tbuckley/cabot-search huggingface dataset:
Interleukin-15 Enhances Anti-GD2 Antibody-Mediated Cytotoxicity in an Orthotopic PDX Model of Neuroblastoma
Authors: Rosa Nguyen, Ardiana Moustaki, Jacqueline L. Norrie, Shantel Brown, Walter J. Akers, Abbas Shirinifard, Michael A. Dyer
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Immunotherapy with IL2, GM-CSF, and an anti-disialoganglioside (GD2) antibody significantly increases event-free survival in children with high-risk neuroblastoma. However, therapy failure in one third of these patients and IL2-related toxicities pose a major challenge. We compared the immunoadjuvant effects of IL15 with those of IL2 for enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) in neuroblastoma. Experimental Design: We tested ADCC against neuroblastoma patient-derived xenografts (PDX) in vitro and in vivo and examined the functional and migratory properties of NK cells activated with IL2 and IL15. Results: In cell culture, IL15-activated NK cells induced higher ADCC against two GD+ neuroblastoma PDXs than did IL2-activated NK cells (P &amp;lt; 0.001). This effect was dose-dependent (P &amp;lt; 0.001) and was maintained across several effector-to-tumor ratios. As compared with IL2, IL15 also improved chemotaxis of NK cells, leading to higher numbers of tumorsphere-infiltrating NK cells in vitro (P = 0.002). In an orthotopic PDX model, animals receiving chemoimmunotherapy with an anti-GD2 antibody, GM-CSF, and a soluble IL15/IL15Rα complex had greater tumor regression than did those receiving chemotherapy alone (P = 0.012) or combined with anti-GD2 antibody and GM-CSF with (P = 0.016) or without IL2 (P = 0.035). This was most likely due to lower numbers of immature tumor-infiltrating NK cells (DX5+CD27+) after IL15/IL15Rα administration (P = 0.029) and transcriptional upregulation of Gzmd. Conclusions: The substitution of IL15 for IL2 leads to significant tumor regression in vitro and in vivo and supports clinical testing of IL15 for immunotherapy in pediatric neuroblastoma.
Phylogenetic Shifts in Gene Body Methylation Correlate with Gene Expression and Reflect Trait Conservation
Authors: Danelle K Seymour, Brandon S Gaut
Journal: Molecular Biology and Evolution (2019)

Abstract A subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.
HyPhy 2.5—A Customizable Platform for Evolutionary Hypothesis Testing Using Phylogenies
Authors: Sergei L Kosakovsky Pond, Art F Y Poon, Ryan Velazquez, Steven Weaver, N Lance Hepler, Ben Murrell, Stephen D Shank, Brittany Rife Magalis, Dave Bouvier, Anton Nekrutenko, Sadie Wisotsky, Stephanie J Spielman, Simon D W Frost, Spencer V Muse
Journal: Molecular Biology and Evolution (2019)

Abstract HYpothesis testing using PHYlogenies (HyPhy) is a scriptable, open-source package for fitting a broad range of evolutionary models to multiple sequence alignments, and for conducting subsequent parameter estimation and hypothesis testing, primarily in the maximum likelihood statistical framework. It has become a popular choice for characterizing various aspects of the evolutionary process: natural selection, evolutionary rates, recombination, and coevolution. The 2.5 release (available from www.hyphy.org) includes a completely re-engineered computational core and analysis library that introduces new classes of evolutionary models and statistical tests, delivers substantial performance and stability enhancements, improves usability, streamlines end-to-end analysis workflows, makes it easier to develop custom analyses, and is mostly backward compatible with previous HyPhy releases.
Color Vision and Color Blindness.
Journal: JAMA (1896)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model
Authors: Min-Soo Kim, Yoonhee Kim, Hyunjung Choi, Woojin Kim, Sumyung Park, Dongjoon Lee, Dong Kyu Kim, Haeng Jun Kim, Hayoung Choi, Dong-Wook Hyun, June-Young Lee, Eun Young Choi, Dong-Sup Lee, Jin-Woo Bae, Inhee Mook-Jung
Journal: Gut (2019)

Objective Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. Design Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLP APT ) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. Results Composition of the gut microbiota in ADLP APT mice differed from that of healthy wild-type (WT) mice. Besides, ADLP APT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLP APT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLP APT recipient mice. Conclusion These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLP APT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.
No deal Brexit will have a “catastrophic” impact on the NHS, BMA warns
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A “no deal” Brexit on 31 October will push the NHS “to the brink” as the service prepares for next winter, the BMA has warned.1

In a briefing paper published on 2 September, the association describes how a departure from the European Union without an agreement could have “catastrophic” consequences for doctors, patients, and services at a time when the NHS is already struggling to cope with rising demand.

The paper demands that the government urgently answer more than 40 questions (see box) on how crashing out of the EU on 31 October will affect crucial areas such as the NHS workforce, access …
Turning the Phage on Treatment of Antimicrobial-Resistant Pneumonia
Authors: Richard G. Wunderink
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Turning the Phage on Treatment of Antimicrobial-Resistant PneumoniaLower respiratory tract infections cause 79% of all infectious disease deaths in the United States each year (1).Many of these pneumonia deaths are from community-acquired pneumonia or severe viral pneumonia, but hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), continues to play a major role.Sixty-four percent of the infections being treated in the ICU on any single day are pneumonia (2).The development of multidrug-resistant, extremely drugresistant, and pandrug-resistant bacterial pathogens is forcing changes in the manual of nosocomial pneumonia treatment.For decades, the backbone of antibiotic treatment for serious gram-negative pneumonia has been a b-lactam (penicillins, cephalosporins, or carbapenems).Of particular concern with regard to antimicrobialresistant (AMR) pneumonia are new and emerging carbapenemresistant pathogens, including Pseudomonas aeruginosa, Acinetobacter spp., and carbapenem-resistant Enterobacteriaceae.Previous "new" chapters in AMR pneumonia treatment have really been edits of prior chapters-adding various b-lactamase inhibitors to address specific resistance mechanisms (3, 4), optimizing pharmacokinetic/pharmacodynamics to treat borderline resistance (5), and even aerosolizing antibiotics to address adverse tissue penetration issues (6).A rereading of truly early chapters has been needed to correctly dose colistin and be reminded of its associated nephrotoxicity (4).Not since linezolid came on the market has a truly new class of antibiotics for HAP/VAP been introduced.The availability of this class of drugs has resulted in substantially less concern regarding the adequacy of treatment for methicillin-resistant S. aureus (MRSA) HAP/VAP (7) and the rare vancomycin-resistant Enterococcal pneumonia in immunocompromised patients.Two complementary studies published in this issue of the Journal suggest that we may be turning the page to a truly new chapter of AMR pneumonia treatment.Both papers demonstrate the potential and the limitations of lytic bacteriophage therapy for pneumonia owing to AMR pathogens.In contrast to the more common temperate phages, which integrate into the host bacterial chromosome as prophages, lytic phages are rapidly bactericidal.In this issue of the Journal, Prazak and colleagues (pp.1126-1133) present a comprehensive evaluation of the benefit of an intravenous cocktail of four bacteriophages in a mouse MRSA pneumonia model (8).They demonstrate that the phage cocktail was equivalent to treatment with teicoplanin, a glycopeptide equivalent to vancomycin.Unfortunately, neither additive nor synergistic effects of combination antibiotic and phage therapy were demonstrated.In contrast to the disappointing results of the animal study, Maddocks and colleagues (pp.
<i>KRAS</i> subset analysis from randomized phase II trials of erlotinib versus erlotinib plus sorafenib or pazopanib in refractory non-small cell lung cancer (NSCLC).
Authors: David Michael Waterhouse, Dawn Michelle Stults, Davey B. Daniel, Paula L. Griner, F Anthony Greco, Howard A. Burris, John D. Hainsworth, David R. Spigel
Journal: Journal of Clinical Oncology (2013)

8091 Background: KRAS mutations are among the most common genetic alterations in NSCLC; however no targeted therapies have been approved to benefit this lung cancer subset. Between 2/2008 and 2/2011 our center conducted two consecutive multicenter randomized phase II trials in patients (pts) with refractory NSCLC comparing erlotinib/placebo versus erlotinib + either sorafenib or pazopanib, both oral multikinase inhibitors (Spigel et al, JCO 2011; Chicago MSTO 2012). Progression-free survival (PFS) was improved with the multikinase regimens in the EGFR wild-type (WT) subsets, but not in the overall populations. An unplanned analysis of the combined KRAS subset data is the subject of this report. Methods: Eligibility criteria for both trials included: stage IIIB/IV NSCLC; 1 to 2 prior regimens; ECOG performance status 0–2; measurable disease. PFS was the primary endpoint of each trial. Treatment groups included: erlotinib/placebo (N=121), erlotinib/sorafenib (N=112), and erlotinib/pazopanib (N=127). 168 pts (47%) in these three groups had sufficient tumor specimens for KRAS analysis. Results: The PFS and OS results based on KRAS results are shown in the Table below. Conclusions: Patients in whom the KRAS mutation status was known achieved a significantly longer PFS with erlotinib and a multikinase inhibitor than with erlotinib alone. Although this unplanned combined analysis has several limitations, the greater PFS and OS benefits in pts with KRAS mutations warrant further study. Clinical trial information: NCT00600015; NCT01027598. [Table: see text]
Prenatal valacyclovir treatment of fetal citomegalovirus infection: A case series
Authors: Marco De Santis, Carmen De Luca, Massimo Apicella, Luisa D'Oria, Antonio Lanzone, Maurizio Sanguinetti, Piero Valentini, Giovanni Scambia, Lucia Masini, Rosaria Santangelo
Journal: Journal of Infection (2019)
Tanycytes Regulate Lipid Homeostasis by Sensing Free Fatty Acids and Signaling to Key Hypothalamic Neuronal Populations via FGF21 Secretion
Authors: Sarah Geller, Yoan Arribat, Citlalli Netzahualcoyotzi, Sylviane Lagarrigue, Lionel Carneiro, Lianjun Zhang, Francesca Amati, Isabel C. Lopez-Mejia, Luc Pellerin
Journal: Cell Metabolism (2019)
Identifying patient-reported anxiety and depression in older adults with cancer.
Authors: Reena Jayani, Can-Lan Sun, Kemeberly Charles, Enrique Soto Perez De Celis, Leana Chien, Elsa Roberts, Jeanine Moreno, William Dale, Supriya Gupta Mohile, Mina S. Sedrak, Marianna Koczywas, Vincent Chung, Marwan Fakih, Joseph Chao, Mihaela C. Cristea, Sumanta K. Pal, Vani Katheria, Arti Hurria, Daneng Li
Journal: Journal of Clinical Oncology (2019)

11556 Background: Anxiety and depression are associated with decreased quality of life, treatment adherence, and survival in patients with cancer. Mental Health Inventory (MHI-17) is a validated screening tool for psychological well-being, but cut points for older adults with cancer are unknown. The goal of this study is to identify cut points on MHI-17 Anxiety (MHI-A) and Depression (MHI-D) subscales which correlate with patient-reported anxiety and depression in older adults with cancer. Methods: This is a secondary analysis of baseline data from a randomized controlled trial in adults aged 65+ with solid tumors starting chemotherapy. At baseline, patients completed MHI-17. MHI-A and MHI-D were calculated (range 0-100; higher scores represent better mental health). Self-reported anxiety was obtained from single-item Linear Analog Scale Assessment (0-5 = low, 6-10 = high). Self-reported depression was obtained from Yale Depression Screen, “Do you often feel sad or depressed?” The association of MHI-A and MHI-D with the patient-reported outcomes was analyzed using logistic regression. Youden’s index was used to determine the optimal cut points for MHI-A and MHI-D for identifying patients with high anxiety and depression. Results: 458 patients (median age 71 (range 65-91), 57% female, 55% non-Hispanic white) were included in this analysis. The most common cancer types were: GI (31%), breast (19%), GU (18%), and pulmonary (16%); 75% had stage IV cancer. Twenty-four percent (N = 110) reported high anxiety and 21% (N = 97) depression. Median scores for MHI-A and MHI-D were 75 (range 0-100) and 80 (range 0-100). The optimal cut point for high anxiety on MHI-A was 65; this had an accuracy of 76.1%, a sensitivity of 71.8%, and a specificity of 77.5%. The optimal cut point for depression on MHI-D was 70; this had an accuracy of 80.1%, a sensitivity of 80.4%, and a specificity of 79.8%. Conclusions: The current study identified optimal cut points for MHI-Anxiety and MHI-Depression subscales to identify older adults with cancer starting chemotherapy with self-reported anxiety and depression. In the absence of patient-reported anxiety and depression, these cut points could be used to identify older patients with cancer at risk for poor mental health.
Donor Simvastatin Treatment in Heart Transplantation
Authors: Antti I. Nykänen, Emil J. Holmström, Raimo Tuuminen, Rainer Krebs, Kishor Dhaygude, Matti Kankainen, Janne J. Jokinen, Jyri Lommi, Ilkka Helanterä, Anne Räisänen-Sokolowski, Simo O. Syrjälä, Karl B. Lemström
Journal: Circulation (2019)

Background: Ischemia-reperfusion injury may compromise the short-term and long-term prognosis after heart transplantation. Experimental studies show that simvastatin administered to the organ donor is vasculoprotective and inhibits cardiac allograft ischemia-reperfusion injury. Methods: Eighty-four multiorgan donors were randomly assigned to receive 80 mg of simvastatin (42 donors) via nasogastric tube after declaration of brain death and upon acceptance as a cardiac donor, or to receive no simvastatin (42 donors). The primary efficacy end point was postoperative plasma troponin T and I levels during the first 24 hours after heart transplantation. Secondary end points included postoperative hemodynamics, inflammation, allograft function, rejections and rejection treatments, and mortality. Results: Organ donor simvastatin treatment significantly reduced the heart recipient plasma levels of troponin T by 34% (14 900 ± 12 100 ng/L to 9800 ± 7900 ng/L, P =0.047), and troponin I by 40% (171 000 ± 151 000 ng/L to 103 000 ± 109 000 ng/L, P =0.023) at 6 hours after reperfusion, the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) by 36% (32 800 ± 24 300 ng/L to 20 900 ± 15 900 ng/L; P =0.011) at 1 week, and the number of rejection treatments with hemodynamic compromise by 53% within the first 30 days ( P =0.046). Donor simvastatin treatment did not affect donor lipid levels but was associated with a specific transplant myocardial biopsy gene expression profile, and a decrease in recipient postoperative plasma levels of CXCL10 (C-X-C motif chemokine 10), interleukin-1α, placental growth factor, and platelet-derived growth factor-BB. Postoperative hemodynamics, biopsy-proven acute rejections, and mortality were similar. No adverse effects were seen in recipients receiving noncardiac solid organ transplants from simvastatin-treated donors. Conclusions: Donor simvastatin treatment reduces biomarkers of myocardial injury after heart transplantation, and—also considering its documented general safety profile—may be used as a novel, safe, and inexpensive adjunct therapy in multiorgan donation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01160978.
Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans
Authors: Slaven Stekovic, Sebastian J. Hofer, Norbert Tripolt, Miguel A. Aon, Philipp Royer, Lukas Pein, Julia T. Stadler, Tobias Pendl, Barbara Prietl, Jasmin Url, Sabrina Schroeder, Jelena Tadic, Tobias Eisenberg, Christoph Magnes, Michael Stumpe, Elmar Zuegner, Natalie Bordag, Regina Riedl, Albrecht Schmidt, Ewald Kolesnik, Nicolas Verheyen, Anna Springer, Tobias Madl, Frank Sinner, Rafael de Cabo, Guido Kroemer, Barbara Obermayer-Pietsch, Jörn Dengjel, Harald Sourij, Thomas R. Pieber, Frank Madeo
Journal: Cell Metabolism (2019)
Ambient Air Pollution and the Risk of Atrial Fibrillation and Stroke: A Population-Based Cohort Study
Authors: Saeha Shin, Richard T. Burnett, Jeffrey C. Kwong, Perry Hystad, Aaron van Donkelaar, Jeffrey R. Brook, Mark S. Goldberg, Karen Tu, Ray Copes, Randall V. Martin, Ying Liu, Alexander Kopp, Hong Chen
Journal: Environmental Health Perspectives (2019)

Background: Although growing evidence links air pollution to stroke incidence, less is known about the effect of air pollution on atrial fibrillation (AF), an important risk factor for stroke. Objectives: We assessed the associations between air pollution and incidence of AF and stroke. We also sought to characterize the shape of pollutant–disease relationships. Methods: The population-based cohort comprised 5,071,956 Ontario residents, age 35–85 y and without the diagnoses of both outcomes on 1 April 2001 and was followed up until 31 March 2015. AF and stroke cases were ascertained using health administrative databases with validated algorithms. Based on annual residential postal codes, we assigned 5-y running average concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) from satellite-derived data, a land-use regression model, and a fusion-based method, respectively, as well as redox-weighted averages of NO2 and O3 (Ox) for each year. Using Cox proportional hazards models, we estimated the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of AF and stroke with each of these pollutants, adjusting for individual- and neighborhood-level variables. We used newly developed nonlinear risk models to characterize the shape of pollutant–disease relationships. Results: Between 2001 and 2015, we identified 313,157 incident cases of AF and 122,545 cases of stroke. Interquartile range increments of PM2.5, NO2, O3, and Ox were associated with increases in the incidence of AF [HRs (95% CIs): 1.03 (1.01, 1.04), 1.02 (1.01, 1.03), 1.01 (1.00, 1.02), and 1.01 (1.01, 1.02), respectively] and the incidence of stroke [HRs (95% CIs): 1.05 (1.03, 1.07), 1.04 (1.01, 1.06), 1.05 (1.03, 1.06), and 1.05 (1.04, 1.06), respectively]. Associations of similar magnitude were found in various sensitivity analyses. Furthermore, we found a near-linear association for stroke with PM2.5, whereas Ox-stroke, PM2.5-, and Ox-AF relationships exhibited sublinear shapes. Conclusions: Air pollution was associated with stroke and AF onset, even at very low concentrations. https://doi.org/10.1289/EHP4883