tbuckley/cabot-search huggingface dataset:
The Proteomic Landscape of Growth Factor Signaling Networks Associated with<i>FAT1</i>Mutations in Head and Neck Cancers
Authors: Zhengjia Chen, Chao Zhang, Jianhong Chen, Dongsheng Wang, Jieqi Tu, Carter Van Waes, Nabil F. Saba, Zhuo G. Chen, Zhong Chen
Journal: Cancer Research (2021)

Abstract FAT1 is frequently mutated in head and neck squamous cell carcinoma (HNSCC), but the biological and clinical effects of FAT1 mutations in HNSCC remain to be fully elucidated. We investigated the landscape of altered protein and gene expression associated with FAT1 mutations and clinical outcomes of patients with HNSCC. FAT1 mutation was stratified with clinical information from The Cancer Genome Atlas HNSCC databases with more than 200 proteins or phosphorylated sites. FAT1 mutation was significantly more prevalent among HPV(−), female, and older patients and was enriched in oral, larynx, and hypopharynx primary tumors. FAT1 mutation was also significantly associated with lower FAT1 gene expression and increased protein expression of HER3_pY1289, IRS1, and CAVEOLIN1. From an independent International Cancer Genome Consortium dataset, FAT1 mutation in oral cancer co-occurred with top mutated genes TP53 and CASP8. Poorer overall survival or progression-free survival was observed in patients with FAT1 mutation or altered HER3_pY1289, IRS1, or CAVEOLIN1. Pathway analysis revealed dominant ERBB/neuregulin pathways linked to FAT1 mutations in HNSCC, and protein signature panels uncovered the heterogeneity of patient subgroups. Decreased pEGFR, pHER2, and pERK and upregulated pHER3 and HER3 proteins were observed in two FAT1 knockout HNSCC cell lines, supporting that FAT1 alterations lead to altered EGFR/ERBB signaling. In squamous cancers of the lung and cervix, a strong association of FAT1 and EGFR gene expressions was identified. Collectively, these results suggest that alteration of FAT1 appears to involve mostly HPV(−) HNSCC and may contribute to resistance to EGFR-targeted therapy. Significance: Integrative bioinformatics and statistical analyses reveal a panel of genes and proteins associated with FAT1 mutation in HNSCC, providing important insights into prospective clinical investigations with targeted therapies.
Comment on Neeland et al. The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 2020;43:3007–3015
Authors: Shay Brikman, Guy Dori
Journal: Diabetes Care (2021)

We read with great interest the leading article by Neeland et al. (1) highlighting the beneficial effects of empagliflozin treatment on several metabolic end points among participants with type 2 diabetes and obstructive sleep apnea (OSA) in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). In addition, the authors observed a lower frequency of new-onset OSA, even when adjusting for baseline BMI. The authors provided few physiological explanations for the favorable effects of empagliflozin, mainly attributing them to the diuretic and natriuretic effects of the drug. Among the latter effects were 1 ) reduction of intrathoracic fluid retention and rostral fluid shifts from …
Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort
Authors: Raphael Carapito, Richard Li, Julie Helms, Christine Carapito, Sharvari Gujja, Véronique Rolli, Raony Guimaraes, Jose Malagon-Lopez, Perrine Spinnhirny, Alexandre Lederle, Razieh Mohseninia, Aurélie Hirschler, Leslie Muller, Paul Bastard, Adrian Gervais, Qian Zhang, François Danion, Yvon Ruch, Maleka Schenck, Olivier Collange, Thiên-Nga Chamaraux-Tran, Anne Molitor, Angélique Pichot, Alice Bernard, Ouria Tahar, Sabrina Bibi-Triki, Haiguo Wu, Nicodème Paul, Sylvain Mayeur, Annabel Larnicol, Géraldine Laumond, Julia Frappier, Sylvie Schmidt, Antoine Hanauer, Cécile Macquin, Tristan Stemmelen, Michael Simons, Xavier Mariette, Olivier Hermine, Samira Fafi-Kremer, Bernard Goichot, Bernard Drenou, Khaldoun Kuteifan, Julien Pottecher, Paul-Michel Mertes, Shweta Kailasan, M. Javad Aman, Elisa Pin, Peter Nilsson, Anne Thomas, Alain Viari, Damien Sanlaville, Francis Schneider, Jean Sibilia, Pierre-Louis Tharaux, Jean-Laurent Casanova, Yves Hansmann, Daniel Lidar, Mirjana Radosavljevic, Jeffrey R. Gulcher, Ferhat Meziani, Christiane Moog, Thomas W. Chittenden, Seiamak Bahram
Journal: Science Translational Medicine (2021)

The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confounding factors such as age and comorbidities, true mediators of this condition have remained elusive. We used a multi-omics analysis combined with artificial intelligence in a young patient cohort where major comorbidities were excluded at the onset. The cohort included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cell proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were used. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. Among differentially expressed genes, we observed up-regulation of the metalloprotease ADAM9 . This gene signature was validated in a second independent cohort of 81 critical and 73 recovered patients with COVID-19 and was further confirmed at the transcriptional and protein level and by proteolytic activity. Ex vivo ADAM9 inhibition decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. We further identified ADAM9 as a driver of disease severity and a candidate therapeutic target.
Adipocyte Induced Antagonism of ALL Growth Highlights a Novel Inhibitory Niche and Potential Therapeutic Opportunity
Authors: Nicholas Warrick, Farideh Miraki-Moud, A Aicher, Linda Ariza McNaughton, Pedro Casado-Izquierdo, Ai Nagano, Rebecca Carroll, Dominique Bonnet, John G. Gribben, Bela Patel
Journal: Blood (2017)
Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial
Authors: John Frater, Katie J Ewer, Ane Ogbe, Mathew Pace, Sandra Adele, Emily Adland, Jasmini Alagaratnam, Parvinder K Aley, Mohammad Ali, M Azim Ansari, Anna Bara, Mustapha Bittaye, Samantha Broadhead, Anthony Brown, Helen Brown, Federica Cappuccini, Enya Cooney, Wanwisa Dejnirattisai, Christina Dold, Cassandra Fairhead, Henry Fok, Pedro M Folegatti, Jamie Fowler, Charlotte Gibbs, Anna L Goodman, Daniel Jenkin, Mathew Jones, Rebecca Makinson, Natalie G Marchevsky, Yama F Mujadidi, Hanna Nguyen, Lucia Parolini, Claire Petersen, Emma Plested, Katrina M Pollock, Maheshi N Ramasamy, Sarah Rhead, Hannah Robinson, Nicola Robinson, Patpong Rongkard, Fiona Ryan, Sonia Serrano, Timothy Tipoe, Merryn Voysey, Anele Waters, Panagiota Zacharopoulou, Eleanor Barnes, Susanna Dunachie, Philip Goulder, Paul Klenerman, Gavin R Screaton, Alan Winston, Adrian V S Hill, Sarah C Gilbert, Andrew J Pollard, Sarah Fidler, Julie Fox, Teresa Lambe, Marion E.E. Watson, Rinn Song, Paola Cicconi, Angela M. Minassian, Sagida Bibi, Simon Kerridge, Nisha Singh, Catherine M. Green, Alexander D. Douglas, Alison M. Lawrie, Elizabeth A. Clutterbuck
Journal: The Lancet HIV (2021)
Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy
Authors: Hannah Reimann, Andrew Nguyen, J Zachary Sanborn, Charles J Vaske, Stephen C Benz, Kayvan Niazi, Shahrooz Rabizadeh, Patricia Spilman, Andreas Mackensen, Matthias Ruebner, Alexander Hein, Matthias W Beckmann, Edith D van der Meijden, Judith Bausenwein, Sascha Kretschmann, Marieke Griffioen, Jeffrey Schlom, James L Gulley, Karin L Lee, Duane H Hamilton, Patrick Soon-Shiong, Peter A Fasching, Anita N. Kremer
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Therapeutic regimens designed to augment the immunological response of a patient with breast cancer (BC) to tumor tissue are critically informed by tumor mutational burden and the antigenicity of expressed neoepitopes. Herein we describe a neoepitope and cognate neoepitope-reactive T-cell identification and validation program that supports the development of next-generation immunotherapies. Methods Using GPS Cancer, NantOmics research, and The Cancer Genome Atlas databases, we developed a novel bioinformatic-based approach which assesses mutational load, neoepitope expression, human leukocyte antigen (HLA)-binding prediction, and in vitro confirmation of T-cell recognition to preferentially identify targetable neoepitopes. This program was validated by application to a BC cell line and confirmed using tumor biopsies from two patients with BC enrolled in the Tumor-Infiltrating Lymphocytes and Genomics (TILGen) study. Results The antigenicity and HLA-A2 restriction of the BC cell line predicted neoepitopes were determined by reactivity of T cells from HLA-A2-expressing healthy donors. For the TILGen subjects, tumor-infiltrating lymphocytes (TILs) recognized the predicted neoepitopes both as peptides and on retroviral expression in HLA-matched Epstein-Barr virus–lymphoblastoid cell line and BC cell line MCF-7 cells; PCR clonotyping revealed the presence of T cells in the periphery with T-cell receptors for the predicted neoepitopes. These high-avidity immune responses were polyclonal, mutation-specific and restricted to either HLA class I or II. Interestingly, we observed the persistence and expansion of polyclonal T-cell responses following neoadjuvant chemotherapy. Conclusions We demonstrate our neoepitope prediction program allows for the successful identification of neoepitopes targeted by TILs in patients with BC, providing a means to identify tumor-specific immunogenic targets for individualized treatment, including vaccines or adoptively transferred cellular therapies.
Association of Child Race/Ethnicity With Parent and Guardian Feelings of Safety From School Security Practices
Authors: Anthony L. Bui, Jessica E. McDade, Hannah C. Deming, Samara Jinks-Chang, Frederick P. Rivara
Journal: JAMA Pediatrics (2021)

Feelings of Safety From School Security PracticesSchool security has increased over the years with an aim to improve student safety, 1,2 but students may experience greater criminalization. 3Of the more than 290 600 students referred to the police in 2015-2016, Black students represented more than twice their proportion of enrollment. 3eneral pediatricians monitor social determinants of health for youths, which should include school safety.Parents and guardians are important stakeholders in school safety. 4We surveyed parents and guardians of students to assess their feelings of safety across various school security practices and examined differences of perceived safety associated with child race/ethnicity.
Genetic Determinants of Somatic Selection of Mutational Processes in 3,566 Human Cancers
Authors: Jintao Guo, Ying Zhou, Chaoqun Xu, Qinwei Chen, Zsófia Sztupinszki, Judit Börcsök, Canqiang Xu, Feng Ye, Weiwei Tang, Jiapeng Kang, Lu Yang, Jiaxin Zhong, Taoling Zhong, Tianhui Hu, Rongshan Yu, Zoltan Szallasi, Xianming Deng, Qiyuan Li
Journal: Cancer Research (2021)

The somatic landscape of the cancer genome results from different mutational processes represented by distinct "mutational signatures." Although several mutagenic mechanisms are known to cause specific mutational signatures in cell lines, the variation of somatic mutational activities in patients, which is mostly attributed to somatic selection, is still poorly explained. Here, we introduce a quantitative trait, mutational propensity (MP), and describe an integrated method to infer genetic determinants of variations in the mutational processes in 3,566 cancers with specific underlying mechanisms. As a result, we report 2,314 candidate determinants with both significant germline and somatic effects on somatic selection of mutational processes, of which, 485 act via cancer gene expression and 1,427 act through the tumor-immune microenvironment. These data demonstrate that the genetic determinants of MPs provide complementary information to known cancer driver genes, clonal evolution, and clinical biomarkers. SIGNIFICANCE: The genetic determinants of the somatic mutational processes in cancer elucidate the biology underlying somatic selection and evolution of cancers and demonstrate complementary predictive power across cancer types.
Invasive mould disease in fatal COVID-19: a systematic review of autopsies
Authors: Brittany E Kula, Cornelius J Clancy, M Hong Nguyen, Ilan S Schwartz
Journal: The Lancet Microbe (2021)

Invasive mould disease (IMD) might affect up to a third of critically ill patients with COVID-19. COVID-19-associated pulmonary aspergillosis (CAPA) is typically diagnosed on the basis of a combination of non-specific clinical, radiographical, and mycological findings, but whether most cases represent invasive disease is unresolved. We systematically reviewed autopsy series of three or more decedents with COVID-19 for evidence of IMD. We searched PubMed, Web of Science, OVID (Embase), and medRxiv for studies in English or French published from Jan 1, 2019, to Sept 26, 2020. We identified 1070 references, of which 50 studies met the criteria. These studies described autopsies from 677 decedents, with individual-level data for 443 decedents. The median age was 70·0 years (IQR 57·0-79·0). Of decedents with individual-level data, 133 (30%) had diabetes, 97 (22%) had pre-existing lung disease, and 27 (6%) had immunocompromising conditions. Of 548 decedents with such data, 320 (58%) received invasive mechanical ventilation; among 140 decedents for whom this was known, ventilation was for a median of 9·0 days (IQR 5·0-20·0). Treatment included immunomodulation in 60 decedents and antifungals in 50 decedents. Autopsy-proven IMD occurred in 11 (2%) of 677 decedents, including eight CAPA, two unspecified IMD, and one disseminated mucormycosis. Among 320 decedents who received mechanical ventilation, six (2%) had IMD. We conclude that IMD, including CAPA, is an uncommon autopsy finding in COVID-19.
Differential Effect of t(11;14) Abnormality on Survival and Depth of Response in African American (AA) and Non-AA (NAA) Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Connect® MM Registry
Authors: Cristina J. Gasparetto, Rafat Abonour, Sundar Jagannath, Brian G.M. Durie, Mohit Narang, Howard R. Terebelo, Kathleen Toomey, James W. Hardin, Lynne Wagner, Shankar Srinivasan, Amani Kitali, E. Dawn Flick, Faiza Zafar, Amit Agarwal, Robert M Rifkin
Journal: Blood (2017)
Abstract 13923: A Screen Using Human Induced Pluripotent Stem Cell-Derived Hepatocytes to Identify Novel Drugs for the Treatment for Hypercholesterolemia
Authors: Jui Tung Liu, Mary P Lamprecht, Steven L Holshouser, Yuri K Peterson, Patrick M Woster, Stephen A Duncan
Journal: Circulation (2019)

Hypercholesterolemia is a key contributor to atherosclerosis and cardiovascular disease. The liver plays an essential role in regulating serum cholesterol levels by producing and recycling low-dens...
Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment
Authors: Sun Yoo, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Changhoon Yoo, Baek-Yeol Ryoo, Jonggi Choi
Journal: Clinical Gastroenterology and Hepatology (2021)
Prestroke Glucose Control and Functional Outcome in Patients With Acute Large Vessel Occlusive Stroke and Diabetes After Thrombectomy
Authors: Jun Young Chang, Wook-Joo Kim, Ji Hyun Kwon, Beom Joon Kim, Joon-Tae Kim, Jun Lee, Jae Kwan Cha, Dae-Hyun Kim, Yong-Jin Cho, Keun-Sik Hong, Soo Joo Lee, Jong-Moo Park, Byung-Chul Lee, Mi Sun Oh, Sang-Hwa Lee, Chulho Kim, Dong-Eog Kim, Kyung Bok Lee, Tae Hwan Park, Jay Chol Choi, Dong-Ick Shin, Sung-Il Sohn, Jeong-Ho Hong, Ji Sung Lee, Hee-Joon Bae, Moon-Ku Han
Journal: Diabetes Care (2021)

To evaluate whether prestroke glucose control is associated with functional outcomes in patients with acute large vessel occlusive stroke and diabetes who underwent intra-arterial thrombectomy (IAT).From the Clinical Research Center for Stroke-Korea registry, we included patients with emergent large vessel occlusive stroke with diabetes who underwent IAT between January 2009 and March 2020. The association between the HbA1c level at admission and functional outcomes (modified Rankin Scale at 3 months after the index stroke) was assessed.A total of 1,351 patients were analyzed. Early neurological deterioration was more common in patients with higher levels of HbA1c at admission (P = 0.02 according to HbA1c quintiles, P = 0.003 according to an HbA1c cutoff value of 7.0%) than in those with lower HbA1c levels. Higher HbA1c levels at admission were significantly associated with decreased odds of favorable functional outcomes at a threshold of 7.0-7.1%. The association was consistently observed in subgroups divided according to age, sex, stroke subtype, occlusion site, degree of recanalization, thrombolysis modalities, time from symptom onset to groin puncture, and treatment period.Prestroke glucose control with a target HbA1c of ≤7.0% may be beneficial for neurological recovery in patients with diabetes undergoing IAT for large vessel occlusive stroke, regardless of stroke subtype, bridging intravenous thrombolysis, occlusion site, degree of recanalization, and treatment period.
Endoscopic ultrasound-guided one-step antegrade metal stent placement with an ultra-slim introducer for preoperative biliary drainage
Authors: Saburo Matsubara, Keito Nakagawa, Kentaro Suda, Tetsuro Fujita, Takeshi Otsuka, Masashi Oka, Sumiko Nagoshi
Journal: Endoscopy (2021)

A 55-year-old-female suffered from advanced obstructive jaundice due to resecetable pancreatic cancer ([Fig. 1]). Preoperative biliary drainage via endoscopic retrograde cholangiopancreatography (ERCP) was attempted but unsuccessful due to duodenal obstruction. We then attempted endoscopic ultrasound-guided antegrade stenting using a novel uncovered self-expandable metal stent (SEMS) with an ultra-slim 5.4-Fr introducer and an ultra-tapered stiff tip (YABUSAME; Kaneka Medix, Osaka, Japan) ([Fig. 2]) after placement of a duodenal stent ([Video 1]). B2 was punctured with a 19-gauge needle via the stomach followed by contrast injection to depict the biliary tree ([Fig. 3 a]). Then, a 0.025-inch angle-tip guidewire (INAZUMA; Kaneka Medix) was successfully manipulated antegrade into the duodenum through the stricture. Just after a removal of the needle, an introducer of a YABUSAME (10 × 60 mm) was inserted into the bile duct without any tract dilation and easily passed through the stricture ([Fig. 3 b]). Finally, the stent was deployed ([Fig. 3 c]). No adverse events had occurred for two weeks until surgery.
Myc媒介SDHAアセチル化は遺伝子発現と腫瘍形成のエピジェネティックな調節を誘発する【JST・京大機械翻訳】
Authors: Li Shi-Ting, Huang De, Shen Shengqi, Cai Yongping, Xing Songge, Wu Gongwei, Jiang Zetan, Hao Yijie, Yuan Mengqiu, Wang Nana, Zhu Lianbang, Yan Ronghui, Yang Dongdong, Wang Lin, Liu Zhaoji, Hu Xin, Zhou Rongbin, Qu Kun, Li Ailing, Duan Xiaotao, Zhang Huafeng, Gao Ping
Journal: Nature Metabolism (2020)
Microbial dysbiosis and epigenetics modulation in cancer development – A chemopreventive approach
Authors: Shafiul Haque, Ritu Raina, Nazia Afroze, Arif Hussain, Ahmad Alsulimani, Vineeta Singh, Bhartendu Nath Mishra, Sanjana Kaul, Ravindra Nath Kharwar
Journal: Seminars in Cancer Biology (2021)
Lung microbiota predict invasive pulmonary aspergillosis and its outcome in immunocompromised patients
Authors: Anaïs Hérivaux, Jesse R Willis, Toine Mercier, Katrien Lagrou, Samuel M Gonçalves, Relber A Gonçales, Johan Maertens, Agostinho Carvalho, Toni Gabaldón, Cristina Cunha
Journal: Thorax (2021)

Rationale Recent studies have revealed that the lung microbiota of critically ill patients is altered and predicts clinical outcomes. The incidence of invasive fungal infections, namely, invasive pulmonary aspergillosis (IPA), in immunocompromised patients is increasing, but the clinical significance of variations in lung bacterial communities is unknown. Objectives To define the contribution of the lung microbiota to the development and course of IPA. Methods and measurements We performed an observational cohort study to characterise the lung microbiota in 104 immunocompromised patients using bacterial 16S ribosomal RNA gene sequencing on bronchoalveolar lavage samples sampled on clinical suspicion of infection. Associations between lung dysbiosis in IPA and pulmonary immunity were evaluated by quantifying alveolar cytokines and chemokines and immune cells. The contribution of microbial signatures to patient outcome was assessed by estimating overall survival. Main results Patients diagnosed with IPA displayed a decreased alpha diversity, driven by a markedly increased abundance of the Staphylococcus , Escherichia , Paraclostridium and Finegoldia genera and a decreased proportion of the Prevotella and Veillonella genera. The overall composition of the lung microbiome was influenced by the neutrophil counts and associated with differential levels of alveolar cytokines. Importantly, the degree of bacterial diversity at the onset of IPA predicted the survival of infected patients. Conclusions Our results reveal the lung microbiota as an understudied source of clinical variation in patients at risk of IPA and highlight its potential as a diagnostic and therapeutic target in the context of respiratory fungal diseases.
Covid-19: Israel advises against foreign travel after recording 125 new cases
Authors: Michael Day
Journal: BMJ (2021)

Covid-19: Israel advises against foreign travel after recording 125 new cases Michael DayIsrael's new prime minister, Naftali Bennett, is reconvening the coronavirus cabinet and has urged Israelis to avoid non-urgent foreign travel after 125 people tested positive for coronavirus on 21 June, most with the delta variant probably caught abroad.
Gastrointestinal Bleeding and Angiodysplasia in Von Willebrand Disease: Results from the Ongoing French HRQoL Study: Wish-Qol
Authors: Annie Borel-Derlon, Dominique Desprez, Fabienne Volot, Herve Chambost, Sophie Bayard, Catherine Chatelanaz, Catherine Doriat-Robin, Yves Gruel, Agnès Veyradier, Jenny Goudemand, Sylvia Von Mackensen
Journal: Blood (2017)