tbuckley/cabot-search huggingface dataset:
OS06.4A Identification of T cell receptors targeting ZFTA-RELA fusion-positive ependymoma
Authors: N Kehl, M Friedrich, M Kilian, T Zheng, K Pajtler, L Bunse, M Platten
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The oncogenic gene fusion between ZFTA (formerly C11orf95) and RELA has in recent years been highlighted as oncogenic driver event ultimately leading to malignant transformation and progression of ependymoma. Representing a genetic hallmark in 17.6% of ependymomas, ZFTA-RELA fusion-positive tumors qualified as separate diagnostic entity in the 2016 revision of the WHO classification of CNS tumors. This tumor entity mainly occurs in pediatric patients and is characterized by poor prognosis and the lack of biology-driven therapy. RESULTS De novo prediction of putative gene fusion-derived neoepitopes in malignant CNS diseases yielded several potential candidates suitable for screening. Of these, vaccination of A2.DR1-transgenic major histocompatibility complex (MHC)-humanized mice with in silico compiled peptide vaccines encompassing the ZFTA-RELA fusion sequence elicited robust antigen-specific CD4+-restricted immune responses. We identified ZFTA-RELA-reactive T cell clones by multiplexed Interferon-γ / Interleukin-2 recall response. Single-cell VDJ-sequencing of reactive T cells demonstrated a highly clonal T cell receptor (TCR) repertoire and shared clonotypes among all vaccinated animals. Matching TCRα/β chains have been assembled from single-cell sequencing data and cloned for functional testing of neoepitope-reactive TCR-transgenic T cells in vitro as well as in vivo using a transposon system-based immunocompetent, MHC-humanized ZFTA-RELA fusion-positive ependymoma model. CONCLUSION Here we identify the oncogenic ZFTA-RELA gene fusion product as a novel tumor-specific neoepitope that is recognized by MHC class II-restricted TCRs. Therapeutic efficacy of TCR-transgenic cell therapy can be further investigated using an immunocompetent MHC-humanized mouse model of ZFTA-RELA fusion-positive ependymoma. Our findings provide initial evidence for neoepitope-specific immunotherapy in pediatric CNS tumors.
Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: J.-P. Machiels, C. René Leemans, W. Golusinski, C. Grau, L. Licitra, V. Gregoire
Journal: Annals of Oncology (2020)
Transposon-triggered innate immune response confers cancer resistance to the blind mole rat
Authors: Yang Zhao, Ena Oreskovic, Quanwei Zhang, Quan Lu, Abbey Gilman, Yifei S. Lin, Junyue He, Zhizhong Zheng, J. Yuyang Lu, Jina Lee, Zhonghe Ke, Julia Ablaeva, Matthew J. Sweet, Steve Horvath, Zhengdong Zhang, Eviatar Nevo, Andrei Seluanov, Vera Gorbunova
Journal: Nature Immunology (2021)
What to do about the leaky gut
Authors: Michael Camilleri, Adrian Vella
Journal: Gut (2021)

### Key messages

The potential role of ‘leaky gut’ or reduced barrier function with increased intestinal permeability has been considered an important factor in intestinal and extraintestinal diseases. Reversing the impairment of barrier function in diseases associated with mucosal damage may be necessary but may not be sufficient to reverse the disease pathogenesis as in inflammatory bowel disease (IBD) or coeliac disease. In these diseases, the underlying immune dysfunction is likely to be a significant factor in perpetuating the disease. Nevertheless, gastrointestinal and extraintestinal diseases that are not associated with predominant inflammation in the small intestine or colon have drawn attention to the potential role of reduced barrier function in disease pathogenesis. These illnesses range from eosinophilic esophagitis to non-alcoholic fatty liver disease and to diverse neuropsychiatric diseases, as summarised elsewhere.1 There are also diverse systemic consequences associated with gut barrier dysfunction including increased inflammation or oxidative stress and decreased insulin sensitivity affecting tissues or organs such as the liver, fat, skeletal, muscle …
Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species
Authors: Xiao-Jing Zhang, Xiaolan Liu, Manli Hu, Guo-Jun Zhao, Dating Sun, Xu Cheng, Hui Xiang, Yong-Ping Huang, Rui-Feng Tian, Li-Jun Shen, Jun-Peng Ma, Hai-Ping Wang, Song Tian, Shanyu Gan, Haibo Xu, Rufang Liao, Toujun Zou, Yan-Xiao Ji, Peng Zhang, Jingjing Cai, Zhao V Wang, Guannan Meng, Qingbo Xu, Yibin Wang, Xin-Liang Ma, Peter P Liu, Zan Huang, Lihua Zhu, Zhi-Gang She, Xin Zhang, Lan Bai, Hailong Yang, Zhibing Lu, Hongliang Li
Journal: Cell Metabolism (2021)
Primary Versus Secondary Anaplastic Thyroid Carcinoma: Perspectives from Multi-institutional and Population-Level Data
Authors: Tam N. M. Ngo, Trang T. B. Le, Thoa Le, Andrey Bychkov, Naoki Oishi, Chan Kwon Jung, Lewis Hassell, Kennichi Kakudo, Huy Gia Vuong
Journal: Endocrine Pathology (2021)
Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases
Authors: Zhi Yu, Jin Jin, Adrienne Tin, Anna Köttgen, Bing Yu, Jingsha Chen, Aditya Surapaneni, Linda Zhou, Christie M. Ballantyne, Ron C. Hoogeveen, Dan E. Arking, Nilanjan Chatterjee, Morgan E. Grams, Josef Coresh
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Genome-wide association studies have uncovered numerous loci influencing kidney function (eGFR), but the relationship of genetic risk to kidney disease incidence or the circulating proteome is unknown. Large genome-wide association samples and recent methods allowed us to calculate a powerful genome-wide polygenic risk score (PRS) incorporating information on 1.5 million single nucleotide polymorphisms. This PRS was significantly associated with risk of CKD, ESKD, kidney failure, and AKI, and with 132 circulating plasma proteins at both midlife and older age. Contemporary kidney function markers, such as eGFR, mediate most of the associations with the plasma proteome. Background Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (eGFR). The relationship between polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS ( n =765,348) and UK Biobank GWAS (90% of the cohort; n =451,508), followed by best-parameter selection using the remaining 10% of UK Biobank data ( n =45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study ( n =8866) with incident CKD, ESKD, kidney failure, and AKI. We also examined associations between the PRS and 4877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results The developed PRS showed a significant association with all outcomes. Hazard ratios per 1 SD lower PRS ranged from 1.06 (95% CI, 1.01 to 1.11) to 1.33 (95% CI, 1.28 to 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin C, collagen α -1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for five proteins, including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.
Impact of COVID-19 pandemic on oncologists’ professional and personal lives: A pre-vaccine study.
Authors: Ajeet Gajra, Yolaine Jeune-Smith, Stephanie Fortier, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2021)

45 Background: The COVID-19 pandemic has adversely impacted healthcare workers globally, leading to high rates of burnout, especially among frontline workers. We conducted a study to assess the pandemic’s impact on community-based medical oncologists and hematologists (mO/H) in the U.S. before the widespread distribution of vaccines. Methods: Between October and December 2020, mO/H participated in a compensated, online survey addressing the impact of COVID-19 on oncologists’ professional and personal lives and other issues in oncology; demographic, clinical, and practice-based questions were also asked. Results are presented using descriptive statistics. Results: A total of 259 geographically diverse mO/H, with a median of 18 (1-42) years in practice, completed the survey. At the time of the study, local trends in COVID-19 cases were reported as increasing, stable, or decreasing by 29%, 51%, and 20%, respectively. The summative view of the pandemic was “proud of my work as a physician in the frontlines” (37%), “a challenge to get through” (35%), and “no significant impact” (23%). Over half reported a moderate to severe impact on their professional (60%) and personal lives (65). The top 3 factors adversely impacting professional life were: concern of transmitting COVID-19 to patients or staff (52%), difficulty providing patient care (45%), and loss of income (41%). The top 4 factors adversely impacting personal life were: concerns of safety for self and family (84%), a sense of anxiety (50%), loss of family income (24%), and a sense of depression/doom (22%). Fifty percent agreed or strongly agreed that they had increased burnout at work since the beginning of the pandemic. However, workload was assessed as stable (51%) or reduced (33%) during the pandemic. The top 3 factors contributing to burnout were: loss of face-to-face patient interaction (46%), financial loss by practice (42%), and reduced patient volume (35%). The factors thought to impact income were: use of virtual patients visits (38%), pay cuts from the employer (33%), and cancellation of elective procedures (31%). Overall, 41% reported receiving funds from government-based programs (e.g., CARES act) during the pandemic. While about half (52%) did not believe that the pandemic would impact their retirement, some felt that the pandemic would likely hasten (17%) or delay (17%) their plans to retire. Conclusions: This study confirms greater feelings of burnout among U.S. community-based mO/H in the wake of the pandemic and offers insight into drivers of professional and personal dissatisfaction. While mO/H have concerns about loss of income, notably, loss of in-person patient interaction is also a key factor impacting their professional satisfaction. Given the high baseline rate of burnout among mO/H, it is critical to prevent, mitigate and control additional risks imposed by pandemic-related factors.
Contemporary antiretrovirals and body-mass index: a prospective study of the RESPOND cohort consortium
Authors: Loveleen Bansi-Matharu, Andrew Phillips, Cristiana Oprea, Katharina Grabmeier-Pfistershammer, Huldrych F Günthard, Stephane De Wit, Giovanni Guaraldi, Jorg J Vehreschild, Ferdinand Wit, Matthew Law, Jan-Christian Wasmuth, Nikoloz Chkhartishvili, Antonella d'Arminio Monforte, Eric Fontas, Jan Vesterbacka, Jose M Miro, Antonella Castagna, Christoph Stephan, Josep M Llibre, Bastian Neesgaard, Lauren Greenberg, Colette Smith, Ole Kirk, Claudine Duvivier, Gordana Dragovic, Jens Lundgren, Nikos Dedes, Andreas Knudsen, Joel Gallant, Vani Vannappagari, Lars Peters, Daniel Elbirt, Mario Sarcletti, Dominique L Braun, Coca Necsoi, Cristina Mussini, Camilla Muccini, Natalie Bolokadze, Jennifer Hoy, Amanda Mocroft, Lene Ryom
Journal: The Lancet HIV (2021)
Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis
Authors: William Whalen, Mustafa Buyukozkan, Bethany Moore, Jong-Seok Moon, Charles S Dela Cruz, Fernando J Martinez, Augustine M K Choi, Jan Krumsiek, Heather Stout-Delgado, Soo Jung Cho
Journal: Thorax (2021)

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear aetiology and poorly understood pathophysiology. Although plasma levels of circulating cell-free DNA (ccf-DNA) and metabolomic changes have been reported in IPF, the associations between ccf-DNA levels and metabolic derangements in lung fibrosis are unclear. Here, we demonstrate that ccf-double-stranded DNA (dsDNA) is increased in patients with IPF with rapid progression of disease compared with slow progressors and healthy controls and that ccf-dsDNA associates with amino acid metabolism, energy metabolism and lipid metabolism pathways in patients with IPF.
Location matters: Profiling diffuse type gastric cancer at the single cell level
Authors: Huocong Huang, Rolf A. Brekken
Journal: Clinical Cancer Research (2021)

Spatial single-cell transcriptomics of primary patient diffuse type gastric cancer reveals distinct cancer and stromal cell differences based on location. Expression of CCL2 by stromal cells in deep tumor regions is highlighted as potentially driving the immunosuppressive microenvironment and enhancing (directly or indirectly) the invasive capacity of tumor cells.
Characterisation of vaccine breakthrough infections of SARS-CoV-2 Delta and Alpha variants and within-host viral load dynamics in the community, France, June to July 2021
Authors: François Blanquart, Clémence Abad, Joëvin Ambroise, Mathieu Bernard, Gina Cosentino, Jean-Marc Giannoli, Florence Débarre
Journal: Eurosurveillance (2021)

We compared PCR results from SARS-CoV-2-positive patients tested in the community in France from 14 June to 30 July 2021. In asymptomatic individuals, Cq values were significantly higher in fully vaccinated than non-fully vaccinated individuals (effect size: 1.7; 95% CI: 1–2.3; p &lt; 10 −6 ). In symptomatic individuals and controlling for time since symptoms, the difference vanished (p = 0.26). Infections with the Delta variant had lower Cq values at symptom onset than with Alpha (effect size: −3.32; 95% CI: −4.38 to −2.25; p &lt; 10 −6 ).
Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy
Authors: James Harber, Tamihiro Kamata, Catrin Pritchard, Dean Fennell
Journal: Journal for ImmunoTherapy of Cancer (2021)

Malignant pleural mesothelioma (MPM) is an incurable cancer with a dismal prognosis and few effective treatment options. Nonetheless, recent positive phase III trial results for immune checkpoint blockade (ICB) in MPM herald a new dawn in the fight to advance effective treatments for this cancer. Tumor mutation burden (TMB) has been widely reported to predict ICB in other cancers, but MPM is considered a low-TMB tumor. Similarly, tumor programmed death-ligand 1 (PD-L1) expression has not been proven predictive in phase III clinical trials in MPM. Consequently, the precise mechanisms that determine response to immunotherapy in this cancer remain unknown. The present review therefore aimed to synthesize our current understanding of the tumor immune microenvironment in MPM and reflects on how specific cellular features might impact immunotherapy responses or lead to resistance. This approach will inform stratified approaches to therapy and advance immunotherapy combinations in MPM to improve clinical outcomes further.
A novel droplet digital polymerase chain reaction for diagnosis of pneumocystis pneumonia (PCP)—a clinical performance study and survey of sulfamethoxazole-trimethoprim resistant mutations
Authors: Anupop Jitmuang, Anapat Nititammaluk, Thitaya Boonsong, Patsharaporn Techasintana Sarasombath, Suree Sompradeekul, Methee Chayakulkeeree
Journal: Journal of Infection (2021)

Objectives To determine the performance of droplet digital polymerase chain reaction (ddPCR) assays in diagnosing Pneumocystis pneumonia (PCP), and to survey the sulfamethoxazole-trimethoprim (SMX-TMP) resistant mutations in our PCP cohort.Methods A prospective study was conducted from January 2017 to June 2018. Adult immunocompromised subjects with pneumonia were enrolled. Bronchoalveolar lavage fluid samples were obtained for standard microscopic testing and ddPCR to quantify the Pneumocystis MSG gene. DHPS and DHFR gene sequencings were performed to detect SMX-TMP resistance.Results Of 54 subjects, 12 had definite PCP, 7 had probable PCP, and 35 were non-PCP. In the PCP cohort, 10 (53%) had HIV infections. Using a cutoff value of ≥ 1.94 copies/µL, the ddPCR exhibited an overall sensitivity of 91.7% (61.5–99.8%) and specificity of 88.1% (74.4–96%). It showed a better performance when different cutoff values were used in subjects with HIV (≥ 1.80 copies/µL) and non-HIV (≥ 4.5 copies/µL). ROC curves demonstrated an AUC of 0.80 (95% CI, 0.56–1.0) for the HIV group, and 0.99 (95% CI, 0.95–1.0) for the non-HIV group. Of 16 PCP samples tested for DHPS- and DHFR-mutations, only DHPS mutations were detected (2). Most of the subjects, including those with DHPS mutations, demonstrated favorable outcomes.Conclusions The ddPCR exhibited a satisfactory diagnostic performance for PCP. Based on very limited data, the treatment outcomes of PCP did not seem to be affected by the DHPS mutations.
Endocrine-Disrupting Chemicals and Child Health
Authors: Akhgar Ghassabian, Laura Vandenberg, Kurunthachalam Kannan, Leonardo Trasande
Journal: The Annual Review of Pharmacology and Toxicology (2021)

While definitions vary, endocrine-disrupting chemicals (EDCs) have two fundamental features: their disruption of hormone function and their contribution to disease and disability. The unique vulnerability of children to low-level EDC exposures has eroded the notion that only the dose makes the thing a poison, requiring a paradigm shift in scientific and policy practice. In this review, we discuss the unique vulnerability of children as early as fetal life and provide an overview of epidemiological studies on programming effects of EDCs on neuronal, metabolic, and immune pathways as well as on endocrine, reproductive, and renal systems. Building on this accumulating evidence, we dispel and address existing myths about the health effects of EDCs with examples from child health research. Finally, we provide a list of effective actions to reduce exposure and subsequent harm that are applicable to individuals, communities, and policy-makers.
PD-3 Impact of RAS status, prior targeted therapy, age, and gender on the activity of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer: Real-world data from the QoLiTrap study
Authors: R. von Moos, J. Thaler, H. Kröning, M. Zahn, F. Scholten, S. Pederiva, S. Anchisi, P. Bohanes, B. Grünberger, C. Windemuth-Kieselbach, G. Piringer, R. Hofheinz
Journal: Annals of Oncology (2021)
Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the <i>ATM</i> Gene
Authors: Fang-Chi Hsu, Nicholas J. Roberts, Erica Childs, Nancy Porter, Kari G. Rabe, Ayelet Borgida, Chinedu Ukaegbu, Michael G. Goggins, Ralph H. Hruban, George Zogopoulos, Sapna Syngal, Steven Gallinger, Gloria M. Petersen, Alison P. Klein
Journal: JAMA Oncology (2021)

Pathogenic germline variants in the ATM gene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATM variants has not been well estimated.To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene.This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germline ATM variant. Data analyses were performed from January 2020 to February 2021.Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis.The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) in ATM variant carriers compared with noncarriers.This multicenter cohort study found that individuals with a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.
Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target
Authors: Wenjing Qian, Mingfang Zhao, Ruoyu Wang, Heming Li
Journal: Journal of Hematology & Oncology (2021)

Abstract Immune checkpoint therapy has achieved significant efficacy by blocking inhibitory pathways to release the function of T lymphocytes. In the clinic, anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) have progressed to first-line monotherapies in certain tumor types. However, the efficacy of anti-PD-1/PD-L1 mAbs is still limited due to toxic side effects and de novo or adaptive resistance. Moreover, other immune checkpoint target and biomarkers for therapeutic response prediction are still lacking; as a biomarker, the PD-L1 (CD274, B7-H1) expression level is not as accurate as required. Hence, it is necessary to seek more representative predictive molecules and potential target molecules for immune checkpoint therapy. Fibrinogen-like protein 1 (FGL1) is a proliferation- and metabolism-related protein secreted by the liver. Multiple studies have confirmed that FGL1 is a newly emerging checkpoint ligand of lymphocyte activation gene 3 (LAG3), emphasizing the potential of targeting FGL1/LAG3 as the next generation of immune checkpoint therapy. In this review, we summarize the substantial regulation mechanisms of FGL1 in physiological and pathological conditions, especially tumor epithelial to mesenchymal transition, immune escape and immune checkpoint blockade resistance, to provide insights for targeting FGL1 in cancer treatment.