tbuckley/cabot-search huggingface dataset:
In vitro and ex vivo gene expression profiling reveals differential kinetic response of HSPs and UPR genes is associated with PI resistance in multiple myeloma
Authors: Amit Kumar Mitra, Harish Kumar, Vijay Ramakrishnan, Li Chen, Linda Baughn, Shaji Kumar, S. Vincent Rajkumar, Brian G. Van Ness
Journal: Blood Cancer Journal (2020)

Extensive inter-individual variation in response to chemotherapy (sensitive vs resistant tumors) is a serious cause of concern in the treatment of multiple myeloma (MM). In this study, we used human myeloma cell lines (HMCLs), and patient-derived CD138+ cells to compare kinetic changes in gene expression patterns between innate proteasome inhibitor (PI)-sensitive and PI-resistant HMCLs following test dosing with the second-generation PI Ixazomib. We found 1553 genes that changed significantly post treatment in PI-sensitive HMCLs compared with only seven in PI-resistant HMCLs (p < 0.05). Genes that were uniquely regulated in PI-resistant lines were RICTOR (activated), HNF4A, miR-16-5p (activated), MYCN (inhibited), and MYC (inhibited). Ingenuity pathway analysis (IPA) using top kinetic response genes identified the proteasome ubiquitination pathway (PUP), and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response as top canonical pathways in Ix-sensitive cell lines and patient-derived cells, whereas EIF2 signaling and mTOR signaling pathways were unique to PI resistance. Further, 10 genes were common between our in vitro and ex vivo post-treatment kinetic PI response profiles and Shaughnessy's GEP80-postBz gene expression signature, including the high-risk PUP gene PSMD4. Notably, we found that heat shock proteins and PUP pathway genes showed significant higher upregulation in Ix-sensitive lines compared with the fold-change in Ix-resistant myelomas.
Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action
Authors: Lance A. Thielen, Junqin Chen, Gu Jing, Omar Moukha-Chafiq, Guanlan Xu, SeongHo Jo, Truman B. Grayson, Brian Lu, Peng Li, Corinne E. Augelli-Szafran, Mark J. Suto, Matt Kanke, Praveen Sethupathy, Jason K. Kim, Anath Shalev
Journal: Cell Metabolism (2020)

Highlights•The small molecule SRI-37330 inhibits TXNIP expression in mouse and human islets•SRI-37330 decreases glucagon secretion and action and blocks hepatic glucose output•Oral SRI-37330 reverses obesity- and STZ-induced diabetes and hepatic steatosis in mice•Its antidiabetic effects and safety profile make SRI-37330 an attractive drug candidateSummaryDiabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.Graphical abstract
The effect of hydrogen bonding on diffusion and permeability in UV-cured Polyacrylate-based networks for controlled release
Authors: Bing Wu, Walter Chassé, Klaus Zick, Michael D. Mantle, Andreas Heise, Dermot F. Brougham, Victor M. Litvinov
Journal: Journal of Controlled Release (2020)

Polyacrylates are important polymers widely used in pharmaceutical industry such as drug coatings due to their low cost, processability and ease of functionalisation. Chemical functionalities (e.g. H-bonding) can be easily included to modulate the transport of low molecular weight drug-like entities through the network. Understanding how such microscopic structural modifications determine macroscopic diffusion is critical for designing next generation responsive polymers. In this study pulsed field gradient (PFG) 1H NMR measurements of the self-diffusion of a dye molecule (Eosin Y) in a series of polyacrylate networks with differing H-bonding strength were undertaken; it was found that the diffusion of Eosin Y is significantly reduced in networks with H-bonding. Detailed analyses by 1H NMR relaxometry and double quantum (DQ) NMR show that H-bonding can also reduce polymer chain mobility. Furthermore, DSC thermoporometry showed a significant increase in the average network mesh size potentially due to the pre-organization of H-bonding containing monomer during network curing. By introducing the H-bonding disrupter, LiClO4, it was found that the diffusivity of solute becomes positively correlated to the average mesh size across the series of networks. Hence, a modified diffusion model based on hydrodynamic theory is proposed to separate the direct (solute-network) H-bonding contribution to solute diffusion from the indirect contribution arising from monomer pre-ordering induced mesh size reduction. Finally, it is shown that the same direct and indirect contributions to microscopic diffusivity, arising from the H-bond strength of the co-monomers, also contribute significantly to the macroscopic membrane permeability which is similarly subject to H-bond disruption.
Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84)
Authors: Pieternella Johanna Lugtenburg, Peter de Nully Brown, Bronno van der Holt, Francesco A. D’Amore, Harry R. Koene, Eva de Jongh, Rob Fijnheer, Joost W. van Esser, Lara H. Böhmer, Johannes F. Pruijt, Gregor E. Verhoef, Mels Hoogendoorn, Memis Y. Bilgin, Marcel Nijland, Nicole C. van der Burg-de Graauw, Margreet Oosterveld, Kon-Siong G. Jie, Thomas Stauffer Larsen, Marjolein W. van der Poel, Maria B. Leijs, Matthijs H. Silbermann, Marinus van Marwijk Kooy, Aart Beeker, Marie J. Kersten, Jeanette K. Doorduijn, Lidwine W. Tick, Rolf E. Brouwer, King H. Lam, Coreline N. Burggraaff, Bart de Keizer, Anne I. Arens, Daphne de Jong, Otto S. Hoekstra, Josée M. Zijlstra-Baalbergen
Journal: Journal of Clinical Oncology (2020)

Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP.A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat.CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections.Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.
Relationship between robotic-assisted radical prostatectomy and retropubic radical prostatectomy in the learning curve of a single surgeon as a novice in radical prostatectomy: A retrospective cohort study
Authors: Wan Song, Sin Woo Lee, Jae Hoon Chung, Minyong Kang, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Hyun Moo Lee, Seong Soo Jeon
Journal: International Journal of Surgery (2020)
Streptococcus pneumoniae serotype distribution and antimicrobial nonsusceptibility trends among adults with pneumonia in the United States, 2009‒2017
Authors: Jose A. Suaya, Rodrigo E. Mendes, Heather L. Sings, Adriano Arguedas, Ralf-René Reinert, Luis Jodar, Raul E. Isturiz, Bradford D. Gessner
Journal: Journal of Infection (2020)
Microtransplantation for Acute Myeloid Leukemia
Authors: Bin Pan, Hillard M. Lazarus, Robert Peter Gale
Journal: JAMA Oncology (2020)

<h3>Importance</h3> There has been recent interest in microtransplantation of hematopoietic cells to treat hematologic cancers, especially acute myeloid leukemia (AML) and, to a lesser extent, myelodysplastic syndrome (MDS). Most of this interest comes from data from relatively small, uncontrolled clinical trials. <h3>Objective</h3> To determine the extent to which published data support the safety and effectiveness of microtransplantation of hematopoietic cells in persons with AML and MDS, examine what clinical data are needed to conclude that microtransplantation is safe and effective, explore microtransplantation's possible mechanisms of action, and determine whether this intervention is appropriately named. <h3>Evidence Review</h3> PubMed was searched from 1966 to April 1, 2020, with the search terms<i>micro-transplantation</i>AND<i>leukemia</i>AND/OR<i>myelodysplastic syndrome</i>with boolean operators. The search identified 14 records; 11 additional records were identified by screening published reviews. A total of 15 records remained after removing duplicates and records without full text, and 14 studies were included in the qualitative synthesis. <h3>Findings</h3> Among the 14 studies including about 600 patients, data from 5 phase 2 studies and 6 case reports of persons with AML included few heterogeneous persons and had obvious selection biases. The single randomized clinical trial also enrolled few persons. There was only 1 phase 2 study of persons with MDS. Point estimates of outcomes in both settings had wide 95% CIs. <h3>Conclusions and Relevance</h3> This study suggests that, to date, there are no convincing data on the safety or effectiveness of microtransplantation in persons with AML or MDS. This strategy should be considered investigational and performed in the setting of controlled clinical trials.
Acute Aortic Dissection Initially Suspected on 18F-FDG PET/CT
Authors: Gary A. Ulaner, Stefan Muehlbauer, Zoe Goldberg
Journal: Clinical Nuclear Medicine (2020)

Abstract A 64-year-old man with anal cancer underwent follow-up 18 F-FDG PET/CT to evaluate chemoradiation therapy response 5 months after an initial PET/CT. The follow-up 18 F-FDG PET/CT demonstrated new FDG-avid curvilinear soft tissue adjacent to the abdominal aorta, interpreted as an aortic dissection. Despite lack of clinical symptoms, the patient was directed to an emergency room the same day, where a contrast-enhanced CT confirmed an aortic aneurysm with dissection. The patient underwent endovascular surgical repair the following day. This case demonstrates that newly FDG-avid aortic soft tissue should be recognized and may need further evaluation to characterize clinically significant vascular pathology.
Vitrectomy Outcomes in Eyes with Diabetic Macular Edema and Vitreomacular Traction
Authors: Julia A Haller, Haijing Qin, Rajendra S Apte, Roy R Beck, Neil M Bressler, David J Browning, Ronald P Danis, Adam R Glassman, Joseph M Googe, Craig Kollman, Andreas K Lauer, Mark A Peters, Margaret E Stockman
Journal: Ophthalmology (2010)
Additive Uncorrelated Relaxed Clock Models for the Dating of Genomic Epidemiology Phylogenies
Authors: Xavier Didelot, Igor Siveroni, Erik M Volz
Journal: Molecular Biology and Evolution (2020)

Abstract Phylogenetic dating is one of the most powerful and commonly used methods of drawing epidemiological interpretations from pathogen genomic data. Building such trees requires considering a molecular clock model which represents the rate at which substitutions accumulate on genomes. When the molecular clock rate is constant throughout the tree then the clock is said to be strict, but this is often not an acceptable assumption. Alternatively, relaxed clock models consider variations in the clock rate, often based on a distribution of rates for each branch. However, we show here that the distributions of rates across branches in commonly used relaxed clock models are incompatible with the biological expectation that the sum of the numbers of substitutions on two neighboring branches should be distributed as the substitution number on a single branch of equivalent length. We call this expectation the additivity property. We further show how assumptions of commonly used relaxed clock models can lead to estimates of evolutionary rates and dates with low precision and biased confidence intervals. We therefore propose a new additive relaxed clock model where the additivity property is satisfied. We illustrate the use of our new additive relaxed clock model on a range of simulated and real data sets, and we show that using this new model leads to more accurate estimates of mean evolutionary rates and ancestral dates.
Outcomes in Radiotherapy-Treated Patients With Cancer During the COVID-19 Outbreak in Wuhan, China
Authors: Conghua Xie, Xiaoyong Wang, Hui Liu, Zhirong Bao, Jing Yu, Yahua Zhong, Melvin L. K. Chua
Journal: JAMA Oncology (2020)

This case series evaluated the delivery of radiotherapy in 209 patients with cancer during the COVID-19 outbreak in Wuhan, China.
Association of bariatric surgery with all-cause mortality and incidence of obesity-related disease at a population level: A systematic review and meta-analysis
Authors: Tom Wiggins, Nadia Guidozzi, Richard Welbourn, Ahmed R. Ahmed, Sheraz R. Markar
Journal: PLoS Medicine (2020)

Previous clinical trials and institutional studies have demonstrated that surgery for the treatment of obesity (termed bariatric or metabolic surgery) reduces all-cause mortality and the development of obesity-related diseases such as type 2 diabetes mellitus (T2DM), hypertension, and dyslipidaemia. The current study analysed large-scale population studies to assess the association of bariatric surgery with long-term mortality and incidence of new-onset obesity-related disease at a national level.A systematic literature search of Medline (via PubMed), Embase, and Web of Science was performed. Articles were included if they were national or regional administrative database cohort studies reporting comparative risk of long-term mortality or incident obesity-related diseases for patients who have undergone any form of bariatric surgery compared with an appropriate control group with a minimum follow-up period of 18 months. Meta-analysis of hazard ratios (HRs) was performed for mortality risk, and pooled odds ratios (PORs) were calculated for discrete variables relating to incident disease. Eighteen studies were identified as suitable for inclusion. There were 1,539,904 patients included in the analysis, with 269,818 receiving bariatric surgery and 1,270,086 control patients. Bariatric surgery was associated with a reduced rate of all-cause mortality (POR 0.62, 95% CI 0.55 to 0.69, p < 0.001) and cardiovascular mortality (POR 0.50, 95% CI 0.35 to 0.71, p < 0.001). Bariatric surgery was strongly associated with reduced incidence of T2DM (POR 0.39, 95% CI 0.18 to 0.83, p = 0.010), hypertension (POR 0.36, 95% CI 0.32 to 0.40, p < 0.001), dyslipidaemia (POR 0.33, 95% CI 0.14 to 0.80, p = 0.010), and ischemic heart disease (POR 0.46, 95% CI 0.29 to 0.73, p = 0.001). Limitations of the study include that it was not possible to account for unmeasured variables, which may not have been equally distributed between patient groups given the non-randomised design of the studies included. There was also heterogeneity between studies in the nature of the control group utilised, and potential adverse outcomes related to bariatric surgery were not specifically examined due to a lack of available data.This pooled analysis suggests that bariatric surgery is associated with reduced long-term all-cause mortality and incidence of obesity-related disease in patients with obesity for the whole operated population. The results suggest that broader access to bariatric surgery for people with obesity may reduce the long-term sequelae of this disease and provide population-level benefits.
Effect of Intravenous Acetaminophen on Postoperative Hypoxemia After Abdominal Surgery
Authors: Alparslan Turan, Hani Essber, Wael Saasouh, Karen Hovsepyan, Natalya Makarova, Sabry Ayad, Barak Cohen, Kurt Ruetzler, Loran Mounir Soliman, Kamal Maheshwari, Dongsheng Yang, Edward J. Mascha, Wael Ali Sakr Esa, Herman Kessler, Conor P. Delaney, Daniel I. Sessler
Journal: JAMA (2020)

<h3>Importance</h3> Opioid-induced ventilatory depression and hypoxemia is common, severe, and often unrecognized in postoperative patients. To the extent that nonopioid analgesics reduce opioid consumption, they may decrease postoperative hypoxemia. <h3>Objective</h3> To test the hypothesis that duration of hypoxemia is less in patients given intravenous acetaminophen than those given placebo. <h3>Design, Setting, and Participants</h3> Randomized, placebo-controlled, double-blind trial conducted at 2 US academic hospitals among 570 patients who were undergoing abdominal surgery, enrolled from February 2015 through October 2018 and followed up until February 2019. <h3>Interventions</h3> Participants were randomized to receive either intravenous acetaminophen, 1 g (n = 289), or normal saline placebo (n = 291) starting at the beginning of surgery and repeated every 6 hours until 48 postoperative hours or hospital discharge, whichever occurred first. <h3>Main Outcomes and Measures</h3> The primary outcome was the total duration of hypoxemia (hemoglobin oxygen saturation [Spo<sub>2</sub>] &lt;90%) per hour, with oxygen saturation measured continuously for 48 postoperative hours. Secondary outcomes were postoperative opioid consumption, pain (0- 10-point scale; 0: no pain; 10: the most pain imaginable), nausea and vomiting, sedation, minimal alveolar concentration of volatile anesthetic, fatigue, active time, and respiratory function. <h3>Results</h3> Among 580 patients randomized (mean age, 49 years; 48% women), 570 (98%) completed the trial. The primary outcome, median duration with Spo<sub>2</sub>of less than 90%, was 0.7 (interquartile range [IQR], 0.1-5.1) minutes per hour among patients in the acetaminophen group and 1.1 (IQR, 0.1-6.6) minutes per hour among patients in the placebo group (<i>P</i> = .29), with an estimated median difference of −0.04 (95% CI,−0.18 to 0.11) minutes per hour. None of the 8 secondary end points differed significantly between the acetaminophen and placebo groups. Mean pain scores within initial 48 postoperative hours were 4.2 (SD, 1.8) in the acetaminophen group and 4.4 (SD, 1.8) in the placebo group (difference, −0.28; 95% CI, –0.71 to 0.15); median opioid use in morphine equivalents was 50 mg (IQR, 18-122 mg) and 58 mg (IQR, 24-151 mg) , respectively, with a ratio of geometric means of 0.86 (95% CI, 0.61-1.21). <h3>Conclusions and Relevance</h3> Among patients who underwent abdominal surgery, use of postoperative intravenous acetaminophen, compared with placebo, did not significantly reduce the duration of postoperative hypoxemia over 48 hours. The study findings do not support the use of intravenous acetaminophen for this purpose. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02156154
Predicting obesity reduction after implementing warning labels in Mexico: A modeling study
Authors: Ana Basto-Abreu, Rossana Torres-Alvarez, Francisco Reyes-Sánchez, Romina González-Morales, Francisco Canto-Osorio, M. Arantxa Colchero, Simón Barquera, Juan A. Rivera, Tonatiuh Barrientos-Gutierrez
Journal: PLoS Medicine (2020)

Background In October 2019, Mexico approved a law to establish that nonalcoholic beverages and packaged foods that exceed a threshold for added calories, sugars, fats, trans fat, or sodium should have an "excess of" warning label. We aimed to estimate the expected reduction in the obesity prevalence and obesity costs in Mexico by introducing warning labels, over 5 years, among adults under 60 years of age. Methods and findings Baseline intakes of beverages and snacks were obtained from the 2016 Mexican National Health and Nutrition Survey. The expected impact of labels on caloric intake was obtained from an experimental study, with a 10.5% caloric reduction for beverages and 3.0% caloric reduction for snacks. The caloric reduction was introduced into a dynamic model to estimate weight change. The model output was then used to estimate the expected changes in the prevalence of obesity and overweight. To predict obesity costs, we used the Health Ministry report of the impact of overweight and obesity in Mexico 1999–2023. We estimated a mean caloric reduction of 36.8 kcal/day/person (23.2 kcal/day from beverages and 13.6 kcal/day from snacks). Five years after implementation, this caloric reduction could reduce 1.68 kg and 4.98 percentage points (pp) in obesity (14.7%, with respect to baseline), which translates into a reduction of 1.3 million cases of obesity and a reduction of US$1.8 billion in direct and indirect costs. Our estimate is based on experimental evidence derived from warning labels as proposed in Canada, which include a single label and less restrictive limits to sugar, sodium, and saturated fats. Our estimates depend on various assumptions, such as the transportability of effect estimates from the experimental study to the Mexican population and that other factors that could influence weight and food and beverage consumption remain unchanged. Our results will need to be corroborated by future observational studies through the analysis of changes in sales, consumption, and body weight. Conclusions In this study, we estimated that warning labels may effectively reduce obesity and obesity-related costs. Mexico is following Chile, Peru, and Uruguay in implementing warning labels to processed foods, but other countries could benefit from this intervention.
Impact of hyperglycemia on neuronal apoptosis after subarachnoid hemorrhage in rodent brain: An experimental research
Authors: Yu-Hua Huang, Chia-Li Chung, Hung-Pei Tsai, Rong-Dar Tzou, Shu-Chuan Wu, Chee-Yin Chai, Tao-Chen Lee, Aij-Lie Kwan
Journal: International Journal of Surgery (2020)
SARS‐CoV‐2 receptor ACE2 protein expression in serum is significantly associated with age
Authors: Ana B. Pavel, Jianni Wu, Yael Renert‐Yuval, Ester Del Duca, Jacob W. Glickman, Rachel L. Miller, Amy S. Paller, James G. Krueger, Emma Guttman‐Yassky
Journal: Allergy (2020)

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