bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPM2‐mediated extracellular Ca2+ entry promotes acinar cell necrosis in biliary acute pancreatitis
Authors: Fanczal Júlia , Pallagi Petra , Görög Marietta , Diszházi Gyula , Almássy János , Madácsy Tamara , Varga Árpád , Csernay‐Biró Péter , Katona Xénia , Tóth Emese , Molnár Réka , Rakonczay Zoltán , Hegyi Péter , Maléth József 
Published: January 2020

Key points
Acute biliary pancreatitis is a significant clinical challenge as currently no specific pharmaceutical treatment exists.
Intracellular Ca2+ overload, increased reactive oxygen species (ROS) production, mitochondrial damage and intra‐acinar digestive enzyme activation caused by bile acids are hallmarks of acute biliary pancreatitis.
Transient receptor potential melastatin 2 (TRPM2) is a non‐selective cation channel that has recently emerged as an important contributor to oxidative‐stress‐induced cellular Ca2+ overload across different diseases.
We demonstrated that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2O2 treatment and contributed to bile acid‐induced extracellular Ca2+ influx in acinar cells, which promoted acinar cell necrosis in vitro and in vivo.
These results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis.
AbstractAcute biliary pancreatitis poses a significant clinical challenge as currently no specific pharmaceutical treatment exists. Disturbed intracellular Ca2+ signalling caused by bile acids is a hallmark of the disease, which induces increased reactive oxygen species (ROS) production, mitochondrial damage, intra‐acinar digestive enzyme activation and cell death. Because of this mechanism of action, prevention of toxic cellular Ca2+ overload is a promising therapeutic target. Transient receptor potential melastatin 2 (TRPM2) is a non‐selective cation channel that has recently emerged as an important contributor to oxidative‐stress‐induced cellular Ca2+ overload across different diseases. However, the expression and possible functions of TRPM2 in the exocrine pancreas remain unknown. Here we found that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2O2 treatment. TRPM2 activity was found to contribute to bile acid‐induced extracellular Ca2+ influx in acinar cells, but did not have the same effect in ductal cells. The generation of intracellular ROS in response to bile acids was remarkably higher in pancreatic acinar cells compared to isolated ducts, which can explain the difference between acinar and ductal cells. This activity promoted acinar cell necrosis in vitro independently from mitochondrial damage or mitochondrial fragmentation. In addition, bile‐acid‐induced experimental pancreatitis was less severe in TRPM2 knockout mice, whereas the lack of TRPM2 had no protective effect in cerulein‐induced acute pancreatitis. Our results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis.
Participation in Domains of Physical Activity Among Australian Youth During the Transition From Childhood to Adolescence: A Longitudinal Study
Authors: Kemp Byron J. , Parrish Anne-Maree , Batterham Marijka , Cliff Dylan P. 
Published: January 2020

Background: Information about the domains of physical activity (PA) that are most prone to decline between late childhood (11 y), early adolescence (13 y), and mid-adolescence (15 y) may support more targeted health promotion strategies. This study explored longitudinal trends in nonorganized PA, organized PA, active transport and active chores/work between childhood and adolescence, and potential sociodemographic moderators of changes. Methods: Data were sourced from the Longitudinal Study of Australian Children (n = 4108). Participation in PA domains was extracted from youth time-use diaries. Potential moderators were sex, Indigenous status, language spoken at home, socioeconomic position, and geographical remoteness. Results: A large quadratic decline in nonorganized PA (−48 min/d, P < .001) was moderated by sex (β = 5.55, P = .047) and home language (β = 8.55, P = .047), with girls (−39 min/d) and those from a non-English speaking background (−46 min/d) declining more between 11 and 13 years. Active chores/work increased between 11 and 13 years (+4 min/d, P < .001) and then stabilized. Active transport increased among boys between 11 and 13 years (+6 min/d, P < .001) and then declined between 13 and 15 years (−4 min/d, P < .001). Organized PA remained stable. Conclusions: The longitudinal decline in PA participation may be lessened by targeting nonorganized PA between childhood and adolescence. Future interventions may target girls or those from non-English speaking backgrounds during this transition.
Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: prospective cohort study
Authors: Li Yanping , Schoufour Josje , Wang Dong D , Dhana Klodian , Pan An , Liu Xiaoran , Song Mingyang , Liu Gang , Shin Hyun Joon , Sun Qi , Al-Shaar Laila , Wang Molin , Rimm Eric B , Hertzmark Ellen , Stampfer Meir J , Willett Walter C , Franco Oscar H , Hu Frank B 
Published: January 2020

Abstract

Objective
To examine how a healthy lifestyle is related to life expectancy that is free from major chronic diseases.

Design
Prospective cohort study.

Setting and participants
The Nurses’ Health Study (1980-2014; n=73 196) and the Health Professionals Follow-Up Study (1986-2014; n=38 366).

Main exposures
Five low risk lifestyle factors: never smoking, body mass index 18.5-24.9, moderate to vigorous physical activity (≥30 minutes/day), moderate alcohol intake (women: 5-15 g/day; men 5-30 g/day), and a higher diet quality score (upper 40%).

Main outcome
Life expectancy free of diabetes, cardiovascular diseases, and cancer.

Results
The life expectancy free of diabetes, cardiovascular diseases, and cancer at age 50 was 23.7 years (95% confidence interval 22.6 to 24.7) for women who adopted no low risk lifestyle factors, in contrast to 34.4 years (33.1 to 35.5) for women who adopted four or five low risk factors. At age 50, the life expectancy free of any of these chronic diseases was 23.5 (22.3 to 24.7) years among men who adopted no low risk lifestyle factors and 31.1 (29.5 to 32.5) years in men who adopted four or five low risk lifestyle factors. For current male smokers who smoked heavily (≥15 cigarettes/day) or obese men and women (body mass index ≥30), their disease-free life expectancies accounted for the lowest proportion (≤75%) of total life expectancy at age 50.

Conclusion
Adherence to a healthy lifestyle at mid-life is associated with a longer life expectancy free of major chronic diseases.
Outcomes of HIV treatment from the private sector in low-income and middle-income countries: a systematic review protocol
Authors: Mburu Gitau , Igbinedion Ewemade , Lim Sin How , Paing Aung Zayar , Yi Siyan , Elbe Stefan , Mwai Grace W 
Published: January 2020

IntroductionPrivate sector provision of HIV treatment is increasing in low-income and middle-income countries (LMIC). However, there is limited documentation of its outcomes. This protocol reports a proposed systematic review that will synthesise clinical outcomes of private sector HIV treatment in LMIC.Methods and analysisThis review will be conducted in accordance with the preferred reporting items for systematic review and meta-analyses protocols. Primary outcomes will include: (1) proportion of eligible patients initiating antiretroviral therapy (ART); (2) proportion of those on ART with <1000 copies/mL; (3) rate of all-cause mortality among ART recipients. Secondary outcomes will include: (1) proportion receivingPneumocystis jirovecipneumonia prophylaxis; (2) proportion with >90% ART adherence (based on any measure reported); (3) proportion screened for non-communicable diseases (specifically cervical cancer, diabetes, hypertension and mental ill health); (iv) proportion screened for tuberculosis. A search of five electronic bibliographical databases (Embase, Medline, PsychINFO, Web of Science and CINAHL) and reference lists of included articles will be conducted to identify relevant articles reporting HIV clinical outcomes. Searches will be limited to LMIC. No age, publication date, study-design or language limits will be applied. Authors of relevant studies will be contacted for clarification. Two reviewers will independently screen citations and abstracts, identify full text articles for inclusion, extract data and appraise the quality and bias of included studies. Outcome data will be pooled to generate aggregative proportions of primary and secondary outcomes. Descriptive statistics and a narrative synthesis will be presented. Heterogeneity and sensitivity assessments will be conducted to aid interpretation of results.Ethics and disseminationThe results of this review will be disseminated through a peer-reviewed scientific manuscript and at international scientific conferences. Results will inform quality improvement strategies, replication of identified good practices, potential policy changes, and future research.PROSPERO registration numberCRD42016040053.
Exposure to tobacco smoke and stillbirth: a national prospective cohort study in rural China
Authors: Qu Yimin , Chen Shi , Pan Hui , Zhu Huijuan , Yan Chengsheng , Zhang Shikun , Jiang Yu 
Published: January 2020

IntroductionParental exposure to tobacco smoke has been associated with an increased risk of stillbirth, while only a few studies took the overall parental tobacco exposure status into consideration. We aim to explore the relationship of parental smoking and passive smoking before and during pregnancy with stillbirth in a large Chinese rural cohort.Design248 501 couples were enrolled in a national prospective cohort study conducted in rural China. Parental exposure to tobacco smoke before and during pregnancy, along with other risk factors, was ascertained by questionnaires. Pregnancy outcomes were recorded by physicians.ResultsThe ORs (Odds Ratios) of maternal active smoking, maternal passive smoking, paternal active smoking and paternal passive smoking were 2.07 (95% CI 1.25 to 3.41), 1.22 (95% CI 1.01 to 1.47), 1.36 (95% CI 1.13 to 1.63) and 1.10 (95% CI 0.87 to 1.39), respectively. The rates of stillbirth increased from 0.31% for the maternal non-smoking group to 0.43% for the smoking cessation during pregnancy group, to 0.64% for the decreased smoking group and 1.28% for the continuing smoking group. A similar pattern was found in the change in paternal smoking status and stillbirth. Stratified by maternal passive smoking, the OR of paternal smoking was 1.35 (95% CI 1.13 to 1.61) in the maternal non-smoking group and 1.67 (95% CI 1.09 to 2.56) in the maternal passive smoking group.ConclusionsParental exposure to tobacco smoke increased the risk of stillbirth, especially for those continuing smoking during pregnancy. Paternal smoking is an independent risk factor for stillbirth despite maternal passive smoking status.
Association between serum choline and betaine concentrations and longitudinal changes of body composition in community-dwelling middle-aged and older Chinese adults
Authors: Zhong Rong-huan , Long Jing-an , Wang Fan , Chen Si , Luo Yun , Lu Xiao-ting , Yishake Dinuerguli , Chen Yu-ming , Fang Ai-ping , Zhu Hui-lian 
Published: January 2020

Previous studies suggest that betaine and choline may be beneficial for body composition. However, no longitudinal study has been conducted to illustrate if choline and betaine have long-term effects on changes in body composition. This study aimed to prospectively investigate the association between serum choline and betaine concentrations and 3-year changes in body composition in community-dwelling Chinese adults. This present analysis used data from 1384 women and 554 men aged 40–75 years. Serum concentrations of betaine and choline at baseline were assessed using high-performance liquid chromatography-tandem mass spectrometry. Body composition parameters, i.e., muscle mass (MM), fat mass (FM), and body fat percentage (FM%) were measured using dual-energy X-ray absorptiometry at the first and the second follow-ups. After adjustment for potential cofounders, higher serum choline concentrations were associated with a lower decrease in MM in men (β = 0.022, P = 0.025) and a lower increase in FM and FM% in women with baseline choline concentrations below 21.5 μmol/L (all P for nonlinearity = 0.007); higher serum betaine concentrations were associated with a lower decline in MM and a lower increase in FM and FM% among men whose betaine concentrations were lower than 55 μmol/L (all P for nonlinearity < 0.05). These findings suggest that higher concentrations of serum choline and betaine may be associated with favorable changes in body composition profiles among men and women who have relatively low concentrations, especially in men. Novelty Higher concentrations of serum choline and betaine were associated with favorable changes in body composition. Such favorable associations were more pronounced in men.
Analysis of the world record time for combined father and son marathon
Authors: Louis Julien B. , Bontemps Bastien , Lepers Romuald 
Published: January 2020

The aim of this study was to examine the physiological profiles and the pacing strategies of the father (59 yr old) and son (34 yr old) who broke the World Record time (4:59:22; father: 2:27:52, son: 2:31:30) for combined father and son marathon in 2019. Oxygen uptake (V̇o2), heart rate (HR), ventilation (V̇e), blood lactate concentration (La), and running economy (RE) were measured during treadmill-running tests. The total distance of the marathon was divided into eight sections of 5 km and one last section of 2.195 km, and the relative average running velocity on each section was calculated individually. V̇o2max, HRmax, V̇emax, and Lamax were 65.4 mL·kg−1·min−1, 165 beats/min, 115 L/min, 5.7 mmol/L for the father and 66.9 mL·kg−1·min−1, 181 beats/min, 153 L/min, 11.5 mmol/L for the son, respectively. At 17 km/h, RE was 210 mL·kg−1·km−1 for the father and 200 mL·kg−1·km−1 for the son, and % V̇o2max sustained was 90.9% for the father and 84.5% for the son, respectively. The father maintained an even running velocity during the marathon (running velocity CV <1%), while the son ran the second half-marathon 7% slower than the first one, and his running velocity markedly dropped from the 35th kilometer. Father and son who broke the World record time for combined father and son marathon had a similar level of performance, but their physiological profiles and pacing strategies during the marathon were different. A more even speed for the son could help them to improve their own record in the near future. NEW & NOTEWORTHY We provide novel data demonstrating that different physiological profiles can lead to the same level of performance in a marathon, even at different ages. The novelty of our study is that we report on the physiological characteristics, training routine, and in-race pacing strategy that allowed a father (59 yr old) and son (34 yr old) to break the World Record time for combined father and son marathon. The father also established a new World record marathon time for the age of 59.
The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome
Authors: Brieghel Christian , da Cunha-Bang Caspar , Yde Christina Westmose , Schmidt Ane Yde , Kinalis Savvas , Nadeu Ferran , Andersen Michael Asger , Jacobsen Line Offenbach , Andersen Mette Klarskov , Pedersen Lone Bredo , Delgado Julio , Baumann Tycho , Mattsson Mattias , Mansouri Larry , Rosenquist Richard , Campo Elias , Nielsen Finn Cilius , Niemann Carsten Utoft 
Published: January 2020

Abstract

Purpose:
Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear.

Experimental Design:
We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing.

Results:
Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways.

Conclusions:
We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.
A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers
Authors: Paik Paul K. , Kim Rachel K. , Ahn Linda , Plodkowski Andrew J. , Ni Ai , Donoghue Mark T.A. , Jonsson Philip , Villalona-Calero Miguel , Ng Kenneth , McFarland Daniel , Fiore John J. , Iqbal Afsheen , Eng Juliana , Kris Mark G. , Rudin Charles M. 
Published: January 2020

Abstract

Purpose:
Gemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic antitumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLC) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the antitumor activity in patients with advanced SQCLCs.

Patients and Methods:
This was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1,000 mg/m2) plus ABP (100 mg/m2) in a 3-week on, 1-week off schedule during stage I and a 2-week on, 1-week off schedule in stage II. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy.

Results:
Thirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient [ORR 59%; 95% confidence interval (CI), 42%–74%]. Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI, 6.7–10.5) months. There were no unexpected toxicities.

Conclusions:
Gemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable with carboplatin plus taxane plus pembrolizumab.
PersonalizingKRAS-Mutant Allele–Specific Therapies
Authors: Falcomatà Chiara , Schneider Günter , Saur Dieter 
Published: January 2020

AbstractSummary:KRAS G12R mutations occur almost exclusively in pancreatic ductal adenocarcinoma. The results of a study that reveals specific differences in KRAS downstream signaling and metabolic rewiring of pancreatic cancer cells harboring KRASG12R mutations promise to improve our possibilities to better stratify patients for individualized therapies.See related article by Hobbs et al., p. 104.
Three-Dimensional Imaging Provides Detailed Atherosclerotic Plaque Morphology and Reveals Angiogenesis After Carotid Artery Ligation
Authors: Becher Tobias , Riascos-Bernal Dario F. , Kramer Daniel J. , Almonte Vanessa M. , Chi Jingy , Tong Tao , Oliveira-Paula Gustavo H. , Koleilat Issam , Chen Wei , Cohen Paul , Sibinga Nicholas E.S. 
Published: January 2020

Rationale:
Remodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex processes evolves, there is a need to develop new imaging techniques to study underlying mechanisms.

Objective:
We used tissue clearing and light-sheet microscopy for 3-dimensional (3D) profiling of the vascular response to carotid artery ligation and induction of atherosclerosis in mouse models.

Methods and Results:
Adipo-Clear and immunolabeling in combination with light-sheet microscopy were applied to image carotid arteries and brachiocephalic arteries, allowing for 3D reconstruction of vessel architecture. Entire 3D neointima formations with different geometries were observed within the carotid artery and scored by volumetric analysis. Additionally, we identified a CD31-positive adventitial plexus after ligation of the carotid artery that evolved and matured over time. We also used this method to characterize plaque extent and composition in the brachiocephalic arteries of ApoE-deficient mice on high-fat diet. The plaques exhibited inter-animal differences in terms of plaque volume, geometry, and ratio of acellular core to plaque volume. A 3D reconstruction of the endothelium overlying the plaque was also generated.

Conclusions:
We present a novel approach to characterize vascular remodeling in adult mice using Adipo-Clear in combination with light-sheet microscopy. Our method reconstructs 3D neointima formation after arterial injury and allows for volumetric analysis of remodeling, in addition to revealing angiogenesis and maturation of a plexus surrounding the carotid artery. This method generates complete 3D reconstructions of atherosclerotic plaques and uncovers their volume, geometry, acellular component, surface, and spatial position within the brachiocephalic arteries. Our approach may be used in a number of mouse models of cardiovascular disease to assess vessel geometry and volume.

Visual Overview:
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