tbuckley/cabot-search huggingface dataset:
Abstract 4316: Frequent microsatellite instability in Chinese solid tumor patients
Authors: Huilin Wang, Jiang Zhu, Guanbiao Liang, Yongyong Wang, Jianji Guo, Min Zheng, Qin Fu, Weiwei Shi
Journal: Cancer Research (2020)

Abstract Background Microsatellite instability (MSI) has important clinical implications related to therapeutic options and prognostic assessment. Few studies have been done on the frequency of MSI in cancers and the correlation between microsatellite status and clinicopathological features in Chinese solid tumor patients. Methods A total of 10149 Chinese solid tumor patients were collected for genome testing using a targeted next-generation sequencing (NGS) panel (OrigiMed, Shanghai). Microsatellite status and other clinicopathological features were examined. Fisher's exact test was used for statistical analysis. Results MSI-high (MSI-H) was observed in 188 solid tumors (1.8%). Cancer subtypes with significantly higher MSI frequencies included colorectal adenocarcinoma (8.4%), gastric adenocarcinoma (6.9%) and intrahepatic cholangiocarcinoma (2.7%). No statistical significant difference was found in the proportion of MSI in women and men (1.9 % vs 1.7%, respectively). The proportion MSI tumors was higher in older patients (1.3% at 60-69 years, 2.8% at 70-79 years,P&amp;lt;0.0001) and younger patients (1.4% at 50-59 years, 3.0% at 40-49 years, P&amp;lt;0.0001). Compared with microsatellite stable (MSS) carcinomas, MSI was significantly correlated with the oldest and youngest age ranges that were tested, tumors found in the stomach and intestine, and in colorectal adenocarcinoma and gastric adenocarcinoma subtypes. In addition, 123 of the 188 samples (65.4%) harbored at least one MMR gene mutations predicted as loss of functions, including nonsense mutations or truncations in MSH2, MSH6 or MLH1. 2.3% (217/9354) MMR gene mutation was detected in MSS samples (p&amp;lt;0.0001). Conclusions This study revealed MSI-H in approximately 1.8% of Chinese solid tumor patients and a significant association between MSI-H and MMR gene mutations. These results suggest that there are specific tumor types and clinicopathological features associated with a higher frequency of MSI, indicating a bias during tumorigenesis. Also, these results may potentially contribute to more effective treatment options and a better prognostic assessment for solid tumor patients. Citation Format: Huilin Wang, Jiang Zhu, Guanbiao Liang, Yongyong Wang, Jianji Guo, Min Zheng, Qin Fu, Weiwei Shi. Frequent microsatellite instability in Chinese solid tumor patients [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 4316.
CDK4/6 inhibition promotes immune infiltration in ovarian cancer and synergizes with PD-1 blockade in a B cell-dependent manner
Authors: Qian-Feng Zhang, Jia Li, Kuo Jiang, Rui Wang, Jun-li Ge, Hong Yang, Shu-Juan Liu, Lin-Tao Jia, Lei Wang, Bi-Liang Chen
Journal: Theranostics (2020)

Great progress has been made in the field of tumor immunotherapy in the past decade. However, the therapeutic effects of immune checkpoint blockade (ICB) against ovarian cancer are still limited. Recently, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6i) has been reported to enhance antitumor immunity in preclinical models. The combined use of CDK4/6i and ICB may be beneficial, but the effects of CDK4/6is on the tumor immune microenvironment and whether they can synergize with ICB in treating ovarian cancer remain unknown. Methods: In this study, we first assessed the antitumor efficacy of abemaciclib, an FDA-approved CDK4/6i, in a syngeneic murine ovarian cancer model. Then, immunohistochemistry, immunofluorescence and flow cytometry were performed to evaluate the number, proportion, and activity of tumor-infiltrating lymphocytes. Cytokine and chemokine production was detected both in vivo and in vitro by PCR array analysis and cytokine antibody arrays. The treatment efficacy of combined abemaciclib and anti-PD-1 therapy was evaluated in vivo, and CD8+ and CD4+ T cell activities were analyzed using flow cytometry. Lastly, the requirement for both CD8+ T cells and B cells in combination treatment was evaluated in vivo, and potential cellular mechanisms were further analyzed by flow cytometry. Results: We observed that abemaciclib monotherapy could enhance immune infiltration, especially CD8+ T cell and B cell infiltration, in the ID8 murine ovarian cancer model. Immunophenotyping analysis showed that abemaciclib induced a proinflammatory immune response in the tumor microenvironment. PCR array analysis suggested the presence of a Th1-polarized cytokine profile in abemaciclib-treated ID8 tumors. In vitro studies showed that abemaciclib-treated ID8 cells secreted more CXCL10 and CXCL13, thus recruiting more lymphocytes than control groups. Combination treatment achieved better tumor control than monotherapy, and the activities of CD8+ and CD4+ T cells were further enhanced when compared with monotherapy. The synergistic antitumor effects of combined abemaciclib and anti-PD-1 therapy depended on both CD8+ T cells and B cells. Conclusion: These findings suggest that combined treatment with CDK4/6i and anti-PD-1 antibody could improve the efficacy of anti-PD-1 therapy and hold great promise for the treatment of poorly immune-infiltrated ovarian cancer.
Prediction of Lifetime and 10-Year Risk of Cancer in Individual Patients With Established Cardiovascular Disease
Authors: Cilie C. van ’t Klooster, Paul M. Ridker, Nancy R. Cook, Joachim G.J.V. Aerts, Jan Westerink, Folkert W. Asselbergs, Yolanda van der Graaf, Frank L.J. Visseren, F.W. Asselbergs, H.M. Nathoe, G.J. de Borst, M.L. Bots, M.I. Geerlings, M.H. Emmelot, P.A. de Jong, T. Leiner, A.T. Lely, N.P. van der Kaaij, L.J. Kappelle, Y. Ruigrok, M.C. Verhaar, J. Westerink
Journal: JACC CardioOncology (2020)

Cardiovascular disease (CVD) and cancer share many common risk factors; patients with CVD also may be at risk of developing cancer.The aim of this study was to derive and externally validate prediction models for the estimation of lifetime and 10-year risk for total, colorectal, and lung cancer in patients with established CVD.Data from patients with established CVD from the UCC-SMART cohort (N = 7,280) were used for model development, and from the CANTOS trial (N = 9,322) for model validation. Predictors were selected based on previously published cancer risk scores, clinical availability, and presence in the derivation dataset. Fine and Gray competing risk-adjusted lifetime models were developed for the outcomes total, colorectal, and lung cancer.Selected predictors were age, sex, smoking, weight, height, alcohol use, antiplatelet use, diabetes, and C-reactive protein. External calibration for the 4-year risk of lung, colorectal, and total cancer was reasonable in our models, as was discrimination with C-statistics of 0.74, 0.64, and 0.63, respectively. Median predicted lifetime and 10-year risks in CANTOS were 26% (range 1% to 52%) and 13% (range 1% to 31%) for total cancer; 4% (range 0% to 13%) and 2% (range 0% to 6%) for colorectal cancer; and 5% (range 0% to 37%) and 2% (range 0% to 24%) for lung cancer.Lifetime and 10-year risk of total, colorectal, and lung cancer can be estimated reasonably well in patients with established CVD with readily available clinical predictors. With additional study, these tools could be used in clinical practice to further aid in the emphasis of healthy lifestyle changes and to guide thresholds for targeted diagnostics and screening.
Abstract 4668: Human CYP1B1 prevents TRAIL-DR4-mediated cancer cell apoptosis through downregulation of miR-375
Authors: Yeo-Jung Kwon, Dong-Jin Ye, Huoung-Seok Baek, Sangyun Shin, Tae-Uk Kwon, Eunah Cho, Hong-Gyu Ahn, Youngjin Chun
Journal: Cancer Research (2020)

Abstract Human cytochrome P450 1B1 (CYP1B1) is an important enzyme that catalyzes metabolism of 17β-estradiol (E2) to catechol estrogens, including carcinogenic metabolite 4-hydroxyestradiol (4-OHE2). CYP1B1 may play a crucial role in estrogen-mediated carcinogenesis since CYP1B1 shows tumor-specific expression pattern in various hormone-responsive tissues. However, the detailed mechanism of CYP1B1-dependent carcinogenesis remains still unclear. Here, we investigated the association between TRAIL, DR4, and CYP1B1 expression in human tumor cells, including MCF-7, MDA-MB-231, and HeLa cells. CYP1B1 can inhibit the expression and release of TRAIL simultaneously with the expression of the death receptor DR4/5, known as TRAIL receptors, to prevent apoptosis. Furthermore, we found that CYP1B1 represses the transcription of DR4 by inducing DNA methylation in the promoter region of DR4. In addition, we revealed that CYP1B1 regulates TRAIL and DR4 through activation of Sp1 transcription factor. CYP1B1 and its enzymatic product, 4-OHE2, promote Sp1 expression levels in both mRNA and protein levels. Interestingly, CYP1B1 elevated Sp1 through downregulation of miR-375, which is a candidate tumor suppressive microRNA and transcriptional inhibitor of Sp1. Taken together, our data suggest that CYP1B1 inhibits TRAIL-DR4-mediated cancer cell apoptosis through induction of Sp1 through repression of miR-375, which promotes cancer cell survival. Citation Format: Yeo-Jung Kwon, Dong-Jin Ye, Huoung-Seok Baek, Sangyun Shin, Tae-Uk Kwon, Eunah Cho, Hong-Gyu Ahn, Youngjin Chun. Human CYP1B1 prevents TRAIL-DR4-mediated cancer cell apoptosis through downregulation of miR-375 [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 4668.
The Tumor Microenvironment Is Independently Prognostic of Conventional and Clinicogenetic Risk Models in Follicular Lymphoma
Authors: Joshua W.D. Tobin, Colm Keane, Peter Mollee, Simone Birch, Clare Gould, Jay Gunawardana, Thanh Hoang, Ti Ma, Emad Uddin Abro, Mohamed Shanavas, Hyung Yoo, Li Li, Paul Scuffham, Valentine Murigneux, Lynn Fink, Nicholas Matigian, Frank Vari, Santiyagu Francis, Maher K Gandhi
Journal: Blood (2017)
p38 MAPK reins in right ventricular growth
Authors: Tongbin Wu, Ju Chen
Journal: Journal of Clinical Investigation (2020)

The right ventricle (RV) is involved in systemic circulation in the fetal mammalian heart but quickly transitions to being solely responsible for pulmonary circulation after birth when the left ventricle (LV) becomes the systemic ventricle. To handle the increased workload, LV growth greatly outpaces that of the RV during postnatal stages. However, the molecular basis for this differential growth pattern between the 2 chambers is largely unknown. In this issue of the JCI, Yokota et al. reveal that the p38 mitogen-activated protein kinase (MAPK)/IRE1α/XBP1 axis specifically controls postnatal RV growth by suppressing cell cycle regulatory genes.
Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History
Authors: Jeroen J van den Broek, Clyde B Schechter, Nicolien T van Ravesteyn, A Cecile J W Janssens, Michael C Wolfson, Amy Trentham-Dietz, Jacques Simard, Douglas F Easton, Jeanne S Mandelblatt, Peter Kraft, Harry J de Koning
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years. Methods Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines. Results Women with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range = 29%-40%) increase in life-years gained and 20% (model range = 16%-24%) more breast cancer deaths averted, but 21% (model range = 17%-23%) more overdiagnoses and 63% (model range = 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%). Conclusions Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected.
Abstract 1452: Hypoxia-induced MIG-6 promotes glucose metabolic reprogramming and tumorigenesis in triple-negative breast cancer
Authors: Jiabei He, Chien-Feng Li, Hong-Jen Lee, Dong-Hui Shin, Bruno De Carvalho, Chia-Hsin Chan
Journal: Cancer Research (2020)

Abstract Treatment of triple-negative breast cancer (TNBC) remains challenging due to a lack of effective targeted therapies. Dysregulated glucose uptake and metabolism are essential for TNBC growth. Identifying the molecular drivers and mechanisms underlying the metabolic vulnerability of TNBC is the key to exploiting dysregulated cancer metabolism for therapeutic applications. Mitogen-inducible gene-6 (MIG-6) has long been thought as a feedback inhibitor that targets activated EGFR and suppresses the growth of tumors driven by constitutive activated mutant EGFR. Here, our bioinformatics and histological analyses uncovered that MIG-6 is upregulated in TNBC and that MIG-6 upregulation is positively correlated with poorer clinical outcomes in TNBC. Metabolic arrays and functional assays revealed that MIG-6 drives glucose metabolism reprogramming toward glycolysis. We found that hypoxia-induced MIG-6 promotes HIF1α protein stabilization and the subsequent upregulation of GLUT1 and other HIF1α-regulated glycolytic genes, substantiating the comprehensive regulation of MIG-6 in glucose metabolism. Moreover, our animal studies demonstrated that MIG-6 regulates GLUT1 expression in tumors and subsequent tumor growth in vivo. Collectively, this work reveals that MIG-6 is a novel prognosis biomarker, metabolism regulator, and molecular driver of TNBC. Citation Format: Jiabei He, Chien-Feng Li, Hong-Jen Lee, Dong-Hui Shin, Bruno De Carvalho, Chia-Hsin Chan. Hypoxia-induced MIG-6 promotes glucose metabolic reprogramming and tumorigenesis in triple-negative breast 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 1452.
Controversies in the Treatment of Peripheral T‐cell Lymphoma
Authors: Emmanuel Bachy, Alessandro Broccoli, Claire Dearden, Laurence de Leval, Philippe Gaulard, Raphael Koch, Franck Morschhauser, Lorenz Trümper, Pier Luigi Zinzani
Journal: HemaSphere (2020)

Abstract Peripheral T‐cell lymphomas are a heterogeneous group of rare diseases with an aggressive behavior and dismal prognosis. Their classification is complex and still evolving, and several biomolecular markers now help refine the prognosis of specific disease entities, although still have limited impact in tailoring the treatment. First‐line treatment strategies can cure only a minority of patients and relapsed‐refractory disease still represents the major cause of failure. Frontline autologous transplantation may have an impact in the consolidation of response; however, its role is still questioned as far as complete responses obtained after induction chemotherapy are concerned. Newer drugs are now being evaluated in clinical trials, but effective salvage strategies for those who experience treatment failures are lacking. Here we review and discuss the most controversial aspects of diagnosis and treatment of peripheral T‐cell lymphomas.
Abstract A25: Withaferin A ameliorates ovarian cancer-induced cachexia through regulation of NF-kB/NLRP3 signaling
Authors: Alex R. Straughn, Mariusz Z. Ratajczak, Sham S. Kakar
Journal: Clinical Cancer Research (2020)

Abstract A majority of ovarian cancer patients exhibit clinical symptoms of cachexia, which accounts for up to 30% of cancer deaths depending on the oncologic setting. Withaferin A is a steroidal lactone with anti-inflammatory properties and is known to inhibit the growth of ovarian cancer and reduce metastasis through targeting cancer cells and cancer stem cells. The purpose of this study was to investigate whether Withaferin A could ameliorate the cachectic phenotype induced by ovarian cancer. We believe that treatment with Withaferin A could rescue body composition and muscle strength changes. The ovarian cancer cell line A2780 was xenografted into severely immunodeficient NSG mice via an intraperitoneal (i.p.) injection. Control mice received an i.p. injection of sterile saline. Following an engraftment period, mice were treated with vehicle or Withaferin A via i.p. injection every 3 days until the end of the study. Body weight and grip strength were assessed on a weekly basis. DEXA scan was performed post mortem, followed by collection/sectioning/staining of tumor samples and various skeletal muscle tissue. Withaferin A treatment significantly reduced the mortality rate associated with ovarian cancer. Treatment with Withaferin A inhibited an accumulation of adipose tissue within the thoracoabdominal region, associated with ovarian cancer progression. Low doses of Withaferin A were protective for forelimb and total limb grip strength, whereas higher doses were initially protective but resulted in a significant reduction. Further, Withaferin A ameliorated the reduction in myofibrillar cross-sectional area induced by ovarian cancer. Additionally, treatment with Withaferin A completely inhibited the slow-to-fast myofiber-type conversion seen in the settings of cancer cachexia. Lastly, using immunohistochemical staining and qPCR, we demonstrate that Withaferin A causes a downregulation of NF-kB-dependent proinflammatory cytokines and inhibits activation of the NLRP3 inflammasome, which are known to mediate cachectic signaling. Collectively, we provide preliminary data indicating that in ovarian cancer-induced cachexia, body composition changes and weakening of the skeletal muscle can be ameliorated through a downregulation of NF-kB-NLRP3 signaling. Citation Format: Alex R. Straughn, Mariusz Z. Ratajczak, Sham S. Kakar. Withaferin A ameliorates ovarian cancer-induced cachexia through regulation of NF-kB/NLRP3 signaling [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 A25.
Covid-19: CDC says vaccine is coming before November US election
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

The Centers for Disease Control and Prevention (CDC) has told public health departments in all 50 US states and five large cities to get ready to distribute a covid-19 vaccine by 1 November, two days before the US presidential election on 3 November.

President Donald Trump said on 27 August during the Republican convention that a vaccine might well be ready by the end of October. On the same day Robert Redfield, head of the CDC, sent the letter alerting public health departments.12

Health and human services …
Few Fixed Variants between Trophic Specialist Pupfish Species Reveal Candidate<i>Cis</i>-Regulatory Alleles Underlying Rapid Craniofacial Divergence
Authors: Joseph A McGirr, Christopher H Martin
Journal: Molecular Biology and Evolution (2020)

Abstract Investigating closely related species that rapidly evolved divergent feeding morphology is a powerful approach to identify genetic variation underlying variation in complex traits. This can also lead to the discovery of novel candidate genes influencing natural and clinical variation in human craniofacial phenotypes. We combined whole-genome resequencing of 258 individuals with 50 transcriptomes to identify candidate cis-acting genetic variation underlying rapidly evolving craniofacial phenotypes within an adaptive radiation of Cyprinodon pupfishes. This radiation consists of a dietary generalist species and two derived trophic niche specialists—a molluscivore and a scale-eating species. Despite extensive morphological divergence, these species only diverged 10 kya and produce fertile hybrids in the laboratory. Out of 9.3 million genome-wide SNPs and 80,012 structural variants, we found very few alleles fixed between species—only 157 SNPs and 87 deletions. Comparing gene expression across 38 purebred F1 offspring sampled at three early developmental stages, we identified 17 fixed variants within 10 kb of 12 genes that were highly differentially expressed between species. By measuring allele-specific expression in F1 hybrids from multiple crosses, we found that the majority of expression divergence between species was explained by trans-regulatory mechanisms. We also found strong evidence for two cis-regulatory alleles affecting expression divergence of two genes with putative effects on skeletal development (dync2li1 and pycr3). These results suggest that SNPs and structural variants contribute to the evolution of novel traits and highlight the utility of the San Salvador Island pupfish system as an evolutionary model for craniofacial development.