tbuckley/cabot-search huggingface dataset:
Abstract P178: Vitamin D Biomarkers with Risk of Hypertension and Renin-Angiotensin System
Authors: Lu Wang, Nancy Cook, JoAnn E Manson, J. Michael Gaziano, Julie E Buring, Howard D Sesso
Journal: Circulation (2016)

Background: Experimental studies suggest that vitamin D may potentially prevent the development of hypertension through down-regulation of the renin-angiotensin system. However, evidence from epidemiologic studies remains limited. Objective: In parallel nested case-control studies of women from the Women’s Health Study (WHS) and men from the Physicians’ Health Study (PHS) with &gt;10 years follow-up, we examined the prospective associations between the circulating biomarkers of vitamin D status with risk of hypertension, as well as the inter-relation between vitamin D biomarkers and renin production. Methods: In each cohort, 500 incident hypertension cases and 500 controls were randomly selected from participants who were free of cardiovascular disease, cancer, and hypertension and provided bloods at baseline. Hypertension cases were identified based on self-reported blood pressure, physician’s diagnosis, or medication use. Controls were matched to cases on gender, age, race, follow-up time, and month of blood draw. Baseline plasma 25(OH)-vitamin D, parathyroid hormone (PTH), and total renin (pro-renin plus active renin) concentrations were measured. Analyses were first performed in each cohort separately and, given the similar results, finally combined for both cohorts. Results: Baseline concentrations of 25(OH)-vitamin D (mean of 26.6 vs. 27.0 ng/mL) and PTH (32.6 vs. 32.2 pg/mL) were similar in hypertension cases and controls. In the crude matched model, the risk of hypertension did not change with 25(OH)-vitamin D or PTH concentrations. Additional adjustment for other known hypertension-related risk factors minimally affected the associations. After adjusting for baseline smoking, alcohol use, exercise, menopausal status and hormone therapy use among women, body mass index, and history of diabetes and hypercholesterolemia, the relative risks of incident hypertension across increasing quintiles of 25(OH)-vitamin D were 1.00, 1.42 (95% CI: 0.94-2.16), 0.94 (95% CI: 0.60-1.48), 0.99 (95% CI: 0.61-1.61), and 1.03 (95% CI: 0.63-1.69) (p, trend, 0.48), and across increasing quintiles of PTH were 1.00, 1.26 (95% CI: 0.83-1.92), 0.91 (95% CI: 0.60-1.40), 1.10 (95% CI: 0.70-1.71), 0.92 (95% CI: 0.59-1.44) (p, trend, 0.50). These associations were similar in men and women. Among controls, plasma 25(OH)-vitamin D was inversely correlated with PTH (Pearson r: -0.24, p&lt;0.0001), while neither 25(OH)-vitamin D (r: -0.02, p=0.53) nor PTH (r: -0.01, p=0.69) was correlated with total renin concentrations. Conclusions: In prospective cohorts of men and women, we found no association between either baseline plasma 25(OH)-vitamin D or PTH with the risk of hypertension, or between either 25(OH)-vitamin D or PTH with total renin concentration. More research is needed to further elucidate the specific effect of vitamin D in the development of hypertension.
Lack of Genetic Association between CDHR3 and Human Rhinovirus C Infection in Hong Kong Children Hospitalized for Respiratory Tract Infections
Authors: Ting Fan Leung, Man Fung Tang, Yu Ping Song, Agnes Sze Yin Leung, Kin Pong Tao, Joseph Gar Shun Tsun, Gary Wing Kin Wong, Renee Wan Yi Chan
Journal: Journal of Allergy and Clinical Immunology (2018)
c-Src plays a role in internalization of epidermal growth factor receptors (EGFR) induced by (-)-epigallocatechin gallate (EGCG) in SW480 colon cancer cells.
Authors: Satoshi To, Seiji Adachi, I. Weinstein
Journal: Cancer Research (2008)

614  EGCG, the major biologically active constituent of green tea, inhibits activation of the EGFR and its downstream signaling pathways in several types of human cancer. We recently discovered that this inhibition is associated with internalization of the EGFR. Although the precise mechanism of ligand-induced EGFR internalization is still unclear, some reports suggest that a src family non-receptor tyrosine kinase may play a role in this process. Therefore, we hypothesized that a src family kinase may also play a role in EGCG-induced EGFR internalization. Using SW480 cells, we conducted a time course study and found that EGCG can activate c-Src in a dose- and time-dependent manner. Activation was detected with as low as 1μM of EGCG and within 10min. This time course is consistent with our previous findings that EGCG can induce EGFR internalization within 30min. We examined whether EGCG can bind to the c-Src protein by affinity chromatography using EGCG-coupled Sepharose beads. SW480 total cell lysates were applied to the EGCG affinity column and eluted fractions were analyzed by western blot analysis. c-Src was detected in the fraction containing proteins that bind to EGCG with high affinity. Next, we investigated the effect of EGCG on the level of cell surface EGFR using a quantitative ELISA assay, and found that EGCG 40μM causes a significant decrease in the amount of cell surface EGFR. This reduction was partially rescued by the src kinase specific inhibitor PP1. We confirmed these findings using fluorescence microscopy by demonstrating that combined treatment with EGCG and PP1 decreased the amount of internalized vesicles containing EGFR. Src family kinases have been shown to bind to and laterally activate EGFR, leading to stimulation of specific downstream signaling pathway and DNA synthesis. Therefore, we examined the phosphorylation status of EGFR by immunoblotting using site-specific and non-specific anti-phospho-tyrosine antibodies. In these studies, treatment with EGCG did not cause phosphorylation of tyrosine residues or increase total tyrosine phosphorylation of EGFR. Taken together, our studies provide the first evidence that EGCG can bind to and preferentially activate c-Src and that this activation may play a role in EGCG-induced internalization of the EGFR in SW480 cells. However, this activation of c-Src does not activate the EGFR and its downstream signaling pathways. Our findings suggest a novel mechanism by which EGCG inhibits the EGFR pathway. Further studies will be required to determine the significance of c-Src activation by EGCG with respect to its anti-cancer effects.
Quality of life in Palestinian patients with end-stage renal disease receiving treatment by haemodialysis: a cross-sectional study
Authors: Sa'ed H Zyoud, Dala N Daraghmeh, Diana O Mezyed, Razan L Khdeir, Mayas N Sawafta, Nora A Ayaseh, Ghada H Tabeeb, Waleed M Sweileh, Rahmat Awang, Samah W Al-Jabi
Journal: The Lancet (2018)
Tuberculosis control interventions targeted to previously treated people in a high-incidence setting: a modelling study
Authors: Florian M Marx, Reza Yaesoubi, Nicolas A Menzies, Joshua A Salomon, Alyssa Bilinski, Nulda Beyers, Ted Cohen
Journal: The Lancet Global Health (2018)

<h2>Summary</h2><h3>Background</h3> In high-incidence settings, recurrent disease among previously treated individuals contributes substantially to the burden of incident and prevalent tuberculosis. The extent to which interventions targeted to this high-risk group can improve tuberculosis control has not been established. We aimed to project the population-level effect of control interventions targeted to individuals with a history of previous tuberculosis treatment in a high-incidence setting. <h3>Methods</h3> We developed a transmission-dynamic model of tuberculosis and HIV in a high-incidence setting with a population of roughly 40 000 people in suburban Cape Town, South Africa. The model was calibrated to data describing local demography, TB and HIV prevalence, TB case notifications and treatment outcomes using a Bayesian calibration approach. We projected the effect of annual targeted active case finding in all individuals who had previously completed tuberculosis treatment and targeted active case finding combined with lifelong secondary isoniazid preventive therapy. We estimated the effect of these targeted interventions on local tuberculosis incidence, prevalence, and mortality over a 10 year period (2016–25). <h3>Findings</h3> We projected that, under current control efforts in this setting, the tuberculosis epidemic will remain in slow decline for at least the next decade. Additional interventions targeted to previously treated people could greatly accelerate these declines. We projected that annual targeted active case finding combined with secondary isoniazid preventive therapy in those who previously completed tuberculosis treatment would avert 40% (95% uncertainty interval [UI] 21–56) of incident tuberculosis cases and 41% (16–55) of tuberculosis deaths occurring between 2016 and 2025. <h3>Interpretation</h3> In this high-incidence setting, the use of targeted active case finding in combination with secondary isoniazid preventive therapy in previously treated individuals could accelerate decreases in tuberculosis morbidity and mortality. Studies to measure cost and resource implications are needed to establish the feasibility of this type of targeted approach for improving tuberculosis control in settings with high tuberculosis and HIV prevalence. <h3>Funding</h3> National Institutes of Health, German Research Foundation.
Autoantibodies Hurt: Transfer of Patient-Derived CASPR2 Antibodies Induces Neuropathic Pain in Mice
Authors: Matthew A. Hunt, Diana S.M. Nascimento, Alex Bersellini Farinotti, Camilla I. Svensson
Journal: Neuron (2018)

In this issue of Neuron, Dawes et al. (2018) show that CASPR2 antibodies (Abs) isolated from patients bind specifically to primary afferent cell bodies and induce neuropathic pain in mice. Consequent decreased expression of Kv1 channels and their aberrant localization along myelinated axons explain the observed hyperexcitability and pain.
The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel
Authors: Christian J. Peters, John M. Gilchrist, Jason Tien, Neville P. Bethel, Lijun Qi, Tingxu Chen, Lynn Wang, Yuh Nung Jan, Michael Grabe, Lily Y. Jan
Journal: Neuron (2018)
Family History and Breast Cancer Risk Among Older Women in the Breast Cancer Surveillance Consortium Cohort
Authors: Dejana Braithwaite, Diana L. Miglioretti, Weiwei Zhu, Joshua Demb, Amy Trentham-Dietz, Brian Sprague, Jeffrey A. Tice, Tracy Onega, Louise M. Henderson, Diana S. M. Buist, Elad Ziv, Louise C. Walter, Karla Kerlikowske
Journal: JAMA Internal Medicine (2018)

First-degree family history is a strong risk factor for breast cancer, but controversy exists about the magnitude of the association among older women.To determine whether first-degree family history is associated with increased risk of breast cancer among older women, and identify whether the association varies by breast density.Prospective cohort study between 1996 and 2012 from 7 Breast Cancer Surveillance Consortium (BCSC) registries located in New Hampshire, North Carolina, San Francisco Bay area, western Washington state, New Mexico, Colorado, and Vermont. During a mean (SD) follow-up of 6.3 (3.2) years, 10 929 invasive breast cancers were diagnosed in a cohort of 403 268 women 65 years and older with data from 472 220 mammography examinations. We estimated the 5-year cumulative incidence of invasive breast cancer by first-degree family history, breast density, and age groups. Cox proportional hazards models were fit to estimate the association of first-degree family history with risk of invasive breast cancer (after adjustment for breast density, BCSC registry, race/ethnicity, body mass index, postmenopausal hormone therapy use, and benign breast disease for age groups 65 to 74 years and 75 years and older, separately). Data analyses were performed between June 2016 and June 2017.First-degree family history of breast cancer.Incident breast cancer.In 403 268 women 65 years and older, first-degree family history was associated with an increased risk of breast cancer among women ages 65 to 74 years (hazard ratio [HR], 1.48; 95% CI, 1.35-1.61) and 75 years and older (HR, 1.44; 95% CI, 1.28-1.62). Estimates were similar for women 65 to 74 years with first-degree relative's diagnosis age younger than 50 years (HR, 1.47; 95% CI, 1.25-1.73) vs 50 years and older (HR, 1.33; 95% CI, 1.17-1.51) and for women ages 75 years and older with the relative's diagnosis age younger than 50 years (HR, 1.31; 95% CI, 1.05-1.63) vs 50 years and older (HR, 1.55; 95% CI, 1.33-1.81). Among women ages 65 to 74 years, the risk associated with first-degree family history was highest among those with fatty breasts (HR, 1.67; 95% CI, 1.27-2.21), whereas in women 75 years and older the risk associated with family history was highest among those with dense breasts (HR, 1.55; 95% CI, 1.29-1.87).First-degree family history was associated with increased risk of invasive breast cancer in all subgroups of older women irrespective of a relative's age at diagnosis.
Combination of the vascular disrupting agent DMXAA (AS1404) with cetuximab produces synergistic antitumor activity in lung cancer xenografts
Authors: Colin Green, Kirti Shah, Grainne McGeever, Donna Dobinson, Hakim Djeha
Journal: Cancer Research (2007)

3996  The anti-EGFR monoclonal antibody cetuximab is approved for use in metastatic colorectal carcinoma, with or without irinotecan, and is being investigated in other tumor types including lung cancer. DMXAA (AS1404) is a small-molecule vascular disrupting agent (VDA) which produced a substantial survival benefit when combined with carboplatin and paclitaxel in a controlled phase II trial in non-small cell lung cancer. Preclinically, DMXAA has shown additive or supra-additive effects in combination with various anti-cancer modalities. We examined the combination of DMXAA with cetuximab.  Xenografts were established in nude, athymic mice following inoculation with the A549 lung carcinoma cell line and allowed to grow to approximately 100 mm3. Mice (10 per group) were treated with DMXAA (21 mg/kg twice weekly in weeks 1 and 4) or cetuximab (1 mg/dose twice weekly for 4 weeks) or both agents in combination (21 mg/kg and 1 mg/dose given as above). Effects on growth were measured and outcomes were classified as complete response (no tumor detected for 2 weeks); partial response (>50% reduction in volume over 2 weeks); progressive disease (>50% increase in volume) or stable disease (all others).  The combination of DMXAA plus cetuximab produced a 28-day tumor regression (median time to return to baseline volume) and a growth delay of 38 days (median time to reach 4 times starting volume) compared to unreated controls. In contrast, both DMXAA and cetuximab alone produced modest (16 and 12-day) delays in tumor growth.  In outcome terms, the DMXAA-cetuximab combination produced 4 partial responses (PRs) and 5 cases of stable disease, whereas there was 1 PR with DMXAA alone and no responses with cetuximab or in untreated controls. The combination increased time to tumor progression by 30 days vs untreated controls; corresponding values for DMXAA and cetuximab were 12 and 0 days, respectively.  In conclusion, combining the vascular disrupting agent DMXAA with the anti-EGFR antibody cetuximab produces a synergistic reduction in the growth of lung cancer xenografts. These results are comparable to those seen in lung and colorectal xenograft models treated with DMXAA plus bevacizumab, and suggest that current clinical trials examining DMXAA in combination with established chemotherapies could be extended to include combinations with therapies targeting signaling pathways.
Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression
Authors: Mi Jeong Heo, Tae Hyun Kim, Jueng Soo You, Delia Blaya, Pau Sancho-Bru, Sang Geon Kim
Journal: Gut (2018)

Objective Alcoholic liver disease (ALD) is a leading cause of death among chronic liver diseases. However, its pathogenesis has not been completely established. MicroRNAs (miRNAs) are key contributors to liver diseases progression. This study investigated hepatocyte-abundant miRNAs dysregulated by ALD, its impact on hepatocyte injury and the underlying basis. Design Alcoholic hepatitis (AH) human and animal liver samples and hepatocytes were used to assess miR-148a levels. Pre-miR-148a was delivered specifically to hepatocytes in vivo using lentivirus. Immunoblottings, luciferase reporter assays, chromatin immunoprecipitation and immunofluorescence assays were carried out in cell models. Results The miRNA profile and PCR analyses enabled us to find substantial decrease of miR-148a in the liver of patients with AH. In mice subjected to Lieber-DeCarli alcohol diet or binge alcohol drinking, miR-148a levels were also markedly reduced. In cultured hepatocytes and mouse livers, alcohol exposure inhibited forkhead box protein O1 (FoxO1) expression, which correlated with miR-148a levels and significantly decreased in human AH specimens. FoxO1 was identified as a transcription factor for MIR148A transactivation. MiR-148a directly inhibited thioredoxin-interacting protein (TXNIP) expression. Consequently, treatment of hepatocytes with ethanol resulted in TXNIP overexpression, activating NLRP3 inflammasome and caspase-1-mediated pyroptosis. These events were reversed by miR-148a mimic or TXNIP small-interfering RNA transfection. Hepatocyte-specific delivery of miR-148a to mice abrogated alcohol-induced TXNIP overexpression and inflammasome activation, attenuating liver injury. Conclusion Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD.
Epigenetics, microbiota, and intraocular inflammation: New paradigms of immune regulation in the eye
Authors: Xiaofeng Wen, Xiao Hu, Li Miao, Xiaofei Ge, Yuhua Deng, Paul W. Bible, Lai Wei
Journal: Progress in Retinal and Eye Research (2018)

Sight threatening immune responses that damage the eye characterize intraocular inflammatory diseases. These diseases including uveitis and age-related macular degeneration are worryingly common and quality of life shattering. Genetic studies in past decades significantly advanced our understanding of the etiology of these devastating diseases. Unfortunately, patient genetics alone failed to adequately explain disease origin, susceptibility, and progression. Non-genetic factors such as the epigenetic regulation of ocular diseases and the environmental factors triggering intraocular inflammation offer new insight into intraocular inflammatory disorders. Importantly, mounting evidence is signaling that dysbiosis of human microbiota leads to rapid epigenomic reprograming of host cells and results in the onset of many diseases. In this review, we discuss how epigenetic mechanisms and microbiota may cooperate to initiate and perpetuate ocular inflammation. Lastly, we propose that the discovery of intraocular microbiota presents a significant shift in thought affecting current approaches to the diagnosis, treatment, and prevention of intraocular inflammatory diseases such as uveitis and age-related macular degeneration. The geographical and genetic background difference in both disease presentation and genetic association of intraocular inflammatory diseases may be due to the variation of intraocular microbiota.
Gum chewing for bowel preparation
Authors: Shengbing Zhao, Shuling Wang, Jun Fang, Zhaoshen Li, Yu Bai
Journal: Endoscopy (2018)

See also: Do adjuvants add to the efficacy and tolerance of bowel preparations? A meta-analysis of randomized trialsEndoscopy 2018; 50(02): 159-176DOI: 10.1055/s-0043-119638
A Ser725Arg mutation in Band 3 abolishes transport function and leads to anemia and renal tubular acidosis
Authors: Elizabeth Yang, Patricia Seo-Mayer, Kimberly Lezon-Geyda, Katherine E. Badior, Jing Li, Joseph R. Casey, Reinhart A. F. Reithmeier, Patrick G. Gallagher
Journal: Blood (2018)
Endoscopic transmural hydro-dissection as a rescue therapy for rectal fibrotic adenoma
Authors: Joaquín Rodríguez Sánchez, Eva de la Santa Belda, Lucia González López, Carlos Sánchez García, Bartolomé López Viedma, José Olmedo Camacho
Journal: Endoscopy (2018)

The rectum is considered a feasible and safe area in which to perform endoscopic submucosal dissection (ESD) [1] [2]. Therefore, ESD is a suitable approach for the treatment of high risk rectal adenomas. However, scarred and fibrotic polyps have recently been described as the only preoperative predictor of failed ESD in the rectum [2] [3]. Transanal endoscopic microsurgery (TEM) has been shown to be an effective treatment for lower rectal carcinomas staged as T1 or T2 [4], owing to the depth of the resection.
The April 20 Cannabis Celebration and Fatal Traffic Crashes in the United States
Authors: John A. Staples, Donald A. Redelmeier
Journal: JAMA Internal Medicine (2018)

tively, for these exclusion-listed medications (Table 2), spending $23.9 million and $624.0 million out-of-pocket, respectively.We estimated that low-income subsidy and non-low-income subsidy beneficiaries could have potentially saved $14.8 million and $479.1 million, respectively ($10.84 and $186.72 per prescription), by substituting generic medications.Discussion | Our analysis suggests that between 2012 and 2015 CMS and Part D program beneficiaries could have realized nearly $3.4 billion in savings if the program had required generic substitution of 62 brand-name medications excluded by 2 large PBMs.Although formulary-excluded drugs represent only a small number of brand-name medications for which lower-cost generic medications might be substituted, and the potential 2015 savings represented only 1% of CMS prescription drug spending, our findings suggest clear opportunities to reduce costs using strategies already in place at large PBMs.This study was limited to brand-name medications excluded by CVS Caremark and Express Scripts; formulary exclusion lists are being increasingly adopted, leading to potentially greater savings.Furthermore, we cannot account for manufacturer rebates and discounts, which are substantial for some brand-name medications.In addition, we may have overestimated CMS spending and potential savings because we assumed complete generic and therapeutic alternative substitution.Other factors, however, including patient-specific risk-benefit considerations, may influence medication choice and not all substitutions may be clinically appropriate.
SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia
Authors: Patricia Johansson, Ludger Klein-Hitpass, Axel Choidas, Peter Habenberger, Bijan Mahboubi, Baek Kim, Anke Bergmann, René Scholtysik, Martina Brauser, Anna Lollies, Reiner Siebert, Thorsten Zenz, Ulrich Dührsen, Ralf Küppers, Jan Dürig
Journal: Blood Cancer Journal (2018)

Abstract T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients of less than two years. Besides characteristic chromosomal translocations, frequent mutations affect the ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed a targeted mutation analysis for 40 genes selected from a RNA sequencing of 10 T-PLL in a collection of 28 T-PLL, and an exome analysis of five further cases. Nonsynonymous mutations were identified in 30 of the 40 genes, 18 being recurrently mutated. We identified recurrently mutated genes previously unknown to be mutated in T-PLL, which are SAMHD1 , HERC1 , HERC2 , PRDM2 , PARP10 , PTPRC , and FOXP1 . SAMHD1 regulates cellular deoxynucleotide levels and acts as a potential tumor suppressor in other leukemias. We observed destructive mutations in 18% of cases as well as deletions in two further cases. Taken together, we identified additional genes involved in JAK/STAT signaling ( PTPRC ), epigenetic regulation ( PRDM2 ), or DNA damage repair ( SAMHD1 , PARP10, HERC1, and HERC2 ) as being recurrently mutated in T-PLL. Thus, our study considerably extends the picture of pathways involved in molecular pathogenesis of T-PLL and identifies the tumor suppressor gene SAMHD1 with ~20% of T-PLL affected by destructive lesions likely as major player in T-PLL pathogenesis.