bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutation on JmjC domain of UTX impaired its antitumor effects in pancreatic cancer via inhibiting G0S2 expression and activating the Toll-like signaling pathway
Authors: Shen Xiao-hua , Xiong Shu-ping , Wang Sheng-peng , Lu Shan , Wan Yi-ye , Zhang Hui-qing 
Published: December 2024

Abstract
Background
Recently, the incidence of pancreatic cancer (PC) has gradually increased. Research has shown that UTX mutants are critical in tumors. However, the underlying mechanisms remain incompletely understood. This study aimed to explore how UTX mutation would affect its related function in PC.

Method
Exome sequencing was used to analyze PC samples. MTT, transwell, and colony formation assays were performed to determine the cellular functions of PC cells. qRT-PCR, Western Blot, TUNEL, immunohistochemistry, CHIP, bioinformatics, and xenograft experiments were used to investigate the mechanism of UTX mutants in PC in vitro and in vivo.

Results
We compared exome sequencing data from 12 PC samples and found a UTX missense mutation on the JmjC structure. Through cellular functions and xenograft experiments, wild-type UTX was found to significantly inhibit PC malignant progression in vitro and in vivo, while UTX mutation notably impaired this effect. Furthermore, G0S2 was identified as the key target gene for UTX, and wild-type UTX significantly increased its expression, while mutant one lost this function to a certain extent both in vitro and in vivo. More importantly, G0S2 overexpression not only inhibited tumor malignant phenotype and drug resistance for Gemcitabine in PC but also effectively reversed the roles of UTX mutant with Toll-like signaling pathway involved. In terms of mechanism, UTX mutation elevated the H3K27me3 modification level of the G0S2 promoter, which decreased its expression in PC cells.

Conclusion
In conclusion, UTX mutant weakened the antitumor effect of wild-type UTX in PC by inhibiting G0S2 expression and activating the Toll-like signaling pathway.
Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade
Authors: Yu Xin , Jiang Juan , Li Cheng , Wang Yang , Ren Zhengrong , Hu Jianlun , Yuan Tao , Wu Yongjie , Wang Dongsheng , Sun Ziying , Wu Qi , Chen Bin , Fang Peng , Ding Hao , Meng Jia , Jiang Hui , Zhao Jianning , Bao Nirong 
Published: December 2024

Abstract
Background
Periprosthetic osteolysis and subsequent aseptic loosening are the leading causes of failure following total joint arthroplasty. Osteogenic impairment induced by wear particles is regarded as a crucial contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress identified as a key underlying mechanism. Therefore, identifying potential therapeutic targets and agents that can regulate ER stress adaption in osteoblasts is necessary for arresting aseptic loosening. Osthole (OST), a natural coumarin derivative, has demonstrated promising osteogenic properties and the ability to modulate ER stress adaption in various diseases. However, the impact of OST on ER stress-mediated osteogenic impairment caused by wear particles remains unclear.

Methods
TiAl6V4 particles (TiPs) were sourced from the prosthesis of patients who underwent revision hip arthroplasty due to aseptic loosening. A mouse calvarial osteolysis model was utilized to explore the effects of OST on TiPs-induced osteogenic impairment in vivo. Primary mouse osteoblasts were employed to investigate the impact of OST on ER stress-mediated osteoblast apoptosis and osteogenic inhibition induced by TiPs in vitro. The mechanisms underlying OST-modulated alleviation of ER stress induced by TiPs were elucidated through Molecular docking, immunochemistry, PCR, and Western blot analysis.

Results
In this study, we found that OST treatment effectively mitigated TiAl6V4 particles (TiPs)-induced osteolysis by enhancing osteogenesis in a mouse calvarial model. Furthermore, we observed that OST could attenuate ER stress-mediated apoptosis and osteogenic reduction in osteoblasts exposed to TiPs in vitro and in vivo. Mechanistically, we demonstrated that OST exerts bone-sparing effects on stressed osteoblasts upon TiPs exposure by specifically suppressing the ER stress-dependent PERK signaling cascade.

Conclusion
Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade. These findings suggest that OST may serve as a potential therapeutic agent for combating wear particle-induced osteogenic impairment, offering a novel alternative strategy for managing aseptic prosthesis loosening.
Metabolomic signature of pediatric diabetic ketoacidosis: key metabolites, pathways, and panels linked to clinical variables
Authors: Spagnolo Paolo , Tweddell David , Cela Enis , Daley Mark , Clarson Cheril , Rupar C. Anthony , Stranges Saverio , Bravo Michael , Cepinskas Gediminas , Fraser Douglas D. 
Published: December 2024

Abstract
Background
Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes (T1D), arising from relative insulin deficiency and leading to hyperglycemia, ketonemia, and metabolic acidosis. Early detection and treatment are essential to prevent severe outcomes. This pediatric case–control study utilized plasma metabolomics to explore metabolic alterations associated with DKA and to identify predictive metabolite patterns.

Methods
We examined 34 T1D participants, including 17 patients admitted with severe DKA and 17 age- and sex-matched individuals in insulin-controlled states. A total of 215 plasma metabolites were analyzed using proton nuclear magnetic resonance and direct-injection liquid chromatography/mass spectrometry. Multivariate statistical methods, machine learning techniques, and bioinformatics were employed for data analysis.

Results
After adjusting for multiple comparisons, 65 metabolites were found to differ significantly between the groups (28 increased and 37 decreased). Metabolomics profiling demonstrated 100% accuracy in differentiating severe DKA from insulin-controlled states. Random forest analysis indicated that classification accuracy was primarily influenced by changes in ketone bodies, acylcarnitines, and phosphatidylcholines. Additionally, groups of metabolites (ranging in number from 8 to 18) correlated with key clinical and biochemical variables, including pH, bicarbonate, glucose, HbA1c, and Glasgow Coma Scale scores.

Conclusions
These findings underscore significant metabolic disturbances in severe DKA and their associations with critical clinical indicators. Future investigations should explore if metabolic alterations in severe DKA can identify patients at increased risk of complications and/or guide future therapeutic interventions.
Elongation factor 2 in cancer: a promising therapeutic target in protein translation
Authors: Jia Xuechao , Huang Chuntian , Liu Fangfang , Dong Zigang , Liu Kangdong 
Published: December 2024

AbstractAberrant elongation of proteins can lead to the activation of oncogenic signaling pathways, resulting in the dysregulation of oncogenic signaling pathways. Eukaryotic elongation factor 2 (eEF2) is an essential regulator of protein synthesis that precisely elongates nascent peptides in the protein elongation process. Although studies have linked aberrant eEF2 expression to various cancers, research has primarily focused on its structure, highlighting a need for deeper exploration into its molecular functions. In this review, recent advancements in the structure, guanosine triphosphatase (GTPase) activity, posttranslational modifications, regulatory factors, and inhibitors of eEF2 are summarized. These findings provide a comprehensive cognition on the critical role of eEF2 and its potential as a therapeutic target in cancer. Furthermore, this review highlights important unanswered questions that warrant investigation in future research.
Graphical Abstract
Haplotype analysis incorporating ancestral origins identified novel genetic loci associated with chicken body weight using an advanced intercross line
Authors: Bu Lina , Wang Yuzhe , Tan Lizhi , Wen Zilong , Hu Xiaoxiang , Zhang Zhiwu , Zhao Yiqiang 
Published: December 2024

Abstract
Background
The genome-wide association study (GWAS) is a powerful method for mapping quantitative trait loci (QTL). However, standard GWAS can detect only QTL that segregate in the mapping population. Crossing populations with different characteristics increases genetic variability but F2 or back-crosses lack mapping resolution due to the limited number of recombination events. This drawback can be overcome with advanced intercross line (AIL) populations, which increase the number recombination events and provide a more accurate mapping resolution. Recent studies in humans have revealed ancestry-dependent genetic architecture and shown the effectiveness of admixture mapping in admixed populations.

Results
Through the incorporation of line-of-origin effects and GWAS on an F9 AIL population, we identified genes that affect body weight at eight weeks of age (BW8) in chickens. The proposed ancestral-haplotype-based GWAS (testing only the origin regardless of the alleles) revealed three new QTLs on GGA12, GGA15, and GGA20. By using the concepts of ancestral homozygotes (individuals that carry two haplotypes of the same origin) and ancestral heterozygotes (carrying one haplotype of each origin), we identified 632 loci that exhibited high-parent (the heterozygote is better than both parents) and mid-parent (the heterozygote is better than the median of the parents) dominance across 12 chromosomes. Out of the 199 genes associated with BW8, EYA1, PDE1C, and MYC were identified as the best candidate genes for further validation.

Conclusions
In addition to the candidate genes reported in this study, our research demonstrates the effectiveness of incorporating ancestral information in population genetic analyses, which can be broadly applicable for genetic mapping in populations generated by ancestors with distinct phenotypes and genetic backgrounds. Our methods can benefit both geneticists and biologists interested in the genetic determinism of complex traits.
A comprehensive guide to study the agreement and reliability of multi-observer ordinal data
Authors: Vanbelle Sophie , Engelhart Christina Hernandez , Blix Ellen 
Published: December 2024

Abstract
Background
A recent systematic review revealed issues in regard to performing and reporting agreement and reliability studies for ordinal scales, especially in the presence of more than two observers. This paper therefore aims to provide all necessary information in regard to the choice among the most meaningful and most used measures and the planning of agreement and reliability studies for ordinal outcomes.

Methods
This paper considers the generalisation of the proportion of (dis)agreement, the mean absolute deviation, the mean squared deviation and weighted kappa coefficients to more than two observers in the presence of an ordinal outcome.

Results
After highlighting the difference between the concepts of agreement and reliability, a clear and simple interpretation of the agreement and reliability coefficients is provided. The large sample variance of the various coefficients with the delta method is presented or derived if not available in the literature to construct Wald confidence intervals. Finally, a procedure to determine the minimum number of raters and patients needed to limit the uncertainty associated with the sampling process is provided. All the methods are available in an R package and a Shiny application to circumvent the limitations of current software.

Conclusions
The present paper completes existing guidelines, such as the Guidelines for Reporting Reliability and Agreement Studies (GRRAS), to improve the quality of reliability and agreement studies of clinical tests. Furthermore, we provide open source software to researchers with minimum programming skills.
Partial-linear single-index Cox regression models with multiple time-dependent covariates
Authors: Lee Myeonggyun , Troxel Andrea B. , Kwon Sophia , Crowley George , Schwartz Theresa , Zeig-Owens Rachel , Prezant David J. , Nolan Anna , Liu Mengling 
Published: December 2024

Abstract
Background
In cohort studies with time-to-event outcomes, covariates of interest often have values that change over time. The classical Cox regression model can handle time-dependent covariates but assumes linear effects on the log hazard function, which can be limiting in practice. Furthermore, when multiple correlated covariates are studied, it is of great interest to model their joint effects by allowing a flexible functional form and to delineate their relative contributions to survival risk.

Methods
Motivated by the World Trade Center (WTC)-exposed Fire Department of New York cohort study, we proposed a partial-linear single-index Cox (PLSI-Cox) model to investigate the effects of repeatedly measured metabolic syndrome indicators on the risk of developing WTC lung injury associated with particulate matter exposure. The PLSI-Cox model reduces the dimensionality of covariates while providing interpretable estimates of their effects. The model’s flexible link function accommodates nonlinear effects on the log hazard function. We developed an iterative estimation algorithm using spline techniques to model the nonparametric single-index component for potential nonlinear effects, followed by maximum partial likelihood estimation of the parameters.

Results
Extensive simulations showed that the proposed PLSI-Cox model outperformed the classical time-dependent Cox regression model when the true relationship was nonlinear. When the relationship was linear, both the PLSI-Cox model and classical time-dependent Cox regression model performed similarly. In the data application, we found a possible nonlinear joint effect of metabolic syndrome indicators on survival risk. Among the different indicators, BMI had the largest positive effect on the risk of developing lung injury, followed by triglycerides.

Conclusion
The PLSI-Cox models allow for the evaluation of nonlinear effects of covariates and offer insights into their relative importance and direction. These methods provide a powerful set of tools for analyzing data with multiple time-dependent covariates and survival outcomes, potentially offering valuable insights for both current and future studies.
Disability justice and collective access to labour and delivery care: a qualitative study
Authors: Evans Meredith , Tarasoff Lesley A. , Lunsky Yona , Welsh Kate , Proulx Laurie , Havercamp Susan M. , Parish Susan L. , Brown Hilary K. 
Published: December 2024

Abstract
Background
People with disabilities experience perinatal health disparities. This qualitative study examines disabled people’s experiences of labour and delivery care from a disability justice lens.

Methods
Semi-structured interviews were conducted between July 2019 and February 2020 with 31 women and transgender people aged 18–45 years with physical, sensory, and/or intellectual/developmental disabilities, who were living in in Ontario, Canada and had given birth in the previous five years.

Results
People with disabilities described negative experiences of provider-driven, disrespectful, and discriminatory labour and delivery care that can be interpreted as examples of disability injustice and obstetric ableism. People with disabilities also described positive experiences of collaborative, respectful, and disability-affirming labour and delivery care that can be interpreted as examples of disability justice, facilitated by what feminist disability justice scholars and activists call collective access.

Conclusions
Collective access to labour and delivery care can improve perinatal health care for people with disabilities and promote disability justice. Reimagining care-related decision-making as an interdependent, collaborative, respectful, and disability-affirming process shared between patients and providers can help to facilitate collective access to labour and delivery care.
The metabolome of male and female individuals with knee osteoarthritis is influenced by 18-months of weight loss intervention: the IDEA trial
Authors: Welhaven Hope D. , Welfley Avery H. , Bothner Brian , Messier Stephen P. , Loeser Richard F. , June Ronald K. 
Published: December 2024

Abstract
Background
The Intensive Diet and Exercise for Arthritis (IDEA) trial was a randomized trial conducted to evaluate the effects of diet and exercise on osteoarthritis (OA), the most prevalent form of arthritis. Various risk factors, including obesity and sex, contribute to OA’s debilitating nature. While diet and exercise are known to improve OA symptoms, cellular and molecular mechanisms underlying these interventions, as well as effects of participant sex, remain elusive.

Methods
Serum was obtained at three timepoints from IDEA participants assigned to groups of diet, exercise, or combined diet and exercise (n = 10 per group). A randomly selected subset of serum samples were extracted and analyzed via liquid chromatography-mass spectrometry combined with metabolomic profiling to unveil mechanisms associated with types of intervention and disease. Extracted serum was pooled and fragmentation patterns were analyzed to identify metabolites that statistically differentially regulated between groups.

Results
Changes in metabolism across male and female IDEA participants after 18-months of diet, exercise, and combined diet and exercise intervention mapped to lipid, amino acid, carbohydrate, vitamin, and matrix metabolism. The diverse metabolic landscape detected across IDEA participants shows that intervention type differentially impacts the serum metabolome of OA individuals. Moreover, dissimilarities in the serum metabolome corresponded with participant sex.

Conclusions
These findings suggest that intensive weight loss among males and females offers potential metabolic benefits for individuals with knee OA. This study provides a deeper understanding of dysregulation occurring during OA development in parallel with various interventions, potentially paving the way for improved interventions, treatments, and quality of life of those impacted by OA.

Trial Registration
clinicaltrials.gov Identifier NCT00381290, Registered, 9/25/2006.
Does the role of family meetings important at the end-of-life? A retrospective national study in Taiwan
Authors: Yu Tsung-Hsien , Wei Chung-Jen , Wu Wei-Wen , Lu Frank Leigh 
Published: December 2024

Abstract
Background
Numerous studies have pointed out the benefits of family meetings, but it is unclear who uses family meetings and what the effects are on use of the end-of-life care.

Aim
The purposes of this study were to explore which characteristics are associated with the use of the family meeting and what effects the family meeting has on end-of-life care.

Design
A retrospective observational study using 2012–2017 data from Taiwan’s National Health Insurance claims database, cancer registry, and death registry.

Setting/participants
People who died between 2013 and 2017 in Taiwan as the study population. The deceased people whose information on gender, marital status, or insured classification that was unknown were excluded from this study.

Results
A total of 792,947 people were included. All demographic characteristics were associated with the use of family meetings, and all demographic characteristics (except for gender and residence area) and hospital characteristics were associated with the initiation time of family meetings. We also found use of family meetings increased the use of hospice care (OR:4.949) and decreased the use of CPR (OR:0.208) at the end of life, initiation time was also associated with the hospice and CPR, but the effects were varied.

Conclusion
This study demonstrated that family meetings affected the care at end-of-life. Although the utilization of family meeting was increased by year, but also variation still existed among demographic and health characteristics, how to promote it is the next concern in the future.
Development and alpha-testing of a patient decision aid for patients with chronic myeloid leukemia regarding dose reduction
Authors: Lokhorst D. N. , Djodikromo M. F. , Hermens R. P. M. G. , Blijlevens N. M. A. , Bekker C. L. 
Published: December 2024

Abstract
Background
Dose reduction of tyrosine kinase inhibitors (TKIs) is an option for some chronic myeloid leukemia (CML) patients to minimize side effects while maintaining efficacy. Shared decision-making (SDM) and patient decision aids (PDAs) are advocated to make informed choices such as reducing the dose of TKIs. This paper describes the development and alpha-testing of a PDA for patients with CML receiving TKI dose reduction.

Methods
The PDA was iteratively developed following IPDAS guidelines. First, a needs assessment with semi-structured interviews was conducted to understand the needs and preferences of patients and healthcare providers. Second, through feedback cycles with the project team and steering group the scope, content, and format were defined. Third, three rounds of alpha-testing were performed via individual “think aloud” sessions with patients (round 1) and healthcare providers (round 2) to qualitatively assess the comprehensibility, acceptability, and desirability of the PDA. Round 3 included quantitative evaluation via an acceptability and usability questionnaire. Qualitative data were categorized, and quantitative data were descriptively analyzed.

Results
The majority valued the development of the PDA during the needs assessment (n = 30). The PDA included disease and treatment information, information about dose reduction, knowledge questions, and a value clarification section. During alpha-testing, the PDA was considered clear, balanced, and helpful for decision-making. A total of 76% of the patients (n = 17) and 100% of the healthcare providers (n = 9) recommended it with overall mean scores of 7.4 and 7.8, respectively. The above average usability score was 68.1.

Conclusion
A well-accepted online PDA for chronic phase CML patients to consider TKI dose reduction was developed.
Basement membranes’ role in immune cell recruitment to the central nervous system
Authors: Wright Shaun A. , Lennon Rachel , Greenhalgh Andrew D. 
Published: December 2024

AbstractBasement membranes form part of the extracellular matrix (ECM), which is the structural basis for all tissue. Basement membranes are cell-adherent sheets found between cells and vascular endothelia, including those of the central nervous system (CNS). There is exceptional regional specialisation of these structures, both in tissue organisation and regulation of tissue-specific cellular processes. Due to their location, basement membranes perform a key role in immune cell trafficking and therefore are important in inflammatory processes causing or resulting from CNS disease and injury. This review will describe basement membranes in detail, with special focus on the brain. We will cover how genetic changes drive brain pathology, describe basement membranes’ role in immune cell recruitment and how they respond to various brain diseases. Understanding how basement membranes form the junction between the immune and central nervous systems will be a major advance in understanding brain disease.