tbuckley/cabot-search huggingface dataset:
Effect of High-Intensity Interval Training on Glycemic Control in Adults With Type 1 Diabetes and Overweight or Obesity: A Randomized Controlled Trial With Partial Crossover
Authors: Angela S. Lee, Nathan A. Johnson, Margaret J. McGill, Jane Overland, Connie Luo, Callum J. Baker, Sergio Martinez-Huenchullan, Jencia Wong, Jeffrey R. Flack, Stephen M. Twigg
Journal: Diabetes Care (2020)

OBJECTIVE To study the effect of 12 weeks of high-intensity interval training (HIIT) on glycemic control in adults with type 1 diabetes and overweight or obesity. RESEARCH DESIGN AND METHODS Thirty inactive adults with type 1 diabetes who had BMI ≥25 kg/m2 and HbA1c ≥7.5% were randomized to 12 weeks of either HIIT exercise intervention consisting of 4 × 4-min HIIT (85–95% peak heart rate) performed thrice weekly or usual care control. In a partial crossover design, the control group subsequently performed the 12-week HIIT intervention. The primary end point was the change in HbA1c from baseline to 12 weeks. Glycemic and cardiometabolic outcomes were measured at 0, 12, and 24 weeks. RESULTS Participants were aged 44 ± 10 years with diabetes duration 19 ± 11 years and BMI 30.1 ± 3.1 kg/m2. HbA1c decreased from 8.63 ± 0.66% at baseline to 8.10 ± 1.04% at 12 weeks in the HIIT intervention group (P = 0.01); however, this change was not significantly different from the control group (HIIT −0.53 ± 0.61%, control −0.14 ± 0.48%, P = 0.08). In participants who undertook at least 50% of the prescribed HIIT intervention, the HbA1c reduction was significantly greater than control (HIIT −0.64 ± 0.64% [n = 9], control −0.14 ± 0.48% [n = 15], P = 0.04). There were no differences in insulin dose, hypoglycemia on continuous glucose monitoring, blood pressure, blood lipids, body weight, or body composition between groups. CONCLUSIONS Overall, there was no significant reduction in HbA1c with a 12-week HIIT intervention in adults with type 1 diabetes. However, glycemic control may improve for people who undertake HIIT with greater adherence.
Abstract 15450: International Validation of the TIMI Risk Score for Secondary Prevention in Post-MI Patients: A Collaborative Analysis of the Chronic Kidney Disease Prognosis Consortium and the Risk Validation Scientific Committee
Authors: Yejin Mok, Shoshana Ballew, Deepak L Bhatt, William E Boden, Marc P Bonaca, Juan-Jesus Carrero, Josef Coresh, C. Raina Elley, Gerry R Fowkes, Sun Ha Jee, Csaba Kovesdy, Kenneth W Mahaffey, Girish Nadkarni, Yingying Sang, Kunihiro Matsushita
Journal: Circulation (2017)

Background: The TIMI Risk Score for Secondary Prevention (TRS2°P), a 0-9 point system based on the presence/absence of 9 clinical factors, stratifies 3-year risk among patients with a recent myocar...
Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity
Authors: Chang Liu, Ashwin Somasundaram, Sasikanth Manne, Angela M. Gocher, Andrea L. Szymczak-Workman, Kate M. Vignali, Ellen N. Scott, Daniel P. Normolle, E. John Wherry, Evan J. Lipson, Robert L. Ferris, Tullia C. Bruno, Creg J. Workman, Dario A. A. Vignali
Journal: Nature Immunology (2020)
The BH3-only protein Bim plays a critical role in cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK pathways in human leukemia cells
Authors: Mohamed Rahmani, Anh Anderson, Joseph Reza Habibi, Timothy Ryan Crabtree, Paul Dent, Steven Grant
Journal: Cancer Research (2008)

2332  Mechanisms underlying apoptosis induced by concomitant interruption of the MEK/ERK1/2 and Akt pathways were investigated in human leukemia cells. Apoptosis induction by perifosine, an alkyl-lysophospholipid (ALP) that inhibits PI3K/Akt and activates ERK1/2, was dramatically potentiated by co-administration of the MEK1/2 inhibitors PD184352 or U0126 in multiple malignant hematopoietic cells. These, events were associated with pronounced JNK1/2 activation, Mcl-1 downregulation, Bim upregulation, and marked Bak/Bax conformational change accompanied by Bax membrane translocation. Enforced expression of constitutively active (myristoylated) Akt sharply reduced perifosine/PD184352-mediated lethality. Genetic or pharmacological inhibition of JNK activation by shRNA directed against JNK1/2 or by the JNK inhibitor SP600125 significantly attenuated PD184352/perifosine-induced apoptosis, but not Mcl-1 downregulation. Notably, ectopic Mcl-1 expression potently inhibited perifosine/PD184352 lethality, as did Bak or Bax knockdown.Notably, knockdown of Bim, but not Bad, with shRNA blocked Bak and Bax conformational change, Bax membrane translocation, and apoptosis induced by perifosine/PD184352. Conversely, enforced expression of mutant Bim (ser55,65,100→ala) that is unphosphorylatable by ERK1/2 significantly enhanced apoptosis induced by PI3/Akt kinase inhibitors (i.e. perifosine, LY294002, PI-103). Collectively, these findings suggest that Bim, Mcl-1, and JNK, but not Bad, integrate death signaling triggered by concomitant disruption of the PI3K/Akt and MEK1/2/ERK1/2 pathways in human leukemia cells.
GSK wins legal case over withdrawal effects of paroxetine after 13 years and £9.33m in costs
Authors: Clare Dyer
Journal: BMJ (2020)

A group action in the High Court in London by scores of claimants over withdrawal problems with the antidepressant paroxetine has ended in a victory for the manufacturer, GlaxoSmithKline (GSK), 13 years after the case was first launched.1

A High Court trial was to start in February 2011 but the action was put on hold after legal aid was withdrawn and 369 claimants dropped their cases. In 2015 the litigation was revived when the remaining 124 claimants instructed new solicitors and found commercial funding.

In 2016 GSK asked the court to bring the case to a permanent halt, but Mr Justice Foskett said he wanted to see how the case progressed in stages before deciding if it should be stopped or go to trial.2

From the beginning, the claimants’ case had been that paroxetine, a selective serotonin reuptake inhibitor (SSRI) known …
P-368 Primary tumor location in synchronous and metachronous liver metastases: Impact on patterns of recurrence and survival after hepatic resection
Authors: I. Garajová, R. Balsano, C. Tommasi, R. Dalla Valle, G. Pedrazzi, M. Ravaioli, A. Spallanzani, F. Leonardi, C. Santini, F. Caputo, F. Gelsomino
Journal: Annals of Oncology (2020)
Abstract 105: Clobetasol-induced quiescence in the vulvar carcinoma cell line UMSCV-4 can be overcome by repeated removal and re-exposure to this ultrapotent corticosteroid
Authors: Nolberto Jaramillo, Nina M. Mustico, Jani E. Lewis
Journal: Cancer Research (2020)

Abstract Vulvar cancer is rare, mostly afflicting women aged 60 and older. The cancer is often preceded by a common vulvar rash, Lichen sclerosis, that is usually treated with the ultra-potent corticosteroid, clobetasol propionate. This treatment may, in turn, be associated with vulvar carcinogenesis. We found that clobetasol slows metabolism and proliferation in the vulvar carcinoma cell line, UMSCV-4 as revealed through MTT and BrdU/Ki67 assays. Upon removal from clobetasol, a subpopulation of UMSCV-4 cells had proliferation rates restabilize to baseline levels. The rate of cell death slightly increased in the presence of clobetasol as shown using trypan blue exclusion, but the majority of cells remained viable. RT-qPCR showed that the cell cycle inhibitors, p16 and p21 were upregulated while cyclin D1 was downregulated after 10 days of clobetasol treatment. The subpopulation removed from clobetasol proliferated at normal levels when re-exposed. These studies suggest that UMSCV-4 cells are a good model for studying quiescence. In addition, these studies highlight the potential for vulvar cancer cells to evade cancer treatments in the presence of clobetasol and lead to selection for more aggressive subpopulations. Citation Format: Nolberto Jaramillo, Nina M. Mustico, Jani E. Lewis. Clobetasol-induced quiescence in the vulvar carcinoma cell line UMSCV-4 can be overcome by repeated removal and re-exposure to this ultrapotent corticosteroid [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 105.
Co-evolution and Co-speciation of Host-Gut Bacteria Systems
Authors: Mathieu Groussin, Florent Mazel, Eric J. Alm
Journal: Cell Host & Microbe (2020)

Mammalian gut microbiomes profoundly influence host fitness, but the processes that drive the evolution of host-microbiome systems are poorly understood. Recent studies suggest that mammals and their individual gut symbionts can have parallel evolutionary histories, as represented by their congruent phylogenies. These "co-phylogenetic" patterns are signatures of ancient co-speciation events and illustrate the cohesiveness of the mammalian host-gut microbiome entity over evolutionary times. Theory predicts that co-speciation between mammals and their gut symbionts could result from their co-evolution. However, there is only limited evidence of such co-evolution. Here, we propose a model that explains cophylogenetic patterns without relying on co-evolution. Specifically, we suggest that individual gut bacteria are likely to diverge in patterns recapitulating host phylogeny when hosts undergo allopatric speciation, limiting inter-host bacterial dispersal and genomic recombination. We provide evidence that the model is empirically grounded and propose a series of observational and experimental approaches to test its validity. Mammalian gut microbiomes profoundly influence host fitness, but the processes that drive the evolution of host-microbiome systems are poorly understood. Recent studies suggest that mammals and their individual gut symbionts can have parallel evolutionary histories, as represented by their congruent phylogenies. These "co-phylogenetic" patterns are signatures of ancient co-speciation events and illustrate the cohesiveness of the mammalian host-gut microbiome entity over evolutionary times. Theory predicts that co-speciation between mammals and their gut symbionts could result from their co-evolution. However, there is only limited evidence of such co-evolution. Here, we propose a model that explains cophylogenetic patterns without relying on co-evolution. Specifically, we suggest that individual gut bacteria are likely to diverge in patterns recapitulating host phylogeny when hosts undergo allopatric speciation, limiting inter-host bacterial dispersal and genomic recombination. We provide evidence that the model is empirically grounded and propose a series of observational and experimental approaches to test its validity.
O-17 A TNM-Immune (TNM-I) classification staging system for predicting survival in colon cancer in a multicenter international SITC study
Authors: B. Mlecnik, C. Bifulco, F. Marliot, A. Lugli, I. Nagtegaal, A. Hartmann, M. Van den Eynde, M. Roehrl, P. Ohashi, E. Zavadova, T. Torigoe, P. Patel, Y. Wang, Y. Kawakami, F. Hermitte, F. Marincola, P. Ascierto, B. Fox, F. Pagès, J. Galon
Journal: Annals of Oncology (2020)
Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression
Authors: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Claire Renard-Guillet, Shingo Tsuji, Akimasa Hayashi, Hiroki Ueda, Shiro Fukuda, Takanori Fujita, Hiroto Katoh, Shumpei Ishikawa, Kyle R. Covington, Chad J. Creighton, Masahiko Sugitani, David A. Wheeler, Tatsuhiro Shibata, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani
Journal: Cancer Research (2020)

Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because β-catenin did not translocate into the nucleus due to the E-cadherin/β-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status. SIGNIFICANCE: In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses.
Covid-19: excess all cause mortality in domiciliary care
Authors: Judith R Glynn, Katherine Fielding, Tom Shakespeare, Oona Campbell
Journal: BMJ (2020)

Piccininni and colleagues show the importance of using excess all cause mortality to measure the impact of covid-19.1 This approach has drawn attention to the shocking rates of covid-19 related deaths in care homes. But domiciliary care remains neglected.

In England from 10 April to 8 May, deaths of recipients of domiciliary care were 2.7 times the three year average for that period.2 From 10 April to 1 May (latest available data), deaths of care home residents were 2.8 times or 3.2 times that of …
Liver graft from donation after circulatory death donor: Real practice to improve graft viability
Authors: Koji Hashimoto
Journal: Clinical and Molecular Hepatology (2020)

Donation after circulatory death (DCD) is an increasing source of liver grafts for transplantation, yet outcomes have been inferior compared to donation after brain death liver transplantation. These worse outcomes are mainly due to the severe graft injury resulting from mandatory warm ischemia during DCD organ recovery. New evidence, however, indicates that improved donor selection and surgical techniques can decrease the risk of graft failure and ischemic cholangiopathy (IC). Under current best practices, DCD organs are retrieved with the super-rapid technique, optimizing timing and protecting the liver graft from detrimental warm ischemia. Graft viability is influenced by both the quantity and quality of warm ischemia, which is unique to each donor and causes various degrees of pathophysiologic consequences. Evidence also shows that the choice of preservation solution and premortem heparin administration influences graft viability. Additionally, although the precise mechanism of IC remains unknown, stasis of blood during donor warm ischemia may cause the formation of microthrombi in the peribiliary vascular plexus and ischemia of the bile duct. Importantly, thrombolytic protocols show a possible preventive modality for IC. Finally, while &lt;i&gt;ex vivo&lt;/i&gt; machine perfusion technology has gained an interest in DCD liver transplantation, further studies are necessary to evaluate the effectiveness of this evolving field to improve graft quality and transplant outcomes.
PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle
Authors: Haejin Yoon, Jessica B. Spinelli, Elma Zaganjor, Samantha J. Wong, Natalie J. German, Elizabeth C. Randall, Afsah Dean, Allen Clermont, Joao A. Paulo, Daniel Garcia, Hao Li, Olivia Rombold, Nathalie Y.R. Agar, Laurie J. Goodyear, Reuben J. Shaw, Steven P. Gygi, Johan Auwerx, Marcia C. Haigis
Journal: Cell Metabolism (2020)
A randomised controlled trial of a novel self-assembling peptide for haemostasis in endoscopic submucosal dissection
Authors: Sharmila Subramaniam, Kesavan Kandiah, Fergus Chedgy, Carole Fogg, Sreedhari Thayalasekaran, Asma Alkandari, Michelle Baker-Moffatt, Joanne Dash, Mark Lyons-Amos, Gaius Longcroft-Wheaton, James Brown, Pradeep Bhandari
Journal: Endoscopy (2020)
Neoepitopes as Difference Makers for General Cancer Vaccines?
Authors: Jessica N. Filderman, Walter J. Storkus
Journal: Clinical Cancer Research (2020)

The cancer mutanome has been associated with disease prognosis as well as response to interventional immunotherapy and provides a substrate for development of personalized vaccines targeting tumor neoepitopes. Recent findings suggest that neoantigen-based vaccines may represent general interventional approaches for patients with solid cancers, regardless of their inherent mutational burden.See related article by Fang et al., p. 4511.
中心体のクラスタリングの新規阻害剤であるGF-15は,In VitroおよびIn Vivoでの腫瘍細胞の増殖を抑制する | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: S Raab Marc, Breitkreutz Iris, Anderhub Simon, H Ronnest Mads, Leber Blanka, O Larsen Thomas, Weiz Ludmila, Konotop Gleb, J Hayden Patrick, Podar Klaus, Fruehauf Johannes, Nissen Felix, Mier Walter, Haberkorn Uwe, D Ho Anthony, Goldschmidt Hartmut, C Anderson Kenneth, H Clausen Mads, Kraemer Alwin
Journal: Cancer Research (2012)
Spinal Cord Involvement in Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
Authors: Shanglin Li, Yicheng Zhu, Ming Yao
Journal: JAMA Neurology (2020)

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Abstract 187: Cardiac Arrest Incidence, Bystander Cardiopulmonary Resuscitation Rates, and Community Characteristics Differ by High and Low Risk Areas
Authors: Rebecca Cash, Madison K Rivard, Eric Cortez, David Keseg, Ashish Panchal
Journal: Circulation (2019)

Introduction: Survival from out-of-hospital cardiac arrest (OHCA) has significant variation which may be due to differing rates of bystander cardiopulmonary resuscitation (BCPR). Defining and understanding the community characteristics of high-risk areas (census tracts with low BCPR rates and high OHCA incidence) can help inform novel interventions to improve outcomes. Our objectives were to identify high and low risk census tracts in Franklin County, Ohio and to compare the OHCA incidence, BCPR rates, and community characteristics. Methods: This was a cross-sectional analysis of OHCA events treated by Columbus Division of Fire in Franklin County, Ohio from the Cardiac Arrest Registry to Enhance Survival between 1/1/2010-12/31/2017. Included cases were 18 and older, with a cardiac etiology OHCA in a non-healthcare setting, with EMS resuscitation attempted. After geocoding to census tracts, Local Moran’s I and quartiles were used to determine clustering in high risk areas based on spatial Empirical Bayes smoothed rates. Community characteristics, from the 2014 American Community Survey, were compared between high and low risk areas. Results: From the 3,841 included OHCA cases, the mean adjusted OHCA incidence per census tract was 0.67 per 1,000 with a mean adjusted BCPR rate of 31% and mean adjusted survival to discharge of 9.4%. In the 25 census tracts identified as high-risk areas, there were significant differences in characteristics compared to low-risk areas, including a higher proportion of African Americans (64% vs. 21%, p&lt;0.001), lower median household income ($30,948 vs. $54,388, p&lt;0.001), and a higher proportion living below the poverty level (36% vs. 20%, p&lt;0.001). There was a 3-fold increase in the adjusted OHCA incidence between high and low risk areas (1.68 vs. 0.57 per 1,000, p&lt;0.001) with BCPR rates of 27% and 31% (p=0.31), respectively. Compared to a previous analysis, 9 (36%) census tracts persisted as high-risk but an additional 16 were newly identified. Conclusions: Neighborhood-level variations in OHCA incidence are dramatic with marked disparities in characteristics between high and low risk areas. It is possible that improving OHCA outcomes requires multifaceted interventions to address social determinants of health.
The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in Patients Treated for Venous Thromboembolism
Authors: Scott D. Berkowitz, Jeffrey I Weitz, Stephan Schmidt, Keith A A Fox, Dirk Garmann, Dagmar Kubitza, Wolfgang Mueck, Gary Peters, Isabel Reinecke, Alexander Solms, Theodore E Spiro, Xiaoyu Yan, Liping Zhang, Stefan Willmann
Journal: Blood (2017)