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Geevers, Liesbeth. "Hoe toegankelijk was de 'papieren koning'? Een informeel communicatiekanaal tussen Lamoraal van Egmont en Willem van Oranje en de Spaanse centrale besluitvorming in de jaren 1559-1564." Tijdschrift voor Sociale en Economische Geschiedenis/ The Low Countries Journal of Social and Economic History 4, no. 1 (March 15, 2007): 39. http://dx.doi.org/10.18352/tseg.558.
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Goosens, Aline. "La fortune du comte Lamoral d'Egmont vers 1567-1568." Revue belge de philologie et d'histoire 70, no. 2 (1992): 357–80. http://dx.doi.org/10.3406/rbph.1992.3826.
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van Noort, Simon, Lubomir Masner, Ovidiu Popovici, Alejandro A. Valerio, Charuwat Taekul, Norman F. Johnson, Nicholas P. Murphy, and Andrew D. Austin. "Systematics and biology of the aberrant intertidal parasitoid wasp Echthrodesis lamorali Masner (Hymenoptera : Platygastridae s.l.): a parasitoid of spider eggs." Invertebrate Systematics 28, no. 1 (2014): 1. http://dx.doi.org/10.1071/is13015.
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The platygastroid wasp Echthrodesis lamorali has been of considerable interest since its description in 1968, primarily because of its highly modified, densely pilose, wingless body, its distribution and unusual biology. The species is endemic to the Cape Peninsula, South Africa, where it is an endoparasitoid of eggs of the marine spiders Desis formidabilis (Desidae) and Amaurobioides africanus (Anyphaenidae) in the intertidal region. Although a highly aberrant monospecific genus, the phylogenetic relationships of Echthrodesis are confused, in part due to convergence in body form across numerous unrelated platygastroid genera. We used sequence data from the nuclear 28S rRNA and 18S rDNA genes, and the mitochondrial cytochrome oxidase 1 (CO1) gene, to determine the phylogenetic affinities of E. lamorali. We present a revised taxonomic description for the genus and species, as well as new morphological information on the structure of its mouthparts and ovipositor system. Phylogenetic analyses of molecular data place E. lamorali within one of two independent clades of platygastroid wasps that use spider eggs as hosts. Echthrodesis is sister to a group of three genera: Neobaeus (New Zealand; host unconfirmed); Mirobaeoides (Australia; spider eggs); and Embidobia (near cosmopolitan; embiid eggs). Details on the biology, behaviour and morphological adaptations of E. lamorali are provided.
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MAGALHÃES, MAYARA D. F., and ADALBERTO J. SANTOS. "The spider family Oecobiidae in Madagascar, including four new species and a new record." Zootaxa 4527, no. 1 (December 3, 2018): 37. http://dx.doi.org/10.11646/zootaxa.4527.1.3.
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Four new species of Oecobiidae Blackwall, 1862 are described based on specimens collected in the Madagascan provinces of Toliara, Mahajanga and Antsiranana. Oecobius kowalskii sp. nov. and Paroecobius skipper sp. nov. are described based on male and female specimens. Paroecobius rico sp. nov. and Paroecobius private sp. nov. are described based only on females. A new diagnosis is proposed for the genus Paroecobius Lamoral, 1981 and a new record for the synanthropic Oecobius marathaus Tikader, 1962 is provided for Madagascar.
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Taufik, Indah Werdiningsih, Faried Effendy, Nania Nuzulita, Ibaneza Griffint Secoria, and Aulia Marcha Rizkasari Putri. "TRAINING AND ASSISTANCE OF ONLINE MARKETING OF PROCESSED MARINE PRODUCTS MICRO-MEDIUM BUSINESS “LAMORA” IN KAUMAN VILLAGE, SOCAH, BANGKALAN." Jurnal Layanan Masyarakat (Journal of Public Services) 6, no. 1 (March 30, 2022): 185–94. http://dx.doi.org/10.20473/jlm.v6i1.2022.185-194.
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Lamora is a cracker and petis industry located in Kauman village, Socah sub-district, Bangkalan district, which has become a pilot MSME. Under the guidance of the Ministry of Industry and Manpower and the Department of Health of Bangkalan Regency, this MSME has had a website (https://kerupukikansocah.com) since 2017. Before the pandemic, Lamora only served orders and purchases directly from individuals or resellers from Bangkalan and its surroundings. However, during the Covid-19 pandemic, sales turnover decreased by more than 60%. This requires serious attention to maintain business continuity. The solution provided is a training and mentoring partnership program to provide MSME actors with the ability to use information technology (IT) as a marketing and sales medium, conduct online marketing on social media, manage online stores in market places and use promotional media design applications for free. The training which lasted for two days has gone well and has achieved the expected goal, namely increasing the understanding of Lamora MSME actors towards online marketing using IT.
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ACOSTA, LUIS E., and VICTOR FET. "Nomenclatural notes in Scorpiones (Arachnida)." Zootaxa 934, no. 1 (April 8, 2005): 1. http://dx.doi.org/10.11646/zootaxa.934.1.1.
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Several previous nomenclatural corrections are analyzed and the valid name determined for each case. These include (a) emendations and subsequent spellings: Brachistosternus weijenberghi (Thorell, 1877a) (Bothriuridae), Urophonius iheringi Pocock, 1893 (Bothriuridae), Lisposoma josehermana Lamoral, 1979 (Bothriuridae), Chactas raymondhansi Francke & Boos, 1986 (Chactidae), Tityus fuhrmanni Kraepelin, 1912 (Buthidae), Parabuthus liosoma (Ehrenberg, 1828) (Buthidae), Hadrurus concolorous Stahnke (Iuridae), Vachoniolus minipectenibus (Levy, Amitai & Shulov, 1973); (b) incorrect reversal of precedence: Hadogenes hahni (Peters, 1862) n. comb. (Liochelidae); (c) genus and species names that never were available: Pucha, Puchale, Repucha (Francke, 1985; Fet, 1997), Transbothriurus (Mello-Leitão, 1945; Lowe & Fet, 2000), Scorpio maurus punicus Fet, 2000 (replacement name for Scorpio maurus tunetanus Birula, 1910) (Scorpionidae)
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Astihorsson, Olafur Svavar. "Records ofEucopia grimaldii, Hansenomysis fyllae, Hemimysis lamornae, andMysis litoralis(Mysidacea) from Icelandic waters." Sarsia 72, no. 1 (February 27, 1987): 37–39. http://dx.doi.org/10.1080/00364827.1987.10419703.
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Prendini, Lorenzo. "Revision of the genus Lisposoma Lawrence, 1928 (Scorpiones: Bothriuridae)." Insect Systematics & Evolution 34, no. 3 (2003): 241–64. http://dx.doi.org/10.1163/187631203788964764.
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AbstractThe endemic Namibian genus Lisposoma Lawrence, 1928, comprising two described species, represents one of two basal African genera in the Gondwanan family Bothriuridae Simon, 1880. All other, more derived genera of Bothriuridae occur in South America, India and Australia. Although the phylogenetic position of Lisposoma has become an increasingly contentious subject, three cladistic analyses based on morphological data have confirmed that it is a basal bothriurid. In view of those findings, the present contribution serves to revise the generic diagnosis of Lisposoma, last revised by Lamoral (1979), who placed the genus in the Scorpionidae Latreille, 1802 and constructed his diagnosis accordingly. A considerable number of new specimens, many representing new records for the two species of Lisposoma, have also accumulated since Lamoral's (1979) revision. These new data justify the provision of revised diagnoses and descriptions for the two species, together with a key to their identification, brief summaries of their ecology and conservation status, and a distribution map plotting all known locality records.
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Owen, C. A., J. A. Coetzee, and S. van Noort. "Distributional Range of the South African Maritime Spider-Egg Parasitoid Wasp,Echthrodesis lamorali(Hymenoptera: Platygastridae: Scelioninae)." African Invertebrates 55, no. 2 (October 2014): 323–32. http://dx.doi.org/10.5733/afin.055.0206.
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Akam, Michael. "Foreseeing fates: a commentary on Manton (1928) ‘On the embryology of a mysid crustacean, Hemimysis lamornae ’." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1666 (April 19, 2015): 20140381. http://dx.doi.org/10.1098/rstb.2014.0381.
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Sidnie Manton became best known for her work on arthropod locomotion, and for proposing radical views on the evolution of arthropods that were accepted for a generation. However, her early training was as an embryologist, and the work that she carried out at the beginning of her career still stands as one of the major twentieth century contributions to the study of crustacean embryology. Here, I review her first major paper, largely completed while she was a graduate student, describing embryonic development in Hemimysis lamornae , a small shrimp-like animal found in the seas around the UK. The clarity of her writing and the quality of her figures set a standard that laid the basis for subsequent work, and although not all of her conclusions have stood the test of time, they remain a standard reference for work today. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society .
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Delgado, L., G. Guerao, C. San Vicente, and C. Ribera. "Population structure and life history of Hemimysis lamornae mediterranea (Malacostraca: Mysida) in the Ebro Delta (NW Mediterranean)." Journal of Sea Research 83 (October 2013): 137–45. http://dx.doi.org/10.1016/j.seares.2013.03.012.
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Shieh, Yiwey, Jacquelyn Roger, Christina Yau, Denise Wolf, Gillian Hirst, Lamorna Swigart, Scott Huntsman, et al. "Abstract PR008: Development and testing of a polygenic risk score for breast cancer. Aggressiveness." Cancer Prevention Research 16, no. 1_Supplement (January 1, 2023): PR008. http://dx.doi.org/10.1158/1940-6215.precprev22-pr008.
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Abstract Background: Aggressive breast cancers have increased proliferation or metastatic potential and portend a poor prognosis. The ability to identify women at elevated risk of aggressive cancers could have major implications for screening and prevention, yet there are no available tools for predicting aggressive cancer risk. We sought to construct a polygenic risk score (PRS) for aggressive breast cancers by leveraging the associations of single nucleotide polymorphisms (SNPs) with tumor gene expression. We used as our measure of aggressiveness the risk of recurrence score weighted on proliferation (ROR-P), a validated tumor prognostic signature. We hypothesized that known breast cancer susceptibility SNPs would have differential associations with ROR-P, which could then be used to construct a PRS for ROR-P. Methods: We developed our PRS in a case-only analysis of 3 studies containing SNP genotypes and tumor gene expression: The Cancer Genome Atlas, METABRIC, and the I-SPY 2 TRIAL (total n=2,363). We used linear regression models to evaluate individual SNP associations with ROR-P, adjusted for genetic ancestry and study. We then constructed PRS using varying p-value thresholds and used cross-validation to identify the PRS with highest model r2. To assess whether the ROR-P PRS was associated with poor prognosis, we performed survival analysis in two longitudinal cohorts of breast cancer patients: the UK Biobank (women with incident invasive cancers only) and the Pathways Study. These studies included 10,196 total cases with 785 deaths. We built Cox proportional hazards models to evaluate the association between the ROR-P PRS (adjusted for genetic ancestry) and breast cancer-specific survival (BCSS) in both studies. We then performed meta-analysis of the Cox model results. We also constructed joint models containing the ROR-P PRS and a PRS representing the case-case risk of ER-negative vs. ER-positive cancer, PRSER-/ER+. Results: We tested the associations between 226 breast cancer susceptibility SNPs and ROR-P. The best-performing PRS contained 76 SNPs and had a cross-validated r2 of 0.051. In the UK Biobank and Pathways Study, higher ROR-P PRS was associated with worse BCSS, with nearly identical effects observed in each study, HR per standard deviation of 1.13 (95% CI 1.05-1.21, p=9.0x10-4) in meta-analysis. The ROR-P PRS’s effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS was providing additional prognostic information beyond ER status. Conclusions: We used breast cancer susceptibility SNPs to construct a PRS for ROR-P, a prognostic signature recapitulating aggressiveness, and found the ROR-P PRS to be associated with worse BCSS. Our findings represent an improvement on current PRS for overall breast cancer risk, which preferentially predict cancers with favorable prognosis. Given that aggressive cancers are more likely to present as advanced cancers even among women undergoing routine screening, our findings could potentially identify women who may benefit from more intensive screening. Citation Format: Yiwey Shieh, Jacquelyn Roger, Christina Yau, Denise Wolf, Gillian Hirst, Lamorna Swigart, Scott Huntsman, Donglei Hu, Jovia Nierenberg, Pooja Middha, Rachel Heise, Linda Kachuri, Qianqian Zhu, Song Yao, Christine Ambrosone, Marilyn Kwan, Bette Caan, John Witte, Lawrence Kushi, Laura van ’T. Veer, Laura Esserman, Elad Ziv. Development and testing of a polygenic risk score for breast cancer. Aggressiveness. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR008.
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Chien, A. Jo, Kevin M. Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I. Olopade, Amrita Basu, et al. "Abstract OT1-10-02: I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): OT1–10–02—OT1–10–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-ot1-10-02.
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Abstract Background: There is no clinical equipoise on the best upfront management of patients with early-stage hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC) that is high-risk by clinicopathologic criteria, and low-risk based on molecular profiling. These patients are unlikely to respond to chemotherapy. However, these patients still have risk, often risk of late recurrence, despite standard adjuvant endocrine therapy. Novel endocrine-based strategies that are more effective and tolerable than current standard therapies are needed for this population. Next-generation orally-bioavailable selective estrogen receptor degraders (oSERDs) with improved pharmacokinetic (PK) properties are promising potential therapies for HR+ BC. The oSERD amcenestrant has demonstrated a favorable safety profile and encouraging efficacy in a phase I/II dose escalation and expansion trial for heavily pre-treated patients with HR+ metastatic BC and is an attractive agent for assessment in the neoadjuvant BC setting. The neoadjuvant setting offers a unique opportunity to study novel agents and to assess early biological endpoints. However, one of the challenges in studying endocrine-based strategies in the neoadjuvant setting is the lack of a robust surrogate endpoint to reliably predict response and benefit. The I-SPY2 Endocrine Optimization Protocol (EOP) is a pilot sub-study within the main I-SPY2 TRIAL that will test amcenestrant alone or in combination with abemaciclib or letrozole. EOP will test the feasibility of using the I-SPY2 platform to test novel endocrine-based strategies in the neoadjuvant setting in patients with clinical high-risk, molecular low-risk, HR+/HER2- tumors, and will generate a rich database of imaging, molecular, and pathologic correlative endpoints that may potentially inform the improved assessment of response to neoadjuvant endocrine therapy. Trial Design/Eligibility/Accrual: The I-SPY2 EOP is a prospective, randomized, open-label trial specifically for patients with HR+/HER2-negative MammaPrint (MP) low-risk tumors that are at least 2.5 cm in size. Eligible patients are identified during the screening process for the parent I-SPY2 trial. The planned total accrual for the EOP is 120 patients. Patients are randomized 1:1:1 to one of 3 oral treatment arms: 1) amcenestrant 200 mg daily; 2) amcenestrant 200 mg daily + abemaciclib 150 mg bid; 3) amcenestrant 200 mg daily + letrozole 2.5 mg daily. Patients are treated for 6 months prior to surgery. Premenopausal women must receive concomitant monthly ovarian suppression. Serial breast MRIs, breast biopsies, blood, and patient reported outcomes (PROs) are being collected, and patients will be followed for 10 years for recurrence and survival. Serial dedicated breast PET (dbPET) scans and PKs will be assessed in a subset of patients. Objectives/Statistics: The primary objective of the EOP is to investigate the feasibility of enrolling and treating molecularly-selected patients with early stage HR+/HER2- MP low-risk BC in a randomized neoadjuvant trial using an oral-SERD backbone. Treatment will be determined to be feasible if ≥75% of enrolled patients complete ≥75% of assigned study therapy. Secondary objectives include the safety, tolerability, PROs, and PKs related to amcenestrant +/- abemacilcib and letrozole, as well as the assessment of imaging, pathologic, and molecular correlative endpoints as potential biomarkers of response to neoadjuvant endocrine therapy. Status: This study opened in May 2021. Accrual is ongoing. Citation Format: A. Jo Chien, Kevin M Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I Olopade, Amrita Basu, Smita M Asare, Paul Henderson, Gillian Hirst, Ruixiao Lu, Ella Jones, Nola Hylton, Lamorna Brown-Swigart, Laura J van 't Veer, Douglas Yee, Ingrid Mayer, Laura J Esserman. I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer [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 OT1-10-02.
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Rosenbluth, Jennifer, Christopher J. Schwartz, Tam Binh Bui, Shruti Warhadpande, Pravin Phadatare, Sigal Eini, Michael Bruck, et al. "Abstract P3-09-01: Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP)." Cancer Research 83, no. 5_Supplement (March 1, 2023): P3–09–01—P3–09–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-p3-09-01.
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Abstract Background: Treatment of estrogen receptor (ER)-positive breast cancer with selective estrogen receptor degraders (SERDs) frequently results in the loss or reduction of ER expression. Whether these changes are due to on-target effects of SERDs degrading ER or arise as a mechanism of tumor resistance with associated changes in cellular phenotypes remains unknown. It is critical to distinguish between these possibilities to accurately assess treatment response and determine the most appropriate subsequent therapy. To this end, we created and conducted molecular analyses on patient-derived organoid cultures from post-treatment tissue in patients receiving neoadjuvant SERD therapy for early-stage ER+ breast cancer in the I-SPY2 Endocrine Optimization Protocol (EOP). Methods: The I-SPY2 EOP study is a prospective, randomized substudy within the I-SPY TRIAL testing the oral SERD amcenestrant alone or in combination with letrozole or abemaciclib in stage 2/3 ER+ Her2-negative breast cancer. Enrollment is ongoing, with patients receiving amcenestrant neoadjuvantly for 6 months until the day before surgery. Tumor tissue is collected at baseline, 3 weeks, and at surgery. Organoids were generated from post-treatment surgical samples. Organoid cultures were optimized based on established methods (Dekkers et al., Nature Protocols, 2021) to assess ER levels and activity. Pre- and post-treatment tissue samples were also assessed for ER, PR, Ki67, and GATA3, a luminal marker and transcription factor that is functionally linked with ER, via immunohistochemistry. Results: In 7 patients with both pre- and post-treatment tissue samples including fresh surgical samples for organoid generation, the ER in baseline tumor tissue was >=90% in all patients, PR ranged from 40-90%, and Ki67 ranged from 5-30%. In post-treatment surgical tissue from these cases, ER ranged from 0-30%, PR from 0-50%, Ki67 from < 1%-10%, and GATA3 was positive in 5 of 5 cases tested to-date. The creation of organoids from residual disease at surgery was attempted for these 7 patients, with organoids successfully propagated in 5 cases thus far. 3 of 5 organoid cultures were ready for analysis and in all cases strong ER and PR expression in organoids was observed after culture for > 1 month in the absence of amcenestrant. Detailed gene expression profiling (including Mammaprint/Blueprint) and gene set enrichment analyses (GSEA) to assess for intrinsic breast cancer subtype and ER activity in each sample and corresponding organoid culture are in progress and will be reported with the full dataset. Conclusion: Patient-derived organoid culturing of residual disease after neoadjuvant endocrine therapy is feasible. Neoadjuvant treatment with a SERD can render ER and PR low or absent at the time of surgical resection, which does not necessarily imply the presence of endocrine therapy resistant disease. The use of organoids and additional IHC markers (GATA3) demonstrate that receptor negativity may be an indicator of the drug hitting its target, suggesting ER signaling is still intact. In general, patient-derived tumor organoid cultures modeling residual disease states can be a useful adjunct to existing methods used to monitor the effects of neoadjuvant endocrine therapy and is being explored in the I-SPY EOP trial. Citation Format: Jennifer Rosenbluth, Christopher J. Schwartz, Tam Binh Bui, Shruti Warhadpande, Pravin Phadatare, Sigal Eini, Michael Bruck, Julissa Molina-Vega, Kami Pullakhandam, Nicole Schindler, Lamorna A. Brown Swigart, Christina Yau, Gillian Hirst, Rita Mukhtar, Karthik V. Giridhar, Olufunmilayo I. Olopade, Kevin Kalinsky, Cheryl A. Ewing, Jasmine M. Wong, Michael D. Alvarado, Laura Van’t Veer, Laura J. Esserman, Jo Chien. Characterization of residual disease after neoadjuvant selective estrogen receptor degrader (SERD) therapy using tumor organoids in the I-SPY Endocrine Optimization Protocol (EOP) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-09-01.
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Magbanua, Mark Jesus Mendoza, Lamorna Brown Swigart, Derrick Renner, Svetlana Shchegrova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, et al. "Abstract LB111: Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB111. http://dx.doi.org/10.1158/1538-7445.am2022-lb111.
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Abstract Background: We compared the predictive and prognostic value of ctDNA dynamics in high-risk hormone receptor-positive/HER2-negative (HR+/HER2-) and triple negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) enrolled in the I-SPY 2 trial (NCT01042379). To our knowledge, this is the largest ctDNA study in breast cancer in the neoadjuvant setting. Methods: Blood samples were collected at pre-treatment (T0), during treatment (T1 at 3 weeks, and T2 at 12 weeks) and after NAC (T3 at 24 weeks) from 106 HR+/HER2- and 97 TNBC patients. Plasma samples (n=734) were analyzed using a personalized and tumor-informed mPCR NGS-based ctDNA test (SignateraTM). Patients, all high risk for recurrence by MammaPrint, received paclitaxel-based treatment +/- experimental therapy followed by anthracycline. The median follow-up was 3.0 years (0.5 to 6.5). The predictive and prognostic value of ctDNA dynamics and status at different timepoints were examined. Our analysis is exploratory and does not adjust for other biomarkers. Results: Pretreatment ctDNA positivity (Fisher p<0.0001) and levels (mean tumor molecules/mL, MTM/mL, t test p=0.0062) were significantly higher in TNBC (90.7%, 14.7 MTM/mL) than in high risk HR+/HER2- (66.0%, 5.5 MTM/mL). Early and late ctDNA clearance during treatment (3 and 12 weeks of NAC) was predictive of pathologic complete response (pCR) and residual cancer burden (RCB), class 0-III, in TNBC but not HR+/HER2- (Table). In both subtypes: (1) ctDNA was a significant negative prognostic factor for distant recurrence-free survival (DRFS) at all timepoints (p<0.05) except at pretreatment; (2) all patients who achieved pCR were ctDNA-negative after NAC; (3) among non-responding patients, ctDNA-negativity after NAC was associated with improved DRFS (Table). Conclusions: The predictive value of ctDNA for prediction of pCR and RCB differed between subtypes (HR+/HER2- vs. TNBC), while similar prognostic value was observed. In TNBC, early clearance of ctDNA at 3 weeks was a significant predictor of favorable response to NAC. Compared to patients who were ctDNA-positive after NAC, ctDNA-negative status in both subtypes was associated with improved DRFS even in patients with residual cancer (no pCR or RCB-II/III). These findings could inform on the design of future studies that seek to demonstrate the utility of ctDNA in the curative setting. Predictive and prognostic significance of ctDNA in early breast cancer in the neoadjuvant setting HR+HER2- (n=106) TNBC (n=97) Predictive value for prediction of pCR and RCB Fisher p-value Fisher p-value Early ctDNA clearance (between T0 and T1) and pCR 0.4521 <0.0001 Late ctDNA clearance (between T0 and T2) and pCR 0.8071 0.0004 Early ctDNA clearance (between T0 and T1) and RCB (0-III) 0.1360 <0.0001 Late ctDNA clearance (between T0 and T2) and RCB (0-III) 0.4869 0.0004 Early ctDNA clearance at T1 and pCR rates pCR rate pCR rate ctDNA clearance (ctDNA+ at T0/ctDNA- at T1) 21% 67% Late ctDNA clearance (betweeNo early clearance (ctDNA+ at T0/ctDNA+ at T1) 13% 14% Prognostic value for prediction of DRFS Log rank p-value Log rank p-value ctDNA at T3 and pCR vs no PCR 0.0002 <0.0001 ctDNA at T3 and RCB (0-I vs II-III) 0.0110 <0.0001 Timepoints: T0 - pretreatment; T1 - three weeks after treatment initiation; T2 - at 12 weeks, between paclitaxel-based and anthracycline regimens; T3- after neoadjuvant chemotherapy prior to surgery Citation Format: Mark Jesus Mendoza Magbanua, Lamorna Brown Swigart, Derrick Renner, Svetlana Shchegrova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Hsin-Ta Wu, Ekaterina Kalashnikova, Amy L. Delson, A. Jo Chien, Debu Tripathy, Smita Asare, Raheleh Salari, Angel Rodriguez, Bernhard Zimmermann, Himanshu Sethi, Alexey Aleshin, Paul Billings, Rita Nanda, Hope S. Rugo, Laura J. Esserman, Minetta C. Liu, Angela DeMichele, Laura van 't Veer. Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB111.
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Wolf, Denise M., Christina Yau, Michael Campbell, Hatem Soliman, Mark Magbanua, Ruixiao Lu, Nicholas O'Grady, et al. "Abstract P5-13-12: Immune signatures and MammaPrint (ultra) high risk class (MP2) as predictors of response to pembrolizumab combined with the TLR9 agonist SD101 in the neoadjuvant I-SPY 2 TRIAL." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–13–12—P5–13–12. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-13-12.
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Abstract Background: Pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, is approved for treatment in multiple cancers and has been shown to increase pathologic complete response (pCR) and survival in the neoadjuvant setting in breast cancer. Pembrolizumab combined with paclitaxel followed by doxorubicin/cyclophosphamide (P+T->AC) was evaluated in HER2- patients in the neoadjuvant I-SPY 2 TRIAL and graduated in the HER2-, HR+HER2- and triple negative (TN) signatures. Our biomarker analysis revealed that immune cell abundance and MP2 class predicts response in HR+HER2- patients whereas tumor-immune proximity scores (multiplex-IF) and signaling signatures (mRNA) predict response in TN patients. In an effort to further improve response, the TLR9 agonist SD101 was added to Pembro (P+S+T -> AC) for testing in I-SPY 2. While P+S increased estimated pCR rates relative to control (T->AC), it did not graduate for efficacy. To better understand the biology underlying response to P+S, we evaluated 31 expression based biomarkers relating to immune, ER and proliferation as predictors of response to P+S overall and within subtypes. Methods: Data from 72 patients (HR+HER2-: 45; TN: 27) treated with P+S were available. Pre-treatment FFPE biopsies were assayed using Agilent gene expression arrays. We evaluated genes/signatures representing 6 immune checkpoint/targets (CD274, PDCD1, TLR9, TIGIT, LAG3, and TIM3), 14 immune cell types (e.g., TILs, T cells, CD8 T cells, Tregs, cytotoxic cells, dendritic cells, mast cells, B cells, macrophages, and neutrophils), 3 T/B-cell prognostic (e.g., ICS5), 5 Tumor-immune signaling (e.g., STAT1, Chemokine12, TIS, and Geparsixto), and 1 TGFB signaling signatures as predictors of response to P+S. We also assess ESR1/PGR and proliferation, and the prognostic marker MP2 class. Signature scores were calculated as previously published. We used logistic modeling to assess biomarker performance (likelihood ratio test, p<0.05). This analysis was also performed in a model adjusting for HR status, and within receptor subsets. For the dichotomous MP1/2, we used Bayesian modeling to estimate the pCR rates of patients in each class. Multiple hypothesis testing adjustment was performed using the Benjamini-Hochberg method. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: Higher levels of most (24/29) immune biomarkers associate with pCR in the population as a whole (BH LR p<0.05). Among target genes, CD274 and PDCD1 strongly associate with pCR; however, TLR9 did not associate with response. As seen in previous biomarker analyses of IO agents including Pembro, there are major differences in predictive biology between receptor subsets. Immune cell subpopulation abundance signatures (13/14) and T/B-cell prognostic signatures (3/3) associate with pCR in HR+HER2- but not TN subsets. Whereas tumor-immune signaling signatures (4/5) dominated by chemokines and cytokines associate with pCR in both HR+HER2- and TN subsets. In addition, high ESR1/PGR and low proliferation signature levels associate with response in HR+HER2-, as does MP1/2 class, with an estimated 45% pCR in MP2 versus 17% pCR in MP1. Analysis of multiplex-IF immune markers is pending. Conclusion: Though TN patients are more responsive to Pembro+SD101 and other immunotherapies than HR+HER2- patients, many more immune biomarkers associate with pCR in the latter group. Only tumor-immune signaling signatures associate with pCR in both HR+HER2- and TN subsets. Response in the HR+HER2- subset is higher in MP2 class, high-proliferation, lower-ER tumors. Lack of predictive signal for TLR9 may help explain why the addition of SD101 to Pembro failed to further boost response. Citation Format: Denise M Wolf, Christina Yau, Michael Campbell, Hatem Soliman, Mark Magbanua, Ruixiao Lu, Nicholas O'Grady, Lamorna Brown-Swigart, Gillian Hirst, Laura Sit, Yvonne M Florence, I-SPY 2 TRIAL Investigators, Smita Asare, Doug Yee, Angie DeMichele, Don Berry, Laura Esserman, Jo Chien, Laura van 't Veer. Immune signatures and MammaPrint (ultra) high risk class (MP2) as predictors of response to pembrolizumab combined with the TLR9 agonist SD101 in the neoadjuvant I-SPY 2 TRIAL [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 P5-13-12.
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Sayaman, Rosalyn W., Denise M. Wolf, Christina Yau, Lamorna Brown Swigart, Gillian L. Hirst, Laura Sit, Nicholas O'Grady, et al. "Abstract P2-01-03: Elucidating the biology of circulating tumor DNA (ctDNA) shedding across receptor subtypes in high-risk early-stage breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–01–03—P2–01–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-01-03.
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Abstract Background: Identifying mechanisms that govern the shedding of ctDNA in blood could inform the use of liquid biopsy in individual patients. Previous studies in the I-SPY2 neoadjuvant trial involving high-risk breast cancer showed that the detection of ctDNA before treatment was associated with aggressive clinical characteristics and residual ctDNA after treatment was associated with poor outcomes. Moreover, ctDNA positivity rates significantly varied across breast cancer subtypes suggesting that ctDNA shedding may in part be driven by subtype-specific etiology. We performed genome-wide transcriptomic analysis to identify genes and biological processes associated with increased ctDNA shedding within and across receptor subtypes. Methods: Our study involved 227 patients in I-SPY2 with tumor gene expression and ctDNA data at pretreatment. All patients were at high risk for recurrence (MammaPrint high). Each subtype: HR+HER2- (n=109), HER2+ (n=19), and triple negative breast cancer (TNBC, n=99) was evaluated independently. We performed differential expression (DE) analysis on the global transcriptome (m=19,134 genes) and curated gene signature (cGS, m=31 signatures developed in I-SPY2) data between ctDNA+ and ctDNA- patients at baseline. Gene-set enrichment analysis (GSEA) was also performed across hallmark (H, m=50), canonical pathway (CP, m=5,501), gene ontology (GO, m=9,996) and immunologic (IM, m=4,872) gene sets. Features were associated with ctDNA shedding if Benjamini-Hochberg adjusted p < 0.05. For subtypes with smaller sample size and unbalanced groups, we also report features with nominally significant p < 0.05. Results: ctDNA positivity rate was significantly higher in TNBC (91%) than in HR+HER2- and HER2+ (65% and 74% respectively, Fisher p <0.001). The HR+HER2- subtype had the most significant hits for DE analysis between ctDNA+ and ctDNA- patients, with 0.2% of genes and 3.2% of cGS. No genes or cGS were differentially expressed in TNBC and HER2+, likely due to imbalance or small size of these groups. For GSEA, we observed the most significant number of enrichments in HR+HER2- subtype, with 58%, 21.8%, 4.4% and 40.3% of H, CP, GO, and IM gene sets enriched, respectively. In the HER2+ subtype, 40% H, 15.7% CP and 36.4% IM gene sets were significantly enriched, while no gene sets were enriched in TNBC. To identify common mechanistic themes across subtypes, we also considered nominally significant features in DE and GSEA. Processes associated with infection and innate immune responses were enriched in ctDNA+ patients, while adaptive immune response and antigen presentation—e.g., T-cell, TCR and MHC II protein complex, and downregulation of MYC targets were enriched in ctDNA- patients. HR+HER2- and HER2+ subtypes shared the most common modulated features with 134 genes and 2,165 gene sets, including up-regulation of cell cycle and proliferation in ctDNA+ patients, as well as up- or down-regulation of specific immunologic and metabolic processes. In contrast, TNBC gene set enrichment was associated with more distinct biologic processes, sharing common enrichment of 113 and 27 gene sets with HR+HER2- and HER2+ subtype, respectively. Conclusions: Findings from our exploratory analysis suggest a key role of immune response pathways in the control of ctDNA release. Additionally, tumor cell proliferation was associated with increased shedding in HR+HER2- and HER2+ subtypes, while down regulation of MYC targets was associated with ctDNA- patients across all subtypes. These suggest an important role of cell cycle in ctDNA shedding. Overall, our analysis revealed common and unique mechanisms potentially associated with ctDNA shedding across and within subtypes. However, due to the unbalanced groups and limited sample sizes, validation in a larger cohort is warranted. Citation Format: Rosalyn W. Sayaman, Denise M. Wolf, Christina Yau, Lamorna Brown Swigart, Gillian L. Hirst, Laura Sit, Nicholas O'Grady, Amy L. Delson, I-SPY2 Investigators, Laura Esserman, Laura J. van 't Veer, Mark Jesus M. Magbanua. Elucidating the biology of circulating tumor DNA (ctDNA) shedding across receptor subtypes in high-risk early-stage breast cancer [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 P2-01-03.
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Goodarzi, Hani, Albertas Navickas, Jefferey Wang, Kristle Garcia, Mark J. Magbanua, Lisa Fish, Lamorna Brown Swigart, et al. "Abstract PD9-04: Tumor-released circulating orphan non-coding RNAs reflect treatment response and survival in breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD9–04—PD9–04. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd9-04.
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Abstract Background: Liquid biopsies have emerged as effective diagnostic tools in disease monitoring and minimal residual disease detection. Circulating tumor DNA (ctDNA) was recently shown to be a predictor of poor response and recurrence in breast cancer. However, ctDNA shedding from breast tumors can rapidly decrease during treatment, resulting in reduced sensitivity in measuring early changes in tumor response or residual cancer burden (RCB) after neoadjuvant chemotherapy (NAC). We recently reported the discovery of orphan non-coding RNAs (oncRNAs), a class of small RNAs that are not present in healthy cells, but emerge from cancer cells. Similar to ctDNA, tumor-released oncRNAs can be used to detect the presence of an underlying tumor; however, since they are actively released by cancer cells, their abundance in the cell-free compartment is substantially higher than ctDNA. Therefore, we hypothesized that monitoring circulating oncRNAs in blood permits a more sensitive approach to measuring treatment response (i.e., pathologic complete response, or pCR) and estimating RCB. Patients and Methods: Cell-free RNA (cfRNA) was extracted from ~1 ml sera of 72 breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with NAC alone or combined with MK-2206 (AKT inhibitor) treatment. For each patient, treatment-naïve samples (T0) were compared with samples from post-treatment and prior to surgery (T3) time-point. RNA samples were subjected to small RNA sequencing (SMARTer), and the presence and abundance of cell-free oncRNA species were then determined by identifying and counting the reads that map to oncRNA loci across samples. Notably, oncRNAs species were pre-annotated from the Cancer Genome Atlas (TCGA), and our approach does not require bespoke personalized assays. We used a machine-learning model to compare abundance of cfRNA species before and after treatment (i.e., T3-T0) to predict pCR and RCB. For this, we split our cohort into a training and a testing set (48 and 24) and trained a model to simultaneously learn the presence of residual disease (pCR vs. no pCR) and its extent (RCB). We then measured the performance of our model on the held-out test data and the entire dataset. To confirm the robustness of our model, we also employed a leave-one-out strategy, whereby pCR and RCBIndex of each patient was predicted using a model that was trained on the other patients in the cohort. Finally, to assess the ability of our oncRNA-based model to risk-stratify patients who fail to achieve pCR (without having been explicitly trained on relapse data), we used the model’s oncRNA score to predict patients at the highest risk of distant recurrence (n=8 out of 36) and performed a multivariate Cox analysis, controlling for HR/Her2 status (median follow-up time was 4.8 years). Results: The model’s accuracy for predicting pCR—based on changes in circulating oncRNA species between T3 and T0—was 85% for the training data and 79% for the held-out test data (positive predictive value of 75% and negative predictive value of 83%) with combined accuracy of 83%; precision 86% and recall 83%; Pearson R=0.5 for RCB. A leave-one-out strategy showed similar performance (area under ROC of 0.77 versus 0.81 in train-test split). Finally, among the patients who failed to achieve pCR, we observed a significantly higher risk of distant recurrence in those with the highest scores (DRFS: hazard-ratio = 8.4, ANOVA P<0.05). Conclusion: In this study, we have shown that the changes in tumor-released oncRNA content of the blood are a significant predictor of clinical outcomes. Our results demonstrate that oncRNA fingerprints are blood-accessible, and allow us to build predictive models of tumor response. We are currently expanding this study to additional cohorts, and we expect to report the results for a longitudinal analysis that includes ~200 patients from I-SPY2. Citation Format: Hani Goodarzi, Albertas Navickas, Jefferey Wang, Kristle Garcia, Mark J Magbanua, Lisa Fish, Lamorna Brown Swigart, Gillian Hirst, Denise Wolf, Christina Yau, Jo Chien, Carol Simmons, Amy Delson, Laura Esserman, Laura van 't Veer. Tumor-released circulating orphan non-coding RNAs reflect treatment response and survival in breast cancer [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 PD9-04.
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Soliman, Hatem, Denise Wolf, Jo Chien, Christina Yau, Michael Campbell, Mark Magbanua, Ruixiao Lu, et al. "Abstract PD10-07: Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD10–07—PD10–07. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd10-07.
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Abstract Background: The CK12 expression signature consists of genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13 and was previously shown to associate with the presence of T and B cell rich tertiary lymphoid structures in melanoma and other cancers, and with better patient survival independent of tumor staging and treatment. I-SPY 2 is a biomarker-rich, phase II neoadjuvant platform trial for high risk early stage breast cancer. Here we leverage the I-SPY 2 biomarker program to test the hypothesis that this signature associates with sensitivity to neoadjuvant immunotherapies and potentially other classes cancer therapeutics in breast cancer. Methods: Data from 1130 patients across 12 arms of I-SPY2 (control (ctr): 210; veliparib/carboplatin (VC): 71; neratinib (N): 114; MK2206: 93; ganitumab: 106; ganetespib: 93; AMG386: 134; TDM1/pertuzumab(P): 52; H/P: 44; pembrolizumab (pembro): 69; durvalumab/olaparib (durva/olap): 71; pembro/SD101: 72) were available for analysis. Pre-treatment FF (n=987) or FFPE (n=143) biopsies were assayed using Agilent gene expression arrays. Signature scores were calculated as the average expression level across the 12 genes, after z-score normalization. We used logistic modeling to assess association with pCR in each arm in a model adjusting for HR and HER2 (likelihood ratio test, p<0.05). This analysis was also performed within HR/HER2 receptor subsets, numbers permitting. We also assessed differences in levels across HR/HER2 subsets using ANOVA and Tukey post-hoc testing. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: CK12 levels associate with HR/HER2 status (ANOVA p=1.07E-14), with higher levels in TN and HR-HER2+ subsets and lower levels in HR+ groups. Overall, patients with higher levels of CK12 were significantly more likely to achieve pCR in all 3 IO arms: pembro (OR=3.4/1SD), pembro/SD101 (OR=4/1SD), and durva/olaparib (OR=2.5/1SD) (LR p<0.05), in a model adjusting for HR status. The CK12 performed favorably in predicting response to pembro/SD101 compared to several other genomic signatures measuring intratumoral immune response. Higher CK12 also associates with response to the ANG1/2 inhibitor AMG386, an agent known to have immune modulatory activity. Higher CK12 was moderately associated with pCR in the control (OR=2.0/1SD), neratinib (OR=1.7/1SD), veliparib/carboplatin (OR=2.0/1SD), ganitumab (OR= 1.7/1SD) and TDM1/P arms (OR=2.1/1SD). Within the HR+HER2- subset, CK12 associated with pCR in all three IO arms, and in the control, AMG386, ganitumab, and ganetespib arms. Within the smaller TN subset, it associated with response in pembro and pembro/SD101 arms but not in durva/olaparib, and in the neratinib and AMG386 arms. Chemokine12 mostly did not associate with pCR in HER2+ subsets, except for HR+HER2+ patients treated with neratinib, and HR-HER2+ patients in the original control arm (trastuzumab). Conclusion: The CK12 signature is highly predictive of complete pathologic response to immuno-oncology agents and other therapeutics supporting the role of the crosstalk within the tumor immune microenvironment in predicting response across subtypes. This gene expression signature can be readily obtained from microarrays and warrants further investigation in future arms of ISPY2 as a predictive biomarker. Citation Format: Hatem Soliman, Denise Wolf, Jo Chien, Christina Yau, Michael Campbell, Mark Magbanua, Ruixiao Lu, Nicholas O'Grady, Lamorna Brown-Swigart, Gillian Hirst, Beverly Parker, Laura Sit, Smita Asare, Doug Yee, Angie DeMichele, Rita Nanda, Lajos Pusztai, Don Berry, Laura Esserman, Laura Van't Veer. Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies [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 PD10-07.
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Magbanua, Mark Jesus M., Hope Rugo, Lamorna A. Brown Swigart, Ziad Ahmed, Gillian L. Hirst, Denise M. Wolf, Ruixiao Lu, et al. "Abstract P5-05-05: Monitoring for response and recurrence in neoadjuvant-treated hormone receptor-positive HER2-negative breast cancer by personalized circulating tumor DNA testing." Cancer Research 83, no. 5_Supplement (March 1, 2023): P5–05–05—P5–05–05. http://dx.doi.org/10.1158/1538-7445.sabcs22-p5-05-05.
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Abstract Background: The detection of circulating tumor DNA (ctDNA) may serve as an early predictor of response and recurrence. In this study, we used a tumor-informed ctDNA test to monitor clinical outcomes in patients with high-risk hormone receptor-positive HER2-negative (HR+HER2-) tumors who received neoadjuvant chemotherapy (NAC) on the I-SPY 2 trial (NCT01042379). Methods: We collected blood samples at pretreatment, during (at 3 and 12 weeks after initiation of paclitaxel-based treatment with or without an investigational drug), after NAC prior to surgery, 4 weeks after surgery, and annually until clinical diagnosis of recurrence. Cell-free DNA was isolated from plasma (N=329 samples) and ctDNA was detected using a personalized, tumor-informed multiplex polymerase chain reaction next generation sequencing-based test (SignateraTM). All patients were at high risk for recurrence by MammaPrint. The response endpoints were pathologic complete response (pCR) and residual cancer burden (RCB), and the survival endpoint was event-free survival (EFS). Results: This analysis included 66 patients with HR+HER2- breast cancer who had blood samples collected before, during, after NAC and had at least one blood sample after surgery with sufficient plasma for analysis. 57.1% (32/56) had grade III disease; 72.4% (42/58) were node-positive; 36.2% (21/58) had T3/T4 disease; and 33.3% (22/66) were MammaPrint High 2. The percent ctDNA positivity rates at pretreatment, after NAC prior to surgery, and 4 weeks after surgery were 79.7% (47/59), 6.5% (4/62), and 2% (1/50), respectively. Significantly higher ctDNA positivity rates at pretreatment were observed in patients with larger tumors (95% in T3/T4 vs. 69% in T1/T2, Fisher’s exact p=0.0387), higher grade tumors (94% in Grade III vs. 67% in Grade I/II, p=0.0147) and by MammaPrint score (100% in High 2 vs. 71% in High 1, p=0.0052). In this high-risk HR+/HER2- cohort, 10/66 (15.2%) achieved pCR/RCB 0, who were all ctDNA-negative at surgery. 56/66 (84.8%) had no-PCR, with RCB I (limited residual cancer), II (moderate) and III (extensive) in 7 (10.6%), 31 (47.0%) and 18 (27.3%), respectively. ctDNA-positivity after paclitaxel-based treatment was significantly associated with RCB II/III status (Fisher’s exact p=0.01). All patients in this cohort with persistent ctDNA subsequently had RCB II or III at surgery. 47 patients had paired samples collected after NAC prior to surgery and at 4 weeks after surgery. Of the 47, 91.5% (43/47) were ctDNA-negative at both time points and 8.5% (4/47) were discordant; 1 was ctDNA-negative and later tested ctDNA-positive, while 3 were ctDNA-positive and later tested ctDNA-negative. 61/66 patients had EFS data with a median of 1.6 years of follow up (range: 0.6 to 5.6). 5 tested ctDNA-positive in at least one time point after surgery. Of these, 2 experienced a recurrence (one local relapse and one distant metastasis) and both tested positive at the time of recurrence. For the patient who developed a distant recurrence it was the only blood sample available at a follow-up time point; for the patient who developed a local recurrence, blood from two earlier follow-up time points had tested negative. To date, no recurrences have been observed in those whose test(s) after surgery were negative for ctDNA. Conclusions: The persistence of ctDNA during neoadjuvant therapy is associated with the extent of residual disease in a cohort of patients with HR+HER2- breast cancer in the I-SPY 2 trial and thus may be useful in identifying patients who are not having an optimal response to therapy. I-SPY 2.2 will test whether ctDNA has utility in redirecting therapy to improve surgical outcome and subsequent prognosis. Citation Format: Mark Jesus M. Magbanua, Hope Rugo, Lamorna A. Brown Swigart, Ziad Ahmed, Gillian L. Hirst, Denise M. Wolf, Ruixiao Lu, Ekaterina Kalashnikova, Derrick Renner, Angel Rodriguez, Minetta C. Liu, Christina Yau, Laura J. Esserman, Laura Van ’t Veer, Angela DeMichele. Monitoring for response and recurrence in neoadjuvant-treated hormone receptor-positive HER2-negative breast cancer by personalized circulating tumor DNA testing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-05.
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Wolf, Denise M., Christina Yau, Julia Wulfkuhle, Rosa I. Gallagher, Lamorna A. Brown Swigart, Gillian L. Hirst, Jean-Philippe Coppe, et al. "Abstract PD5-04: PD5-04 Characterizing the HER2-/Immune-/DNA repair (DRD-) response predictive breast cancer subtype: the hunt for new protein targets in a high-needs population with low response to all I-SPY2 agents." Cancer Research 83, no. 5_Supplement (March 1, 2023): PD5–04—PD5–04. http://dx.doi.org/10.1158/1538-7445.sabcs22-pd5-04.
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Abstract Background: In previous work we leveraged the I-SPY2 trial to create treatment response predictive subtypes (RPS) incorporating tumor biology beyond clinical HR/HER2, to better predict drug responses in an expanded treatment landscape that includes platinum agents, dual HER2-targeting regimens and immunotherapy [1]. We showed that best performing schemas incorporate Immune, DRD and HER2/Luminal phenotypes, and that treatment allocation based on these would increase the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. The RPS schema has been selected for prospective evaluation in I-SPY2. Using the RPS, one would prioritize platinum-based therapy for HER2-/Immune-/DRD+, immunotherapy for HER2-/Immune+, and dual-anti-HER2 for HER2+ that are not luminal. HER2+/Luminal patients have low response rates to dual-anti-HER2 therapy but may respond better to anti-AKT. However, there is still a considerable ‘biomarker-negative’ group of resistant cancers (HER2-/Immune-/DRD-) with very low pCR rates to all tested agents, that require a new therapeutic approach. Here we characterize the protein signaling architecture of these tumors to identify new target candidates. Methods: 987 I-SPY 2 patients from 10 arms of the trial were considered for this analysis. All have gene expression, pCR and RPS; 944 have distant recurrence free survival (DRFS) data; and 736 have reverse phase protein array (RPPA) data from laser capture microdissected tumor epithelium. These data – known collectively as the I-SPY2-990 mRNA/RPPA Data Resource - were recently made public on NCBI’s Gene Expression Omnibus [GEO: GSE196096]. We focus on HER2-/Immune-/DRD- tumors, applying Wilcoxon and t-tests to identify phosphoproteins that differ between HR+HER2-/Immune-/DRD- and other HR+HER2- tumors; and between TN/Immune-/DRD- and other TNs. The Benjamini-Hochberg (BH) method is used to adjust p-values for multiple hypothesis testing. In addition, the Kaplan-Meier method is used to estimate DRFS. Results: 201/736 I-SPY 2 patients with RPPA data are classified HER2-/Immune-/DRD- (HR+HER2-: n=138; TN: n=63). Of these, 8.5% (17/201) achieved pCR. Non-responding HER2-/Immune-DRD- had worse outcomes than responders (~75% vs. ~95% DRFS at 5 years). 60/139 phospho-proteins differ significantly between HR+HER2-/Immune-/DRD- and other HR+HER2- tumors (n=122). These tumors are relatively ‘cold’, in that 90% (54/60) of the phosphoprotein activities characterizing this group are at lower levels than in the overall HR+HER2- population; including immune (e.g. pPDL1, pJAK/STAT) and proliferation (e.g., Ki67, CyclinB1, pAURK) endpoints. Phosphoproteins showing higher levels in this subset include ERBB2 (BH p=1.7E-06), Cyclin D1 (BH p=1.4E-05), pAR (BH p=1.4E-05), and ER (BH p=3E-04). Within the TN subset, only 3/139 phospho-proteins differed significantly between TN/Immune-/DRD- and other TN tumors (n=189). These were all immune-related (pPDL1, pSTAT1, and HLA DR), with lower expression in the TN/Immune-/DRD- group. Conclusion: HR+HER2- and TN patients who are Immune-Low and DRD-Low have very low pCR rates to all tested therapeutics in I-SPY2 including standard chemotherapy, platinum, and immunotherapy. Senolytics (possibly targeting Cyclin D1), HER2low agents, and AR modulators may overcome resistance in HR+HER2-/Immune-/DRD-, whereas an immune activator beyond checkpoint inhibition is suggested for TN/Immune-/DRD- patients. [1] Wolf et. al., Redefining Breast Cancer Subtypes to Guide Treatment Prioritization and Maximize Response: Predictive Biomarkers across 10 Cancer Therapies. Cancer Cell 2022 Citation Format: Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Rosa I. Gallagher, Lamorna A. Brown Swigart, Gillian L. Hirst, Jean-Philippe Coppe, Mark Jesus M. Magbanua, Rosalyn Sayaman, I-SPY2 Investigators, Laura Sit, Nola M. Hylton, Angela DeMichele, Donald A. Berry, Lajos Pusztai, Douglas Yee, Laura J. Esserman, Emanuel F. Petricoin, Laura Van ’t Veer. PD5-04 Characterizing the HER2-/Immune-/DNA repair (DRD-) response predictive breast cancer subtype: the hunt for new protein targets in a high-needs population with low response to all I-SPY2 agents [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-04.
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Bui, Tam Binh V., Denise M. Wolf, Kaitlin Moore, Isaac S. Harris, Pravin Phadatare, Christina Yau, Lamorna A. Brown Swigart, et al. "Abstract PD5-02: PD5-02 An Organoid Model System to Study Resistance Mechanisms, Predictive Biomarkers, and New Strategies to Overcome Therapeutic Resistance in Early-Stage Triple-Negative Breast Cancer." Cancer Research 83, no. 5_Supplement (March 1, 2023): PD5–02—PD5–02. http://dx.doi.org/10.1158/1538-7445.sabcs22-pd5-02.
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Abstract Background: While new treatments and improved subtyping schemas are anticipated to improve treatment response in triple-negative breast cancer (TNBC) patients, therapeutic resistance remains a significant challenge. Moreover, there is an urgent need for additional research model systems to study resistance and residual disease in breast cancer, including aggressive subtypes of breast cancer. Organoid culture is a promising technology used for growing breast cancer cells with high efficiency; however, the extent to which treatment resistance can be modeled using this system is unknown. This research used patient-derived organoid cultures in the context of computational analyses of large molecular and clinical datasets to study resistance mechanisms, biomarkers, and alternative treatment strategies to overcome drug resistance in early-stage TNBC. Methods: Organoid cultures were derived from breast tumor samples (taken from lumpectomy, mastectomy, or core biopsy samples), digested to the organoid level using collagenase, and grown in three dimensional cultures using a basement membrane extract and a fully-defined organoid medium (Dekkers et al. Nat Protoc 2021). An evaluation of all available I-SPY2 biomarker data (Wolf et al. Cancer Cell 2022) was performed focusing on genes, proteins, and pathways associated with resistance. These were then used to study whether resistance biomarkers identified in patient tumors are also present in organoids propagated from breast cancer post-treatment residual disease. To this end, bulk RNA sequencing data of organoids were normalized and merged with the TCGA dataset (Hoadley et al. Cell 2018) to enable analysis in a larger context, and immunofluorescence staining of organoids was performed. A high-throughput 386 anti-cancer drug compound screen and subsequent synergy testing with the most promising compounds were performed to identify and predict alternative treatment strategies. Additional assays to explore kinome activity in this organoid model are in progress. Results: A TNBC organoid biobank was established (n=31), which was enriched for inflammatory breast cancer (IBC; n=15), an aggressive form of breast cancer. Most organoids were derived from residual disease after neoadjuvant therapy. Bulk RNA sequencing analysis performed on 10 TNBC organoids revealed 3 subsets that were characterized predominantly by either normal-like/luminal androgen receptor or basal-like features or expressed distinct gene expression profiles, with IBC cases present in all 3 subsets. Intriguingly, the IBC organoids were characterized by higher expression of a number of immune-related signatures, despite an absence of clear immune cells in culture. A residual disease IBC/TNBC organoid resistant to chemotherapy was used to perform the 386-drug compound screen. The organoid model showed resistance to veliparib-cisplatin, consistent with the expression of gene/protein biomarkers predictive of drug resistance found in I-SPY2 (low PARPi7 levels and high pFOXO1 and pMEK1/2 expression). In addition, the screen identified multiple classes of inhibitors as promising synergistic/additive candidates for overcoming resistance to cisplatin. Conclusion: In this proof-of-principle study, we demonstrated the utility of matching I-SPY2 resistance biomarkers and signatures to residual disease tumor organoid cultures. We show that tumor organoid cultures modeling drug resistance states are a useful complement to existing research models of breast cancer and can be used for compound testing. We have developed a pipeline to propagate residual tumors from patients enrolled in I-SPY2 into organoid cultures to create a broader platform for preclinical drug testing informed by tumor biology with the ultimate goal of enabling faster, more successful translational studies and increased treatment options for resistant disease. Citation Format: Tam Binh V. Bui, Denise M. Wolf, Kaitlin Moore, Isaac S. Harris, Pravin Phadatare, Christina Yau, Lamorna A. Brown Swigart, Laura J. Esserman, Jean-Philippe Coppe, Julia Wulfkuhle, Emanuel F. Petricoin, Michael Campbell, Laura M. Selfors, Deborah A. Dillon, Beth Overmoyer, Filipa Lynce, Laura Van ’t Veer, Jennifer Rosenbluth. PD5-02 An Organoid Model System to Study Resistance Mechanisms, Predictive Biomarkers, and New Strategies to Overcome Therapeutic Resistance in Early-Stage Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-02.
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Nathan, Remya, Marina Feigenson, Joshua Lamora, Claire C. Tseng, Ffolliott Fisher, Jasbir Seehra, and Jenn Lachey. "Rker-050 Rescued Ruxolitinib (Rux)-Associated Reductions in Red Blood Cell Volume." Blood 138, Supplement 1 (November 5, 2021): 934. http://dx.doi.org/10.1182/blood-2021-152729.
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Abstract Myelofibrosis (MF) is characterized by the dysfunctional Janus kinase/signal transducers and activators of transcription signaling (JAK/STAT) pathways leading to progressive proliferation of granulocytic and megakaryocytic cells in the bone marrow at the expense of other hematopoietic lineages. Clinical signs of MF include cytopenias, splenomegaly and transformation to acute leukemia. Jakafi® (ruxolitinib, or rux), a JAK2 inhibitor, is a therapeutic for MF and functions to impair the activated mutations that cause the expansion of megakaryocytic precursors. However, JAK2 also transduces signals of the erythropoietin receptor, thrombopoietin receptor, and the granulocyte colony-stimulating factor receptor. Therefore, individuals being treated with rux are susceptible to treatment-associated effects on normal hematopoiesis resulting in thrombocytopenia, neutropenia and anemia. The TGF-β superfamily plays a vital role in the regulation of hematopoiesis; specifically, SMAD 2/3 activation results in cell quiescence and inhibits precursors from progressing through later stages of hematopoiesis. KER-050, a modified ActRIIA extracellular domain fused to the Fc of human IgG1, is designed to inhibit ligands including activin A, activin B, GDF8 and GDF11, that activate SMAD 2/3. In a preclinical study, administration of KER-050 in mice led to upregulation of erythropoiesis by mobilizing early- and late-stage erythroid precursors and facilitating their terminal maturation into red blood cells (RBCs). In a Phase 1 clinical study, administration of KER-050 to healthy volunteers led to sustained increases in RBCs and hemoglobin (HGB) along with increases in platelets. Given the observed effect of KER-050 on increasing RBCs, we evaluated whether treatment with a research form of KER-050 (RKER-050) could reverse rux-associated reductions in RBCs. Additionally, preclinical studies have shown that KER-050 potentially functioned as a muscle anabolic by increasing lean mass in rodents. We first established anemia in C57Bl/6 mice by dosing with rux before administering RKER-050. Anemia was confirmed on study day 37; mice receiving 120 mg/kg rux via oral gavage (PO) BID had significantly lower RBC (-7.4%, p=0.0001), HGB (-4.0%, p=0.002) and hematocrit (HCT; -5.7%, p=0.0006) levels compared to the control group. Treatment with RKER-050 was initiated on study day 41 and mice received 7.5 mg/kg RKER-050 or vehicle intraperitoneally (IP) twice weekly for approximately 14 days. Mice receiving rux alone continued their decline in RBCs and, on day 55, continued to have significant reductions in RBC (-6.7%, p<0.0001), HGB (-6.0, p<0.00001) and HCT (-5.6%, p=0.0002) levels compared to the control group. These findings are consistent with the progressive effect of JAK2 inhibition on suppressing erythrocyte development and production. In contrast, treatment with RKER-050 abrogated the observed rux-associated reductions in RBCs, HGB, and HCT in the rux-RKER-050 cohort with significant observed increases (+15.8%, +12.2%, +11.2%, respectively, all p<0.0001) when compared to the rux-vehicle group. The rux-RKER-050 cohort also had significantly increased body mass, measured between study day 41 and study day 55 versus the rux-vehicle group (+9.9%, p= 0.006, and +0.69%, respectively). These data demonstrate that rux treatment reduced RBCs, HGB, and HCT in mice, and that coadministration of RKER-050 reversed rux-associated reductions in RBC parameters. Therefore, treatment with KER-050 has the potential to mitigate the dose limiting effects of rux and enhance duration of therapy in MF patients. RKER-050 also increased body weight in mice receiving rux through its anabolic effect on muscle, a potential benefit in elderly MF patients. These data support the potential benefit of KER-050 as a monotherapy and in combination with rux in patients with MF and anemia. KER-050 will be assessed in a Phase 2 clinical trial (KER050-MF-301), which we expect to commence in 2021. Disclosures Nathan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Feigenson: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lamora: Keros Therapeutics: Current Employment. Tseng: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fisher: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.
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Feigenson, Marina, Remya Nathan, Joshua Lamora, Ffolliott Fisher, Claire C. Tseng, Jasbir Seehra, and Jenn Lachey. "Ker-050, an Inhibitor of TGF- β Superfamily Signaling, Promoted Thrombopoiesis and Reversed Immune Thrombocytopenia in a Mouse Model of Disease." Blood 138, Supplement 1 (November 5, 2021): 2068. http://dx.doi.org/10.1182/blood-2021-152814.
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Abstract KER-050 is a modified ActRIIA ligand trap that is designed to inhibit the activity of the TGF-β ligands, including activin A, activin B, GDF8 and GDF11, that act through the SMAD2/3 signaling cascade. Notably, in a Phase 1 clinical study we observed that, in addition to increases in red blood cells and hemoglobin, treatment with KER-050 elicited a robust and sustained increase in platelets (PLTs) in healthy volunteers. While ActRII ligand traps have been shown to increase erythropoiesis in preclinical and clinical studies, their role in thrombopoiesis has not yet been well-elucidated. A variety of conditions exist where hematopoiesis is impaired and cytopenia persists, including comorbidities associated with aging, diseases causing ineffective hematopoiesis such as myelodysplastic syndrome (MDS) and myelofibrosis (MF), and acute bleeding. Thrombocytopenia can arise from primary or secondary causes due to multiple etiologies and treatments are limited, aiming at treating the root cause of disease or replacing PLTs through transfusion. Therefore, there is an unmet medical need for more targeted treatments to correct thrombocytopenia. Here, in a series of preclinical studies, we investigated the mechanism of action of KER-050 on thrombopoiesis and evaluated its ability to accelerate recovery from acute platelet depletion. First, we examined how RKER-050 (a research form of KER-050) affected thrombopoiesis under homeostatic conditions. We observed that a single intraperitoneal dose of RKER-050 (10 mg/kg) to 11-week-old mice resulted in a 2-fold increase in PLTs compared to vehicle-treated mice 12 hours after treatment. The timing of the effect is suggestive of a direct effect of RKER-050 on terminal platelet maturation. Additionally, there was a 35% increase in the number of bone marrow (BM) megakaryocyte (Mk) progenitors (Lin -; sca1 -; cKit -; CD41 + cells), demonstrating that RKER-050 affected earlier stages of the PLT formation process. We also evaluated the effect of RKER-050 on the polyploidization of Mks, a hallmark of Mk differentiation. At 24 hours after treatment with RKER-050, there was an increase in BM CD41 + cells with ploidy greater than 16N compared to vehicle-treated mice, demonstrating that RKER-050 treatment resulted in a greater number of Mk that are potentially primed for platelet production. Taken together, these data are consistent with RKER-050 affecting multiple stages of thrombopoiesis in a preclinical model. We next tested whether RKER-050 affects PLTs in a mouse model of immune thrombocytopenia (IT) where antibodies directed against mouse GPIbα result in acutely reduced PLT numbers. In this model, mice receiving anti-GPIbα had a 25% reduction in PLT number at 4 days post-dose compared to IgG control-treated mice. At this point, the anti-GPIba cohort was divided into receiving either a single dose of vehicle or RKER-050. On day 7 following anti-GPIbα treatment, PLT counts in vehicle-treated mice were 62% lower compared to IgG-control-treated mice. In contrast, the GPIbα-mediated effect on PLT count was stabilized in the anti-GPIbα + RKER-050 group, which had 55% more platelets compared to the anti-GPIba + vehicle group. These data suggest that RKER-050 promoted thrombopoiesis in mice even under conditions when the system is acutely challenged and potentially could promote faster recovery from thrombocytopenia. Additionally, we observed a 25% increase in the number of CD41 + cells in the BM of the RKER-050-treated group compared to the vehicle-treated group at day 10 after PLT depletion, suggesting that under acute thrombocytopenia, RKER-050 treatment promoted differentiation of Mks as a mechanism of the accelerated recovery in platelet-depleted mice. In summary, our preclinical data demonstrate a potentially novel effect of RKER-050 on thrombopoiesis. RKER-050 treatment resulted in a rapid increase in PLTs, consistent with an effect on terminal maturation. Treatment also increased the number of Mk progenitors and increased the number of polyploid Mks, demonstrating an effect on early stages of thrombopoiesis. These findings support that RKER-050-targeted ligands regulate multiple stages of the thrombopoiesis pathway in mice. Additionally, our data demonstrate that KER-050 has the potential to accelerate the rate of PLT recovery due to acute depletion, and could represent a potential novel treatment option for thrombocytopenia in patients with MDS, MF and IT. Disclosures Feigenson: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nathan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lamora: Keros Therapeutics: Current Employment. Fisher: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tseng: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.
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Venner, Gerard. "De bemoeienis van gouverneur Keverberg met de plannen voor een monument voor Lamoraal van Egmont te Zottegem (1818-1819)." Handelingen der Maatschappij voor Geschiedenis en Oudheidkunde te Gent 71 (July 5, 2019). http://dx.doi.org/10.21825/hmgog.v71i0.11474.
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"Cicely Lamorna Hingston, MBE (Military), formerly Honorary Consultant Psychiatrist, the Royal Sussex County Hospital." Psychiatric Bulletin 13, no. 5 (May 1989): 264. http://dx.doi.org/10.1192/pb.13.5.264.
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San Vicente, Carlos, Lidia Delgado, Esteban Hernandez, and Guillermo Guerao. "A record of the mysid Hemimysis lamornae mediterranea (Crustacea: Mysida) from the western Mediterranean, with a complete morphological description." Marine Biodiversity Records 4 (May 19, 2011). http://dx.doi.org/10.1017/s1755267211000315.
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Bonelli, D., S. Scalercio, and T. Bonacci. "First comprehensive contribution to the knowledge of the lepidopteran fauna of Gioia Tauro Plain, South Italy (Lepidoptera)." Journal of Entomological and Acarological Research 53, no. 2 (August 24, 2021). http://dx.doi.org/10.4081/jear.2021.9632.
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In this paper, we investigated for the first time on the composition of nocturnal Lepidoptera of the Gioia Tauro Plain, Calabria region (South Italy). The main goal was to acquire information on the biodiversity of this insect order in an area little investigated and subject to strong anthropic pressures. The study was carried out for one year in 4 sites characterized by different habitats. Sampling was carried out about twice a month through the use of UV-LED light traps. In total, 791 specimens belonging to 97 species were collected. The species richness of the study area was rather low compared to a more natural habitat sampled near to the study area in previous years. However, we found species very interesting from a faunistic point of view. In detail, Morophaga morella (Duponchel, 1838) is a new record for the continental Italy. 15 species are new for the fauna of the Calabria region: Ornativalva tamaricella (Zeller, 1850), Cnephasia (Cnephasia) genitalana Pierce & Metcalfe, 1915, Euzophera lunulella (O. Costa, 1836), Hellula undalis (Fabricius, 1794), Raphimetopus ablutella (Zeller, 1839) Achyra nudalis (Hübner, 1796), Dioryctria mendacella (Staudinger, 1859), Ematheudes punctella (Treitschke, 1833), Endotricha flammealis (Denis & Schiffermüller, 1775), Oxybia transversella (Duponchel, 1836), Lamoria anella (Denis & Schiffermüller, 1775), Anania crocealis (Hübner, 1796), Evergestis isatidalis (Duponchel, 1833), Udea ferrugalis (Hübner, 1796), and Uresiphita gilvata (Fabricius, 1794).