bluuebunny/crossref_metadata_2025_split huggingface dataset:
MAPK Pathway–Activating Alteration and Immunotherapy Efficacy in Squamous Cell Lung Carcinoma: Results from the Randomized, Prospective SQUINT Trial
Authors: Cappuzzo Federico , Ricciuti Biagio , Delmonte Angelo , Bonanno Laura , Wang Xiaoyue , Lye Weng Kit , Görtz Andreas , Andrikou Kalliopi , Dal Maso Alessandro , Minuti Gabriele , Papi Maximilian , Alessi Joao Victor , Di Federico Alessandro , Rodig Scott , Awad Mark Magdi , Metro Giulio , Attili Ilaria , Vitiello Fabiana , Pilotto Sara , Gori Stefania , Rossi Giulio , Buglioni Simonetta , Giannarelli Diana , Landi Lorenza 
Published: January 2025

Abstract

Purpose:
The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in patients with lung squamous cell carcinoma (LSCC) is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.

Patients and Methods:
SQUINT was an open-label, randomized, parallel, noncomparative, phase II trial of NI versus N-CT in chemo-naïve adult patients with metastatic or recurrent LSCC. The study was conducted across 15 Italian centers from September 2017 to February 2022 (ClinicalTrials.gov ID: NCT03823625).

Results:
Forty-five patients were included in the NI arm and 46 patients in the N-CT arm. At 12 months, the overall survival (OS) rate was 62% in the NI arm and 50% in the N-CT arm. In total, 74 patients were included in the analyses for individual biomarkers. In patients with mutations or copy-number variations of genes involved in the MAPK pathway, we observed higher response to immunotherapy (43% vs. 15%), longer progression-free survival (P = 0.03), and OS (P &lt; 0.001). A higher density of CD8+PD1+ T cells (P = 0.04) among MAPK-altered tumors versus that in wild-type tumors, together with an increased CD8+PD1+/FOXP3 ratio (P = 0.047), was observed. In the validation cohort of patients not exposed to immunotherapy, OS was similar between MAPK1/3-mutant and wild-type LSCC.

Conclusions:
We showed for the first time that MAPK pathway–activating alterations influence the outcome of LSCC treated with immunotherapy, highlighting the relevance of gene profiling.
Development of a microvessel density gene signature and its application in precision medicine
Authors: Kuronishi Megumi , Ozawa Yoichi , Kimura Takayuki , Li Shuyu Dan , Kato Yu 
Published: January 2025

Abstract
Combination therapy with anti-angiogenic drugs and immune checkpoint inhibitors has shown enhanced clinical activity and has been approved for the treatment of multiple tumor types. Despite extensive research, predictive biomarkers for combination therapy remain poorly understood. Microvessel density (MVD), a surrogate marker for aberrant angiogenesis measured by immunohistochemistry (IHC), has been associated with response to monotherapy with anti-angiogenesis inhibitors. However, obtaining tumor tissue with a sufficient mass for IHC analysis is not always practical, and IHC-based MVD measurements are unavailable in large public datasets. In this study, we developed an MVD gene score based on RNA-sequencing data that reflects MVD by using RNA-seq and MVD measured by IHC in 12 mouse syngeneic tumor models. We explored the relationship between the MVD gene score and a gene signature predicting the response to anti-PD-1 therapy in mouse and human tumor datasets. The MVD gene score correlated with the antitumor activity of lenvatinib, a multiple tyrosine kinase inhibitor mainly targeting VEGFRs and FGFRs, in mouse tumor models and MVD measured by IHC in commercially available human formalin-fixed, paraffin-embedded tumor samples. Tumor types in The Cancer Genome Atlas were classified into four subgroups based on the MVD gene score and T-cell inflamed gene expression profile (TcellinfGEP), which were correlated with clinical indications for treatment. In conclusion, the newly developed MVD gene score enables the estimation of MVD in large public datasets where IHC data are unavailable and has potential clinical utility together with the TcellinfGEP to characterize patients’ tumors for precision medicine.
Pitch Types and Their Influence on Elbow Varus Torque and Spin Rate in Professional Baseball Pitchers
Authors: Hodakowski Alexander J. , Dowling Brittany , Streepy John T. , Olmanson Bjorn , Schmitt Logan , Richard Marc J. , Verma Nikhil N. , Garrigues Grant E. 
Published: January 2025

Background: Elbow injuries are prevalent among professional baseball pitchers as nearly 25% undergo ulnar collateral ligament reconstruction. Pitch type, ball velocity, and spin rate have been previously hypothesized to influence elbow varus torque and subsequent risk of injury, but existing research is inconclusive. Purpose: To examine elbow varus torque, cumulative torque, and loading rate within professional pitchers throwing fastball, curveball, change-up, and slider pitches, as well as to identify potential influences of ball spin on the elbow. Study Design: Descriptive laboratory study. Methods: A total of 31 professional pitchers (mean height, 189.0 ± 5.7 cm; mean weight, 91.7 ± 8.2 kg) were analyzed using motion capture (480 Hz) and TrackMan while throwing a full bullpen of pitches consisting of fastballs, curveballs, change-ups, and sliders. Elbow varus torque, loading rate, cumulative torque, and spin rate were calculated and analyzed using linear regression to establish within-player and mixed-effects models to establish between-player differences in pitch types. Results: Analyzed by individual pitcher, fastballs exhibited significantly higher mean ball velocity and elbow varus torque (40.4 ± 0.6 m/s; 90.1 ± 3.5 N·m) (all P < .001) and peak elbow varus torque compared with curveballs (33.4 ± 0.6 m/s; 87.5 ± 2.7 N·m), change-ups (36.4 ± 0.6 m/s; 81.3 ± 2.4 N·m), and sliders (36.2 ± 0.7 m/s; 87.7 ± 2.7 N·m). Fastball pitches had a significantly greater cumulative elbow varus torque and loading rate compared to all pitch types within a pitcher ( P < .001). Despite the lower peak elbow varus torque and loading rate, the change-up pitch had the second highest cumulative torque. Curveballs were found to have the lowest cumulative elbow varus torque. No significant relationship was found between spin rates and elbow varus torque across pitch types. Conclusion: Fastballs produced the greatest ball velocity, peak elbow varus torque, loading rate, and cumulative torque among the 4 pitch types analyzed in professional pitchers. Although spin rate has become a popular topic in modern pitching strategies and analyses, this study found no significant relationship between spin rate and elbow varus torque across pitch types, suggesting that spin rate alone may not be a reliable predictor of elbow torque or injury. Clinical Relevance: These findings suggest that pitch type, rather than spin rate, should be considered when assessing risk of elbow injuries in professional pitchers.
Clinical outcomes among COVID-19 patients initiated on molnupiravir in Denmark – A national registry study
Authors: Larsen Carsten S , Westergaard Caroline L , Stærke Nina B , Arnet Urs , Liu Gui , Kantsø Line R , Kjellberg Jakob 
Published: January 2025

Background Molnupiravir (MOV) is an orally bioavailable ribonucleoside with antiviral activity against all tested SARS-CoV-2 variants. We describe the demographic, clinical, and treatment characteristics of non-hospitalized Danish patients treated with MOV and their clinical outcomes following MOV initiation. Method Among all adults (>18 years) who received MOV between 16 December 2021 and 30 April 2022 in an outpatient setting in Denmark, we summarized their demographic and clinical characteristics at baseline and post-MOV outcomes using descriptive statistics. Outcomes were emergent hospitalization and all-cause mortality during the 28 days after MOV initiation. We estimated the odds ratios (OR) of outcomes by time from positive test to treatment using logistic regression. Results We identified 3691 MOV-treated patients, of whom 45.8% were male and mean age was 70.1 years. Most patients (76.2%) initiated MOV within 0–2 days after a positive SARS-CoV-2 test and 16.8% within 3–5 days. Over a 28-day period, rates for all-cause, respiratory- or COVID-19-related, and COVID-19-related hospitalization were 4.8%, 2.6% and 1.5%, respectively. All-cause mortality was 1.6%. Initiation of MOV 3–5 days after a positive SARS-CoV-2 test compared to 1–2 days was associated with an increased risk of all-cause (OR 1.85, 95% CI 1.29–2.67) and respiratory or COVID-19-related (OR 1.78, 95% CI 1.07–2.94) hospitalization, and all-cause mortality (OR 2.90, 95% CI 1.64–5.15). Conclusion MOV was primarily prescribed to vaccinated elderly persons with multiple comorbidities. The all-cause hospitalization and mortality rates in this population were low. Early initiation of MOV reduced the risk of hospitalization and death compared with late initiation.
Exploring predementia: Understanding the characteristics of subjective cognitive decline plus from India
Authors: S Monisha , Roy Dwaiti , Menon Anjana J , G Sandhya , Gupta Anant , Basavaraju Nimisha , Singh Sadhana , Sundarakumar Jonas S , Kommaddi Reddy , Issac Thomas Gregor 
Published: January 2025

Background Subjective cognitive decline (SCD) is the early predementia syndrome. that occurs even before the development of objective cognitive decline. SCD plus refers to an additional set of criteria that increases the likelihood of developing mild cognitive impairment and further progressing to Alzheimer's disease (AD). Studying the progression of SCD-plus participants will help in understanding the importance of diagnosing this condition at an early stage and delaying its onset. Objective The present tries to examine neurocognitive changes in individuals who met the criteria of SCD-plus patients. The study also investigated the imaging correlates of these individuals in both cohorts. Methods This study included 94 participants from Srinivaspura Aging, Neuro Senescence, and COGnition (SANSCOG) and Tata Longitudinal Study of Aging (TLSA) cohorts who satisfy the criteria of SCD plus. Mann-Whitney U test was used to compare the SCD plus participants and healthy controls. Regression analysis was performed to find the association between SCD plus and cognition. Results The SCD-plus group performed poorer than the healthy group in episodic memory delayed recall (p = 0.049), name face recognition (p = 0.023), and letter fluency (p = 0.004) tasks. The generalized linear model revealed that the SCD-plus group had lower left cerebellar cortex (p = 0.010) and right inferior occipital cortex (p = 0.016) volumes than the healthy control group. Conclusions The participants in the SCD-plus group performed poorly on memory and language-related tasks, and the volumes of the associated brain regions decreased. This study suggested that the SCD-plus group had characteristics similar to AD group and can help in identifying AD at the earliest.
SGLT2 inhibition, circulating biomarkers, and Alzheimer's disease: A Mendelian randomization study
Authors: Yang Hao , Ning Yuye , Chen Meilin , Jia Jianping 
Published: January 2025

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors is a novel category of medications for diabetes, exhibiting neuroprotective potential. However, evidence regarding whether the use of SGLT2 inhibitors effectively reduces the risk of Alzheimer's disease (AD) remains unclear. Objective Our study employed Mendelian randomization (MR) analysis to investigate potential causal relationships between SGLT2 inhibition, metabolites, and AD. Methods In our research, we used a two-sample MR method to explore the link between SGLT2 inhibitor use and AD, addressing both its late-onset and early-onset forms. Furthermore, we executed a two-step MR analysis to explore how circulating metabolites, primarily endogenous in nature due to SGLT2 inhibition, mediate the relationship between SGLT2 inhibition and AD. The genetic instruments for SGLT2 inhibition were pinpointed through their association with SLC5A2 gene expression and the decreased glycated hemoglobin (HbA1c) levels. Results Genetic analysis indicated that SGLT2 inhibition, which effectively reduces HbA1c by enhancing renal glucose excretion and improving glycemic control, was associated with a lower likelihood of developing AD for every 1 SD decrease in HbA1c (OR = 0.48, [0.36, 0.63], p < 0.001). Our MR analysis revealed that SGLT2 inhibition significantly affected 27 of the 123 metabolites examined, adhering to a Bonferroni correction threshold (p < 4.06 × 10-4). Among these 27 significant metabolites, citrate was also associated with AD, showing a significant association (0.81 [0.79, 0.83], p < 0.001). Conclusions The study provides strong evidence linking SGLT2 inhibition with a lower AD risk, highlighting citrate's potential mediating role for subsequent clinical research.
Modulation of mitochondrial functions contributes to the protection of lamotrigine against Alzheimer's disease
Authors: Fu Xin-Xin , Wei Bin , Huang Zhi-Hang , Duan Rui , Deng Yang , E Yan , Wang Shi-Yao , Chen Shuai-Yu , Zhang Ying-Dong , Jiang Teng 
Published: January 2025

Background Our previous studies have established that the broad-spectrum anti-epileptic drug lamotrigine (LTG) confers protection against cognitive impairments, synapse and nerve cell damage, as well as characteristic neuropathologies in APP/PS1 mice, a mouse model of Alzheimer's disease (AD). However, the precise molecular mechanisms responsible for this protective effect induced by LTG remain largely elusive. Objective In this study, we aimed to investigate the mechanisms underlying the beneficial effects of LTG against AD. Methods Five-month-old APP/PS1 mice were treated with 30 mg/kg of LTG daily for three consecutive months. Subsequently, high-throughput ribosome profiling sequencing was conducted to identify differentially translated genes (DTGs) rescued by LTG in the brains of these mice. To gain further insights into the potential functions and pathways of these LTG-rescued DTGs, gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. RNA expression, protein levels, and translational efficiency were assessed to explore how LTG regulated gene expression processes in AD-related DTGs. Additionally, Aβ42 peptide-stimulated primary neurons were used to uncover the potential mechanisms and signaling pathway by which LTG mitigated oxidative stress under AD context. Results For the first time, we reveal that LTG inactivates mitochondrial complexes in the brains of APP/PS1 mice by suppressing the translational efficiency of mitochondrial complexes-related genes. More importantly, we demonstrate that LTG mitigates mitochondrial-mediated oxidative stress in neurons within the context of AD by activation of SIRT6/PGC-1α pathway. Conclusions These findings provide further insights into the mechanisms underlying the protective effects of LTG against AD.
Effectiveness of digital behaviour change interventions for promoting physical activity in adolescents with overweight and obesity: A systematic review and meta-analysis
Authors: Jahn Kassim Puteri Shanaz , Muhammad Noor Azimah , Abdul Rahman Nur Faraheen , Sidik Sherina Mohd , Essau Cecilia A. , Shah Shamsul Azhar 
Published: January 2025

Background Obesity in adolescence is associated with many adverse health and well-being outcomes. Physical activity plays an important role in the prevention of obesity; however, many adolescents with overweight and obesity are physically inactive. Digital behaviour change interventions (DBCI) are increasingly used to increase physical activity; however, there is insufficient evidence on their use in promoting physical activity among adolescents with overweight and obesity, including its active components. This review aims to evaluate the effectiveness of DBCIs in promoting physical activity among adolescents with overweight and obesity and to identify the behaviour change techniques (BCTs) used in these interventions. Methods Seven electronic databases were searched for randomized controlled trials and quasi-experimental studies evaluating DBCIs for physical activity promotion in adolescents with overweight and obesity aged 10–19 years. The risk of bias in the included studies was assessed using Cochrane's Risk of Bias tool 2 and ROBINS-I tool. Meta-analyses were performed using random effects models. The BCTs used within the DBCIs were coded using the Behaviour Change Technique taxonomy (v1). Results Eighteen studies involving 1769 participants were included. DBCIs showed a large, significant positive effect on total physical activity (SMD = 1.61, 95% CI: [0.56, 2.66], p = 0.003), but non-significant effects on moderate-to-vigorous physical activity (MVPA) (SMD = 0.16, 95% CI: [−0.39, 0.71], p = 0.56) and step count (SMD = −0.10, 95% CI: [−0.52, 0.32], p = 0.65). High heterogeneity was observed in total physical activity and MVPA analyses. The most frequently used BCTs were information about health consequences, goal setting, self-monitoring, feedback on behaviour and social support. Conclusion DBCIs can effectively promote overall physical activity among adolescents with overweight and obesity, although their impact on MVPA and step count remains unclear. Future research should focus on optimizing BCT combinations and improving long-term engagement while addressing intervention effect variability. Systematic review registration PROSPERO CRD42021270008
Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system
Authors: Vashisht Shikha , Parisi Costantino , Winata Cecilia L. 
Published: January 2025

Abstract
Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the identification of a comprehensive set of single-nucleotide polymorphisms (SNPs). Notably, 90–95% of these variants reside in the noncoding genome, complicating the understanding of their underlying mechanisms. Here, we developed a systematic computational pipeline for the identification and analysis of CHD-associated SNPs spanning both coding and noncoding regions of the genome. Initially, we curated a thorough dataset of SNPs from GWAS-catalog and ClinVar database and filtered them based on CHD-related traits. Subsequently, these CHD-SNPs were annotated and categorized into noncoding and coding regions based on their location. To study the functional implications of noncoding CHD-SNPs, we cross-validated them with enhancer-specific histone modification marks from developing human heart across 9 Carnegie stages and identified potential cardiac enhancers. This approach led to the identification of 2,056 CHD-associated putative enhancers (CHD-enhancers), 38.9% of them overlapping with known enhancers catalogued in human enhancer disease database. We identified heart-related transcription factor binding sites within these CHD-enhancers, offering insights into the impact of SNPs on TF binding. Conservation analysis further revealed that many of these CHD-enhancers were highly conserved across vertebrates, suggesting their evolutionary significance. Utilizing heart-specific expression quantitative trait loci data, we further identified a subset of 63 CHD-SNPs with regulatory potential distributed across various cardiac tissues. Concurrently, coding CHD-SNPs were represented as a protein interaction network and its subsequent binding energy analysis focused on a pair of proteins within this network, pinpointed a deleterious coding CHD-SNP, rs770030288, located in C2 domain of MYBPC3 protein. Overall, our findings demonstrate that SNPs have the potential to disrupt gene regulatory systems, either by affecting enhancer sequences or modulating protein-protein interactions, which can lead to abnormal developmental processes contributing to CHD pathogenesis.
Correlation and diagnostic significance of CD4 T cell subsets and NLRP3 inflammasome in ulcerative colitis: the role of the NLRP3/T-bet/GATA3 axis
Authors: Hu Yingnan , Tang Jingyi , Yu Dian , Su Shuo , Fang Jintao , Xia Linying , Xu Wenjun , Zhu Weihan , Song Ninping , Wang Fengyong , Diao Dechang , Zhang Wei 
Published: January 2025

Abstract

Background and aim
Ulcerative colitis (UC) is characterized by complex immunological interactions involving CD4 T cell subsets and the NLRP3 inflammasome, which influence inflammatory responses. This investigation focused on delineating the activation profiles of these components and their correlation with disease severity and activity, assessing their diagnostic implications in UC.

Methods
We conducted immunohistochemistry and ELISA assays to measure markers expression of CD4 T cell subsets and the NLRP3 inflammasome in UC patients versus controls. Findings were validated using correlation analysis, molecular docking and ROC curves.

Results
UC patients displayed increased Th1 (T-bet, TNF-α), Th2 (GATA3, IL-6), and Th17 (RORγt, IL-17, IL-22, IL-23) markers versus controls. Additionally, Th1 and Th2 cytokines (IL-2 and IL-4) were significantly elevated in severe UC, while Treg markers (FOXP3, IL-10, TGF-β1) were elevated only in mild-to-moderate UC. Enhanced NLRP3 inflammasome activation, indicated by elevated NLRP3, Caspase-1, and IL-1β levels. These molecular patterns, confirmed through correlation analysis and molecular docking, underscored strong correlations among NLRP3, T-bet, and GATA3, supporting the proposed NLRP3/T-bet/GATA3 axis. This axis, along with other biomarkers, showed strong associations with UC severity, Mayo score, UCEIS, demonstrated relatively high diagnostic value.

Conclusion
The NLRP3/T-bet/GATA3 axis provides a referable strategy for multi-targeted combined treatment of UC and may serve as potential biomarkers for enhancing diagnostic accuracy and guiding therapy.
Lifetime progression of IgA nephropathy: a retrospective cohort study with extended long-term follow-up
Authors: Rivedal Mariell , Nordbø Ole Petter , Haaskjold Yngvar Lunde , Bjørneklett Rune , Knoop Thomas , Eikrem Øystein 
Published: January 2025

Abstract

Background
IgA nephropathy (IgAN) exhibits an unpredictable trajectory, creating difficulties in prognostication, monitoring, treatment, and research planning. This study provides a comprehensive depiction of the progression of kidney function throughout the disease course, from diagnosis to a span of 36 years post-diagnosis.

Methods
We utilized a cohort of 400 Norwegian IgAN patients, from diagnosis to the occurrence of death, initiation of kidney replacement therapy (KRT), or the latest follow-up. Recorded proteinuria (n = 2676) and creatinine (n = 8738) measurements were retrieved. Patients were divided into subgroups based on their specific estimated glomerular filtration rate (eGFR) slopes.

Results
Median follow-up was 16 years. During this period, 34% of patients either died or initiated KRT. Among patients who reached endpoint, the median duration from diagnosis to the initiation of KRT or death was 8 years. Notably, 34% of the cohort exhibited a stable disease course, characterized by an eGFR decline of less than 20% between two consecutive measurements. Differences in subsequent disease trajectories among two subgroups with similar eGFR levels at diagnosis could not be accounted for by variations in treatment strategies. Among patients with proteinuria < 1 g/24 h in less than half of the measurements, KRT was five times more prevalent compared to those with more than half of the measurements recording proteinuria < 1 g/24 h (p-value = 0.001).

Conclusions
While a significant proportion of IgAN patients reach kidney failure within their lifetimes, outcomes vary widely. Clinical data at diagnosis offer limited insights into long-term risks. Enhanced risk stratification necessitates data collection at multiple time points.