bluuebunny/crossref_metadata_2025_split huggingface dataset:
TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling
Authors: Epstein Shochet Gali , Brook Elizabetha , Bardenstein-Wald Becky , Shitrit David 
Published: February 2020

Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Since the microenvironment is known to affect cell behavior, activated fibroblasts can in turn activate healthy neighboring cells. Thus, we investigated IPF paracrine signaling in human lung fibroblasts (HLFs) derived from patients with IPF.

Methods
Primary human fibroblast cultures from IPF (IPF-HLF) and control donor (N-HLF) lung tissues were established and their supernatants were collected. These supernatants were then added to N-HLFs for further culture. Protein and RNA were extracted from IPF/ N-HLFs at baseline. Interleukin-6 (IL-6) and TGF-β-related signaling factors (e.g. STAT3, Smad3) were evaluated by western blot and qPCR. IL-6 levels were measured by ELISA. IL-6 signaling was blocked by Tocilizumab (TCZ) (10 ng/ml).

Results
IPF-HLFs were found to significantly overexpress IL-6 receptor (IL-6R), suppressor of cytokine signaling 3 (SOCS3), phospho-STAT3-Y705 and phospho-Smad3 in comparison to N-HLFs (p < 0.05). In addition, they were found to proliferate faster, secrete more IL-6 and express higher levels of the soluble IL-6R. IPF-HLF increased proliferation was inhibited by TCZ. Moreover, IPF-HLF derived supernatants induced both direct and indirect STAT3 activation that resulted in Smad3 phosphorylation and elevated Gremlin levels in N-HLFs. These effects were also successfully blocked by TCZ.

Conclusions
IPF-HLF paracrine signaling leads to IL-6R overexpression, which in turn, affects N-HLF survival. The IL-6/STAT3/Smad3 axis facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by TCZ.
In vitro antibacterial activity and cytocompatibility of magnesium-incorporated poly(lactide-co-glycolic acid) scaffolds
Authors: Ma Rui , Wang Wei , Yang Pei , Wang Chunsheng , Guo Dagang , Wang Kunzheng 
Published: February 2020

Abstract
Background
Bone defects are often combined with the risk of infection in the clinic, and artificial bone substitutes are often implanted to repair the defective bone. However, the implant materials are carriers for bacterial growth, and biofilm can form on the implant surface, which is difficult to eliminate using antibiotics and the host immune system. Magnesium (Mg) was previously reported to possess antibacterial potential.

Methods
In this study, Mg was incorporated into poly(lactide-co-glycolic acid) (PLGA) to fabricate a PLGA/Mg scaffold using a low-temperature rapid-prototyping technique. All scaffolds were divided into three groups: PLGA (P), PLGA/10 wt% Mg with low Mg content (PM-L) and PLGA/20 wt% Mg with high Mg content (PM-H). The degradation test of the scaffolds was conducted by immersing them into the trihydroxymethyl aminomethane–hydrochloric acid (Tris–HCl) buffer solution and measuring the change of pH values and concentrations of Mg ions. The antibacterial activity of the scaffolds was investigated by the spread plate method, tissue culture plate method, scanning electron microscopy and confocal laser scanning microscopy. Additionally, the cell attachment and proliferation of the scaffolds were evaluated by the cell counting kit-8 (CCK-8) assay using MC3T3-E1 cells.

Results
The Mg-incorporated scaffolds degraded and released Mg ions and caused an increase in the pH value. Both PM-L and PM-H inhibited bacterial growth and biofilm formation, and PM-H exhibited higher antibacterial activity than PM-L after incubation for 24 and 48 h. Cell tests revealed that PM-H exerted a suppressive effect on cell attachment and proliferation.

Conclusions
These findings demonstrated that the PLGA/Mg scaffolds possessed favorable antibacterial activity, and a higher content of Mg (20%) exhibited higher antibacterial activity and inhibitory effects on cell attachment and proliferation than low Mg content (10%).
Addressing noncommunicable diseases among urban refugees in the Middle East and North Africa - a scoping review
Authors: McNatt Zahirah Z. 
Published: February 2020

Abstract
Background
More than 5.5 million Syrian refugees have fled violence and settled in mostly urban environments in neighboring countries. The Middle East and North Africa (MENA) region accounts for 6% of the global population but 25% of the population are ‘of concern’ to the UN Refugee Agency. In addition to large amounts of forced migration, the region is also undergoing an epidemiologic transition towards a heavier burden of noncommunicable diseases (NCDs), which in 2018 accounted for 74% of all deaths in the region. To address NCD needs globally, a myriad of policies and interventions have been implemented in low-income stable country settings. However, little is known about which policies and interventions are currently being implemented or are best suited for refugee hosting countries across the Middle East and North Africa.

Methods
A scoping review of peer-reviewed literature was conducted to identify policies and interventions implemented in the Middle East and North Africa to address the needs of urban refugees with noncommunicable diseases.

Results
This scoping review identified 11 studies from Jordan, Lebanon, Iran, West Bank, Gaza and Syria. These studies addressed three foci of extant work, (1) innovative financing for expensive treatments, (2) improvements to access and quality of treatment and, (3) efforts to prevent new diagnoses and secondary complications. All interventions targeted refugee populations including Palestinians, Sudanese, Syrians, Afghans and Iraqis.

Discussion
The scoping review highlighted five key findings. First, very few studies focused on the prevention of noncommunicable diseases among displaced populations. Second, several interventions made use of health information technologies, including electronic medical records and mHealth applications for patients. Third, the vast majority of publications were solely focused on tackling NCDs through primary care efforts. Fourth, the literature was very sparse in regard to national policy development, and instead favored interventions by NGOs and UN agencies. Last, the perspectives of refugees were notably absent.

Conclusion
Opportunities exist to prioritize prevention efforts, scale up eHealth interventions, expand access to secondary and tertiary services, address the scarcity of research on national policy, and incorporate the perspectives of affected persons in the broader discourse.
Adapting a family intervention to reduce risk factors for sexual exploitation
Authors: Bounds Dawn T. , Otwell Caitlin H. , Melendez Adrian , Karnik Niranjan S. , Julion Wrenetha A. 
Published: February 2020

Abstract
Background
Sexually exploited youth are disconnected from societal tethers and need support systems, which makes them some of the most vulnerable of youth. This heightened level of vulnerability increases their risk for violence, abuse, ongoing sexual exploitation and all its sequelae. The purpose of this study was to examine an evidence-based intervention called STRIVE (support to reunite, involve and value each other) that has been a successful family re-engagement strategy with newly homeless youth. We sought to explore its contextual relevance for youth with risk factors for sexual exploitation and identify necessary adaptations to reduce risk factors for sexual exploitation. We deliberately took an intersectional approach in conducting this study.

Methods
Six community-based focus groups were conducted with youth at risk for sexual exploitation and their service providers. Each group was recorded, transcribed, coded, and thematically analyzed.

Results
Results from 29 youth and 11 providers indicate that there are unique considerations that must be taken into account while working with youth at risk for sexual exploitation to ensure effective service delivery and/or ethical research. Emergent themes included: setting the stage by building rapport and acknowledging experiences of structural violence, protect and hold which balances youth’s need for advocacy/support with their caregivers’ need for validation/understanding, and walking the safety tightrope by assessing risks and safety planning.

Discussion
Focus groups are an effective methodology when working with traditionally disempowered populations particularly in gaining a range of perspectives to meet unique needs/preferences. Youth at risk for commercial sexual exploitation needs require strengths-based, individualized, multi-systemic approaches.
TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer
Authors:   on behalf of the Translational Breast Cancer Research Consortium (TBCRC), Vaklavas Christos , Roberts Brian S. , Varley Katherine E. , Lin Nancy U. , Liu Minetta C. , Rugo Hope S. , Puhalla Shannon , Nanda Rita , Storniolo Anna Maria , Carey Lisa A. , Saleh Mansoor N. , Li Yufeng , Delossantos Jennifer F. , Grizzle William E. , LoBuglio Albert F. , Myers Richard M. , Forero-Torres Andres 
Published: February 2020

Abstract
Background
In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting.

Methods
Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate.

Results
Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7–24.1%) achieved pCR and 4 (9%; 95% CI, 2.5–21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0–14.2%). The rates of downstaging were 44.4% (95% CI, 29.6–60.0%) and 37.5% (95% CI, 18.8–59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort.

Conclusion
In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy.

Trial registration
This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.
A framework for transcriptome-wide association studies in breast cancer in diverse study populations
Authors: Bhattacharya Arjun , García-Closas Montserrat , Olshan Andrew F. , Perou Charles M. , Troester Melissa A. , Love Michael I. 
Published: February 2020

AbstractBackgroundThe relationship between germline genetic variation and breast cancer survival is largely unknown, especially in understudied minority populations who often have poorer survival. Genome-wide association studies (GWAS) have interrogated breast cancer survival but often are underpowered due to subtype heterogeneity and clinical covariates and detect loci in non-coding regions that are difficult to interpret. Transcriptome-wide association studies (TWAS) show increased power in detecting functionally relevant loci by leveraging expression quantitative trait loci (eQTLs) from external reference panels in relevant tissues. However, ancestry- or race-specific reference panels may be needed to draw correct inference in ancestrally diverse cohorts. Such panels for breast cancer are lacking.ResultsWe provide a framework for TWAS for breast cancer in diverse populations, using data from the Carolina Breast Cancer Study (CBCS), a population-based cohort that oversampled black women. We perform eQTL analysis for 406 breast cancer-related genes to train race-stratified predictive models of tumor expression from germline genotypes. Using these models, we impute expression in independent data from CBCS and TCGA, accounting for sampling variability in assessing performance. These models are not applicable across race, and their predictive performance varies across tumor subtype. Within CBCS (N = 3,828), at a false discovery-adjusted significance of 0.10 and stratifying for race, we identify associations in black women nearAURKA,CAPN13,PIK3CA, andSERPINB5via TWAS that are underpowered in GWAS.ConclusionsWe show that carefully implemented and thoroughly validated TWAS is an efficient approach for understanding the genetics underpinning breast cancer outcomes in diverse populations.
Temperature is a common climatic descriptor of lachryphagous activity period in Phortica variegata (Diptera: Drosophilidae) from multiple geographical locations
Authors: Pombi Marco , Marino Valentina , Jaenike John , Graham-Brown John , Bernardini Ilaria , Lia Riccardo P. , Beugnet Fred , Miro Guadalupe , Otranto Domenico 
Published: February 2020

AbstractBackgroundThe drosophilidPhortica variegatais known as vector ofThelazia callipaeda, the oriental eyeworm native to Asia that has become an emergent zoonotic agent in several European regions. Unlike almost all other arthropod vectors of pathogens, onlyP. variegatamales feed of lachrymal secretions of animals, ingesting first-stage larvae (L1) of the worm living in the orbital cavities of the host, and allowing with the same behaviour the introduction of infective L3. Despite the increased detection ofT. callipaedain many European countries, information about the length of the lachryphagous activity period ofP. variegataand a deep knowledge of the environmental and climatic variables involved are still limited.MethodsWe herein present the results of a multicentre study involving five sites from four different countries (Italy, Spain, UK and USA) where canine thelaziosis is endemic and/or where it has already been ascertained the presence ofP. variegata. Field data have been obtained on a fortnightly basis from mid-April to the end of November 2018 from a contemporary standardized sampling (same sampling effort and time of collection in all sites) of lachryphagous flies collected around the eyes of a human bait using an entomological net. These data have been associated to data collection of local climatic variables (day length, temperature, wind speed, barometric pressure and relative humidity).ResultsOverall, a total of 4862P. variegataflies (4637 males and 224 females) were collected, with high differences in densities among the different sampling sites. Significant positive correlations were found betweenP. variegatamale density and temperature and wind speed, while negative correlations were observed for barometric pressure and relative humidity. However, the above significant differences are confirmed in each sampling site separately only for the temperature.ConclusionsThis multicentre study highlights that temperature is the major common environmental driver in describing the lachryphagous activity ofP. variegatain Europe and USA and, therefore, the transmission risk of thelaziosis.
First report on aberrant Ascaris suum infection in a dog, China
Authors: Xie Yue , Liu Yunjian , Gu Xiaobin , Zhou Xuan , Peng Xuerong , He Ran , Guo Hongrui , Zuo Zhicai , Yang Guangyou 
Published: February 2020

AbstractAn aberrantAscaris suuminfection in a domestic dog in China in 2019 is described for the first time. This pathogen is a common roundworm of pigs with few reported cases in domestic animals. Our findings suggest a wider infection range with a possible transmission ofA. suumto domestic animals that interact with humans.
Plasma concentrations of vitamin A and E and risk of dysglycemia in first-trimester pregnant Saudi women
Authors: Kutbi Hebah Alawi , Hammouda Sahar Ali 
Published: February 2020

AbstractBackgroundExisting evidence suggest that low concentrations of vitamin A and E may have a contribution to the development of diabetes complications; however, data regarding the status of vitamin A and E among individuals with prediabetes are lacking. This study aimed to examine the association of plasma concentrations of vitamin A and E with the glycemic control status among first trimester pregnant Saudi women.MethodsIn this cross-sectional study, 1102 first trimester pregnant Saudi women were recruited from antenatal clinics. Sociodemographic and anthropometric information were collected, and laboratory analyses of blood glycated hemoglobin (A1C) and plasma vitamins A and E were performed. Subjects were classified as normoglycemic, prediabetic, or undiagnosed diabetic. Multinomial regression models adjusted for age estimated the adjusted odds ratios (aORs) and [95% confidence intervals (CIs)].ResultsAmong the sample, 78.8% (n = 868) had normal glycemic control, while 19.1% (n = 211) had prediabetes and 2.1% (n = 23) had undiagnosed diabetes. Plasma concentrations of vitamin A and E of prediabetic participants were at a level midway between that of normoglycemic and diabetic participants (p < 0.01). Compared to subjects with normoglycemic status, those with higher concentrations of vitamin A and E had lower odds of being prediabetic (aOR = 0.27 [0.21–0.35] and aOR = 0.95 [0.94–0.96], respectively) or diabetic (aOR = 0.18 [0.13–0.24] and aOR = 0.93 [0.92–0.94], respectively).ConclusionsOur findings indicate a possible contribution of vitamins A and E to the progression of prediabetes to diabetes. Future longitudinal studies are needed to elucidate the association between the antioxidant status and dysglycemia. Clinicians should monitor the glycemic and the antioxidant status closely and provide dietary guidance where needed.
Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease—a meta-analysis
Authors: Morata-Tarifa Cynthia , Macías-Sánchez María del Mar , Gutiérrez-Pizarraya Antonio , Sanchez-Pernaute Rosario 
Published: February 2020

Abstract
Background
Graft-versus-host disease (GvHD) is the main life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty to 80% of GvHD patients do not respond to first-line treatment and a second-line treatment is not universally established. Based on their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed for the prevention and the treatment of GvHD in patients undergoing HSCT. Unfortunately, previous studies reported conflicting results regarding the prophylactic and therapeutic effects of MSC for GvHD. Consequently, we carried out a meta-analysis to clarify whether MSC administration can improve the dismal outcome of these patients.

Methods
We carried out a systematic review and selected studies (2004–2019) reporting data about the administration of allogeneic MSC for the prevention (n = 654 patients) or treatment of acute (n = 943 patients) or chronic (n = 76 patients) GvHD after HSCT. Our primary outcome was overall survival at the last follow-up. The secondary outcomes were the response and development of GvHD. Subgroup analyses included age, MSC dose, first infusion day after HSCT, number of organs and organ-specific involvement, acute GvHD grade (I–IV), and chronic GvHD grade (limited or extensive).

Results
Patients infused with MSC for GvHD prophylaxis showed a 17% increased overall survival (95% CI, 1.02–1.33) and a reduced incidence of acute GvHD grade IV (RR = 0.22; 95% CI, 0.06–0.81) and chronic GvHD (RR = 0.64; 95% CI, 0.47–0.88) compared with controls. Overall survival of acute GvHD patients (0.50; 95% CI, 0.41–0.59) was positively correlated with MSC dose (P = 0.0214). The overall response was achieved in 67% (95% CI, 0.61–0.74) and was complete in 39% (95% CI, 0.31–0.48) of acute patients. Organ-specific response was higher for the skin. Twenty-two percent (95% CI, 0.16–0.29) of acute patients infused with MSC developed chronic GvHD. Sixty-four percent (95% CI, 0.47–0.80) of chronic patients infused with MSC survived; the overall response was 66% (95% CI, 0.55–0.76) and was complete in 23% (95% CI 0.12–0.34) of patients.

Conclusions
Our meta-analysis indicates that allogeneic MSC could be instrumental for the prophylaxis and treatment of GvHD. Future trials should investigate the effect of the administration of MSC as an adjuvant therapy for the treatment of patients with GvHD from the onset of the disease.
Multiobjective de novo drug design with recurrent neural networks and nondominated sorting
Authors: Yasonik Jacob 
Published: February 2020

AbstractResearch productivity in the pharmaceutical industry has declined significantly in recent decades, with higher costs, longer timelines, and lower success rates of drug candidates in clinical trials. This has prioritized the scalability and multiobjectivity of drug discovery and design. De novo drug design has emerged as a promising approach; molecules are generated from scratch, thus reducing the reliance on trial and error and premade molecular repositories. However, optimizing for molecular traits remains challenging, impeding the implementation of de novo methods. In this work, we propose a de novo approach capable of optimizing multiple traits collectively. A recurrent neural network was used to generate molecules which were then ranked based on multiple properties by a nondominated sorting algorithm. The best of the molecules generated were selected and used to fine-tune the recurrent neural network through transfer learning, creating a cycle that mimics the traditional design–synthesis–test cycle. We demonstrate the efficacy of this approach through a proof of concept, optimizing for constraints on molecular weight, octanol-water partition coefficient, the number of rotatable bonds, hydrogen bond donors, and hydrogen bond acceptors simultaneously. Analysis of the molecules generated after five iterations of the cycle revealed a 14-fold improvement in the quality of generated molecules, along with improvements to the accuracy of the recurrent neural network and the structural diversity of the molecules generated. This cycle notably does not require large amounts of training data nor any handwritten scoring functions. Altogether, this approach uniquely combines scalable generation with multiobjective optimization of molecules.