tbuckley/cabot-search huggingface dataset:
Abstract B78: Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist
Authors: Noor Shakfa, Elizabeth Lightbody, Afrakoma Afriyie-Asante, Vinicius Kannen, Madhuri Koti
Journal: Clinical Cancer Research (2020)

Abstract High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy, with high rates of chemotherapy resistance and poor outcomes. We previously showed that tumors from chemotherapy-resistant patients show an immunologically cold phenotype, exhibiting lower density of CD8+ T cells and low expression of interferon genes. Subsequently, using the ID8-Trp53−/− murine model of HGSC, we further demonstrated the potential of Stimulator of Interferon Genes (STING) pathway activation in enhancing response of HGSC to carboplatin chemotherapy. Currently, we aim to better characterize the effect of cancer cell genotype on response to treatment in HGSC. The evolution of the tumor immune microenvironment (TIME) as immunologically hot or cold can be to some extent dictated by cancer cell-specific genetic alterations. While loss of the tumor suppressor TP53 is a universal mutation (&amp;gt;96% of cases), previous reports in HGSC have shown that patients with BRCA1 mutations (~25% of cases) have higher CD8+ T-cell infiltration and higher chemosensitivity. In contrast, loss of PTEN (seen in ~20% of cases) is associated with poor outcomes and chemoresistance. We hypothesized that HGSC tumors with loss of PTEN expression can benefit via immunomodulatory treatment approaches that activate the STING pathway following chemotherapy. C57/BL6 mice were implanted with either ID8-Trp53−/−; Brca1−/− cells or ID8-Trp53−/−; Pten−/− cells and subjected to one of three treatment groups: vehicle, carboplatin, or carboplatin + STING agonist. Characterization of the TIME generated from ID8-Trp53−/−; Brca1−/− cells, and those from ID8-Trp53−/−; Pten−/− cells, through local and systemic immune profiling, showed significant immunologic differences between different genotypes. Addition of STING agonist significantly increased chemosensitivity and improved overall response in ID8-Trp53−/−; Pten−/− injected mice compared to those treated with carboplatin alone. This study helps to determine the potential of STING pathway activation in inducing an activated tumor immune state in genotypes of HGSC that result in a “cold” TIME, such as loss of PTEN, to augment responses to chemotherapy and prolong survival. Citation Format: Noor Shakfa, Elizabeth Lightbody, Afrakoma Afriyie-Asante, Vinicius Kannen, Madhuri Koti. Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B78.
Diversity of the reaction mechanisms of SAM-dependent enzymes
Authors: Qiu Sun, Mengyuan Huang, Yuquan Wei
Journal: Acta Pharmaceutica Sinica B (2020)

S-adenosylmethionine (SAM) is ubiquitous in living organisms and is of great significance in metabolism as a cofactor of various enzymes. Methyltransferases (MTases), a major group of SAM-dependent enzymes, catalyze methyl transfer from SAM to C, O, N, and S atoms in small-molecule secondary metabolites and macromolecules, including proteins and nucleic acids. MTases have long been a hot topic in biomedical research because of their crucial role in epigenetic regulation of macromolecules and biosynthesis of natural products with prolific pharmacological moieties. However, another group of SAM-dependent enzymes, sharing similar core domains with MTases, can catalyze nonmethylation reactions and have multiple functions. Herein, we mainly describe the nonmethylation reactions of SAM-dependent enzymes in biosynthesis. First, we compare the structural and mechanistic similarities and distinctions between SAM-dependent MTases and the non-methylating SAM-dependent enzymes. Second, we summarize the reactions catalyzed by these enzymes and explore the mechanisms. Finally, we discuss the structural conservation and catalytical diversity of class I-like non-methylating SAM-dependent enzymes and propose a possibility in enzymes evolution, suggesting future perspectives for enzyme-mediated chemistry and biotechnology, which will help the development of new methods for drug synthesis.
Abstract 316: Cardiac Arrest Rhythm Transitions in Drug Overdose-Related Resuscitation
Authors: Allison C Koller, David D Salcido, James J Menegazzi
Journal: Circulation (2018)

Introduction: The prehospital electrocardiogram (ECG) may inform treatment of out-of-hospital cardiac arrest (OHCA) patients regardless of etiology. While drug overdose (OD)-OHCA is increasingly common, little is known about the characteristics and utility of the intra-resuscitation OD-OHCA ECG signal. In this study, we sought to investigate the evolving ECG rhythm state of OD-OHCA patients to identify potentially informative patterns or phenomena. Methods: Case data, including electronic defibrillator files, for emergency medical services treated OD-OHCA were obtained from the Resuscitation Outcomes Consortium, a multi-site clinical research network in the US and Canada. OD-OHCA case status was previously established by site-level data abstractors reviewing prehospital and in-hospital electronic medical records for evidence of drug involvement. Continuous ECG traces were extracted and chest compression-free ECG segments were parsed with custom MATLAB (vR2017a) software. Each ECG segment was manually rhythm-classified by a research specialist. Rhythm transitions were identified as changes in rhythm between sequential analyzable rhythm segments. Transitions were tabulated and summarized by their rhythms and timing. Results: Complete prehospital ECG data were available for 130 patients, comprising 1,112 ECG segments of which 771 (69.3%) were analyzable. The mean (SD) age was 33.6 (11.3) years and 68.3% were male. The most commonly observed rhythm at the segment level was low amplitude (“fine”) ventricular fibrillation (VF), accounting for 44.1% of all segments, although at the case level asystole was the most common rhythm, present in 47.7% of all cases. We recorded 292 rhythm transitions, with a mean (SD) 2.5 (1.5) transitions per case. Mean (SD) time to first transition was 11.1 (6.9) minutes and mean (SD) time to last transition was 19.8(8.8) minutes. The most frequently observed transition was from asystole to low amplitude ventricular fibrillation (17.1%). Conclusions: The OD-OHCA ECG is varied and dynamic, presenting in numerous rhythms and transitioning between rhythms throughout the course of resuscitation.
USMLE Step 1 Scoring System Change to Pass/Fail—An Opportunity for Change
Authors: Angela L. Neville, Brian R. Smith, Christian de Virgilio
Journal: JAMA Surgery (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Abstract 3870: Patterns of CD112R expression in normal lymphatic tissues, inflammation and cancer
Authors: Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Claudia Hube-Magg, Guido Sauter, Ronald Simon, Christoph Fraune, Maximilian Lennartz, Sören A. Weidemann, Katharina Möller, Doris Höflmayer
Journal: Cancer Research (2020)

Abstract CD112R is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies, but little is known about its molecular epidemiology in healthy and diseased tissues. To study the prevalence and expression level of CD112R+ immune cells, we analyzed more than 200 samples of normal lymphatic, inflamed and cancerous tissues in a microenvironment tissue microarray format (4mm tissue spot diameter) and large sections using fluorescent multiplex immunohistochemistry. CD112R expression was detected at variable intensity levels in 47% of CD8+ cytotoxic lymphocytes, 49% of CD4+ T helper cells, 30% of FOXP3+ regulatory T helper cells and in 25% of CD56+ natural killer cells, but no expression was seen in CD11c+ dendritic cells and CD68+ macrophages. All analyzed compartments across normal and diseased tissues showed a small subset (CD8: 9±18%, CD4: 5±15%, FOXP3: 2±5%) of immune cells with supramaximal CD112R expression. The highest fraction of cells with supramaximal CD112R expression was found in the subset of CD8+ cytotoxic T cells in the Peyer's patches of ileum (62%), the intergranuloma area of lymph node sarcoidosis (27%) and in ovarian cancer (37%). In cancerous tissues, the density and the fraction cytotoxic T cells with supramaximal CD112R expression was highly variable and ranged from 5% in bladder cancer to 3% in lung cancer and 36% in ovarian cancer. A high variability of the number of cells with supramaximal CD112R expression was also seen within every tumor entity. In summary, our analysis shows that CD112R expression is abundant in various subsets of immune cells but identifies a small fraction of cells with exceedingly high CD112R levels. The widespread occurrence of CD112R+ cytotoxic T cells in the cancer microenvironment may suggest considerable opportunities for checkpoint inhibitors targeting CD112R. Citation Format: Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Claudia Hube-Magg, Guido Sauter, Ronald Simon, Christoph Fraune, Maximilian Lennartz, Sören A. Weidemann, Katharina Möller, Doris Höflmayer. Patterns of CD112R expression in normal lymphatic tissues, inflammation and cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3870.
Abstract 2572: Compound C inhibits metabolic programming of ovarian cancer
Authors: Alia Dawlat Ghoneum, Daniela Gonzalez, Neveen Said
Journal: Cancer Research (2020)

Abstract High grade serous ovarian carcinoma (HGSC) exhibits elevated energy demands to sustain rapid proliferation, survival and invasiveness. We have shown that Compound C, also known as Dorsomorphin, inhibits ovarian cancer growth, invasiveness and survival as well as interactions with mesothelial cells and macrophages. However, the effect of Compound C on metabolic programming has not been reported. The purpose of this study is to determine whether Compound C inhibits the malignant phenotypes of ovarian cancer through suppression of energy production. Therefore, we performed comprehensive metabolic profiling of ovarian cancer cells treated with Compound C. Our findings indicate that Compound C significantly inhibits ATP production in the ovarian cancer cell lines: OVCAR3, SKOV3 and IGROV1. Compound C inhibited basal and maximal mitochondrial respiration as well as the non-mitochondrial oxygen consumption in these three cell lines. Compound C had no effect on basal, induced or compensatory glycolysis. However, it significantly decreased the ratio of mitochondrial oxygen consumption rate to glycolytic proton efflux rate (mitoOCR/glycoPER), indicating a direct inhibitory effect of Compound C on mitochondrial electron transport chain and a bioenergetic shift from oxidative phosphorylation towards glycolysis. These results demonstrate for the first time, the direct inhibitory effect of Compound C on mitochondrial function as a novel mechanism of inhibition of the malignant phenotype of ovarian cancer cells. Citation Format: Alia Dawlat Ghoneum, Daniela Gonzalez, Neveen Said. Compound C inhibits metabolic programming of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2572.
Abstract 4037: <i>In vitro</i> cytotoxicity of CPX-351 plus venetoclax compared with hypomethylating agents or cytarabine plus venetoclax
Authors: Aparna Gupta, Robin Humphreys, Derek Hanson, Qi Wang
Journal: Cancer Research (2020)

Abstract Introduction: Current treatment options for AML patients who are older or unfit for intensive chemotherapy are limited and associated with less than ideal outcomes, even with newly approved regimens of venetoclax plus low-dose cytarabine or DNA hypomethylating agents. CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, was approved by the US FDA in 2017 and EMA in 2018 for treatment of adults with newly diagnosed therapy-related AML and AML with myelodysplasia-related changes. The objective of this study was to assess the cytotoxic effects of CPX-351 plus venetoclax versus combinations of venetoclax plus cytarabine, decitabine, or azacitidine. Methods: Three AML and three ALL cell lines were treated with single-agent CPX-351, venetoclax, cytarabine, decitabine, or azacitidine, or with combinations of CPX-351 plus venetoclax, venetoclax plus cytarabine, venetoclax plus decitabine, or venetoclax plus azacitidine. The cells were plated 24 hours prior to treatment and incubated with the test agents for 72 hours. Cytotoxicity was measured with a luminescent Cell Viability Assay. Results: As a single agent, all tested drugs demonstrated cytotoxicity to all cell lines, but with different potencies. CPX-351 plus venetoclax showed synergistic or additive effects in all AML and ALL cell lines tested (Table). Combinations of venetoclax with cytarabine, decitabine, or azacitidine showed variable responses (synergistic, additive, and antagonistic effects). In addition, data suggest the highest combination doses with CPX-351 may attain greater cell killing versus the other drug combinations tested. TableCICell lineCell originCPX-351 + venetoclaxCytarabine + venetoclaxAzacitidine + venetoclaxDecitabine + venetoclaxHL-60AML0.701.010.711.66SKM-1AML0.911.931.291.14KG-1AML0.530.950.590.77CCRF-CEMALL0.700.990.861.99MOLT-3ALL0.740.680.630.73Jurkat E6-1ALL0.791.331.141.40CI was calculated using the Chou and Talalay method, where CI of &amp;lt;1 = synergistic, 1 = additive, and &amp;gt;1 = antagonistic. Conclusions: These data demonstrated that the combination of CPX-351 and venetoclax is synergistic or additive in all cell lines tested. Future studies confirming these findings in in vivo hematologic malignancy models can help to design a novel dose-regimen, which may provide the best benefit with good tolerability. Citation Format: Aparna Gupta, Robin Humphreys, Derek Hanson, Qi Wang. In vitro cytotoxicity of CPX-351 plus venetoclax compared with hypomethylating agents or cytarabine plus venetoclax [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4037.
Prevalence of Depression Symptoms in US Adults Before and During the COVID-19 Pandemic
Authors: Catherine K. Ettman, Salma M. Abdalla, Gregory H. Cohen, Laura Sampson, Patrick M. Vivier, Sandro Galea
Journal: JAMA Network Open (2020)

The coronavirus disease 2019 (COVID-19) pandemic and the policies to contain it have been a near ubiquitous exposure in the US with unknown effects on depression symptoms. To estimate the prevalence of and risk factors associated with depression symptoms among US adults during vs before the COVID-19 pandemic. This nationally representative survey study used 2 population-based surveys of US adults aged 18 or older. During COVID-19, estimates were derived from the COVID-19 and Life Stressors Impact on Mental Health and Well-being study, conducted from March 31, 2020, to April 13, 2020. Before COVID-19 estimates were derived from the National Health and Nutrition Examination Survey, conducted from 2017 to 2018. Data were analyzed from April 15 to 20, 2020. The COVID-19 pandemic and outcomes associated with the measures to mitigate it. Depression symptoms, defined using the Patient Health Questionnaire-9 cutoff of 10 or higher. Categories of depression symptoms were defined as none (score, 0-4), mild (score, 5-9), moderate (score, 10-14), moderately severe (score, 15-19), and severe (score, ≥20). A total of 1470 participants completed the COVID-19 and Life Stressors Impact on Mental Health and Well-being survey (completion rate, 64.3%), and after removing those with missing data, the final during-COVID-19 sample included 1441 participants (619 participants [43.0%] aged 18-39 years; 723 [50.2%] men; 933 [64.7%] non-Hispanic White). The pre-COVID-19 sample included 5065 participants (1704 participants [37.8%] aged 18-39 years; 2588 [51.4%] women; 1790 [62.9%] non-Hispanic White). Depression symptom prevalence was higher in every category during COVID-19 compared with before (mild: 24.6% [95% CI, 21.8%-27.7%] vs 16.2% [95% CI, 15.1%-17.4%]; moderate: 14.8% [95% CI, 12.6%-17.4%] vs 5.7% [95% CI, 4.8%-6.9%]; moderately severe: 7.9% [95% CI, 6.3%-9.8%] vs 2.1% [95% CI, 1.6%-2.8%]; severe: 5.1% [95% CI, 3.8%-6.9%] vs 0.7% [95% CI, 0.5%-0.9%]). Higher risk of depression symptoms during COVID-19 was associated with having lower income (odds ratio, 2.37 [95% CI, 1.26-4.43]), having less than $5000 in savings (odds ratio, 1.52 [95% CI, 1.02-2.26]), and exposure to more stressors (odds ratio, 3.05 [95% CI, 1.95-4.77]). These findings suggest that prevalence of depression symptoms in the US was more than 3-fold higher during COVID-19 compared with before the COVID-19 pandemic. Individuals with lower social resources, lower economic resources, and greater exposure to stressors (eg, job loss) reported a greater burden of depression symptoms. Post-COVID-19 plans should account for the probable increase in mental illness to come, particularly among at-risk populations.
Abstract LB-098: The anti-tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models
Authors: Jill Hallin, Andrew Calinisan, Lauren Hargis, Ruth Aranda, Lars D. Engstrom, David M. Briere, Matthew A. Marx, Peter Olson, James G. Christensen
Journal: Cancer Research (2020)

Abstract The ability to develop effective therapies for KRAS mutant cancers has remained elusive despite decades of research. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor presently under evaluation in clinical trials. MRTX849 inhibits only inactive GDP-bound KRASG12C, a mutation known to be dependent on nucleotide cycling and extrinsic factors which regulate the activation state of KRAS. Preclinical and early clinical data suggest KRASG12C inhibitors induce tumor regression/response in a subset of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models and patients. Previous work in tumor xenograft models demonstrated activation of pathways upstream or downstream of KRAS through additional mutations or relief of feedback inhibition can limit the single agent activity of MRTX849 in the less responsive tumors. These data indicated that activation of receptor tyrosine kinases (RTKs) through relief of feedback inhibition was one mechanism implicated in modulating the response to MRTX849. As KRAS G12C mutations are present in ~4% of colon cancer, MRTX849 was further evaluated in CRC models to identify combination strategies that might optimize anti-tumor activity. A range of responses to single agent MRTX849 were observed across cell line and patient-derived xenograft (PDX) models. The combination of MRTX849 plus cetuximab demonstrated the best anti-tumor activity in multiple models. The combination of MRTX849 and cetuximab demonstrated increased KRASG12C modification and MAPK pathway inhibition suggesting these therapies converge to more fully inhibit KRASG12C. Despite the fact that cetuximab-based therapy is contra-indicated for KRAS-mutant CRC, these data suggest co-targeting EGFR and KRAS may more comprehensively inhibit KRAS mediated signaling and more effectively treat a subset of CRC patients with KRASG12C-mutant cancers. Citation Format: Jill Hallin, Andrew Calinisan, Lauren Hargis, Ruth Aranda, Lars D. Engstrom, David M. Briere, Matthew A. Marx, Peter Olson, James G. Christensen. The anti-tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-098.