tbuckley/cabot-search huggingface dataset:
Germinal mutations landscape, which is responsible for cancer predisposition in multinational Republic of Bashkortostan.
Authors: Alexnder Valerievich Sultanbaev, Oleg Lipatov, Nadezda Sultanbaeva, Adel Izmailov, Ainur Nasretdinov, Shamil Musin, Konstantin Menshikov, Vasiliy Pushkarev, Alexey Pushkarev
Journal: Journal of Clinical Oncology (2021)

e22504 Background: In oncology hereditary forms of malignant neoplasms occupy a special position due to the frequent cases at a young age and poor prognostic factors. The aim of this work is to determine in cancer patients germinal mutations which are responsible for cancer predisposition. Methods: The study included patients with burdened family history or those with a manifestation of malignant neoplasm at a young age residing on the territory of multinational Republic of Bashkortostan. The patients were diagnosed with one of these diseases: breast cancer, prostate cancer, pancreatic cancer, gastric cancer, colon cancer. The study is based on analyses of the molecular genetic blood testing n cancer patients using real-time polymerase chain reaction (PCR) for detection of 8 widely spread mutations among Russian population: in BRCA 1 gene were detected such mutations as 185delAG, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT, 300T&gt;G, 2080delA; in gene BRCA 2 - 6174delT. Blood samples of the rest amount of patients which proved no mutations by PCR method was tested by the “next-generation” sequencing method (NGS). Results: The results of the study showed territorial features of presence of germinal mutations of Russian multinational region. The results of the study aimed to reveal the spectrum and frequency of gene mutations characteristic for the particular region: BRCA 1 - c.5266dupC, c.3143delG, c.5161C&gt;T, c.5382 insC, c.3819delGTAAA, c.300T&gt;G, c.5136G&gt;A, 185delAG, 4153delA, 2080delA; BRCA 2 - c.6621_6622del, с.39-1_39delGA, c.961_962insAA; CHEK2 - c.470T&gt;C, c.444+1G&gt;A; PALB2 - c.1592delT; RAD50 - c.2157delA; MLH1 - c.1637A&gt;G; MSH6 - c.2554_2556del; STK11 - c.368A&gt;G; MSH2 - c.815C&gt;T. According to the mutation detection the patient consulted a geneticist for making a genealogic tree for future molecular genetics exam. Hereinafter the control group included relatives of patients who remain potential carriers of pathogenic mutations of the proband using Sanger sequencing method. When penetrate mutations are identified in healthy population, a set of measures is taken to prevent and early diagnose malignant tumors. Conclusions: The results of the study showed features of presence of each detected mutation which is characteristic for south-eastern part of the Russian multinational region. This study plays an important role in the process of optimization of screening of germinal mutation carriers among healthy population and as a result it helps to conduct prophylactic measures to early diagnose malignant neoplasms.
Abstract AP30: BRCA1 INTRON RETENTION GENERATES TRUNCATED PROTEINS THAT AVOID BRCT MUTATION MISFOLDING AND PROMOTE PARP INHIBITOR RESISTANCE
Authors: Yifan Wang, Andrea J. Bernhardy, Joseph Nacson, John J. Krais, Yin-Fei Tan, Michael Slifker, Suraj Peri, Neil Johnson
Journal: Clinical Cancer Research (2019)

Abstract INTRODUCTION: BRCA1 BRCT domain mutations result in protein structural defects, and consequently misfolded proteins are subject to proteasomal degradation. Loss of BRCA1 protein activity results in sensitivity to PARP inhibitor (PARPi) therapy. EXPERIMENTAL PROCEDURES: In this study, we examined PARPi resistance using the SNU-251 human endometrial ovarian cancer cell line. SNU-251 cells harbor a nonsense mutation c.5444G&amp;gt;A (E1815X) in BRCA1 exon 23; that disrupts BRCT domain folding. Cells were cultured in the presence of increasing concentrations of the PARPi rucaparib until resistant cells emerged. RT-PCR, Western blotting and mass spectrometry were used to measure BRCA1 mRNA and protein levels. RESULTS: PARPi resistant cell lines all demonstrated elevated BRCA1 protein levels that could be detected with N- but not C-terminal specific antibodies. Notably, the gel migration and molecular weight of BRCA1 was different from the mutation-induced stop codon expected size. Mass spectrometric analyses identified BRCA1 peptides encoded by exons 2-15; however, despite harboring a mutation in exon 23, no peptides encoded by exons 16-24 were present in SNU-251 cells. RT-PCR analyses showed that SNU-251 cells translated protein from exon 15 and into intron 15, terminating at an intron 15 generated stop codon. We overexpressed BRCA1 cDNA that harbored stop codons located in either the BRCT domain or in intron 15. BRCT mutation containing constructs had undetectable protein levels due to protein misfolding, and cells were highly PARPi sensitive. In contrast, cells expressing the BRCA1 intron 15 encoded stop codon had robust protein expression, demonstrated RAD51 foci and chemotherapy resistance in vitro and in vivo. CONCLUSIONS: In summary, we discovered that BRCA1 intron translation generates new stop codons resulting in loss of the entire BRCT domain. BRCTless proteins avoid mutant protein folding problems and promote residual DNA repair and chemotherapy resistance. Citation Format: Yifan Wang, Andrea J. Bernhardy, Joseph Nacson, John J. Krais, Yin-Fei Tan, Michael Slifker, Suraj Peri and Neil Johnson. BRCA1 INTRON RETENTION GENERATES TRUNCATED PROTEINS THAT AVOID BRCT MUTATION MISFOLDING AND PROMOTE PARP INHIBITOR RESISTANCE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP30.
Finding the Optimal Partner to Pair with Bispecific Antibody Therapy for Multiple Myeloma
Authors: Cedric Louvet, Omar Nadeem, Eric L. Smith
Journal: Blood Cancer Discovery (2021)

Abstract Summary: BCMA/CD3ϵ-targeted bispecific antibody (BsAb) therapy represents a promising T cell–redirecting immunotherapy to treat relapsed and refractory multiple myeloma. However, rational combination strategies will most likely be key to achieve a long-lasting immune response. In this issue, Meermeier and colleagues investigate BsAb therapy in a syngeneic multiple myeloma model and elucidate that partnering with cyclophosphamide is associated with tempered activation, mitigated exhaustion of T cells, and is superior to pomalidomide or bortezomib in enhancing durable anti–multiple myeloma efficacy. See related article by Meermeier et al., p. 354.
Corrigendum to “Macrophage membrane-coated nanocarriers Co-Modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer's disease mice” [Bioactive materials 6 (2021) 529–542]
Authors: Yang Han, Chunhong Gao, Hao Wang, Jiejie Sun, Meng Liang, Ye Feng, Qianqian Liu, Shiyao Fu, Lin Cui, Chunsheng Gao, Yi Li, Yang Yang, Baoshan Sun
Journal: Bioactive Materials (2021)
Geonomics: Forward-Time, Spatially Explicit, and Arbitrarily Complex Landscape Genomic Simulations
Authors: Drew E Terasaki Hart, Anusha P Bishop, Ian J Wang
Journal: Molecular Biology and Evolution (2021)

Understanding the drivers of spatial patterns of genomic diversity has emerged as a major goal of evolutionary genetics. The flexibility of forward-time simulation makes it especially valuable for these efforts, allowing for the simulation of arbitrarily complex scenarios in a way that mimics how real populations evolve. Here, we present Geonomics, a Python package for performing complex, spatially explicit, landscape genomic simulations with full spatial pedigrees that dramatically reduces user workload yet remains customizable and extensible because it is embedded within a popular, general-purpose language. We show that Geonomics results are consistent with expectations for a variety of validation tests based on classic models in population genetics and then demonstrate its utility and flexibility with a trio of more complex simulation scenarios that feature polygenic selection, selection on multiple traits, simulation on complex landscapes, and nonstationary environmental change. We then discuss runtime, which is primarily sensitive to landscape raster size, memory usage, which is primarily sensitive to maximum population size and recombination rate, and other caveats related to the model's methods for approximating recombination and movement. Taken together, our tests and demonstrations show that Geonomics provides an efficient and robust platform for population genomic simulations that capture complex spatial and evolutionary dynamics.
Single-lesion PSMA protein expression and response to Lu-177 PSMA therapy in patients with castration-resistant prostate cancer.
Authors: Judith Stangl-Kremser, Sazan Rasul, Jeffrey J. Tosoian, Simpa Salami, Alexander Zaslavsky, Aaron M. Udager, Peter Mazal, Renate Kain, Eva Comperat, Carmen Pozo Salido, Christina Steinbach, Melanie Hassler-Di Fratta, Gero Kramer, Shahrokh Shariat, Ganesh S. Palapattu
Journal: Journal of Clinical Oncology (2021)

5065 Background: The recent introduction of Lu-177 PSMA for the treatment of castration-resistant prostate cancer (CRPC) has been met with much excitement. Initial reports of clinical response are promising, despite known inter- and intra-patient molecular heterogeneity. In this study, we examined the utility of PSMA protein expression in metastatic tumor tissues as a predictor of lesion-specific response to Lu-177 PSMA therapy in men with CRPC. Methods: Between 2015-2020, 19 patients with metastases at multiple sites underwent metastatic lesion biopsy, Ga-68 PSMA PET imaging, and subsequent treatment with three cycles of Lu-177 PSMA. A monoclonal anti-PSMA antibody (EPITOMICS (USA), 1:50) was used to semi-quantitatively assess PSMA protein expression in the biopsy specimen. The histoscore (range 0-300) was derived from intensity and extent of the immunohistochemistry staining and was determined by experienced genitourinary pathologists. Imaging evaluation was performed according to the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria. We assessed the association of the PSMA protein expression in metastatic tumor tissues and the lesion-specific response to Lu-177 PSMA therapy. Results: In 12 patients with biopsy specimens available for staining, PSMA expression correlated with enhancement (SUV max ) of the biopsy site on Ga-68 PSMA PET imaging (r s = 0.63). Of the nine patients with repeat imaging after Lu-177 PSMA therapy, five (55.6%) had a lesion-specific response at the site of biopsy. PSMA expression on immunohistochemistry was unable to accurately predict lesion-specific response in univariable analysis (p = 0.81, 95% CI 94.6-76.6). Among the five men with a lesion-specific response, three (60%) experienced overall progression based on PERCIST. There was no association between lesion-specific response and overall progression (p = 0.64). Conclusions: In patients with multiple metastases, PSMA protein expression from a single site biopsy was not predictive of site-specific Lu-177 PSMA response based on PERCIST. Additional studies are necessary to further interrogate the clinical consequence of PSMA expression heterogeneity in metastatic sites as well as the mechanisms underpinning resistance to Lu-177 PSMA in patients with CRPC.
Is age-related worsening in ovarian cancer prognosis linked to changes in body composition and pharmacokinetics?
Authors: Martine Extermann, Christine Marie Walko, Asmita Mishra, Kerry Thomas, Biwei Cao, Hye Sook Chon, Mihaela C. Cristea, Mian M. Shahzad, Jing-Yi Chern, Mitchell S Hoffman, Jongphil Kim, Douglas C. Marchion, Samer Sansil, Marina Sehovic
Journal: Journal of Clinical Oncology (2021)

e17553 Background: The prognosis of ovarian cancer worsens markedly with age. Yet few data are available to explain this phenomenon. Two hypotheses can be made. Changes in pharmacokinetics and treatment tolerance limit the dosing of chemotherapy. And/or changes in tumor and host-tumor biology limit treatment efficacy. Methods: We conducted a prospective cohort study of women with stage III/IV high-grade serous ovarian cancers treated with neoadjuvant intravenous carboplatin(C) AUC 5 every 3 weeks and paclitaxel(P) dosed either weekly at 80 mg/m2 or every 3 weeks at 175 mg/m2. Body composition was assessed using baseline CT scans at the L3 level. Total muscle mass, total fat mass, skeletal muscle index (SMI) and fat index were computed. Plasma concentrations were collected at pre-established time points for both C1D1 of C and P and concentration-time data was analyzed by non-compartmental methods. Area under the curve (AUC)0-INF, volume of distribution(Vd), clearance (Cl), half-life, and mean residence time were calculated. Free C concentrations were determined in plasma ultrafiltrate and assayed, along with P plasma concentrations, by liquid chromatography-tandem mass spectrometry. Toxicity was assessed as first cycle nadir ANC and G4 hematologic(H) or grade 3-4 non-hematologic(NH) toxicity by CTCAE 4.0 criteria over a 3 cycles follow-up. The correlation between continuous measures was assessed by Spearman correlation coefficient, and the association with toxicity was evaluated by Wilcoxon rank sum test. Results: Seventeen patients, ages 38 to 86 (median 61) were eligible. All patients but one received 3 cycles of chemotherapy and median dose intensity was 100% (range 33.3-100%). Mean 1 st cycle nadir ANC was 1.29 (range 0.06-9.0). 10/17 (59%) patients experienced G4 H and/or G3-4 NH toxicity. SMI was associated with C AUC (r -0.50, p &lt; 0.05), and both total muscle (r = 0.61) and total fat (r = 0.53) were associated with C Vd. We did not find a correlation of P pharmacokinetics with body composition. A lower SMI was associated with 1 st cycle G4H toxicity (p = 0.02), while C AUC had a borderline trend only (p = 0.15). Age was associated with a lower Vd (r -0.63, p = 0.009) and Cl (r -0.67, p = 0.004) of C. There was no significant age trend in the body composition parameters. Conclusions: Neoadjuvant treatment delivery was high in an academic setting. Toxicity appeared driven by low skeletal muscle index, in part via affecting carboplatin pharmacokinetics, and showed no significant age trend. The explanation for age-related changes in prognosis is more likely to lay with changes in tumor and host-tumor biology, which are being analyzed.
Cardiolipin remodeling by ALCAT1 links hypoxia to coronary artery disease by promoting mitochondrial dysfunction
Authors: Dandan Jia, Jun Zhang, Jia Nie, John-Paul Andersen, Samantha Rendon, Yue Zheng, Xueling Liu, Zhenjun Tian, Yuguang Shi
Journal: Molecular Therapy (2021)

Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining cardiac health. A loss of tetralinoleoyl cardiolipin (TLCL), the predominant cardiolipin species in the healthy mammalian heart, is implicated in the pathogenesis of coronary heart disease (CHD) through poorly defined mechanisms. Here, we identified acyl-coenzyme A:lysocardiolipin acyltransferase-1 (ALCAT1) as the missing link between hypoxia and CHD in an animal model of myocardial infarction (MI). ALCAT1 is an acyltransferase that promotes mitochondrial dysfunction in aging-related diseases by catalyzing pathological remodeling of cardiolipin. In support of a causative role of ALCAT1 in CHD, we showed that ALCAT1 expression was potently upregulated by MI, linking myocardial hypoxia to oxidative stress, TLCL depletion, and mitochondrial dysfunction. Accordingly, ablation of the ALCAT1 gene or pharmacological inhibition of the ALCAT1 enzyme by Dafaglitapin (Dafa), a potent and highly specific ALCAT1 inhibitor, not only restored TLCL levels but also mitochondrial respiration by attenuating signal transduction pathways mediated by hypoxia-inducible factor 1α (HIF-1α). Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa effectively mitigated CHD and its underlying pathogenesis, including dilated cardiomyopathy, left ventricle dysfunction, myocardial inflammation, fibrosis, and apoptosis. Together, the findings have provided the first proof-of-concept studies for targeting ALCAT1 as an effective treatment for CHD.
Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development
Authors: Mengyu Shi, Ziyang Chen, Meiqi Chen, Jingping Liu, Jing Li, Zhe Xing, Xiaogang Zhang, Shuaijun Lv, Xinyao Li, Shaowen Zuo, Shi Feng, Ying Lin, Gang Xiao, Liping Wang, Yumei He
Journal: Cellular and Molecular Immunology (2021)
Epidemiology, Cytogenetic and Molecular Abnormalities and Outcome of Childhood Acute Myeloid Leukemia- an Israeli Retrospective Multicenter Study
Authors: Nira Arad-Cohen, Shlomit Barzilai, Myriam Ben-Arush, Miri Ben Harosh, Bela Bielorai, Ronit Elhasid, Sarah Elitzur, Joseph Kapelushnik, Mira Kharit, Hila Rosenfeld, Amos Toren, Michael Weintraub, Isaac Yaniv, Batia Stark
Journal: Blood (2017)
Unmasking New Promises: Expanding the Antigen Landscape For Antibody–Drug Conjugates
Authors: Honey K. Oberoi, Elena Garralda
Journal: Clinical Cancer Research (2021)

Abstract Cross-reactivity with normal tissues is one of the key concerns for target selection for antibody–drug conjugates. Probody therapeutics are masked antibodies that can selectively be activated by proteases in the tumor. CX-2029, is a first-in-class Probody targeting CD71 with preliminary efficacy and a tolerable safety profile. See related article by Johnson et al., p. 4521
Circulating tumor DNA (ctDNA) analysis by low-coverage whole genome sequencing (lcWGS) of resectable esophageal adenocarcinoma (rEAC) patients.
Authors: Tom van den Ende, Aafke Creemers, Ymke van der Pol, Dries Boers, Mark I. Van Berge Henegouwen, Suzanne S. Gisbertz, E. Debby Geijsen, Maarten C.C.M. Hulshof, Frederike Dijk, Nicole C.T. van Grieken, D. Michiel Pegtel, Sarah Derks, Maarten F. Bijlsma, Florent Moulière, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2021)

4033 Background: ctDNA is becoming an established marker to assess tumor burden, relapse after surgery, and to identify responders in immunotherapy studies. In the phase II PERFECT trial rEAC patients were treated with neoadjuvant chemoradiotherapy (nCRT) and a PD-L1 inhibitor (van den Ende et al. CCR. 2021). Here we evaluated the potential of cell-free DNA (cfDNA) to predict pathological complete response (pCR) and recurrence. Methods: The cohort consisted of 40 patients and 145 plasma samples. EDTA blood samples were drawn at baseline (B, N = 40), in week 5 of nCRT (W5, N = 40), before surgery (OR, N = 33) and 3 months after surgery (FU, N = 32). cfDNA was isolated by affinity columns (CNAkit, QIAgen) quantified by spectrofluorometer (BioAnalyzer, Agilent), sequencing libraries were prepared for lcWGS ( &lt; 5-fold coverage, Tag-seq, Takara) and sequenced on a NovaSeq (S4, PE150). Sequencing data were processed with an in-house pipeline. Copy number aberrations (CNA) and the tumor fraction were estimated using the ichorCNA tool. Insert sizes were recovered and we determined a Tumor Enriched Fragment Fraction (TEFF), calculated by doing the ratio of fragments between 90-150 bp and 250-320 bp (enriched in tumor signal) and fragments between 150-250 bp and 320-360 bp (poor in tumor signal). ichorCNA and TEFF were used to quantify the ctDNA fraction in plasma samples. pCR was defined as ypT0N0. Residual tumor, progression or death before surgery were considered non-pCR. Relapse-free survival (RFS) was defined as the time after surgery until recurrence. Results: The pCR rate was 25% (10/40). The median fold change TEFF between B and W5 was -0.15 (range -0.67 to 0.44) in the pCR group and 0.16 (range -1.40 to 0.76) in the non-pCR group (Mann–Whitney U; p = 0.047). Of the 17 patients in whom ctDNA was detected (TEFF≥0.3 and/or ichorCNA≥0.03) in the FU sample, 13 (76%) showed a recurrence. Of the 15 patients with no ctDNA detected 5 (33%) showed a recurrence. Patients with ctDNA detected at FU had worse RFS, HR = 2.72 (95%CI 0.96-7.71; p = 0.050). Recurrences were detected earlier by FU ctDNA than by imaging due to physical complaints with a median of 312 days (163-798 days). Conclusions: lcWGS appears to be a useful tool to predict pCR and recurrence in resectable esophageal cancer. These lcWGS results will be further combined with fragmentomics analysis and targeted mutational data (Ion Torrent next-generation sequencing) in order to assess response to immunotherapy. Clinical trial information: NCT03087864.
Outcomes with COVID-19 in hematopoietic stem cell transplant and cellular therapy patients.
Authors: Muhammad Umair Mushtaq, Mary Luder, Moazzam Shahzad, Nausheen Ahmed, Haitham Abdelhakim, Rajat Bansal, Ramesh Balusu, Sibgha Gull Chaudhary, Shaun DeJarnette, Clint Divine, Robert Kribs, Leyla Shune, Anurag K Singh, Sunil H. Abhyankar, Siddhartha Ganguly, Joseph McGuirk
Journal: Journal of Clinical Oncology (2021)

7033 Background: The Coronavirus Disease 2019 (COVID-19) has caused over 25 million infections in the US with over 0.4 million deaths. Hematogenic stem cell transplant (HCT) or cellular therapy (CT) recipients have a high risk of mortality with COVID-19 due to profound immune dysregulation. We aimed to assess the outcomes with COVID-19 in HCT/CT recipients. Methods: A single-center prospective study was conducted, including all (n=40) adult HCT/CT patients who were diagnosed with COVID-19 at the University of Kansas from Apr 2020 to Jan 2021. Baseline and disease-related characteristics were ascertained from medical records. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were conducted. Results: The study included 40 COVID-19 patients (72.5% Oct 2020-Jan 2021), including allogeneic HCT (n=25), autologous HCT (n=13) and CAR-T CT (n=2) with median time since HCT/CT of 12.4 (1-201.9), 37.2 (0.4-118.7), and 3.8 (2.8-4.8) months. Seventy percent were Caucasians and 17.5 were Hispanics. Primary hematologic malignancy was myeloid (37.5%), lymphoid (35%) or plasma cell disorder (27.5%). Myeloablative conditioning was performed in 65% of patients. Donors were autologous (37.5%), matched sibling (17.5%), matched unrelated (22.5%) and haploidentical (22.5%). COVID-19 was mild (42.5%), moderate (42.5%) or severe (15%). Clinical findings included pneumonia (62.5%), hypoxia (25%) and ICU admission (17.5%) while therapies included remdesivir (47.5%), convalescent plasma (40%), dexamethasone (25%) and monoclonal antibodies (17.5%). Concurrent cancer treatment, other infections and active GVHD were reported in 25% (all myeloma), 20% and 32.5% of patients. After a median follow-up of 74 days (7-269), the mortality rate was 12.5% in all patients and 20% in allo-HCT patients. Significant predictors of COVID-19 severity included allogeneic HCT, concurrent immune suppression and elevated inflammatory markers. (Table). Conclusions: Hematopoietic stem cell transplant recipients have an increased risk of mortality with COVID-19. Our findings confirm the need for vaccination prioritization, close monitoring, and aggressive treatment in HCT/CT patients.[Table: see text]