrechou, Naïs Prade et al. "Genomics of Hyperleukocytic Acute Myeloid Leukemia". Blood 138, Supplement 1 (5 novembre 2021): 1294. http://dx.doi.org/10.1182/blood-2021-147497.
Abstract (sommario):
Abstract Hyperleukocytic AML (HL-AML) is characterised by a high risk of early death and poor prognosis. We previously reported the impact of adding dexamethasone (DEX) to intensive chemotherapy in this situation (Bertoli et al, Haematologica 2018). The aim of this study was to give a comprehensive description of HL-AML at the molecular level and to investigate interactions between molecular lesions and DEX treatment. In the earlier study which included 160 patients (pts) (18 - 75 years old) with WBC > 100 x 10 9/L or > 50 x 10 9/L with leukostasis symptoms, multivariate analyses had shown that DEX treatment was significantly associated with better DFS, EFS and OS (Bertoli S, Haematologica 2018). In this pre-midostaurin registration patient cohort (2004-2015), no pt received a FLT3 inhibitor. Diagnostic samples for NGS analyses were available for 154 pts (96.3% of the initial cohort), 59 pts who received DEX with 3+7 induction chemotherapy and 95 pts who did not. The presence of FLT3-ITD was tested as described (Larochelle O, Oncotarget 2011). CEBPA screening was performed by Sanger sequencing (Pabst T, Nat Genet 2001). Extended DNA resequencing was performed using an Illumina NextSeq500 and Sureselect target enrichment system (Agilent, Santa Clara, CA), targeted on the complete coding regions of 79 genes commonly mutated in myeloid malignancies. The cytogenetic risk was favorable, intermediate or adverse in 15 (9.7%), 121 (78.6%) and 18 (11.7%) pts. A total of 616 mutations were identified with an average of 4 mutations/pt (0 to 10 mutations/pt). Only one pt with inv(16) had no mutation detected. The most frequently mutated genes were FLT3 (62%), NPM1 (53%), DNMT3A (34%), TET2 (23%), NRAS (21%), IDH2 (12%), WT1 (11%), PTPN11 (10%), RUNX1 (10%), KRAS (9%) and IDH1 (9%). Of the 71 pts (46%) with FLT3-ITD mutations, 32 (45.1%) had an allelic ratio > 0.5. Mutations in the RAS pathway were detected in 67 pts (44%), including NRAS (n=32, 21%), PTPN11 (n=15, 10%), KRAS (n=14, 9%) and NF1 (n=6, 4%). Overall, a large majority of pts had mutations in signaling genes (n=131, 85.1%). Drug-actionable mutations such as FLT3 (n=96), IDH2 (n=17), IDH1 (n=14), KIT (n=11), TP53 (n=4) or JAK2 (n=1) were detected in 113 patients (73.4%). In patients with FLT3 mutations (n=96), 12 had co-mutations in IDH1 and 12 pts had co-mutations in IDH2. The prognostic impact of the AML genomic classification (Papaemmanuil E, NEJM 2018), NPM1/FLT3-ITD/DNMT3A status, functional gene categories (Bullinger L, JCO 2017) ELN 2017 classification and individual genes was assessed. AML with inv(16)/CBFB-MYH11, CEBPA mutations, NPM1 mutations and myeloid transcription factor gene fusions or mutations were significantly and independently associated with better OS whereas the chromatin-modifying gene subset, NPM1/FLT3-ITD/DNMT3A triple mutations, ELN 2017-adverse risk and DNMT3A mutations were associated with poorer OS. NPM1/FLT3-ITD/DNMT3A triple mutations were observed in 25 pts (16%), 23 of whom died. Compared to this triple mutated subset, lower HRs were found in double mutant NPM1mut/FLT3-ITD (HR, 0.43; 95%CI: 0.19-0.97; P=0.041) or NPM1mut/DNMT3Amut (HR, 0.47; 95% CI: 0.21-1.07; P=0.074). The prognostic impact of each individual gene was assessed using the LASSO statistical method. CBFB-MYH11 (HR, 0.10; 95% CI: 0.02-0.43; P=0.002), CEBPA (HR, 0.22; 95% CI: 0.09-0.53; P=0.001), NPM1 (HR, 0.33; 95% CI: 0.19-0.58; P<0.001) and surprisingly, RUNX1 mutations (HR, 0.40; 95% CI: 0.18-0.92; P=0.030) were independently associated with better OS. DNMT3A mutations were independently predictive of poor OS (HR, 1.76; 95% CI: 1.02-3.03; P=0.043). Median DFS (13.6 months vs 66.3, P=0.002), EFS (11.3 vs 39.4, P=0.002) and OS (18.3 vs not reached, P=0.006) were significantly better in pts who received DEX. In multivariate analyses, no significant interaction between DEX and classifications or gene mutations was found, indicating that the effect of DEX did not differ significantly between the various genetic subsets. This may be due to insufficient numbers or DEX may have broader effects on biological phenomena such as inflammation. Since more than 80% of pts have mutations in signaling genes, inhibition of signaling pathways could improve prognosis of HL-AML. The impact of midostaurin will be interesting to analyse in this setting. Inhibition of the RAS pathway could also be a valuable avenue. Figure 1 Figure 1. Disclosures Bertoli: Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tavitian: Novartis: Consultancy. Vergez: Pierre Fabre Laboratory: Research Funding; Roche: Research Funding. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Delabesse: Novartis: Consultancy; Astellas: Consultancy. Recher: Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: dexamethasone in hyperleukocytic AML.
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Nicolini, Franck E., Gabriel Etienne, Francoise Huguet, Agnès Guerci-Bresler, Aude Charbonnier, Martine Escoffre-Barbe, Viviane Dubruille et al. "Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial". Blood 138, Supplement 1 (5 novembre 2021): 2553. http://dx.doi.org/10.1182/blood-2021-146412.
Abstract (sommario):
Abstract Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19], p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Adamia, Sophia, Zuzana Chyra, Morgan O'Keefe, Shruti Bhatt, Kenneth Wen, Geoffrey G. Fell, Yu-Tzu Tai et al. "Identification of Novel Targets Based on Splicing Alterations for Undruggable RAS/CDK Signaling Cascade in Multiple Myeloma". Blood 138, Supplement 1 (5 novembre 2021): 2688. http://dx.doi.org/10.1182/blood-2021-152986.
Abstract (sommario):
Abstract Background: RAS/CDK-dependent pathways play essential roles in multiple myeloma (MM) pathogenesis. Targeting these pathways represents a novel therapeutic strategy in MM. Our ongoing studies (>420 patients) demonstrate that aberrantly spliced transcript expressions can predict MM patient survival outcomes better than gene expression alone, indicating a significant role of splicing mechanism in MM pathophysiology. These studies also identified intron retentions as the predominant recurrent alterations (~32% of spliced genes were retained introns) in MM. We evaluated splicing alterations associated with pathway-level responses after RAS/CDK inhibition in order to identify and validate novel molecular targets. Methods/results: MM cells were treated with selected Erk1/2 and CDK4/6 inhibitors (Ei, Ci) to inhibit RAS and CDK pathways. Our studies demonstrated strong synergistic (IC<0.5) MM cytotoxicity triggered by this combination treatment, which triggered dose-dependent manner G0/G1 phase growth arrest. We assessed early death cascade in MM cells after Ei+Ci treatment, and demonstrated significant priming to selective peptides BIM, BAD, and MS1 or HRK, suggesting dependency on BCL2 and MCL1 or on BCL-XL proteins. Our studies showed that Ei+Ci treatment induced inhibition of key target molecules in Erk1/2 and CDK4/6 signaling including c-myc, p-RSK, p-S6, p-RB, and E2F1, suggesting on-target activity of Ei and Ci. Patient MM cells co-cultured with or without autologous BM stromal cells remain equally sensitive to Ei+Ci, suggesting that this combination can overcome the protective effects of the MM BM milieu. Moreover, our in vivo study demonstrated a significant (P=0.0004) MM burden decrease in Ei+Ci-treated mice. We evaluated the effect of Ei+Ci treatment on target gene expression in BM cells isolated from flushed femurs of treated animals with Ei, Ci or Ei+Ci, and observed downregulation of Erk1/2-CDK4/6-dependent gene signature. Therefore, we suggest that these inhibitors selectively target Erk1/2, CDK4/6 and their downstream substrates both in vitro/vivo. We next evaluated aberrantly spliced transcript expression in MM cells, with/without Erk1/2 knockdown (KD) or with Ei+Ci treatment. Unsupervised clustering of deregulated genes showed dose-dependent treatment effects. This observation was further supported by principal component analyses: upregulation in response to Erk1/2 KD and downregulation due to treatment with Ei+Ci were considered spliced gene-signatures linked to RAS/CDK modulation. Gene/pathway enrichment analyses of these genes showed their involvement in cell proliferation and regulation of epigenetic networks in MM. Importantly, these analyses suggest that overexpression of RAVER1/SNRPB core splicing regulator genes are associated with RAS/CDK pathway regulation. These genes encode subunits of U1/2/4/5 spliceosome complex and are involved in intron retention processes, a marker of malignant transformation. We compared signature-gene expressions from 558 MM patient samples to the signature-genes in plasma cells from normal donors and observed significant (p<2e-11) upregulation of genes with progression from MGUS to sMM, and, also to overt MM . SNRPB overexpression is associated with shorter overall patient survival (p<0.01), while RAVER1 is linked with poor outcomes. SNRPB proteins are also overexpressed in MM cells. Our studies evaluating SNRPB effects on RNA splicing showed both upregulation of transcripts with full intron retention and transcripts with cryptic stop codons utilizing intronic sequences causing their partial retention. We evaluated RAVER1 and SNRPB expression in BM cells from animals treated with Ei and Ci alone or in combination. We observed significant downregulation of RAVER1/SNRPB (p=0.001) in BM samples obtained from animals treated with Ei+Ci. We observed decreased intron retention events in genes in treated samples, consistent with our in vitro analyses in MM cell lines and patient samples. Thus, RAVER1/SNRPB overexpression contributes to the aberrant transcriptome splicing associated with RAS/CDK cascade in MM. Conclusions: Our studies 1) show an association between RNA processing and RAS-CDK pathways in MM, 2) identify a core splicing protein, SNRPB/RAVER1, as a novel target for modulating this cascade, and 3) suggest that targeting spliceosome complexes represents a promising therapy in MM. Disclosures Letai: Zentalis Pharmaceuticals: Other: equity holding member of the scientific advisory board; Dialectic Therapeutics: Other: equity holding member of the scientific advisory board; Flash Therapeutics: Other: equity holding member of the scientific advisory board. Anderson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.
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Wexler, Mark N., e Judy Oberlander. "Robo-advisors (RAs): the programmed self-service market for professional advice". Journal of Service Theory and Practice 31, n. 3 (8 gennaio 2021): 351–65. http://dx.doi.org/10.1108/jstp-07-2020-0153.
Abstract (sommario):
PurposeThis conceptual paper draws together an interdisciplinary approach to robo-advisors (RAs) as an example of an early and successful example of automated, programmed professional services.Design/methodology/approachLittle is known about the forces driving this change in the delivery of professional service. This work explores the drivers of RAs, the degree of disruption incurred by the introduction of RAs, and how, as RAs advance, trust in algorithmic authority aids in legitimating RAs as smart information.FindingsFrom the firms' perspective, the drivers include rebranding occasioned by the financial crisis (2008), the widening of the client base and the “on-trend” nature of algorithmic authority guided by artificial intelligence (AI) embedded in RAs. This examination of the drivers of RAs indicates that professional service automation is aligned with information society trends and is likely to expand.Practical implicationsExamining RAs as an indicator of the future introduction of programmed professional services suggests that success increases when the algorithmic authority in the programmed serves are minimally disruptive, trustworthy and expand the client base while keeping the knowledge domain of the profession under control of the industry.Originality/valueTreating RAs as an early instance of successfully embedding knowledge in AI and algorithmically based platforms adds to the early stages of theory and practice in the monetization and automation of professional knowledge-based services.
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Carande, Robert. "Reference Advisory Systems (RAS): Some Practical Issues". Reference Services Review 17, n. 3 (marzo 1989): 87–90. http://dx.doi.org/10.1108/eb049069.
11
Rivera, Daniel, Hagop M. Kantarjian, Gautam Borthakur, Marina Konopleva, Rashmi Kanagal-Shamanna, Naveen Pemmaraju, Naval Daver et al. "Implications of RAS Mutational Status in Subsets of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) across Therapy Groups". Blood 136, Supplement 1 (5 novembre 2020): 20–22. http://dx.doi.org/10.1182/blood-2020-142043.
Abstract (sommario):
Introduction Activating mutations in RAS have been reported in about 10-15% of patients with AML. Previous studies have not identified a prognostic significance for RAS mutations in AML treated with conventional chemotherapy. However, RAS mutations have emerged as a potential mechanism of resistance to treatment with small molecule inhibitors of FLT3, IDH, and BCL2. With broader availability of next generation sequencing, and the identification of wider heterogeneity in AML, we aimed to better characterize the genomic landscape of RAS mutated AML and outcomes within various subsets. Methods We conducted a retrospective analysis in 1410 consecutive patients with newly diagnosed (ND) AML) treated at out institution from 12/2011 to 01/2020, who had a baseline genomic testing available. Patients were treated with a variety of therapies, classified as: HMA-alone, HMA+Venetoclax (Ven), Intensive chemotherapy (HiDAC based), Intensive+Ven, low intensity double nucleoside analogue (cladribine+LDAC; Clad/LDAC), and Clad/LDAC + Ven. Response rates and outcomes were analyzed by age, cytogenetic prognostic subgroup (favorable [FAV], diploid [DIP], other intermediate [INT], adverse [ADV]), and type of therapy in the context of mutated (RAS-mut) or wild type RAS (RAS-WT). We sought to characterize the impact of RAS mutations on AML outcomes in the era of targeted therapy. Results Baseline patient and disease characteristics are detailed in table 1. Among 1410 patients with ND AML, 273 (20%) were RAS-mut; of these, 196 (72%) had NRAS-mut, 47(17%) had KRAS-mut, and 29(11%) had both. Patients with RAS-mut were younger(median age 62 vs. 66 years; P=0.001) and had higher a median WBC (P=0.02) and platelet count (P=0.01) at diagnosis compared to those with RAS-WT. Among the cytogenetic groups: FAV, INT, DIPLOID, ADV, RAS-mut were present in 39%, 20%, 16%, and 6%, respectively. Patients with RAS-mut were more likely to have concomitant mutations in ASXL1 (13%; P=0.03), , RUNX1 (10%; P=0.03), and less likely to have concomitant mutations in JAK2 (1%; P=0.03) and TP53 (8%; P<0.01). Outcomes by subset and by therapy group are summarized in Table 2. Although there was a trend in favor of RAS-mut, there was no significant difference in OS among pts younger or older than 60 yrs of age by RAS mutation. There was no difference in OS by NRAS or KRAS mutation (median OS 16 vs. 16.5 m; P=0.45). Pts with RAS-mut AML classified as non-secondary/de novo AML (P=0.003), therapy-related AML (P=0.02), and those who received intensive therapy had a significantly better OS compared to RAS-WT. The addition of Ven to each therapy group was associated with higher response rates and median OS but were not statistically significant (Figure 1). Response rates among patients with or without RAS mutations were similar, with a trend for better responses with araC-based therapy, compared to non-araC based. Compared to RAS-WT, RAS-mut was associated higher response among pts with diploid karyotype, de novo AML, and those treated with intensive therapy. Among pts with MLL-rearrangements (P=0.09) and MECOM translocation (P=0.06), RAS-mut was associated with lower response rates compared to RAS-WT. Among patients with TP53 mutated AML, co-mutation with RAS was associated with worse outcomes compared to RAS-WT (CR rates of 4% vs. 16% P<0.001; median OS 3.4 vs. 5.8 months, P=0.77). Conclusion RAS mutations are present across AML subsets, with higher representation among pts with FAV cytogenetics and relative underrepresentation among pts with ADV karyotype and TP53-mutations. Among patients with DIP cytogenetics, de novo AML, and those treated with intensive therapy, RAS-mut are associated with higher response rates and more favorable outcomes. Early observations suggest modest improvements in ORR with the addition of Ven to chemotherapy but no OS benefit. Targeting the RAS pathway among specific AML subsets remains an important area of further research. Figure 1 Disclosures Kantarjian: Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Takeda: Honoraria. Borthakur:Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; FTC Therapeutics: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. Konopleva:AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Kisoji: Consultancy; Genentech: Consultancy, Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; AstraZeneca: Research Funding; Calithera: Research Funding. Pemmaraju:Samus Therapeutics: Research Funding; Blueprint Medicines: Honoraria; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Celgene: Honoraria; Cellectis: Research Funding; Pacylex Pharmaceuticals: Consultancy; AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. DiNardo:Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Calithera: Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding. Kadia:Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; JAZZ: Honoraria, Research Funding.
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Smith, Catherine C., Mark J. Levis, Alexander E. Perl, Giovanni Martinelli, Andreas Neubauer, Ellin Berman, Pau Montesinos et al. "Emerging Mutations at Relapse in Patients with FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia Who Received Gilteritinib Therapy in the Phase 3 Admiral Trial". Blood 134, Supplement_1 (13 novembre 2019): 14. http://dx.doi.org/10.1182/blood-2019-122620.
Abstract (sommario):
Introduction: The phase 3 ADMIRAL trial demonstrated that gilteritinib, a novel, potent, oral FLT3 inhibitor, significantly prolonged overall survival and resulted in higher remission rates compared with salvage chemotherapy in patients with FLT3-mutation-positive (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML; Perl AE, et al. AACR 2019), even in the presence of common co-occurring AML mutations (DNMT3A, NPM1, and WT1) (Levis MJ, et al. J Clin Oncol. 2019;37[suppl 15]:7000). However, as with other FLT3 inhibitors, patients often develop resistance after an initial response to gilteritinib. Evidence suggests that expansion of leukemic clones containing mutations in Ras/MAPK pathway genes NRAS and KRAS mediates secondary resistance to gilteritinib in patients with FLT3mut+ R/R AML, and confirms that cells with Ras/MAPK pathway mutations are FLT3mut+ (McMahon CM, et al. Cancer Discov. 2019; doi: 10.1158/2159-8290). We evaluated emerging mutations in patients who relapsed while receiving gilteritinib therapy in the ADMIRAL trial. Methods: Blood or bone marrow samples were available for 361 patients at baseline (97.3% of the intention-to-treat population [N=371]) and for 40 patients who relapsed on gilteritinib treatment. Samples were analyzed by next-generation sequencing using the Archer Core Myeloid Panel. Data were analyzed using Archer Analysis software; the variant allele frequency (VAF) cutoff was ≥2.7%. Results: Of 371 patients enrolled in the ADMIRAL trial, 247 were assigned to 120-mg/day gilteritinib and 75 (30.5%) relapsed during the study. Most relapses (n=72/75; 96.0%) occurred ≤4 weeks from the last gilteritinib dose. Forty patients who had samples available at baseline also had samples at relapse for comparison. No samples were available from patients who relapsed on chemotherapy. At relapse, 27/40 patients (67.5%) had new mutations, including mutations in Ras/MAPK pathway genes (n=18), FLT3 (n=6), WT1 (n=3), IDH1 (n=1), and GATA2 (n=1) (Table). Thirteen patients (32.5%) had no new mutations. Of the 18 patients with Ras/MAPK pathway gene mutations at relapse, 11 (61.1%) had >1 new mutation at relapse (range, 2-6). The most frequently mutated Ras/MAPK pathway gene was NRAS (n=11). Patients were also assessed for Ras/MAPK gene pathway mutations prior to gilteritinib therapy. Among all FLT3mut+ patients analyzed for co-mutated genes at baseline (n=361), 25 (6.9%) had Ras/MAPK pathway gene mutations detected (gilteritinib, n=18; salvage chemotherapy, n=7; median VAF, 13% [range, 3.4%-50%]). In contrast to the 12.0% of patients (n=3/25) who had >1 Ras/MAPK pathway gene mutation at baseline, 61.1% (n=11/18) had >1 Ras/MAPK pathway gene mutation at relapse. Notably, a considerable number of gilteritinib-treated patients who had Ras/MAPK pathway gene mutations at baseline achieved remission: the rate of CRc (ie, composite complete remission: complete remission [CR] or CR with incomplete hematologic/platelet recovery) was 38.9% (n=7/18); the rate of CR/CRh (ie, CR or CR with partial hematologic recovery) was 27.8% (n=5/18). Six patients acquired new FLT3 mutations at relapse. Five of these six patients acquired a F691L gatekeeper mutation; one of these five patients also acquired a FLT3 juxtamembrane domain point mutation. Of the three patients who acquired a WT1 mutation at relapse, one also acquired a FLT3 F691L gatekeeper mutation. The acquisition of Ras/MAPK pathway gene mutations and FLT3 F691L gatekeeper mutations at relapse was mutually exclusive. Conclusions: In patients with FLT3mut+ R/R AML who relapsed on gilteritinib therapy, Ras/MAPK pathway gene mutations and FLT3 F691L gatekeeper mutations were the most common mutational events. The presence of a Ras/MAPK pathway gene mutation at baseline did not preclude benefit from gilteritinib therapy, possibly due to fewer Ras/MAPK pathway gene mutations per patient at baseline than at relapse. The acquisition of multiple Ras/MAPK pathway gene mutations at relapse likely mediates continued engagement of Ras/MAPK signaling in patients with FLT3mut+ R/R AML receiving gilteritinib. The frequency of emergent FLT3 F691 gatekeeper mutations at relapse in patients who received 120-mg/day gilteritinib in the ADMIRAL study was similar to that observed in relapsed patients who received 20- to 450-mg/day gilteritinib (Levis MJ, et al. Blood. 2017;130[suppl 1]:2705). Table Disclosures Smith: Revolution Medicines: Research Funding; Astellas Pharma: Research Funding; fujiFilm: Research Funding; Abbvie: Research Funding. Levis:Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Daiichi Sankyo Inc: Consultancy, Honoraria. Perl:Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; BioMed Valley Discoveries: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Bayer: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding. Martinelli:Daiichi Sankyo: Consultancy, Honoraria; Roche: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Janssen: Consultancy, Other: trial grant; Amgen: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant. Berman:Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Abbvie: Research Funding; Astellas: Research Funding; Al Therapeutics: Research Funding; Forma: Research Funding; Incyte: Research Funding; Kite: Research Funding; Takeda: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Yokoyama:Astellas: Other: Travel expenses. Recher:Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yoon:MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Janssen: Consultancy; Genentech, Inc.: Research Funding; Amgen: Consultancy, Honoraria; Yuhan Pharma: Research Funding; Novartis: Consultancy, Honoraria. Hill:Astellas: Employment; Ligacept, LLC.: Other: Stock, Patents & Royalties. Rosales:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties.
13
Ball, Brian J., Meier Hsu, Sean M. Devlin, Christopher Famulare, Sheng F. Cai, Andrew Dunbar, Zachary D. Epstein-Peterson et al. "RAS Mutations Are Independently Associated with Decreased Overall Survival and Event-Free Survival in Patients with AML Receiving Induction Chemotherapy". Blood 134, Supplement_1 (13 novembre 2019): 18. http://dx.doi.org/10.1182/blood-2019-125319.
Abstract (sommario):
Background: Activating mutations of NRAS and KRAS genes are common in newly diagnosed acute myeloid leukemia (AML), occurring in 11-16% and 4-5% of patients, respectively. RAS mutations are frequently acquired at time of progression from MDS to AML and are associated with poor survival. Next generation sequencing (NGS) at diagnosis and during complete remission has shown that RAS mutations have high clearance rates with induction chemotherapy. In the CALGB 8525 study, RAS-mutant younger patients (age <60 years) randomized to treatment with high-dose cytarabine consolidation had a lower 10-year cumulative incidence of relapse when compared to RAS WT patients. We performed a single center retrospective study to determine the outcomes of NRAS and KRAS mutated AML in patients receiving induction chemotherapy. Methods: We retrospectively reviewed the charts of patients with newly diagnosed AML treated at Memorial Sloan Kettering Cancer Center between January 1, 2014 to May 15, 2019. Patients with pathologic confirmation of AML and treatment with induction chemotherapy were included. Age < 18 years old, treatment with a pediatric induction regimen, a diagnosis of biphenotypic AML, unknown RAS mutation status at diagnosis, or treatment an outside institution were criteria for exclusion. All patients underwent NGS from a diagnostic bone marrow aspirate (BMA) with MiSeq or MSK-IMPACT platforms. Mutations present with a variant allele frequency (VAF) ≥ 1% were retained. Response was evaluated per ELN 2017 criteria. Immunophenotypic MRD was identified in BMA by multiparameter flow cytometry. Any level of residual disease was considered MRD+. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to summarize OS and EFS. Multivariable cox regression, including time-dependent variables was performed on univariate factors with p<0.05. Results: 202 patients, including 162 WT and 40 RAS mutant met inclusion criteria for further analysis. Mutations in NRAS and KRAS occurred in 14%, and 8% of patients, respectively with 6 patients having co-occurring NRAS and KRAS mutations. At baseline, the RAS mutant AML cohort had a significantly greater proportion of patients with AML-MRC and a trend toward fewer patients receiving allogeneic stem cell transplant. (Table 1.) Cytogenetic abnormalities were similar among RAS and WT patients. Sequencing at diagnosis revealed an increased frequency of FLT3 TKD, RUNX1, TET2, WT1, and ETV6 mutations and a decreased frequency of FLT3-ITD and TP53 mutations in the RAS mutant cohort. Response rates and MRD negative remission rates to induction chemotherapy were similar between RAS and WT AML patients (Table 2). With a median follow up of 25 months among survivors, RAS mutant AML was associated with a significant decrease in median EFS (4.9 vs. 11.4 months, p< 0.01) and a near significant decrease in median OS (12 vs. 30.1 months, p=0.057) (Figure 1 and 2). After controlling for variables with p<0.05 on univariate analysis including age, prior myeloid malignancy, AML classification, ELN risk, transplantation, and re-induction, RAS mutation was independently associated with an increased risk of death (HR 1.85, p=0.016) and decreased EFS (HR 2.19, p< 0.01) on multivariate analyses (Tables 3 and 4). Among 77 patients with paired sequencing at diagnosis and at time of CR or CRi, all RAS mutations (n=17) were cleared (Figure 3). Additionally, other RAS pathway mutations had high clearance rates including PTPN11 (n=8, 100%), NF1 (n=3, 100%, and CBL (n= 4, 80%) (Figure 3). RAS mutation clearance also occurred in 3 out of 8 patients (38%) not achieving CR or CRi after induction. RAS mutation clearance persisted in 6 out of 10 responding patients at time of relapse. Conclusions: In summary, the presence of RAS mutations in patients with AML receiving induction chemotherapy was associated with decreased overall and event free survival. RAS mutant AML was enriched among patients with AML-MRC and prior myeloid neoplasms, which was also associated with decreased survival. Lastly, treatment with chemotherapy led to a high rate of RAS mutation clearance in responders that persisted at the time of disease relapse. The poor prognosis of RAS mutant AML despite RAS mutation clearance suggests that other therapies are needed in combination with chemotherapy to improve outcomes in this high-risk population. Disclosures Cai: Imago Biosciences, Inc.: Consultancy. Viny:Hematology News: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Other: Sponsored travel. Goldberg:American Society of Clinical Oncology: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Research Funding; American Society of Hematology: Research Funding; DAVA Oncology: Honoraria; Pfizer: Research Funding; Arog Pharmaceuticals: Research Funding; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Celgene: Consultancy. Tallman:BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy; Cellerant: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein:Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees.
14
Tasakis, Rafail Nikolaos, Alessandro Lagana, Violetta Leshchenko, David Melnekoff, Itai Beno, Jonathan J. Keats, Daniel Auclair et al. "ADAR1 Drives Disease Progression in Multiple Myeloma By Acting Both As an RNA Editor of Specific Transcripts and As a DNA Mutator of Their Cognate Genes". Blood 134, Supplement_1 (13 novembre 2019): 3092. http://dx.doi.org/10.1182/blood-2019-130669.
Abstract (sommario):
RNA editing is an epitranscriptomic modification of emerging relevance to disease development and manifestations. Here we identify a novel role of the RNA editing enzyme ADAR1 in multiple myeloma (MM) progression as inducer of cognate DNA mutations. We have previously demonstrated (Lagana et al, ASH 2017) that ADAR1, which resides on human chromosome 1q21, is an RNA editor whose over-expression, either by IFN induction or through gene amplification, is associated with poor outcomes in MM. We now demonstrate robust and reproducible ADAR-mediated RNA editing in MM that increases with disease progression. At the same time, since disease progression is also correlated with the acquisition of new mutations, we asked whether ADAR1 could play the dual role of RNA editor and DNA mutator in MM, especially in the context of relapse. In fact, previous work has revealed that ADAR can exert its functions by acting on DNA/RNA hybrids in vitro (Zheng et al, Nucleic Acids Research 2017), and that DNA mutations at edited sites occur more often than at unedited sites in human and D melanogaster (Popitsch et al, BioRxiv 2017). We performed a careful bioinformatic dissection of matched pre-and post-relapse samples from 21 patients in the MMRF CoMMpass Study. Samples were profiled both with whole-exome sequencing (WES) to identify DNA mutations, and with RNAseq to identify editing instances. WES raw data was processed according to GATK Best Practices to generate alignment files, which were then processed with Samtools to identify mutations. RNAseq data was mapped using the tool GSNAP and processed using REDItools to identify editing events. Downstream analysis revealed a correlation between locations of RNA editing at diagnosis and of DNA mutation at relapse, with regions mutated matching known MM mutational hotspots in genes participating in several pathways that are relevant in MM, such as IFNa, IFNg response, IL2-STAT5 and TNF-NFkB. Finally, we demonstrated that editing at those locations is reproducible in a number of tumor cell lines, and that targeted editing of those locations could also result in the generation of mutations, similar to those we observed from patient data. Overall, we have shown that the RNA editor ADAR1, can also mutate the DNA cognate to the targeted transcript, generating specific mutational signatures at predetermined locations. We further hypothesize that this dual role of RNA editor and DNA mutator might be shared by other deaminases, and we suggest that in some contexts, DNA mutation might be the result of collateral damage on the genome by an editing enzyme whose primary job is to re-code the cognate transcript toward specific functional outcomes. Disclosures Madduri: undation Medicine: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Takeda: Consultancy. Richter:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Chari:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cho:Agenus: Research Funding; Genentech: Honoraria, Research Funding; BMS: Consultancy; GSK: Consultancy; Takeda: Research Funding; Celgene: Honoraria, Research Funding; The Multiple Myeloma Research Foundation: Employment. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy. Parekh:Foundation Medicine Inc.: Consultancy; Karyopharm Inc.: Research Funding; Celgene Corporation: Research Funding.
15
Houdyshell, Michael, Charles Xiaoxue Wang e Matthew Plescia. "Remote Academic Advising with a Synchronous Communication Technology: A Case Study". Research on Education and Media 14, n. 2 (1 dicembre 2022): 71–81. http://dx.doi.org/10.2478/rem-2022-0024.
Abstract (sommario):
Abstract As the COVID-19 pandemic shut down most face-to-face instructions and services in higher education, universities struggled to continue teaching and serving students. In particular, student services like academic advising were significantly impacted, as most advising is conducted in person. The use of synchronous communication technology was suddenly increased to continue advising students, employing Remote Academic Advising (RAA). Three researchers at a state university in the southeast USA conducted a case study to understand the experiences of using RAA by academic advisors. The study included 11 academic advisors from different academic colleges and areas who were engaged in RAA to provide advising service to students during the 2020–2021 academic year. Four themes emerged after a reiterative process of coding and analysing the interview responses. The four themes were a slow transition to using RAA, RAA can also be relational, RAA can promote more awareness of mental health and RAA should be part of regular advising practice. The discussion section includes recommendations for advancing RAA as regular practice through a concerted effort of promotion, leadership and effective use of RAA with synchronous communication technology among the advising community on campus.
16
Huang, Zengyi, Chang Che, Haotian Zheng e Chen Li. "Research on Generative Artificial Intelligence for Virtual Financial Robo-Advisor". Academic Journal of Science and Technology 10, n. 1 (26 marzo 2024): 74–80. http://dx.doi.org/10.54097/30r2kk80.
Abstract (sommario):
This research explores the intersection of artificial intelligence and finance, focusing on the emergence of intelligent investment advisers, commonly known as Robo-advisers (RAs). These RAs utilize robust computer models and artificial intelligence algorithms to deliver personalized asset management investment plans for users. Notably, Wealthfront is highlighted as a prominent platform in this field, offering automated investment management services aimed at optimizing investment returns. The study investigates the impact of users' past investment performance on their adoption of intelligent advisers, considering factors such as previous defaults and recent investment performance. It reveals that frequent adjustments to the use of intelligent advisers may hinder long-term investment objectives, emphasizing the importance of consistent usage to fully capitalize on their benefits. Furthermore, the research emphasizes the significance of transparency, user-friendly interaction design, and tailored financial services to foster user trust and enhance the optimization of intelligent advisers' design.
17
Hosry, Jeff, Felipe Samaniego, Francesco Turturro, Minas P. Economides e Harrys A. Torres. "Effect of Lenalidomide on Hepatitis C Viremia in Cancer Patients: A Case Series". Blood 128, n. 22 (2 dicembre 2016): 5691. http://dx.doi.org/10.1182/blood.v128.22.5691.5691.
Abstract (sommario):
Abstract Background: T cells play an important role in controlling hepatitis C virus (HCV) infection. Immunomodulatory drugs affecting T cells such as thalidomide and lenalidomide are used in the treatment of some hematologic cancers (mainly multiple myeloma). Lenalidomide is up to 1000 times more potent than thalidomide in stimulating T cell proliferation, interferon-γ and interleukin-2 production. HCV reactivation (increase of HCV-RNA by at least 1 log10IU/mL) with hepatitis flare after thalidomide therapy was recently reported (Mahale et al., Open Forum Infect Dis. 2015); however, the effect of lenalidomide on HCV-viremia has not been studied yet. Methods: HCV-infected cancer patients treated with lenalidomide at MD Anderson Cancer Center (11/2012-3/2016) were studied. HCV-RNA levels were measured before and after lenalidomide use. Since chronically infected patients have stable HCV-RNA levels that only varies ∼0.5 log10 IU/m, a significant change in HCV viremia was defined as a change of HCV-RNA ≥ 1 log10IU/ml from baseline. Hepatitis flare was defined by an increase of ALT level to ≥ 3 times upper limit of normal (or >170 IU/ml). Results: Five HCV-infected cancer patients treated with lenalidomide were studied. All the patients were males with a median age of 56 years. They had multiple myeloma (n=4) or large B-cell lymphoma (n=1). Four patients had HCV genotype 1 (80%) and 1 had genotype 2 (20%). Two patients (40%) were cirrhotics. The 5 patients studied received 6 different lenalidomide-containing regimens: 2 with lenalidomide monotherapy, 2 lenalidomide + rituximab and 2 lenalidomide + steroids. HCV-RNA levels were measured between week 4 (1, 17%) and week 12 (5, 83%) on lenalidomide treatment. A decrease of HCV-RNA was seen with all the 6 regimens (100%) (Figs 1A, 1B and 1C). Nonetheless, a significant decrease (>1 log10IU/ml) was noted in 4 out of the 6 regimens: two on lenalidomide monotherapy (1.21 and 1.49 log10IU/ml) and two on lenalidomide + rituximab (1.15 and 1.3 log10IU/ml). Hepatitis flare was only seen in one patient treated with lenalidomide + rituximab but he did not have concomitant HCV-RNA changes. Conclusion: Unlike thalidomide,lenalidomide does not cause HCV reactivation. On the contrary, this agent seems to inhibit HCV replication. Figure 1 Figure 1. Disclosures Samaniego: Karus Therapeutics: Research Funding. Torres:Pfizer: Other: Scientific advisor; Theravance Biopharma: Other: Scientific advisor; Astellas Pharma: Other: Scientific advisor; Novartis: Other: Scientific advisor; Genentech: Other: Scientific advisor; Janssen Pharmaceuticals: Other: Scientific advisor; Vertex Pharmaceuticals: Other: Scientific advisor, Research Funding; Merck & Co.: Other: Scientific advisor, Research Funding; Gilead Sciences: Other: Scientific advisor, Research Funding.
18
Haebe, Sarah, Tanaya Shree, Anuja Sathe, Grady Day, HoJoon Lee, Debra K. Czerwinski, Susan Grimes, Hanlee Ji e Ronald Levy. "Site to Site Comparison of Follicular Lymphoma Biopsies By Single Cell RNA Sequencing". Blood 134, Supplement_1 (13 novembre 2019): 297. http://dx.doi.org/10.1182/blood-2019-129445.
Abstract (sommario):
Follicular lymphoma (FL) originates from a single B cell that has rearranged one copy of its BCL2 gene on chromosome 18 to the Ig locus on chromosome 14 and in addition has acquired a mutation in a histone modifying gene such as CREBBP or KMTD2. By the time the disease is diagnosed the progeny of this original cell harbors additional mutations and is usually found at multiple lymphoid sites throughout the body. At each of these sites the malignant cells are accompanied by a rich network of follicular dendritic cells, T cells and other immune cells. This tumor microenvironment (TME) is clearly an important feature of the biology of FL and can impact the clinical behavior of the disease (Dave et al., NEJM, 2004). It remains unknown whether tumor clonal heterogeneity and the composition of the TME differ between various lymphoma sites within the same patient. Single cell RNA sequencing facilitates a detailed and unbiased view of both the tumor clone and the complex TME. To profile the TME and explore FL tumor evolution, we obtained fine needle aspirates (FNAs) at 2 different sites in the body and peripheral blood specimens all on the same day and subjected these samples to single cell RNA sequencing and immune repertoire analysis. These biopsies were taken prior to therapy from patients entering immunotherapy clinical trials (NCT02927964, NCT03410901). Single cell RNA sequencing of FNA and blood samples was performed using the 10X Genomics platform to an average targeted depth of 50,000 reads/cell. We have prepared sequencing libraries from 15 tumor FNA and peripheral blood samples from 5 patients thus far. Typically, 3,000-10,000 cells have been sequenced per sample, with excellent sequencing quality metrics. By applying Uniform Manifold Approximation and Projection (UMAP), a dimensionality reduction algorithm, we found the TME of these FL patients to be richly populated by many phenotypically discrete non-malignant cells, including many subpopulations of T cells, B-cells, myeloid cells, NK cells and dendritic cells. Evaluating the combined dataset containing all tumor samples for all 5 patients, we found that malignant B cells from different patients clearly clustered apart from each other, a feature not dependent on immunoglobulin clonality or HLA type. Each patient's tumor population contained 3-5 distinct subpopulations, presumably a result of multiclonal tumor evolution. Nonetheless, we were able to define several malignant B-cell sub-phenotypes common to all patients. Intriguingly, compared to malignant B cells, infiltrating non-malignant B cells showed higher MHC I expression, activation markers, and an enrichment in interferon-induced genes. Of note, we could also detect circulating tumor cells in peripheral blood samples of several patients, and these exhibited a distinct gene expression profile compared to their counterparts within lymph nodes. Analysis of the diverse T cell subpopulations within tumors revealed distinct functional states. For example, in regulatory and T follicular helper cells, we identified activated clusters (CD27, BATF, TNFRSF4) and putative resting clusters (SELL, KLF2, IL7R), while effector T cells resided in separate cytotoxic (GZMA, GZMB, GNLY) and exhausted (TIGIT, CXCL13, LAG3) clusters. Tumor B cell gene expression and composition of the TME from site to site within the same patient were similar in some cases and remarkably divergent in others. For example, we detected a significant upregulation of interferon signaling pathways in the tumor B cells and an enrichment of effector T cells in only one of the two sites within one patient. Analysis of B cell and T cell antigen receptor sequences to evaluate tumor subclonality and TCR clonotype diversity are ongoing. To the best of our knowledge, this is the first study to compare different sites of FL in the same patients at the single cell level. Our analyses characterize inter- and intra-patient heterogeneity in malignant and immune cell subsets and provide a baseline for eventual comparison of alterations occurring over time as these patients receive experimental immunotherapy interventions. Disclosures Levy: XCella: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Five Prime: Membership on an entity's Board of Directors or advisory committees; Corvus: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Checkmate: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Abpro: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; 47 Inc: Membership on an entity's Board of Directors or advisory committees.
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Canovas Nunes, Sara, Haiming Xu, Serena De Vita, Andrew Anighoro, Francois Autelitano, Edward Beaumont, Pamela Klingbeil et al. "Small Molecule Inhibition of PDE6D-RAS Interaction Suppresses the Growth of Acute Lymphoblastic Leukemia Cell Lines". Blood 138, Supplement 1 (5 novembre 2021): 1199. http://dx.doi.org/10.1182/blood-2021-147009.
Abstract (sommario):
Abstract The activation of RAS signaling has been shown to act as the driver of both de novo and relapsed, chemotherapy resistant acute lymphoblastic leukemia (ALL). Full RAS transformation requires the activity of the small RAS-related C3 botulinum toxin substrate (RAC) protein family, including the hematopoietic-specific RAC2 GTPase and we have previously demonstrated the role of RAC in specific leukemia types. Even though relapsed ALL patients have a 34% overall prevalence of RAS-activating mutations, KRASG12C mutations were not present, suggesting that the only RAS inhibitor currently available (G12C-specific) would not be effective in treating these patients. Phosphodiester 6 subunit delta (PDE6D), initially identified as a subunit of rod-specific photoreceptor phosphodiesterase, is now also known as a transporter of prenylated cargo. In fact, PDE6D has been shown to modulate the activity of RAS family proteins by regulating their subcellular location. When active, RAS proteins migrate to the cell membrane where they interact with a number of effectors triggering pro-survival downstream pathways including the mitogen-activated protein kinase / extracellular signaling-regulated kinase (MAPK/ERK) and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT). MAPK/ERK and PI3K/AKT pathways in particular are believed to synergize to induce survival and cellular transformation. We carried out a biological screen of small molecular compounds that assessed the inhibition of RAS-mutated ALL cell lines' proliferation through MTT assays, inhibition of RAC activation and the absence of inhibition of normal hematopoietic progenitor growth in colony forming unit (CFU) assays. Lead compounds were further evaluated for their lipophilicity, solubility and potency of biological activity. Here we report the identification of DW0254 which demonstrates arrest of proliferation and induction of apoptosis in RAS-mutant human B- and T-ALL cell lines. We have identified PDE6D as the putative target of this compound through photoaffinity labeling mass spectroscopy (PAL-MS). The cocrystal structure of DW0254 with recombinant PDE6D demonstrated that this small molecule fits inside the hydrophobic pocket and forms hydrogen bond interactions with residues Q88, Y149 and R61. From a molecular perspective, the occupation of the pocket by DW0254 leads to decreased interaction between PDE6D and farnesylated RAS. This impairment of PDE6D's ability to transport RAS leads to the delocalization of both mutant-NRAS and -KRAS4B proteins from the cell membrane to the cytosol, confirmed by real-time fluorescent imaging of recombinant GFP-RAS proteins. Ultimately, RAS delocalization upon DW0254 binding to PDE6D leads to decreased activation of both MAPK/ERK and PI3K/AKT pathways, and potent inhibition of RAC GTPases. CRISPR Cas9 saturating mutagenesis experiments confirmed that mutations in the farnesyl binding pocket leads to compound resistance, giving direct evidence that leukemia growth arrest is caused by molecule binding to PDE6D. Cells that showed increased IC 50 to DW0254 after mutagenesis did not exhibit resistance to Deltarasin, a previously described PDE6D inhibitor. DW0254 anti-leukemic activity was confirmed in an ex vivo murine xenograft model using short-term treated human NRAS-mutated ALL cell line P12-ICHIKAWA. After transplant, DW0254 treated cells showed impaired tumorigenic and engraftment potential when compared to vehicle controls. In conclusion, we have identified DW0254, a PDE6D inhibitor that has anti-leukemic activity in RAS-mutated ALL cell lines. We have successfully co-crystalized this compound with PDE6D showing binding to its farnesyl binding pocket and confirmed that the mechanisms of action of this inhibitor involve the loss of membrane localization of RAS and consequent inhibition of signaling to its downstream effectors. Pocket mutations validate the hypothesis that the effects observed derive from the binding of DW0254 to PDE6D and not from off-target effects. Ex vivo experiments show promising anti-leukemic effects and set the basis for future compound optimization. Disclosures De Vita: Novartis: Current Employment. Anighoro: Relation Therapeutics: Current Employment; Evotec SAS: Ended employment in the past 24 months. Autelitano: Evotec SAS: Current Employment. Beaumont: Evotec SAS: Current Employment. Klingbeil: Evotec SAS: Current Employment. Ermann: Evotec SAS: Ended employment in the past 24 months. Williams: BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding.
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Ribeiro, Zilah Maria de Oliveira Barros, Francisca Juliana Miranda Linhares e Rogeane Morais Ribeiro. "Capacidades turísticas de Jericoacoara – Ceará com base nos dados do Trip Advisor". Research, Society and Development 11, n. 14 (31 ottobre 2022): e407111436398. http://dx.doi.org/10.33448/rsd-v11i14.36398.
Abstract (sommario):
Em um ambiente extremamente volátil, hotéis buscam melhorias em serviços e produtos em oferta. Isso ocorre principalmente em virtude da competitividade e concorrência vivenciada pelo setor. A dificuldade em permanecer de quem integra o segmento torna-se sua principal preocupação. E, diante disso, despertar atitudes estratégicas e competitivas são necessárias ao bem estar e sobrevivência dos integrantes do setor em questão. Nesse contexto, o objetivo desse estudo é identificar as capacidades turísticas que contribuem efetivamente para a vantagem competitiva do segmento hoteleiro com base nos dados do Tripadvisor. Teve por metodologia, analisar, de forma qualitativa, as avaliações de usuários do serviço de hotelaria que demostraram insatisfação com a experiência de hospedagem e deixaram suas opiniões no site Tripadvisor. Na pesquisa, utilizou-se para tal o método Grounded Theory (GT) em sua segunda geração (Charmaz, 2006), e teve como locus a Vila de Jericoacoara, localizada no município de Jijoca de Jericoacoara. O tratamento dos dados e indicadores sobre turismo e hospedagem na vila ocorreu por meio de categorização, em prol do uso dos softwares Atlas TI e Iramuteq. Foi realizada a técnica análise do conteúdo por meio de informações baseadas em avaliações feitas por hóspedes que se mostraram mais que insatisfeitos em suas hospedagens. Com base nos resultados apresentados, observou-se que o objetivo do estudo foi alcançado, pois conseguiu-se identificar quais capacidades turísticas contribuem, de modo efetivo, à vantagem competitiva dos negócios hoteleiros, com base nos dados coletados na agência de viagens online pesquisada.
21
Bal, Susan, Kwangmin Choi, Omer Jamy, Saulius K. Girnius, Heather J. Landau e Luciano J. Costa. "Genomic Landscape of Sex Disparities in Multiple Myeloma". Blood 134, Supplement_1 (13 novembre 2019): 3067. http://dx.doi.org/10.1182/blood-2019-127429.
Abstract (sommario):
Background While survival of patients with multiple myeloma (MM) continues to improve, disparities in care are widely prevalent. While sex-based differences in cancer outcomes are apparent in several malignancies, these have not been studied as extensively in MM and consequently, the biology underlying these differences are unknown. Methods We utilized the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA11) to evaluate the outcomes of MM by sex. The CoMMpass database includes over 1000 newly-diagnosed MM patients with enriched tumor samples analyzed using RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were predicted from RNA-seq data using the limma-voom method after TMM normalization, then gene set enrichment analyses using GSEA and WebGestalt and ClueGo were performed to assess for highly enriched pathways. We then performed multiple linear regression analysis using sex as the dependent variable. Other known high-risk prognostic markers were used as independent categorical or numeric variables. Categorical variables included age (</>65 years), beta2 microglobulin (>5.5 mg/L), elevated LDH (>ULN), presence of del 17p, t(4;14), t(14;16), gain chr 1q, del 1p and hyperdiploid status. Numeric variables included genes from the EMC-92 gene signature. Overall survival (OS) was estimated by Kaplan Meier method and log-rank test. Results Among patients with available data, females accounted for 44% (N=384) and males 56% (N=487) patients. Male sex is associated with inferior overall survival, with median survival (men 55 months vs women NR) (p=0.00024). GSEA detected 310 out of 668 gene sets to be up-regulated in the female cohort of which 69 gene sets were significantly up-regulated (FDR q <25%). While in males, 358 out of the 668 gene sets queried were up-regulated and no gene set was significantly upregulated at FDR q<25%. Compared to males, significantly enriched gene sets in females were those involved oxidative metabolism (oxidative phosphorylation, respiratory electron transfer, and TCA cycle) which have been shown to be a function of B cell differentiation to support increased antibody production and may suggest a more differentiated plasma cell phenotype in women. We then performed WebGestalt over-representation analysis (ORA) using up and down DEGs which showed that cell-cell junction, ECM proteoglycans, IFN gamma signaling, L1CAM interactions and axon guidance pathways were affected when comparing by sex. Using the limma-voom method to predict DEGs (after TMM normalization), the up-regulated genes in women included those involved in protective processes such as inhibition of JAK/STAT mediated signaling (SOCS3), increased glutathione S transferase to detoxify products of oxidative stress (GSTM1), promotion of autophagy (DEPP1) as well as development of long term T cell immunity (TNFRSF4). Downregulated genes in women include those associated with increased proliferative potential such as cell-cell adhesion and signaling (LPHN2, EPHB1, LSAMP, NCAM1, CADM1, CD44, ANK3, CD99), cell cycle regulation (ZNF256, TEAD1, PDGFD), cytoskeletal proteins (MAP9, HYDIN, TMSB4X, TIAM1) and angiogenesis (PDE3B, VASH2). Multiple linear regression analysis with sex as dependent variable showed no differences in the independent categorical variables tested between the male and female groups. 14 genes of the EMC-92 gene signature were also noted to significantly differ between the female and male groups (EHBP1L1, FGFR3, C1S, GRB14, HMGB3, ITM2B, LBR, MRPL41, RAB2A, RPS28, RPS4X, SPATS2L, TOP2A, TMEM97) along with genes expressed in multiple high-risk gene expression profiling signatures (TMEM97, ITM2B). These genes have been associated with cell survival, proliferation, differentiation and angiogenesis which may explain the differences in survival outcomes. Conclusion Female sex was associated with improved overall survival in the MMRF CoMMpass database. Over expression of several protective signatures and under expression of genes associated with increased proliferative signal may explain the differences in disease biology. Validation of these results in an independent cohort will help clarify these interesting and novel findings. Disclosures Girnius: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Landau:Caelum: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa:GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau.
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Shree, Tanaya, Sarah Haebe, Anuja Sathe, Grady Day, HoJoon Lee, Debra K. Czerwinski, Susan Grimes, Hanlee Ji e Ronald Levy. "Dynamic Immune Modulation Seen By Single Cell RNA-Sequencing of Serial Lymphoma Biopsies in Patients Undergoing in Situ Vaccination". Blood 134, Supplement_1 (13 novembre 2019): 1479. http://dx.doi.org/10.1182/blood-2019-131684.
Abstract (sommario):
It is increasingly evident that the composition of the tumor microenvironment (TME) and the interplay between malignant and immune cells determine the efficacy of antitumor immune responses, whether pre-existing or induced by therapy. To profile the complexity and plasticity of the TME and track antitumor immunity, we performed single cell RNA sequencing on tumor fine needle aspirates and peripheral blood of lymphoma patients undergoing immunotherapy on a clinical trial (NCT02927964). In this in situ vaccination study motivated by compelling preclinical data (Sagiv-Barfi et al., Blood 2015), patients with low-grade lymphoma receive local low-dose radiation and a TLR9 agonist (CpG) intratumorally to one site of disease. In the second week, after the second of 5 intratumoral CpG injections, they begin taking oral ibrutinib. Tumor fine needle aspirates (FNAs)and peripheral blood samples are obtained prior to treatment, and at 1 week and 6 weeks after treatment start. Single cell preparations of FNA and blood samples are processed using the 10X Genomics platform (based on Zheng et al., Nat Commun 2017). Libraries are sequenced to an average targeted depth of 50,000 reads/cell. Identification of variable genes, principal component and graph-based clustering, and differential expression analysis of single-cell gene expression data is performed using the Seurat algorithm (Butler et al., Nat Biotech, 2018). We have prepared sequencing libraries from 58 tumor FNA and peripheral blood samples from 7 patients thus far. For the first 6 patients, approximately 3,000-10,000 cells per sample have been sequenced, with excellent sequencing quality metrics. Evaluating treatment-induced changes at the CpG-injected site across patients, we found a loss of tumor B cells and T follicular helper cells (Tfh) along with increases in CD8 and CD4 effector cells. Genes associated with cell death, DNA damage response, interferon response, and antigen presentation were induced in tumor B cells after treatment, while genes associated with several signaling pathways, including Myc, Wnt/beta-catenin, and MTOR were down-regulated. In contrast, treatment-induced changes in the tumor-resident T-cells were dominated by a strong interferon response (to both interferon-alpha and -gamma), strongest in CD4 effector and memory populations and weakest in T follicular helper cells and exhausted T cells. T-cells also showed induction of genes associated with TNF-alpha signaling, IL6 signaling, and inflammatory chemokines and cytokines. Interestingly, at the distal, non-injected site, similar changes occurred with smaller magnitude and more so at the week 6 timepoint. Further expression analysis, sequencing and analysis of single cell TCR clonotypes, and relation of results to clinical data is ongoing. Deep profiling of serial biopsies offers a comprehensive view of the evolving immune microenvironment during immunotherapy. By sampling multiple tumors over time in patients undergoing in situ vaccination, we identify significant and distinct transcriptional shifts in different tumor microenvironmental subpopulations at both the injected and un-injected sites, including activation of T-cells both sites with different dynamics. Our approach represents successful application of single-cell genomics to a clinical trial, illuminating cellular dynamics induced by treatment. Disclosures Levy: Apexigen: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; 47 Inc: Membership on an entity's Board of Directors or advisory committees; XCella: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Five Prime: Membership on an entity's Board of Directors or advisory committees; Corvus: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Checkmate: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Abpro: Membership on an entity's Board of Directors or advisory committees.
23
Lamm, Kevan W., Alexa J. Lamm, Kristin Davis e B. Jyothi Swaroop. "Identifying Knowledge Management Capacity Needs of Rural Advisory Service Networks". Journal of International Agricultural and Extension Education 24, n. 2 (15 agosto 2017): 93–106. http://dx.doi.org/10.5191/jiaee.2017.24207.
Abstract (sommario):
Knowledge management is the creation, coordination, transfer, and integration of knowledge so it is accessible and usable by specific stakeholders. Knowledge management has been shown to facilitate the development of networks, as well as to sustain established networks, based on the appropriate collection and subsequent application of embedded social capital. For rural advisory service (RAS) networks, knowledge management can be an important tool to ensure that both explicit and tacit knowledge is shared amongst network members with the anticipated benefit of increased capacity of the network. Although the importance of knowledge management is well documented within the literature, there are limited guidelines for what specific knowledge management capacities a RAS network should develop. Using the Delphi process, a panel of 31 experts from 24 countries arrived at consensus on 34 specific knowledge management capacities associated with effective RAS networks. The results of the research provide a practical framework for RAS providers and networks to focus knowledge management capacity assessment and capacity-building activities.
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Sklavenitis-Pistofidis, Romanos, Ankit K. Dutta, Sylvia Ujwary, Robert A. Redd, Alexandra Savell, Léa Fléchon, François Aguet et al. "Single-Cell RNA-Sequencing Identifies Immune Biomarkers of Response to Immunotherapy in Patients with High-Risk Smoldering Myeloma". Blood 138, Supplement 1 (5 novembre 2021): 330. http://dx.doi.org/10.1182/blood-2021-147623.
Abstract (sommario):
Abstract Background Patients with Smoldering Multiple Myeloma (SMM) are typically observed until progression to overt Multiple Myeloma (MM), but early treatment of high-risk patients may improve outcomes. Clinical and genomic biomarkers can help to identify SMM patients at high risk of progression, but whether parallel profiling of the tumor immune microenvironment can further improve our models remains to be determined. Methods We performed single-cell RNA sequencing on CD138- immune cells from 40 samples of 14 patients with high-risk SMM enrolled in a Phase II trial of Elotuzumab, Lenalidomide, and Dexamethasone (NCT02279394), to develop biomarkers for optimal patient selection and monitoring of response to treatment. This study was approved by the Dana-Farber Cancer Institute's Institutional Review Board (#14-338). Specifically, we used the Chromium Single Cell 3' Gene Expression system by 10X Genomics to profile 33 magnetically sorted (Miltenyi Biotec) CD138- bone marrow (BM) samples collected at baseline (n=11), cycle 9 day 1 (C9D1, n=13), and end of treatment (EOT, n=9), and 7 peripheral blood mononuclear cell (PBMC) samples collected at baseline (n=4) and C9D1 (n=3). We integrated this data with our cohort of non-trial patients with Monoclonal Gammopathy of Undetermined Significance (n=5), low-risk SMM (n=3), high-risk SMM (n=8), newly diagnosed MM (n=9) and healthy donors (n=10), reaching a total of 75 samples. Results We found that higher abundance of mature B-cells, Th17, and Granzyme K (GZMK)+ T-cells, as well as gene expression signatures marked by type 17 genes and GZMK, are associated with significantly longer progression-free survival (PFS) in SMM patients under treatment. Although immunoparesis is a significant predictor of PFS in our cohort and could thus be confounding our B-cell signal, we showed that immunoparesis is not associated with lower number of B-cells in the BM and is instead associated with the upregulation of transcription factor Kruppel-like Factor 2 (KLF2, q=2e-05), which we hypothesize may oppose differentiation into antibody-secreting plasma cells. We found that these differences in abundance can be summarized by how normal-like the patients' immune composition is at baseline, whereby patients whose immune composition is not normal-like have significantly longer PFS (p=0.031). This model suggests that at least some of the compositional changes observed in disease may reflect the immune system's capacity to react successfully to the immune challenge posed by the tumor, which we termed 'immune reactivity'. Baseline immune reactivity may help to identify patients who will benefit the most from early treatment. Furthermore, we found that the expansion of tissue-resident NK cells and exhausted GZMK+ CD8+ T-cells at C9D1 of treatment, as well as higher levels of a gene expression signature marked by amphiregulin (AREG), are associated with significantly shorter PFS (p=0.039). These biomarkers may improve monitoring of response to immunotherapy, which may not be fully explained by residual tumor burden alone. Lastly, patients whose immune profile was normal-like at EOT (Post-therapy Immune Normalization, PIN), potentially signifying the resolution of the immune challenge, had significantly longer biochemical PFS (p=0.04). Assessment of PIN at EOT may improve stratification of patients with minimal residual disease. Importantly, we found that biomarker status could be assessed in both the patients' peripheral blood and their BM, suggesting that minimally invasive immune profiling for prognostication and monitoring may be feasible. Conclusions Our study has nominated novel immune biomarkers for optimal patient selection and assessment of response to immunotherapy and uncovered a previously unappreciated mechanism of B-cell immunosuppression in MM, which could lead to the development of novel therapeutics. Our findings may usher in a next generation of clinical assays that assess both tumor biology and immune state, as well as common clinical biomarkers, in the marrow or blood, to accurately predict who may benefit from early treatment, monitor response to immunotherapy, and improve patient outcomes. Disclosures Dutta: Menarini Silicon Biosystems: Consultancy. Haradhvala: Constellation Pharmaceuticals a MorphoSys Company: Consultancy. Zavidij: Constellation Pharmaceuticals: Current Employment. Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Rosenblatt: Attivare: Consultancy; Imaging Endpoints: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Parexel: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Zonder: Caelum Biosciences: Consultancy; Intellia: Consultancy; Alnylam: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. Bhutani: Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding; Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau. Usmani: Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau. Yee: Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy; Janssen: Consultancy; GSK: Consultancy; Adaptive: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Jakubowiak: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Manier: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nadeem: GSK: Consultancy; Adaptive: Consultancy; Bristol Myer Squibb: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Richardson: GlaxoSmithKline: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy; Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Regeneron: Consultancy; Secura Bio: Consultancy; Protocol Intelligence: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Badros: J&J: Research Funding; BMS: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Mateos: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.
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Braun, Theodore, Theresa Lusardi, Trevor Enright, Zachary Schonrock, Cody Coblentz, Hisham Mohamed, Brian J. Druker e Julia E. Maxson. "Single Cell RNA Sequencing Identifies a Crucial Role for ASXL1 in Neutrophil Development". Blood 134, Supplement_1 (13 novembre 2019): 212. http://dx.doi.org/10.1182/blood-2019-125022.
Abstract (sommario):
Single Cell RNA Sequencing Identifies a Crucial Role for ASXL1 in Neutrophil Development Additional sex combs-like 1 (ASXL1) is a polycomb-associated protein that is essential for normal hematopoiesis. ASXL1 is recurrently mutated across the spectrum of myeloid malignancies including myelodysplastic syndromes, myeloproliferative neoplasms and Acute Myeloid Leukemia. ASXL1 mutations are also found in the premalignant disorders clonal hematopoiesis of indeterminate potential and clonal cytopenias of indeterminate potential. In all cases, ASXL1 mutations are associated with more aggressive disease biology and resistance to treatment. Mutations in ASXL1 broadly dysregulate the hematopoietic system, opening chromatin at genes associated with differentiation and self-renewal, predisposing to malignant transformation. However, in spite of this, the specific role of ASXL1 at different phases of hematopoiesis remains unknown. Indeed, the development of therapeutic approaches for ASXL1-mutant malignancies will require a nuanced understanding of the role of ASXL1 in directing normal blood development to maximize on target effects and minimize toxicity. ASXL1 mutations are commonly identified in myeloid disorders with dysplasia. In the neutrophil lineage, morphologic dysplasia is associated with nuclear-cytoplasmic dyssynchrony, where neutrophils demonstrate differences in nuclear and cytoplasmic differentiation (i.e. hypolobated nuclei or hypogranular cytoplasm). Given its associated with dysplasia, we hypothesized that ASXL1 plays a fundamental role in neutrophil maturation. To investigate this, we performed single cell RNA sequencing (scRNA-seq) on lineage depleted bone marrow from MX-1 Cre/Asxl1FL/FL mice (Asxl1KO) or cre negative littermate controls (Asxl1WT). This analysis revealed a loss of multi-lineage differentiation potential in response to Asxl1 deletion with the most prominent effects noted in myeloid differentiation. Although the neutrophil-primed granulocyte-macrophage progenitors appeared relatively normal, a differentiation block was identified at the transition between promyelocytes and myelocytes. Specifically, Asxl1KO mice demonstrated a failure to normally upregulate specific granule constituents. Although key differentiation-associated transcription factors are present in the appropriate precursor populations, they appear to require normal Asxl1 function to effectively initiate transcription of specific granule genes. This is the first description of a crucial role for Asxl1 in terminal neutrophil differentiation. Furthermore, the failure to effectively upregulate specific granule genes in Asxl1 deficient mice may provide a mechanistic explanation for the dysplasia-associated hypogranular neutrophils present in dysplastic disorders with mutant ASXL1. Disclosures Druker: Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; CureOne: Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Monojul: Other: former consultant; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Cepheid: Consultancy, Honoraria; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Gilead Sciences: Other: former member of Scientific Advisory Board; Celgene: Consultancy; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding.
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Dhawan, Abhishek, Meghan Ferrall-Fairbanks, Brian Johnson, Hannah Newman, Virginia Volpe, Christopher Letson, Anthony M. Hunter et al. "Single Cell Deconvolution of Myeloblasts Reveals Depletion of HSCs and Expansion of Inflammatory Granulocyte-Monocyte Progenitors (GMPs) Associated with Adverse Outcomes in Chronic Myelomonocytic Leukemia (CMML)". Blood 138, Supplement 1 (5 novembre 2021): 319. http://dx.doi.org/10.1182/blood-2021-151348.
Abstract (sommario):
Abstract Myeloblasts are associated with adverse outcomes and define transformation to acute myeloid leukemia in all chronic myeloid neoplasms. Myeloblasts represent hematopoietic stem and progenitor cells (HSPCs) that express CD34, but are never resolved into stem and progenitor subpopulations during clinical evaluation. Therefore, how expansion of myeloblasts reshapes the HSPC compartment and its impact on clinical outcomes remains undefined. To address this important feature of disease progression, we transcriptionally and immunophenotypically mapped CD34 + HSPCs at single cell resolution for 66 samples from 45 patients with CMML. Single cell-RNA sequencing was performed on 137,578 CD34 + enriched HSPCs from 39 CMML samples and integrated with 63,672 publicly available CD34 + normal HSPCs (Fig A). We overlaid each CMML sample on a pseudotime projection of differentiation trajectories from normal samples to establish sample-specific aberrancies in HSPC states. This mapping classified samples into HSPC-biased groups of monocyte (mono)-bias, megakaryocyte erythroid (ME)-bias, and normal-like, respectively enriched for GMP, MEP, and HSC transcriptional signatures (Fig B). These groups were associated with distinct clinical genomic characteristics and were congruent with patient-specific bulk sequencing. For example, ME biased cases had statistically higher hemoglobin and mono-bias cases were associated with adverse survival, inflammatory clinical correlates, and RAS pathway mutations (Fig C). Importantly, we identified significant depletion of HSC across CMML that was most pronounced in the mono-bias group. This was validated by flow cytometry in 26 CD34 + enriched samples, which showed HSC numbers decreased as myeloblasts expanded and disease progressed (Fig D,E). The mono-biased group strongly correlated to the fraction of cells that were transcriptionally enriched for cytokine receptor (CR) signaling (cluster 2, Fig F). These cluster 2 cells constituted a subset of GMPs that could be identified by CD120b expression based on COMET analysis (Fig F), were depleted after therapy in sequential samples, and were associated with high CTNNB1 and low IRF8 expression, suggesting that they are self-renewing GMPs as previously reported in murine models (Herault Nature 2017). To validate the clinical relevance of CR signaling in HSPCs, we established a CR high-parameter flow cytometry panel by prioritizing CRs from primary CMML CD34 + RNA-sequencing data and quantified their expression using PE-conjugated antibodies to screen CR expression and density. This led to a 30-parameter panel that accounted for CR co-expression, spectral overlap, enabled us to both map CRs on HSCs, CMPs, MEPs, and GMPs, and calculate the CR Shannon diversity in 26 CMML and 5 normal controls (Fig G). Patients with CD120b + GMPs had inferior survival, were associated with higher-risk, proliferative disease, and higher CR diversity (Fig H). Further, increased CR diversity was associated with inferior survival across all HSPC compartments. Given the expansion of GMPs in mono-biased patients, we hypothesized that prior periods of stress-induced hematopoiesis (SIH) could contribute to the development of this adverse HSPC differentiation trajectory during disease progression. We modeled SIH by performing BMT experiments with NRAS Q61R/WT bone marrow cells and controls as RAS mutations were associated with a mono-bias state. These experiments identified a depletion of HSC and expansion of CD120b + GMPs compared to controls recapitulating the HSPC compartment in human mono-biased cases (Fig I,J). We modeled the impact of SIH in human CMML by chronically treating RAS mutated CMML PDX models with LPS or vehicle and similarly observed HSC depletion and CD120b + GMP expansion in LPS-treated mice (Fig K,L). Our data suggests that HSC depletion is a characteristic of myeloblast expansion during disease progression. Further, even in a disease with homogenous hematopoietic output (monocytosis), progenitor expansion of HSPCs can occur in three distinct skewed states. The mono-biased state is associated with poor outcomes and can be recapitulated by modeling SIH in CMML. PDX studies are ongoing to validate these results and the effects of SIH on survival. Deconvolution of HSPCs at single cell resolution of other myeloid neoplasms and strategies to mitigate triggers of SIH to prevent the mono-biased state should be explored. Figure 1 Figure 1. Disclosures Komrokji: Acceleron: Consultancy; AbbVie: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sallman: Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Takeda: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Bejar: Gilead: Consultancy, Honoraria; Takeda: Research Funding; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Silence Therapeutics: Consultancy; Astex: Consultancy; Epizyme: Consultancy, Honoraria; BMS: Consultancy, Research Funding. Padron: BMS: Research Funding; Incyte: Research Funding; Kura: Research Funding; Blueprint: Honoraria; Taiho: Honoraria; Stemline: Honoraria.
27
Sax, Paul E., Edwin Dejesus, Gordon Crofoot, Douglas Ward, Paul Benson, Lilian Wei, Kirsten White et al. "A Randomized Trial of Bictegravir or Dolutegravir with Emtricitabine and Tenofovir Alafenamide (F/TAF) Followed by Open Label Switch to Bictegravir/F/TAF Fixed Dose Combination". Open Forum Infectious Diseases 4, suppl_1 (2017): S426—S427. http://dx.doi.org/10.1093/ofid/ofx163.1076.
Abstract (sommario):
Abstract Background Integrase strand transfer inhibitors (INSTIs) are widely recommended for initial HIV-1 treatment. Bictegravir (BIC, B) is a novel, once-daily INSTI with potent antiviral activity being developed in coformulation with emtricitabine and tenofovir alafenamide (F/TAF). Methods In this Phase 2 study, treatment naïve, HIV-infected adults were randomized 2:1 to receive blinded treatment with BIC or dolutegravir (DTG) coadministered with open label F/TAF (200/25 mg). After all participants completed 48 weeks, they were unblinded and switched to a single fixed-dose combination tablet of B/F/TAF 50/200/25 mg. The proportion of participants with HIV-1 RNA <50 copies/mL (c/mL) was assessed at Week (W) 24 and W48 of the blinded phase and 12 weeks after switching to open label B/F/TAF (W72). Results Of 98 participants enrolled in the blinded treatment phase, 65 were randomized to BIC+F/TAF and 33 to DTG+F/TAF. Most were male, had asymptomatic HIV infection, with median HIV-1 RNA 4.4–4.5 log10 c/mL. The proportion of subjects with HIV-1 RNA <50 c/mL at W24 was 97% for the BIC arm and 94% for the DTG arm, and at W48 was 97% and 91%, respectively (Table). All 92 participants who completed the blinded phase were switched to B/F/TAF at W60. At W72 or 12 weeks after switching to open-label B/F/TAF, 99% (91/92) maintained HIV-1 RNA <50 c/mL (98% prior BIC arm [N = 62]; 100% prior DTG arm [N = 30]) and one individual withdrew prior to the analysis. No viral resistance was detected in participants treated with BIC. No participants discontinued open label B/F/TAF due to an adverse event, there were no treatment-related serious adverse events and no deaths. One individual on BIC previously discontinued due to an adverse event of urticaria following the W24 visit. Conclusion All participants switched from DTG+F/TAF to open-label B/F/TAF maintained virologic suppression, with none discontinuing due to adverse events. During 72 weeks of follow-up, no treatment-emergent resistance to any components was detected in participants taking B/F/TAF. B/F/TAF demonstrated durable virologic suppression in naïve patients through W72 and was safe and effective after switching from DTG + F/TAF, further study in treatment naïve and experienced populations is warranted. Disclosures P. E. Sax, Gilead: Consultant and Investigator, Consulting fee, Research grant and Research support; BMS: Consultant and Investigator, Consulting fee, Research grant and Research support; GlaxoSmithKline/ViiV: Consultant and Investigator, Consulting fee, Research grant and Research support; AbbVie: Consultant, Consulting fee; Janssen: Consultant, Consulting fee; Merck: Consultant, Consulting fee; E. Dejesus, Gilead Sciences: Consultant, Investigator and Speaker’s Bureau, Consulting fee and Speaker honorarium; Janssen: Consultant, Investigator and Speaker’s Bureau, Consulting fee and Speaker honorarium; G. Crofoot, Gilead: Investigator and Scientific Advisor, Advisory honorarium and Research grant; ViiV: Investigator and Scientific Advisor, Advisory honorarium, Research grant and Research support; D. Ward, Gilead: Investigator, Research support; P. Benson, Gilead Sciences: Investigator, Shareholder and Speaker’s Bureau, Research support and Speaker honorarium; ViiV Healthcare: Investigator, Research support; L. Wei, Gilead: Employee and Shareholder, Salary; K. White, Gilead Sciences, Inc.: Employee and Shareholder, Salary; S. Collins, Gilead: Employee and Shareholder, Salary; H. Martin, Gilead Sciences: Employee, Salary; A. Cheng, Gilead: Employee and Shareholder, Salary; E. Quirk, Gilead: Employee and Shareholder, Salary
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Morelli, Eugenio, Anil Aktas-Samur, Mehmet K. Samur, Annamaria Gulla, Leon Wert-Lamas, Caroline Ribeiro, Jonathan E. Henninger et al. "Identifying Long Noncoding RNA Dependencies Using CRISPR Interference (CRISPRi)-Based Platform in Multiple Myeloma". Blood 138, Supplement 1 (5 novembre 2021): 894. http://dx.doi.org/10.1182/blood-2021-151705.
Abstract (sommario):
Abstract To identify therapeutically actionable genetic dependencies we have pursued various approaches to derive a deeper understanding of the oncogenic hallmarks of myelomagenesis. We have studied the long noncoding RNA (lncRNA) landscape in multiple myeloma (MM) and identified a large number of differentially expressed lncRNAs in MM versus normal plasma cells. These lncRNAs presumably drive the tumorigenesis and MM cell growth, and in turn be susceptible to therapeutic intervention. To this end, we have developed and utilized a CRISPR interference (CRISPRi)-based platform for decoding and targeting the lncRNA dependencies (LongDEPs) in MM. In this study, we have used RNA-seq of patient-derived CD138+ MM cells (n=360) and MM cell lines (n=70) to generate a priority list of 913 expressed intergenic lncRNAs. Then, to systematically interrogate the role of these lncRNAs in MM cell growth, we have performed a CRISPRi viability screen transducing 3 MM cell lines engineered to express a dCAS9-KRAB fusion protein, with a pooled library consisting of 7 sgRNAs against each of the 913 transcription start sites (TSS) and 576 negative control sgRNAs. Relative representation of sgRNAs was assessed by deep sequencing after 3 weeks and analyzed using the MAGeCK robust rank aggregation (RRA) algorithm. The most enriched or depleted sgRNAs were further tested in a secondary CRISPRi viability screen. Focusing on depleted sgRNAs, we have identified >30 unique LongDEPs; which were further validated via an antisense oligonucleotide (ASO)-based loss-of-function study in a panel of MM cell lines (n=11). A comparative transcritpomic analysis comparing data from 360 newly-diagnosed and clinically-annotated MM patients and 16 healthy donors showed significant upregulation of these LongDEPs in MM patient cells. Of note, specific longDEPs were found selectively upregulated in genetically-defined patient subsets, including high-risk MM carrying t(4;14), 1q gain or del17p. Moreover, at least 18 LongDEPs were identified as independent risk-predictors of clinical outcome in newly-diagnosed MM patients. The lncRNA RROL was identified as a leading LongDEP, with a dependency score on a par with positive controls such as IRF4 or MYC. This lncRNA is specifically overexpressed in MM patients after disease relapse, and its higher expression in newly diagnosed MM patients could predict a worse clinical outcome. We have validated the essential role of RROL in support of the proliferation and survival of MM cells both in vitro and in vivo in NOD SCID mice, using ASO-based loss-of-function studies. To explain this effect, we have characterized its role in the control of the pro-survival de novo lipogenesis (DNL) pathway via an unbiased lipid profiling and by measuring the incorporation of C 14-radiolabeled glucose into the lipid pool. Mechanistically, we have shown that RROL promotes the DNL pathway via transcriptional regulation of rate-limiting enzymes including ACC1. Using in vitro (RNA protein pull down) and in cellulo (RNA yeast-3-hibrid) assays, we have identified the transcription factor c-MYC as a relevant protein interactor of RROL. This interaction occurs at the chromatin level and is required for i) MYC occupancy at DNL gene loci (e.g. ACC1), as shown by both ChIP-qPCR and single molecule dual RNA FISH coupled with immunofluorescence; ii) MYC interaction with a number of transcriptional co-activators, including WDR82, as assessed in vitro in 3 MM cell lines using co-immunoprecipitation followed by Mass spectrometry (Co-IP/MS) and in cellulo using the proximity-dependent biotin identification assay (BioID) in Flp-In T-REx cells expressing a FLAG-BirA*-MYC fusion protein. Overall, our data indicate that RROL provides the chromatin scaffold to assemble a transcriptionally activated ribonucleoprotein complex - minimally composed by RROL, MYC and WDR82 - at gene regulatory loci of DNL rate-limiting enzymes. To develop therapeutic inhibitors of LongDEPs, starting with RROL, we have tested >70 ASOs following a multi-step screening approach. The anti-MM activity of 2 leading compounds was demonstrated in vitro and in vivo in 2 clinically relevant animal models, including a BLI-based orthotopic model. In conclusion, our work establish LongDEPs as an additional source of genetic dependencies in MM paving the way for their biologic, clinical and therapeutic characterization in this disease context. Disclosures Young: Dewpoint: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Camp4 Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees; Omega Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Gryaznov: MAIA Therapeutics: Current Employment. Anderson: Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Munshi: Novartis: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Celgene: Consultancy; Adaptive Biotechnology: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Legend: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy.
29
Albitar, Maher, Zijun Yidan Xu-Monette, Babak Shahbaba, Ivan De Dios, Yingjun Wang, Deng Manman, Alexandar Tzankov et al. "Cell of Origin Classification of DLBCL Using Targeted NGS Expression Profiling and Deep Learning". Blood 134, Supplement_1 (13 novembre 2019): 2891. http://dx.doi.org/10.1182/blood-2019-126927.
Abstract (sommario):
Introduction: Targeted RNA sequencing using Next Generation Sequencing (NGS) has significant advantages over transcriptome sequencing. In addition to information on mutations, fusion and alternative splicing, RNA quantification using targeted RNA sequencing is sensitive, reproducible and provides better dynamic range. We used targeted RNA sequencing for RNA profiling of diffuse large B-cell lymphoma (DLBCL) and explored its utility in the sub-classification of DLBC to ABC and GCB. Method: RNA extracted from 441 FFPE lymphnode samples with DLBC lymphoma and sequenced targeting 1408 genes. These cases were previously subclassified as ABC vs GCB using expression profiling and immunohistochemistry. We first normalized RNA expression data to PAX5 expression, then we tried to narrow down important markers using univariate significance tests. Setting the cutoff for false discovery rate at 0.0001, 48 variables remained significant, including 46 RNA levels and two genes (MYD88 and EZH2) mutation status. Using 60% of samples as training set, we used multiple statistical approaches for classification. Deep learning emerged as the best approach. We used autoencoder with 5 hidden layers and developed a model for classification of ABC vs GCB. To further improve on classification, we divided patients in each subgroup based on survival using simple tree model. In this tree model, expression level of CD58 emerged as a powerful prognostic marker for the ABC group and RLTPR expression in the GCB group. Results: Using probability of scoring developed based on deep learning and logestic regression, approximately 30% of the cases had a score between 0.5 and 0.75. For the remaining 70% of patients, the ABC vs GCB classification showed sensitivity and specificity of 96% and 97% for the testing set. We also applied the same approach to 60 independent cases classified using NanoString (Lymph2Cx). Our model showed sensitivity and specificity of 96% and 97% in the NanoString independent cases. Using the tree model for further classification of the ABC and GCB classes, CD58 mRNA levels separated the ABC group into two subgroups (ABC1 and ABC2) and RLTPR mRNA separated the GCB into two subgroups (GCB1 and GCB2) with significant difference in overall survival (P=0.0010) and progression-free survival (PFS) (P=0.0027). Conclusion: Targeted RNA sequencing is very reliable and practical for the subclassification of DLBCL and can provide clinical-grade reproducible test for prognostically subclassification of DLBCL. Figure Disclosures Albitar: Genomic Testing Ccoperative: Employment, Equity Ownership. De Dios:Genomic Testing Ccoperative: Employment. Tam:Takeda: Consultancy; Paragon Genomics: Consultancy. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Ferreri:Roche: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kite: Consultancy. Piris:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding. Kantarjian:Ariad: Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; BMS: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding.
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Lamontagne-Godwin, Dorward, Aslam e Cardey. "Analysing Support Towards Inclusive and Integrated Rural Advisory Systems". Social Sciences 8, n. 10 (22 ottobre 2019): 295. http://dx.doi.org/10.3390/socsci8100295.
Abstract (sommario):
Public Rural Advisory Services (RAS) have adapted to different socio-economic scenarios in politically diverse countries with the help of the third sector supporting dedicated RAS programmes. The Plantwise (PW) programme, led by the Centre for Agriculture and Bioscience International (CABI) and designed to increase food security in over 30 countries, is a good example of a public/NGO partnership, although recent evaluations have questioned its impacts on gendered agricultural information access. This study aims to investigate Plantwise’s gender impacts from individual and institutional viewpoints, interviewing smallholder farmers and extension staff involved in and outside of, the Plantwise programme in Bahawalpur and Jhang district in the Punjab province of Pakistan. This serves to highlight the programme’s impacts on systemic processes which ultimately have the potential to contribute to gender-transformative change and a more efficient and sustainable RAS. Results show differences between extension workers in a PW district and a non-PW district and between plant doctors and non-plant doctors in a PW district, though none were significant from a gendered perspective. There were interesting findings highlighting the plant clinic’s capacity as an agent of change but the low turnout of women at clinics did not reinforce the clinics’ capacity for change from a female perspective. Information from systemic, male and female-specific analyses are important to consider for PW from a practical perspective, such as the importance of spiritual locations. This study into the Pakistani PW initiative also offers an opportunity to contribute to the growing body of academic literature on the individual and institutional impacts of international development programmes, helping to understand wider aspects of international development involvement in RAS. From a practical perspective, this study also enables PW and other international development initiatives to better understand and interpret stakeholders’ perceptions, highlighting the importance of design and investment in participatory approaches to enable longer term impacts, especially focused on gender. It will also help the PW programme assess and understand implementation challenges in order to attain impact on the ground and be a driver of positive change in the country.
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Becker, Marcus, Mikhail Beketov e Manuel Wittke. "Machine Learning in Automated Asset Management Processes 4.1". Die Unternehmung 75, n. 3 (2021): 411–31. http://dx.doi.org/10.5771/0042-059x-2021-3-411.
Abstract (sommario):
The traditional (human driven) process of Asset Management has become automatized by algorithmic decision trading with so called Robo Advisors (RAs). With an increasing amount of publicly available financial data, the foundation for applying machine learning (ML) algorithms has been paved. We examine the question in which process steps of automated investment advice ML algorithms could be applied and investigate which implementations have already been placed on the market. As the following study shows, (surprisingly) ML is globally still under its development phase in Robo Advisory. German and Swiss FinTech companies thereby contribute about a third to the ML solutions in our sample. The most promising technique is the usage of Text Mining for sentiment analyses, which can be used for monitoring and rebalancing purposes or future performance forecasting. Furthermore, Text Mining algorithms can be helpful for reducing information asymmetries. Embedded into early warning systems, the derived sentiment scores can be used for hedging against future price losses. This approach would be inevitably linked to an increased access of highly sensible data. Furthermore, we try to provide an explanation for the lack of acceptance of the application of ML in RA distributions. Possible reasons for this can be found in the current MiFID II regulations, which are not specified for ML. Based on these insights, we formulate first recommendations for both the provider of RA solutions as well as for the regulator.
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Albitar, Maher, Zijun Yidan Xu-Monette, Wanlong Ma, Yingjun Wang, Deng Manman, Alexandar Tzankov, Carlo Visco et al. "Higher Stability of Mutant mRNA As Compared to Wild-Type mRNA in Diffuse Large B-Cell Lymphoma". Blood 134, Supplement_1 (13 novembre 2019): 1499. http://dx.doi.org/10.1182/blood-2019-128516.
Abstract (sommario):
Cellular RNA levels are tightly regulated by very complex nuclear and cytoplasmic processes. The regulation of mutant mRNA in cancer cells is rarely studied. We explored the effects of mutations on mRNA levels in patients with diffuse large B-cell lymphoma (DLBCL). Using next generation sequencing (NGS) and variant allele frequency (VAF) of mutant RNA, we compared relative mutant mRNA or variant allele frequency (RNA-VAF) with variant allele frequency of mutant DNA (DNA-VAF) in the same samples from patients with DLBCL. Methods: RNA and DNA were extracted from 427 FFPE samples from patients with DLBCL. We sequenced the DNA using 177 gene panel and the RNA using 1408 gene panel. The DNA sequencing is based on Single Primer Extension (SPE) library preparation with unique molecular identifier (UMI) (Qiagen, Germantown, MD). The RNA sequencing is based on hybrid capture. Sequencing data of DNA is analyzed using the DRAGEN Platform. Sequence duplicates were removed before calculating VAF. The RNA sequencing data is analyzed using Illumina basespace. RNA VAF is calculated also after removing duplicates using Isaac variant caller. Only mutations detected by both DNA and RNA variant callers are compared. Results: A total of 1770 mutations were detected using the DNA panel and 2207 mutations were detected using the larger RNA sequencing panel. We focused on the most commonly mutated genes that included in both DNA and RNA panels and compared the VAF of the same mutations between DNA and RNA. The selected genes are: KMT2D, NOTCH2, CARD11, MYC, MYD88, EZH2, TP53, CD79B, BCL2, and TET2. The overall VAF in the RNA was significantly higher (P<0.00001) (median:43.9%, minimum: 6%, maximum: 100%) as compared with that of the DNA (median: 28.8%, minimum: 3.5%, maximum: 95%). When each gene is considered individual, all genes showed significantly higher VAF in RNA as compared with DNA. As expected some mutations were detected in DNA, but not in in RNA and vice versa. However, the number of mutations detected in these 10 genes using DNA sequencing was significantly (P= 0.0001) higher (#658) as compared with mutations detected in RNA (#471). Most of the missed mutations by RNA were termination mutations. The most striking RNA-missed mutations were in NOTCH2. The DNA testing showed 81 mutations, while the RNA testing listed only 19 mutations. Almost all NOTCH2 mutations missed by RNA sequencing wer Pro6ArgfsTer27, which leads to early termination of mRNA (loss of function). When we looked at overall NOTCH2 mRNA levels, NOTCH2 mRNA was significantly higher (P=0.002, Kruskal-Wallis ANOVA) in samples with NOTCH2 mutation detected in both DNA and RNA as compared with mutations detected in DNA only. The NOTCH2 mRNA levels were also lower in samples with mutations detected in DNA only (P=0.046) as compared with wild-type NOTCH2. Conclusion: This data suggests that stability of mutant mRNA is significantly higher for most mutations and most genes. However, there are exceptions, especially when the mutations are termination at early amino acid. NOTCH2 pro6ArgfsTer27 mutation is an example of early termination of transcription, which leads to significant instability and reduction in NOTCH2 mRNA levels acting as a tumor suppressor, while other mutations in the gene lead to over expression and more oncogenenic function. This data suggests that molecular profiling of cancer should include evaluating RNA mutations and expression levels and not all mutations detected in a gene are the same. Furthermore, increased stability of most mutant mRNA may have some implication on methods used for detected minimal residual disease. Figure Disclosures Albitar: Genomic Testing Ccoperative: Employment, Equity Ownership. Tam:Takeda: Consultancy; Paragon Genomics: Consultancy. Hsi:Abbvie: Research Funding; Jazz: Consultancy; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2. Piris:Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees. Kantarjian:Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding.
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Walker, Christopher J., Junke Wang, Alyssa I. Clay-Gilmour, Krzysztof Mrózek, Deedra Nicolet, Christopher C. Oakes, Jessica Kohlschmidt et al. "Meta-Analysis of Genome-Wide Association Studies of Acute Myeloid Leukemia (AML) Patients Identifies Variants Associated with Risk of 11q23/KMT2A-Translocated and Core-Binding Factor (CBF) AML and Suggests a Role for Transcription Elongation in Leukemogenesis". Blood 136, Supplement 1 (5 novembre 2020): 29–30. http://dx.doi.org/10.1182/blood-2020-141653.
Abstract (sommario):
The first three authors contributed equally. The last three authors share senior authorship. Background: Although there has been an increased recognition of the contribution of germline variants to development of myeloid neoplasms, only two large-scale case-control genome-wide association studies (GWASs) have been conducted to identify variants that predispose to AML. Importantly, these studies were dedicated to AML predisposition in general, without investigation of molecularly distinct AML subtypes. Thus, we performed the first dedicated meta-analysis combining the two GWASs to investigate predisposing variants to cytogenetic AML subsets characterized by recurrent translocations and inversions. Methods: Two sets of adult de novo AML patients treated on Alliance for Clinical Trials in Oncology (Alliance) protocols, and two sets of adult de novo AML patients reported to CIBMTR (2000-11) from DISCOVeRY-BMT cohorts were compared with four sets of population-matched non-leukemic individuals of European ancestry. Illumina Infinium arrays were used for genotyping. The haplotype reference consortium was used for imputation and comparisons were performed using SNPtest and METAL with fixed-effects, for CBF-AML (n=251, including t(8;21), n=115; inv(16), n=136) and AML with 11q23/KMT2A translocations (n=177). Blood or bone marrow samples from subsets of these patients and additional AML patients with other cytogenetic abnormalities were used for total transcriptome RNA sequencing with Illumina instruments. Results: Two risk loci reached genome-wide significance in AML patients with 11q23/KMT2A translocations (Fig 1A). The most significant single nucleotide polymorphism (SNP) in the 4q21.3 risk locus, rs17668899[A] (P = 2.32 x 10-8, odds ratio [OR] = 3.92 [2.43-6.32]) is in intron 6 of the AFF1 gene (also called AF4) (Fig 1B), within an enhancer that interacts with the AFF1 transcription start site (Fig 1C, left). KMT2A-translocated AML patients with the risk allele had higher blast expression of AFF1 compared to those homozygous for the non-risk allele, although the trend did not reach significance (Fig 1D). Notably, AFF1 encodes a subunit of the super-elongation-complex (SEC) that acts as Pol II-associated master regulator of global transcription elongation. AFF1 is a common translocation partner of KMT2A in patients with acute lymphoblastic leukemia with t(4;11)(q21;q23), and is required for KMT2A-mediated leukemogenesis. We observed significantly higher AFF1 expression in both KMT2A-translocated AML and cytogenetically normal (CN) AML compared to CBF-AML (Fig 1E). The suggested role of AFF1/SEC is consistent with recent studies showing an important role for DOT1L, H3K79 methylation, and transcriptional elongation in NPM1-mutant AML (the most common subtype of CN-AML). Outcome analysis showed higher expression of AFF1 associated with shorter disease-free (DFS) in patients < 60 years treated on Alliance studies (hazard ratio [HR] = 1.36, P=0.04; Fig 1F). The second KMT2A-translocated AML risk locus was located at 22q13.31, and the most significant SNP was rs62231468[A] (P = 4.95 x 10-9, OR = 3.25). rs62231468 is immediately 5' of the LDOC1L gene (a retrotransposon GAG-related gene, also called RTL6), and analysis of expression quantitative trait loci (eQTL) showed association of rs62231468[A] with higher LDOC1L expression, consistent with its location in an active enhancer (Fig 1C, right). The association between rs62231468[A] and higher LDOC1L expression was validated in leukemic blast expression from a set of 449 AML patients of any cytogenetic subset (Fig 1G). Notably, higher LDOC1L expression was associated with shorter DFS and overall survival (OS) in Alliance patients < 60 years (DFS, HR = 1.25, P=0.03; OS, HR = 1.46, P<0.001; Fig 1H-I). Analysis of patients with CBF-AML identified rs71568004[C] as more common in CBF-AML patients compared to controls (P = 3.84 x 10-8 , OR = 3.05 [2.05-4.53]). This SNP is ~50kb 5' of the MARCKS gene located at 6q21, but genomic context analysis did not reveal any clear associations with MARCKS expression. Conclusions: Our first assessment of risk alleles for cytogenetic subsets of AML identified two novel independent risk loci associated with 11q23/KMT2A-translocated AML, and one risk locus associated with CBF-AML. These data suggest an important, subtype-specific role for transcriptional elongation in AML and that functional studies of retro transposition elements should be undertaken in leukemogenesis. Figure Disclosures Walker: Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy. Powell:Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Genentech: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Kolitz:Pfizer: Membership on an entity's Board of Directors or advisory committees; Magellan: Membership on an entity's Board of Directors or advisory committees. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. McCarthy:Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding. Stone:AbbVie: Consultancy, Research Funding; Actinium: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Arog: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Biolinerx: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Takeda: Consultancy; Daiichi-Sankyo: Consultancy; Elevate: Consultancy; Gemoab: Consultancy; Janssen: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy; Stemline: Consultancy; Syndax: Consultancy; Syntrix: Consultancy; Syros: Consultancy. Byrd:Trillium: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Syndax: Research Funding; Vincera: Research Funding; Acerta Pharma: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau. Eisfeld:Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy.
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Albitar, Maher, Hong Zhang, Andrew L. Pecora, Andrew Ip, Andre H. Goy, Spiraggelos Antzoulatos, Ivan De Dios et al. "Bone Marrow-Based Biomarkers for Predicting aGVHD Using Targeted RNA Next Generation Sequencing and Machine Learning". Blood 138, Supplement 1 (5 novembre 2021): 2892. http://dx.doi.org/10.1182/blood-2021-147583.
Abstract (sommario):
Abstract Introduction: Acute graft-vs.-host disease (aGVHD) remains a major diagnostic and clinical problem in patients after allogenic hematopoietic stem cell transplant (HSCT). Finding biomarkers that play a role in aGVHD not only helps in predicting and diagnosing aGVHD, but might help in developing prophylaxis and therapeutic approaches. Using Next Generation Sequencing (NGS) and targeted RNA sequencing along with a machine learning approach to predict, we investigated the potential of discovering new biomarkers that can predict aGVHD. Methods: RNA extracted from bone marrow aspiration samples collected around day 90 post HSCT from 46 patients were sequenced using 1408 targeted genes. cDNA was first generated, then adapters were ligated. The coding regions of the expressed genes were captured from this library using sequence-specific probes to create the final library. Sequencing was performed using an Illumina NextSeq 550 platform. Ten million reads per sample in a single run were required. Read length was 2 × 150 bp. Expression profile was generated using Cufflinks. A machine learning system is developed to predict the GVHD cases and to discover the relevant genes. A subset of genes relevant to GVHD is automatically selected for the classification system, based on a k-fold cross-validation procedure (with k=10). For an individual gene, a Naïve Bayesian classifier was constructed on the training of k-1 subsets and tested on the other testing subset. To eliminate the underflow problem commonly associated with the standard Naïve Bayesian classifiers, we applied Geometric Mean Naïve Bayesian (GMNB) as the classifier to predict GVHD. The processes of gene selection and GVHD classification are applied iteratively to obtain an optimal classification system and a subset of genes relevant to GVHD. Results: The analyzed bone marrow samples included patients transplanted for aplastic anemia (#1), acute lymphoblastic leukemia (#9), acute myeloid leukemia (#16), mixed phenotype acute leukemia (#1), myelodysplastic syndrome (#10), chronic myelomonocytic leukemia (#5), and myeloproliferative neoplasm (#4). Of the 46 patients, 30 (65%) had a diagnosis of aGVHD (grade 2-4). The GMNB modified Bayesian model selected 7 genes as top classifiers. These top classifier genes included Class II Major Histocompatibility gene (CIITA), B-cell markers genes (CD19 and CD22), early T-cell related gene (TCL1A), hematopoietic-specific transcription factor (IKZF3), a gene involved in protein-protein interaction, and a gene involved in DNA helicase nucleotide excision repair (ERCC3). When these 7 genes were used in GMNB-modified classifier with 10-fold cross validation to predict aGVHD, the model classified 28 of the 30 positive cases accurately and 14 of the 16 negative cases accurately. The sensitivity was 93% (95% CI, 76%-99%). The specificity was 87.5% (95% CI: 60%-97%). The positive predictive value (PPV) was 93% (95% CI: 76%-99%) and the negative predictive value (NPV) was 87.5% (95% CI: 60%-98%). Conclusion: While most biomarker discovery has been focused on inflammatory cytokines, chemokines, and their receptors, our data suggest that hematopoietic proliferation and transcription regulators in bone marrow might provide important information for the diagnosis and prediction of aGVHD. This data suggests that biomarkers related to B-cell, T-cell, and MHC play a role in aGVHD at the bone marrow level. These findings also suggest that targeting these biomarkers in the bone marrow might be a realistic approach for prophylaxis and treatment that needs to be explored. Although further validation is needed, this study suggests that targeted RNA sequencing by NGS combined with machine learning algorithm can be a practical and cost-effective approach for the diagnosis and prediction of aGVHD. Figure 1 Figure 1. Disclosures Pecora: Genetic testing cooperative: Other: equity investor; Genetic testing cooperative: Membership on an entity's Board of Directors or advisory committees. Goy: Rosewell Park: Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Acerta: Consultancy, Research Funding; Genentech/Hoffman la Roche: Research Funding; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xcenda: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; OncLive Peer Exchange: Honoraria; Xcenda: Consultancy, Honoraria; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Infinity/Verastem: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Honoraria, Other; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Hoffman la Roche: Consultancy; Michael J Hennessey Associates INC: Consultancy; LLC(Targeted Oncology): Consultancy; Medscape: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Constellation: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Phamacyclics: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Rowley: ReAlta Life Sciences: Consultancy.
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Munshi, Nikhil C., Stephane Minvielle, Yu-Tzu Tai, Mariateresa Fulciniti, Mehmet K. Samur, Paul G. Richardson, Michel Attal et al. "Deep Igh Sequencing Identifies an Ongoing Somatic Hypermutation Process with Complex and Evolving Clonal Architecture in Myeloma". Blood 126, n. 23 (3 dicembre 2015): 21. http://dx.doi.org/10.1182/blood.v126.23.21.21.
Abstract (sommario):
Abstract Introduction: Immunoglobulin (Ig) gene rearrangement is a hallmark of early B-cell development. Multiple myeloma (MM), a malignancy of plasma cells, typically have mutated Ig sequences but are thought to be stable throughout the course of the disease. We previously observed that multiple Ig sequences related by somatic hypermutation (SHM) may be present in some MM patients at diagnosis. Here we provide an expanded observation and investigate whether there is ongoing evolution in Ig sequences over the course of the disease. Methods: 550 MM patientsenrolled in IFM/DFCI study were included in this analysis. The next-generation sequencing (NGS)-based immunosequencing platform was used to detect evidence of oligoclonality at the Ig heavy chain loci. Using universal primer sets, we amplified IGH variable, diversity, and joining gene segments from DNA and/or RNA isolated from purified CD138+ MM cells collected at the time of diagnosis. Amplified products were sequenced and analyzed (Faham et al., Blood 2012). MM-specific clonotypes were identified for each patient based on their high frequency (5%) within the B-cell repertoire in the diagnostic (dx) sample. The highest frequency MM clonotype in a dx sample is termed the Òindex clonotype.Ó DNA and/or RNA isolated from dx AND post-treatment bone marrow samples were assessed for evidence of evolved MM clonotypes. A clonotype was considered ÒevolvedÓ based on CDR3 sequence homology to the dx Òindex clonotype.Ó Results: We identified Ig clones in 340 RNA samples and 311 DNA samples from the IFM/DFCI cohort.We first looked at V segment usage in these MM clones comparedto a database of ~30 million Ig VDJ sequences derived from normal B cells. The frequencies for 6 V segments were found to be significantly different from this dataset compared to the database.We then looked for cases with evidence that Myeloma cells have two unrelated origins. We found 9/550 (1.6%) cases which had evidence of unrelated clones as evident by having three IgH or two functional sequences. We then considered cases where we find two IgH sequences that are related to each other by SHM. 128/340 (37.6%) of RNA dx samples showed evidence of evolved clones via SHM, with 69/128 (53.9%) having 3 or more related clones, while 15/311 patients (4.8%) showed evidence of evolved clones related to the index clone via SHM in DNA samples from diagnosis. Of note, the majority of RNA evolved clones were found at low frequency (<10-3) which would have been impossible to observe in the limited cell input DNA samples available for testing. Out of the 15 patients with evidence of evolved clones related to the index clone, we tested RNA from 8 of them. In 4/8 cases, the index and the related clones were present at a similar ratio in the DNA and RNA, while in 3/8 cases the index clone was found in the RNA but not the related clone. 249 post-treatment samples from 164 patients were MRD positive and were assessed for the presence of clonal evolution. In 19/249 follow-up samples (7.6%), an evolved clone related to the index clone was observed. In 6/19 patients, a substantial change in the relative index and evolved clone frequencies was observed from the dx to post-treatment time points suggesting a differential sensitivity to treatment. For example, in one case, the evolved ÒnewÓ clonotype was not observed at diagnosis but appears in the post-maintenance sample only. In another case, the evolved clonotype either increased or decreased in the post-maintenance sample relative to the index clonotype (Fig 1). Conclusions: We observed multiple evolved clonotypes in a substantial percentage of dx MM samples (37.6%). The presence of multiple clonotypes related by SHM indicates that this mechanism remains active after myeloma development in at least a portion of the cells. We also found marked changes in the relative frequency of the MM clonotypes in post-treatment samples and emergence of new Ig clones which may not be due to selective advantage of the newly acquired mutations in the Ig gene, but rather some other ongoing genomic mutation process. Thus, these evolved myeloma clonotypes may be useful as surrogate markers for other oncogenic mutations providing resistance to therapy. Figure 1. Evolution of related clones in the post-maintenance time point. Below are the sequences of two related clones, with one base difference bolded and underlined. Figure 1. Evolution of related clones in the post-maintenance time point. Below are the sequences of two related clones, with one base difference bolded and underlined. Disclosures Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Honoraria. Anderson:Celgene Corporation: Consultancy; Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; acetylon pharmaceuticals: Equity Ownership; Oncocorp: Equity Ownership. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder. Avet-Loiseau:BMS: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.
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Albitar, Maher, Xu‐Monette Y. Zijun, Yingjun Wang, Deng Manman, Alexandar Tzankov, Carlo Visco, Govind Bhagat et al. "MYC and BCL2 mRNA Expression As Determined By NGS Predicts Survival in DLBCL in GCB but Not in ABC Subgroup". Blood 134, Supplement_1 (13 novembre 2019): 5092. http://dx.doi.org/10.1182/blood-2019-128492.
Abstract (sommario):
Introduction: RNA expression profiling using Next Generation Sequencing (NGS) provides important and reproducible information on expression levels of various genes. We studied the expression levels of MYC and BCL2 in patients with diffuse large B-Cell lymphoma (DLBCL) using NGS targeted RNA sequencing. We correlated levels of expression of these genes with outcome. Methods: RNA extracted from 441 FFPE samples with DLBC lymphoma and sequenced targeting 1408 genes. The RNA sequencing is based on hybrid capture and the number of reads ranged from 5 to 10 million. RNA quantification was performed using Cufflinks. The RNA levels were normalized to PAX5 mRNA levels. Of these cases, 380 were subclassified as ABC or GCB using expression profiling. The rest were classified as "undetermined", therefore were not included in further analysis. All patients were treated with R-CHOP. Results: The expression of MYC and BCL2 mRNA was slightly higher in ABC as compared with GCB (P=0.01 and P=0.02, respectively). However, in the GCB subtype, patients with MYC expression above the median showed significantly shorter survival as compared with those below the median (P=0.0007, Log-rank test). In contrast, there was no significant difference in survival using median of MYC expression as cutoff in patients classified as ABC subtype (P=0.38). Using upper 15% cut-off point for BCL2 mRNA expression, GCB patients with high BCL2 expression had significantly shorter survival (P=0.005). In contrast, there was no significant difference in survival between high and low BCL2 expression groups in the ABC subtype (P=0.1). When both MYC and BCL2 are considered, patients with high expression of both BCL2 and MYC (double-RNA expression) had significantly shorter survival as compared with patients with low expression of both MYC and BCL2 (P=0.0009) when both GCB and ABC groups are considered. Patients with high BCL2 expression also had poor survival similar to those double-RNA expression. Considering only patients with GCB, high expressor of both MYC and BCL2 had significantly worse outcome (P=0.0015) as compared with low expressors of both MYC and BCL2, but patients with high BCL2 also had significantly poor outcome as compared to low expressor of both MYC and BCL2 (P=0.0005). In contrast, there was no difference in survival for high or low MYC and BCL2 expressor in the ABC group. Conclusion: The data support the concept that in DLBCL, MYC and BCL2 mRNA expression levels are clinically relevant in GCB, but not ABC subtype. Furthermore, targeted RNA sequencing might provide a reliable and practical objective approach for the subclassification of DLBCL and determining double-RNA expression lymphoma. Figure Disclosures Albitar: Genomic Testing Cooperative: Employment, Equity Ownership. Tam:Takeda: Consultancy; Paragon Genomics: Consultancy. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Piris:Calgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding. Kantarjian:Immunogen: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Research Funding.
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Tasker, Séverine, Diane D. Addie, Herman Egberink, Regina Hofmann-Lehmann, Margaret J. Hosie, Uwe Truyen, Sándor Belák et al. "Feline Infectious Peritonitis: European Advisory Board on Cat Diseases Guidelines". Viruses 15, n. 9 (31 agosto 2023): 1847. http://dx.doi.org/10.3390/v15091847.
Abstract (sommario):
Feline coronavirus (FCoV) is a ubiquitous RNA virus of cats, which is transmitted faeco-orally. In these guidelines, the European Advisory Board on Cat Diseases (ABCD) presents a comprehensive review of feline infectious peritonitis (FIP). FCoV is primarily an enteric virus and most infections do not cause clinical signs, or result in only enteritis, but a small proportion of FCoV-infected cats develop FIP. The pathology in FIP comprises a perivascular phlebitis that can affect any organ. Cats under two years old are most frequently affected by FIP. Most cats present with fever, anorexia, and weight loss; many have effusions, and some have ocular and/or neurological signs. Making a diagnosis is complex and ABCD FIP Diagnostic Approach Tools are available to aid veterinarians. Sampling an effusion, when present, for cytology, biochemistry, and FCoV RNA or FCoV antigen detection is very useful diagnostically. In the absence of an effusion, fine-needle aspirates from affected organs for cytology and FCoV RNA or FCoV antigen detection are helpful. Definitive diagnosis usually requires histopathology with FCoV antigen detection. Antiviral treatments now enable recovery in many cases from this previously fatal disease; nucleoside analogues (e.g., oral GS-441524) are very effective, although they are not available in all countries.
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Zuppelli, Ashley R., Michael Mancenido, Jacob Scutaru, Alexandra Danforth, Robert Biernbaum, Roberto Corales e William M. Valenti. "1039. Real World Community-Based HIV Rapid Start Antiretroviral with BFTAF Versus Conventional HIV Antiretroviral Therapy Start – The RoCHaCHa Study, a Pilot Study". Open Forum Infectious Diseases 7, Supplement_1 (1 ottobre 2020): S549—S550. http://dx.doi.org/10.1093/ofid/ofaa439.1225.
Abstract (sommario):
Abstract Background Trillium Health (TH) is a FQHC in Rochester, NY providing primary and specialty care, including HIV prevention and treatment. Rapid Start ART (RSA) has been shown to decrease time to virologic suppression while increasing linkage to and retention in care. However, data on BFTAF with these benefits is limited. We aim to prove RSA with BFTAF is advantageous in time to viral load suppression, linkage to and retention in care, and patient satisfaction and acceptance. Methods We included data from ART-naive newly diagnosed PLWH enrolled between October 2018 and March 2020 with baseline assessment and started BFTAF. Follow up visits were done per protocol though 48 weeks. The primary study endpoints include median times from: diagnosis to clinic presentation, clinic presentation to ART, and ART to undetectable viral load (VL), < 200 copies/mL and < 50 copies/mL. Linkage to and retention in care were measured at 3 months. Study results were compared with non-RSA historical control data. Patient reported outcomes were evaluated at study completion. Results Of the 27 eligible, 25 participants enrolled. Thirteen received their diagnosis at TH: screening for PrEP (6), community-based HIV/STI/HCV testing (3), community outreach (1), or routine patient screening in primary care (3). Twelve were diagnosed externally: university health centers (2), other health clinic (9), or at-home rapid HIV test (1). All accepted the RSA treatment with BFTAF; two eligible patients declined the study, but accepted RSA. 73.9% of participants were seen within 14 days of Day 84, compared with 50% of historical control group. 12 of 25 completed the primary endpoint of which 100% were highly satisfied with RSA. There were no regimen changes or virologic failures through 48 weeks. RoCHaCHa Study Results Conclusion RSA with BFTAF reduced time to virologic suppression in all participants newly diagnosed with HIV-1 compared with historical non-RSA model. Disclosures Ashley R. Zuppelli, PHARMD, BCACP, AAHIVP, Gilead Sciences, Inc. (Grant/Research Support)Gilead Sciences, Inc. (Advisor or Review Panel member, Research Grant or Support) Michael Mancenido, DO, AAHIVS, Gilead Sciences, Inc. (Grant/Research Support) Jacob Scutaru, MD, Gilead Sciences, Inc. (Grant/Research Support) Alexandra Danforth, PHARMD, BCACP, AAHIVP, Gilead Sciences, Inc. (Grant/Research Support) Robert Biernbaum, DO, MS, FAAEM, AAHIVS, Gilead Sciences, Inc. (Grant/Research Support, Advisor or Review Panel member, Speaker’s Bureau) Roberto Corales, DO, AAHIVS, Gilead Sciences (Employee) William M. Valenti, MD, FIDSA, Gilead Sciences, Inc. (Grant/Research Support, Speaker’s Bureau)
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Lauber, T. Bruce, Nancy A. Connelly, Jeff Niederdeppe e Barbara A. Knuth. "Effects of an Advisory Brochure on Fish Consumption of Urban Anglers in the Great Lakes Region". Risk Analysis 38, n. 7 (19 dicembre 2017): 1405–21. http://dx.doi.org/10.1111/risa.12953.
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Lamontagne-Godwin, Julien, Peter Dorward, Irshad Ali, Naeem Aslam e Sarah Cardey. "An Approach to Understand Rural Advisory Services in a Decentralised Setting". Social Sciences 8, n. 3 (26 marzo 2019): 103. http://dx.doi.org/10.3390/socsci8030103.
Abstract (sommario):
As populations increase, so do the challenges in feeding the world. Rural Advisory Services (RAS) contribute positively to food security by ensuring rural populations have access to vital knowledge increasing yields and rural incomes. For historical reasons however, national RAS have often developed into complex networks of stakeholders which can confuse, and even in some cases provide conflicting advice. In order to improve internal and external knowledge of an advisory service, this article investigates the benefits and limitations of an approach that combines qualitative and quantitative stakeholder perception activities at a local and national level. Local and national workshops were held using focus group and open fora techniques in order to portray and visualise a crop health advisory system in Pakistan, a dynamic and complex case study. The approach manages to expose key differences between local and national perceptions of a crop health RAS: whilst both local and national workshop participants decidedly agree on the importance of local (provincial and district level) extension departments, local perceptions clearly identified the strength and value of private sector and community level interactions. At the national workshop, interpretations of ground level activities were vague, yet their mentions of microcredit initiatives, large scale Non-Government Organisation activities and semi-autonomous institutions demonstrate knowledge at a different scale. This approach demonstrates the value of an accessible methodology to measure and understand RAS. Whilst this approach is a key component in assessing the system’s dynamism prior to any future development initiative, it needs to refine its integration of gendered perceptions.
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Yao, Lijun, Tianjiao Wang, Sato Kazuhiro, Reyka G. Jayasinghe, William Pilcher, Edgar Gonzalez-Kozlova, Yered Pita-Juarez et al. "Single-Cell RNA-Seq Analysis of CD138-Depleted Bone Marrow Samples Reveals Genetic Alterations and Disease Progression Correlate with Tumor and Bone Marrow Immune Microenvironment in the Mmrf Commpass Study". Blood 138, Supplement 1 (5 novembre 2021): 2691. http://dx.doi.org/10.1182/blood-2021-154081.
Abstract (sommario):
Abstract Multiple Myeloma (MM) is the second most common hematologic malignancy, marked by uncontrolled clonal expansion of plasma cells. MM genome is complex and heterogeneous, with a high frequency of structural variants (SVs) and copy-number abnormalities (CNAs). Single-cell sequencing technologies offer advantages over traditional bulk methods in cancer genomics research for evaluating cellular heterogeneity and investigating evolution of cellular subpopulations within the tumor. Thus, there is an impetus to translate the growing understanding of the genomic landscape of MM into dissecting the tumor heterogeneity using scRNA-seq. So far, there are no reported studies systematically comparing tumor and immune populations differences between MM NON-progressors (NPs) and RAPID-progressor (RPs) and investigating how clonal plasma cells contribute to progression in a large cohort. In addition, the bone marrow microenvironment plays an important role in the evolution of premalignant MM and MM progression. A previous study of single-cell transcriptomics analysis of Monoclonal gammopathy of undetermined significance (MGUS) and MM tumor microenvironment (TME) revealed that natural killer (NK) cell abundance is frequently increased in the early stages and associated with altered chemokine receptor expression. This study shed the light on the role of immune cells on disease progression from asymptomatic MGUS to symptomatic MM. However to date, how immune cells influence disease progression within symptomatic MM is still unclear. Here, we subjected 344 CD138-negative Bone Marrow Mononuclear cells (BMMC) samples to scRNA-seq. To control for the first line therapy, 272 patients were treated with RVD and Autologous stem cell transplant (ASCT) and were stratified into 3 groups based on progression: 200 NON-progressors (NPs) (PFS> 5 years), 7 Intermediate Progressors (IPs, PFS 2-4 years) and 38 RAPID-progressors (RPs) (PFS<=18 months). In addition, there are 72 subjects treated with RVD but without ASCT, including 34 NPs, 2 IPs and 36 RPs. From MMRF CoMMpass study (NCT01454297), we also have whole exome sequencing (WES) and bulk RNA-seq from CD138-positive fraction of BMMC samples. Our preliminary analysis of scRNA-seq of 6 samples treated by the same first-line therapies (RVD but without ASCT) revealed that plasma cells (PCs) from two patients (MMRF2550 and MMRF2562) with chromosome 13q deletion clustered together, whereas PCs from a patient (MMRF2187) with t(8;14) Myc translocation formed a distinct cluster. Interestingly, PCs from a patient (MMRF2271) with both chromosome 13q deletion and t(8;14) formed another independent cluster. These observations highlight the important role of genetic drivers in transcriptome profiles of plasma cells. In addition, we further investigated how progression features correlate with the immune microenvironment and identified differentially expressed genes between NK cells from RPs versus those from NPs, which could potentially serve as MM progression markers. Interestingly, several cytotoxicity genes are significantly upregulated in FPs, such as GZMB and KLRB1 (log Fold Change=1.44, and 8.41 respectively). Overall, our preliminary results provide a small glimpse of the interconnected nature of driver genetic alterations and progression features in MM tumor and TME. This study will provide a sufficiently broad, deep, and diverse vast dataset for accurately characterizing MM at single-cell resolution to help interrogate how genetic alterations and disease progression interplay MM tumor and TME. We hope this study could identify novel candidate targets for therapeutic approaches, and ultimately stratify patients by risk of progression for early intervention in the clinic. Disclosures Kumar: Roche-Genentech: Consultancy, Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Carsgen: Research Funding; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy.
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Rapaport, Franck, Jay Patel, Jie He, Timothy A. Brennan, Michelle Nahas, Sohail Balassubramanian, Geoff Otto et al. "Integrated DNA/RNA Profiling for Somatic Alterations in Adult B-Cell ALL". Blood 126, n. 23 (3 dicembre 2015): 1422. http://dx.doi.org/10.1182/blood.v126.23.1422.1422.
Abstract (sommario):
Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy observed in the pediatric population. Recent genomic studies have made considerable strides in improving our understanding of the molecular pathogenesis of pediatric B-cell ALL. This includes the discovery of recurrent somatic alterations targeting B-cell transcription factors, mutations in epigenetic regulators, and oncogenic mutations which activate signaling effectors, including in Ph-like B-ALL. However, the molecular pathogenesis of adult B-cell ALL has been less well studied, and there is a need to identify novel therapeutic targets in adult B-ALL. We therefore performed detailed genomic profiling in adults with B-cell ALL. We performed targeted DNA/RNA capture and sequencing of 189 patients with B-cell ALL enrolled on the ECOG E2993 clinical trial. All samples were taken at the time of diagnosis before patients were treated with multi-agent chemotherapy and followed for clinical outcomes including overall survival and remission/relapse duration and kinetics. We used the FoundationOne® Heme assay for our genomics study. This platform allows us to identify short events (point substitutions, short insertions/deletions) copy number and fusion events present in DNA and/or RNA. Of the 203 samples profiled, 189 had sufficient quality genomic data with a median coverage of 435 on DNA sequencing and 7.85 million on target distinct reads per case on RNA sequencing. In all, we identified cancer-related mutations in 108 genes, 55 of these genes being mutated in more than one sample. We identified a median of 2.98 genomic alterations per sample (standard deviation of 1.78) in the target gene set, which included all genes known to be altered in B-ALL and in other hematologic malignancies. The most common genomic events were the BCR-ABL1 fusion (69 samples, 36.5%), followed by CDKN2A loss (57 samples, 30%), CDKN2B loss (35 samples, 18%), NRAS and KRAS point mutations (32 samples, 16.9%), and MLL fusion genes with a spectrum of partners (25 samples, 13.2%). Notably, we found that BCR-ABL1 fusion are mutually exclusive with both RAS mutations (p<10^-7) and MLL mutations (p<5*10^-4). We next investigated the spectrum and frequency of alterations observed in different classes of oncogenes/tumor suppressors. We identified mutations which result in activation of oncogenic signaling pathways in 130 cases or 68.7% of our cohort. This included known mutations/fusions, such as BCR-ABL, RAS-MAPK pathway mutations, and JAK-STAT pathway alterations, and included missense alleles, insertion/deletion events, and fusion genes targeting a spectrum of genes including ABL, PDGFRB, and CRLF2. In aggregate, 33.8% of the cohort had mutations which activate signaling exclusive of BCR-ABL, demonstrating the high prevalence of the Ph-like B-ALL subtype in adult B-ALL. We identified mutations affecting key transcription factors, including PAX5 and IKZF1, in 31.2% of our cohort including missense, nonsense and deletion events. To confirm our ability to detect small deletions of PAX5 and IKZF1, we performed array CGH of 50 cases and compared copy number calls using high-throughput sequencing and CGH. Of note, all deletions targeting PAX5 and IKZF1 identified by NGS were confirmed by CGH. We also identified mutations in epigenetic regulators in 30.6% of cases, including MLL fusions, mutations in the DNA methylation/hydroxymethylation the pathway (DNMT3A, TET1, TET2), and mutations targeted chromatin modulators. Detailed analyses of the mutational spectra and their relationship to clinical outcome will be presented at the meeting. Taken together, these data show we can use a clinically validated sequencing assay to identify known and novel somatic mutations in adult B-ALL, including sequence alterations, rearrangements and copy number aberrations. These data demonstrate the feasibility of combined DNA and RNA study to identify a complex landscape of fusions and short mutations with prognostic and therapeutic relevance, and inform the use of genomic profiling in B-ALL in the clinical context. Figure 1. Figure 1. Disclosures He: Foundation Medicine, Inc.: Employment, Equity Ownership. Brennan:Foundation Medicine, Inc.: Employment, Equity Ownership. Nahas:Foundation Medicine, Inc.: Employment, Equity Ownership. Balassubramanian:Foundation Medicine, Inc.: Employment, Equity Ownership. Otto:Foundation Medicine, Inc.: Employment, Equity Ownership. Lipson:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Merck: Honoraria; Regeneron: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.
43
Hershberger, Courtney, James Hiznay, Rosemary Dietrich, Xiaorong Gu, Cassandra M. Hirsch, Amy Graham, Bartlomiej P. Przychodzen et al. "LUC7L2 Is a Novel RNA-Splicing Regulatory Factor Mutated in Myelodysplastic Syndromes". Blood 132, Supplement 1 (29 novembre 2018): 3073. http://dx.doi.org/10.1182/blood-2018-99-112838.
Abstract (sommario):
Abstract Myelodysplastic syndromes (MDS) are unique among cancers because of the frequent occurrence of somatic mutations impacting spliceosome machinery. At least 65% of MDS patients harbor a mutation in one of several splicing factors including U2AF1, SF3B1 and SRSF2. Whole exome sequencing of MDS bone marrow uncovered somatic frameshift mutations in LUC7L2, the mammalian ortholog of a yeast splicing factor. LUC7L2 is located in the most commonly deleted region of chromosome 7. Deletions and frameshifts lead to haploinsufficient expression and therefore it can be approximated that a combined 14% of MDS patients have low expression of LUC7L2. Restoring expression of LUC7L2 in del(7q)-iPSCs partially rescues the differentiation of iPSCs into CD45+ myeloid progenitors. Although perhaps partly due to associated losses of other genes on chromosome 7, low expression of LUC7L2 correlates with a poorer patient prognosis, so its haploinsufficiency may play an important role in bone marrow failure. While U2AF1, SF3B1, and SRSF2 are well-characterized splicing factors, the function of LUC7L2 in pre-mRNA splicing is unexamined and its role in the MDS pathogenesis is undefined. We hypothesize that low expression of LUC7L2 results in the aberrant splicing of oncogenes and tumor suppressor gene transcripts thus reducing expression or altering function and contributing to the pathogenesis of MDS. We have characterized LUC7L2 as an alternative splicing regulatory protein that plays a repressive role in the regulation of alternative RNA splicing. We generated HEK-293 cells overexpressing V5-tagged LUC7L2 for immunoprecipitation-mass spectrometry, to ascertain protein interactions with LUC7L2. LUC7L2 co-immunoprecipitated with splicing regulators which are involved in splice site recognition. We performed cross-linking-IP-high-throughput-sequencing (CLIP-seq) to identify LUC7L2 binding sites on RNA. We identified 301 LUC7L2 RNA-binding sites as well as binding sites on U1 and U2 which is common for splicing regulatory proteins. Metagene analysis of these binding sites showed that LUC7L2 bound near splice sites in exonic sequences. We knocked down LUC7L2 expression in HEK293 and K562 cells to phenocopy the frameshifts and deletions observed in MDS patients. We used a PCR-based assay to measure the splicing efficiency of introns near LUC7L2-binding sites. Knockdown of LUC7L2 increased the splicing efficiency of 8/13 selected introns; this suggests that LUC7L2 represses selective splice site usage. We also performed RNA-seq to characterize global mis-splicing events. Analysis of RNA transcripts revealed a multitude of splicing changes, including enhanced exclusion of alternative introns. Knockdown LUC7L2 cells exhibited-altered expression of other splicing factors; this could have further contributed to the vast number of splicing changes observed. To identify specific splicing changes that could contribute to the pathogenesis of MDS, we compared the splicing profiles of LUC7L2-knockdown in K562 cells with RNA-seq data from K562 cells expressing U2AF1S34F, SRSF2P95H or SF3B1K700E. This analysis yielded several exon-skipping splicing patterns in cancer-relevant transcripts, such as oncogene PRC1, splicing factor PTBP1 and MRPL33. Additionally, we noticed commonly mis-spliced transcripts among the four datasets in which the missplicing events occurred in the functional domain, potentially conferring a functional change. Surprisingly, we observed missplicing of U2AF1 in LUC7L2-knockdown, SRSF2P95H, and SF3B1K700E K562 cells, which altered the length of the RNA-recognition UHM domain by inclusion of a mutually exclusive exon or retention of an intron. In this way, low expression of LUC7L2, or point mutants U2AF1S34F, SRSF2P95H, and SF3B1K700E,could alter U2AF1 function as a distal convergence point. In summary, we identified a novel splicing factor implicated in the pathogenesis of MDS. We characterized LUC7L2 as a splicing repressor and discovered many splicing changes caused by low expression of LUC7L2. Several genes were also mis-spliced in U2AF1S34F, SRSF2P95H and SF3B1K700E K562 cells targeting these for further study. Commonly mis-spliced targets such as U2AF1 may indicate that some of the novel therapeutics may have spliceosome mutation agnostic effects. If this applies to the LUC7L2 mutations, then they may also be effective in del7/del7q cases. Disclosures Carraway: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; FibroGen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Consultancy, Speakers Bureau. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Saunthararajah:Novo Nordisk, A/S: Patents & Royalties; EpiDestiny, LLC: Patents & Royalties. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy.
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Eastburn, Dennis J., Christine M. McMahon, Robert Durruthy-Durruthy, Martin Carroll, Catherine C. Smith e Alexander E. Perl. "Longitudinal Monitoring of AML Tumors with High-Throughput Single-Cell DNA Sequencing Reveals Rare Clones Prognostic for Disease Progression and Therapy Response". Blood 132, Supplement 1 (29 novembre 2018): 1476. http://dx.doi.org/10.1182/blood-2018-99-119869.
Abstract (sommario):
Abstract AML (acute myeloid leukemia) is increasingly being treated with precision medicine. To better inform treatment, the mutational content of patient samples must be determined. However, current tumor sequencing paradigms are inadequate to fully characterize many instances of the disease. A major challenge has been the unambiguous identification of potentially rare and genetically heterogeneous neoplastic cell populations, capable of critically impacting tumor evolution and the acquisition of therapeutic resistance. Standard bulk population sequencing is unable to identify rare alleles and definitively determine whether mutations co-occur within the same cell. Single-cell sequencing has the potential to address these key issues and transform our ability to accurately characterize clonal heterogeneity in AML. Previous single-cell studies examining genetic variation in AML have relied upon laborious, expensive and low-throughput technologies that are not readily scalable for routine analysis of the disease. We applied a newly developed platform technology to perform targeted single-cell DNA sequencing on over 140,000 cells and generated high-resolution maps of clonal architecture from AML tumor samples. Marrow and/or peripheral blood samples were collected prior to, during treatment, and at clinical progression to the FLT3 inhibitor gilteritinib given on a clinical trial for relapsed/refractory AML with FLT3 mutation. Single-cell sequencing of multiple patient samples demonstrated that relapse clones acquired oncogenic RAS mutations. We utilized the high-throughput and sensitivity of our single-cell approach to more definitively assess where in the course of treatment these RAS mutated clones were acquired. Oncogenic RAS harboring clones, comprising between 0.4%, and 0.1% of tumor populations, were identified in patient samples either prior to or shortly after onset of treatment. Significantly, these RAS variant alleles were not detectable with targeted bulk sequencing. Throughout the course of treatment with the FLT3 inhibitor gilteritinib, the RAS mutant clones selectively expanded and were responsible for resistance to therapy and relapse. These findings point to the presence of underlying genetic heterogeneity in AML and demonstrate the utility of sensitively assaying clonal architecture to better inform patient stratification and therapy selection. Disclosures Eastburn: Mission Bio, Inc.: Employment, Equity Ownership. Durruthy-Durruthy:Mission Bio, Inc.: Employment, Equity Ownership. Smith:Astellas Pharma: Research Funding. Perl:Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Arog: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees.
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Ambrogi, Federica. "Elisa Paini (1863-1924). Wife and «unbeatable collaborator» of Luigi Credaro". Rivista di Storia dell’Educazione 7, n. 2 (4 dicembre 2020): 133–44. http://dx.doi.org/10.36253/rse-9865.
Abstract (sommario):
The life of Luigi Credaro’s wife, Elisa Paini, allows us to observe some aspects of Credaro’s life in a new light. Through unpublished archival documents and letters of the spouses, the role of his wife is revealed, who was not only a trusted advisor but also a very reserved collaborator of the “Rivista Pedagogica” [Educational Journal] and the Unione Magistrale Nazionale, the Elementary school teachers national union. Elisa also represented the reference point for Credaro’s friends and colleagues and for anyone who wanted to reach him, to such an extent that she replaced her husband in his written communication.
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Klever, Marius-Konstantin, Eric Sträng, Julius Jungnitsch, Uirá Souto Melo, Sara Hetzel, Anna Dolnik, Robert Schöpflin et al. "Integration of Hi-C and Nanopore Sequencing for Structural Variant Analysis in AML with a Complex Karyotype: (Chromothripsis)²". Blood 136, Supplement 1 (5 novembre 2020): 28. http://dx.doi.org/10.1182/blood-2020-133787.
Abstract (sommario):
Background. Acute myeloid leukemia (AML) with a complex karyotype (CK-AML) is an AML subtype with a still dismal outcome despite recent therapeutic advances. The prognosis is even worse when the underlying structural variants (SVs) lead to an extremely complex pattern of rearrangements, called chromothripsis, with a median overall survival of only 120 days. Except for the presence of inactivating TP53 aberrations in about 70% of all AML-CK cases, the pathogenesis is poorly understood. To gain novel insights into the molecular mechanisms underlying CK-AML reliable high precision SV delineation is needed, which so far has been a major limitation in cancer research. Aim. We developed a SV detection pipeline by integrating Oxford Nanopore Technology (ONT) based whole genome sequencing (WGS) and Hi-C sequencing. This pipeline generated precise characterization of SVs for which the impact on gene expression and the emergence of novel fusion genes was studied by RNA-seq and ONT transcriptome sequencing. Patients and Methods. We applied our WGS and Hi-C SV detection pipeline to a cohort of 11 AML-CK cases. Nanopore DNA Sequencing was performed until a genomic coverage >10x per patient was reached. The samples of 9 patients were also subjected to Nanopore cDNA sequencing for fusion gene analysis and Illumina based RNA-seq for transcript quantification. As controls for Hi-C and Illumina RNA sequencing, CD34+ hematopoietic stem cell enriched samples from five healthy donors were used. Results. Our SV detection pipeline enabled us to fully reconstruct the derivate chromosome structure even of very complex, chromothriptic rearrangements in CK-AML. This enabled us to identify features of chromothripsis, that could previously not be detected using conventual technologies. We found local clustering of breakpoints in three of the patients with up to 31 Inversions and Translocations located in a genomic region of just 2.7 kb. These breakpoints were present in the Hi-C as well as in our Nanopore SV dataset. Our SV pipeline also showed that in these highly clustered regions, the very small rejoined fragments (in many cases less than 1 kb in size) often showed an elevated copy number (CN) state, i.e. small amplifications. We termed this newly discovered phenomenon chromothripsis-in-chromothripsis or (chromothripsis)². The precise knowledge about these breakpoints, which were validated by two different technologies, enabled us to study the pathogenesis of CK-AML at a so far unprecedented resolution. Fusion transcripts could be very precisely mapped and the impact of the breakpoints and CN changes on gene expression levels could be validated, thereby indicating functional relevance of the respective aberrations. Conclusions. The combination of Hi-C and long-read sequencing for SV detection proved to be a powerful tool for precise SV detection. Our SV pipeline allowed us to discover a new level of complexity in chromothripsis. Application of this pipeline to leukemias as well as other types of cancer can improve the precision of SV detection, thereby raising new opportunities for functional interpretation of complex genomic aberrations of pathogenic relevance. Disclosures Döhner: Sunesis Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Consultancy; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Arog: Research Funding; Roche: Consultancy; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Abbvie: Consultancy; Agios: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Celgene: Consultancy, Honoraria. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Bullinger:Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees.
47
O'Sullivan, Jennifer, Aaron T. Gerds, Claire N. Harrison, Stephen T. Oh, Angela Hamblin, Sarah A. Buckley, Alan F. List e Adam J. Mead. "Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis". Blood 138, Supplement 1 (5 novembre 2021): 3584. http://dx.doi.org/10.1182/blood-2021-149666.
Abstract (sommario):
Abstract Introduction: Patients with myelofibrosis who discontinue treatment with the JAK1/2 inhibitor ruxolitinib have a poor prognosis that is often associated with advanced phases of disease and severe cytopenias. While these patients are more likely to have high molecular risk genomic markers, biological drivers of disease in this advanced population are not well characterized. PAC203, a Phase 2 dose-finding study in patients with symptomatic myelofibrosis who were intolerant of or resistant to ruxolitinib, represents an opportune cohort for analyzing the association between high molecular risk (HMR) mutations and disease phenotype. Patients had advanced disease at study entry, with profound cytopenias and high mutational burden [O'Sullivan J et al. Blood (2019) 134 (Sup_1):4214.]. Here, we analyzed the interaction between high-risk mutations and cytokine profiles of patients treated in PAC203. Methods: Cytokine and mutation data were available in 108 (of total 164 recruited; 161 treated) patients. Using the Myriad RBM platform, a microsphere-based immuno-multiplexing technology, 47 cytokines were assessed. Mutation profiles were determined using an ISO accredited Illumina TruSeq Custom Amplicon Panel, composed of mutational-hotspots/exons from 32 genes (~36,000 bp, 287 amplicons). CALR mutation screening was carried out independently. Accepted coverage was achievement of a depth of ≥100 reads per base in ≥95% of targeted bases. The initial analysis assessed possible relationships between individual plasma cytokine levels and specific somatic gene mutation and clinical demographic data. An unsupervised approach was then used applying hierarchical agglomerative clustering to identify related sets of cytokines. Associations between cluster scores, based on the median overall cytokine concentration within each cluster for each patient, and clinical and genomic data was assessed. Results: The median baseline platelet count was 64 x10 9/L (38% with platelets <50 x10 9/L) and baseline Hb <10g/dL in 68% of patients. The median age was 68 (37-87) years. The mutation profile of this cohort was previously described, with JAK2 V617F mutations (78%) the most prevalent driver mutation, followed by CALR mutations (13%), MPL mutations (7%), and patients were "triple-negative" in 2% of cases. Non-MPN driver mutations (NDM) were present in 76%, most commonly mutated-ASXL1 and -TET2 (27% and 24% respectively). Overall, 41% of patients had a high molecular risk mutation (HMR; IDH1/2, SRSF2, ASXL1, SRSF2, U2AF1Q157), splicing factor (SF) gene mutations were detected in 32% of patients and RAS pathway mutations (KRAS/NRAS) were found at a higher frequency than previously in MF cohorts (18%). Analysis of cytokine data using unsupervised learning identified 6 clusters (Figure 1). Among these, elevations in clusters 2 (p=0.009) and 4 (p=0.006) were associated with presence of HMR mutations. Higher cluster 2 scores were also associated with driver mutation variant allele frequencies≥50%, p=0.007. Notably, the pro-inflammatory cytokines in cluster 2 linked to HMR mutations (HMR+) represented a transcriptional cluster regulated by the NF-κB pathway. The presence of a HMR mutation was associated with higher IL-8 levels (40.5pg/ml) as compared with absence (24.5pg/ml), p<0.0001. Elevated tumour necrosis factor-alpha (TNF- α) and IL-18 levels were also associated with HMR mutations; TNF-α 61pg/ml in HMR+ vs. 48.5pg/ml for HMR-. Although RAS-pathway mutations were not associated with a specifc cluster scores, these patients did have higher levels of the NF-kB-associated cytokine IL12P40 (1.1ng/ml) as compared with RAS-pathway wild-type patients (0.6ng/ml), p=0.001. There was no association between cytokine cluster scores and recent exposure to RUX at trial entry. Conclusions: In this high-risk cohort of previously RUX-treated MF patients enriched for HMR and RAS-pathway mutations, we report for the first time a relationship between HMR somatic gene mutations and an NF-κB directed pro-inflammatory cytokine signature, implicating the activation of a distinct biological signaling pathway operative in this molecularly-defined cohort. Figure 1 Figure 1. Disclosures Gerds: CTI BioPharma: Research Funding; AbbVie: Consultancy; Sierra Oncology: Consultancy; PharmaEssentia Corporation: Consultancy; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Harrison: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Buckley: CTI Biopharm: Current Employment. List: CTI Biosciences: Consultancy; Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy. Mead: Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau.
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Chiaretti, Sabina, Taherinasab Akram, Canichella Martina, Monica Messina, Alfonso Piciocchi, Cyril Šálek, Katerina Machova et al. "The Validation of the BCR/ABL1-like Predictor across Laboratories Shows Reproducibility of Results". Blood 134, Supplement_1 (13 novembre 2019): 5211. http://dx.doi.org/10.1182/blood-2019-122116.
Abstract (sommario):
Background BCR/ABL1-like (alias Ph-like) acute lymphoblastic leukemia (ALL) is a clinically challenging subgroup. Its incidence varies from 10% in children to 30% in adult ALL. The underlying genomic background, usually characterized by the presence of kinase activating lesions, opens the way to targeted treatment. However, one of the major issues of this subset is represented by the identification of a standardized assay for their recognition at diagnosis. Indeed, while gene expression profile (GEP) and next-generation sequencing (NGS) are efficient techniques to identify these cases, they are difficult to be implemented in the diagnostic routine. Our group previously developed a rapid, simple and cost-effective algorithm based on a quantitative real time-polymerase chain reaction (Q-RT-PCR) named "BCR/ABL1-like predictor". Briefly, the expression levels of 10 genes - NUDT4, SEMA6A, ADGRE5, SOCS2, JCHAIN, CRLF2, TP53INP1, CD99, IFITM1 and IFITM2 - are used to generate a score: cases with a score ≥-0.3 are classified as BCR/ABL1-like. Aims After developing the BCR/ABL1-like predictor, we sought to: further refine the ability of this model to correctly predict BCR/ABL1-like ALL by evaluating NGS and RNA-sequencing of BCR/ABL1-like and non-BCR/ABL1-like cases, and to define the incidence of specific lesions;evaluate the reproducibility of the predictor when performed in external laboratories or when samples with a known genetic background were analyzed in house by the predictor. Results NGS and RNA-sequencing were carried out in 28 BCR/ABL1-like cases: CRLF2 overexpression, was found 35.7% of cases, with 3 harboring a CRLF2 rearrangement and 1 with a concomitant CRLF2 mutation. Furthermore, 13 JAK/STAT pathway mutations - JAK1, n=5; JAK2, n=3; IL7R and CRLF2, n=2 each, JAK3, n=1 - were identified in 33.3% of cases. Finally, RNA-sequencing and/or FISH experiments of the BCR/ABL1-like ALL cases revealed 11 lesions: 5 ABL-class fusion genes (3 NUP214/ABL1, 1 ZC3HAV1/ABL2 and 1 EBF1/PDGFRB), 2 BCR/JAK2, 3 CRLF2-r and 1 DDX3X/USP9X. In order to verify the reproducibility of the predictor, a collaboration was started across Europe with the Institute of Hematology and Blood Transfusion (ÚHKT, Prague), Josep Carreras Leukaemia Research Institute (Barcelona) and Munich Leukemia Laboratory (Munich), through the exchange of material and/or data. The first collaboration was carried out with the ÚHKT and Josep Carreras Leukaemia Research Institute laboratories: 11 cDNA samples (from 1 μg of total RNA), previously studied by our laboratory and classified as BCR/ABL1-like (n=5) and non-BCR/ABL1-like (n=6) ALL were shipped blindly and evaluated for the model in these laboratories. The technical set-up was sent to each laboratory, consisting of experimental procedures, PCR protocol and the threshold for Q-RT-PCR analysis. We received the raw data (i.e. 2^(-ΔCt) values) and uploaded them in the on-line BCR/ABL1-like predictor tool. We had 100% concordance with the ÚHKT and 81.8% with the Josep Carreras Leukaemia Research Institute. The main discrepancies were with 2/5 BCR/ABL1-like cases resulted as non-BCR/ABL1-like in the external laboratory: 1 was a p210 BCR/ABL1-positive case, used as control, which proved borderline, and the second was a BCR/ABL1-like case that, on the other hand, was not studied for the genetic features. A further collaboration was carried out with the MLL laboratory: we received 12 RNA samples - already analyzed by NGS and FISH - for evaluation by the BCR/ABL1-like predictor. The BCR-ABL1-like predictor classified 5 cases as BCR/ABL1-like and 7 as non-BCR-ABL1-like: all 5 BCR/ABL1-like carried a typical signature, consisting of a CRLF2 rearrangement plus JAK/STAT pathway mutations. Discordant cases were represented by 2 non-BCR-ABL1-like cases: one had a CRLF2 rearrangement plus JAK/STAT mutations and the other an ABL1 rearrangement. It is important to underline that the latter case had a borderline score (-0.482). Thus, the concordance rate was 83.3%. Conclusions This study shows that the BCR/ABL1-like predictor is a valid and reproducible tool across laboratories to identify rapidly these cases, with the goal of introducing genetic-driven therapeutic approaches upfront. One critical aspect is represented by borderline cases: in these patients, NGS experiments are required to define the underlying genomic lesion. Further investigations are currently underway. Disclosures Chiaretti: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Machova:Novartis: Consultancy; Incyte: Consultancy; BMS: Consultancy, Research Funding. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Foà:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau.
49
Dolnik, Anna, Nikolaus Jahn, Eric Sträng, Sibylle Cocciardi, Frank G. Rücker, Ekaterina Panina, Tamara J. Blätte et al. "Mutational Landscape of Relapsed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)". Blood 136, Supplement 1 (5 novembre 2020): 42. http://dx.doi.org/10.1182/blood-2020-142392.
Abstract (sommario):
Background: Acute myeloid leukemias (AML) with rearrangements of core-binding factor (CBF) complex genes (CBF-AML), comprising t(8;21) and inv(16) subgroups, are considered as diseases with favorable outcome. Nevertheless, CBF-AML relapse rates remain high, with ~40% of patients (pts) relapsing after standard intensive chemotherapy. Aim: To dissect the biology of relapse in CBF-AML, we performed whole exome sequencing (WES) in a large cohort of 101 cases at the time of diagnosis and for 47 cases also at the time of relapse. Methods: All pts were treated either with standard chemotherapy or with standard chemotherapy and kinase inhibitor dasatinib within clinical trials of the German-Austrian AML Study Group (AMLSG). Using the Nextera Rapid Capture Exome kit (Illumina) we performed WES of paired diagnostic (dx), remission and relapse samples of 47 pts, namely 21 pts with t(8;21) and 26 pts with inv(16). RNAseq was performed in 18 of these pts using the Ribo Zero RNA-sequencing kit (Illumina). To better define genomic signatures related to CBF-AML relapse, we included WES data previously published by our group (Faber et al. Nat Genet 2016). This set comprised dx samples of 8 t(8;21) and 10 inv(16) pts who relapsed as well as a control group of 20 t(8;21) and 16 inv(16) CBF-AML pts, who did not experience relapse. Results: For the new cohort, WES sequencing of 47 pts was performed with a mean coverage of 127-fold. In t(8;21), we identified a median of 3.5 mutations exclusively present at dx (range: 0-8), 11.6 mutations persistent from dx to relapse (range: 4-19), and 4.0 mutations gained at relapse (range: 2-7). For the inv(16) subgroup a median of 2.0 mutations were dx specific (0-7), 6.0 mutations persisted during tumor evolution (3-26) and 2.5 were gained at relapse (0-9). As previously reported, the spectrum of genes affected by mutations showed little overlap between t(8;21) and inv(16), except for commonly affected 'signaling' genes such as KIT, RAS, FLT3 and epigenetic players such as TET2. In total, in t(8;21) we identified 94 relapse-specific mutations or mutations displaying a strong increase in variant allele frequency (VAF) at relapse, and 63 of such relapse-specific alterations in inv(16) pts. In addition to the previously reported RUNX1 and cohesin complex gene mutations showing an increase in VAF at relapse, we found recurrent novel relapse-specific mutations in LAMC3, which occurred exclusively in the t(8;21) subgroup affecting 9% of pts. In inv(16), recurrent mutations in the tumor suppressor gene WT1 occurred in 12% of pts, either acquired at relapse or already present at dx as a minor subclone. Remarkably, mutations in relapsed t(8;21) pts often affected genes involved in PI3K-AKT and in cell cycle regulation pathways. In the inv(16) relapse group, in addition to dysregulation of the MAPK signaling pathway, we found several non-recurrent mutations in genes involved in ribosomal RNA metabolism, like in PRNAD1. Conclusion: Our WES sequencing results already provide first insights into the molecular composition and mechanisms underlying relapse in CBF-AML which often affect pathways linked to proliferation, such as PI3K-AKT and MAPK signaling. While we are currently validating additional hits, updated results will be provided at the ASH meeting, which will also address combinatorial mutation patterns underlying chemotherapy resistance in t(8;21) and inv(16) positive AML. Disclosures Götze: Celgene: Research Funding. Fiedler:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; ARIAD/Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: support for meeting attendance, Patents & Royalties, Research Funding; Daiichi Sankyo: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Jazz Pharmaceuticals: Honoraria, Other: support for meeting attendance; Abbvie: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Thol:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Heuser:PriME Oncology: Honoraria; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Karyopharm: Research Funding; Roche: Research Funding; Bayer: Consultancy, Research Funding; Amgen: Research Funding; BerGenBio ASA: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Research Funding. Ganser:Novartis: Consultancy; Celgene: Consultancy. Paschka:Agios Pharmaceuticals: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Consultancy; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Otsuka: Consultancy; Pfizer: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Consultancy; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Amgen: Other; Janssen Oncology: Other; BerGenBio ASA: Research Funding. Döhner:GEMoaB: Consultancy, Honoraria; AROG: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Sunesis: Research Funding. Döhner:Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Abbvie: Consultancy; Sunesis Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; Roche: Consultancy; Arog: Research Funding. Bullinger:Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
50
Melo Neto, João José de, e Isabel Lausanne Fontgalland. "Share portfolio advisory: Use of the Markowitz method to optimize the risk/return ratio in individual investor shares portfolio". Research, Society and Development 11, n. 2 (23 gennaio 2022): e26011225921. http://dx.doi.org/10.33448/rsd-v11i2.25921.
Abstract (sommario):
With the growing development of the Brazilian financial market, the interest of small investors was visible, from the year 2019 and until june 2020 the entry of individual investors in the stock exchange had a growth of 174.7% reaching 2,824,239 people according to B3. Despite this significant number, only 3% of the population that has some investment product owns shares of publicly traded companies, given this information is really the niche market that can be exploited. In most cases this small percentage is due to the profile of the Brazilian investor, which can be termed as conservative. Even investors who own a stock portfolio have a low value intended for this type of capital market product. This fear can be attributed to the lack of time to study the market and even by not having knowledge of it, another point that we have to take into account is the emotional and psychological insecurity of gains and losses in the small investor's portfolio, tied to poor risk management. Given the scenario, we advise some stock portfolios by reducing their risks or optimizing their returns by Markowitz's method that uses statistical and rational methods. It became apparent during the study the cost benefit and assertiveness of the same. For the development of this work, the Design Thinking method was used.