bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Novel Glutamine Antagonist Prodrug JHU395 Has Antitumor Activity in Malignant Peripheral Nerve Sheath Tumor
Authors: Lemberg Kathryn M. , Zhao Liang , Wu Ying , Veeravalli Vijayabhaskar , Alt Jesse , Aguilar Joanna Marie H. , Dash Ranjeet P. , Lam Jenny , Tenora Lukáš , Rodriguez Chabely , Nedelcovych Michael T. , Brayton Cory , Majer Pavel , Blakeley Jaishri O. , Rais Rana , Slusher Barbara S. 
Published: October 2019

Abstract
The carbon and nitrogen components of glutamine are used for multiple biosynthetic processes by tumors. Glutamine metabolism and the therapeutic potential of glutamine antagonists (GA), however, are incompletely understood in malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma observed in patients with neurofibromatosis type I. We investigated glutamine dependence of MPNST using JHU395, a novel orally bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within target tissues. Human MPNST cells, compared with Schwann cells derived from healthy peripheral nerve, were selectively susceptible to both glutamine deprivation and GA dose-dependent growth inhibition. In vivo, orally administered JHU395 delivered active GA to tumors with over 2-fold higher tumor-to-plasma exposure, and significantly inhibited tumor growth in a murine flank MPNST model without observed toxicity. Global metabolomics studies and stable isotope–labeled flux analyses in tumors identified multiple glutamine-dependent metabolites affected, including prominent effects on purine synthesis. These data demonstrate that glutamine antagonism is a potential antitumor strategy for MPNST.
Functional Analysis of Aberrantly Spliced Caspase8 Variants in Adult T-Cell Leukemia Cells
Authors: Nakano Kazumi , Iwanaga Masako , Utsunomiya Atae , Uchimaru Kaoru , Watanabe Toshiki 
Published: October 2019

Abstract

The genetic and molecular alterations responsible for leukemogenesis and progression of HTLV-infected adult T-cell leukemia (ATL) have not been fully clarified. Previously, we reported that various genes are not only overexpressed but also abnormally spliced in ATL cells. Here, we identified various CASP8 transcript variants in PBMCs from a smoldering-type ATL patient, which encode aberrant truncated caspase 8 (Casp8) isoforms. Among those, we focus on the three transcript variants, CASP8L (including the first 136 bp of the intron 8 between exon 8 and exon 9), CASP8-ΔE4 (without the exon 4), and CASP8-ΔE7 (without the exon 7), because they encode isoforms, Casp8L, Casp8-ΔE4, and Casp8-ΔE7, respectively, without the C-terminal catalytic domains. In this study, we conducted in vitro characterization and functional analysis of those mutant Casp8 isoforms to clarify their changed functions compared with the wild-type (WT)-Casp8. We demonstrated that these abnormal Casp8 isoforms showed lower ability to induce apoptosis than WT-Casp8 due to their dominant-negative interactions with WT-Casp8, which impair WT-Casp8 homodimerization that is essential for induction of apoptosis. Moreover, Casp8L and Casp8-ΔE7, which have only two death-effector domains, significantly activated NFκB by forming filament-like structures, which probably function as scaffolds for the IKK complex formation. In view of increasing levels of these abnormal CASP8 transcripts in primary PBMCs from HTLV-1 carriers and patients with ATL, we propose a possibility that overexpression of those Casp8 mutants, with lower proapoptotic activities and higher NFκB-activating functions than WT-Casp8, may be one of the molecular abnormalities causing malignant transformation and growth of ATL cells.

Implications:
We describe naturally occurring CASP8 transcription variants in PBMCs from patients with ATL, which encode truncated Casp8-mutant isoforms with lower proapoptotic activities and higher NFκB-activating functions compared with WT-Casp8.
Dog Ownership and Survival
Authors: Kramer Caroline K. , Mehmood Sadia , Suen Renée S. 
Published: October 2019

Background:
Dog ownership has been associated with decreased cardiovascular risk. Recent reports have suggested an association of dog companionship with lower blood pressure levels, improved lipid profile, and diminished sympathetic responses to stress. However, it is unclear if dog ownership is associated with improved survival as previous studies have yielded inconsistent results. Thus, we performed a systematic review and meta-analysis to evaluate the association of dog ownership with all-cause mortality, with and without prior cardiovascular disease, and cardiovascular mortality.

Methods and Results:

Studies published between 1950 and May 24, 2019 were identified by searching Embase and PubMed. Observational studies that evaluated baseline dog ownership and subsequent all-cause mortality or cardiovascular mortality. Two independent reviewers extracted the data. We assessed pooled data using random-effects model. A possible limitation was that the analyses were not adjusted for confounders. Ten studies were included yielding data from 3 837 005 participants (530 515 events; mean follow-up 10.1 years). Dog ownership was associated with a 24% risk reduction for all-cause mortality as compared to nonownership (relative risk, 0.76; 95% CI, 0.67–0.86) with 6 studies demonstrating significant reduction in the risk of death. Notably, in individuals with prior coronary events, living in a home with a dog was associated with an even more pronounced risk reduction for all-cause mortality (relative risk, 0.35; 95% CI, 0.17–0.69;
I
2
, 0%). Moreover, when we restricted the analyses to studies evaluating cardiovascular mortality, dog ownership conferred a 31% risk reduction for cardiovascular death (relative risk, 0.69; 95% CI, 0.67–0.71;
I
2
, 5.1%).

Conclusions:
Dog ownership is associated with lower risk of death over the long term, which is possibly driven by a reduction in cardiovascular mortality.

Systematic Review Registration

URL:
http://www.crd.york.ac.uk/prospero/
. Unique identifier: CRD42018111048.
Tropical Cyclone as a Possible Remote Controller of Air Quality over South Korea through Poleward-Propagating Rossby Waves
Authors: Park Doo-Sun R. , Ho Chang-Hoi , Kim Dasol , Kang Nam-Young , Han Yeojin , Oh Hye-Ryun 
Published: October 2019

AbstractAir quality depends as much on large-scale tropospheric circulation as on the amount of pollutant emissions. Many studies have found a relationship between air quality and midlatitude synoptic weather systems. A stable low-level troposphere and airflow from polluted areas are conditions that favor air pollution in a region. However, few studies have focused on the possible remote effect of tropical cyclone (TC) activity in the tropics on air quality in the midlatitude East Asian countries. Here, we found that TCs in the South China Sea (SCS) can increase the concentration of particulate matter with aerodynamic diameters less than 10 μm (PM10) over South Korea through poleward-propagating Rossby waves. According to our analyses, intense divergence due to a TC causes a barotropic Rossby wave train from the SCS to the North Pacific Ocean. Anomalous highs over the Korean Peninsula (part of the Rossby wave train) result in stable air conditions and cause polluted air inflow to increase the PM10 concentration up to 65 μg m−3. Our finding suggests that TC activity in the tropics should be considered for more accurate forecasts of air quality in South Korea.
Transvaginal excision of rectal stromal tumors: case reports and a literature review
Authors: Shizhuo Wang , Liuyuan  , Sha Ni , Xueting Chen , He Wang , Nannan Luan , Xiaoxin Ma 
Published: October 2019

AbstractBackgroundGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Rectal locations are very rare, and minimally invasive surgery is a good choice for the treatment of rectal GISTs.Case presentationTwo women each had a mass located on the lower vaginal-rectal space as determined by transvaginal ultrasound (TV-US), pelvis MR imaging, and colonoscopy. The patients successfully underwent transvaginal excision. The spindle-shaped cells were found in pathological test. The immunohistochemical analysis showed that CD117 and Dog-1 were stained positively. These results confirmed the masses as GISTs. The postoperative period was uneventful without anal dysfunction. Two patients were received adjuvant treatment with imatinib after surgery.ConclusionTransvaginal excision could be a minimally invasive and safe alternative treatment in the management of rectal GISTs in lower locations.
Local excision followed by early radical surgery in rectal cancer: long-term outcome
Authors: Junginger Theodor , Goenner Ursula , Hitzler Mirjam , Trinh Tong T. , Heintz Achim , Wollschläger Daniel 
Published: October 2019

Abstract

Background
In rectal cancers, radical surgery should follow local excisions, in cases of unexpected, unfavorable tumor characteristics. The oncological results of this completion surgery are inconsistent.
This retrospective cohort study assessed the clinical and long-term oncological outcomes of patients that underwent completion surgery to clarify whether a local excision compromised the results of radical surgery.

Methods
Forty-six patients were included, and the reasons for completion surgery, intraoperative complications, residual tumors, local recurrences (LRs), distant metastases, and cancer-specific survival (CSS) were assessed. The results were compared to 583 patients that underwent primary surgery without adjuvant therapy, treated with a curative intention during the same time period.

Results
The median follow-up was 14.6 years. The reasons for undergoing completion surgery were positive resection margins (24%), high-risk cancer (30%), or both (46%). Intraoperative perforations occurred in 10/46 (22%) cases. Residual tumor in the rectal wall or lymph node involvement occurred in 12/46 (26%) cases. The risk of intraoperative perforation and residual tumor increased with the pT category. Intraoperative perforations did not increase postoperative complications, but they increased the risk of LRs in cases of intramural residual tumors (p = 0.003). LRs occurred in 2.6% of pT1/2 and 29% of pT3 tumors. Both the 5- and 10-year CSS rates were 88.8% (95% CI 80.0–98.6). Moreover, the LRs of patients with pT1/2 cancers were lower in patients with completion surgery than in patients with primary surgery.

Conclusions
Rectal wall perforations at the local excision site and residual cancer were the main risks for poor oncological outcomes associated with completion surgery. Local excisions followed by early radical surgery did not appear to compromise outcomes compared to patients with primary surgery for pT1/2 rectal cancer. Improvements in clinical staging should allow more appropriate selection of patients that are eligible for a local excision of rectal cancer.
Predictors of loss to follow-up in art experienced patients in Nigeria: a 13 year review (2004–2017)
Authors: Aliyu Ahmad , Adelekan Babatunde , Andrew Nifarta , Ekong Eunice , Dapiap Stephen , Murtala-Ibrahim Fati , Nta Iboro , Ndembi Nicaise , Mensah Charles , Dakum Patrick 
Published: October 2019

AbstractBackgroundExpanded access to antiretroviral therapy (ART) leads to improved HIV/AIDS treatment outcomes in Nigeria, however, increasing rates of loss to follow-up among those on ART is threatening optimal standard achievement. Therefore, this retrospective cross-sectional study is aimed at identifying correlates and predictors of loss to follow-up in patients commencing ART in a large HIV program in Nigeria.MethodsRecords of all patients from 432 US CDC Presidents Emergency Plan for AIDS Relief (PEPFAR) supported facilities across 10 States and FCT who started ART from 2004 to 2017 were used for this study. Bivariate and multivariate analysis of the demographic and clinical parameters of all patients was conducted using STATA version 14 to determine correlates and predictors of loss to follow-up.ResultsWithin the review period, 245,257 patients were ever enrolled on anti-retroviral therapy. 150,191 (61.2%) remained on treatment, 10,960 (4.5%) were transferred out to other facilities, 6926 (2.8%) died, 2139 (0.9%) self-terminated treatment and 75,041 (30.6%) had a loss to follow-up event captured. Males (OR: 1.16), Non-pregnant female (OR: 4.55), Patients on ≥ 3-monthly ARV refills (OR: 1.32), Patients with un-suppressed viral loads on ART (OR: 4.52), patients on adult 2nd line regimen (OR: 1.23) or pediatric on 1st line regimen (OR: 1.70) were significantly more likely to be lost to follow-up.ConclusionDespite increasing access to anti-retroviral therapy, loss to follow-up is still a challenge in the HIV program in Nigeria. Differentiated care approaches that will focus on males, non-pregnant females and paediatrics is encouraged. Reducing months of Anti-retroviral drug refill to less than 3 months is advocated for increased patient adherence.
Benchmark of computational methods for predicting microRNA-disease associations
Authors: Huang Zhou , Liu Leibo , Gao Yuanxu , Shi Jiangcheng , Cui Qinghua , Li Jianwei , Zhou Yuan 
Published: October 2019

AbstractBackgroundA series of miRNA-disease association prediction methods have been proposed to prioritize potential disease-associated miRNAs. Independent benchmarking of these methods is warranted to assess their effectiveness and robustness.ResultsBased on more than 8000 novel miRNA-disease associations from the latest HMDD v3.1 database, we perform systematic comparison among 36 readily available prediction methods. Their overall performances are evaluated with rigorous precision-recall curve analysis, where 13 methods show acceptable accuracy (AUPRC > 0.200) while the top two methods achieve a promising AUPRC over 0.300, and most of these methods are also highly ranked when considering only the causal miRNA-disease associations as the positive samples. The potential of performance improvement is demonstrated by combining different predictors or adopting a more updated miRNA similarity matrix, which would result in up to 16% and 46% of AUPRC augmentations compared to the best single predictor and the predictors using the previous similarity matrix, respectively. Our analysis suggests a common issue of the available methods, which is that the prediction results are severely biased toward well-annotated diseases with many associated miRNAs known and cannot further stratify the positive samples by discriminating the causal miRNA-disease associations from the general miRNA-disease associations.ConclusionOur benchmarking results not only provide a reference for biomedical researchers to choose appropriate miRNA-disease association predictors for their purpose, but also suggest the future directions for the development of more robust miRNA-disease association predictors.
Clinically relevant effect of rupatadine 20 mg and 10 mg in seasonal allergic rhinitis: a pooled responder analysis
Authors: Mullol Joaquim , Izquierdo Iñaki , Okubo Kimihiro , Canonica Giorgio Walter , Bousquet Jean , Valero Antonio 
Published: October 2019

Abstract

Background
Different clinical trials showed the superior efficacy of rupatadine compared to placebo at improving seasonal allergic rhinitis (SAR) symptoms, but no study has assessed if the response promoted is clinically meaningful.

Methods
This study is a pooled analysis of data of seven randomized, double-blind, placebo-controlled SAR studies comparing responder proportions upon treatment with rupatadine (10 or 20 mg) or placebo. We evaluated the following symptom scores at baseline (Visit 1) and over 14 days of treatment: Total 4 Nasal Symptom Score (T4NSS), Total 2 Ocular Symptom Score (T2OSS) and Total 6 Symptom Score (T6SS). The proportion of responders (50% and 75% response) and the time to response were compared between groups on days 7 (Visit 2) and 14 (Visit 3). Responder rates were compared between groups on days 7 and 14 for the complete/near-to-complete response for T4NSS (TN4SS score ≤ 2 and each symptom score ≤ 1) and T6SS (T6SS score ≤ 3 and each symptom score ≤ 1).

Results
Data from 1470 patients were analyzed: 332 treated with placebo, 662 with rupatadine 10 mg and 476 with rupatadine 20 mg. The reduction in T4NSS, T2OSS and T6SS over 14 days of treatment relative to baseline was statistically higher in rupatadine groups vs the placebo group, with greater improvements in the 20 mg group. A statistically higher proportion of patients reached the 50% and 75% response for T4NSS, T2OSS and T6SS in rupatadine groups compared to the placebo group across the visits. Among rupatadine-treated patients, those receiving 20 mg compared favourably for both cut-off responses. The time to achieve a proportion of responders was shorter in the rupatadine 20 mg group than in the rupatadine 10 mg and placebo groups for all the symptom scores. The number of patients who achieved a complete/near-to-complete response for both symptom scores was higher in rupatadine groups than in the placebo group, with higher proportions in the 20 mg group.

Conclusions
This responder analysis confirms the superior efficacy of rupatadine vs placebo to treat SAR. Rupatadine promoted higher proportions of responders according to stringent response criteria and in a dose-dependent manner, with faster and higher response rates in the 20 mg group.
Community perceptions of mass drug administration for soil-transmitted helminthiasis and schistosomiasis in selected schools in the Philippines
Authors: Lorenzo Pauline Joy , Manzanilla Duane Raphael , Cortel Dazzle Kane , Tangog Ekaterina 
Published: October 2019

Abstract

Background
Soil-transmitted helminthiasis (STH) and schistosomiasis are parasitic infections prevalent in tropical and subtropical countries, such as the Philippines. The prevalence of these infections remain high in certain Philippine provinces, despite established mass drug administration (MDA) programs in endemic communities. This study aimed to understand community knowledge and perceptions of these infections to determine their implications on the current control and elimination strategies, including possible barriers to MDA compliance.

Methods
The study was conducted in Northern Samar and Sorsogon, two provinces with the highest STH and schistosomiasis prevalence in the country. Focus group discussions with separate parent and children groups were utilized to gather knowledge and perceptions on STH and schistosomiasis causes, symptoms, treatment, and prevention; and on the deworming drugs and overall program implementation. Data collection in Northern Samar were done in August 2017, while the sessions in Sorsogon took place in May 2018. A cultural construction of disease framework will show how several factors affect MDA participation.

Results
Results showed that participants held mostly correct biomedical notions of the infections and expressed willingness to participate in MDA program. However, reservations remained due to a reported lack of information dissemination, lack of confidence in the drugs used, and widespread fear of adverse side effects.

Conclusion
Addressing these concerns - improving the conduct of the deworming program, incorporating suggestions from the community, and managing potential adverse events - may help raise MDA participation and encourage better personal preventive practices, reducing STH and schistosomiasis prevalence.

Trial Registration
N/A
Emerging role of a novel small non-coding regulatory RNA: tRNA-derived small RNA
Authors: Jin Fangfang , Guo Zhigang 
Published: October 2019

Abstract
The discovery of small non-coding RNAs, such as miRNA and piRNA, has dramatically changed our understanding of the role RNA plays in organisms. Recent studies show that a novel small non-coding RNA generated from cleavage of tRNA or pre-tRNA, called tRNA-derived small RNA (tsRNA), serves as a new regulator of gene expression. tsRNA has been determined participate in regulating some specific physiological and pathological processes. Although knowledge regarding the biological roles of miRNA and piRNA is expanding, whether tsRNAs play similar roles remains poorly understood. Here, we review the current knowledge regarding the mechanisms of action and biological functions of tsRNAs in intracellular, extracellular and intergenerational inheritance, and highlight the potential application of tsRNAs in human diseases, and present the current problems and future research directions.
Methylarene-Based PAH Synthesis via Domino Cyclization of 1,1-Difluoro-1-alkenes
Authors: Fuchibe Kohei , Takao Go , Takahashi Hiroki , Ijima Shiori , Ichikawa Junji 
Published: October 2019

Abstract
Polycyclic aromatic hydrocarbons (PAHs) containing 4–7 benzene rings were synthesized via a methylarene-based protocol. Trimethyl[2-(trifluoromethyl)allyl]silane was electrophilically benzylated with Ar1CH2Br (prepared from Ar1CH3) to afford 2-trifluoromethyl-1-alkenes that were in turn nucleophilically benzylated with Ar2CH2Li (prepared from Ar2CH3) through an SN2′-type reaction to produce 1,1-difluoroethylenes, which are cyclization precursors bearing two 2-arylethyl groups. Magic acid efficiently promoted the domino Friedel–Crafts-type cyclization of these precursors, followed by dehydrogenation that enabled the connection among two aryl groups (Ar1 and Ar2) by forming two benzene rings between them, facilitating the synthesis of the desired higher-order PAHs. With the proposed protocol, the combination of even a limited number of methylarenes can yield a variety of PAHs in diverse configurations.
A CRISPR/Cas9 genome editing pipeline in the EndoC-βH1 cell line to study genes implicated in beta cell function
Authors: Grotz Antje K. , Abaitua Fernando , Navarro-Guerrero Elena , Hastoy Benoit , Ebner Daniel , Gloyn Anna L. 
Published: October 2019

Type 2 diabetes (T2D) is a global pandemic with a strong genetic component, but most causal genes influencing the disease risk remain unknown. It is clear, however, that the pancreatic beta cell is central to T2D pathogenesis. In vitro gene-knockout (KO) models to study T2D risk genes have so far focused on rodent beta cells. However, there are important structural and functional differences between rodent and human beta cell lines. With that in mind, we have developed a robust pipeline to create a stable CRISPR/Cas9 KO in an authentic human beta cell line (EndoC-βH1). The KO pipeline consists of a dual lentiviral sgRNA strategy and we targeted three genes (INS, IDE, PAM) as a proof of concept. We achieved a significant reduction in mRNA levels and complete protein depletion of all target genes. Using this dual sgRNA strategy, up to 94 kb DNA were cut out of the target genes and the editing efficiency of each sgRNA exceeded >87.5%. Sequencing of off-targets showed no unspecific editing. Most importantly, the pipeline did not affect the glucose-responsive insulin secretion of the cells. Interestingly, comparison of KO cell lines for NEUROD1 and SLC30A8 with siRNA-mediated knockdown (KD) approaches demonstrate phenotypic differences. NEUROD1-KO cells were not viable and displayed elevated markers for ER stress and apoptosis. NEUROD1-KD, however, only had a modest elevation, by 34%, in the pro-apoptotic transcription factor CHOP and a gene expression profile indicative of chronic ER stress without evidence of elevated cell death. On the other hand, SLC30A8-KO cells demonstrated no reduction in KATP channel gene expression in contrast to siRNA silencing. Overall, this strategy to efficiently create stable KO in the human beta cell line EndoC-βH1 will allow for a better understanding of genes involved in beta cell dysfunction, their underlying functional mechanisms and T2D pathogenesis.