bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells
Authors: Orge Iasmim Diniz , Gadd Victoria L. , Barouh Judah Leão , Rossi Erik Aranha , Carvalho Rejane Hughes , Smith Ian , Allahdadi Kyan James , Paredes Bruno Diaz , Silva Daniela Nascimento , Damasceno Patrícia Kauanna F. , Sampaio Gabriela Louise , Forbes Stuart J. , Soares Milena Botelho Pereira , Souza Bruno Solano de Freitas 
Published: April 2020

Abstract
Background
Hepatocyte-like cells (iHEPs) generated by transcription factor-mediated direct reprogramming of somatic cells have been studied as potential cell sources for the development of novel therapies targeting liver diseases. The mechanisms involved in direct reprogramming, stability after long-term in vitro expansion, and safety profile of reprogrammed cells in different experimental models, however, still require further investigation.

Methods
iHEPs were generated by forced expression of Foxa2/Hnf4a in mouse mesenchymal stromal cells and characterized their phenotype stability by in vitro and in vivo analyses.

Results
The iHEPs expressed mixed hepatocyte and liver progenitor cell markers, were highly proliferative, and presented metabolic activities in functional assays. A progressive loss of hepatic phenotype, however, was observed after several passages, leading to an increase in alpha-SMA+ fibroblast-like cells, which could be distinguished and sorted from iHEPs by differential mitochondrial content. The resulting purified iHEPs proliferated, maintained liver progenitor cell markers, and, upon stimulation with lineage maturation media, increased expression of either biliary or hepatocyte markers. In vivo functionality was assessed in independent pre-clinical mouse models. Minimal engraftment was observed following transplantation in mice with acute acetaminophen-induced liver injury. In contrast, upon transplantation in a transgenic mouse model presenting host hepatocyte senescence, widespread engraftment and uncontrolled proliferation of iHEPs was observed, forming islands of epithelial-like cells, adipocyte-like cells, or cells presenting both morphologies.

Conclusion
The results have significant implications for cell reprogramming, suggesting that iHEPs generated by Foxa2/Hnf4a expression have an unstable phenotype and depend on transgene expression for maintenance of hepatocyte-like characteristics, showing a tendency to return to the mesenchymal phenotype of origin and a compromised safety profile.
A comprehensive analysis of antigen-specific autoimmune liver disease related autoantibodies in patients with multiple sclerosis
Authors: Tsouris Zisis , Liaskos Christos , Dardiotis Efthymios , Scheper Thomas , Tsimourtou Vana , Meyer Wolfgang , Hadjigeorgiou George , Bogdanos Dimitrios P. 
Published: April 2020

Abstract
Introduction
Abnormal liver function tests are frequently seen in patients with multiple sclerosis (MS) and their origin at times is attributed to the possible co-occurrence or the de novo induction of autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but comprehensive analysis of AILD-related autoantibody has not been carried out.

Aim
To assess the presence of AILD-related autoantibodies in a well-defined cohort of MS patients, and to assess their clinical significance.

Materials and methods
133 MS (93 female) patients (102 RRMS, 27 SPMS, and 5 PPMS), mean age 42.7 ± 11.9 SD years, mean duration of disease 11.2 ± 7.2 years were studied. 150 age and sex-matched healthy individuals were tested as normal controls (NCs).Autoantibody testing was performed by indirect immunofluorescence (IF) using triple tissue and HEp-2, a multiparametric line immunoassay detecting anti-LKM1(anti-CYP2D6), anti-LC1(anti-FTCD), soluble liver antigen/liver-pancreas(anti-SLA/LP), AMA-M2, and AMA-MIT3 (BPO), PBC-specific ANA (anti-gp210, anti-sp100 and anti-PML), and ELISA for anti-F-actin SMA and anti-dsDNA antibodies.

Results
Reactivity to at least one autoantibody was more frequent in MS patients compared to NCs (30/133, 22.6% vs 12/150, 8%) NCs (p = 0.00058). SMAs by IIF were more frequent in MS patients (18/133, 13.53%) compared to NCs (6/150, 4%, p = 0.002%). The AIH-1 related anti-F-actin SMA by ELISA were present in 21 (15.8%), at relatively low titres (all but three of the SMA-VG pattern by IF); anti-dsDNA in 3 (2.3%), and anti-SLA/LP in none; AIH-2 anti-LKM1 autoantibodies in 1 (0.8%, negative by IF), and anti-LC1 in none; PBC-specific AMA-M2 in 2 (1.5%, both negative for AMA-MIT3 and AMA by IF) and PBC-specific ANA anti-PML in 6 (4.5%), anti-sp100 in 1 (0.8%) and anti-gp210 in 1 (0.8%). Amongst the 30 MS patients with at least one autoantibody positivity, only 4 (3%) had overt AILD (2 AIH-1 and 2 PBC). Autoantibody positivity did not differ between naïve MS patients and patients under treatment.

Conclusions
Despite the relatively frequent presence of liver autoantibodies, tested either by IF or molecular assays, overt AILD is rather infrequent discouraging autoantibody screening strategies of MS patients in the absence of clinical suspicion.
GEN: highly efficient SMILES explorer using autodidactic generative examination networks
Authors: van Deursen Ruud , Ertl Peter , Tetko Igor V. , Godin Guillaume 
Published: April 2020

AbstractRecurrent neural networks have been widely used to generate millions of de novo molecules in defined chemical spaces. Reported deep generative models are exclusively based on LSTM and/or GRU units and frequently trained using canonical SMILES. In this study, we introduce Generative Examination Networks (GEN) as a new approach to train deep generative networks for SMILES generation. In our GENs, we have used an architecture based on multiple concatenated bidirectional RNN units to enhance the validity of generated SMILES. GENs autonomously learn the target space in a few epochs and are stopped early using an independent online examination mechanism, measuring the quality of the generated set. Herein we have used online statistical quality control (SQC) on the percentage of valid molecular SMILES as examination measure to select the earliest available stable model weights. Very high levels of valid SMILES (95–98%) can be generated using multiple parallel encoding layers in combination with SMILES augmentation using unrestricted SMILES randomization. Our trained models combine an excellent novelty rate (85–90%) while generating SMILES with strong conservation of the property space (95–99%). In GENs, both the generative network and the examination mechanism are open to other architectures and quality criteria.
SIME: synthetic insight-based macrolide enumerator to generate the V1B library of 1 billion macrolides
Authors: Zin Phyo Phyo Kyaw , Williams Gavin , Fourches Denis 
Published: April 2020

AbstractWe report on a new cheminformatics enumeration technology—SIME, synthetic insight-based macrolide enumerator—a new and improved software technology. SIME can enumerate fully assembled macrolides with synthetic feasibility by utilizing the constitutional and structural knowledge extracted from biosynthetic aspects of macrolides. Taken into account by the software are key information such as positions in macrolide structures at which chemical components can be inserted, and the types of structural motifs and sugars of interest that can be synthesized and incorporated at those positions. Additionally, we report on the chemical distribution analysis of the newly SIME-generated V1B (virtual 1 billion) library of macrolides. Those compounds were built based on the core of the Erythromycin structure, 13 structural motifs and a library of sugars derived from eighteen bioactive macrolides. This new enumeration technology can be coupled with cheminformatics approaches such as QSAR modeling and molecular docking to aid in drug discovery for rational designing of next generation macrolide therapeutics with desirable pharmacokinetic properties.
Directed evolution of a transcription factor PbrR to improve lead selectivity and reduce zinc interference through dual selection
Authors: Jia Xiaoqiang , Ma Yubing , Bu Rongrong , Zhao Tingting , Wu Kang 
Published: April 2020

AbstractDirected evolution has been proven as a powerful tool for developing proteins and strains with novel or enhanced features. In this study, a dual selection system was designed to tune the binding specificity of a transcription factor to a particular ligand with the ampicillin resistance gene amp (ON selection) as the positive selection marker and the levansucrase gene sacB (OFF selection) as the negative selection marker. It was applied to the lead responsive transcription factor PbrR in a whole-cell lead biosensor previously constructed in our lab (Jia et al. in Fems Microbiol Lett 365:fny157, 2018). After multiple rounds of ON–OFF selection, two mutants with higher specificity for lead were selected. Structural analysis revealed that the mutation C134 located on the metal-binding loop at the C-terminal of PbrR is likely associated with the enhanced binding to both lead and cadmium. The double mutations D64A and L68S close to the metal-binding residue C79 may lead to the reduced binding specificity toward zinc ions. This dual selection system can be applied to engineer the specificity of other transcription factors and provide fine-tuned tools to synthetic biology.
Sustained effects of a multimodal campaign aiming at hand hygiene improvement on compliance and healthcare-associated infections in a large gynaecology/obstetrics tertiary-care centre in Vietnam
Authors: Phan Hang Thi , Zingg Walter , Tran Hang Thi Thuy , Dinh Anh Pham Phuong , Pittet Didier 
Published: April 2020

Abstract
Background
Hung Vuong Hospital (HVH) is a 900-bed maternity hospital in Ho-Chi-Minh-City, Vietnam. Due to low compliance, a quasi-experimental, observational study was conducted with the aim to improve hand hygiene.

Methods
A multimodal promotion strategy was established in 2010 and further developed towards ongoing, repetitive and inventive campaigns including patient participation. Hand hygiene compliance was monitored by direct observation and healthcare-associated infections (HAIs) by applying standard definitions.

Results
Between 2010 and 2018, a total of 43,711 hand hygiene opportunities were observed. Compliance improved from 21.5% (95%CI: 20.2–22.8%) in 2010 to 75.1% (73.9–76.2%) in 2018 (incidence rate ratio, IRR , 1.10; 95%CI, 1.10–1.11). This was achieved through increasing recourse to alcohol-based hand rubbing. A total of 554,720 women were admitted to HVH during the study period for 353,919 deliveries (198,679 vaginal; 155,240 by C-section) and 257,127 surgical procedures. The HAI-incidence decreased significantly from 1.10 episodes per 1000 patient-days in 2010 to 0.45 per 1000 patient-days in 2018 (IRR 0.85; 95%CI, 0.79–0.90). Significant improvement was observed also for surgical site infections after gynaecological surgery (IRR 0.95; 95%CI, 0.92–0.99) and endometritis after abortion (IRR 0.80; 95%CI, 0.68–0.93).

Conclusions
A multimodal strategy aiming at behaviour change significantly improved and sustained hand hygiene, which contributed to the reduction of healthcare-associated infections.
Determinants of credit constraints and its impact on the adoption of climate change adaptation strategies among rice farmers in South-West Nigeria
Authors: Ojo T. O. , Baiyegunhi L. J. S. 
Published: April 2020

AbstractInterventions on climate change adaptation strategies, involve capital outlays, mostly constrained in supply in developing nations. This study analysed the impact of credit constraints on climate change adaptation strategies among smallholder rice farmers in South-West Nigeria. The nexus between systems of credit constraints and choice of climate change adaptation strategies was estimated using Generalized Method of Moments with Instrumental Variable (IV-GMM) and the seemingly unrelated regression (SUR) model. A principal component analysis (PCA) was used to reduce the multidimensionality of the adaptation strategies and the loading with the highest eigenvalue was chosen and renamed as an improved technology. The results of the study show that risk credit-constrained smallholder rice farmers are less likely to adopt climate change adaptation strategies. The quantitative analysis from this study also points to the fact that age of the household, source of credit, and distance to the source of credit, interest rate, access to extension and climate information were the determinants of credit constraint amongst the smallholder rice farmers in South-West Nigeria. Considering the nexus between climatic factors and credit constraints as noted in this study, increasing awareness about how the credit market works and information on the provision of climate change can help farmers to better adapt to climate change. Therefore, it is recommended that the government frame an agriculture credit policy addressing the issues of smallholder farmers, particularly in areas that are vulnerable to climate change. The income from non-farm activities can be reinvested into farm operations to improve farmers’ adaptive capacity and subsequently increase productivity. It could also be recommended that policies enhancing and strengthening institutional support may also be valuable in augmenting the adaptation strategies of smallholder farmers. A necessary addition should be developed to the assistance already being provided under Nigeria Incentive-Based Risk Sharing System for Agricultural Lending (NIRSAL) in the form of loan guarantees and other risk-sharing incentives, such as a regulatory environment that supports the modern contractual obligations that are characteristic of well-functioning agricultural financing.
Serial change of neutrophil extracellular traps in tracheal aspirate of patients with acute respiratory distress syndrome: report of three cases
Authors: Ojima Masahiro , Yamamoto Norihisa , Hirose Tomoya , Hamaguchi Shigeto , Tasaki Osamu , Kojima Takashi , Tomono Kazunori , Ogura Hiroshi , Shimazu Takeshi 
Published: April 2020

Abstract
Background
Neutrophil extracellular traps (NETs) are fibrous structures released from activated neutrophils. NET formation has been reported to be associated with acute respiratory distress syndrome (ARDS). However, there are no reports dealing with serial changes of NET formation in tracheal aspirate of ARDS patients.

Case presentation
We report three cases of ARDS. Case 1 is a 69-year-old man with necrotizing fasciitis of the buttocks, case 2 is a 49-year-old woman with extensive burns (80% of total body surface), and case 3 is a 73-year-old woman with severe bacterial pneumonia. We found abundant expression of citrullinated histone H3 (Cit-H3) and the formation of NETs at the onset of ARDS in all cases. The amounts of Cit-H3 and NETs decreased with the amelioration of respiratory failure in cases 1 and 2. In case 2, the amounts of Cit-H3 and NETs increased with aggravation of infection and respiratory status. In case 3, the abundant expression of Cit-H3 and NETs persisted; the patient did not recover from ARDS and eventually died. Cit-H3 and NETs were found in tracheal aspirates even if the patients had no direct injury to the lung as in cases 1 and 2.

Conclusions
In these three cases, the formation of NETs was observed in tracheal aspirate of patients with ARDS by either direct or indirect insults to the lung. The amount of NET formation changed dynamically over the clinical course of each patient.
Validation of a cost-effective alternative for a radiochromatography method to be used in a developing country
Authors: Ekoume F. P. , Boersma H. H. , Dong à Zok F. , Rubow S. M. 
Published: April 2020

Abstract
Introduction
The radiochemical purity (RCP) of technetium-99m labelled radiopharmaceuticals (RP) is important to ensure optimal scintigraphic image quality. In low-income settings, it may not be possible to use compendial analytical methods or expensive equipment for radiochemical purity analysis. All radiochemical analysis methods should however be validated against compendial or otherwise proven methods. To ensure the efficacy of RP prepared at Yaoundé General Hospital (YGH) Cameroon, this study cross-validated a cost-effective routine chromatographic method using a simple survey meter technique. A GMP-compliant method used at the University Medical Center Groningen (UMCG), the Netherlands was used as the comparator.

Methods
Sestamibi, HMDP and DMSA kits currently used at YGH were reconstituted at UMCG with about 2000 MBq of freshly eluted sodium pertechnetate as described by the manufacturer, and spiked with eluate of the same generator to obtain a range of impurity concentrations. Samples of technetium-99m RP were spotted on 1 × 10 cm iTLC-SG strips and developed in appropriate mobile phases. Each strip was first scanned on the chromatogram-scanner used at the UMCG (standard method), and immediately thereafter the strip was cut in two pieces and radioactivity from each portion was counted with a small survey meter from YGH. The percentage RCP for each TLC strip was calculated using both counting methods. Internationally recommended validation parameters and acceptance criteria were used. Student’s paired t-test or ANOVA were used with ‘no significant difference’ designated at a 95% confidence-interval (P ≥ 0.05). Linearity of the survey meter was determined for Tc-99m. Readings obtained with the survey meter were also plotted against the scanner results.

Results and discussion
The proposed method proved to be accurate (CV of mean RCP < 2), precise (RSD < 2%), linear (slope close to 1, r2 ≥ 0.99) within the RCP range of approximately 80% to 100%, and robust (P > 0.05). LOD and LOQ were determined for the survey meter. Specificity depends on chemical separation. As we were validating the suitability of a method to quantify radioactivity, specificity was not included in the validation parameters.

Conclusion
The proposed method compared well with the standard method and is suitable as a reliable low cost method for limited resource settings.
Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010): An Open-Label, Randomized, Multicenter, Phase III Trial
Authors: Li Junjie , Yu Keda , Pang Da , Wang Changqin , Jiang Jun , Yang Suisheng , Liu Yunjiang , Fu Peifen , Sheng Yuan , Zhang Guojun , Cao Yali , He Qi , Cui Shude , Wang Xijing , Ren Guosheng , Li Xinzheng , Yu Shiyou , Liu Pengxi , Qu Xiang , Tang Jinhai , Wang Ouchen , Fan Zhimin , Jiang Guoqin , Zhang Jin , Wang Jiandong , Zhang Hongwei , Wang Shui , Zhang Jianguo , Jin Feng , Rao Nanyan , Ma Binlin , He Pingqing , Xu Binghe , Zhuang Zhigang , Wang Jianfeng , Sun Qiang , Guo Xiaofeng , Mo Miao , Shao Zhimin ,   on behalf of the CBCSG010 Study Group
Published: April 2020

PURPOSE Standard adjuvant chemotherapy for triple-negative breast cancer (TNBC) includes a taxane and an anthracycline. Concomitant capecitabine may be beneficial, but robust data to support this are lacking. The efficacy and safety of the addition of capecitabine into the TNBC adjuvant treatment regimen was evaluated. PATIENTS AND METHODS This randomized, open-label, phase III trial was conducted in China. Eligible female patients with early TNBC after definitive surgery were randomly assigned (1:1) to either capecitabine (3 cycles of capecitabine and docetaxel followed by 3 cycles of capecitabine, epirubicin, and cyclophosphamide) or control treatment (3 cycles of docetaxel followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide). Randomization was centralized without stratification. The primary end point was disease-free survival (DFS). RESULTS Between June 2012 and December 2013, 636 patients with TNBC were screened, and 585 were randomly assigned to treatment (control, 288; capecitabine, 297). Median follow-up was 67 months. The 5-year DFS rate was higher for capecitabine than for control treatment (86.3% v 80.4%; hazard ratio, 0.66; 95% CI, 0.44 to 0.99; P = .044). Five-year overall survival rates were numerically higher but not significantly improved (capecitabine, 93.3%; control, 90.7%). Overall, 39.1% of patients had capecitabine dose reductions, and 8.4% reported grade ≥ 3 hand-foot syndrome. The most common grade ≥ 3 hematologic toxicities were neutropenia (capecitabine, 136 [45.8%]; control, 118 [41.0%]) and febrile neutropenia (capecitabine, 50 [16.8%]; control, 46 [16.0%]). Safety data were similar to the known capecitabine safety profile and generally comparable between arms. CONCLUSION Capecitabine when added to 3 cycles of docetaxel followed by 3 cycles of a 3-drug anthracycline combination containing capecitabine instead of fluorouracil significantly improved DFS in TNBC without new safety concerns.
Ultraviolet Radiation Exposure, Risk, and Protection in Military and Outdoor Athletes
Authors: Wolf S. Tony , Kenney Lauren E. , Kenney W. Larry 
Published: April 2020

AbstractOverexposure to ultraviolet radiation (UVR) from the sun is associated with deleterious health effects including, but not limited to, increased risk of skin cancers. Military personnel and those who participate in outdoor exercise or sports represent two potential populations at elevated risk of negative health consequences of UVR exposure due to large amounts of time spent outdoors, often in harsh UVR environments. Despite exposure to high and/or frequent doses of UVR in recreational and tactical athletes, adequate sun-protection practices are often disregarded or not well understood by many within these at-risk populations, resulting in heightened risk of negative UVR effects. The focus of this review is to examine the available literature regarding UVR exposure, risk of adverse health effects of UVR exposure, and sun protection practices in outdoor exercisers, athletes, and military personnel.
Potentials of Digitalization in Sports Medicine: A Narrative Review
Authors: Rigamonti Lia , Albrecht Urs-Vito , Lutter Christoph , Tempel Mathias , Wolfarth Bernd , Back David Alexander 
Published: April 2020

Abstract
Digital transformation is becoming increasingly common in modern life and sports medicine, like many other medical disciplines, it is strongly influenced and impacted by this rapidly changing field. This review aims to give a brief overview of the potential that digital technologies can have for health care providers and patients in the clinical practice of sports medicine. We will focus on mobile applications, wearables, smart devices, intelligent machines, telemedicine, artificial intelligence, big data, system interoperability, virtual reality, augmented reality, exergaming, or social networks. While some technologies are already used in current medical practice, others still have undiscovered potential. Due to the diversity and ever changing nature of this field, we will briefly review multiple areas in an attempt to give readers some general exposure to the landscape instead of a thorough, deep review of one topic. Further research will be necessary to show how digitalization applications could best be used for patient treatments.
The Effects of Electronic Nicotine Delivery Systems on Athletes
Authors: Young Scott E. , Henderson Colin A. , Couperus Kyle S. 
Published: April 2020

AbstractThe rapid rise in popularity of Electronic Nicotine Delivery Systems (ENDS), or vaping, has not eluded the athletic population. Increasing use of youth sports participants, as well as collegiate and professionals, means sports medicine providers and coaches alike should be familiar with the effects of these devices. Current evidence demonstrates an impact on both the cardiovascular and pulmonary systems. These effects appear less significant than smoking tobacco cigarettes, but the extent and longevity of the consequences of ENDS use is unclear. Mechanisms for recovery, such as sleep and injury healing, also are affected. Lastly, the emergence of life-threatening pulmonary disease associated with ENDS use may have devastating effects on an athlete. This article will highlight the recent literature on the impact of ENDS on athletes and athletic performance, as well as the potentially life-threatening consequences of use.