tbuckley/cabot-search huggingface dataset:
Long-Term Outcomes of Laparoscopic Distal Gastrectomy for Locally Advanced Gastric Cancer: The KLASS-02-RCT Randomized Clinical Trial
Authors: Woo Jin Hyung, Han-Kwang Yang, Young-Kyu Park, Hyuk-Joon Lee, Ji Yeong An, Wook Kim, Hyoung-Il Kim, Hyung-Ho Kim, Seung Wan Ryu, Hoon Hur, Min-Chan Kim, Seong-Ho Kong, Gyu Seok Cho, Jin-Jo Kim, Do Joong Park, Keun Won Ryu, Young Woo Kim, Jong Won Kim, Joo-Ho Lee, Sang-Uk Han
Journal: Journal of Clinical Oncology (2020)

PURPOSE It is unclear whether laparoscopic distal gastrectomy for locally advanced gastric cancer is oncologically equivalent to open distal gastrectomy. The noninferiority of laparoscopic subtotal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer compared with open surgery in terms of 3-year relapse-free survival rate was evaluated. PATIENTS AND METHODS A phase III, open-label, randomized controlled trial was conducted for patients with histologically proven locally advanced gastric adenocarcinoma suitable for distal subtotal gastrectomy. The primary end point was the 3-year relapse-free survival rate; the upper limit of the hazard ratio (HR) for noninferiority was 1.43 between the laparoscopic and open distal gastrectomy groups. RESULTS From November 2011 to April 2015, 1,050 patients were randomly assigned to laparoscopy (n = 524) or open surgery (n = 526). After exclusions, 492 patients underwent laparoscopic surgery and 482 underwent open surgery and were included in the analysis. The laparoscopy group, compared with the open surgery group, suffered fewer early complications (15.7% v 23.4%, respectively; P = .0027) and late complications (4.7% v 9.5%, respectively; P = .0038), particularly intestinal obstruction (2.0% v 4.4%, respectively; P = .0447). The 3-year relapse-free survival rate was 80.3% (95% CI, 76.0% to 85.0%) for the laparoscopy group and 81.3% (95% CI, 77.0% to 85.0%; log-rank P = .726) for the open group. Cox regression analysis after stratification by the surgeon revealed an HR of 1.035 (95% CI, 0.762 to 1.406; log-rank P = .827; P for noninferiority = .039). When stratified by pathologic stage, the HR was 1.020 (95% CI, 0.751 to 1.385; log-rank P = .900; P for noninferiority = .030). CONCLUSION Laparoscopic distal gastrectomy with D2 lymphadenectomy was comparable to open surgery in terms of relapse-free survival for patients with locally advanced gastric cancer. Laparoscopic distal gastrectomy with D2 lymphadenectomy could be a potential standard treatment option for locally advanced gastric cancer.
Early type I IFN blockade improves the efficacy of viral vaccines
Authors: Nicole Palacio, Tanushree Dangi, Young Rock Chung, Yidan Wang, Juan Luis Loredo-Varela, Zhongyao Zhang, Pablo Penaloza-MacMaster
Journal: The Journal of Experimental Medicine (2020)

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor–blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient “spike” in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.
Assessment of Costs of Avoidable Delays in Intensive Care Unit Discharge
Authors: Sean M. Bagshaw, Dat T. Tran, Dawn Opgenorth, Xiaoming Wang, Danny J. Zuege, Armann Ingolfsson, Henry T. Stelfox, Nguyen X. Thanh
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Delays in transfer for discharge-ready patients from the intensive care unit (ICU) are increasingly described and contribute to strained capacity. <h3>Objective</h3> To describe the epidemiological features and health care costs attributable to potentially avoidable delays in ICU discharge in a large integrated health care system. <h3>Design, Setting, and Participants</h3> This population-based cohort study was performed in 17 adult ICUs in Alberta, Canada, from June 19, 2012, to December 31, 2016. Participants were patients 15 years or older admitted to a study ICU during the study period. Data were analyzed from October 19, 2018, to May 20, 2020. <h3>Exposures</h3> Avoidable time in the ICU, defined as the portion of total ICU patient-days accounted for by avoidable delay in ICU discharge (eg, waiting for a ward bed). <h3>Main Outcomes and Measures</h3> The primary outcome was health care costs attributable to avoidable time in the ICU. Secondary outcomes were factors associated with avoidable time, in-hospital mortality, and measures of use of health care resources, including the number of hours in the ICU and the number of days of hospitalization. Multilevel mixed multivariable regression was used to assess associations between avoidable time and outcomes. <h3>Results</h3> In total, 28 904 patients (mean [SD] age, 58.3 [16.8] years; 18 030 male [62.4%]) were included. Of these, 19 964 patients (69.1%) had avoidable time during their ICU admission. The median avoidable time per patient was 7.2 (interquartile range, 2.4-27.7) hours. In multivariable analysis, male sex (odds ratio [OR], 0.92; 95% CI, 0.87-0.98), comorbid hemiplegia or paraplegia (OR 1.47; 95% CI, 1.23-1.75), liver disease (OR 1.20; 95% CI, 1.04-1.37), admission Acute Physiology and Chronic Health Evaluation II score (OR, 1.03; 95% CI, 1.02-1.03), surgical status (OR, 0.90; 95% CI, 0.82-0.98), medium community hospital type (OR, 0.12; 95% CI, 0.04-0.32), and admission year (OR, 1.16; 95% CI, 1.13-1.19) were associated with avoidable time. The cumulative avoidable time was 19 373.9 days, with estimated attributable costs of CAD$34 323 522. Avoidable time accounted for 12.8% of total ICU bed-days and 6.4% of total ICU costs. Patients with avoidable time before ICU discharge showed higher unadjusted in-hospital mortality (1115 [5.6%] vs 392 [4.4%];<i>P</i> &lt; .001); however, in multivariable analysis, avoidable time was associated with reduced in-hospital mortality (adjusted hazard ratio, 0.74; 95% CI, 0.64-0.85). Results were similar in sensitivity analyses. <h3>Conclusions and Relevance</h3> In this study, potentially avoidable discharge delay occurred for most patients admitted to ICUs across a large integrated health system and translated into substantial associated health care costs.
The immunogenicity of the U.K. group B meningococcal vaccine (4CMenB) schedule against group B and C meningococcal strains: outcomes of the Sched3 randomised clinical trial.
Authors: K Davis, M Valente Pinto, N Andrews, D Goldblatt, R Borrow, H Findlow, J Southern, J Partington, E Plested, S Patel, A Holland, M Matheson, A England, B Hallis, E Miller, M Snape
Journal: The Lancet Infectious Diseases (2020)
Diffuse Large B-Cell Lymphoma’s New Genomics: The Bridge and the Chasm
Authors: Jennifer L. Crombie, Philippe Armand
Journal: Journal of Clinical Oncology (2020)

Key ObjectiveHow can we successfully implement precision medicine strategies in diffuse large B-cell lymphoma (DLBCL)?In this review, we describe the recently proposed genomic categories of DLBCL and their potential use for personalized treatment. Knowledge GeneratedWe examine the foundation for the traditional classification tools that remain in use for DLBCL as well as the previous unsuccessful efforts to personalize therapy on the basis of them.We subsequently highlight the recently discovered genomic categories and their potential to transform the management of DLBCL as well as the challenges that this will entail.Relevance This review discusses the promises and barriers of novel genomic classifications in DLBCL.
Abstract 6426: Novel mechanism of PIM2 inhibition leads to significant effect on solid tumors
Authors: Eriko Katsuta, Kazuaki Takabe, Alex Adjei, Mateusz Opyrchal
Journal: Cancer Research (2020)

Abstract Background: PIM2 is overexpressed in hematopoietic and solid cancers, and is involved in multiple signaling pathways. In hematologic malignancies, PIM2 has been shown to be a pro-survival factor and demonstrated to be a possible therapeutic target. However, the role of PIM2 as a therapeutic target in solid cancers has not been fully elucidated. Methods: PIM2 expression was compared between normal and cancer tissues in The Cancer Genome Atlas (TCGA) datasets. Pan-PIM inhibitor treatment, as well as PIM2 overexpression/knockdown technique was utilized to investigate the PIM2 role in solid cancers. Multiple cancer models were utilized for in vitro and in vivo experiments to investigate if PIM2 as a therapeutic target and examine mechanism of anti-tumor activity by JP11646. Results: PIM2 was overexpressed in several types of cancer tissues, including breast, esophageal, head-neck, kidney, liver and endometrial cancers in TCGA. PIM2 overexpression promoted tumor growth in in vivo breast cancer mouse model. PIM2 inhibition by siRNA as well as pan-PIM inhibitor JP11646 activated apoptosis as seen by increased cleaved PARP. JP11646 treatment inhibited cancer cell proliferation in a dose-dependent manner in vitro in various types of solid cancers, including head-neck, ovarian, breast, prostate, liver, pancreatic, colorectal and non-small cell lung cancers. Interestingly, treatment with pan-PIM inhibitor JP11646 resulted in selective downregulation of PIM2 protein expression, but not PIM1 or PIM3 in breast cancer cell lines, BT549 and MDA-MB-231. The treatment also resulted in downregulation of phosphorylated downstream targets, 4EBP1 and TSC2 in breast cancer cells. However, additional proteasome inhibitor treatment blocked PIM2 downregulation and apoptosis activation was not seen. The result suggests that proteasome complex is required for PIM2 degradation which is necessary to induce apoptosis. JP11646 treatment inhibited tumor growth in breast, liver, pancreas, and non-small cell lung cancer in vivo xenograft models and was compared to multiple standard of care treatments showing advantage in lung tumors. Conclusion: We found that PIM2 promoted cancer progression in solid tumors. We show novel mechanism of JP11646 targeting PIM2 for degradation and induction of apoptosis. We show that PIM2 may serve as a novel therapeutic target for multiple types of solid cancers with enhanced therapeutic effect through protein degradation rather than kinase inhibition alone. Citation Format: Eriko Katsuta, Kazuaki Takabe, Alex Adjei, Mateusz Opyrchal. Novel mechanism of PIM2 inhibition leads to significant effect on solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6426.
Out of the Orphanage and into the Clinic — Therapeutic Targeting of GATA3
Authors: Bruce S. Bochner, Robert P. Schleimer
Journal: New England Journal of Medicine (2015)

In 1986, Mosmann et al. reported that T-cell lines can be divided into type 1 (Th1) and type 2 (Th2) on the basis of patterns of cytokine production.1 This classification of T cells according to their products subsequently expanded to include Th9, Th17, Th22, regulatory T cells, and follicular helper T cells. During the decade that followed, discoveries in microarray-based genomics led to the emergence of a collection of "orphan" genes that encode transcription factors responsible for driving the differentiation of these T-cell subsets, including GATA3, T-bet, ROR-γt, FOXP3, and others.2 Each subset drives distinct immune and inflammatory responses and . . .
Molecular and Immunologic Signatures are Related to Clinical Benefit from Treatment with Vocimagene Amiretrorepvec (Toca 511) and 5-Fluorocytosine (Toca FC) in Patients with Glioma
Authors: William P. Accomando, Aliz R. Rao, Daniel J. Hogan, Aaron M. Newman, Aki Nakao, Ash A. Alizadeh, Maximilian Diehn, Oscar R. Diago, Dawn Gammon, Ali Haghighi, Harry E. Gruber, Douglas J. Jolly, Derek Ostertag
Journal: Clinical Cancer Research (2020)

Abstract Purpose: High-grade gliomas (HGGs) are central nervous system tumors with poor prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is a retroviral replicating vector encoding cytosine deaminase, which converts extended release 5-fluorocytosine (Toca FC) into the anticancer agent, 5-fluorouracil. According to preclinical studies, this therapy kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to T-cell–mediated antitumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunologic indicators of clinical benefit from therapy. Patients and Methods: In a phase I clinical trial (NCT01470794), patients with recurrent HGG treated with Toca 511 and Toca FC showed improved survival relative to historical controls, and some had durable complete responses to therapy. As a part of this trial, we performed whole-exome DNA sequencing, RNA-sequencing, and multiplex digital ELISA measurements on tumor and blood samples. Results: Genetic analyses suggest mutations, copy-number variations, and neoantigens are linked to survival. Quantities of tumor immune infiltrates estimated by transcript abundance may potentially predict clinical outcomes. Peak values of cytokines in peripheral blood samples collected during and after therapy could indicate response. Conclusions: These results support an immune-related mechanism of action for Toca 511 and Toca FC, and suggest that molecular and immunologic signatures are related to clinical benefit from treatment.
Optimising outcomes of exercise and corticosteroid injection in patients with subacromial pain (impingement) syndrome: a factorial randomised trial
Authors: Edward Roddy, Reuben O Ogollah, Raymond Oppong, Irena Zwierska, Praveen Datta, Alison Hall, Elaine Hay, Sue Jackson, Sue Jowett, Martyn Lewis, Julie Shufflebotham, Kay Stevenson, Danielle A van der Windt, Julie Young, Nadine E Foster
Journal: British Journal of Sports Medicine (2020)

Objectives To compare the clinical effectiveness of (1) physiotherapist-led exercise versus an exercise leaflet, and (2) ultrasound-guided subacromial corticosteroid injection versus unguided injection for pain and function in subacromial pain (formerly impingement) syndrome (SAPS). Methods This was a single-blind 2×2 factorial randomised trial. Adults with SAPS were randomised equally to one of four treatment groups: (1) ultrasound-guided corticosteroid injection and physiotherapist-led exercise, (2) ultrasound-guided corticosteroid injection and an exercise leaflet, (3) unguided corticosteroid injection and physiotherapist-led exercise and (4) unguided corticosteroid injection and an exercise leaflet. The primary outcome was the Shoulder Pain and Disability Index (SPADI), collected at 6 weeks, 6 and 12 months and compared at 6 weeks for the injection interventions and 6 months for the exercise interventions by intention to treat. Results We recruited 256 participants (64 treatment per group). Response rates for the primary outcome were 94% at 6 weeks, 88% at 6 months and 80% at 12 months. Greater improvement in total SPADI score was seen with physiotherapist-led exercise than with the exercise leaflet at 6 months (adjusted mean difference −8.23; 95% CI −14.14 to -2.32). There were no significant differences between the injection groups at 6 weeks (−2.04; −7.29 to 3.22), 6 months (−2.36; −8.16 to 3.44) or 12 months (1.59; −5.54 to 8.72). Conclusions In patients with SAPS, physiotherapist-led exercise leads to greater improvements in pain and function than an exercise leaflet. Ultrasound guidance confers no additional benefit over unguided corticosteroid injection. Trial registration number ISRCTN42399123 .
Abstract 6361: Identification of mitochondrial RNA polymerase inhibitors via deep convolutional neural networks: A therapeutic strategy for cancer metabolism
Authors: Noor-Ul-Ain Khalid, Jeffrey M. Warrington, Rebecca Rachelle Laposa
Journal: Cancer Research (2020)

Abstract Dysregulated metabolism is a hallmark of cancer and a substantial subset of many cancers rely on oxidative phosphorylation (OXPHOS) for growth and viability, including AML, breast cancer, lung cancer, glioblastoma, ovarian and pancreatic cancer. The electron transport chain (ETC) in mitochondria contains both nuclear DNA- and mitochondrial DNA-encoded subunits. Mitochondrial DNA-encoded subunits are essential for ETC function and are transcribed by the mitochondrial RNA polymerase POLRMT. We have previously validated POLRMT as an anticancer target in acute myeloid leukemia models. The challenge of inhibiting POLRMT with small molecules will arise from both a) selectivity to off targets and b) transport of the drug to the mitochondria. There exist several small nucleoside / nucleotide analogues that are known to inhibit RNA polymerase. However, this target space is rife with the opportunity for off-target activities and toxicity. Therefore, we targeted a novel pocket with the aim of finding novel chemical matter. Using AtomNet, an artificial intelligence platform that utilizes deep convolutional neural networks to predict small molecule recognition, a virtual library of 8 million compounds was screened against POLRMT. The top 72 hit compounds were tested in OCI-AML2 human acute myeloid leukemia cells for a potential decrease of mitochondrial RNA levels (MT-ND1) using reverse transcriptase polymerase chain reaction (RT-PCR). OCI-AML2 cells were treated with compounds at 0.1, 1 or 10 micromolar for 72 hours, 3 days or 6 days or with the positive control POLRMT ribonucleoside analogue inhibitor, 4'-azidocytidine. Gene expression was normalized to 18S. Twelve compounds demonstrated a time-dependent decrease in mitochondrial gene expression. In summary, these data indicate that functional inhibitors of human POLRMT can be identified rapidly via deep convolutional neural networks and machine learning techniques. Financial relationships: RL received an Artificial Intelligence Molecular Screening Award from Atomwise, and funding from the Centre for Collaborative Drug Research, Toronto, Canada. JW is an employee of Atomwise. Citation Format: Noor-Ul-Ain Khalid, Jeffrey M. Warrington, Rebecca Rachelle Laposa. Identification of mitochondrial RNA polymerase inhibitors via deep convolutional neural networks: A therapeutic strategy for cancer metabolism [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6361.
Left Atrial Strain Predicts Heart Failure and Cardiovascular Death in Patients Undergoing Coronary Artery Bypass Grafting
Authors: Lisa S. Duus, Søren Lindberg, Flemming J. Olsen, Thomas Fritz-Hansen, Sune Pedersen, Allan Iversen, Søren Galatius, Gunnar Gislason, Rasmus Møgelvang, Raúl S.J. Estépar, Tor Biering-Sørensen
Journal: JACC. Cardiovascular imaging (2020)
Association of Depression With Past-Month Cannabis Use Among US Adults Aged 20 to 59 Years, 2005 to 2016
Authors: Lauren R. Gorfinkel, Malki Stohl, Deborah Hasin
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Despite studies showing that repeated cannabis use may worsen depressive symptoms, the popular media increasingly presents cannabis as beneficial to mental health, and many members of the public view cannabis as beneficial for depression. Therefore, cannabis use among individuals with depression may be becoming more prevalent. <h3>Objective</h3> To examine the association of depression with past-month cannabis use among US adults and the time trends for this association from 2005 to 2016. <h3>Design, Setting, and Participants</h3> This repeated cross-sectional study used data from 16 216 adults aged 20 to 59 years who were surveyed by the National Health and Nutrition Examination Survey, a national, annual, cross-sectional survey in the United States, between 2005 and 2016. Data analysis was conducted from January to February 2020. <h3>Exposures</h3> Survey year and depression, as indicated by a score of at least 10 on the Patient Health Questionnaire–9. <h3>Main Outcomes and Measures</h3> Any past-month cannabis use (ie, ≥1 use in the past 30 days) and daily or near-daily past-month cannabis use (ie, ≥20 uses in the past 30 days). Logistic regression was used to examine time trends in the prevalence of cannabis use, depression, and the association between cannabis use and depression from 2005 to 2016. <h3>Results</h3> The final analysis included 16 216 adults, of whom 7768 (weighted percentage, 48.9%) were men, 6809 (weighted percentage, 66.4%) were non-Hispanic White participants, and 9494 (weighted percentage, 65.6%) had at least some college education. They had a weighted mean age of 39.12 (95% CI, 38.23-39.40) years. Individuals with depression had 1.90 (95% CI, 1.62-2.24) times the odds of any past-month cannabis use and 2.29 (95% CI, 1.80-2.92) times the odds of daily or near-daily cannabis use compared with those without depression. The association between cannabis use and depression increased significantly from 2005 to 2016. The odds ratio for depression and any past-month cannabis use increased from 1.46 (95% CI, 1.07-1.99) in 2005 to 2006 to 2.30 (95% CI, 1.82-2.91) in 2015 to 2016. The odds ratio for depression and daily or near-daily past-month cannabis use increased from 1.37 (95% CI, 0.81-2.32) in 2005 to 2006 to 3.16 (95% CI, 2.23-4.48) in 2015 to 2016. <h3>Conclusions and Relevance</h3> The findings of this study indicate that individuals with depression are at increasing risk of cannabis use, with a particularly strong increase in daily or near-daily cannabis use. Clinicians should be aware of these trends and the evidence that cannabis does not treat depression effectively when discussing cannabis use with patients.
Polymyalgia Rheumatica and Giant Cell Arteritis
Authors: Frank Buttgereit, Eric L. Matteson, Christian Dejaco
Journal: JAMA (2020)

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