bluuebunny/crossref_metadata_2025_split huggingface dataset:
Compressive mechanical stress enhances susceptibility to interleukin-1 by increasing interleukin-1 receptor expression in 3D-cultured ATDC5 cells
Authors: Takeda Yuki , Niki Yasuo , Fukuhara Yusuke , Fukuda Yoshitsugu , Udagawa Kazuhiko , Shimoda Masayuki , Kikuchi Toshiyuki , Kobayashi Shu , Harato Kengo , Miyamoto Takeshi , Matsumoto Morio , Nakamura Masaya 
Published: March 2021

Abstract
Background
Mechanical overload applied on the articular cartilage may play an important role in the pathogenesis of osteoarthritis. However, the mechanism of chondrocyte mechanotransduction is not fully understood. The purpose of this study was to assess the effects of compressive mechanical stress on interleukin-1 receptor (IL-1R) and matrix-degrading enzyme expression by three-dimensional (3D) cultured ATDC5 cells. In addition, the implications of transient receptor potential vanilloid 4 (TRPV4) channel regulation in promoting effects of compressive mechanical loading were elucidated.

Methods
ATDC5 cells were cultured in alginate beads with the growth medium containing insulin-transferrin-selenium and BMP-2 for 6 days. The cultured cell pellet was seeded in collagen scaffolds to produce 3D-cultured constructs. Cyclic compressive loading was applied on the 3D-cultured constructs at 0.5 Hz for 3 h. The mRNA expressions of a disintegrin and metalloproteinases with thrombospondin motifs 4 (ADAMTS4) and IL-1R were determined with or without compressive loading, and effects of TRPV4 agonist/antagonist on mRNA expressions were examined. Immunoreactivities of reactive oxygen species (ROS), TRPV4 and IL-1R were assessed in 3D-cultured ATDC5 cells.

Results
In 3D-cultured ATDC5 cells, ROS was induced by cyclic compressive loading stress. The mRNA expression levels of ADAMTS4 and IL-1R were increased by cyclic compressive loading, which was mostly prevented by pyrollidine dithiocarbamate. Small amounts of IL-1β upregulated ADAMTS4 and IL-1R mRNA expressions only when combined with compressive loading. TRPV4 agonist suppressed ADAMTS4 and IL-1R mRNA levels induced by the compressive loading, whereas TRPV4 antagonist enhanced these levels. Immunoreactivities to TRPV4 and IL-1R significantly increased in constructs with cyclic compressive loading.

Conclusion
Cyclic compressive loading induced mRNA expressions of ADAMTS4 and IL-1R through reactive oxygen species. TRPV4 regulated these mRNA expressions, but excessive compressive loading may impair TRPV4 regulation. These findings suggested that TRPV4 regulates the expression level of IL-1R and subsequent IL-1 signaling induced by cyclic compressive loading and participates in cartilage homeostasis.
Validation of self-administered tests for screening for chronic pregnancy-related pelvic girdle pain
Authors: Fagevik Olsén Monika , Körnung Paulina , Kallin Sophie , Elden Helen , Kjellby Wendt Gunilla , Gutke Annelie 
Published: March 2021

Abstract
Background
Many women develop pelvic girdle pain (PGP) during pregnancy and about 10% have chronic pain several years after delivery. Self-administered pain provocation tests are one way to diagnose and evaluate this pain. Their validity in post-partum women is not yet studied.
The purpose of this study was to evaluate the validity of self-administered test for assessment of chronic pregnancy-related PGP several years after delivery.

Methods
Women who previously have had PGP during pregnancy and who participated in one of three RCT studies were invited to a postal follow up of symptoms including performance of self-administered tests after two, 6 or 11 years later, respectively. In total, 289 women returned the questionnaire and the test-results. Of these, a sub-group of 44 women with current PGP underwent an in-person clinical examination. Comparisons were made between test results in women with versus without PGP but also, in the sub-group, between the self-administered tests and those performed during the clinical examination.

Results
Fifty-one women reported PGP affecting daily life during the last 4 weeks, and 181 reported pain when performing at least one of the tests at home. Those with chronic PGP reported more positive tests (p < 0.001). There was no significant difference between diagnosis from the self-administered tests compared to tests performed during the in-person clinical examination (p = 0.305), either for anterior or posterior PGP. There were no significant differences of the results between the tests performed self-administered vs. during the clinical examination.

Conclusion
A battery of self-administered tests combined with for example additional specific questions or a pain-drawing can be used as a screening tool to diagnose chronic PGP years after delivery. However, the modified SLR test has limitations which makes its use questionable.
Open-label phase 3 study of diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate: ONO-5704/SI-613) for treatment of osteoarthritis: 1-year follow-up
Authors: Nishida Yoshihiro , Kano Kazuyuki , Osato Taiki , Seo Takayuki 
Published: March 2021

Abstract
Background
We evaluated the 1-year safety and efficacy of diclofenac etalhyaluronate (DF-HA), a diclofenac-conjugated hyaluronate, in patients with osteoarthritis (OA).

Methods
In this multi-centre, open-label, noncomparative phase 3 study in Japan, patients with a diagnosis of knee, shoulder, elbow, hip, or ankle OA received an intra-articular (IA) injection of DF-HA 30 mg every 4 weeks for 1 year (13 times in total). The safety outcomes included treatment-emergent adverse events (TEAEs) and target joint structural changes by X-ray imaging tests. Efficacy outcomes included joint pain scores on an 11-point numerical rating scale. Concomitant use of analgesics was not restricted.

Results
Overall, 166 eligible patients were enrolled, comprising knee OA (n = 126) and other OA (n = 40). All TEAEs were experienced by 126/166 patients (75.9%). The incidence of treatment-related TEAEs was not associated with the treatment period. No significant worsening of joint status was observed in X-ray imaging tests at week 52 or at last assessment. The mean joint pain scores (± standard deviation) were 5.9 ± 1.2, 4.9 ± 1.9, and 3.1 ± 2.3 at baseline, and weeks 2 and 52, respectively. Improvement of pain score was observed after the first injection and was maintained until week 52 regardless of knee OA or other joint OA.

Conclusions
Repeated IA injections of DF-HA every 4 weeks for 1 year were well tolerated with no clinically significant adverse events indicating they might lead to the long-term improvement of OA symptoms. DF-HA might be a useful treatment for patients with OA.

Trial registration number
JapicCTI-183855 (First registered date: 6th February 2018).
Preoperatively elevated RDW-SD and RDW-CV predict favorable survival in intrahepatic cholangiocarcinoma patients after curative resection
Authors: Li Xingchen , Chen Qichen , Bi Xinyu , Zhao Jianjun , Li Zhiyu , Zhou Jianguo , Huang Zhen , Zhang Yefan , Mao Rui , Zhao Hong , Cai Jianqiang 
Published: March 2021

Abstract
Background
Recent studies suggest red blood cell distribution width (RDW) was a prognostic factor in various types of cancer patients, although the results are controversial. The objective of this study was to investigate the significance of RDW in patients with intrahepatic cholangiocarcinoma (ICC) after radical resection.

Method
The relationship between the preoperative serum RDW value and clinic pathological characteristics was analyzed in 157 ICC patients between January 2012 and June 2018 who underwent curative resection. X-tile software was used to determine 40.2 fl, 12.6% as the optimal cut-off value for RDW-SD and RDW-CV respectively. 153 patients were classified into the low RDW-SD (≤ 40.2, n = 53) group and the high RDW-SD (> 40.2, n = 104) group, low RDW-CV (≤ 12.6, n = 94) group and the high RDW-CV (> 12.6, n = 63). Based on the RDW-SD combined with RDW-CV (SCC), classified into SCC = 0, 1 and 2 group. Kaplan–Meier survival analysis and Cox proportional hazard models were used to examine the effect of RDW on survival.

Results
Kaplan–Meier curve analysis showed that Patients with RDW-SD > 40.2 were significantly associated with better OS (P = 0.004, median OS: 68.0 months versus 17.0 months). Patients with RDW-CV > 12.6 were significantly associated with better OS (p = 0.030, median OS: not reach versus 22.0 months). Compared with a SCC = 0 or SCC = 1, SCC = 2 was significantly associated with better OS (p < 0.001, median OS: not reach versus 33.0 months versus 16, respectively). In the multivariate analysis, RDW-SD > 40.2 fl (HR = 0.446, 95% CI: 0.262–0.760, p = 0.003), RDW-CV > 12.6% (HR = 0.425, 95%CI: 0.230–0.783, p = 0.006), SCC = 2 (HR = 0.270, 95%CI: 0.133–0.549, p < 0.001) were associated with favorable OS. The multivariate analysis showed RDW-SD, RDW-CV and SCC level were not independent prognostic factors for DFS.

Conclusions
Preoperative low levels of RDW are associated with poor survival in ICC after curative resection. This provides a new way for predicting the prognosis of ICC patients and more targeted intervention measures.
The impact of a training programme incorporating the conceptual framework of the International Classification of Functioning (ICF) on knowledge and attitudes regarding interprofessional practice in Rwandan health professionals: a cluster randomized control trial
Authors: Sagahutu Jean Baptiste , Kagwiza Jeanne , Cilliers Francois , Jelsma Jennifer 
Published: March 2021

Abstract
Background
The first step in improving interprofessional teamwork entails training health professionals (HP) to acknowledge the role and value the contribution of each member of the team. The International Classification of Functioning, Disability and Health (ICF) has been developed by WHO to provide a common language to facilitate communication between HPs.

Objective
To determine whether ICF training programme would result in improved knowledge and attitudes regarding interprofessional practice within Rwandan district hospitals.

Design, setting and participants
A cluster randomised, single blinded, control trial design was used to select four district hospitals. Participants included physicians, social workers, physiotherapists, nutritionists, clinical psychologists/mental health nurses.

Intervention
Health professionals either received one day’s training in interprofessional practice (IPP) based on the ICF (experimental group) as a collaborative framework or a short talk on the topic (control group).

Outcome measures
Validated questionnaires were used to explore changes in knowledge and attitudes. Ethical approval was obtained from the relevant authorities.

Results
There were 103 participants in the experimental and 100 in the control group. There was no significant difference between Knowledge and Attitude scales at baseline. Post-intervention the experimental group (mean = 41.3, SD = 9.5) scored significantly higher on the knowledge scale than the control group (mean = 17.7, SD = 4.7 (t = 22.5; p < .001)). The median scores on the Attitude Scale improved in the Experimental group from 77.8 to 91.1%, whereas the median scores of the control remained approximately 80% (Adjusted Z = 10.72p < .001).

Conclusion
The ICF proved to be a useful framework for structuring the training of all HPs in IPP and the training resulted in a significant improvement in knowledge and attitudes regarding IPP. As suggested by the HPs, more training and refresher courses were needed for sustainability and the training should be extended to other hospitals in Rwanda. It is thus recommended that the framework can be used in interprofessional education and practice in Rwanda and possibly in other similar countries.

Trial registration
Name of the registry: Pan African Clinical Trial Registry.
Trial registration number:PACTR201604001185358.
Date of registration: 22/04/2016.
URL of trial registry record:www.pactr.org
Determining mutational burden and signature using RNA-seq from tumor-only samples
Authors: Jessen Erik , Liu Yuanhang , Davila Jaime , Kocher Jean-Pierre , Wang Chen 
Published: March 2021

Abstract
Background
Traditionally, mutational burden and mutational signatures have been assessed by tumor-normal pair DNA sequencing. The requirement of having both normal and tumor samples is not always feasible from a clinical perspective, and led us to investigate the efficacy of using RNA sequencing of only the tumor sample to determine the mutational burden and signatures, and subsequently molecular cause of the cancer. The potential advantages include reducing the cost of testing, and simultaneously providing information on the gene expression profile and gene fusions present in the tumor.

Results
In this study, we devised supervised and unsupervised learning methods to determine mutational signatures from tumor RNA-seq data. As applications, we applied the methods to a training set of 587 TCGA uterine cancer RNA-seq samples, and examined in an independent testing set of 521 TCGA colorectal cancer RNA-seq samples. Both diseases are known associated with microsatellite instable high (MSI-H) and driver defects in DNA polymerase ɛ (POLɛ). From RNA-seq called variants, we found majority (> 95%) are likely germline variants, leading to C > T enriched germline variants (dbSNP) widely applicable in tumor and normal RNA-seq samples. We found significant associations between RNA-derived mutational burdens and MSI/POLɛ status, and insignificant relationship between RNA-seq total coverage and derived mutational burdens. Additionally we found that over 80% of variants could be explained by using the COSMIC mutational signature-5, -6 and -10, which are implicated in natural aging, MSI-H, and POLɛ, respectively. For classifying tumor type, within UCEC we achieved a recall of 0.56 and 0.78, and specificity of 0.66 and 0.99 for MSI and POLɛ respectively. By applying learnt RNA signatures from UCEC to COAD, we were able to improve our classification of both MSI and POLɛ.

Conclusions
Taken together, our work provides a novel method to detect RNA-seq derived mutational signatures with effective procedures to remove likely germline variants. It can leads to accurate classification of underlying driving mechanisms of DNA damage deficiency.
Risk for recurrent cardiovascular disease events among patients with diabetes and chronic kidney disease
Authors: Hubbard Demetria , Colantonio Lisandro D. , Rosenson Robert S. , Brown Todd M. , Jackson Elizabeth A. , Huang Lei , Orroth Kate K. , Reading Stephanie , Woodward Mark , Bittner Vera , Gutierrez Orlando M. , Safford Monika M. , Farkouh Michael E. , Muntner Paul 
Published: March 2021

Abstract
Background
Adults who have experienced multiple cardiovascular disease (CVD) events have a very high risk for additional events. Diabetes and chronic kidney disease (CKD) are each associated with an increased risk for recurrent CVD events following a myocardial infarction (MI).

Methods
We compared the risk for recurrent CVD events among US adults with health insurance who were hospitalized for an MI between 2014 and 2017 and had (1) CVD prior to their MI but were free from diabetes or CKD (prior CVD), and those without CVD prior to their MI who had (2) diabetes only, (3) CKD only and (4) both diabetes and CKD. We followed patients from hospital discharge through December 31, 2018 for recurrent CVD events including coronary, stroke, and peripheral artery events.

Results
Among 162,730 patients, 55.2% had prior CVD, and 28.3%, 8.3%, and 8.2% had diabetes only, CKD only, and both diabetes and CKD, respectively. The rate for recurrent CVD events per 1000 person-years was 135 among patients with prior CVD and 110, 124 and 171 among those with diabetes only, CKD only and both diabetes and CKD, respectively. Compared to patients with prior CVD, the multivariable-adjusted hazard ratio for recurrent CVD events was 0.92 (95%CI 0.90–0.95), 0.89 (95%CI: 0.85–0.93), and 1.18 (95%CI: 1.14–1.22) among those with diabetes only, CKD only, and both diabetes and CKD, respectively.

Conclusion
Following MI, adults with both diabetes and CKD had a higher risk for recurrent CVD events compared to those with prior CVD without diabetes or CKD.
Geographical variation and clustering are found in atrial fibrillation beyond socioeconomic differences: a Danish cohort study, 1987–2015
Authors: Wodschow Kirstine , Bihrmann Kristine , Larsen Mogens Lytken , Gislason Gunnar , Ersbøll Annette Kjær 
Published: March 2021

Abstract
Background
The prevalence and incidence rate of atrial fibrillation (AF) increase worldwide and AF is a risk factor for more adverse cardiovascular diseases including stroke. Approximately 44% of AF cases cannot be explained by common individual risk factors and risk might therefore also be related to the environment. By studying geographical variation and clustering in risk of incident AF adjusted for socioeconomic position at an individual level, potential neighbourhood risk factors could be revealed.

Methods
Initially, yearly AF incidence rates 1987–2015 were estimated overall and stratified by income in a register-based cohort study. To examine geographical variation and clustering in AF, we used both spatial scan statistics and a hierarchical Bayesian Poisson regression analysis of AF incidence rates with random effect of municipalities (n = 98) in Denmark in 2011–2015.

Results
The 1987–2015 cohort included 5,453,639 individuals whereof 369,800 were diagnosed with an incident AF. AF incidence rate increased from 174 to 576 per 100,000 person-years from 1987 to 2015. Inequality in AF incidence rate ratio between highest and lowest income groups increased from 23% in 1987 to 38% in 2015. We found clustering and geographical variation in AF incidence rates, with incidence rates at municipality level being up to 34% higher than the country mean after adjusting for socioeconomic position.

Conclusions
Geographical variations and clustering in AF incidence rates exist. Compared to previous studies from Alberta, Canada and the United States, we show that geographical variations exist in a country with free access to healthcare and even when accounting for socioeconomic differences at an individual level. An increasing social inequality in AF was seen from 1987 to 2015. Therefore, when planning prevention strategies, attention to individuals with low income should be given. Further studies focusing on identification of neighbourhood risk factors for AF are needed.
CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway
Authors: Wang Lei , Zhou Yehui , Jiang Liang , Lu Linlin , Dai Tiantian , Li Aoshuang , Chen Yan , Zhang Lifeng 
Published: March 2021

Abstract
Background
Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs).

Methods
TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC.

Results
CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor.

Conclusions
CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.
Structure-dependent absorption of atypical sphingoid long-chain bases from digestive tract into lymph
Authors: Mikami Daisuke , Sakai Shota , Nishimukai Megumi , Yuyama Kohei , Mukai Katsuyuki , Igarashi Yasuyuki 
Published: March 2021

Abstract
Background
Dietary sphingolipids have various biofunctions, including skin barrier improvement and anti-inflammatory and anti-carcinoma properties. Long-chain bases (LCBs), the essential backbones of sphingolipids, are expected to be important for these bioactivities, and they vary structurally between species. Given these findings, however, the absorption dynamics of each LCB remain unclear.

Methods
In this study, five structurally different LCBs were prepared from glucosylceramides (GlcCers) with LCB 18:2(4E,8Z);2OH and LCB 18:2(4E,8E);2OH moieties derived from konjac tuber (Amorphophallus konjac), from GlcCers with an LCB 18(9Me):2(4E,8E);2OH moiety derived from Tamogi mushroom (Pleurotus cornucopiae var. citrinopileatus), and from ceramide 2-aminoethyphosphonate with LCB 18:3(4E,8E,10E);2OH moiety and LCB 18(9Me):3(4E,8E,10E);2OH moiety derived from giant scallop (Mizuhopecten yessoensis), and their absorption percentages and metabolite levels were analyzed using a lymph-duct-cannulated rat model via liquid chromatography tandem mass spectrometry (LC/MS/MS) with a multistage fragmentation method.

Results
The five orally administered LCBs were absorbed and detected in chyle (lipid-containing lymph) as LCBs and several metabolites including ceramides, hexosylceramides, and sphingomyelins. The absorption percentages of LCBs were 0.10–1.17%, depending on their structure. The absorption percentage of LCB 18:2(4E,8Z);2OH was the highest (1.17%), whereas that of LCB 18:3(4E,8E,10E);2OH was the lowest (0.10%). The amount of sphingomyelin with an LCB 18:2(4E,8Z);2OH moiety in chyle was particularly higher than sphingomyelins with other LCB moieties.

Conclusions
Structural differences among LCBs, particularly geometric isomerism at the C8–C9 position, significantly affected the absorption percentages and ratio of metabolites. This is the first report to elucidate that the absorption and metabolism of sphingolipids are dependent on their LCB structure. These results could be used to develop functional foods that are more readily absorbed.