tbuckley/cabot-search huggingface dataset:
The role of ubiquitination and deubiquitination in cancer metabolism
Authors: Tianshui Sun, Zhuonan Liu, Qing Yang
Journal: Molecular Cancer (2020)

Abstract Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.
Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population
Authors: Nicolas Chapelle, Myriam Martel, Esther Toes-Zoutendijk, Alan N Barkun, Marc Bardou
Journal: Gut (2020)

Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. Its development is a multistep process that spans more than 15 years, thereby providing an opportunity for prevention and early detection. The high incidence and mortality rates emphasise the need for prevention and screening. Many countries have therefore introduced CRC screening programmes. It is expected, and preliminary evidence in some countries suggests, that this screening effort will decrease CRC-related mortality rates. CRC prevention involves a healthy lifestyle and chemoprevention—more specifically, oral chemoprevention that can interfere with progression from a normal colonic mucosa to adenocarcinoma. This preventive effect is important for individuals with a genetic predisposition, but also in the general population. The ideal chemopreventive agent, or combination of agents, remains unknown, especially when considering safety during long-term use. This review evaluates the evidence across 80 meta-analyses of interventional and observational studies of CRC prevention using medications, vitamins, supplements and dietary factors. This review suggests that the following factors are associated with a decreased incidence of CRC: aspirin, non-steroidal anti-inflammatory drugs, magnesium, folate, a high consumption of fruits and vegetables, fibre and dairy products. An increased incidence of CRC was observed with frequent alcohol or meat consumption. No evidence of a protective effect for tea, coffee, garlic, fish and soy products was found. The level of evidence is moderate for aspirin, β-carotene and selenium, but is low or very low for all other exposures or interventions.
Biocompatible sulfated valproic acid-coupled polysaccharide-based nanocarriers with HDAC inhibitory activity
Authors: Marie Kühne, Henry Lindemann, Christian Grune, Daniel Schröder, Zoltán Cseresnyés, Maren Godmann, Andreas Koschella, Marc Thilo Figge, Christian Eggeling, Dagmar Fischer, Thomas Heinze, Thorsten Heinzel
Journal: Journal of Controlled Release (2020)
Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy
Authors: Eduardo Huarte, Roddy S. O'Connor, Michael T. Peel, Selene Nunez-Cruz, John Leferovich, Ashish Juvekar, Yan-ou Yang, Lisa Truong, Taisheng Huang, Ahmad Naim, Michael C. Milone, Paul A. Smith
Journal: Clinical Cancer Research (2020)

Abstract Purpose: T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including IFNγ and IL6. Experimental Design: Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, antitumor activity, and cytokine levels in in vitro and in vivo models. Results: We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T cells adoptively transferred into CD19+ tumor-bearing immunodeficient animals was unabated by oral itacitinib treatment. Conclusions: Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T cell–induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).
Abstract 366: Cardiac Strain From Magnetic Resonance Imaging Offers Sensitive Detection of Therapeutic Efficacy Following Transplantation of Tissue Engineered Heart Muscles
Authors: Xulei Qin, Johannes Riegler, Malte Tiburcy, Thomas Denney, Wolfram Zimmermann, Joseph Wu
Journal: Circulation Research (2016)

Background: Myocardial infarction (MI) leads to gradually decreased cardiac contractility that can ultimately cause heart failure or sudden death. One potential therapy to recover this MI-impaired contractile function is the regenerative approach that integrates both tissue engineering and exogenously produced cardiomyocytes. Although this contractile recovery has been assessed by different imaging methods in previous studies, these assessments in global cardiac performance are plagued by their relatively low sensitivity. As this treatment is locally performed, the sensitivity of its therapeutic assessment can be improved by myocardial strain imaging that assesses regional contractility. Methods: We first made tissue engineered heart muscles (EHMs) by casting human embryonic stem cell-derived cardiomyocytes (ESC-CMs) with collagen in preformed molds. Then we transplanted these EHMs (n=12) into the post-MI rat hearts one month after this injure. We also performed sham surgeries on a control group (n=9) without EHM transplantation. Meanwhile, strain imaging from cardiac magnetic resonance imaging (MRI) and ultrasound were performed prior to and four weeks after EHM transplantations. In addition, global cardiac performance such as left ventricular ejection fraction (EF) was estimated from cardiac MRI. Results: Based on the measurements, regional myocardial strain measured from tagged MRI detected the preserved systolic function in the EHM-treated group compared to control group (P=0.04). In contrary, the global function EF was unable to detect this significant difference between both groups (P=0.38). Similarly, myocardial strain measured from cardiac ultrasound also failed to detect the significance between both treatment and control groups (P=0.24). Conclusions: This study for the first time confirmed that regional assessment of contractile function offered higher sensitivity compared to the conventional measure of global systolic performance. This finding highlights the feasibility and sensitivity of cardiac strain derived from tagged MRI as a sensitive method to assess the efficacy of regenerative therapies in both preclinical and clinical studies.
Association of a Prior Psychiatric Diagnosis With Mortality Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Infection
Authors: Luming Li, Fangyong Li, Frank Fortunati, John H. Krystal
Journal: JAMA Network Open (2020)

psychiatric condition.The finding is similar to previous findings: individuals with concurrent psychiatric and medical diagnoses had poorer outcomes and higher mortality. 4,5 is unclear why psychiatric illness predisposes to COVID-19-related mortality.Psychiatric symptoms may arise as a marker of systemic pathophysiologic processes, such as inflammation, that may, in turn, predispose to mortality.Similarly, psychiatric disorders may augment systemic inflammation and compromise the function of the immune system, while psychotropic medications may also be associated with to mortality risk. 6e limitations to the study include the fact that those individuals not hospitalized for COVID-19 or who died outside the hospital were not used in the analysis.In addition, diagnosis codes were used to assess for any psychiatric diagnosis, without accounting for the status of psychiatric treatment (patient with active, in-remission, or recovered psychiatric disorder).The data also do not include COVID-19 treatment information.
The mosaic genome of indigenous African cattle as a unique genetic resource for African pastoralism
Authors: Kwondo Kim, Taehyung Kwon, Tadelle Dessie, DongAhn Yoo, Okeyo Ally Mwai, Jisung Jang, Samsun Sung, SaetByeol Lee, Bashir Salim, Jaehoon Jung, Heesu Jeong, Getinet Mekuriaw Tarekegn, Abdulfatai Tijjani, Dajeong Lim, Seoae Cho, Sung Jong Oh, Hak-Kyo Lee, Jaemin Kim, Choongwon Jeong, Stephen Kemp, Olivier Hanotte, Heebal Kim
Journal: Nature Genetics (2020)
Two-in-one strategy: a remineralizing and anti-adhesive coating against demineralized enamel
Authors: Ailin Hou, Jun Luo, Min Zhang, Jianshu Li, Wenlin Chu, Kunneng Liang, Jiaojiao Yang, Jiyao Li
Journal: International Journal of Oral Science (2020)

Abstract Tooth enamel is prone to be attacked by injurious factors, leading to a de/remineralization imbalance. To repair demineralized enamel and prevent pulp inflammation caused by biofilm accumulation, measures are needed to promote remineralization and inhibit bacterial adhesion on the tooth surface. An innovative material, poly (aspartic acid)-polyethylene glycol (PASP-PEG), was designed and synthesized to construct a mineralizing and anti-adhesive surface that could be applied to repair demineralized enamel. A cytotoxicity assay revealed the low cytotoxicity of synthesized PASP-PEG. Adsorption results demonstrated that PASP-PEG possesses a high binding affinity to the hydroxyapatite (HA)/tooth surface. In vitro experiments and scanning electron microscopy (SEM) demonstrated a strong capacity of PASP-PEG to induce in situ remineralization and direct the oriented growth of apatite nanocrystals. Energy dispersive X-ray spectroscopy (EDS), X-ray diffraction analysis (XRD) and Vickers hardness tests demonstrated that minerals induced by PASP-PEG were consistent with healthy enamel in Ca/P ratio, crystal form and surface micro-hardness. Contact angle tests and bacterial adhesion experiments demonstrated that PASP-PEG yielded a strong anti-adhesive effect. In summary, PASP-PEG could achieve dual effects for enamel repair and anti-adhesion of bacteria, thereby widening its application in enamel repair.
T-cell agonists in cancer immunotherapy
Authors: Yeonjoo Choi, Yaoyao Shi, Cara L Haymaker, Aung Naing, Gennaro Ciliberto, Joud Hajjar
Journal: Journal for ImmunoTherapy of Cancer (2020)

Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.
Mortality, Stroke, and Hospitalization Associated With Deferred vs Expedited Aortic Valve Replacement in Patients Referred for Symptomatic Severe Aortic Stenosis During the COVID-19 Pandemic
Authors: Christoph Ryffel, Jonas Lanz, Noé Corpataux, Nicole Reusser, Stefan Stortecky, Stephan Windecker, Thomas Pilgrim
Journal: JAMA Network Open (2020)

This cohort study evaluates the outcomes associated with deferred vs expedited aortic valve replacement in patients with severe aortic stenosis during the COVID-19 pandemic.
BATF3 programs CD8+ T cell memory
Authors: Marco A. Ataide, Karl Komander, Konrad Knöpper, Annika E. Peters, Hao Wu, Sarah Eickhoff, Tea Gogishvili, Justus Weber, Anika Grafen, Axel Kallies, Natalio Garbi, Hermann Einsele, Michael Hudecek, Georg Gasteiger, Michael Hölzel, Martin Vaeth, Wolfgang Kastenmüller
Journal: Nature Immunology (2020)
Lower Daily Carbohydrate Intake Is Associated With Improved Glycemic Control in Adults With Type 1 Diabetes Using a Hybrid Closed-Loop System
Authors: Vera Lehmann, Thomas Zueger, Anna Zeder, Sam Scott, Lia Bally, Markus Laimer, Christoph Stettler
Journal: Diabetes Care (2020)

OBJECTIVE To assess the association between daily carbohydrate (CHO) intake and glycemic control in adult hybrid closed-loop (HCL) users with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Mean individual daily CHO intake (MIDC) and relative deviation from MIDC (≤80% low, 81–120% medium, &amp;gt;120% high CHO consumption) were compared with parameters of glycemic control assessed by continuous glucose monitoring. RESULTS Records from 36 patients (26 male, 10 female; age 36.9 ± 13.5 years; HbA1c 7.1 ± 0.9% [54 ± 10 mmol/mol]) provided 810 days of data (22.5 ± 6.7 days per patient). Time in range (70–180 mg/dL) for low, medium, and high CHO consumption was 77.4 ± 15.4%, 75.2 ± 16.7%, and 70.4 ± 17.8%, respectively (P &amp;lt; 0.001). Time above range (&amp;gt;180 mg/dL) was 20.1 ± 14.7%, 22.0 ± 16.9%, and 27.2 ± 18.4%, respectively (P &amp;lt; 0.001). There was no between-group difference for time in hypoglycemia (&amp;lt;70 mg/dL; P = 0.50). CONCLUSIONS Daily CHO intake was inversely associated with glycemic control in adults with T1D using an HCL system. Lower CHO intake may be a strategy to optimize glucose control in HCL users.
Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development
Authors: Egle Katkeviciute, Larissa Hering, Ana Montalban-Arques, Philipp Busenhart, Marlene Schwarzfischer, Roberto Manzini, Javier Conde, Kirstin Atrott, Silvia Lang, Gerhard Rogler, Elisabeth Naschberger, Vera S. Schellerer, Michael Stürzl, Andreas Rickenbacher, Matthias Turina, Achim Weber, Sebastian Leibl, Gabriel E. Leventhal, Mitchell Levesque, Onur Boyman, Michael Scharl, Marianne R. Spalinger
Journal: Journal of Clinical Investigation (2020)

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set out to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC), as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. In particular, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T cells, and increased PTPN2 levels negatively correlated with expression of PD-1, CTLA4, STAT1, and granzyme A. In vivo, T cell– and DC-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T cells, as well as CD8+ T cell infiltration and cytotoxicity in the tumor. In direct relevance to CRC treatment, T cell–specific PTPN2 deletion potentiated anti–PD-1 efficacy and induced antitumor memory formation upon tumor rechallenge in vivo. Our data suggest a role for PTPN2 in suppressing antitumor immunity and promoting tumor development in patients with CRC. Our in vivo results identify PTPN2 as a key player in controlling the immunogenicity of CRC, with the strong potential to be exploited for cancer immunotherapy.
Carbon Monoxide Poisoning, Myocardial Injury, and Mortality—Reply
Journal: JAMA (2006)

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The Clinical Spectrum of Myocardial Infarction and Ischemia With Nonobstructive Coronary Arteries in Women
Authors: Inge J. van den Hoogen, Umberto Gianni, Malissa J. Wood, Viviany R. Taqueti, Fay Y. Lin, Sharonne N. Hayes, Gudrun M. Feuchtner, Alexander R. van Rosendael, Nanette K. Wenger, Janet Wei, C. Noel Bairey Merz, Carl J. Pepine, Leslee J. Shaw
Journal: JACC. Cardiovascular imaging (2020)
Sixty seconds on . . . vitamin D
Authors: Zosia Kmietowicz
Journal: BMJ (2020)

Indeed, as we enter the season of mists and mellow fruitfulness, thoughts have been turning to the sunshine vitamin and its potential role in beating covid-19.

Health secretary Matt Hancock put his foot in it when he told the House of Commons last week that he had ordered a trial to see if vitamin D reduced the incidence or effects of covid-19 and that “the results were that it does not …
Abstract IA02: Next targets for immune checkpoint blockade in melanoma
Authors: Joe-Marc Chauvin, Mignane Ka, Ornella Pagliano, Julien Foucade, Carmine Menna, Diwakar Davar, John Kirkwood, Vijay Kuchroo, Ana Anderson, Alan Korman, Hassane Zarour
Journal: Cancer Research (2020)

Abstract Multiple mechanisms of melanoma-induced immune escape contribute to the failure of T-cell responses to control tumor growth in humans. Many inhibitory pathways play a critical role in impeding T-cell responses to tumor antigens (TAs), including PD-1, the T-cell immunoglobulin and mucin-domain containing-protein 3 (Tim-3), and the T-cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors (IRs) are upregulated by TA-specific CD8+T cells in the tumor microenvironment (TME) while their respective ligands are expressed by antigen-presenting cells (APCs) and tumor cells. Circulating TA-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) that coexpress PD-1, TIGIT and Tim-3 exhibit different levels of T-cell dysfunction. Dysfunctional/exhausted CD8+ TILs are not totally inert and can exhibit cytolytic functions but are likely kept in check by multiple inhibitory pathways that can be targeted by immune checkpoint blockade. TIGIT is an attractive target for the next-generation immune checkpoint blockade for several reasons. First, it is highly expressed by the majority of CD8+ TILs together with PD-1. Second, the TIGIT ligands, CD155/PVR, and CD112, are highly expressed in the TME by melanoma cells and APCs. Third, dual PD-1/TIGIT blockade augments the expansion and function of human TA-specific CD8+ T cells in vitro and promotes tumor rejection in animal models. Fourth, TIGIT also acts in Tregs and NK cells to regulate antitumor immune responses. CD8+ TILs in melanoma and other solid tumors downregulate the costimulatory molecule DNAM-1/CD226, which competes with TIGIT for binding to the same ligands CD155 and CD112. Therefore, in addition to the TIGIT-mediated T-cell intrinsic inhibitory effects, the downregulation of CD226 expression by CD8+TILs in the TME also contributes to impede T-cell responses to melanoma. Collectively, our findings provide the rationale for dual PD-1/TIGIT blockade together with therapeutic strategies to counteract CD226 downregulation in the TME to improve the clinical benefits of single PD-1 blockade in patients with melanoma and other solid tumors. Citation Format: Joe-Marc Chauvin, Mignane Ka, Ornella Pagliano, Julien Foucade, Carmine Menna, Diwakar Davar, John Kirkwood, Vijay Kuchroo, Ana Anderson, Alan Korman, Hassane Zarour. Next targets for immune checkpoint blockade in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA02.