tbuckley/cabot-search huggingface dataset:
USP22 deficiency in melanoma mediates resistance to T cells through IFNγ-JAK1-STAT1 signal axis
Authors: Min Li, Yanqin Xu, Jie Liang, Hao Lin, Xinyue Qi, Fanlin Li, Ping Han, Yanfeng Gao, Xuanming Yang
Journal: Molecular Therapy (2021)

Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated 9 (Cas9)-mediated loss-of-function screens are powerful tools for identifying genes responsible for diverse phenotypes. Here, we perturbed genes in melanoma cells to screen for genes involved in tumor escape from T cell-mediated killing. Multiple interferon gamma (IFNγ) signaling-related genes were enriched in melanoma cells resistant to T cell killing. In addition, deletion of the deubiquitinating protease ubiquitin specific peptidase 22 (USP22) in mouse melanoma (B16-OVA) cells decreased the efficacy of T cell-mediated killing, both in vitro and in vivo, while overexpression enhanced tumor-cell sensitivity to T (OT-I) cell-mediated killing. USP22 deficiency in both mouse and human melanoma cells showed impaired sensitivity to interferon pathway and USP22 was positively correlated with key molecules of interferon pathway in clinical melanoma samples. Mechanistically, USP22 may directly interact with signal transducer and activator of transcription 1 (STAT1), deubiquitinate it, and improve its stability in both human and mouse melanoma cells. Our findings identified a previously unknown function of USP22 and linked the loss of genes in tumor cells that are essential for escaping the effector function of CD8+ T cells during immunotherapy. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated 9 (Cas9)-mediated loss-of-function screens are powerful tools for identifying genes responsible for diverse phenotypes. Here, we perturbed genes in melanoma cells to screen for genes involved in tumor escape from T cell-mediated killing. Multiple interferon gamma (IFNγ) signaling-related genes were enriched in melanoma cells resistant to T cell killing. In addition, deletion of the deubiquitinating protease ubiquitin specific peptidase 22 (USP22) in mouse melanoma (B16-OVA) cells decreased the efficacy of T cell-mediated killing, both in vitro and in vivo, while overexpression enhanced tumor-cell sensitivity to T (OT-I) cell-mediated killing. USP22 deficiency in both mouse and human melanoma cells showed impaired sensitivity to interferon pathway and USP22 was positively correlated with key molecules of interferon pathway in clinical melanoma samples. Mechanistically, USP22 may directly interact with signal transducer and activator of transcription 1 (STAT1), deubiquitinate it, and improve its stability in both human and mouse melanoma cells. Our findings identified a previously unknown function of USP22 and linked the loss of genes in tumor cells that are essential for escaping the effector function of CD8+ T cells during immunotherapy.
Intestinal Inflammation as a Dysbiosis of Energy Procurement: New Insights into an Old Topic
Authors: J. Scott Lee, Ruth X. Wang, Erica E. Alexeev, Sean P. Colgan
Journal: Gut Microbes (2021)

Inflammatory bowel disease (IBD) coincides with profound shifts in microbiota and host metabolic energy supply and demand. The gastrointestinal epithelium is anatomically positioned to provide a selective barrier between the anaerobic luminal microbiota and host lamina propria, with the microbiota and epithelium participating in an intricate energy exchange necessary for homeostasis. Maintenance and restoration of the barrier requires high energy flux and places significant demands on available substrates to generate ATP. It is recently appreciated that components of the microbiota contribute significantly to a multitude of biochemical pathways within and outside of the mucosa. Decades-old studies have appreciated that byproducts of the microbiota provide essential sources of energy to the intestinal epithelium, especially the colon. More recent work has unveiled the existence of numerous microbial-derived metabolites that support energy procurement within the mucosa. It is now appreciated that disease-associated shifts in the microbiota, termed dysbiosis, places significant demands on energy acquisition within the mucosa. Here, we review the topic of host- and microbial-derived components that influence tissue energetics in health and during disease.
Abstract 17541: Impact of Therapeutic Hypothermia on Hemodynamics and Prognosis of Acute Coronary Syndrome After Resuscitation From Out-of-hospital Cardiac Arrest
Authors: Taiji Yoshida, Kenji Sakata, Tetsuo Konno, Kenshi Hayashi, Masa-aki Kawashiri, Masaki Okajima, Takumi Taniguchi, Masakazu Yamagishi
Journal: Circulation (2015)

Backgrounds: Although therapeutic hypothermia is recommended for neurologically unconscious patients after resuscitation from cardiac arrest, few data exist regarding clinical management during therapeutic hypothermia in acute coronary syndrome (ACS), requiring emergent coronary intervention. Therefore, we analyzed the impact of hypothermia on hemodynamics and prognosis of unconscious ACS patients. Methods and Results: We investigated consecutive 21 ACS patients (16 men, mean age 62.8±9.1) who were unconscious and induced hypothermia after resuscitation from out-of-hospital cardiac arrest between April 2009 to March 2014. Invasive hemodynamic monitoring with a pulmonary artery catheter was used during hypothermia with the target body temperature 34°C. ACS was diagnosed with emergent coronary angiography before or during cooling in all cases, and 18 patients had underwent emergent percutaneous coronary intervention. Average required time for the target body temperature from cardiac arrest were 6.8±2.6 hours. During hypothermia, mean blood pressure and cardiac index decreased significantly from 91.3 to 72.7 mmHg and 2.5 to 1.5 l/min/m2, respectively (p&lt;0.05), except for 5 patients with percutaneous cardiopulmonary support (PCPS). Under these conditions, 14 patients had hypokalemia and required potassium replacement and 7 patients had anemia and required a transfusion of red cell concentrates. Therapeutic hypothermia was discontinued early in 8 patients (fatal arrhythmia or circulatory instability in 5 patients, death in 3 patients with PCPS). Average length of stay in our hospital was 26.9 days (1-75 days). Importantly, 8 patients had a good functional outcome as defined by a cerebral performance category scale (CPC) 1-2, 7 patients had CPC 4 at the time of discharge, although there were still 6 death cases. Interestingly, of 8 patients with hypothermia early discontinued, 6 patients (75%) had a good functional outcome (CPC 1-2). Shorter time until return of spontaneous circulation was the most significant factor for a good neurological outcome. Conclusions: These results demonstrate that with hypothermia the outcome of ACS was favorable as far as maintaining hemodynamic state, probably due to less occurrence of fatal arrhythmias.
Brice Pitt: emeritus professor of old age psychiatry
Authors: Joanna Lyall
Journal: BMJ (2021)

Credit: Guy Drayton

Optimism, Brice Pitt once remarked, “is a piece of evolutionary equipment that carried us through millennia of setbacks.” Colleagues found it one of his defining characteristics. “Brice loved everybody and everything,” said David Jolley, former chair of the section of old age psychiatry at the Royal College of Psychiatrists. “He loved the world, and was emotionally and spiritually rich.”

“He could breeze into any meeting and infuse it with life and cheerfulness,” he added.

A man of wide interests, Pitt, who has died aged 89, wrote widely and with ease for a variety of audiences. “His letters to GPs were works of literary art,” said Tim Stevens, consultant in old age psychiatry at St Margaret’s Hospital, Epping, Essex, who inherited some of Pitt’s patients.

Psychogeriatrics , a textbook first published in 1974, was reprinted five times. As a registrar at …
White matter aging drives microglial diversity
Authors: Shima Safaiyan, Simon Besson-Girard, Tuğberk Kaya, Ludovico Cantuti-Castelvetri, Lu Liu, Hao Ji, Martina Schifferer, Garyfallia Gouna, Fumere Usifo, Nirmal Kannaiyan, Dirk Fitzner, Xianyuan Xiang, Moritz J. Rossner, Matthias Brendel, Ozgun Gokce, Mikael Simons
Journal: Neuron (2021)
Noncancer Deaths in the PETACC 6 Trial
Authors: Piotr Potemski, Krzysztof Bujko
Journal: Journal of Clinical Oncology (2021)

The PETACC 6 randomized trial (1,094 patients) reported recently by Schmoll et al 1 compared capecitabine-based preoperative chemoradiation followed by postoperative adjuvant capecitabine, both without (control arm) or with (experimental arm) oxaliplatin.There were no significant differences between the two arms in terms of overall survival and disease-free survival.However, we learned with interest that compared with the control arm, 18 fewer patients in the experimental arm had distant metastases, but 12 more patients died.From the above findings, we concluded that there were an excessive number of deaths from causes other than cancer in the experimental arm.This may be directly or indirectly related to the higher early or long-term toxicity of the chemotherapy used in the experimental arm.Indeed, the perioperative complication rate was 1.5-fold higher in the experimental arm, and fewer patients in the experimental arm started and completed adjuvant chemotherapy.Therefore, we kindly ask the authors to provide an exploratory analysis comparing the cumulative incidence of noncancer deaths (defined as those occurring in patients without recurrence or incurable cancer at the outset) between the two arms.Such an analysis may provide a hypothesis for a possible cause of the negative results of the PETACC 6 trial.
Efficacy and safety of dapagliflozin according to aetiology in heart failure with reduced ejection fraction: insights from the <scp>DAPA‐HF</scp> trial
Authors: Jawad H. Butt, Jose C. Nicolau, Subodh Verma, Kieran F. Docherty, Mark C. Petrie, Silvio E. Inzucchi, Morten Schou, Mikhail N. Kosiborod, Anna Maria Langkilde, Felipe A. Martinez, Piotr Ponikowski, Marc S. Sabatine, Mikaela Sjöstrand, Scott D. Solomon, Olof Bengtsson, Pardeep S. Jhund, John J.V. McMurray, Lars Køber
Journal: European Journal of Heart Failure (2021)
Efficacy of everolimus in patients with HR+/HER2- high risk early stage breast cancer
Authors: T. Bachelot, F. Dalenc, S. Chabaud, P. Cottu, D. Allouache, E. Brain, J-P. Jacquin, J. Grenier, L. Venat Bouvet, M. Brunt, M. Campone, F. Del Piano, M. Debled, A-C. Hardy Bessard, S. Giacchetti, J. Bliss, J-L. Canon, J. Lemonnier, D. Cameron, F. André
Journal: Annals of Oncology (2021)
Abstract 14282: Cold Saline Infusion is an Effective Method to Achieve Intra-Cardiopulmonary Resuscitation Therapeutic Hypothermia
Authors: Adamantios Tsangaris, Timothy R Matsuura, Michael C Lick, Jason A Bartos, Scott H McKnite, Kadambari Chandra Shekar, Jennifer N Rees, Demetris Yannopoulos
Journal: Circulation (2015)

Objective: Therapeutic hypothermia (TH) is thought to improve neurologically intact survival when applied after return of spontaneous circulation (ROSC) is achieved in patients who suffer a cardiac arrest. Intra-CPR cooling may accelerate the time to reach TH and thus enhance its neurological benefit. Sodium nitroprusside enhanced cardiopulmonary resuscitation (SNPeCPR), consisting of active compression decompression (ACD) with an impedance threshold device (ITD), abdominal binding, and bolus doses of SNP, has been shown to accelerate intra-CPR cooling compared to standard CPR. The aim of this study is to compare the rate of cooling achieved during CPR using various cooling methods as part of the resuscitation effort. Methods: This study included 24 intubated and anesthetized swine. Brain temperature probes were surgically placed. After induction of ventricular fibrillation (VF), animals were randomized to one of the following groups: 500cc cold saline infusion (group A), 500cc cold saline infusion plus surface cooling with ice packs (group B), surface cooling with ethanol soaked towels (group C) or control (group D). After 10 minutes of VF, ACD-ITD CPR was initiated. One minute after the initiation of CPR, the randomized intervention was initiated and abdominal binding was applied. SNP (2 mg) was administered at minutes 1, 4 and 8. Animals were defibrillated at minute 10. Results: Group A and Group B had the fastest decrease in temperature during CPR with a rate of 0.12 °C/min and 0.13 °C/min, respectively. This was compared to a rate of 0.03 °C/min, and 0.02 °C/min in the ethanol based surface cooling and control groups, respectively (using ANOVA, p&lt;0.05 between group A and C, A and D, B and C, B and D). Conclusions: A cold saline infusion initiated at the start of CPR was determined as the most effective method to achieve intra-CPR TH during SNPeCPR. Further studies will assess the potential neurologic benefit of the combination of SNPeCPR with intra-CPR infusion of cold saline.
Early detection of SARS-CoV-2 infection cases or outbreaks at nursing homes by targeted wastewater tracking
Authors: Laura Davó, Raimundo Seguí, Pilar Botija, María José Beltrán, Eliseo Albert, Ignacio Torres, Pablo Ángel López-Fernández, Rafael Ortí, Juan Francisco Maestre, Gloria Sánchez, David Navarro
Journal: Clinical Microbiology and Infection (2021)
Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment
Authors: Tim H. H. Coorens, Grace Collord, Wanhua Lu, Emily Mitchell, Jannat Ijaz, Thomas Roberts, Thomas R. W. Oliver, G. A. Amos Burke, Michael Gattens, Emmy Dickens, Jyoti Nangalia, Marc Tischkowitz, John Anderson, Adam Shlien, Anna L. Godfrey, Matthew J. Murray, Sam Behjati
Journal: Blood (2021)
Abstract 16182: Virtual Reality for Visualization and Assessment of Mitral Valve Geometry in Structural Heart Disease
Authors: Ahmed H Aly, Robert C Gorman, Michael Stauffer, Prakash A Patel, Joseph H Gorman, Alison M Pouch
Journal: Circulation (2019)

Introduction: Interactive 3D modeling of the mitral valve (MV) in echocardiography involves visualizing the valve in a volume-rendered image and a series of cross-sectional planes on a standard com...
The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity
Authors: Crystal S. Conn, Haojun Yang, Harrison J. Tom, Kenji Ikeda, Juan A. Oses-Prieto, Hieu Vu, Yasuo Oguri, Supna Nair, Ryan M. Gill, Shingo Kajimura, Ralph J. DeBerardinis, Alma L. Burlingame, Davide Ruggero
Journal: Nature Metabolism (2021)
Artificial Intelligence to Identify Commonly Asked Questions via an Electronic Patient Portal - Lessons From a Cardiology Department Within a Large Health System
Authors: Jedrek Wosik, Shijing Si, Ricardo Henao, Lawrence Carin, Manesh R. Patel
Journal: Circulation (2019)

Introduction: Electronic patient portals, such as Epic MyChart provide a new method for patients and their healthcare team to share personal medical information and request medical advice. The volu...
Inclisiran: First Approval
Authors: Yvette N. Lamb
Journal: Drugs (2021)

Inclisiran (Leqvio®; Novartis) is a first-in-class, cholesterol-lowering small interfering RNA (siRNA) conjugated to triantennary N-acetylgalactosamine carbohydrates (GalNAc). Inclisiran received its first approval in December 2020 in the EU for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet. It is intended for use in combination with a statin or a statin with other lipid-lowering therapies in patients unable to reach low-density lipoprotein cholesterol goals with the maximum tolerated statin dose. In patients who are statin-intolerant or for whom a statin is contraindicated, inclisiran can be used alone or in combination with other lipid-lowering therapies. Inclisiran is administered as a twice-yearly subcutaneous injection. This article summarizes the milestones in the development of inclisiran leading to this first approval for primary hypercholesterolaemia or mixed dyslipidaemia.
ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma
Authors: Grzegorz S. Nowakowski, Annalisa Chiappella, Randy D. Gascoyne, David W. Scott, Qingyuan Zhang, Wojciech Jurczak, Muhit Özcan, Xiaonan Hong, Jun Zhu, Jie Jin, David Belada, Juan Miguel Bergua, Francesco Piazza, Heidi Mócikova, Anna Lia Molinari, Dok Hyun Yoon, Federica Cavallo, Monica Tani, Kazuhito Yamamoto, Koji Izutsu, Koji Kato, Myron Czuczman, Sarah Hersey, Adrian Kilcoyne, Jacqueline Russo, Krista Hudak, Jingshan Zhang, Steve Wade, Thomas E. Witzig, Umberto Vitolo
Journal: Journal of Clinical Oncology (2021)

PURPOSE Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL. METHODS Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review. RESULTS A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% v 48%), anemia (22% v 14%), thrombocytopenia (17% v 11%), and leukopenia (14% v 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and P = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease. CONCLUSION ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.
Do Circulating Monocytes Promote and Predict Idiopathic Pulmonary Fibrosis Progression?
Authors: Isis E. Fernandez, Daniel J. Kass
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

be the decision to proceed with transplant listing and surgery, as survival with advanced CF lung disease on ETI will undoubtedly improve, allowing individuals to safely delay transplant.As additional data accumulate to provide clarity on best practices, individuals with CF, their families, and providers should continue to celebrate the transformative impact of CFTR modulators on quality of life and survival.
Abstract PS11-34: Time to completion of breast cancer treatment and survival
Authors: Debra Ann Pratt, Talia Burneikis, Chao Tu, Stephen R. Grobmyer
Journal: Cancer Research (2021)

Abstract Background:Modern breast cancer (BC) treatment involves the use of multimodality therapy. Treatment delays are common and can be multifactorial. There are few studies examining the association between the duration of the time from diagnosis to completion of all acute BC treatment modalities and survival. This study is designed to determine if there is an association between time to complete treatment and survival. Study Design:A retrospective analysis was performed using data from The National Cancer Database (NCDB) to determine whether an association exists between the duration of time from diagnosis to completing all acute BC treatment (surgery, chemotherapy and radiation therapy) and survival. A second analysis was performed to determine if the association between treatment duration and survival varies by receptor status. Results:The NCDB data from BC patients diagnosed in 2010 was analyzed. The inclusion criteria included less than 80 years of age with a single cancer diagnosis, Stage I through III invasive breast cancer who required treatment with surgery, chemotherapy and radiation therapy. A total of 28,284 patients were included in the analysis. Median follow-up was 5.8 years. The order of treatment included 20,772 patients had treatment in the order of surgery, chemotherapy and radiation therapy and 7,512 patients had treatment order chemotherapy, surgery and radiation therapy. A Cox proportional hazards model was developed and identified a cut off showing the risk of delaying completion of all treatment beyond 38 weeks was associated with decrease in overall survival. This was statistically significant with an adjusted hazard Ratio of 1.21. This cut off of 38 weeks was found to be significant regardless of receptors type. The statistically significant Hazard ratios for receptor subtypes include: Triple negative (HR: 1.188, 95%CI: 1.06-1.34), ER+PR+Her2- (HR: 1.22, 95%CI: 1.09-1.36), ER-PR-Her2+ (HR: 1.29, 95%CI: 1.004-1.67) and ER+PR+Her2+ (HR: 1.32, 95%CI: 1.01-1.72). The patients with treatment duration greater than 38 weeks were comprised of 4768(63.47%) neo-adjuvant chemotherapy patients and 8191 (39.43%) of the surgery first group. Conclusion: Efforts to improve the efficiency of multimodality BC treatment and reduce treatment delays should be a priority to optimize BC patient outcomes. Citation Format: Debra Ann Pratt, Talia Burneikis, Chao Tu, Stephen R. Grobmyer. Time to completion of breast cancer treatment and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-34.
The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis
Authors: Charissa A C Jessurun, Alexander F C Hulsbergen, Anouk E de Wit, Ishaan A Tewarie, Tom J Snijders, Joost J C Verhoeff, John G Phillips, David A Reardon, Rania A Mekary, Marike L D Broekman
Journal: Neuro-Oncology (2021)

Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies.After screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS (HR = 1.84, 95% CI 1.22-2.77) and systemic progression-free survival (PFS; HR = 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR = 1.31, 95% CI 0.42-4.07).Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.