tbuckley/cabot-search huggingface dataset:
Reduced Salt Intake for Heart Failure
Authors: Kamal R. Mahtani, Carl Heneghan, Igho Onakpoya, Stephanie Tierney, Jeffrey K. Aronson, Nia Roberts, F. D. Richard Hobbs, David Nunan
Journal: JAMA Internal Medicine (2018)

Recent estimates suggest that more than 26 million people worldwide have heart failure. The syndrome is associated with major symptoms, significantly increased mortality, and extensive use of health care. Evidence-based treatments influence all these outcomes in a proportion of patients with heart failure. Current management also often includes advice to reduce dietary salt intake, although the benefits are uncertain.To systematically review randomized clinical trials of reduced dietary salt in adult inpatients or outpatients with heart failure.Several bibliographic databases were systematically searched, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and CINAHL. The methodologic quality of the studies was evaluated, and data associated with primary outcomes of interest (cardiovascular-associated mortality, all-cause mortality, and adverse events, such as stroke and myocardial infarction) and secondary outcomes (hospitalization, length of inpatient stay, change in New York Heart Association [NYHA] functional class, adherence to dietary low-salt intake, and changes in blood pressure) were extracted.Of 2655 retrieved references, 9 studies involving 479 unique participants were included in the analysis. None of the studies included more than 100 participants. The risks of bias in the 9 studies were variable. None of the included studies provided sufficient data on the primary outcomes of interest. For the secondary outcomes of interest, 2 outpatient-based studies reported that NYHA functional class was not improved by restriction of salt intake, whereas 2 studies reported significant improvements in NYHA functional class.Limited evidence of clinical improvement was available among outpatients who reduced dietary salt intake, and evidence was inconclusive for inpatients. Overall, a paucity of robust high-quality evidence to support or refute current guidance was available. This review suggests that well-designed, adequately powered studies are needed to reduce uncertainty about the use of this intervention.PROSPERO Identifier: CRD42015019504.
Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease
Authors: JoAnn E. Manson, Nancy R. Cook, I-Min Lee, William Christen, Shari S. Bassuk, Samia Mora, Heike Gibson, David Gordon, Trisha Copeland, Denise D’Agostino, Georgina Friedenberg, Claire Ridge, Vadim Bubes, Edward L. Giovannucci, Walter C. Willett, Julie E. Buring
Journal: New England Journal of Medicine (2018)

It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited.
Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma
Authors: Haoyu Sun, Qiang Huang, Mei Huang, Hao Wen, Renyong Lin, Meijuan Zheng, Kun Qu, Kun Li, Haiming Wei, Weihua Xiao, Rui Sun, Zhigang Tian, Cheng Sun
Journal: Hepatology (2018)

Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Coinhibitory CD96 and T‐cell immunoglobulin and ITIM domain (TIGIT), together with costimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine‐tunes immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT, and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin‐embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and mean fluorescence intensity (MFI) of CD96 + NK cells are significantly increased in the intratumoral tissues of HCC and break the balance between three receptors. Human CD96 + NK cells are functionally exhausted with impaired interferon‐gamma (IFN‐γ) and tumor necrosis factor‐alpha (TNF‐α) production, high gene expression of interleukin (IL)‐10 and transforming growth factor‐beta 1 (TGF‐β1), and low gene expression of T‐bet, IL‐15, perforin, and granzyme B. In addition, blocking CD96‐CD155 interaction specifically increases lysis of HepG2 cells by NK cells. HCC patients with a high level of CD96 or CD155 expression within tumor are strongly associated with deteriorating disease condition and shorter disease‐free survival (DFS) and overall survival times. Patients with a higher cumulative percentage of CD96 + NK cells within tumor also exhibit shorter DFS. High plasma level of TGF‐β1 in HCC patients up‐regulates CD96 expression and dynamically shifts the balance between CD96, TIGIT, and CD226 in NK cells. Blocking TGF‐β1 specifically restores normal CD96 expression and reverses the dysfunction of NK cells. Conclusion: These findings indicate that human intratumoral CD96 + NK cells are functionally exhausted and patients with higher intratumoral CD96 expression exhibit poorer clinical outcomes. Blocking CD96‐CD155 interaction or TGF‐β1 restores NK cell immunity against tumors by reversing NK cell exhaustion, suggesting a possible therapeutic role of CD96 in fighting liver cancer.
GENE-30. INCREASED TUMOR MUTATIONAL LOAD AFTER RADIOTHERAPY AND TEMOZOLOMIDE IN PROGRESSING GLIOBLASTOMA A PROSPECTIVE STUDY
Authors: Dorte Schou Nørøxe, Christina Westmose Yde, Olga Østrup, Finn Cilius Nielsen, Jane Skjøth-Rasmussen, Jannick Brennum, Petra Hamerlik, Hans Poulsen, Ulrik Lassen
Journal: Neuro-Oncology (2018)

Tumor mutational load (TML) is the number of nonsynonymous mutations in a tumor sample. TML has proved predictive of response to immune therapy (IT) in other TML-high tumors. Research in TML in glioblastoma (GBM) is limited and has to our knowledge not been done prospectively in paired samples before and after treatment. Over a 2-year period from February 2016 to March 2018, 27 patients with newly diagnosed GBM were included. All patients had one biopsy at diagnosis and another when having secondary surgery due to progression. Three patients had three surgeries. We noted clinical and pathological data. Blood samples were extracted and whole exome sequencing has been performed. We are now investigating TML including clonal and subclonal mutations, mutations in mismatch repair genes and the aberrant cell fraction. TML will be reported as per Megabase exome and will be adjusted for coverage in each sample. All the included patients had primary GBM with isocitrate dehydrogenase (IDH) wild type. O-6-methylguanine-DNA methyltransferase (MGMT) was methylated in 6 patients (22%) and the majority of patients have been treated with chemo/radiation with Temozolomide. Since the patients were included from our daily clinical oncological department, the clinical characteristics resembled the average GBM patient according to age, performance status, treatment, progression-free survival and overall survival. Analyses are forthgoing and will be ready at the time of the SNO-meeting. An agreement of how to report TML is strongly needed and TML should be included in future trials in GBM.
IMMU-67. PERSONALIZED TUMOR MRNA LOADED LIPID NANOPARTICLES PRIME THE SYSTEMIC AND INTRATUMORAL GBM MILIEU FOR RESPONSE TO IMMUNOTHERAPY
Authors: Elias Sayour, Adam Grippin, Gabriel De Leon, Brian Stover, Jianping Huang, Loic Deleyrolle, Bikash Sahay, Sheila Carrera-Justiz, Hector Mendez-Gomez, Duane Mitchell
Journal: Neuro-Oncology (2018)

In a randomized phase III study for recurrent glioblastoma (GBM), combination therapy with immune checkpoint inhibitors (ICIs) nivolumab and ipilimumab failed to improve overall survival. Since ICIs appear to be dependent on host-myeloid (and not tumor-cell) expression of PD-L1 (Tang et al. JCI, 2018), we sought to assess if tumor-mRNA nanoparticles (NPs) could prime the systemic and intratumoral GBM milieu with activated PD-L1+ host-myeloid cells sensitizing immunologically ‘cold’ tumors to immunotherapy. We systemically administered personalized tumor-derived mRNA encapsulated in translatable lipid-NPs with excess positive charge for enhanced delivery and transfection of peripheral/intratumoral antigen presenting cells (APCs) in murine and large animal canine malignant glioma models. RNA-NPs activate systemic immunity within twenty-four hours, inducing significant increases in the percentage of CD11c+ myeloid-cells expressing PD-L1 and CD86. After only a single RNA-NP vaccine, the bulk of APCs within the spleen, liver, lymph nodes, bone marrow and tumor display an activated phenotype. These PD-L1+ APCs (CD11c+MHC-II+CD86+PD-L1+ cells from intracranial tumors) did not suppress immunity, but rather, heightened interferon-(IFN)-γ reactivity. Addition of ICIs (to animals primed with RNA-NPs) augmented peripheral/intratumoral PD-1+CD8+ cells and mediated synergistic anti-tumor efficacy in settings where ICIs alone did not confer therapeutic benefit. These synergistic effects were mediated by type–I-interferon released from PD-L1+ plasmacytoid dendritic-cells. In translational studies, personalized mRNA-NPs (from whole tumor-transcriptome) were safe and active in a client-owned canine with a spontaneous malignant glioma. In this patient, RNA-NPs elicited robust immunologic activity with increased percentages of activated PD-L1+ APCs and IFNγ+CD8+ cells. RNA-NPs elicit widespread immune activation concomitant with inducible PD-L1 expression on intratumoral APCs that can be therapeutically exploited. Since RNA-NPs bypass cost/complexity of cellular therapeutics, are amenable to central distribution, and can be made within days of tumor resection, these formulations can be expeditiously translated as biomodulators of GBM immunogenicity.
DDIS-08. DEVELOPMENT OF BRAIN-PENETRANT EGFR INHIBITORS FOR GLIOBLASTOMA
Authors: Jonathan Tsang, Lorenz Urner, Gyudong Kim, Kingsley Chow, Peter Clark, Timothy Cloughesy, Michael Jung, David Nathanson
Journal: Neuro-Oncology (2018)

The epidermal growth factor receptor (EGFR) is altered in nearly 60% of glioblastoma (GBM) tumors, however, EGFR tyrosine kinase inhibitors (TKIs) have failed to improve outcomes for GBM patients. This can be attributed to the inability of conventional EGFR TKIs (e.g., erlotinib, gefitinib, lapatinib, afatinib) to effectively cross the blood-brain-barrier (BBB) and reach adequate pharmacological levels for a tumor response. For example, less than 10% of plasma drug concentrations are achieved in the brain for all FDA approved EGFR TKIs. Herein, we performed a structure-activity relationship (SAR) from the 4-anilinoquinazoline scaffold to improve brain penetrance by modifications of physiochemical properties amenable to BBB penetration. Our synthesis scheme aimed to develop EGFR TKIs with low molecular weight and polar surface area, few rotatable bonds and hydrogen bond donors and acceptors, while having high lipophilicity. This yielded novel EGFR TKIs with nanomolar potency against EGFR mutant, GBM patient-derived cells in culture, high BBB penetration (200% brain to plasma), and efficacy against patient-derived orthotopic GBM xenografts. Current efforts are aimed at improving metabolic stability and bioavailability to obtain a clinical EGFR TKI drug candidate for the treatment of GBM.
British competitiveness at risk from visa system that rejects conference delegates, warn scientists
Authors: Nigel Hawkes
Journal: BMJ (2018)

Medical conferences may have to be moved abroad unless the Home Office changes policy over the issuing of visas, the head of the London School of Hygiene and Tropical Medicine has warned.

Peter Piot said that 17 would-be delegates were prevented from attending the Women Leaders in Global Health conference, held at the school on 8-9 November, because they were denied visas by the Home Office. He called for an urgent review of the rejected applications and wrote to the home secretary, Sajid Javid, warning that British competitiveness was being affected.

His complaints have been backed by the president of the Royal Society, Venti Ramakrishnan, and the director of the Wellcome Trust, Jeremy Farrar. …
TMOD-37. IN VIVO SYNERGISTIC EFFECT OF CHECKPOINT BLOCKADE AND RADIATION THERAPY AGAINST CHORDOMAS IN A HUMANIZED MOUSE MODEL
Authors: Wataru Ishida, Kyle McCormick, Aayushi Mahajan, Eric Feldstein, Michael Lim, Jeffrey Bruce, Peter Canoll, Sheng-fu Lo
Journal: Neuro-Oncology (2018)

Currently, there are no murine chordoma cell lines nor transgenic mouse models of chordomas, which prevents us from investigating the interaction between murine chordomas and murine immune cells. Thus, to scrutinize immunotherapy (IT) against chordomas, the development of a humanized mouse model of chordomas, where human thymus, CD34+ stem cells, and chordomas are co-transplanted to engraft human immune system into mice, is imperative. We aimed to investigate synergistic effect between IT and radiation therapy (RT) against chordomas using this model. Fifteen 10-12-week-old NSG mice were sub-lethally irradiated and then implanted with human fetal thymic tissue and CD34+ stem cells, whose HLA-type is partially-matched with that of the U-CH1 chordoma cell line. Reconstitution of immune cells in NSG mice was confirmed eight weeks post-transplantation, and then each animal was injected with U-CH1 subcutaneously. Next, they were treated for four weeks as follows: (A) control (n=3), (B) anti-human-PD-1 antibodies (n=4), (C) RT + isotype antibodies (n=3, 8Gy x 4), (D) anti-human-PD-1 antibodies and RT (n=5). Anti-tumor activities were monitored via tumor size, flow cytometry, immunohistochemistry, and qRT-PCR. One week after the treatment, on the irradiated side, (D) demonstrated lowest tumor volume, highest number of human peripheral blood mononuclear cells, highest percentages of CD8+ human T cells and CD45RO+CD4+ human T cells, and lowest percentage of PD-1+CD8+ human T cells in the tumors via flow cytometry and immunohistochemistry, and highest mRNA level of IFN-gamma in the tumors via qRT-PCR, amongst the four groups with statistical significance. We demonstrated that this humanized mouse model could be a revolutionary platform to investigate IT against rare cancers such as chordomas, where murine equivalents are unavailable. The direct synergistic effect between IT and RT against chordoma was observed, evidenced by lowest tumor volume, highest cytotoxic T cells, and memory T cells.
COMP-08. SURVIVING BY EXPLORING: COULD GLIOBLASTOMA CELLS FOLLOW THE THEORY OF EXPLORATORY ADAPTATION?
Authors: Orieta Celiku, Mark Gilbert, Orit Lavi
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) prognosis remains abysmal despite decades of research. Standard approaches to treatment target the tumor growth mechanisms, and novel ones attempt to better recruit the immune system. However, cancer has a remarkable ability to adapt, surviving the introduced stress signals and thriving in new microenvironment settings. Understanding these fundamental processes of adaptation, and mechanisms specific to GBM, would enable a robust treatment approach that considers how cells utilize compensatory mechanisms. We adapted a recent theory of exploratory adaptation -- prescribing how small random perturbations to the regulatory network could be propagated to changes in the cellular phenotype -- to examine the question of how GBM cells adapt across their microenvironment. We studied the transcriptomic profiles of spatially-separated tumor anatomical structures using patient-derived data from the IVY Glioblastoma Atlas Project. First, we asked how exploratory adaptation might explain the ability of cells to change their phenotype given their initial anatomical location; second, we tested if tumor cells from one location can adapt over time to resemble cells in neighboring locations. We defined the cellular phenotype at the functional pathway activity level and introduced notions of phenotype similarity and convergence. We simulated the dynamics of the pathway activities while cells attempt to obtain the phenotypes of cells from a different spatial environment. We estimated the distribution of each pathway activity over time, and observed some transitions (for example, the sulfur metabolism pathway shifting from a unimodal to a bimodal distribution) suggestive of exploratory adaptation. Several DNA repair pathways, including mismatch repair and non-homologous end-joining increased their distribution spread over time. Some pathways reached the tested destination distributions, but the global phenotypes did not meet our convergence criteria. Our results suggest that exploratory adaptation could partially explain adaptation in GBM, but could not fully account for it.
The role of sex hormone-binding globulin (SHBG) in the androgen response of human prostate cancer cells
Authors: Scott Kahn, Yu Li, Atif Nakhla, Daniel Hryb, Richard Friedman, Jenny Xiang, William Rosner, Nicholas Romas, Nicholas Wagar
Journal: Cancer Research (2008)

1230  The role of androgens in prostate cancer is well established; yet not all facets of androgen signaling are well understood. Sex hormone-binding globulin (SHBG), which binds androgens in plasma, mediates a rapid androgen response in prostate cells through a specific membrane-based receptor (RSHBG) independent of the androgen receptor (AR). SHBG and its associated signaling pathways could provide potential therapeutic targets for prostate cancer. SHBG mRNA and protein is expressed by prostate cells, suggesting autocrine/paracrine properties. We hypothesize that SHBG regulates gene expression through RSHBG, and also acts as an intracellular buffer for androgens to modulate AR activation. The SHBG and p53 tumor suppressor genes colocalize on chromosome 17 to a region often deleted in tumors, implicating a role in prostate cancer for aberrant SHBG expression. In this study, we used microarray analysis to acertain the effects of SHBG on androgen signaling in the LNCaP prostate cell line. L5S2, a LNCaP-derived clonal cell line, reproducibly induces SHBG overexpression upon Ponasterone A (PonA) treatment. L5V4 is its noniducible isogenic sister vector control cell line. L5S2 and L5V4 cells were grown in androgen depleted medium, treated for 24hrs with PonA to induce SHBG or vehicle alone, then with DHT or vehicle alone for another 24 hours. Experiments were performed in triplicate. Cellular RNAs were isolated, labeled, and hybridized to Affymetrix Human Genome U133 Plus 2.0 Array chips. In response to SHBG overexpression and DHT, 1131 genes were significantly induced or repressed by conditions resulting in RSHBG activation and 187 DHT responsive genes were modulated by SHBG. Real-time PCR analysis was used to validate microarray results. Our results support a biologic role for RSHBG signaling in LNCaP cells. We also provide the first evidence that intracellular SHBG may regulate AR activity- decreased SHBG expression in prostate tumors may allow the AR to function under reduced intracellular androgen concentrations. Putative downstream targets of SHBG + DHT signaling include STEAP4, FKBP5, TIMP2, GPR89a, GPR30, and c-MYC, genes with important and provocative cellular functions with respect to androgen signaling and prostate cancer. If confirmed, we plan to identify intermediaries in SHBG-mediated androgen signaling, and address the functional role of dysregulated SHBG expression in prostate cancer.
Abstract 11582: Increased Burden of Diagnosed Vascular Diseases in Quebec, Canada Between 2000 and 2015
Authors: Claudia Blais, Louis Rochette, Thao Huynh
Journal: Circulation (2018)

Introduction: Vascular diseases, including coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral artery disease (PAD) are leading causes of the overall cardiovascular burden in...
Stress-Related Disorders and Autoimmune Disease
Authors: Jianbo Liu, Jianping Lu, Xuerong Luo
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Association of Opioid Prescribing With Opioid Consumption After Surgery in Michigan
Authors: Ryan Howard, Brian Fry, Vidhya Gunaseelan, Jay Lee, Jennifer Waljee, Chad Brummett, Darrell Campbell, Elizabeth Seese, Michael Englesbe, Joceline Vu
Journal: JAMA Surgery (2018)

<h3>Importance</h3> There is growing evidence that opioids are overprescribed following surgery. Improving prescribing requires understanding factors associated with opioid consumption. <h3>Objective</h3> To describe opioid prescribing and consumption for a variety of surgical procedures and determine factors associated with opioid consumption after surgery. <h3>Design, Setting, and Participants</h3> A retrospective, population-based analysis of the quantity of opioids prescribed and patient-reported opioid consumption across 33 health systems in Michigan, using a sample of adults 18 years and older undergoing surgery. Patients were included if they were prescribed an opioid after surgery. Surgical procedures took place between January 1, 2017, and September 30, 2017, and were included if they were performed in at least 25 patients. <h3>Exposures</h3> Opioid prescription size in the initial postoperative prescription. <h3>Main Outcomes and Measures</h3> Patient-reported opioid consumption in oral morphine equivalents. Linear regression analysis was used to calculate risk-adjusted opioid consumption with robust standard errors. <h3>Results</h3> In this study, 2392 patients (mean age, 55 years; 1353 women [57%]) underwent 1 of 12 surgical procedures. Overall, the quantity of opioid prescribed was significantly higher than patient-reported opioid consumption (median, 30 pills; IQR, 27-45 pills of hydrocodone/acetaminophen, 5/325 mg, vs 9 pills; IQR, 1-25 pills;<i>P</i> &lt; .001). The quantity of opioid prescribed had the strongest association with patient-reported opioid consumption, with patients using 0.53 more pills (95% CI, 0.40-0.65;<i>P</i> &lt; .001) for every additional pill prescribed. Patient-reported pain in the week after surgery was also significantly associated with consumption but not as strongly as prescription size. Compared with patients reporting no pain, patients used a mean (SD) 9 (1) more pills if they reported moderate pain and 16 (2) more pills if they reported severe pain (<i>P</i> &lt; .001). Other significant risk factors included history of tobacco use, American Society of Anesthesiologists class, age, procedure type, and inpatient surgery status. After adjusting for these risk factors, patients in the lowest quintile of opioid prescribing had significantly lower mean (SD) opioid consumption compared with those in the highest quintile (5 [2] pills vs 37 [3] pills;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> The quantity of opioid prescribed is associated with higher patient-reported opioid consumption. Using patient-reported opioid consumption to develop better prescribing practices is an important step in combating the opioid epidemic.