tbuckley/cabot-search huggingface dataset:
Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis
Authors: Mingrui Zhu, Yi Huang, Matthew E. Bender, Luc Girard, Rahul Kollipara, Buse Eglenen-Polat, Yujiro Naito, Trisha K. Savage, Kenneth E. Huffman, Shohei Koyama, Atsushi Kumanogoh, John D. Minna, Jane E. Johnson, Esra A. Akbay
Journal: Cancer Research (2021)

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with SCLC. This may reflect defects in immune surveillance. Here we illustrate that evading natural killer (NK) surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK-cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. Chromatin immunoprecipitation sequencing showed NKG2DL loci in SCLC are inaccessible compared with NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Likewise, histone deacetylase inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma. SIGNIFICANCE: This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.
The impact of sociodemographic characteristics on gastric cancer outcomes: A retrospective review of a large single center study.
Authors: Dawood Findakly, Arnold Forlemu, Dimas Kosa, Surabhi Amar
Journal: Journal of Clinical Oncology (2021)

172 Background: Gastric cancer (GC) remains a pervasive condition in the US with high morbidity and mortality. Race/ethnicity, lack of insurance, and poverty may all be contributing to this burden, especially in select populations. We evaluated the impact of these sociodemographic factors on GC outcomes at a hospital with high immigrant-patient populations. Methods: We conducted a retrospective study to identify patients diagnosed with GC between year 2010 and 2019. Data obtained from our institution database regarding patients' sociodemographic factors, including age, gender, race/ethnicity, insurance status and type, and neighborhood socioeconomic status. Likewise, information on tumor histology, anatomic location, and stage were also obtained. Kaplan-Meier analysis was used to plot survival curves and analyze the impact of insurance on survival outcome. Results: One hundred eleven patients were analyzed in this study, with a male-to-female ratio of 1.26:1. The median age at the time of GC diagnosis was 52.9 (range 27-87) years, with median survival time (±SD, range) of 12.7 (±17.7, 0.25-84) months. Most patients (69.4%) were uninsured—out of which 76.7% presented with advanced-stage disease. Among those, the majority (70.3%) were Hispanic, and 60.4% were non-U.S. citizens. The most common tumor histology was diffuse-type adenocarcinoma in 55% of patients. Patients insured were on public coverage (Medicaid), private insurance, and Medicare at 11.7%, 9.9%, and 9.0%, respectively. In terms of survival, lack of insurance (p = 0.012) and Medicaid insurance (p = 0.046) were associated with the worst survival outcomes in GC patients. Conclusions: Our study reflects the trends in GC outcomes distinctly linked to significant sociodemographic disparities. Patients who lack insurance coverage had the worst survival outcomes. Therefore, efforts such as increasing healthcare access for this population-type at risk of sociodemographic incongruities may enhance outcomes and are crucial in fighting GC.
Association of Social and Demographic Factors With COVID-19 Incidence and Death Rates in the US
Authors: Monita Karmakar, Paula M. Lantz, Renuka Tipirneni
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Descriptive data have revealed significant racial/ethnic disparities in coronavirus disease 2019 (COVID-19) cases in the US, but underlying mechanisms of disparities remain unknown. <h3>Objective</h3> To examine the association between county-level sociodemographic risk factors and US COVID-19 incidence and mortality. <h3>Design, Setting, and Participants</h3> This cross-sectional study analyzed the association between US county-level sociodemographic risk factors and COVID-19 incidence using mixed-effects negative binomial regression, and COVID-19 mortality using zero-inflated negative binomial regression. Data on COVID-19 incidence and mortality were collected from January 20 to July 29, 2020. The association of social risk factors with weekly cumulative incidence and mortality was also examined by interacting time with the index measures, using a random intercept to account for repeated measures. <h3>Main Outcomes and Measures</h3> Sociodemographic data from publicly available data sets, including the US Centers for Disease Control and Prevention's Social Vulnerability Index (SVI), which includes subindices of socioeconomic status, household composition and disability, racial/ethnic minority and English language proficiency status, and housing and transportation. <h3>Results</h3> As of July 29, 2020, there were a total of 4 289 283 COVID-19 cases and 147 074 COVID-19 deaths in the US. An increase of 0.1 point in SVI score was associated with a 14.3% increase in incidence rate (incidence rate ratio [IRR], 1.14; 95% CI, 1.13-1.16;<i>P</i> &lt; .001) and 13.7% increase in mortality rate (IRR, 1.14; 95% CI, 1.12-1.16;<i>P</i> &lt; .001), or an excess of 87 COVID-19 cases and 3 COVID-19 deaths per 100 000 population for a SVI score change from 0.5 to 0.6 in a midsize metropolitan county; subindices were also associated with both outcomes. A 0.1-point increase in the overall SVI was associated with a 0.9% increase in weekly cumulative increase in incidence rate (IRR, 1.01; 95% CI, 1.01-1.01;<i>P</i> &lt; .001) and 0.5% increase in mortality rate (IRR, 1.01; 95% CI, 1.01-1.01;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In this cross-sectional study, a wide range of sociodemographic risk factors, including socioeconomic status, racial/ethnic minority status, household composition, and environmental factors, were significantly associated with COVID-19 incidence and mortality. To address inequities in the burden of the COVID-19 pandemic, these social vulnerabilities and their root causes must be addressed.
Two-step strategy for the identification of SARS-CoV-2 variant of concern 202012/01 and other variants with spike deletion H69–V70, France, August to December 2020
Authors: Antonin Bal, Gregory Destras, Alexandre Gaymard, Karl Stefic, Julien Marlet, Sébastien Eymieux, Hadrien Regue, Quentin Semanas, Constance d’Aubarede, Geneviève Billaud, Frédéric Laurent, Claudia Gonzalez, Yahia Mekki, Martine Valette, Maude Bouscambert, Catherine Gaudy-Graffin, Bruno Lina, Florence Morfin, Laurence Josset
Journal: Eurosurveillance (2021)

We report the strategy leading to the first detection of variant of concern 202012/01 (VOC) in France (21 December 2020). First, the spike (S) deletion H69–V70 (ΔH69/ΔV70), identified in certain SARS-CoV-2 variants including VOC, is screened for. This deletion is associated with a S-gene target failure (SGTF) in the three-target RT-PCR assay (TaqPath kit). Subsequently, SGTF samples are whole genome sequenced. This approach revealed mutations co-occurring with ΔH69/ΔV70 including S:N501Y in the VOC.
Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial
Authors: Francois Guilhot, Françoise Rigal-Huguet, Joëlle Guilhot, Agnès-Paule Guerci-Bresler, Frédéric Maloisel, Delphine Rea, Valérie Coiteux, Martine Gardembas, Christian Berthou, Anne Vekhoff, Eric Jourdan, Marc Berger, Loïc Fouillard, Magda Alexis, Laurence Legros, Philippe Rousselot, Alain Delmer, Pascal Lenain, Martine Escoffre Barbe, Emmanuel Gyan, Claude-Eric Bulabois, Viviane Dubruille, Bertrand Joly, Bertrand Pollet, Pascale Cony-Makhoul, Hyacinthe Johnson-Ansah, Melanie Mercier, Denis Caillot, Aude Charbonnier, Jean-Jacques Kiladjian, Jacques Chapiro, Amélie Penot, Véronique Dorvaux, Iona Vaida, Alberto Santagostino, Lydia Roy, Hacene Zerazhi, Eric Deconinck, Herve Maisonneuve, Isabelle Plantier, Delphine Lebon, Yazid Arkam, Nathalie Cambier, Kamel Ghomari, Jean-Michel Miclea, Sylvie Glaisner, Jean-Michel Cayuela, Jean-Claude Chomel, Marc Muller, Ludovic Lhermitte, Marc Delord, Claude Preudhomme, Gabriel Etienne, François-Xavier Mahon, Franck- Emmanuel Nicolini, Francois Guilhot, Francoise Rigal-Huguet, Joëlle Guilhot, Agnès-Paule Guerci-Bresler, Delphine Rea, Valérie Coiteux, Martine Gardembas, Anne Vekhoff, Marc Berger, Laurence Legros, Philippe Rousselot, Pascal Lenain, Martine Escoffre Barbe, Viviane Dubruille, Pascale Cony-Makhoul, Hyacinthe Johnson-Ansah, Melanie Mercier, Charbonnier Aude, Lydia Roy, Nathalie Cambier, Jean-Michel Cayuela, Jean-Claude Chomel, Marc Delord, Claude Preudhomme, Gabriel Etienne, François-Xavier Mahon, Franck-Emmanuel Nicolini
Journal: Leukemia (2021)
Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation
Authors: Konrad Bork, Karin Wulff, Britta S. Möhl, Lars Steinmüller-Magin, Günther Witzke, Jochen Hardt, Peter Meinke
Journal: Journal of Allergy and Clinical Immunology (2021)
Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆
Authors: P.G. Casali, A. Le Cesne, A.P. Velasco, D. Kotasek, P. Rutkowski, P. Hohenberger, E. Fumagalli, I.R. Judson, A. Italiano, H. Gelderblom, N. Penel, J.T. Hartmann, F. Duffaud, D. Goldstein, J. Martin-Broto, A. Gronchi, E. Wardelmann, S. Marréaud, J.R. Zalcberg, S. Litière, J.-Y. Blay
Journal: Annals of Oncology (2021)
AB0130 Chest expansion in rheumatic diseases
Authors: Y Alici, S Masatlioglu, I Fresko, E Habiboglu, F Kara, H Yazici
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Decreased chest expansion is a time honoured sign in patients with ankylosing spondylitis (AS). However, the clinical usefulness of this measurement and the frequency with which it is used remains largely unknown. <h3>Objectives</h3> We studied: 1) the frequency of its clinical use among rheumatologists and 2) its inter and intra-observer variation along with its sensitivity and specificity among a group of patients with AS and suitable controls. <h3>Methods</h3> A total of 300 rheumatologists in the United States and in Europe were contacted by e-mail. The frequency they measured chest expansion in their daily practices and the characteristics of their patients they performed the test on, were inquired. Thirty patients with AS, 36 with rheumatoid arthritis (RA), 31 with systemic lupus erythematosus (SLE) who were regularly followed in the Rheumatology Department of Cerrahpasa Medical Faculty and 76 healthy controls (HC) who consisted of healthy hospital staff were recruited. Chest expansion was measured at the 4th intercostal space by two independent observers in the morning (between 8–10 AM) in the afternoon (between 2–4 PM) and one week after the initial determinations. The relationship between the chest expansion and gender, age and vital capacity (VC), body mass index (BMI) were determined in all the patients and controls. <h3>Results</h3> Eighty-two (27%) of the 300 rheumatologists responded. Three of the responders (4%) stated that they measured chest expansion in every patient whereas 72 (87%) said that they performed the test only in patients suspected to have ankylosing spondylitis. Seven rheumatologists (9%) reported that they never measured chest expansion. There was a good intra and inter-observer agreement in chest expansion measurements as judged by a difference of less than 1 cm in 80% of the calculations. A chest expansion of less than 2.5 cm had a sensitivity of 23% in patients with AS whereas it had a specificity of 49% (2 patients with RA, 1 with SLE and 5 HC had values below 2.5 cm). There was a significant correlation between vital capacity and chest expansion only in male patients with AS (r = 0.51, p = 0.005). Chest expansion decreased with age in all groups (r<sup>2</sup> = 0.083, F = 0.0001). There was no relationship between the chest expansion either with gender or with BMI, both among the patients and the controls. <h3>Conclusion</h3> Most of the rheumatologists measure chest expansion only in patients suspected to have AS. It is a test that has good intra and inter-observer reliability. However it has a limited sensitivity and specificity in AS and its value in differential diagnosis is limited.
Diagnostic blood RNA profiles for human acute spinal cord injury
Authors: Nikos Kyritsis, Abel Torres-Espín, Patrick G. Schupp, J. Russell Huie, Austin Chou, Xuan Duong-Fernandez, Leigh H. Thomas, Rachel E. Tsolinas, Debra D. Hemmerle, Lisa U. Pascual, Vineeta Singh, Jonathan Z. Pan, Jason F. Talbott, William D. Whetstone, John F. Burke, Anthony M. DiGiorgio, Philip R. Weinstein, Geoffrey T. Manley, Sanjay S. Dhall, Adam R. Ferguson, Michael C. Oldham, Jacqueline C. Bresnahan, Michael S. Beattie
Journal: The Journal of Experimental Medicine (2021)

Diagnosis of spinal cord injury (SCI) severity at the ultra-acute stage is of great importance for emergency clinical care of patients as well as for potential enrollment into clinical trials. The lack of a diagnostic biomarker for SCI has played a major role in the poor results of clinical trials. We analyzed global gene expression in peripheral white blood cells during the acute injury phase and identified 197 genes whose expression changed after SCI compared with healthy and trauma controls and in direct relation to SCI severity. Unsupervised coexpression network analysis identified several gene modules that predicted injury severity (AIS grades) with an overall accuracy of 72.7% and included signatures of immune cell subtypes. Specifically, for complete SCIs (AIS A), ROC analysis showed impressive specificity and sensitivity (AUC: 0.865). Similar precision was also shown for AIS D SCIs (AUC: 0.938). Our findings indicate that global transcriptomic changes in peripheral blood cells have diagnostic and potentially prognostic value for SCI severity.
Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity
Authors: Hadley E. Sheppard, Alessandra Dall’Agnese, Woojun D. Park, M. Hamza Shamim, Julien Dubrulle, Hannah L. Johnson, Fabio Stossi, Patricia Cogswell, Josh Sommer, Joan Levy, Tanaz Sharifnia, Mathias J. Wawer, Behnam Nabet, Nathanael S. Gray, Paul A. Clemons, Stuart L. Schreiber, Paul Workman, Richard A. Young, Charles Y. Lin
Journal: Cell Reports Medicine (2021)

Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition, leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape and autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition, which globally downregulates transcription, leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop.
Mapping and role of T cell response in SARS-CoV-2–infected mice
Authors: Zhen Zhuang, Xiaomin Lai, Jing Sun, Zhao Chen, Zhaoyong Zhang, Jun Dai, Donglan Liu, Yuming Li, Fang Li, Yanqun Wang, Airu Zhu, Junxiang Wang, Wenhui Yang, Jicheng Huang, Xiaobo Li, Lingfei Hu, Liyan Wen, Jianfen Zhuo, Yanjun Zhang, Dingbin Chen, Suxiang Li, Shuxiang Huang, Yongxia Shi, Kui Zheng, Nanshan Zhong, Jingxian Zhao, Dongsheng Zhou, Jincun Zhao
Journal: The Journal of Experimental Medicine (2021)

Virus-specific T cells play essential roles in protection against multiple virus infections, including SARS-CoV and MERS-CoV. While SARS-CoV-2–specific T cells have been identified in COVID-19 patients, their role in the protection of SARS-CoV-2–infected mice is not established. Here, using mice sensitized for infection with SARS-CoV-2 by transduction with an adenovirus expressing the human receptor (Ad5-hACE2), we identified SARS-CoV-2–specific T cell epitopes recognized by CD4+ and CD8+ T cells in BALB/c and C57BL/6 mice. Virus-specific T cells were polyfunctional and were able to lyse target cells in vivo. Further, type I interferon pathway was proved to be critical for generating optimal antiviral T cell responses after SARS-CoV-2 infection. T cell vaccination alone partially protected SARS-CoV-2–infected mice from severe disease. In addition, the results demonstrated cross-reactive T cell responses between SARS-CoV and SARS-CoV-2, but not MERS-CoV, in mice. Understanding the role of the T cell response will guide immunopathogenesis studies of COVID-19 and vaccine design and validation.
Genomic profiling of gastrointestinal cancers by comprehensive tumor-normal sequencing.
Authors: Fadel S. Alyaqoub, Pawan Noel, Szabolcs Szelinger, Thanemozhi G. Natarajan, Susan M. Dombrowski, Audrey A. Ozols, Laurie Jane Goodman, Janine LoBello, Thomas Royce, Gargi D. Basu
Journal: Journal of Clinical Oncology (2021)

109 Background: Gastrointestinal cancers (GIC) account for 26% of global cancer incidence and 35% of cancer-related deaths. We investigated the molecular landscape and therapeutic targets across 18 types of GIC using whole exome (WES) and whole transcriptome sequencing (WTS). Methods: GEM ExTra assay was performed on 603 paired samples (ages 18-90 years, median = 61 years). Targeted sequence coverage was 180X for germline DNA and 400X for tumor DNA. Reportable somatic alterations included single base substitutions, indels, Copy Number Alterations, gene fusions, alternate transcripts, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. Germline subtraction identified somatic-specific alterations. Results: Analysis of 603 GIC patient samples, including esophageal, gastric cancer (GC), biliary tract (BT), pancreatic cancer (PC), colorectal cancer (CRC), and other cancers, identified 434 actionable targets. The median number of alterations was 3 per GIC patient. The 5 most common actionable alterations were in APC, KRAS, CDKN2A, ARID1A and PIK3CA. Activation of Wnt signaling was found in 264/603 (44%), with the majority being in CRC cases. Alterations in cell cycle genes including CDKN2A, CDK4/6 and others were noted in 129/603 (21%) cases, with the majority in PC, suggesting benefit from CDK4/6 inhibitors. Activation of PI3K/PTEN/Akt/mTOR pathway was noted in 105/603 (17%), with the majority harbored in CRC, suggesting benefit from targeting this pathway. ERBB2 amplification and mutations were noted in 22/603 (4%) across different GIC tumor types. Alterations in homologous recombination genes predicting platinum and PARP inhibitor response was noted in 181/603 (30%) samples distributed across GIC subtypes. KRAS (G12C) mutation was found in 7% of all KRAS mutations across GIC subtypes, thus allowing patients to enroll in clinical trials with G12C-specific inhibitors. The majority of cases with MSI- and TMB-high status were identified in GC and CRC tumors and may be predictive of response to immunotherapy. WTS identified actionable fusions, including FGFR1/2/3 and novel NRG1 fusions in BT cancers. Conclusions: Our study revealed actionable targets used in patient selection for precision therapies, in addition to other mutational profiles of clinical significance. Overall, comprehensive genomic profiling enabled detection of established and novel actionable alterations, including fusions, which may have gone undetected using hotspot panels.
Increased mortality and decreased registrations in cirrhosis registry during COVID-19 era
Authors: L. Skladaný, J. Vnencakova, D. J. Havaj, S. Adamcova-Selcanova, L. Barekova, N. Bystrianska, D. Jancekova, L. Laffers, P. Molcan, J. Strachan, V. Durajova, T. Koller
Journal: Hepatology (2020)

Background: Our HEGITO liver unit provides the in- and out-patient (pt) tertiary referral services including liver transplantation (LT) Since 2014, HEGITO has kept registry (RH7) of patients hospitalized with cirrhosis / advanced chronic liver disease (ACLD) The social distancing policy restrictions were introduced in Slovakia on March 16, 2020 and they have substantially changed the usual provision of HEGITO services: We 1 deferred or diverted to telemedicine most of planned and on-demand outpatient services, 2 deferred planned and delimited to region-proper lower-rank institutions acute hospitalizations and, 3 deferred LT except for urgent indications In this study, we aimed to analyze the registrations to and mortality in RH7 pre- and during the COVID-19 era Methods: Using a sample of pt registered to RH7 anytime from its start in 2014 and passing away before March 16, 2020 (PRE-COVID COHORT), we conducted a survival analysis using a Cox proportional hazard model with following factors: gender, age, BMI, CTP, MELD, LFI, ACLF, TSF, DYNAMO, CRP, LEU We used this model to predict individual median residual lifetime for remaining 563 pt from RH7 who were alive at March 16 (COVID COHORT) We compared actual cumulative number of deaths between March 16 and June 6, with predictions based on the Cox PH model Deaths were ascertained by the weekly reports from the Healthcare Surveillance Authority with the special query for COVID 19 code Results: We identified 1091 pt in PRECOVID COHORT with median age 56 8, MELD 16, 60 8% male, and 563 pt in COVID COHORT with median age 55 7, MELD 14, 57 2% male, respectively Registry data shows a significant drop in weekly new registrations to RH7: four in March 2020 vs 17 8 average in March 2014-2019, followed by a sharp increase after these policies were lifted (Figure) Registered mortality in COVID COHORT was higher than mortality predicted by the Cox PH model using PRE-COVID COHORT (28 vs 22) Of note, there was no death related to COVID 19 in the COVID COHORT Conclusion: Analysis of our cirrhosis registry has revealed significantly decreased regsitrations and increased mortality during COVID 19 era We speculate that they are causally related to the impact of the pandemic on the quality of cirrhosis care (Tapper, J Hep 20;73: 441)