bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad Spectrum Epidemiological Contribution of Cannabis, Tobacco and Alcohol to the Teratological Profile of Northern New South Wales: Geospatial and Causal Inference Analysis
Authors: Reece Albert Stuart , Hulse Gary Kenneth 
Published: August 2020

Abstract
Background. Whilst cannabis commercialization is occurring rapidly guided by highly individualistic public narratives, evidence that all congenital anomalies (CA) increase alongside cannabis use in Canada, a link with 21 CA’s in Hawaii, and rising CA’s in Colorado indicate that transgenerational effects can be significant and impact public health. It was therefore important to study Northern New South Wales (NNSW) where cannabis use is high.Methods. Design: Cohort. 2008–2015. Setting: NNSW and Queensland (QLD), Australia. Participants. Whole populations. Exposures. Tobacco, alcohol, cannabis. Source: National Drug Strategy Household Surveys 2010, 2013. Main Outcomes. CA Rates. NNSW-QLD comparisons. Geospatial and causal regression.Results. Cardiovascular, respiratory and gastrointestinal anomalies rose with falling tobacco and alcohol but rising cannabis use rates across Queensland. Maternal age NNSW-QLD was not different (2008–2015: 4,265/22,084 v. 96,473/490,514 > 35 years, Chi.Sq.=1.687, P = 0.194). A higher rate of NNSW cannabis-related than cannabis-unrelated defects occurred (prevalence ratio (PR) = 2.13, 95%C.I. 1.80–2.52, P = 3.24 × 10− 19). CA’s rose more potently with rising cannabis than with rising tobacco or alcohol use. Exomphalos and gastroschisis had the highest NNSW:QLD PR (6.29(2.94–13.48) and 5.85(3.54–9.67)) and attributable fraction in the exposed (84.11%(65.95–92.58%) and 82.91%(71.75–89.66%), P = 2.83 × 10− 8 and P = 5.62 × 10− 15). In multivariable geospatial models cannabis was significantly linked with cardiovascular (atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus), genetic (chromosomal defects, Downs syndrome), gastrointestinal (small intestinal atresia), body wall (gastroschisis, diaphragmatic hernia) and other (hypospadias) (AVTPCDSGDH) CA’s. In linear modelling cannabis use was significantly linked with anal stenosis, congenital hydrocephalus and Turner syndrome (ACT) and was significantly linked in borderline significant models (model P < 0.1) with microtia, microphthalmia, and transposition of the great vessels. At robust and mixed effects inverse probability weighted multivariable regression cannabis was related to 18 defects. E-Values in spatial models were generally > 1.3 ranging up to 3.8 × 1030 making uncontrolled confounding unlikely.Conclusions. These results suggest that population level CA’s react more strongly to small rises in cannabis use than tobacco or alcohol; cardiovascular, chromosomal, body wall and gastrointestinal CA’s rise significantly with small increases in cannabis use; that cannabis is a bivariate correlate of AVTPCDSGDH and ACT anomalies, is robust to adjustment for other substances; and is causal.
CircSOD2 Induced Epigenetic Alteration Drives Hepatocellular Carcinoma Progression Through Activating JAK2/STAT3 Signaling Pathway
Authors: Zhao Zhongwei , Song Jingjing , Zhang Dengke , Wu Fazong , Tu Jianfei , Xu Min , Ji Jiansong 
Published: August 2020

Abstract
Background: Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq found a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods: The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results: In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and promote its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion: The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.
CD4+ T Cell Depletion Does Not Affect the Level of Viremia in Chronically SHIVSF162P3N-Infected Chinese Cynomolgus Monkeys
Authors: Liu Hang , Liu Jin-Biao , Meng Feng-Zhen , Xu Xi-Qiu , Wang Yong , Xian Qiao-Yang , Zhou Run-Hong , Xiao Qian-Hao , Huang Zhi-Xiang , Zhou Li , Li Jie-Liang , Li Xiang-Dong , Wang Xu , Ho Wen-Zhe , Zhuang Ke 
Published: August 2020

Abstract
Background: Peripheral blood CD4+ T cell counts are a clinical marker for assessing disease progression in HIV-infected patients as well as in SIV-/SHIV–infected macaques. However, it is clinically debatable about whether this marker is a sole indicator for assessing HIV disease progression and need for ART in HIV-infected individuals. Studies with SIV-or SHIV-infected Indian rhesus macaques and sooty mangabeys have generated the conflicting data regarding the association of CD4+ T cell depletion with viral loads and disease progression. Results: In the present study, we used cynomolgus monkeys, a suitable non-human primate model for chronic HIV infection studies, to determine the effects of the antibody-mediated acute CD4+ cell depletion on viral load as well as on the immunological factors associated with disease progression. We found that as compared with the control animals, CD4+ T cell-depleted animals with chronic SHIV infection showed (i) little alteration in plasma viral load over the period of 22 weeks after the depletion; (ii) increased CD4+ T cell proliferation and turnover of macrophages at the early phase of the depletion, but subsequent decline to the basal levels; and (iii) little impact on the expression of the inflammatory cytokines and CC chemokines associated with disease progression. Conclusions: These findings indicate that the antibody-mediated acute CD4+ T cell depletion had minimal impact on plasma viral load and disease progression in chronically SHIVSF162P3N-infected cynomolgus monkeys. Future investigations are necessary to identify novel and more reliable clinical markers correlated with viremia and disease progression in HIV-infected individuals.
Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen
Authors: Giubilaro Jenna , Schuetz Doris , Namkung Yoon , Khoury Etienne , Marquez Monica , Campbell Shirley , Beautrait Alexandre , Armando Sylvain , Radresa Olivier , Duchaine Jean , Lamarche-Vane Nathalie , Claing Audrey , Bouvier Michel , Marinier Anne , Laporte Stéphane 
Published: August 2020

Abstract
Internalization and intracellular trafficking of hormone receptors, like receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), play pivotal roles in cell responsiveness homeostasis. Dysregulation in receptor trafficking can lead to aberrant signaling and cell behavior, prevalent in cancer. Here, using an endosomal BRET-based assay in a high-throughput screen with the prototypical GPCR angiotensin II type 1 receptor (AT1R), we sought to identify inhibitors of receptor trafficking from a library of ~115,000 small molecules. We identified a novel dual Ras and ARF6 inhibitor that blocks agonist-mediated internalization of AT1R and other GPCRs, which we named Rasarfin. Rasarfin also potently inhibited agonist-induced ERK1/2 signaling by GPCRs, and MAPK and Akt signaling by EGFR, as well as prevented cancer cell proliferation. In silico modeling and in vitro studies revealed a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a new class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses.
Analysis of Social Aspects Associated with Osteoarthritis in the Brazilian Population: A Cross-sectional Study Based on the National Health Survey in Brazil (PNS 2013).
Authors: Souza Clécio Gabriel , Souza Marcelo Cardoso , Silva Hugo Jario , Assis Sanderson , Dantas Diego Sousa 
Published: August 2020

Abstract
Background: Osteoarthritis (OA) is considered the third most prevalent chronic non-communicable disease in the Brazilian population, being responsible for a high rate of physical disability and reduced quality of life. Little has been discussed about the social factors associated with this health condition. This study aimed to analyze the social factors associated with OA in the Brazilian population. Methods: This is a cross-sectional study based on data from the 2013 National Health Survey in Brazil with OA as its main outcome. Gender, age, body weight, usual activities, physical activity, self-perceived health and diagnosis of depression were analyzed as independent variables. Descriptive and inferential statistics were used. Poisson multiple regression was performed, and the prevalence ratio (PR) and confidence interval (CI) of 95% were calculated using a significance level of 5% (p≤0.05). Results: A total of 60,202 individuals of both genders took part in this study and the OA prevalence was 6.4%. The individual factors associated with a higher prevalence of OA were female gender (PR = 2.09; CI = 1.95-2.25), age over 35 years (PR = 2.88; CI = 2.57-3.24) and excess body weight (PR = 1.61; CI = 1.25-2.07). The presence of OA showed an association with lower performance of usual activities (PR = 1.61; CI = 1.50-1.73) and self-perceived health as very poor (PR = 3.96; CI = 3.31-4.72). In addition, it was associated with a higher prevalence of mental illnesses such as depression (PR = 1.77; CI = 1.64-1.90). Conclusion: Social and modifiable factors which are associated with a higher prevalence of osteoarthritis can be controlled through incentive measures such as social participation and physical activity.
Associations of perceived daily walking duration with residential food outlets in small Chinese cities: a cross-sectional study
Authors: Sun Ziwen , Scott Iain , Bell Simon , Zhang Xiaomeng , Wang Lan 
Published: August 2020

Abstract
Background: The impact of food outlets (particularly those trading in fast food) on weight gain has been evidenced by numerous studies, but the potential health benefits of these amenities have received less attention. This study aims to examine the associations between residential food environments and perceived daily walking duration (DailyWalk) in small Chinese cities. Methods: The study draws upon two interviewer-administered questionnaire surveys (n=354) conducted in Yuncheng and Suihua between 2017-2018. Logistic regression models were used to examine the associations of DailyWalk (i.e. >60 minutes and ≤60 minutes per day) with seven different typologies of food outlet (i.e. market, fruit/vegetable street vending, snack/breakfast street vending, grocery store, supermarket, restaurant and café/tea house) at three levels of walking distance (i.e. 1–5 minutes, 6–10 minutes and over 10 minutes). The associations were further explored through two different age groups (i.e. 18–35 and 36–59) and by food environment diversity.Results: With the exception of café/tea house, the other six food amenities were positively associated with DailyWalk. After adjusting for socio-economic variables, the associations of grocery store and supermarket weakened. Higher levels of food environment diversity were associated with a longer DailyWalk. Among the two age groups studied, food outlets were more associated with older adults’ DailyWalk.Conclusions: Our study provides the first quantitative investigation of the walking benefits of food outlets including informal street vendors in small Chinese cities. These findings can help urban designers and policy makers to increase physical activity and create a healthy living environment.
circEPS15 Overexpression in Hepatocellular Carcinoma Modulates Tumor Invasion and Migration
Authors: Tian Maolin , Li Gang , Jiang Bin , Abuduhaibaier Sadula , Xiu Dianrong , Yuan Chunhui , Bing Yuntao 
Published: August 2020

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Recent evidence indicates that circular RNAs (circRNAs) play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs are involved in HCC progression and encode functional proteins remains largely unknown.Methods: Circular RNA microarrays were performed using three pathologically diagnosed HCC samples and their paired adjacent normal liver tissues. Cell invasion, migration, cell cycle, and apoptosis after circRNA overexpression were measured using a transwell culture system, a wound healing assay, and flow cytometry . Full-length, mutated, and truncated sequences of circEPS15 with a FLAG tag were inserted inside a circular expression vector. Western blotting was used to confirm circEPS15 expression and the requirement of internal ribosomal entry site (IRES) elements within the circRNA. The miRNA and mRNA expression profiles were obtained by analyzing data retrieved from The Cancer Genome Atlas (TCGA) database. We then constructed a ceRNA network of mRNAs, miRNAs, and circEPS15. Using tissue samples from own patients, we also verified certain analytical results with quantitative real-time PCR (qRT-PCR).Results: The expression of circEPS15 was downregulated in HCC tissues, and the survival curves showed that low circEPS15 levels were associated with poor overall survival in HCC patients. Overexpression of circEPS15 suppressed tumor invasion and migration by inhibiting the TJP1/CDH2/VIM signaling pathway and retarded cell cycle progression, but it had no effect on cell apoptosis. ceRNA analysis and qRT-PCR showed that there might be a circRNA (circEPS15)-miRNA (miR-24-3p)-mRNA (CIDEA) network in HCC. The spanning junction open reading frame in circEPS15 driven by IRES encoded a novel protein.Conclusions: Endogenous circEPS15 plays a novel role in repressing HCC through the ceRNA network and encoding a functional protein.
An Ultra-low Magnetic Field Thermal Demagnetizer for High-precision Paleomagnetism
Authors: Qin Huafeng , Zhao Xiang , Liu Shuangchi , Paterson Greig , Jiang Zhaoxia , Cai Shuhui , Li Jinhua , Liu Qingsong , Zhu Rixiang 
Published: August 2020

Abstract
Thermal demagnetization furnaces are widely used paleomagnetic facilities for progressive removal of naturally acquired magnetic remanence or the imparting of well controlled laboratory magnetization. An ideal thermal demagnetizer should maintain “zero” magnetic field in the sample chamber during thermal treatments. However, magnetic field noises, including the residual magnetic fields of the construction material and the induced fields caused by the alternating current (AC) in the heating element are always present, which often greatly contaminate the paleoamgnetic results at the elevated temperatures or for the magnetically weak samples. Here, we designed a new structure of heating wire named named straight core solenoid to develop a new demagnetization furnace with ultra-low magnetic field noise. Simulation and practical measurement show that the heating current magnetic field can be greatly reduced by using the new technology. Thermal demagnetization experiments demonstrate that the new demagnetizer can yield low noise results even for weakly magnetic samples.
To Include, or Not Include, that is the Question: An Empirical Analysis of Dealing with Patients who are Lost to Follow-up when Developing Prognostic Models Using a Cohort Design
Authors: Reps Jenna M , Rijnbeek Peter , Cuthbert Alana , Ryan Patrick B , Pratt Nicole , Schuemie Martijn J 
Published: August 2020

Abstract
Background: Researchers developing prediction models are faced with numerous design choices that may impact model performance. One of the main decisions is how to include patients who are lost to follow-up. In this paper we perform a large-scale empirical evaluation investigating the impact of this decision. In addition, we aim to provide guidelines for how to deal with loss to follow-up. Methods: We generate a synthetic dataset with complete follow-up and simulate loss to follow-up based either on random selection or on selection based on comorbidity. We investigate four simple strategies for developing models using data containing some patients with loss to follow-up. Three strategies employ a binary classifier with data that: i) include all patients (including those lost to follow-up), ii) exclude all patients lost to follow-up or iii) only exclude patients lost to follow-up who do not have the outcome before being lost to follow-up. The fourth strategy uses a survival model with data that include all patients. In addition to our synthetic data study, we empirically evaluate the discrimination and calibration performance of these strategies across 21 prediction problems using real-world data. Results: The synthetic data study results show that excluding patients lost to follow-up can introduce bias when loss to follow-up is common and does not occur at random. However, when loss to follow-up was completely at random, the choice of addressing it had negligible impact on the model performance. Our empirical results showed that the four design choices investigated to deal with loss to follow-up resulted in comparable performance when the time-at-risk was 1-year, but demonstrated differential bias when we looking into 3-year time-at-risk. Removing patients who are lost to follow-up before the outcome but keeping patients who are loss to follow-up after the outcome can bias a model and should be avoided. Conclusion: Based on this study we therefore recommend i) developing models using data that includes patients that are lost to follow-up and ii) evaluate the discrimination and calibration of models twice: on a test set including patients lost to follow-up and a test set excluding patients lost to follow-up.
Rhenium N-heterocyclic Carbene Complexes Block Growth of Aggressive Cancers by Inhibiting FGFR- and SRC-Mediated Signalling
Authors: Domenichini Alice , Casari Ilaria , Simpson Peter V , Desai Nima Maheshkumar , Chen Lingfeng , Dustin Christopher , Edmands Jeanne S , Vliet Albert van der , Mohammadi Moosa , Massi Massimiliano , Falasca Marco 
Published: August 2020

Abstract
Background: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies.Methods: Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds.Results: We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts.Conclusions: Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.
NOX1 Inhibition Attenuates the Development of a Pro-Tumorigenic Environment in Experimental Hepatocellular Carcinoma
Authors: Vandierendonck Astrid , Degroote Helena , Vanderborght Bart , Devisscher Lindsey , Vlierberghe Hans Van 
Published: August 2020

Abstract
Background The poor prognosis of advanced HCC and limited efficacy of current systemic treatments emphasize the need for new or combined targeted therapies. The development of HCC is a multistage process in which liver injury appears in a complex microenvironment associated with oxidative stress. NOX enzymes are the main source of ROS during hepatocarcinogenesis and NOX1 in particular has shown correlation with poor prognosis of HCC patients. This study evaluates the effect of pharmacological NOX1 inhibition on the development and progression of HCC and its effect on the tumor microenvironment.Methods The in vitro cytotoxic effects of the NOX1 inhibitor GKT771 (Genkyotex) on human Huh7 and Hep3B and murine Hepa1-6 HCC cell lines, and murine macrophages were evaluated via MTT, LDH activity and CaspGlo® assays. In order to induce in vivo HCC, male SV129 wild-type mice received weekly IP injections of diethylnitrosamine (DEN) (35 mg/kg) for 20-25 weeks. Mice were treated with vehicle or GKT771 (30 mg/kg) via oral gavage. Treatment duration and frequency (daily or twice daily) varied in the preventive and therapeutic studies. mRNA transcript levels in the tumor and liver tissue were determined by RT-qPCR. Fibrosis was visualized by Sirius Red staining and quantified by the Metavir​ score. Results A concentration-dependent reduction in cellular activity of the human HCC cell lines without cytotoxicity was observed. GKT771 treatment reduced LPS-induced pro-inflammatory bone-marrow derived macrophage polarization. DEN injections resulted in 100% tumor formation and the induction of HCC markers which could be reduced by twice daily dosing of GKT771 at early onset of advanced HCC. DEN-induced HCC resulted in an upregulation of pro-inflammatory, angiogenic and fibrotic markers which was less pronounced in GKT771 treated mice in all treatment regimens. In line, liver fibrosis was induced in HCC mice and this to a lesser extend upon GKT771 treatment.Conclusion NOX1 inhibition showed to be safe and well tolerated and was able to attenuate the induction of a pro-inflammatory, angiogenic and pro-fibrotic microenvironment suggesting that this might be a promising adjuvant therapeutic strategy in the treatment of advanced HCC.