bluuebunny/crossref_metadata_2025_split huggingface dataset:
Equality, diversity, and inclusion in oncology clinical trials: an audit of essential documents and data collection against INCLUDE under-served groups in a UK academic trial setting
Authors: Patel Dhrusti , Kilburn Lucy , Fox Lisa , Hall Emma , Bliss Judith , Lewis Rebecca 
Published: November 2023

Abstract
Background
Clinical trials should be as inclusive as possible to facilitate equitable access to research and better reflect the population towards which any intervention is aimed. Informed by the UK’s National Institute for Health and Care Research (NIHR) Innovations in Clinical Trial Design and Delivery for the Under-served (INCLUDE) guidance, we audited oncology trials conducted by the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London (ICR-CTSU) to identify whether essential documents were overtly excluding any groups and whether sufficient data were collected to assess diversity of trial participants from groups suggested by INCLUDE as under-served by research in the UK.

Methods
Thirty cancer clinical trials managed by ICR-CTSU and approved between 2011–2021 were audited. The first ethics approved version of each trial’s protocol, patient information sheet, and patient completed questionnaire, together with the first case report forms (CRFs) version were reviewed. A range of items aligned with the INCLUDE under-served groups were assessed, including age, sex and gender, socio-economic and health factors. The scope did not cover trial processes in participating hospitals.

Results
Data relating to participants’ age, ethnic group and health status were well collected and no upper age limit was specified in any trials’ eligibility criteria. 23/30 (77%) information sheets used at least one gendered term to address patients. Most CRFs did not specify whether they were collecting sex or gender and only included male or female categories. The median reading age for information sheets was 15–16 years (IQR: 14–15 – 16–17). Socio-economic factors were not routinely collected and not commonly mentioned in trial protocols.

Conclusions
No systemic issues were identified in protocols which would explicitly prevent any under-served group from participating. Areas for improvement include reducing use of gendered words and improving readability of patient information. The challenge of fully assessing adequate inclusion of under-served populations remains, as socio-economic factors are not routinely collected because they fall beyond the data generally required for protocol-specified trial endpoint assessments. This audit has highlighted the need to agree and standardise demographic data collection to permit adequate monitoring of the under-served groups identified by the NIHR.
The mediation of health-promoting lifestyle on self-perceived health status and quality of life among nurses: a cross-sectional study
Authors: Wang Kuei-Ying , Chien Ching-Ming , Lee Huan-Fang , Yobelina Yohana 
Published: November 2023

Abstract
Background
Nurses with busy workloads lack the time to maintain health, leading to a decline in physical and mental health and quality of life. It is widely accepted that self-perception of health triggers health-promoting behaviors and impacts the quality of life; however, the relationship between these factors among nurses is unclear. The purpose of this study was to investigate the ability of a health-promoting lifestyle to mediate the relationship between self-perceived health and quality of life among nurses.

Methods
A cross-sectional survey was conducted in four regional Taiwanese teaching hospitals with over 500 beds. The survey used stratified random sampling of 600 nurses who had worked for more than six months. The Self-Perceived Health Questionnaire, the Health-Promoting Lifestyle Profile, and the World Health Organization Quality of Life Scale were used to measure nurses’ self-perceived health (SPH), health-promoting lifestyle (HPL), and quality of life (QoL). A Hayes PROCESS analysis and bootstrapping method were used for the mediation analysis.

Results
A total of 518 nurses’ data was included in the analysis. Nurses perceived their health status as less favorable than their colleagues, but frequently adopted health promotion behaviors. Nurses reported a moderate QoL. QoL and SPH were correlated (r = .33) and a high correlation between QoL and HPL (r = .64) was found. SPH and HPL both affect QoL (B = 0.077 and 0.070). SPH and HPL explained 42.6% of the variation in QoL. HPL played a partial mediation role.

Conclusions
The study confirmed that HPL has an important role in mediating nurses’ SPH and QoL. Nurse administrators are advised to encourage nurses to monitor their health status and provide health promotion mechanisms to improve their quality of life.
Adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations and risk of 14 lifestyle-related cancers in the UK Biobank prospective cohort study
Authors: Malcomson Fiona C. , Parra-Soto Solange , Ho Frederick K. , Lu Liya , Celis-Morales Carlos , Sharp Linda , Mathers John C. 
Published: November 2023

Abstract
Background
The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations are lifestyle-based recommendations which aim to reduce cancer risk. This study investigated associations between adherence, assessed using a standardised scoring system, and the risk of all cancers combined and of 14 cancers for which there is strong evidence for links with aspects of lifestyle in the UK.

Methods
We used data from 94,778 participants (53% female, mean age 56 years) from the UK Biobank. Total adherence scores (range 0–7 points) were derived from dietary, physical activity, and anthropometric data. Associations between total score and cancer risk (all cancers combined; and prostate, breast, colorectal, lung, uterine, liver, pancreatic, stomach, oesophageal, head and neck, ovarian, kidney, bladder, and gallbladder cancer) were investigated using Cox proportional hazard models, adjusting for age, sex, deprivation index, ethnicity, and smoking status.

Results
Mean total score was 3.8 (SD 1.0) points. During a median follow-up of 8 years, 7296 individuals developed cancer. Total score was inversely associated with risk of all cancers combined (HR: 0.93; 95%CI: 0.90–0.95 per 1-point increment), as well as breast (HR: 0.90; 95%CI: 0.86–0.95), colorectal (HR: 0.90; 95%CI: 0.84–0.97), kidney (HR: 0.82; 95%CI: 0.72–0.94), oesophageal (HR: 0.84; 95%CI: 0.71–0.98), ovarian (HR: 0.76; 95%CI: 0.65–0.90), liver (HR: 0.78; 95%CI: 0.63–0.97), and gallbladder (HR: 0.70; 95%CI: 0.53–0.93) cancers.

Conclusions
Greater adherence to lifestyle-based recommendations was associated with reduced risk of all cancers combined and of breast, colorectal, kidney, oesophageal, ovarian, liver, and gallbladder cancers. Our findings support compliance with the Cancer Prevention Recommendations for cancer prevention in the UK.
Butterflies in the gut: the interplay between intestinal microbiota and stress
Authors: Lai Tzu-Ting , Liou Chia-Wei , Tsai Yu-Hsuan , Lin Yuan-Yuan , Wu Wei-Li 
Published: November 2023

AbstractPsychological stress is a global issue that affects at least one-third of the population worldwide and increases the risk of numerous psychiatric disorders. Accumulating evidence suggests that the gut and its inhabiting microbes may regulate stress and stress-associated behavioral abnormalities. Hence, the objective of this review is to explore the causal relationships between the gut microbiota, stress, and behavior. Dysbiosis of the microbiome after stress exposure indicated microbial adaption to stressors. Strikingly, the hyperactivated stress signaling found in microbiota-deficient rodents can be normalized by microbiota-based treatments, suggesting that gut microbiota can actively modify the stress response. Microbiota can regulate stress response via intestinal glucocorticoids or autonomic nervous system. Several studies suggest that gut bacteria are involved in the direct modulation of steroid synthesis and metabolism. This review provides recent discoveries on the pathways by which gut microbes affect stress signaling and brain circuits and ultimately impact the host’s complex behavior.
METTL3-mediated m6A RNA methylation induces the differentiation of lung resident mesenchymal stem cells into myofibroblasts via the miR-21/PTEN pathway
Authors: Lu Yi , Liu Zeyu , Zhang Yunjiao , Wu Xiuhua , Bian Wei , Shan Shan , Yang Danrong , Ren Tao 
Published: November 2023

Abstract
Background
The accumulation of myofibroblasts is the key pathological feature of pulmonary fibrosis (PF). Aberrant differentiation of lung-resident mesenchymal stem cells (LR-MSCs) has been identified as a critical source of myofibroblasts, but the molecular mechanisms underlying this process remain largely unknown. In recent years, N6-methyladenosine (m6A) RNA modification has been implicated in fibrosis development across diverse organs; however, its specific role in promoting the differentiation of LR-MSCs into myofibroblasts in PF is not well defined.

Methods
In this study, we examined the levels of m6A RNA methylation and the expression of its regulatory enzymes in both TGF-β1-treated LR-MSCs and fibrotic mouse lung tissues. The downstream target genes of m6A and their related pathways were identified according to a literature review, bioinformatic analysis and experimental verification. We also assessed the expression levels of myofibroblast markers in treated LR-MSCs and confirmed the involvement of the above-described pathway in the aberrant differentiation direction of LR-MSCs under TGF-β1 stimulation by overexpressing or knocking down key genes within the pathway.

Results
Our results revealed that METTL3-mediated m6A RNA methylation was significantly upregulated in both TGF-β1-treated LR-MSCs and fibrotic mouse lung tissues. This process directly led to the aberrant differentiation of LR-MSCs into myofibroblasts by targeting the miR-21/PTEN pathway. Moreover, inhibition of METTL3 or miR-21 and overexpression of PTEN could rescue this abnormal differentiation.

Conclusion
Our study demonstrated that m6A RNA methylation induced aberrant LR-MSC differentiation into myofibroblasts via the METTL3/miR-21/PTEN signaling pathway. We indicated a novel mechanism to promote PF progression. Targeting METTL3-mediated m6A RNA methylation and its downstream targets may present innovative therapeutic approaches for the prevention and treatment of PF.
SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1
Authors: Wang Weijie , Li Yilan , Zhang Yanxiu , Ye Tao , Wang Kui , Li Shuijie , Zhang Yao 
Published: November 2023

Abstract
Background
Endothelial–mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium–glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated.

Methods
Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs).

Results
Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT.

Conclusions
Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.

Graphical Abstract
Cost-effectiveness of finerenone in chronic kidney disease associated with type 2 diabetes in The Netherlands
Authors: Quist Sara W. , van Schoonhoven Alexander V. , Bakker Stephan J. L. , Pochopień Michał , Postma Maarten J. , van Loon Jeanni M. T. , Paulissen Jeroen H. J. 
Published: November 2023

Abstract
Background
In the Netherlands, more than one million patients have type 2 diabetes (T2D), and approximately 36% of these patients have chronic kidney disease (CKD). Yearly medical costs related to T2D and CKD account for approximately €1.3 billion and €805 million, respectively. The FIDELIO-DKD trial showed that the addition of finerenone to the standard of care (SoC) lowers the risk of CKD progression and cardiovascular (CV) events in patients with CKD stages 2–4 associated with T2D. This study investigates the cost-effectiveness of adding finerenone to the SoC of patients with advanced CKD and T2D compared to SoC monotherapy.

Methods
The validated FINE-CKD model is a Markov cohort model which simulates the disease pathway of patients over a lifetime time horizon. The model was adapted to reflect the Dutch societal perspective. The model estimated the incremental costs, utilities, and incremental cost-effectiveness ratio (ICER). Sensitivity and scenario analyses were performed to assess the effect of parameter uncertainty on model robustness.

Results
When used in conjunction with SoC, finerenone extended time free of CV events and renal replacement therapy by respectively 0.30 and 0.31 life years compared to SoC alone, resulting in an extension of 0.20 quality-adjusted life years (QALYs). The reduction in renal and CV events led to a €6136 decrease in total lifetime costs per patient compared to SoC alone, establishing finerenone as a dominant treatment option. Finerenone in addition to SoC had a 83% probability of being dominant and a 93% probability of being cost-effective at a willingness-to-pay threshold of €20,000.

Conclusion
By reducing the risk of CKD progression and CV events, finerenone saves costs to society while gaining QALYs in patients with T2D and advanced CKD in the Netherlands.
Prognostic value of triglyceride-glucose index in patients with chronic coronary syndrome undergoing percutaneous coronary intervention
Authors: Tao Shiyi , Yu Lintong , Li Jun , Xie Zicong , Huang Li , Yang Deshuang , Tan Yuqing , Zhang Wenjie , Huang Xuanchun , Xue Tiantian 
Published: November 2023

Abstract
Background
The triglyceride-glucose (TyG) index has been proposed as a reliable surrogate marker of insulin resistance and an independent predictor of major adverse cardiovascular events (MACEs). Several recent studies have shown the relationship between the TyG index and cardiovascular outcomes; however, the role of the TyG index in chronic coronary syndrome (CCS) progression has not been extensively assessed especially in population after revascularization. This study aimed to investigate the prognostic value of the TyG index in predicting MACEs in CCS patients undergoing percutaneous coronary intervention (PCI).

Methods
The data for the study were taken from the Hospital Information System database in China-Japan Friendship Hospital over the period 2019–2021. Eligible participants were divided into groups according to the TyG index tertiles. The Boruta algorithm was performed for feature selection. Multivariate Cox proportional hazards models and restricted cubic spline (RCS) analysis were applied to examine the dose–response relationship between the TyG index and endpoint, and the results were expressed with hazard ratio (HR) and 95% confidence interval (CI) values. The area under the receiver operating characteristic (ROC) curve (AUC), decision curve analysis (DCA), and clinical impact curve (CIC) were plotted to comprehensively evaluate the predictive accuracy and clinical value of the model. The goodness-of-fit of models was evaluated using the calibration curve and χ2 likelihood ratio test.

Results
After applying inclusion and exclusion criteria, 1353 patients with CCS undergoing PCI were enrolled in the study. After adjusting for all confounders, we found that those with the highest TyG index had a 59.5% increased risk of MACEs over the 1-year follow-up (HR 1.595, 95% CI 1.370 ~ 1.855). Using the lowest TyG index tertile as the reference (T1), the fully adjusted HRs (95% CIs) for endpoints was 1.343 (1.054 ~ 1.711) in the middle (T2) and 2.297 (1.842 ~ 2.864) in highest tertile (T3) (P for trend < 0.001). The TyG index had an excellent predictive performance according to the results of AUC 0.810 (0.786, 0.834) and χ2 likelihood ratio test (χ2 = 7.474, P = 0.486). DCA and CIC analysis also suggested a good overall net benefit and clinical impact of the multivariate model. The results in the subgroup analysis were consistent with the main analyses. RCS model demonstrated that the TyG index was nonlinearly associated with the risk of MACEs within one year (P for nonlinear < 0.001).

Conclusion
The elevated TyG index is associated with an increased risk of cardiovascular events and predicts future MACEs in patients with CCS undergoing PCI independently of known cardiovascular risk factors, indicating that the TyG index may be a potential marker for risk stratification and prognosis in CCS patients undergoing PCI.
Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice
Authors: Amor Melina , Bianco Valentina , Buerger Martin , Lechleitner Margarete , Vujić Nemanja , Dobrijević Anja , Akhmetshina Alena , Pirchheim Anita , Schwarz Birgit , Pessentheiner Ariane R. , Baumgartner Franziska , Rampitsch Katharina , Schauer Silvia , Klobučar Iva , Degoricija Vesna , Pregartner Gudrun , Kummer Daniel , Svecla Monika , Sommer Gerhard , Kolb Dagmar , Holzapfel Gerhard A. , Hoefler Gerald , Frank Saša , Norata Giuseppe Danilo , Kratky Dagmar 
Published: November 2023

Abstract
Background
Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear.

Methods
We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16–20 weeks.

Results
DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs.

Conclusion
We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.
Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors
Authors: Llinàs-Arias Pere , Ensenyat-Mendez Miquel , Íñiguez-Muñoz Sandra , Orozco Javier I. J. , Valdez Betsy , Salomon Matthew P. , Matsuba Chikako , Solivellas-Pieras Maria , Bedoya-López Andrés F. , Sesé Borja , Mezger Anja , Ormestad Mattias , Unzueta Fernando , Strand Siri H. , Boiko Alexander D. , Hwang E Shelley , Cortés Javier , DiNome Maggie L. , Esteller Manel , Lupien Mathieu , Marzese Diego M. 
Published: November 2023

Abstract
Background
Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process.

Methods
We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens.

Results
We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 − 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 − 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01).

Conclusion
Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.