bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artesunate remarkably alleviates interstitial cystitis/bladder pain syndrome in a murine model: Novel molecular signature deciphered by bulk tissue and single‐cell transcriptomic analysis
Authors: Wu Yanyuan , Shi Bowen , He Yedie , Wang Song , Zhou Jiatong , Qi Jun , Ding Jie , Wang Zongping 
Published: December 2024

AbstractInterstitial cystitis/bladder pain syndrome is a chronic pain syndrome of elusive etiology, accompanied by lower urinary tract symptoms. Over the past decades, many studies have been carried out for exploration of more effective therapies against IC/BPS. However, the results have been inconsistent, probably due to the multifactorial nature of IC/BPS. We establish a model of IC/BPS in mice by combining protamine sulfate /lipopolysaccharide and phenylephrine. Typical histological changes and symptoms were observed. We then explored the effectiveness of artesunate (ART), which has been reported to alleviate autoimmune diseases. Phenotypic tests demonstrated a significant reduction in symptoms. Histological staining showed pathological improvement. WGCNA identified three gene modules specifically related to IC/BPS, and six genes were identified as hub genes. CIBERSORT analysis showed that the activated NK cells seem to be decreased in IC modeling group and partially restored in IC + ART group, whereas the resting NK cells showed the opposite trend. Single‐cell transcriptomic analysis elaborated on the changing trends of subgroups of infiltrated immune cells, including T cells, NK cells, and dendritic cells. Our study represents our effort in establishing a reliable and reproducible IC/BPS murine model, and the first study using scRNA‐seq in exploring the immune microenvironment of the IC/BPS murine model, and the possible molecular mechanisms of ART treatment in IC/BPS. Further studies are needed to confirm the effect of ART in IC/BPS patients.
One Concentration Does Not Fit All: It is Time to Personalize the Therapeutic Range of Infliximab in Crohn Disease
Authors: Franck Bénédicte , Tron Camille , Verdier Marie-Clémence , Bellissant Eric , Peaucelle Anne-Sophie , Roblin Xavier , Lemaitre Florian , Bouguen Guillaume 
Published: December 2024

Background:
Therapeutic drug monitoring of infliximab is commonly performed based on trough concentration. However, doses and dosing intervals may be adapted to patient outcomes, and this trough concentration target may correspond to a large range of exposures in terms of the area under the concentration–time curve (AUC). The objectives of this study were to assess the real-life exposure to intravenous infliximab in patients with Crohn disease in remission at year 1 and to assess the evolution of exposure in patients who switched to subcutaneous infliximab.

Methods:
The authors conducted a retrospective observational pharmacokinetic study in patients with Crohn disease who had available infliximab concentrations during intravenous and subcutaneous infliximab maintenance therapy as per the standard of care. Infliximab exposure parameters (AUCs and trough concentrations, C0) were compared for different dosing regimens of intravenous infliximab before (intravenous) and after (subcutaneous) the switch.

Results:
A total of 113 patients had 383 intravenous infliximab concentrations. Dosing intervals ranged from 4 to 12 weeks. The median/range/CV% C0, AUC0-t, and AUC0–8weeks were 5.3 mcg/mL [<LLoQ-49.6]/71.6%, 37,792 mcg.h/mL [4971–116,366]/33.1%, and 41,582 mcg.h/mL [7953–232,048]/43.9%, respectively. Forty-one patients had available paired C0 after both intravenous and subcutaneous administration. A poor correlation was found between preswitch intravenous infliximab C0 and postswitch subcutaneous infliximab C0.

Conclusions:
In this study, the authors suggested that in patients treated with IV IFX, different targets of C0 should be proposed according to treatment schemes and that AUC0-t might be a relevant determinant of clinical remission. Moreover, exposure did not remain stable throughout the switch from IV to SC IFX in any patient. These variations may depend on the intravenous dosing interval before switching.
Perceived Social Support Mediates the Relationship Between Benefit Finding and Depressive Symptoms Among Young and Middle-Aged Stroke Survivors and Their Spouse Caregivers
Authors: Liu Ya-ting , Zhang Si-xun , Xiang Dan-dan , Ge Song , Liu Zhi-wei , Fan Bao-yu , Zhang Zhen-xiang , Li Xin , Mei Yong-xia 
Published: December 2024

Background
Existing literature indicates that benefit finding and social support play protective roles against depressive symptoms. However, there is a lack of understanding regarding the interplay between benefit finding, social support, and depressive symptoms within the dyadic context of stroke survivor-spousal caregiver relationships.

Objective
The objective of this study is to investigate the relationships among benefit finding, social support, and depressive symptoms in young and middle-aged stroke survivors and their spouse caregivers. In addition, the mediating role of social support in the association between benefit finding and depressive symptoms is explored.

Methods
A total of 203 pairs of stroke survivor-spouse caregiver were included in the study. Depressive symptoms, social support, and benefit finding were measured using the Patient Health Questionnaire-9, the Perceived Social Support Scale, the Benefit Finding Scale, and the Caregiver Benefit Finding Scale. The Actor-Partner Interdependence Mediation Model was used to assess direct and indirect effect.

Results
The findings revealed a significant negative association between higher levels of benefit finding and lower depressive symptoms in both stroke survivors (actor effect, −0.126) and spousal caregivers (partner effect, −0.044). Perceived social support emerged as a significant mediator in the relationship between benefit finding and depressive symptoms in spousal caregivers (indirect effect, −0.024). Furthermore, spousal caregivers' perceived social support served as a mediating variable between caregiver benefit finding and depressive symptoms in stroke survivors (indirect effect, −0.023).

Conclusion
The study underscores the interdependence between stroke survivors and spousal caregivers, highlighting the mutual influence they have on each other. Consequently, targeted interventions addressing both members of the dyad, with a focus on enhancing benefit finding and social support, could prove beneficial in ameliorating depressive symptoms in stroke survivor-spousal caregiver.
Efficacy and Safety of Dose Increase From 40 mg/d to 80 mg/d of Lurasidone in Patients With Schizophrenia
Authors: Takeuchi Hiroyoshi , Uchida Hiroyuki 
Published: December 2024

Abstract

Objectives
The primary objective of this study was to evaluate the efficacy and safety of increasing the dose of lurasidone from 40 mg/d to 80 mg/d in patients with schizophrenia.

Methods
This post hoc analysis focused on patients who completed a 6-week double-blind, placebo-controlled trial of lurasidone and transitioned to a subsequent 12-week open-label extension trial. Patients initially assigned to lurasidone (40 mg/d) or placebo during the double-blind trial (DBT-LUR group or DBT-PLA group, respectively) received lurasidone (40 mg/d) during the extension. Clinicians could increase the dose to 80 mg/d based on clinical judgment. The efficacy outcomes included the change in the Positive and Negative Syndrome Scale (PANSS) total score from the start to the end of the lurasidone (80 mg/d) treatment period. Safety outcome was the rate of newly emergent adverse events.

Results
Of 287 patients in the intention-to-treat population, 153 received an increased dose of lurasidone from 40 mg/d to 80 mg/d. Significant reductions in the PANSS total scores were observed in both groups (all P values, ≤0.001). Additionally, 35.9% of the DBT-LUR group and 40.0% of the DBT-PLA group achieved a ≥20% reduction in the PANSS total score. New adverse events emerged in 47.4% of the DBT-LUR group and 48.0% of the DBT-PLA group during the lurasidone (80 mg/d) treatment period.

Conclusions
Increasing the dose of lurasidone from 40 mg/d to 80 mg/d may be effective and well tolerated in patients with schizophrenia. Because of the lack of a control group and blinding, the results should be interpreted with caution.
The impact of lymph node involvement on adjuvant chemotherapy and survival in patients with resected invasive intraductal papillary mucinous neoplasm: a propensity score matching study based on SEER database and external validation
Authors: Gan Wei , Pu Ning , Han Jiande , Yin Hanlin , Chen Qiangda , Zhang Lei , Wu Wenchuan , Xu Huaxiang , Shi Chenye , He Junyi , Jin Yun , Lou Wenhui , Wang Wenquan , Liu Liang 
Published: December 2024

Background:
Limited knowledge and guidelines exist for invasive intraductal papillary mucinous neoplasm (IPMN). This study aims to explore the significance of lymph node involvement on adjuvant chemotherapy (ACT) for invasive IPMN.

Materials and Methods:
Patients diagnosed with invasive IPMN were selected from both the SEER database and our hospital. Kaplan-Meier analysis, Cox proportional hazards model, and propensity score matching (PSM) were employed in this study.

Results:
In the SEER group, multivariate analysis involving 775 patients revealed that several factors including age, tumor differentiation, AJCC-T staging, N staging, and TNM stage significantly influenced overall survival (OS) and cancer-specific survival (CSS). Turning to the Zhongshan Hospital group (ZS group), which had 94 recruited patients, multivariate analysis for OS, CSS, and recurrence-free survival (RFS) showed that AJCC N staging emerged as the most significant risk factor, with HR values of 4.664, 4.955, and 3.175, respectively. In subgroup analysis, ACT provided survival advantages for patients with positive lymph node metastasis (LNM). In a PSM analysis focused on patients with positive LNM, the comparison revealed that ACT emerged as a critical factor influencing both OS and CSS (both p<0.005). Especially, these patients younger than 60 year old, or those with AJCC-T2-N+ staging were found to get apparently benefit from ACT as revealed by our subgroup interaction analysis.

Conclusion:
LNM plays a pivotal role in the management of invasive IPMN patients underwent surgery, and ACT might be a beneficial therapeutic option for individuals concurrent with LNM, particularly among those younger than 60 year old, or with AJCC-T2-N+ staging.
Fast score is associated with patient-reported outcomes in patients with metabolic dysfunction-associated steatotic liver disease
Authors: Hashida Ryuki , Kawaguchi Takumi , Nakano Dan , Tsutsumi Tsubasa , Kawaguchi Machiko , Takahashi Hirokazu , Tajima Hiroshi , Matsuse Hiroo , Golabi Pegah , Gerber Lynn H. , Younossi Zobair M. , Hiraoka Koji 
Published: December 2024

Backgrounds
People with metabolic dysfunction-associated steatotic liver disease (MASLD) frequently report fatigue. This symptom is associated with hepatic inflammation and fibrosis. FibroScan-aspartate aminotransferase (FAST) score is a noninvasive measurement tool that can be used to assess the severity of MASLD. We aimed to investigate the independent factors associated with patient-reported outcomes (PROs) including fatigue, and their FAST scores.

Methods
We enrolled 116 patients with MASLD. PROs were assessed by the Chronic Liver Disease Questionnaire for nonalcoholic fatty liver disease (CLDQ-NAFLD), which consists of six domains including fatigue. Each domain score that was less than 6 was classified into the impairment group. A cutoff value of 0.67 in the FAST score was used to categorize a high or low FAST score. Independent factors associated with impaired PROs and fatigue were analyzed using logistic regression analysis and a graphical model.

Results
For factor total, in the logistic regression analysis, the high FAST score was only identified as a negative independent factor for impaired total CLDQ-NAFLD (odds ratio: 5.9, 95% confidence interval: 1.11–31.20, P = 0.034). The graphical model revealed that FAST score, BMI, and age directly interact with impaired total CLDQ-NAFLD. For fatigue, there was no statistically significant factor in the logistic regression analysis. The graphical model revealed that the FAST score, BMI, estimated glomerular filtration rate, and age directly interact with fatigue.

Conclusion
We found that the FAST score directly interacted with total CLDQ-NAFLD and the domain of fatigue. The FAST score may be a useful tool to assess impaired CLDQ-NAFLD.
The effect of catecholamine versus non-catecholamine vasopressors on renal function and recovery in vasodilatory shock: A systematic review of preclinical and clinical studies
Authors: Vernon-Elliot Jake , Goradia Shruti , Bellomo Rinaldo , Lankadeva Yugeesh R. , Burrell Louise M. , See Emily J. 
Published: December 2024

ABSTRACT

Background: Acute kidney injury (AKI) is a common complication of vasodilatory shock. AKI is associated with an increased risk of death, prolonged hospital stays, and subsequent transition to chronic kidney disease. Catecholamines have historically been used as the first-line vasopressors for vasodilatory shock; however, they may adversely affect renal function and recovery.

Objectives: To compare the effects of catecholamine and non-catecholamine vasopressors on AKI risk and recovery in preclinical and clinical studies of vasodilatory shock.

Methods: Medline, Embase, and Cochrane Central Register of Controlled Trials were systematically searched to identify studies reporting renal outcomes associated with catecholamine (norepinephrine, epinephrine, metaraminol, phenylephrine, dopamine) and non-catecholamine vasopressors (vasopressin, angiotensin II), in preclinical models or adult cohorts of vasodilatory shock. Two independent reviewers screened studies and extracted data using a prespecified form for qualitative synthesis and risk of bias assessment.

Results: Of 3,504 citations, 90 studies were eligible for inclusion: 41 preclinical studies, 17 non-randomized clinical studies, 28 randomized clinical studies, and 4 post-hoc analyses. Risk of bias was generally low in preclinical studies and low to moderate in clinical studies. In preclinical studies, catecholamine vasopressors exacerbated medullary hypoxia and intrarenal inflammation compared to non-catecholamine vasopressors. In clinical studies, catecholamines were associated with higher serum creatinine, lower urine output, and increased requirements for renal replacement therapy (RRT) compared to non-catecholamine vasopressors. In patients on high dose catecholamines, adjunctive angiotensin II was associated with improved RRT liberation.

Conclusions: Preclinical and clinical studies suggest that non-catecholamine vasopressors may confer renal benefits compared to catecholamine vasopressors. These hypothesis-generating observations suggest the need for comparative studies focused on renal outcomes.

Systematic Review Registration: PROSPERO 2024 CRD42024527773
Baicalin alleviates LPS-induced cytotoxicity in acute lung injury through mediating METTL14/SOX6 axis
Authors: Chen Yuexuan , Gu Yuhai , Gao Zhihan 
Published: December 2024

Abstract

Background
Baicalin (C21H18O11) is a flavonoid component extracted from scutellaria baicalensis with biological activity in various types of diseases, including acute lung injury (ALI). The relevant mechanism behind baicalin in ALI needs further investigation.

Methods
ALI model in vitro was established by lipopolysaccharide (LPS) in WI-38 cells (lung fibroblast). Cell growth was determined via MTT assay and EdU assay. Apoptosis was assessed using flow cytometry, caspase 3 assay and TUNEL assay. Oxidative indicators and inflammatory cytokines were detected by commercial kits. Interaction between methyltransferase-like 14 (METTL14) and SRY-Box Transcription Factor 6 (SOX6) was studied using Methylated RNA Immunoprecipitation (MeRIP) and dual-luciferase reporter assay. RT-qPCR and western blot were applied for examining gene levels.

Results
Baicalin enhanced cell growth and reduced apoptosis, oxidative stress, inflammation after ALI was induced by LPS. Downregulation of SOX6 weakened LPS-induced cytotoxicity in WI-38 cells. Baicalin prevented from LPS-induced lung cell injury via reducing SOX6 expression. SOX6 expression was stabilized by METTL14 through its methylation modification. METTL14/SOX6 axis was related to the regulation of baicalin in LPS-treated WI-38 cells.

Conclusion
Therefore, baicalin played an important role to inhibit LPS-induced cytotoxicity in vitro via METTL14-mediated methylation of SOX6.
LNS8801: An enantiomerically pure agonist of the G protein-coupled estrogen receptor suitable for clinical development
Authors: Natale Christopher A. , Mercado Sophia , Zhuang Richard , Aguirre-Portolés Cristina , Olayide Israel , Arnatt Christopher K. , Seykora John T. , Garyantes Tina K. , Luke Wayne , Ridky Todd W. 
Published: December 2024

AbstractEstrogen effects in tissue are mediated in part through activation of the surface estrogen receptor GPER, a broadly expressed G protein-coupled receptor that impacts a wide range of normal and pathologic processes, including metabolism, vascular health, inflammation, and cancer. A commonly used synthetic and specific GPER agonist, named G-1, antagonizes tumors by promoting cellular differentiation and enhancing tumor immunogenicity. G-1 is a racemic compound, and since its discovery, the question of whether both enantiomers display agonist activity or the agonist activity resides primarily in a single enantiomer has never been fully resolved. Herein, we disclose the isolation of the pure enantiomers of G-1 and determine that the desirable activity resides exclusively in 1 enantiomer, named LNS8801, whose configuration we have unambiguously determined by single crystal x-ray structure analysis. Using preclinical models, we show that LNS8801 suppresses cancer in a GPER-dependent manner and that LNS8801 is efficacious when administered orally. Further, we show that GPER is widely, but not ubiquitously, expressed in both normal and malignant human tissues. In addition, an attenuated response to LNS8801 is observed in a common germline coding variant in human GPER. These findings support ongoing human cancer trials with LNS8801 and suggest that the germline GPER genotype may serve as a predictive biomarker of therapeutic response.
LRRK2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis
Authors: Pei Jessica , Oliveira Nathalia L. , Recinto Sherilyn J. , Kazanova Alexandra , Queiroz-Junior Celso M. , Li Ziyi , Couto Katalina , Westfall Susan , King Irah L. , Ribeiro Camila T. , Milnerwood Austen J. , Desjardins Michel , Thanabalasuriar Ajitha , Stratton Jo Ann , Gruenheid Samantha 
Published: December 2024

AbstractParkinson’s Disease (PD) is a progressive, neurodegenerative disorder characterised by motor and non-motor symptoms. Emerging evidence suggests a link between PD and gastrointestinal dysfunction. Constipation is frequently observed years prior to development of motor dysfunction in PD, and people with inflammatory bowel disease (IBD) are more likely to develop PD. Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) account for approximately 1% of all PD cases and are associated with increased risk for IBD. Among them, LRRK2 Gly2019Ser (G2019S), located within the kinase domain, is the most common PD-associated mutation and increases kinase activity. It is unknown how LRRK2 mutation affects susceptibility to intestinal inflammation or pathogenesis of PD. Using single cell RNA sequencing (scRNAseq), we demonstrate that LRRK2 G2019S mutation promotes a dysregulated gene profile, especially within neutrophil, monocyte and γδ T cell populations, followingCitrobacter rodentiuminfection in mice. Transcriptionally, LRRK2 G2019S neutrophils have a greater pro- inflammatory type I and II IFN response compared to those of WT mice. This is accompanied by an increase in neutrophil numbers in the lamina propria in LRRK2 G2019S mice. We also uncover cell-intrinsic functional defects in LRRK2 G2019S neutrophils, including increased chemotaxis, degranulation and neutrophil extracellular traps (NETosis) formation. Increased neutrophil infiltration is associated with an upregulation in Th17 immune responses, which may together contribute to the observed increase in colon pathology during infection. These findings increase our understanding of the role of PD-associated genes in immune cells and their contribution to immune dysregulation. Understanding the early perturbations driven by the LRRK2 G2019S mutation in gastrointestinal pathology may facilitate the development of biomarkers for early diagnosis and intervention in PD.
Quantitative Attributions with Counterfactuals
Authors: Adjavon Diane-Yayra , Eckstein Nils , Bates Alexander S. , Jefferis Gregory S.X.E. , Funke Jan 
Published: December 2024

AbstractWe address the problem of explaining the decision process of deep neural network classifiers on images, which is of particular importance in biomedical datasets where class-relevant differences are not always obvious to a human observer. Our proposed solution, termed quantitative attribution with counterfactuals (QuAC), generates visual explanations that highlight class-relevant differences by attributing the classifier decision to changes of visual features in small parts of an image. To that end, we train a separate network to generate counterfactual images (i.e., to translate images between different classes). We then find the most important differences using novel discriminative attribution methods. Crucially, QuAC allows scoring of the attribution and thus provides a measure to quantify and compare the fidelity of a visual explanation. We demonstrate the suitability and limitations of QuAC on two datasets: (1) a synthetic dataset with known class differences, representing different levels of protein aggregation in cells and (2) an electron microscopy dataset ofD. melanogastersynapses with different neurotransmitters, where QuAC reveals so far unknown visual differences. We further discuss how QuAC can be used to interrogate mispredictions to shed light on unexpected inter-class similarities and intra-class differences.
CycleDesigner: Leveraging RFdiffusion and HighFold to Design Cyclic Peptide Binders for Specific Targets
Authors: Zhang Chenhao , Xu Zhenyu , Lin Kang , Zhang Chengyun , Xu Wen , Duan Hongliang 
Published: December 2024

AbstractCyclic peptides are potentially therapeutic in clinical applications, due to their great stability and activity. Yet, designing and identifying potential cyclic peptide binders targeting specific targets remains a formidable challenge, entailing significant time and resources. In this study, we modified the powerful RFdiffusion model to allow the cyclic peptide structure identification and integrated it with ProteinMPNN and HighFold to design binders for specific targets. This innovative approach, termed cycledesigner, was followed by a series of scoring functions that efficiently screen. With the combination of effective cyclic peptide design and screening, our study aims to further broaden the scope of cyclic peptide binder design.