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1
Sun, Kaiming, Ruzanna Atoyan, Mylissa A. Borek, Steven Dellarocca, Garrett Rhyasen, Ali Fattaey, and David P. Tuck. "The Combination of Venetoclax and CUDC-907 Exhibits Synergistic Activity in Venetoclax-Refractory DLBCL." Blood 128, no. 22 (December 2, 2016): 4184. http://dx.doi.org/10.1182/blood.v128.22.4184.4184.
Повний текст джерелаАнотація:
Abstract CUDC-907 is a first-in-class, oral, dual inhibitor of Class I and II HDAC, as well as Class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6 and 10 and PI3K-alpha, delta and beta isoform. Preclinical studies demonstrate that CUDC-907 has potent effects on acetylated histone-regulated genes and PI3K signaling. CUDC-907 showed potent antitumor activity in multiple preclinical tumor models as well as in patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL), with objective responses reported in multiple patients, including complete responses. It is currently being investigated in a Phase 2 study in patients with RR DLBCL, including those with MYC-alterations. Preclinical studies of CUDC-907 in combination with chemotherapeutic and targeted agents are in progress. Venetoclax, a BH3 mimetic and selective BCL2 inhibitor, was recently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) whose tumors had a 17p deletion. Results from a Phase 1 study of venetoclax monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma showed that patients with DLBCL exhibited short-lived responses to venetoclax. Thus, combination approaches may be required to achieve durable responses to venetoclax in DLBCL. In our preclinical studies, we examined the combination of venetoclax and CUDC-907 in DLBCL cell lines. Interestingly, the combination exhibited the most synergy, as measured by fold-improvement over predicted additive effect, in cell lines insensitive to venetoclax. For example, OCI-Ly3 cells were insensitive to single agent venetoclax with an IC50 >10uM; however, in combination with a fixed dose (12nM) of CUDC-907, venetoclax resulted in >10000-fold improvement in potency with a combination IC50 of 0.001uM. Synergy was also observed in tumor growth inhibition studies in xenograft models. Western blot analysis showed that single-agent CUDC-907 simultaneously increased pro-apoptotic BIM protein and decreased anti-apoptotic BCL2 protein levels. Interestingly, the low nano-molar concentrations of CUDC-907 that were shown to regulate the BCL-2 family member proteins could also potentiate pro-apoptotic effects of venetoclax when used together in combination in WSU-DLCL2 cell line which carries MYC and BCL2 translocations. Thus, the effect of CUDC-907 on BCL2 family members appears to be the basis for the observed synergy with venetoclax, which functions to displace BIM from BCL2. These results provide a mechanistic rationale for the use of CUDC-907 in combination with venetoclax for the treatment of patients with DLBCL. Disclosures Sun: Curis: Employment, Equity Ownership. Atoyan:Curis: Employment, Equity Ownership. Borek:Curis: Employment, Equity Ownership. Dellarocca:Curis: Employment, Equity Ownership. Rhyasen:Curis: Employment, Equity Ownership. Fattaey:Curis: Employment, Equity Ownership. Tuck:Curis, Inc.: Employment, Equity Ownership.
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Knight, Tristan, Xinan Qiao, Jun Ma, Holly Edwards, Lisa Polin, Juiwanna Kushner, Sijana H. Dzinic, et al. "The Combination of CUDC-907 and Gilteritinib Shows Promising Antileukemic Activity in Vitro and In Vivo in Preclinical Models of FLT3-ITD AML." Blood 134, Supplement_1 (November 13, 2019): 1262. http://dx.doi.org/10.1182/blood-2019-123793.
Повний текст джерелаАнотація:
Introduction FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are found in approximately one quarter of acute myeloid leukemia (AML) cases. Its presence results in constitutive activation of the FLT3 receptor tyrosine kinase and its downstream growth/pro-survival pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT, and confers a poor prognosis. Gilteritinib is a selective inhibitor of FLT3 recently approved by the Food and Drug Administration for treatment of patients with relapsed/refractory AML and a FLT3 mutation. However, gilteritinib exposure induces upregulation of FLT3 - a mechanism of resistance. Previously, we showed that CUDC-907, a dual PI3K/histone deacetylase inhibitor, downregulates FLT3 expression (Li X, et al. Haematologica. 2019; epub ahead of print). We therefore hypothesized that combining CUDC-907 with gilteritinib would abrogate FLT3 upregulation and expression, resulting in synergistic antileukemic activities against FLT3-mutated AML. Methods FLT3-ITD AML cell lines and primary patient samples were treated with gilteritinib or CUDC-907, alone or in combination at clinically achievable concentrations, and subjected to annexin V/propidium iodide staining and flow cytometry analysis to quantify apoptosis. Protein levels of FLT3, Bcl-2 family proteins, and key components of the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways were examined using western blotting. The impact of the observed alterations upon apoptosis were confirmed via overexpression, knockdown, and targeted inhibitor experiments. Real-time RT-PCR was used to determine FLT3 transcript levels. The FLT3-ITD AML cell line MV4-11 was used to generate a xenograft mouse model to assess in vivo efficacy of the two agents. Results CUDC-907 and gilteritinib demonstrated potent synergistic antileukemic effects in FLT3-ITD AML cell lines in vitro and patient samples ex vivo, with combined therapy. CUDC-907 abolished gilteritinib-induced expression of FLT3 in both cell lines and primary patient samples. Gilteritinib treatment reduced p-AKT, p-S6, and p-STAT5 and increased p-ERK, while CUDC-907 reduced p-AKT and p-ERK, and upregulated p-STAT5. The combination of gilteritinib and CUDC-907 decreased not only p-AKT and p-S6, but also p-ERK and p-STAT5. Targeted inhibition of ERK and JAK2/STAT5 signaling by SCH772984 and AZD1480, respectively, confirmed their roles in resistance to gilteritinib and CUDC-907 monotherapies, respectively. Combined gilteritinib and CUDC-907 treatment reduced expression of the anti-apoptotic BCL-2 family member Mcl-1 and increased expression of the pro-apoptotic protein Bim. MCL-1 overexpression and BIM knockdown partially rescued FLT3-ITD AML cells upon drug treatment, confirming their role in the antileukemic activity of combined gilteritinib and CUDC-907. To determine in vivo efficacy of the two agents, NSGS mice were injected with MV4-11 cells. Three days later, the mice were randomized into vehicle control (n=5), 40 mg/kg gilteritinib (oral gavage; n=5), 100 mg/kg CUDC-907 (oral gavage; n=5) or combination (40 mg/kg gilteritinib + 100 mg/kg CUDC-907; n=6) groups. CUDC-907 was given daily for 5 days on, 2 days off, for a total of 4 cycles. Gilteritinib was administered daily for 28 days. Both agents were well tolerated; maximal weight loss was 5.5%, 0.9%, and 6.7% in the CUDC-907, gilteritinib, and combination groups, respectively. Median survival of mice in the vehicle control group was 43 days. Median survival in the CUDC-907 monotherapy and gilteritinib monotherapy arm was 40.5 days and 104 days, respectively. One mouse in the combination therapy arm died on day 138, while the remaining 5 mice in the combination therapy arm continue to survive, as of time of writing (day 168), and are asymptomatic (Figure 1). Conclusion We confirmed that the combination of CUDC-907 plus gilteritinib synergistically induces apoptosis in both FLT3-ITD AML cell lines and primary patient samples, and that gilteritinib-induced FLT3 expression is abolished by CUDC-907. Cooperative inhibition of the PI3K-AKT, JAK-STAT, and RAS-RAF pathways, as well as upregulation of Bim/downregulation of Mcl-1 all appear to contribute to this observed antileukemic synergy. Our cell line-derived xenograft mouse model provides strong evidence of in vivo efficacy and robust grounds for clinical translation of this therapeutic combination. Disclosures No relevant conflicts of interest to declare.
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Younes, Anas, Jesus G. Berdeja, Manish R. Patel, Kevin R. Kelly, Ian W. Flinn, John F. Gerecitano, Sattva S. Neelapu, et al. "Phase 1 Trial Testing Single Agent CUDC-907, a Novel, Oral Dual Inhibitor of Histone Deacetylase (HDAC) and PI3K: Initial Assessment of Patients with Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL), Including Double Expressor (DE) Lymphoma." Blood 126, no. 23 (December 3, 2015): 257. http://dx.doi.org/10.1182/blood.v126.23.257.257.
Повний текст джерелаАнотація:
Abstract DLBCL, the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma (NHL) with significant heterogeneity in terms of gene expression, prognosis and response to treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN activity and/or activating mutations in PI3K and AKT have been shown to reduce apoptosis and promote cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in various DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 translocation and over-expresses cMYC and BCL6, and the WSU-DLCL-2 GCB DLBCL model that harbors EZH2 mutation. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients (pts) with various hematologic cancers. Sixty-three heavily pre-treated pts with lymphoma or multiple myeloma have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that pts received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. A dose expansion using the 60 mg 5/2 dose and schedule is ongoing. Thus far, CUDC-907 has demonstrated a manageable side effect profile and sustained clinical efficacy, particularly in the subset of pts with RR DLBCL. The most common treatment-related adverse events (AEs) were diarrhea (54%; 5% Grade ≥3), fatigue (37%; 3% Grade ≥3), nausea (22%) and thrombocytopenia (18%; 14% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. Among 11/18 subjects with RR DLBCL who were evaluable for disease response, 6/11 (55%) achieved objective responses (2 CRs and 4 PRs); lasting a median of 119 days (range: 48 - 354+). Of 7 pts with sufficient tissue, 3 response-evaluable pts were found to over-express MYC and BCL2 by IHC, meeting criteria applied to "double-expressor" (DE) DLBCL. On CUDC-907 monotherapy, 2/3 confirmed pts with DE DLBCL have attained objective responses: 1 ongoing CR (followed by autologous stem cell transplant) and 1PR (lasting 132 days). The third response-evaluable pt with DE DLBCL has experienced lengthy stabilization of disease (171+ days). Signals emerging from preclinical and clinical studies suggest that pts with DLBCL, including those with particularly aggressive disease, may derive benefit from treatment with CUDC-907. Enrollment of pts with RR DLBCL is ongoing into the expansion phase of the Phase 1 trial that is testing CUDC-907 on the 60 mg 5/2 RP2D as monotherapy and in combination with rituximab. Tissue obtained from pts with RR DLBCL treated with CUDC-907 will be assessed for MYC, BCL2, and other genetic aberrations that will be correlated with clinical outcomes observed in the trial. A Phase 2 trial of CUDC-907 in RR NHL is currently being planned, with emphasis on MYC aberrations. Disclosures Younes: Celgene: Honoraria; Incyte: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Novartis: Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding; Curis: Research Funding; Takeda Millenium: Honoraria. Berdeja:Acetylon: Research Funding; Onyx: Research Funding; Abbvie: Research Funding; Curis: Research Funding; Celgene: Research Funding; Takeda: Research Funding; MEI: Research Funding; Novartis: Research Funding; Janssen: Research Funding; BMS: Research Funding; Array: Research Funding. Flinn:Celgene Corporation: Research Funding. Clancy:Curis: Employment, Equity Ownership. Ma:Curis: Employment, Equity Ownership. Sun:Curis: Employment, Equity Ownership. Tian:Curis: Employment, Equity Ownership. Wang:Curis: Employment, Equity Ownership. Viner:Curis: Employment, Equity Ownership.
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Shulman, David Stephen, Clay Gustafson, Kieuhoa Tran Vo, Elizabeth Fox, Jodi Ann Muscal, Jeffrey G. Supko, Andrew E. Place, et al. "Phase 1 multicenter trial of CUDC-907 in children and young adults with relapsed or refractory solid tumors, CNS tumors, and lymphoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS10576. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps10576.
Повний текст джерелаАнотація:
TPS10576 Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777.
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Zhang, Dongyun, Robert Damoiseaux, Lilit Babayan, Everett Kanediel Rivera-Meza, Yingying Yang, Marvin Bergsneider, Marilene B. Wang, William H. Yong, Kathleen Kelly, and Anthony P. Heaney. "Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease." Journal of Clinical Endocrinology & Metabolism 106, no. 1 (September 28, 2020): e232-e246. http://dx.doi.org/10.1210/clinem/dgaa699.
Повний текст джерелаАнотація:
Abstract Context Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by and large exert no action on tumor growth. Objective To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth. Design High throughput screen employing a novel “gain of signal” ACTH AlphaLISA assay. Setting Academic medical center. Patients Corticotroph tumor tissues from patients with CD. Interventions None. Main outcome measures Potent inhibitors of corticotroph tumor ACTH secretion and growth. Results From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV [cm3], control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH [pg/mL] control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone [ng/mL] control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion. Conclusions Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD.
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Soosainathan, Arany, Joanna Nikitorowicz-Buniak, Sunil Pancholi, Marjan Iravani, John Alexander, Syed Haider, Stephen R. Johnston, Mitchell Dowsett, Lesley A. Martin, and Clare M. Isacke. "Abstract P4-02-05: Exploiting novel models of endocrine-resistant breast cancer to identify new therapeutic targets." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–02–05—P4–02–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-02-05.
Повний текст джерелаАнотація:
Abstract Introduction: While endocrine therapy is an effective, well-tolerated treatment for estrogen receptor positive breast cancer (ER+BC), a large proportion of initial responders will develop hormone therapy resistance, and relapse. A major challenge in determining the mechanisms underlying endocrine therapy resistance is our limited ability to recapitulate inter- and intra-tumour heterogeneity in vitro. In this study we developed ER+BC cells resistant to estrogen deprivation, and to palbociclib treatment, and subjected these to 2D and 3D high-throughput drug and siRNA screens, in order to elucidate the pathways underpinning the development of endocrine resistance. Methods: ER+BC cell lines modelling relapse on aromatase inhibitor therapy were derived by long-term culture in the absence of exogenous estrogen, and were termed long-term estrogen deprived (LTED). Two of these lines were then used to generate additional resistance to palbociclib, thus modelling endocrine-resistant, palbociclib-resistant disease. These lines were then subjected to screens performed in 2D and 3D. Effects of the siRNAs and drug compounds were assessed by measuring cell viability, with a robust Z score of -2 taken as a threshold of significance. Table 1 outlines the key characteristics of the cell lines, the details of the drug screens performed, and the top 3 drugs with their corresponding targets. The siRNA screens were performed in 2D and 3D with a 709 kinome library. Results: The siRNA screens highlighted PI3K-AKT-mTOR signalling as being dysregulated in multiple 3D and 2D models, while the drug screens showed that compounds targeting phosphoinositide 3-kinase alpha (PI3Kα) were significant common hits. This is consistent with the recent success of the BYLieve trial in targeting PI3Kα. A second key area of dependency was in cell cycle regulation, with CDK7 and CDK9 found to be significant hits in multiple models. The 709 kinase screens in 2D and 3D demonstrated broadly similar results (43 vs 37 median number of significant hits 2D vs 3D; Z-score <-2), while drug screening in 3D (Table 1) provided increased discrimination in identifying key vulnerabilities. CDK7 and CDK9 were selected for further study. siRNA-mediated knockdown of CDK9 had a significant effect on cell viability in endocrine-sensitive, endocrine-resistant, and palbociclib-resistant settings, whereas CDK7 knockdown did not. However, the CDK7 inhibitors THZ1 and ICEC0942, and the CDK9 inhibitors NVP-2 and AZD4573, were equally effective in endocrine-sensitive, endocrine-resistant, and palbociclib-resistant settings. Importantly, presence of a PIK3CA mutation was required for entry into the BYLieve trial, while CDK7 and CDK9 inhibitors were effective in the PIK3CA wild-type and mutant setting. Furthermore, while the presence of the ESR1 mutation is associated with poorer PFS with certain therapies, such as exemestane, the CDK7 and CDK9 inhibitors were equally effective in the ESR1 mutant and wild-type setting. Finally, combination treatment of palbociclib with CDK7 and CDK9 inhibitors showed synergism in palbociclib-resistant models. Conclusions: Targeted inhibition of CDK7 and/or CDK9 is effective in the LTED palbociclib-resistant setting, thus opening future avenues for the treatment of advanced, endocrine-resistant, palbociclib-resistant breast cancer. Table 1.Cell line characteristics and drug screen findingsCell line and key characteristics2D drug screen of 396 compounds, at 3 concentrations*3D drug screen of 70 compounds at 1 concentrationNumber of significant drug screen hits (Z score <-2). The top 3 hits and their targets are shownMCF7 LTEDWT6812PIK3CA mutantDinaciclib (CDKs 2/5/1/9)CUDC-907 (PI3Kα/HDAC)ESR1 wild typeTHZ1 (CDK7)PIK-75 HCl (PI3K)PIK-75 HCl (PI3Kα)Flavopiridol (CDKs 1/2/4/6)MCF7 LTEDY537C849PIK3CA mutantCUDC-907 (PI3Kα/HDAC)CUDC-907 (PI3Kα/HDAC)Activating ESR1 mutation (Y537C)THZ1 (CDK7)BGT226 (PI3K/mTOR)PIK-75 HCl (PI3Kα)NVP-2 (CDK9)MCF7 LTEDY537C-PalboR(n/a)8As MCF7 LTEDY537CCUDC-907 (PI3Kα/HDAC)Palbociclib resistantPIK-75 HCl (PI3Kα)NVP-2 (CDK9)SUM44 LTEDY537S6717PIK3CA mutantDinaciclib (CDKs 2/5/1/9)NVP-2 (CDK9)Activating ESR1 mutation (Y537S)CUDC-907 (PI3Kα/HDAC)WYE-125132 (mTOR)E-cadherin nullBGT226 (PI3K/mTOR)CUDC-907 (PI3Kα/HDAC)HCC1428 LTED5114PIK3CA wild typeCUDC-907 (PI3Kα/HDAC)CUDC-907 (PI3Kα/HDAC)ESR1 wild typeBGT226 (PI3K/mTOR)BGT226 (PI3K/mTOR)Torin-2 (mTOR)Sapanisertib (mTOR)HCC1428 LTEDPalboR(n/a)11As HCC1428 LTEDCUDC-907 (PI3Kα/HDAC)Palbociclib resistantCUDC-101 (EGFR)BGT226 (PI3K/mTOR)T47D LTED5712PIK3CA mutantCUDC-907 (PI3Kα/HDAC)CUDC-907 (PI3Kα/HDAC)Loss of ER expression in adapting to LTEDDinaciclib (CDKs 2/1/5/9)PIK-75 HCl (PI3Kα)THZ1 (CDK7)CUDC-101 (EGFR)ZR75.1 LTED29(n/a)PTEN nullDinaciclib (CDKs 2/5/1/9)Loss of ER expression in adapting to LTEDTHZ1 (CDK7)Omipalisib (PI3K/mTOR)LTED: long-term estrogen deprived*Number of significant hits at 100 nM dose are shown Citation Format: Arany Soosainathan, Joanna Nikitorowicz-Buniak, Sunil Pancholi, Marjan Iravani, John Alexander, Syed Haider, Stephen R Johnston, Mitchell Dowsett, Lesley A Martin, Clare M Isacke. Exploiting novel models of endocrine-resistant breast cancer to identify new therapeutic targets [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-05.
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Younes, Anas, Ian W. Flinn, Yasuhiro Oki, Amanda Copland, Ali Fattaey, Cheng-Jung Lai, Robert Laliberte, Maurizio Voi, and Jesus G. Berdeja. "A First-In-Man Phase 1 Study Of CUDC-907, a First-In-Class Chemically-Designed Dual Inhibitor Of PI3K and HDAC In Patients With Refractory Or Relapsed Lymphoma and Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 4363. http://dx.doi.org/10.1182/blood.v122.21.4363.4363.
Повний текст джерелаАнотація:
Abstract Background PI3K and HDAC inhibitors have demonstrated single agent clinical activity in patients (pts) with a variety of B-cell malignancies, including lymphoma and multiple myeloma (MM). Preclinical experiments indicated synergistic effects between HDAC and PI3K pathway inhibitors. CUDC-907 is a chemically-designed small molecule that combines the active hydroxamate moiety of HDAC inhibitors with a PI3K inhibitor morpholinopyrimidine pharmacophore. CUDC-907 potently inhibits class I PI3K (alpha, beta, and delta) as well as HDACs class I and II enzymes. Preclinical experiments demonstrated that CUDC-907 inhibits the PI3K-AKT-mTOR pathway and compensatory MEK/ERK and STAT3 signaling pathways. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells, including human B-cell tumor xenograft models. Here we present the preliminary results of a First-In-Human Phase 1 study of CUDC-907. Methods This is a Phase 1 study using a standard 3+3 dose escalation design. CUDC-907 was orally administered to pts with lymphoma and MM. Patients were eligible if they had relapsed or refractory disease after at least 2 prior regimens and adequate bone marrow and organ functions. The starting dose was 30mg given continuously once daily in 21-day cycles without rest, with planned escalations until the maximum tolerated dose was reached. In the absence of dose limiting toxicities (DLTs), pts were allowed to continue treatment until disease progression. DLTs were defined so as to include ≥ Grade 3 adverse events (AE) or any Grade AE resulting in dose delay ≥7 days. Tumor response was assessed every 2 cycles using standard criteria appropriate for the disease type. Blood samples for pharmacokinetic (PK) and pharmacodynamic analyses were collected during Cycle 1. Results At the time of this abstract, 6 pts were treated on study: 3 each at 30 and 60 mg/day dose. The median age was 70 years (range 61-77) and 2 pts had MM, 3 Non-Hodgkin’s lymphoma and 1 Hodgkin's lymphoma. The median number of prior regimens was 3 (range 2-8) and 3 pts had prior bone marrow transplant. The most common treatment-related AEs were diarrhea (6 pts, Grade 1-3) and thrombocytopenia (5 pts, Grade 1-4). The severity and time to onset of these events appear to be dose-related. In general, thrombocytopenia recovered quickly by withholding treatment and diarrhea was well controlled with loperamide co-administration. However, 1 pt at the 60 mg/day dose level with a history of diabetes and poor co-medication compliance (i.e., loperamide and insulin) developed multiple DLTs including diarrhea (Grade 3), thrombocytopenia (Grade 4) and hyperglycemia (Grade 4). Of the 6 pts, 2 remain on treatment at ≥ 5 cycles with stable disease. CUDC-907 was rapidly transformed to 2 metabolites, M1 and M2, with M2 retaining potent PI3K inhibition activity. While CUDC-907 had low plasma exposure and a short half-life, M2 levels increased during the 24 hour PK sampling period. Conclusion To address AEs and further dose escalate, with consideration of the PK profile of the parent and M2 metabolite, the protocol was modified to include 2 additional dosing schedules: 2x/week and 3x/week administration. In addition, the 30mg continuous daily dose cohort was expanded to further assess the tolerability of this schedule. Updated results from pts treated with the 3 schedules will be presented. Disclosures: Younes: Gilead: Honoraria; Seattle Genetics: Honoraria; Millenium: Honoraria; Celgene: Honoraria; Johnson & Johnson: Honoraria; Pharmacyclics: Honoraria. Fattaey:Curis, Inc.: Employment. Lai:Curis, Inc.: Employment. Laliberte:Curis, Inc.: Employment. Voi:Curis, Inc.: Employment.
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Li, Xinyu, Jun Ma, Yongwei Su, Jianyun Zhao, Holly Edwards, Yue Wang, Jay Yang, Jeffrey W. Taub, Hai Lin, and Yubin Ge. "Combination of Venetoclax and CUDC-907 Shows Superior Antileukemic Activity Against Acute Myeloid Leukemia Ex Vivo." Blood 128, no. 22 (December 2, 2016): 1571. http://dx.doi.org/10.1182/blood.v128.22.1571.1571.
Повний текст джерелаАнотація:
Abstract Overall survival rates for adults and children with acute myeloid leukemia (AML) remain unacceptably low. Resistance to chemotherapy is the major factor contributing to such dismal overall survival rates. Chemoresistance in leukemia cell line models has been associated with overexpression of the anti-apoptotic Bcl-2 family members. As such, small molecule Bcl-2 inhibitors represent a promising strategy for treating AML. Venetoclax (ABT-199) is a Bcl-2-selective inhibitor that has demonstrated promising antileukemic activity against AML. However, initial resistance to ABT-199 remains a concern. In our most recent study, we identified a novel Mcl-1-mediated intrinsic mechanism of resistance to ABT-199 in AML cells: ABT-199 treatment results in increased sequestration of Bim by Mcl-1, preventing Bim from inducing apoptosis (Niu X, et al. Clinical Cancer Research. 2016; epub ahead of print). We also found that ABT-199 in combination with DNA damaging agents results in enhanced DNA damage and synergistic antileukemic activity against AML cells. Based on these findings, we hypothesized that simultaneously downregulating Mcl-1, upregulating Bim, and enhancing DNA replication stress and/or DNA damage would maximally enhance ABT-199-induced cell death, leading to potent synergistic antileukemic activity against AML. CUDC-907, a dual histone deacetylase inhibitor (HDACI) and PI3K inhibitor, is currently being tested in Phase I and Phase II clinical trials for the treatment of lymphoma, multiple myeloma, and advanced/relapsed solid tumors (www.clinicaltrials.gov). It inactivates both PI3K/AKT and MEK/ERK signaling pathways in different cancer cell types. Inhibition of these pathways has been shown to cause downregulation of Mcl-1 and upregulation of Bim and HDACIs have been demonstrated to downregulate CHK1 and Wee1, as well as upregulate Bim, leading to DNA damage and cell death. Furthermore, CHK1 and Wee1 inhibitors have been shown to cause DNA replication stress through downregulation of ribonucleotide reductase (RNR). Therefore, CUDC-907 would be an ideal compound to combine with ABT-199 to enhance its antileukemic activity against AML. In this study, we investigated the antileukemic activity of CUDC-907 alone and in combination with ABT-199 in both AML cell lines and primary patient samples. CUDC-907 treatment resulted in increased Bim expression and decreased Mcl-1, CHK-1, Wee1, and RRM1 (the regulatory subunit of RNR) expression in both AML cell lines and primary patient samples. Ectopic overexpression of Mcl-1 and shRNA knockdown of Bim demonstrated that both were at least partially involved in CUDC-907-induced apoptosis. Treatment with a CHK1-selective inhibitor LY2603618, the Wee1-selective inhibitor MK-1775, or hydroxyurea (RNR inhibitor) enhanced CUDC-907-induced apoptosis in a synergistic fashion, demonstrating that downregulation of Wee1, CHK1, and RRM1 was also an important contributor to CUDC-907-induced apoptosis. Consistent with our hypothesis, the combination of CUDC-907 and ABT-199 resulted in significantly increased apoptosis compared to single drug treatment and excellent synergy in both AML cell lines (n=6) and primary patient samples (n=18), regardless of their sensitivities to ABT-199. Synergy was also detected when AML cells were treated with CUDC-907 first for 16 h and then followed by ABT-199 treatment for another 8 h. Western blots revealed that combined treatment caused further decrease of Mcl-1, CHK1, and Wee1, while comet assays revealed that the combination caused significantly increased DNA strand breaks in both AML cell lines and primary patient samples. Our results demonstrate that CUDC-907 synergizes with ABT-199 in AML cells, and support the clinical development of the combination of CUDC-907 and ABT-199 in the treatment of AML. Disclosures Yang: Seattle Genetics: Research Funding.
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Ruz-Maldonado, Inmaculada, Patricio Atanes, Guo Cai Huang, Bo Liu, and Shanta J. Persaud. "Direct Stimulatory Effects of the CB2 Ligand JTE 907 in Human and Mouse Islets." Cells 10, no. 3 (March 22, 2021): 700. http://dx.doi.org/10.3390/cells10030700.
Повний текст джерелаАнотація:
Aims: The endocannabinoid system is a complex cell-signaling network through which endogenous cannabinoid ligands regulate cell function by interaction with CB1 and CB2 cannabinoid receptors, and with the novel cannabinoid receptor GPR55. CB1, CB2, and GPR55 are expressed by islet β-cells where they modulate insulin secretion. We have previously shown that administration of the putative CB2 antagonist/inverse agonist JTE 907 to human islets did not affect the insulinotropic actions of CB2 agonists and it unexpectedly stimulated insulin secretion on its own. In this study, we evaluated whether the lack of antagonism could be related to the ability of JTE 907 to act as a GPR55 agonist. Materials and Methods: We used islets isolated from human donors and from Gpr55+/+ and Gpr55−/− mice and quantified the effects of incubation with 10 μM JTE 907 on dynamic insulin secretion, apoptosis, and β-cell proliferation by radioimmunoassay, luminescence caspase 3/7 activity, and immunofluorescence, respectively. We also measured islet IP1 and cAMP accumulation using fluorescence assays, and monitored [Ca2+]i elevations by Fura-2 single cell microfluorometry. Results: JTE 907 significantly stimulated insulin secretion from islets isolated from human donors and islets from Gpr55+/+ and Gpr55−/− mice. These stimulatory effects were accompanied by significant elevations of IP1 and [Ca2+]i, but there were no changes in cAMP generation. JTE 907 also significantly reduced cytokine-induced apoptosis in human and mouse islets and promoted human β-cell proliferation. Conclusion: Our observations show for the first time that JTE 907 acts as a Gq-coupled agonist in islets to stimulate insulin secretion and maintain β-cell mass in a GPR55-independent fashion.
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Nayak, Satyaprakash, Dooyoung Lee, Steven Arkin, Steven W. Martin, Anne C. Heatherington, William S. Denney, Paolo Vicini, and Fei Hua. "A Quantitative Systems Pharmacology Model for the Coagulation Network Describes Biomarker Changes Observed in a Clinical Study with FXa Variant and Predicts Age-Associated Biomarker Variations." Blood 126, no. 23 (December 3, 2015): 3502. http://dx.doi.org/10.1182/blood.v126.23.3502.3502.
Повний текст джерелаАнотація:
Abstract It is known that the coagulation factor levels change with age. In this work, we have applied a quantitative systems pharmacology (QSP) model of the coagulation network to predict whether age related changes in coagulation factor levels will impact dose response for PF-05320907 on various pharmacodynamic endpoints. PF-05230907 (PF-907) is a variant of FXa, in which the conformational transition from zymogen to active protease is impaired. Binding to activated factor V facilitates its transition to the active conformation, rescues procoagulant activity and is hypothesized to localize PF-907 hemostatic effect to sites of hemorrhage. It is currently in development for the indication of intracerebral hemorrhage (ICH). Pharmacokinetic (PK) and pharmacodynamic (PD) data are available from the healthy subjects phase 1 study of single dose escalation of intravenous bolus infusion of PF-907. The next study for PF-907 will be conducted in ICH patients, who will have a much higher median age than the median age in the healthy subjects in the Phase 1 study. Our group has implemented a QSP model for the coagulation network to enable integrated understanding of all the data and underlying pharmacology1. The model has been optimized to describe in vitro biomarker changes including; thrombin generation assay (TGA), activated partial thromboplastin time (aPTT) and prothrombin time (PT) as well as in vivo biomarker changes including prothrombin fragment 1+2 (PF1+2), thrombin-anti-thrombin III complex (TAT) and D-dimer. In this simulation study, we used the model to first describe biomarker changes with treatment of FXa variant in hemostatic normal subjects and then used model simulations to predict the behavior of important biomarkers in an older ICH population. A single compartment PK model for PF-907 was first established to describe the PK data obtained from the phase 1 study. The PK model was then combined with the QSP model to predict biomarker changes following PF-907 treatment. Comparison with observed clinical data showed that the model adequately predicted dose-dependent change in TGA parameters, aPTT, PF1+2, TAT and D-dimer. In addition, the model also predicted that there would be no change in PT, which was consistent with observed first in human results with the PF-907 treatment. After model validation using FIH data, the model was then used to predict biomarker changes for older subjects using literature reported changes in baseline levels of coagulation factors for subjects over a period of 40 years. The simulation predicted minimal shifts in the PD responses suggesting that the dose-response to PF-907 may not change significantly between young and older populations. The model, however, did not consider other characteristics beyond coagulation factor level changes in older populations, which may impact the safety profile of PF-907 treatment. In summary, this study indicates that it is possible to predict the response of a hemostatic agent with a QSP model. Following validation, the model can also extrapolate from a standard subject to new patient populations and indicates that no dose adjustment due to age is required. Reference 1. Nayak, S., Lee, D., Patel-Hett, S., Pittman, D., Martin, S., Heatherington, A., Vicini, P. and Hua, F. (2015), Using a Systems Pharmacology Model of the Blood Coagulation Network to Predict the Effects of Various Therapies on Biomarkers. CPT: Pharmacometrics & Systems Pharmacology. doi:10.1002/psp4.50 Disclosures Nayak: Pfizer Inc: Employment. Lee:Pfizer Inc.: Employment. Arkin:Pfizer Inc: Employment. Martin:Pfizer Inc: Employment. Heatherington:Pfizer Inc.: Employment. Denney:Pfizer Inc.: Employment. Vicini:Pfizer Inc.: Employment. Hua:Pfizer Inc: Employment.
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Boyle, Jordan N., Caroline R. Kim, Hui Guo, Taylor Bell, Shengjian Huang, Carrie J. Li, Yang Liu, et al. "CUDC-907: An Oral HDAC/PI3K Dual Inhibitor with Strong Preclinical Efficacy in MCL Model." Blood 128, no. 22 (December 2, 2016): 4183. http://dx.doi.org/10.1182/blood.v128.22.4183.4183.
Повний текст джерелаАнотація:
Abstract Introduction Mantle cell lymphoma (MCL) is an aggressive lymphoma with elevated B-cell receptor activity. Ibrutinib (IBN), a Bruton's tyrosine kinase (BTK) inhibitor, has been shown to have a response rate of 68% in relapsed or refractory MCL patients. However, with the emergence of IBN-resistant lymphomas, new therapies are needed. It is suspected that upregulation of the PI3K-Akt-mTOR pathway allows survival in the presence of IBN. CUDC-907 is a next generation PI3K and HDAC dual-inhibitor currently in phase II clinical trials. Our objective is to investigate the effects of CUDC-907 in IBN-resistant MCL cells in vitro and in PDX model. Methods MCL cells were seeded at 10,000 cells per well in 96-well plate and were treated with various doses of compounds at the following concentrations: CUDC-907/Ibrutinib 0.015, 0.05, 0.15, 0.5, 1.5, 5, and 15 uM. Cell viability was tested by CellTiter-Glo luminescent cell viability assay (Promega) after a 72-hour incubation. Next, MCL cells were incubated with IBN at varying doses (0.39 uM, 1.56 uM, 6.25 uM), CUDC-907 (0.39 uM, 1.56 uM, 6.25 uM), and IBN+CUDC-907 (0.39 uM, 1.56 M, 6.25 uM) for 24 hours. Apoptosis was detected by Annexin V-binding assay. In patient derived xenograft (PDX) model: CUDC-907 was administered at a dose of 50 mg/kg in ibrutinib-resistant MCL-bearing PDX mice daily. Tumor volumes were measured as the length X width2 X 0.5 weekly. Toxicity was also observed every week. Mice were sacrificed once diameter of tumor mass reached 15 mm size. Results CUDC-907 inhibited the growth of both ibrutinib-sensitive and resistant MCL cells in vitro. Sensitive cell lines include: Rec-1, Mino, and JVM-13 with IC50 values of 1.1 nM, 1.0 nM, and 5 nM respectively. Resistant cell lines include: Granta-519, Maver-1, and Z-138 with IC50 values of 2 nM, 3 nM, and 1.5 nM respectively. All tested cell lines were more sensitive to CUDC-907 than to ibrutinib. In addition, combination treatments of CUDC-907 and IBN increased cell death in comparison to single agent treatments. Next, one pair of MCL cell lines, Jeko-1 (sensitive to IBN) and Jeko-R (resistant to IBN) were treated for 24 hours with varying doses of CUDC-907 or ibrutinib either as single agent inhibitors or in combination therapies. The results demonstrated that CUDC-907 induced apoptosis in both Jeko-1 and Jeko-R cell lines in a dose-dependent manner. Combination therapies increased cell death in a dose-dependent manner as well. In PDX model, tumor volume in treated mice of ibrutinib-resistant PDX decreased significantly compared with vehicle control (pvalue = 0.032). Control mice also weighed considerably more than treated mice (p value = 0.073). Common toxicities included a decrease in body mass for first 28 days of treatment. Conclusion CUDC-907, a dual inhibitor of PI3K-Akt-mTOR and HDAC, inhibits tumor growth of ibrutinib-resistant MCL in vitro and in PDX model. It would be a potential drug for the patients with ibrutinib-resistant/relapsed MCL. Disclosures Wang: Celgene: Research Funding; Onyx: Research Funding; Kite Pharma: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Research Funding; Juno Therapeutics: Research Funding; Asana BioSciences: Research Funding.
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Landsburg, Daniel J., Radhakrishnan Ramchandren, Amir Hafeez, Robert Gharavi, Tania Chander, Anna Ma, Micah M. Burch, and Yasuhiro Oki. "Open-Label, Phase 2 Study to Evaluate the Efficacy and Safety of CUDC-907 in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Including Patients with MYC Alterations." Blood 128, no. 22 (December 2, 2016): 5422. http://dx.doi.org/10.1182/blood.v128.22.5422.5422.
Повний текст джерелаАнотація:
Abstract Patients (pts) with relapsed and/or refractory (RR) MYC-altered diffuse large B-Cell lymphoma (DLBCL) respond poorly to available therapeutic options. Due to acquired chemoresistance, these patients are often ineligible for or relapse following autologous stem cell transplantation (ASCT), and do not respond well to additional cytotoxic therapy. Our previous translational studies have demonstrated that combined pharmacologic inhibition of HDAC and PI3K signaling, via CUDC-907, effectively suppresses MYC activity through transcriptional and translational mechanisms. In MYC-dependent DLBCL and NUT midline carcinoma cell lines, CUDC-907 treatment has demonstrated dose-dependent decreases in MYC protein expression and a more potent inhibition of MYC expression than various HDAC and PI3K inhibitors, either alone or in combination. CUDC-907 has also shown greater in vitro and in vivo activity than single-target HDAC or PI3K inhibitors, especially in MYC-altered DLBCL models. In a phase 1 study, RR MYC-altered DLBCL pts achieved objective, durable responses while treated with CUDC-907, including complete responses (CRs). As of 15 March 2016, among the 5 response evaluable pts with RR MYC-altered DLBCL, 4 (80%) achieved objective responses (3 CRs and 1 partial response [PR]). All 3 CRs observed occurred in subjects with MYC gene copy number gain. In addition, to support our diagnostic plan, we evaluated MYC in a panel of DLBCL samples to better understand the prevalence of alterations. This ongoing phase 2 study is designed to further examine the efficacy of CUDC-907 in RR DLBCL pts with MYC-altered disease. Up to 200 pts with RR DLBCL, including those who have MYC-altered disease per central testing, will be enrolled to receive either CUDC-907 alone or in combination with rituximab. Within each treatment cohort (n= ~60), pts will be stratified based on MYC status as determined by central testing: MYC translocation by FISH (Groups A and D) versus MYC copy number gain by FISH or ≥40% of cells scored as MYC protein expression positive by immunohistochemistry (Groups B and E). Pts with negative testing for MYC-altered disease will still be eligible for treatment (Groups C and F). Other key eligibility criteria include: Age ≥ 18 years, ECOG performance status score ≤ 2, measurable disease on CT imaging, at least 2 but no more than 4 prior lines of therapy for DLBCL which may include ASCT, and confirmed availability of adequate viable tissue (fresh or most recent archival) for central testing. Pts with transformed follicular lymphoma will be eligible. However, other B-cell lymphomas including B- cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma and Burkitt lymphoma are not eligible. All pts will take 60 mg of CUDC-907 orally once a day on a 5 days on/2 days off schedule in 21-day cycles. Pts assigned to the combination arm will also receive rituximab 375 mg/m2 IV on Day 1 of each cycle for the first 6 cycles. Response will be evaluated every other cycle per Cheson criteria by central review and survival assessments will occur every 12 weeks. The primary endpoint is objective response rate (ORR); secondary endpoints include duration of response (DOR), disease control rate (DCR), progression free survival (PFS), median and 6-month PFS, and overall survival (OS). Other disease associated biomarkers, including BCL-2 and BCL-6, will also be evaluated. Clinical trial information: NCT02674750. Disclosures Hafeez: Curis, Inc.: Employment. Gharavi:Curis: Employment. Chander:Curis Inc.: Employment. Ma:Curis Inc: Employment. Oki:Novartis: Research Funding.
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Kraft, Tuomas. "Yksilöt vetäytymistaisteluiden kaaoksessa." Ennen ja nyt: Historian tietosanomat 24, no. 2 (May 28, 2024): 73–81. http://dx.doi.org/10.37449/ennenjanyt.144306.
Повний текст джерела
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Amalia, Lia, Ai Komariah, and Ilma Hilmayanti. "Stability and Adaptability Genotype of Hybrid Rice in the West Java Province of Indonesia." Asian Journal of Agriculture and Rural Development 9, no. 2 (September 24, 2019): 204–15. http://dx.doi.org/10.18488/journal.1005/2019.9.2/1005.2.204.215.
Повний текст джерелаАнотація:
Experiments to study the stability and adaptability genotype of hybrid rice were conducted in two locations in West Java: 1. the Jelekong Village Baleendah Bandung region, 2. the Arjasari Village Leuwisari Tasikmalaya region. The altitude of the Baleendah Bandung region is 650 and that of the Leuwisari Tasikmalaya region is 450 meters above sea level. The experiments were arranged in a randomized block design and used with 9 genotypes and 3 replications. The 9 genotypes of hybrid rice are SW-907, SW-804, SW-902, US-915, SW-82, SW-923, Intani-2, SL 8 SHS, and SHS 04 WM. The result of the experiment showed that the whole genotypes A = SW-907, B = SW-804, C = SW-902, D = US-915, E = SW-82, F = SW- 923, G = WM 4 SHS, H = SL 8 SHS, and I = Intani 2 measured the height of the plants, the number of productive tillers, the length of the panicles, the number of grains per panicle, the number of filled grains per panicle, the weight of 1000 grains, and the grain yield per plot, and were unstable and unadaptive in Bandung and Tasikmalaya.
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Kweon, Yonghun, Yoshiaki Miyazato, Sungjae Jung, Nobuaki Kondoh, and Toshiyuki Aoki. "907 An Experimental Study on a Noise Phenomenon in Over-Expanded Supersonic Jets(2)." Proceedings of the Fluids engineering conference 2006 (2006): _907–1_—_907–4_. http://dx.doi.org/10.1299/jsmefed.2006._907-1_.
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Nakamura, K., and Takeyoshi Tanaka. "Predicting Capability Of A Multiroom Fire Model." Fire Safety Science 2 (1989): 907–16. http://dx.doi.org/10.3801/iafss.fss.2-907.
Повний текст джерела
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Cutter, Charles. "Serially Speaking." Judaica Librarianship 2, no. 1-2 (January 1, 1986): 83. http://dx.doi.org/10.14263/2/1985/907.
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Pincus, S. H., K. Wehrly, E. Tschachler, S. F. Hayes, R. S. Buller, and M. Reitz. "Variants selected by treatment of human immunodeficiency virus-infected cells with an immunotoxin." Journal of Experimental Medicine 172, no. 3 (September 1, 1990): 745–57. http://dx.doi.org/10.1084/jem.172.3.745.
Повний текст джерелаАнотація:
An immunotoxin has been made by coupling anti-human immunodeficiency virus (HIV) envelope antibody 907 to ricin A chain (907-RAC). 907 recognizes an epitope within the immunodominant PB-1 loop of gp120. Variant cells were selected by cloning persistently infected H9/human T lymphocyte virus IIIB cells in the presence of the immunotoxin. Clones resistant to 907-RAC arose at a frequency of 0.1-1.0%. Seven clones were selected for intensive analysis. When studied, these clones fell into two distinct groups, members of which appeared to be identical, suggesting that the variation arose before the selection process. In contrast to the parent cells, none of the cloned variants produced infectious HIV. The first set of clones, designated the "E" variants, expressed decreased levels of the HIV envelope on the cell surface. However, levels of intracellular HIV antigens and reverse transcriptase were equal to or greater than that of the parental cell line. Radioimmunoprecipitation demonstrated that the gp160 was truncated to 145 kD (gp120 was normal length), capable of binding to CD4, and, unlike normal gp160, was released in its unprocessed form into the cellular supernatant. Sequence analysis demonstrated that a deletion at codon 687 of the envelope gene resulted in the production of this truncated protein. Ultrastructural analysis of E variants demonstrated some budding forms of virus, but also large numbers of HIV within intracellular vesicles. The second set of variants, the "F" series, produced no HIV antigens, reverse transcriptase, nor was there ultrastructural evidence of virus. However, proviral DNA was present. Virus could not be induced with agents known to activate latent HIV. These cells also lacked cell surface CD4 and could not be infected with HIV. These studies demonstrate that variation in HIV can affect the phenotype of the cells carrying the altered virus, allowing for escape from immunologic destruction. The E variants may serve as prototypes for attenuated HIV, which could be used as a vaccine. We have reconstructed the mutation found in the E variants within the infectious HIV clone HXB-2 and demonstrated that the resulting virus retains its noninfectious phenotype.
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de Lima, Aline Cecy Rocha, Felipe Teixeira Lopes, Vanessa de Oliveira Freitas, Michele Nascimento Assad, Renata Santos de Sousa, Janete Silvana Souza Gonçalves, Jayanne Lílian Carvalho Gomes, et al. "Prevalence and Risk Factors for HTLV-1/2 Infection inRiverside and Rural Populations of the State of Pará." Viruses 14, no. 10 (October 15, 2022): 2262. http://dx.doi.org/10.3390/v14102262.
Повний текст джерелаАнотація:
Human T-lymphotropic viruses 1 and 2 (HTLV-1 and HTLV-2) infection has been described in several Amazonian populations; however, there is still a lack of data on the prevalence of the virus in riparian populations living in rural areas of the state of Pará. The present study aimed to evaluate the prevalence of HTLV-1/2 infection in four riverine communities and one rural area in the state of Pará and to describe the possible risk factors for infection. A total of 907 individuals responded to an epidemiological survey and gave blood samples collected for anti-HTLV-1/2 antibodies by immunoenzymatic assay (EIA). The serum-reactive samples were subjected to confirmation by an in-line assay (Inno-Lia) and by proviral DNA screening using real-time PCR (qPCR). The total prevalence was 0.8% (7/907) for HTLV-1/2 (CI: 0.2−1.3%), with 0.66% HTLV-1 and 0.11% HTLV-2. The prevalence by sex was 0.7% in women (4/565) and 0.9% in men (3/342). Among seropositive patients, 83.3% (5/7) reported being sexually active, and 57.1% (4/7) reported not having the habit of using condoms during their sexual relations. Intrafamily infection was also observed. The results reinforce the need for public policies to prevent and block the spread of HTLV, especially in riparian communities that are subject to difficulties in accessing the Unified Health System (Sistema Único de Saúde/SUS) because infected individuals need clinical monitoring for surveillance and early diagnosis of symptoms associated with HTLV-1.
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Adityo, Adityo, and Ahmad Robiul Awal Udin. "UJI KARAKTERISTIK MESIN BENSIN DUA LANGKAH DENGAN BAHAN BAKAR CAMPUR MINYAK ATSIRI DAN ACETON." MUSTEK ANIM HA 7, no. 3 (December 3, 2018): 257–65. http://dx.doi.org/10.35724/mustek.v7i3.1737.
Повний текст джерелаАнотація:
Penelitian ini bertujuan untuk mencari efektivitas campuran bahan bakar dengan minyak atsiri dan aceton guna menunjang unjuk kerja mesin dua langkah. Minyak atsiri dapat berfungsi sebagai pelumas campur yang diharapkan ramah lingkungan dan bersifat renewable. Hal yang dirasa kurang dalam perbaikan mutu pembakaran dapat diperbaiki dengan penggunaan zat aditif. Pengujian dilakukan secara nyata. Dengan mengamati kinerja motor bensin dua langkah tipe KW6-R berbahan bakar campur minyak atsiri dan aceton pada mesin uji dynotest. Luaran berupa data yang terekam dari alat uji. Berupa nilai daya (aktual dan koreksi), torsi, kerugian daya, putaran mesin, serta kecepatan (berdasar putaran roda penggerak motor). Hasil pengujian a. Pada pengujian keadaan standart ( menggunakan sistem lumas injeksi dengan pelumas semi sintetis) diperoleh daya maksimal 26,4 HP (pengulangan 3), kerugian daya 9,7 HP @ 121 km/h / 5460 (1/min) (pengulangan 2), serta torsi 40 kgm (wheel) @ 66 (km/h) / 2946 (1/min)(pengulangan 3); b. Pada pengujian berbahan bakar campur pelumas sintetis diperoleh daya maksimal 27,4 HP (pengulangan 2), kerugian daya 6,4 HP @ 121 km/h / 5424 (1/min) (pengulangan 2), serta torsi 39 kgm (wheel) @ 33 (km/h) / 1500 (1/min)(pengulangan 1); c. Pada pengujian berbahan bakar campur minyak atsiri 5ml dan aceton 5 ml diperoleh daya maksimal 28,4 HP (pengulangan 2), kerugian daya 4,4 HP @ 106 km/h / 4742 (1/min) (pengulangan 2), serta torsi 47 kgm (wheel) @ 47 (km/h) / 2119 (1/min)(pengulangan 3); d. Pada pengujian berbahan bakar campur minyak atsiri 10ml dan aceton 5 ml diperoleh daya maksimal 27,8 HP (pengulangan 3), kerugian daya 4,3 HP @ 73 km/h / 3296 (1/min) (pengulangan 3), serta torsi 76 kgm (wheel) @ 20 (km/h) / 907 (1/min)(pengulangan 3); e. Pada pengujian berbahan bakar campur minyak atsiri 15ml dan aceton 5 ml diperoleh daya maksimal 27,8 HP (pengulangan 1), kerugian daya 5,6 HP @ 115 km/h / 5182 (1/min) (pengulangan 1), serta torsi 71 kgm (wheel) @ 20 (km/h) / 907 (1/min)(pengulangan 1). Dari hasil pengujian nampak bahwa daya terbesar dapat diraih pada campuran bahan bakar minyak atsiri 5ml dan aceton 5ml sebesar 28,4 HP dengan torsi 47 kgm @ 47 (km/h) 2119 (1/min). Sedangkan torsi maksimum dapat diraih pada campuran bahan bakar minyak atsiri 10 ml dan aceton 5ml dengan 76 kgm (wheel) @ 20 (km/h) / 907 (1/min).
Kata kunci: minyak jarak, aseton, uji bahan bakar
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Giribabu, Lingamallu, Varun Kumar Singh, Challuri Vijay Kumar, Yarasi Soujanya, Veerannagari Gopal Reddy, and Paidi Yella Reddy. "Organic-Ruthenium(II) Polypyridyl Complex Based Sensitizer for Dye-Sensitized Solar Cell Applications." Advances in OptoElectronics 2011 (July 24, 2011): 1–8. http://dx.doi.org/10.1155/2011/294353.
Повний текст джерелаАнотація:
A new high molar extinction coefficient organic-ruthenium(II) polypyridyl complex sensitizer (RD-Cou) that contains 2,,6,-tetramethyl-9-thiophene-2-yl-2,3,5,6,6a,11c-hexahydro1H,4H-11oxa-3a-aza-benzoanthracene-10-one as extended -conjugation of ancillary bipyridine ligand, 4,-dicaboxy-2, ,-bipyridine, and a thiocyanate ligand in its molecular structure has been synthesized and completely characterized by CHN, Mass, 1H-NMR, UV-Vis, and fluorescence spectroscopies as well as cyclic voltammetry. The new sensitizer was tested in dye-sensitized solar cells using a durable redox electrolyte and compared its performance to that of standard sensitizer Z-907.
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Xie, Shi-Chen, Yang Zou, Zhao Li, Jian-Fa Yang, Xing-Quan Zhu, and Feng-Cai Zou. "Molecular Detection and Genotyping of Enterocytozoon bieneusi in Black Goats (Capra hircus) in Yunnan Province, Southwestern China." Animals 11, no. 12 (November 26, 2021): 3387. http://dx.doi.org/10.3390/ani11123387.
Повний текст джерелаАнотація:
Enterocytozoon bieneusi is a fungus-like protist that can parasitize in the intestines of humans and various animals causing a threat to public health. However, there has been no data for E. bieneusi prevalence and genotypes in black goats in Yunnan Province, Southwestern China. In this study, 907 fecal samples were collected from black goats in 5 counties from Yunnan Province. The prevalence and genotypes of E. bieneusi were examined by nested PCR amplification targeting the nuclear internal transcribed spacer (ITS). Multi-locus sequence typing (MLST) was used to further examine the potential occurrence of genetic segregation. The overall prevalence of E. bieneusi in black goats in Yunnan Province was 10.3% (93/907). Statistical analysis revealed that E. bieneusi prevalence was significantly associated with the region, age and gender of black goats (p < 0.001). Four new genotypes (CYG-1, CYG-2, CYG-3, CYG-4) and 11 known genotypes (CHG1, CHG2, CHG3, CHG5, CHG28, J, D, BEB6, Wildboar3, CD6, SDD1) of E. bieneusi were identified. At the microsatellite and minisatellite loci, 15, 2, 17, and 33 sequences were obtained, respectively, forming one new multi-locus genotype (MLG27). Phylogenetic analysis revealed that all 15 genotypes were clustered into group 1 and group 2, with zoonotic potential. This is the first report of E. bieneusi prevalence and genotypes in black goats in Yunnan Province, China. Effective control strategies and measures should be taken to reduce the risk of E. bieneusi transmission between black goats, other animals, and humans.
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OHTANI, Yasunao, Kenkichi OHBA, Atsushi SAKURAI, and Tsutomu TAJIKAWA. "907 Airflow in Branching Tube Group of Pulmonary Airways." Proceedings of Conference of Kansai Branch 2004.79 (2004): _9–13_—_9–14_. http://dx.doi.org/10.1299/jsmekansai.2004.79._9-13_.
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Santos, Ariston Pinto, Carlos Eduardo Silva Volpato, and Maria Cristina Cavalheiro Tourino. "Desempenho de três semeadoras-adubadoras de plantio direto para a cultura do milho." Ciência e Agrotecnologia 32, no. 2 (April 2008): 540–46. http://dx.doi.org/10.1590/s1413-70542008000200030.
Повний текст джерелаАнотація:
Objetivou-se avaliar tecnicamente três semeadoras para plantio direto de milho, montou-se um experimento em área do Departamento de Engenharia Agrícola da UFLA, sob Latossolo Vermelho Distroférrico argiloso (LVdf), utilizando-se as seguintes semeadoras: S1 - Semeato SHM 11/13; S2 - John Deere RT 907 e S3 - John Deere RT 907, com diferentes sistemas de abertura de sulcos para deposição de adubo, deslocando-se a três velocidades distintas, de V1 (1,38 m.s-1), V2 (1,8 m.s-1) e V3 (2,22 m.s-1). As variáveis quantificadas foram: patinagem, força média na barra de tração, potência média por mecanismo de semeadura, consumo horário e específico de combustível e capacidade de campo teórica. Adotou-se um delineamento estatístico em blocos casualizados, com parcelas subdivididas. A partir dos resultados obtidos, foi possível concluir que, com relação ao desempenho operacional do conjunto trator-semeadora, ocorreram diferenças significativas entre os três conjuntos quanto à força na barra e ao consumo de combustível. Quanto à patinagem e a potência, não ocorreu diferença significativa entre os conjuntos 1 e 2, apresentando menor valor, diferindo do conjunto 3. Para os parâmetros técnico-operacionais avaliados, a condição de melhor desempenho foi observada para S1V3 (Semeato SHM 11/13 e 2,22 m.s-1).
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Hirano, Mitsuhito, Yoichi Imai, Takahiko Murayama, Kota Sato, Junichi Yamamoto, Takumi Ito, Muneyoshi Futami, et al. "Combined Inhibition of HDAC and AKT As a Strategy to Overcome Multi-Drug Resistance in Patients with Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 4325. http://dx.doi.org/10.1182/blood-2019-122662.
Повний текст джерелаАнотація:
Nowadays, patients with multiple myeloma (MM) have multiple choices of therapy including monoclonal antibodies, proteasome inhibitors, and immunomodulatory drugs (IMiDs), whereas some patients still develop resistance to these drugs and require novel therapeutic modalities. Here, we focused on inhibition of HDAC and AKT to overcome drug resistance. Lenalidomide (Len) selectively binds to cereblon (CRBN), which mediates recruitment of specific substrates like IKZF1 to E3 ubiquitin ligase and subsequent degradation, resulting in downregulation of IRF-4 and c-Myc. Then, we developed Len-resistant myeloma cells by RNAi-mediated downregulation of CRBN. Treatment of these cells with HDAC inhibitors reduced IKZF1 mRNA, suggesting potential efficacy of HDAC inhibitors against CRBN-low expressing or mutated MM. According to the integrated database for expression profile and disease prognosis (GenomicScape, http://www.genomicscape.com), higher expression of MICA was significantly associated with better overall survival in MM. MICA is an NK cell-activating ligand and plays an important role in ADCC. We observed that ADCC activity of both daratumumab and elotuzumab against MM cells was enhanced in the presence of HDAC inhibitors, which was compatible with our previous data that HDAC inhibitors upregulated MICA mRNA expression via inhibition of IKZF1 (ASH2018 abstract #4435). We also observed that HDAC inhibitors upregulated MICA mRNA in CRBN-deficient cells, suggesting promise of the combination of HDAC inhibitors and monoclonal antibodies against Len-resistant MM. Len-resistance is also affected by phosphorylation status of GSK-3. PI3K/AKT pathway is frequently activated in MM cells, and AKT inactivates GSK-3 by direct phosphorylation, resulting in c-Myc stabilization. Enhanced phosphorylation of GSK-3 was observed in CRBN-deficient H929 cells after long-term culture with Len, and such a phosphorylation status of GSK-3 was correlated with less CRBN amount and higher Len concentration (Figure 1). Afuresertib, an AKT inhibitor, suppressed GSK-3 phosphorylation (p-GSK-3) with or without ACY-1215, an HDAC inhibitor, leading to a substantial decrease of c-Myc (Figure 2). On the other hand, CHIR 99021, a GSK-3 inhibitor, partially counteracted to cytotoxic effect of afuresertib on H929 cells (Figure 3). These results suggest that increased p-GSK-3 is involved in acquired Len-resistance, and that combined inhibition of HDAC and AKT can overcome Len-resistance through decreased p-GSK-3. Furthermore, we examined the efficacy of CUDC-907, a dual HDAC and PI3K inhibitor. CUDC-907 had a cytotoxic effect on the MM cell lines including those had low CRBN expression. Bortezomib, doxorubicin, and dexamethasone resistant MM cell lines were also sensitive to CUDC-907. CUDC-907 upregulated MICA mRNA expression, but downregulated IKZF1 mRNA expression. Treatment of RPMI-8226 cells with CUDC-907 enhanced the ADCC activity of daratumumab (Figure 4). Furthermore, CUDC-907 was effective on primary MM cells which were resistant to bortezomib and Len (Figure 5). Thus, dual inhibition of HDAC and AKT with or without monoclonal antibodies is a promising therapeutic approach to multi-drug resistant MM. Disclosures Imai: Celgene: Honoraria, Research Funding; Janssen Parmaceutical K.K.: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Futami:Torii Pharmaceutical: Research Funding. Ri:Janssen Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical: Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Novartis Pharma: Research Funding; Gilead Sciences: Research Funding; Astellas Pharma: Research Funding; Teijin Pharma: Research Funding. Yasui:TokioTHERA Holdings, Inc.: Equity Ownership. Iida:Teijin Pharma: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas: Research Funding; Gilead: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding. Tojo:Torii Pharmaceutical: Research Funding; AMED: Research Funding.
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MAZARIEGOS, C., H. Ferrer, C. Avendaño, and V. Sánchez-Polo. "POS-907 COVID-19 AND SARS-CoV-2 VACCINE IN HEMODIALYSIS PATIENTS. EXPERIENCE IN A GUATEMALAN CENTER." Kidney International Reports 7, no. 2 (February 2022): S394—S395. http://dx.doi.org/10.1016/j.ekir.2022.01.946.
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Alcaraz, Diego, and F. Alhama. "Numerical Estimation of Thermal Conductivity in Copper and Superalloy Matrix Composites." Materials Science Forum 475-479 (January 2005): 985–88. http://dx.doi.org/10.4028/www.scientific.net/msf.475-479.985.
Повний текст джерелаАнотація:
Using a steady-state 2-D network model to simulate the thermal behaviour of copper and superalloy matrix composites, reinforced with different types of randomly distributed continuous fibers, the limit values of thermal conductivity are established for the analysed composites. A large number of random distributions for each matrix-fiber combination is tested to assess the accuracy of the numerical results. The influence of the type of fiber, its distribution and its proportion is shown graphically. Examples of continuous fiber metal matrix composites (continuous MMCs), such as those of copper and Incoloy 907 matrices, are studied.
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REUL, J. M. H. M., E. R. DE KLOET, F. J. VAN SLUIJS, A. RIJNBERK, and J. ROTHUIZEN. "Binding Characteristics of Mineralocorticoid and Glucocorticoid Receptors in Dog Brain and Pituitary." Endocrinology 127, no. 2 (August 1990): 907–15. http://dx.doi.org/10.1210/endo-127-2-907.
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MIYAMOTO, TAKAHIDE, KAZUO ICHIKAWA, KIYOSHI HASHIZUME, YUTAKA NISHII, TEIJI TAKEDA, MUTSUHIRO KOBAYASHI, SATORU SUZUKI, and TAKASHI YAMADA. "Purification and Characterization of Thyroid Hormone-Responsive Rat Hepatic Proteins." Endocrinology 129, no. 2 (August 1991): 907–14. http://dx.doi.org/10.1210/endo-129-2-907.
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Fell, Jack W., Henri Roeijmans, and T. Boekhout. "Cystofilobasidiales, a new order of basidiomycetous yeasts." International Journal of Systematic and Evolutionary Microbiology 49, no. 2 (April 1, 1999): 907–13. http://dx.doi.org/10.1099/00207713-49-2-907.
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Abraham, A. M., P. M. Sudhir, and G. Bantwal. "907 – Barriers to self care, illness perceptions and their relationship with self care in type 2 diabetes mellitus." European Psychiatry 28 (January 2013): 1. http://dx.doi.org/10.1016/s0924-9338(13)76068-1.
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Landsburg, Daniel J., Radhakrishnan Ramchandren, Petronella J. Lugtenburg, Kevin R. Kelly, Anas Younes, Robert Gharavi, David P. Tuck, and Stefan Klaus Barta. "A Pooled Analysis of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients Treated with the Dual PI3K and HDAC Inhibitor Fimepinostat (CUDC-907), Including Patients with MYC-Altered Disease." Blood 132, Supplement 1 (November 29, 2018): 4184. http://dx.doi.org/10.1182/blood-2018-99-112527.
Повний текст джерелаАнотація:
Abstract Introduction Patients with relapsed or refractory (R/R) MYC-altered DLBCL have poor outcomes, and other than for a subset of patients who may benefit from chimeric antigen receptor T cell therapy, no treatment has shown a significant durable benefit or impact on survival outcomes. Fimepinostat is a first-in-class, well-tolerated, oral small molecule inhibitor of HDAC and PI3K enzymes. There is particular interest in evaluating fimepinostat in patients with MYC-dependent tumors as nonclinical studies demonstrated that fimepinostat inhibits transcription of MYC and a subset of MYC-associated genes. Additionally, MYC protein levels were downregulated by fimepinostat in part through inhibition of PI3K-mediated ubiquitination. Pharmacodynamic inhibition of HDAC and PI3K has also been demonstrated in human studies. Here we report the outcome of R/R DBLCL patients treated with fimepinostat in a Phase 1 and Phase 2 study, with an emphasis on outcomes for patients with MYC-altered disease. Patients and Methods A total of 105 R/R DLBCL patients were enrolled on the Phase 1 study CUDC-907-101 (n = 37) and the Phase 2 study CUDC-907-201 (n = 68). In CUDC-907-101, 14 patients were found to have MYC-altered disease, defined as presence of MYC rearrangement by either central or local testing by fluorescent in situ hybridization or MYC protein expression ≥40%) by immunohistochemistry (IHC). In CUDC-907-201, 46 patients had confirmed MYC-altered disease by central IHC testing. Across both studies, patients without available tissue or prior test results were deemed as MYC-status unknown (n = 23). Results A total of 19 responses (9 CR, 10 partial responses [PR]) were reported across both studies. The objective response rate (ORR) in MYC altered patients was 23.3% (14/60). Responses showed encouraging durability with a median duration of response of 13.6 months (range: 2.8 to Not Calculable [NC]). Five MYC-altered responses were ongoing as of the data-cut. Two MYC-altered patients achieving CR discontinued treatment early to pursue stem cell transplantation. Responses associated with fimepinostat often require multiple cycles of treatment to manifest (median time to first response = 2.5 months for MYC-altered patients), and of patients who were treated for ≥2 months, a large proportion (17/33; 52%) achieved a response. Patients with low disease burden at screening (tumor lesions diameters ≤ 5 cm and lactate dehydrogenase [LDH] < 1.5 x upper limit of normal [ULN]) generally continued treatment longer and were most likely to derive clinical benefit (Table 2). Conclusions The biologic rationale, tolerable safety profile, and evidence of durable anti-tumor activity in MYC-altered R/R DLBCL support the continued development of fimepinostat in this poor-prognosis patient population. Patients with low disease burden features may be more likely to have sufficient duration of drug exposure to allow clinical benefit. Future enrollment will focus on patients with screening characteristics most likely to derive the greatest benefit from fimepinostat treatment. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Ramchandren:Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Lugtenburg:Millennium/Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Roche: Consultancy; BMS: Consultancy; Sandoz: Consultancy; Genmab: Consultancy. Younes:Takeda: Honoraria; Abbvie: Honoraria; BMS: Honoraria, Research Funding; Novartis: Research Funding; Curis: Research Funding; Incyte: Honoraria; Seattle Genetics: Honoraria; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; J&J: Research Funding; Pharmacyclics: Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Genentech: Research Funding. Tuck:Curis, Inc: Employment, Equity Ownership. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding.
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EGAMI, Kazutaka, Syuhei KUROKAWA, Toshiro DOI, Osamu OHMSHI, Midhio UNEDA, and Kazunori KADOMURA. "907 Condition of Grain on CMP Conditioner and Pad Surface Analysis." Proceedings of Conference of Kyushu Branch 2012.65 (2012): 319–20. http://dx.doi.org/10.1299/jsmekyushu.2012.65.319.
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Takada, Mitsuhiro, Tomoki Tajiri, and Yogo Takada. "907 Motorable Path Planning under Off-road Environment." Proceedings of Conference of Kansai Branch 2013.88 (2013): _9–7_. http://dx.doi.org/10.1299/jsmekansai.2013.88._9-7_.
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Volk, Kathryn, and Christa Van Laerhoven. "Dynamical Classifications of Multi-opposition TNOs as of 2023 December." Research Notes of the AAS 8, no. 1 (January 30, 2024): 36. http://dx.doi.org/10.3847/2515-5172/ad22d4.
Повний текст джерелаАнотація:
Abstract We report the dynamical classifications of 3357 observed outer solar system objects listed as transneptunian objects (TNOs) or Centaurs by the Minor Planet Center. We use the Gladman et al. classification scheme to identify 28 Jupiter-coupled objects (all secure), 168 Centaurs (all secure), 234 scattering TNOs (70 secure/164 insecure), 204 detached TNOs (118 secure/86 insecure), 1650 classical TNOs (1494 secure/156 insecure), and 1073 resonant TNOs (907 secure, 166 insecure). Among the resonant TNOs, the most observationally populated resonance is the close-in 3:2 MMR with 452 objects, followed by the 2:1 with 105 objects, the 7:4 with 103 objects, the 5:3 with 68 objects, and the 5:2 with 56 objects. We discuss a few notable objects here, but all classifications and plots of the 10 Myr integrations are available in a linked GitHub repository.
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Yang, Hong, and Li Guo. "Design of a Reader Antenna for UHF RFID." Advanced Materials Research 936 (June 2014): 2220–24. http://dx.doi.org/10.4028/www.scientific.net/amr.936.2220.
Повний текст джерелаАнотація:
A compact and circular polarized antenna for UHF band RFID handset reader was designed, and realized by cutting slits in the antenna patch and etching slots on the ground. Numerical simulation was performed for the characteristics of the antenna with the software HFSS 13.0.The simulation results show that when the size of antenna patch is 68mm×68mm, -10dB return loss impedance bandwidth is 49MHz,VSWR is less than 2 and the largest gain is -0.61dB for antenna in 907～931MHz. Compared with the traditional reader antenna with the same material of the substrate，the improved antenna has a much higher gain．and the size was reduced by 20% and the max gain is raised -0.11dB.
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Kumar, SV Kiran, Soumya Sinha, Meghana V. Prabha, and Surapaneni Haragopal. "Maxillary Molar with Two Palatal Canals." Journal of Contemporary Dental Practice 13, no. 6 (2012): 905–7. http://dx.doi.org/10.5005/jp-journals-10024-1251.
Повний текст джерелаАнотація:
ABSTRACT The endodontic treatment of maxillary molar with an aberrant root canal morphology can be diagnostically and technically challenging.1 Unusual root canal morphology in multirooted teeth is a constant challenge for diagnosis and successful endodontic treatment. Presence of extra canals, lateral canals, deltas is commonly encountered.2 This case report is presented to illustrate and describe the endodontic treatment of maxillary first molar with an unusual morphological variation of palatal root. The palatal root had two canals that appeared to unite in the apical third of the canal. How to cite this article Prabha MV, Sinha S, Kumar SVK, Haragopal S. Maxillary Molar with Two Palatal Canals. J Contemp Dent Pract 2012;13(6):905-907.
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Kieboom, Jasper, and Tjakko Abee. "Arginine-Dependent Acid Resistance in Salmonella enterica Serovar Typhimurium." Journal of Bacteriology 188, no. 15 (August 1, 2006): 5650–53. http://dx.doi.org/10.1128/jb.00323-06.
Повний текст джерелаАнотація:
ABSTRACT Salmonella enterica serovar Typhimurium does not survive a pH 2.5 acid challenge under conditions similar to those used for Escherichia coli (J. W. Foster, Nat. Rev. Microbiol. 2:898-907, 2004). Here, we provide evidence that S. enterica serovar Typhimurium can display arginine-dependent acid resistance (AR) provided the cells are grown under anoxic conditions and not under the microaerobic conditions used for assessment of AR in E. coli. The role of the arginine decarboxylase pathway in Salmonella AR was shown by the loss of AR in mutants lacking adiA, which encodes arginine decarboxylase; adiC, which encodes the arginine-agmatine antiporter; or adiY, which encodes an AraC-like regulator. Transcription of adiA and adiC was found to be dependent on AdiY, anaerobiosis, and acidic pH.
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Scandrett, Clyde. "Erratum: Scattering and active acoustic control from a submerged spherical shell [J. Acoust. Soc. Am. 111(2), 893–907 (2002)]." Journal of the Acoustical Society of America 122, no. 1 (July 2007): 677. http://dx.doi.org/10.1121/1.2735103.
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Andini, Ary. "ANALISA KADAR Fe (III) AIR DI KECAMATAN TANGGULANGIN SIDOARJO." Medical Technology and Public Health Journal 2, no. 1 (August 24, 2018): 19–24. http://dx.doi.org/10.33086/mtphj.v2i1.313.
Повний текст джерелаАнотація:
Decent water consumption has a characteristic of colorless, odorless, tasteless and no solids dissolved. One of the heavy metals that harmful to health body if excessive contained in water is Iron (III) (Fe(III). The method used in 2 main stages for analyzing of Fe (III) content those were determination standard curve and Fe (III) content in water with UV-Vis spectrophotometer at 480 nm wavelength. The result of this research showed that Fe (III) content in water in 10 samples of well water in Tanggulangin sub-district of Sidoarjo regency is quite feasible for daily use because the result of Fe (III) all sample were < 0,3 mg / L, its based on maximum concentration iron in drinking water as the Minister of Health Decree No.907 / MENKES / SK / VII / 2002.
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Andini, Ary. "ANALISA KADAR Fe (III) AIR DI KECAMATAN TANGGULANGIN SIDOARJO." Medical Technology and Public Health Journal 2, no. 1 (August 24, 2018): 19–24. http://dx.doi.org/10.33086/mtphj.v2i1.763.
Повний текст джерелаАнотація:
Decent water consumption has a characteristic of colorless, odorless, tasteless and no solids dissolved. One of the heavy metals that harmful to health body if excessive contained in water is Iron (III) (Fe(III). The method used in 2 main stages for analyzing of Fe (III) content those were determination standard curve and Fe (III) content in water with UV-Vis spectrophotometer at 480 nm wavelength. The result of this research showed that Fe (III) content in water in 10 samples of well water in Tanggulangin sub-district of Sidoarjo regency is quite feasible for daily use because the result of Fe (III) all sample were < 0,3 mg / L, its based on maximum concentration iron in drinking water as the Minister of Health Decree No.907 / MENKES / SK / VII / 2002.
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Hong, Chuan, Rui Duan, Lingzhen Zeng, Rebecca A. Hubbard, Thomas Lumley, Richard D. Riley, Haitao Chu, Stephen E. Kimmel, and Yong Chen. "The Galaxy Plot: A New Visualization Tool for Bivariate Meta-Analysis Studies." American Journal of Epidemiology 189, no. 8 (January 13, 2020): 861–69. http://dx.doi.org/10.1093/aje/kwz286.
Повний текст джерелаАнотація:
Abstract Funnel plots have been widely used to detect small-study effects in the results of univariate meta-analyses. However, there is no existing visualization tool that is the counterpart of the funnel plot in the multivariate setting. We propose a new visualization method, the galaxy plot, which can simultaneously present the effect sizes of bivariate outcomes and their standard errors in a 2-dimensional space. We illustrate the use of the galaxy plot with 2 case studies, including a meta-analysis of hypertension trials with studies from 1979–1991 (Hypertension. 2005;45(5):907–913) and a meta-analysis of structured telephone support or noninvasive telemonitoring with studies from 1966–2015 (Heart. 2017;103(4):255–257). The galaxy plot is an intuitive visualization tool that can aid in interpreting results of multivariate meta-analysis. It preserves all of the information presented by separate funnel plots for each outcome while elucidating more complex features that may only be revealed by examining the joint distribution of the bivariate outcomes.
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ITAKURA, Yoshiya. "907 PET Bottle Rocket as a Teaching Material." Proceedings of Conference of Kanto Branch 2012.18 (2012): 315–16. http://dx.doi.org/10.1299/jsmekanto.2012.18.315.
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IMAE, Tomohiko, Haruka YASUOKA, Masayuki KANEDA, and Kazuhiko SUGA. "907 Molecular dynamics simulation of flows in single-walled carbon nanotubes." Proceedings of Conference of Kansai Branch 2014.89 (2014): _9–6_. http://dx.doi.org/10.1299/jsmekansai.2014.89._9-6_.
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Stevens, B. R., A. Fernandez, and C. del Rio Martinez. "Angiotensin converting enzyme in brush-border membranes of avian small intestine." Journal of Experimental Biology 135, no. 1 (March 1, 1988): 1–8. http://dx.doi.org/10.1242/jeb.135.1.1.
Повний текст джерелаАнотація:
Angiotensin converting enzyme activity was identified in brush-border membranes purified from the small intestinal epithelium of the common grackle, Quiscalus quiscula. Angiotensin converting enzyme was enriched 20-fold in the membrane preparation, compared with intestinal epithelial cell scrapes, and was coenriched with the brush-border markers, alkaline phosphatase and aminopeptidase N. The kinetics of hydrolysis of N-[3-(2-furyl)acryloyl]-L-phenylalanylglycylglycine (FAPGG) gave a Vmax of 907 +/− 41 units g-1 and a Km of 55 +/− 6 mumol l-1. The avian intestinal angiotensin converting enzyme was inhibited by the antihypertensive drug, Ramipril, with a median inhibitory concentration (IC50) of 1 nmol l-1. In the light of previous studies on angiotensin converting enzyme in mammalian epithelia, these results may implicate a physiological role for angiotensin converting enzyme in regulating electrolyte and fluid uptake in bird small intestines.
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Barranco, Joseph A. "THREE-DIMENSIONAL SIMULATIONS OF KELVIN-HELMHOLTZ INSTABILITY IN SETTLED DUST LAYERS IN PROTOPLANETARY DISKS." Astrophysical Journal 691, no. 2 (January 28, 2009): 907–21. http://dx.doi.org/10.1088/0004-637x/691/2/907.
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Maggiore, Michele, and Antonio Riotto. "THE HALO MASS FUNCTION FROM EXCURSION SET THEORY. I. GAUSSIAN FLUCTUATIONS WITH NON-MARKOVIAN DEPENDENCE ON THE SMOOTHING SCALE." Astrophysical Journal 711, no. 2 (February 19, 2010): 907–27. http://dx.doi.org/10.1088/0004-637x/711/2/907.
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Holder, Gilbert P., Kenneth M. Nollett, and Alexander van Engelen. "ON POSSIBLE VARIATION IN THE COSMOLOGICAL BARYON FRACTION." Astrophysical Journal 716, no. 2 (May 25, 2010): 907–13. http://dx.doi.org/10.1088/0004-637x/716/2/907.
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ISHIMURA, Mitsutoshi, Toshiyuki SAWA, Yasumasa SHOJI, and Hiroshi YAMANAKA. "907 Study on Loosening of Bolted Joints under Transverse Repeated Loadings." Proceedings of Conference of Kansai Branch 2009.84 (2009): _9–7_. http://dx.doi.org/10.1299/jsmekansai.2009.84._9-7_.
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Sadowska, Karolina, Tomasz Ragiń, Marcin Kochanowicz, Piotr Miluski, Jan Dorosz, Magdalena Leśniak, Dominik Dorosz, et al. "Analysis of Excitation Energy Transfer in LaPO4 Nanophosphors Co-Doped with Eu3+/Nd3+ and Eu3+/Nd3+/Yb3+ Ions." Materials 16, no. 4 (February 14, 2023): 1588. http://dx.doi.org/10.3390/ma16041588.
Повний текст джерелаАнотація:
Nanophosphors are widely used, especially in biological applications in the first and second biological windows. Currently, nanophosphors doped with lanthanide ions (Ln3+) are attracting much attention. However, doping the matrix with lanthanide ions is associated with a narrow luminescence bandwidth. This paper describes the structural and luminescence properties of co-doped LaPO4 nanophosphors, fabricated by the co-precipitation method. X-ray structural analysis, scanning electron microscope measurements with EDS analysis, and luminescence measurements (excitation 395 nm) of LaPO4:Eu3+/Nd3+ and LaPO4:Eu3+/Nd3+/Yb3+ nanophosphors were made and energy transfer between rare-earth ions was investigated. Tests performed confirmed the crystal structure of the produced phosphors and deposition of rare-earth ions in the structure of LaPO4 nanocrystals. In the range of the first biological window (650–950 nm), strong luminescence bands at the wavelengths of 687 nm and 698 nm (5D0 → 7F4:Eu3+) and 867 nm, 873 nm, 889 nm, 896 nm, and 907 nm (4F3/2 → 4I9/2:Nd3+) were observed. At 980 nm, 991 nm, 1033 nm (2F5/2 → 2F7/2:Yb3+) and 1048 nm, 1060 nm, 1073 nm, and 1080 nm (4F3/2 → 4I9/2:Nd3+), strong bands of luminescence were visible in the 950 nm–1100 nm range, demonstrating that energy transfer took place.