bluuebunny/crossref_metadata_2025_split huggingface dataset:
MyBackPain—evaluation of an innovative consumer-focused website for low back pain: study protocol for a randomised controlled trial
Authors: Hall Leanne M , Ferreira Manuela , Setchell Jenny , French Simon , Kasza Jessica , Bennell Kim L , Hunter David , Vicenzino Bill , Dickson Chris , Hodges Paul 
Published: May 2019

IntroductionDespite the prevalence of low back pain (LBP) worldwide, many people with the condition do not receive evidence-based care or achieve the best possible outcomes. There is a gap in the dissemination of evidence-based information across the globe. The advent of the internet has changed the way people obtain health information. As such, trustworthy, tailored and validated LBP resources may help bridge the gap. This study aims to measure the effectiveness of a new website (MyBackPain) in improving spinal health literacy, treatment preferences and clinical outcomes for people with LBP, in comparison with other online resources.Methods and analysisThis online, pragmatic, randomised controlled trial will comprise 440 people with non-specific LBP of any duration. In addition to access to publicly available online information (control group), the intervention group will be given access to the MyBackPain.org.au website. Participants and research staff, including the biostatistician, will be blinded to treatment allocation. Data will be collected at baseline, 1, 3 (primary end-point), 6 and 12 months via online surveys and questionnaires. The primary outcome is spinal health literacy. Secondary outcomes include quality of treatment preferences (stated and observed) and LBP clinical outcomes (pain, disability and quality of life). Analyses will be by intention-to-treat and include outcome data on all randomised participants. Descriptive statistics will be presented for demographic and clinical characteristics.Ethics and disseminationThis trial has been prospectively registered with the Australian New Zealand Clinical Trials Registry and has ethical approval from the University of Queensland Human Research Ethics Committee (2017000995). Trial outcomes will be shared via national and international conference presentations and peer-reviewed journal publications.Trial registration numberACTRN12617001292369; Pre-results.
Efficacy of coenzyme Q10 in patients with chronic kidney disease: protocol for a systematic review
Authors: Xu Yongxing , Liu Juan , Han Enhong , Wang Yan , Gao Jianjun 
Published: May 2019

IntroductionCoenzyme Q10 (CoQ10) is a fat-soluble vitamin-like quinone that exerts antioxidative functions and is also an important factor in mitochondrial metabolism. Plasma concentrations of CoQ10 are depressed in patients with chronic kidney disease (CKD). CoQ10 supplement can reduce adverse cardiovascular events, improve mitochondrial function and decrease oxidative stress in patients with non-dialysis CKD and dialysis CKD. We performed this study as a systematic review to comprehensively assess the effect of CoQ10 supplement on patients with CKD.Methods and analysisThe present systematic review protocol is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols guidelines. The MEDLINE, EMBASE and Cochrane library databases will be searched without language restrictions in December 2018. Two reviewers will independently screen the references in two stages: screening of the title/abstract and then of the full-text, to identify references meeting the inclusion criteria. A descriptive overview and tabular and/or graphical summaries will be generated, and directed content analysis will be carried out on the extracted data.Ethics and disseminationThis systematic review will evaluate the efficacy and safety of CoQ10 in patients with CKD. Ethical approval is not required for this study. The results of this systematic review will be presented in relevant conferences and published in a peer-review journal.PROSPERO registration numberCRD42019120201
Low systemic arterial compliance is associated with increased cardiovascular morbidity and mortality in aortic valve stenosis
Authors: Bahlmann Edda , Cramariuc Dana , Saeed Sahrai , Chambers John B , Nienaber Christoph A , Kuck Karl-Heinz , Lønnebakken Mai Tone , Gerdts Eva 
Published: May 2019

ObjectiveLower systemic arterial compliance (SAC) is associated with increased cardiovascular morbidity and mortality in hypertension, but this has not been assessed in a prospective study in aortic valve stenosis (AS).MethodsData from 1641 patients (38% women) with initially asymptomatic mild-moderate AS enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study was used. Median follow-up was 4.3 years. SAC was assessed from Doppler stroke volume index to central pulse pressure ratio and considered low if ≤0.64 mL/m², corresponding to the lower tertile in the population. The association of SAC with outcome was assessed in Cox regression analysis and reported as HR and 95% CI.ResultsLow SAC at baseline was characterised by older age, female sex, hypertension, obesity, presence of a small aortic root, lower mean aortic gradient and more severe AS by effective aortic valve area (all p<0.01). In Cox regression analysis adjusting for factors, low SAC was associated with higher HRs for cardiovascular death (HR 2.13(95% CI 1.34 to 3.40) and all-cause mortality (HR 1.71(95% CI 1.23 to 2.38)), both p=0.001). The results did not change when systolic or diastolic blood pressure, other measures of AS severity or presence of discordantly graded AS were included in subsequent models. Presence of low SAC did not improve mortality prediction in reclassification analysis.ConclusionsIn patients with AS without diabetes and known cardiovascular disease, but a high prevalence of hypertension, low SAC was associated with higher cardiovascular and all-cause mortality independent of well-known prognosticators.Trial registration numberNCT00092677; Post-results.
Waiting for a miracle or best medical practice? End-of-life medical ethical dilemmas in Bahrain
Authors: Alwadaei Sayed , Almoosawi Barrak , Humaidan Hani , Dovey Susan 
Published: May 2019

Background and objectivesIn Bahrain, maintaining life support at all costs is a cultural value considered to be embedded in the Islamic religion. We explore end-of-life decision making for brain dead patients in an Arab country where medical cultures are dominated by Western ideas and the lay culture is Eastern.MethodsIn-depth interviews were conducted from February to April 2018 with 12 Western-educated Bahraini doctors whose medical practice often included end-of-life decision making. Discussions were about who should make withdrawal of life support decisions, how decisions are made and the context for decision making. To develop results, we used the inductive method of thematic analysis.ResultsInformants considered it difficult to engage non-medical people in end-of-life decisions because of people’s reluctance to talk about death and no legal clarity about medical responsibilities. There was disagreement about doctors’ roles with some saying that end-of-life decisions were purely medical or purely religious but most maintaining that such decisions need to be collectively owned by medicine, patients, families, religious advisors and society. Informants practised in a legal vacuum that made their ethics interpretations and clinical decision making idiosyncratic regarding end-of-life care for brain dead patients. Participants referred to contrasts between their current practice and previous work in other countries, recognising the influences of religious and cultural dimensions on their practice in Bahrain.ConclusionsEnd-of-life decisions challenge Western-trained doctors in Bahrain as they grapple with aligning respect for local culture with their training in the ethical practice of Western medicine.
Drug-eluting stents in large coronary vessels improve both safety and efficacy compared with bare-metal stents in women: a pooled analysis of the BASKET-PROVE I and II trials
Authors: Bjerking Louise Hougesen , Hansen Kim Wadt , Sørensen Rikke , Prescott Eva , Biering-Sørensen Tor , Jeger Raban , Kaiser Christoph , Pfisterer Matthias , Galatius Søren 
Published: May 2019

BackgroundDrug-eluting stents (DES) have proven superior to bare-metal stents (BMS) in terms of safety and efficacy. However, inference to the female subgroup has been limited by low enrolment rates of women in clinical trials. The objective of this study was to investigate the safety and efficacy of DES versus BMS in women and men.MethodsIn a pooled analysis of two all-comers randomised trials (Basel Stent Kosten-Effektivitäts Trial–Prospective Validation Examination (BASKET-PROVE) and BASKET-PROVE II) (n=4605), we examined safety and efficacy of DES versus BMS according to sex. Patients were followed 2 years for a composite endpoint of cardiac death, non-fatal myocardial infarction (MI) and clinically driven target-vessel revascularisation not related to MI.ResultsAmong the 1076 women and 3529 men included in the analysis, 65.6% of the women and 67.2% of the men were randomised to receive DES. At baseline, men had more complex coronary artery disease than women. After 2 years, DES reduced rates of major adverse cardiac events (MACE) compared with BMS in both women (cumulative incidence, 6.1% vs 14.7%; adjusted HR 0.36 (95% CI 0.24 to 0.54)) and men (7.7 vs 12.1%, HR 0.62 (0.50 to 0.77)), although the reduction in MACE rates was more pronounced in women (adjusted p=0.02 for sex-stent interaction). Event rates were lower in DES for both safety and efficacy outcomes, with the largest effect seen for non-MI TVR, in both women (2.3 vs 9.2%, adjusted HR 0.24 (0.13 to 0.44)) and men (4.0 vs 7.8%, adjusted HR 0.48 (0.36 to 0.64)) (adjusted p=0.049 for sex-stent interaction).ConclusionsIn patients requiring stenting of large coronary arteries, DES were associated with improved safety in women and superior efficacy in both sexes as compared with BMS.
Gut and immune effects of bioactive milk factors in preterm pigs exposed to prenatal inflammation
Authors: Ren Shuqiang , Hui Yan , Goericke-Pesch Sandra , Pankratova Stanislava , Kot Witold , Pan Xiaoyu , Thymann Thomas , Sangild Per T. , Nguyen Duc Ninh 
Published: May 2019

Prenatal inflammation may predispose to preterm birth and postnatal inflammatory disorders such as necrotizing enterocolitis (NEC). Bioactive milk ingredients may help to support gut maturation in such neonates, but mother’s milk is often insufficient after preterm birth. We hypothesized that supplementation with bioactive ingredients from bovine milk [osteopontin (OPN), caseinoglycomacropeptide (CGMP), colostrum (COL)] supports gut, immunity, and NEC resistance in neonates born preterm after gram-negative infection before birth. Using preterm pigs as a model for preterm infants, fetal pigs were given intraamniotic injections of lipopolysaccharide (LPS; 1 mg/fetus) and delivered 3 days later (90% gestation). For 5 days, groups of LPS-exposed pigs were fed formula (FOR), bovine colostrum (COL), or formula enriched with OPN or CGMP. LPS induced intraamniotic inflammation and postnatal systemic inflammation but limited effects on postnatal gut parameters and NEC. Relative to FOR, COL feeding to LPS-exposed pigs showed less diarrhea, NEC severity, reduced gut IL-1β and IL-8 levels, greater gut goblet cell density and digestive enzyme activities, and blood helper T-cell fraction. CGMP improved neonatal arousal and gut lactase activities and reduced LPS-induced IL-8 secretion in intestinal epithelial cells (IECs) in vitro. Finally, OPN tended to reduce diarrhea and stimulated IEC proliferation in vitro. No effects on villus morphology, circulating cytokines, or colonic microbiota were observed among groups. In conclusion, bioactive milk ingredients exerted only modest effects on gut and systemic immune parameters in preterm pigs exposed to prenatal inflammation. Short-term, prenatal exposure to inflammation may render the gut less sensitive to immune-modulatory milk effects. NEW & NOTEWORTHY Prenatal inflammation is a risk factor for preterm birth and postnatal complications including infections. However, from clinical studies, it is difficult to separate the effects of only prenatal inflammation from preterm birth. Using cesarean-delivered preterm pigs with prenatal inflammation, we documented some beneficial gut effects of bioactive milk diets relative to formula, but prenatal inflammation appeared to decrease the sensitivity of enteral feeding. Special treatments and diets may be required for this neonatal population.
Clathrin and GRK2/3 inhibitors block δ-opioid receptor internalization in myenteric neurons and inhibit neuromuscular transmission in the mouse colon
Authors: DiCello Jesse J. , Rajasekhar Pradeep , Eriksson Emily M. , Saito Ayame , Gondin Arisbel B. , Veldhuis Nicholas A. , Canals Meritxell , Carbone Simona E. , Poole Daniel P. 
Published: May 2019

Endocytosis is a major mechanism through which cellular signaling by G protein-coupled receptors (GPCRs) is terminated. However, recent studies demonstrate that GPCRs are internalized in an active state and continue to signal from within endosomes, resulting in effects on cellular function that are distinct to those arising at the cell surface. Endocytosis inhibitors are commonly used to define the importance of GPCR internalization for physiological and pathophysiological processes. Here, we provide the first detailed examination of the effects of these inhibitors on neurogenic contractions of gastrointestinal smooth muscle, a key preliminary step to evaluate the importance of GPCR endocytosis for gut function. Inhibitors of clathrin-mediated endocytosis (Pitstop2, PS2) or G protein-coupled receptor kinase-2/3-dependent phosphorylation (Takeda compound 101, Cmpd101), significantly reduced GPCR internalization. However, they also attenuated cholinergic contractions through different mechanisms. PS2 abolished contractile responses by colonic muscle to SNC80 and morphine, which strongly and weakly internalize δ-opioid and μ-opioid receptors, respectively. PS2 did not affect the increased myogenic contractile activity following removal of an inhibitory neural influence (tetrodotoxin) but suppressed electrically evoked neurogenic contractions. Ca2+ signaling by myenteric neurons in response to exogenous ATP was unaffected by PS2, suggesting inhibitory actions on neurotransmitter release rather than neurotransmission. In contrast, Cmpd101 attenuated contractions to the cholinergic agonist carbachol, indicating direct effects on smooth muscle. We conclude that, although PS2 and Cmpd101 are effective blockers of GPCR endocytosis in enteric neurons, these inhibitors are unsuitable for the study of neurally mediated gut function due to their inhibitory effects on neuromuscular transmission and smooth muscle contractility. NEW & NOTEWORTHY Internalization of activated G protein-coupled receptors is a major determinant of the type and duration of subsequent downstream signaling events. Inhibitors of endocytosis effectively block opioid receptor internalization in enteric neurons. The clathrin-dependent endocytosis inhibitor Pitstop2 blocks effects of opioids on neurogenic contractions of the colon in an internalization-independent manner. These inhibitors also significantly impact cholinergic neuromuscular transmission. We conclude that these tools are unsuitable for examination of the contribution of neuronal G protein-coupled receptor endocytosis to gastrointestinal motility.
Cancer-Associated Fibroblasts Produce Netrin-1 to Control Cancer Cell Plasticity
Authors: Sung Pei-Ju , Rama Nicolas , Imbach Jeromine , Fiore Stephany , Ducarouge Benjamin , Neves David , Chen Huei-Wen , Bernard David , Yang Pan-Chyr , Bernet Agnès , Depil Stephane , Mehlen Patrick 
Published: May 2019

Abstract

Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature. Both colon and lung CAF secreted netrin-1 when cocultured with respective cancer cells, and netrin-1 upregulation in CAF was associated with increased cancer cell stemness. Pharmacologic inhibition of netrin-1 with a netrin-1–mAb (Net1–mAb) abrogated the CAF-mediated increase of cancer stemness both in coculture experiments and in mice. Net-1–mAb inhibited intercellular signaling between CAF and cancer cells by modulating CAF-mediated expression of cytokines such as IL6. Together these data demonstrate that netrin-1 is upregulated not only in cancer cells but also in cancer-associated stromal cells. In addition to its direct activity on cancer cells, inhibition of netrin-1 may reduce proneoplastic CAF–cancer cell cross-talk, thus inhibiting cancer plasticity.

Significance:
Netrin-1, a navigation cue during embryonic development, is upregulated in cancer-associated fibroblasts and regulates cancer cell stemness.
Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway
Authors: Xia Yingfeng , Ye Bingwei , Ding Jane , Yu Yajie , Alptekin Ahmet , Thangaraju Muthusamy , Prasad Puttur D. , Ding Zhi-Chun , Park Eun Jeong , Choi Jeong-Hyeon , Gao Bei , Fiehn Oliver , Yan Chunhong , Dong Zheng , Zha Yunhong , Ding Han-Fei 
Published: May 2019

Abstract

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy.

Significance:
This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.
See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818
DFMO and 5-Azacytidine Increase M1 Macrophages in the Tumor Microenvironment of Murine Ovarian Cancer
Authors: Travers Meghan , Brown Stephen M. , Dunworth Matthew , Holbert Cassandra E. , Wiehagen Karla R. , Bachman Kurtis E. , Foley Jackson R. , Stone Meredith L. , Baylin Stephen B. , Casero Robert A. , Zahnow Cynthia A. 
Published: May 2019

Abstract

Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumor microenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1R-blocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival.

Significance:
Combined epigenetic and polyamine-reducing therapy stimulates M1 macrophage polarization in the tumor microenvironment of an ovarian cancer mouse model, resulting in decreased tumor burden and prolonged survival.
Oncolytic Herpes Virus Armed with Vasculostatin in Combination with Bevacizumab Abrogates Glioma Invasion via the CCN1 and AKT Signaling Pathways
Authors: Tomita Yusuke , Kurozumi Kazuhiko , Yoo Ji Young , Fujii Kentaro , Ichikawa Tomotsugu , Matsumoto Yuji , Uneda Atsuhito , Hattori Yasuhiko , Shimizu Toshihiko , Otani Yoshihiro , Oka Tetsuo , Kaur Balveen , Date Isao 
Published: May 2019

Abstract
Anti-VEGF treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab has also been reported to induce invasiveness of glioma. In this study, we examined the effects of rapid antiangiogenesis mediated by oncolytic virus (RAMBO), an oncolytic herpes simplex virus-1 expressing vasculostatin, on bevacizumab-induced glioma invasion. The effect of the combination of RAMBO and bevacizumab in vitro was assessed by cytotoxicity, migration, and invasion assays. For in vivo experiments, glioma cells were stereotactically inoculated into the brain of mice. RAMBO was intratumorally injected 7 days after tumor inoculation, and bevacizumab was administered intraperitoneally twice a week. RAMBO significantly decreased both the migration and invasion of glioma cells treated with bevacizumab. In mice treated with bevacizumab and RAMBO combination, the survival time was significantly longer and the depth of tumor invasion was significantly smaller than those treated with bevacizumab monotherapy. Interestingly, RAMBO decreased the expression of cysteine-rich protein 61 and phosphorylation of AKT, which were increased by bevacizumab. These results suggest that RAMBO suppresses bevacizumab-induced glioma invasion, which could be a promising approach to glioma therapy.