bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease
Authors: Cliff C. L. , Squires P. E. , Hills C. E. 
Published: July 2024

Abstract
Background
Accompanied by activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, aberrant connexin 43 (Cx43) hemichannel-mediated ATP release is situated upstream of inflammasome assembly and inflammation and contributes to multiple secondary complications of diabetes and associated cardiometabolic comorbidities. Evidence suggests there may be a link between Cx43 hemichannel activity and inflammation in the diabetic kidney. The consequences of blocking tubular Cx43 hemichannel-mediated ATP release in priming/activation of the NLRP3 inflammasome in a model of diabetic kidney disease (DKD) was investigated. We examined downstream markers of inflammation and the proinflammatory and chemoattractant role of the tubular secretome on macrophage recruitment and activation.

Methods
Analysis of human transcriptomic data from the Nephroseq repository correlated gene expression to renal function in DKD. Primary human renal proximal tubule epithelial cells (RPTECs) and monocyte-derived macrophages (MDMs) were cultured in high glucose and inflammatory cytokines as a model of DKD to assess Cx43 hemichannel activity, NLRP3 inflammasome activation and epithelial-to-macrophage paracrine-mediated crosstalk. Tonabersat assessed a role for Cx43 hemichannels.

Results
Transcriptomic analysis from renal biopsies of patients with DKD showed that increased Cx43 and NLRP3 expression correlated with declining glomerular filtration rate (GFR) and increased proteinuria. In vitro, Tonabersat blocked glucose/cytokine-dependant increases in Cx43 hemichannel-mediated ATP release and reduced expression of inflammatory markers and NLRP3 inflammasome activation in RPTECs. We observed a reciprocal relationship in which NLRP3 activity exacerbated increased Cx43 expression and hemichannel-mediated ATP release, events driven by nuclear factor kappa-B (NFκB)-mediated priming and Cx43 hemichannel opening, changes blocked by Tonabersat. Conditioned media (CM) from RPTECs treated with high glucose/cytokines increased expression of inflammatory markers in MDMs, an effect reduced when macrophages were pre-treated with Tonabersat. Co-culture using conditioned media from Tonabersat-treated RPTECs dampened macrophage inflammatory marker expression and reduced macrophage migration.

Conclusion
Using a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes.
The intratumoral microbiota biomarkers for predicting survival and efficacy of immunotherapy in patients with ovarian serous cystadenocarcinoma
Authors: Qin Hao , Liu Jie , Qu Yi , Li Yang-Yang , Xu Ya-Lan , Yan Yi-Fang 
Published: July 2024

Abstract
Background
Ovarian serous cystadenocarcinoma, accounting for about 90% of ovarian cancers, is frequently diagnosed at advanced stages, leading to suboptimal treatment outcomes. Given the malignant nature of the disease, effective biomarkers for accurate prediction and personalized treatment remain an urgent clinical need.

Methods
In this study, we analyzed the microbial contents of 453 ovarian serous cystadenocarcinoma and 68 adjacent non-cancerous samples. A univariate Cox regression model was used to identify microorganisms significantly associated with survival and a prognostic risk score model constructed using LASSO Cox regression analysis. Patients were subsequently categorized into high-risk and low-risk groups based on their risk scores.

Results
Survival analysis revealed that patients in the low-risk group had a higher overall survival rate. A nomogram was constructed for easy visualization of the prognostic model. Analysis of immune cell infiltration and immune checkpoint gene expression in both groups showed that both parameters were positively correlated with the risk level, indicating an increased immune response in higher risk groups.

Conclusion
Our findings suggest that microbial profiles in ovarian serous cystadenocarcinoma may serve as viable clinical prognostic indicators. This study provides novel insights into the potential impact of intratumoral microbial communities on disease prognosis and opens avenues for future therapeutic interventions targeting these microorganisms.
Methionine sulfoxide reductase B2 protects against cardiac complications in diabetes mellitus
Authors: Lee Seung Hee , Cho Suyeon , Lee Jong Youl , Kim Ji Yeon , Kim Suji , Jeong Myoungho , Hong Jung Yeon , Kim Geun-Young , Lee Seung Woo , Kim Eunmi , Kim Jihwa , Kim Jee Woong , Hwa John , Kim Won-Ho 
Published: July 2024

AbstractDiabetes mellitus (DM) is a progressive, chronic metabolic disorder characterized by high oxidative stress, which can lead to cardiac damage. Methionine sulfoxylation (MetO) of proteins by excessive reactive oxygen species (ROS) can impair the basic functionality of essential cellular proteins, contributing to heart failure. Methionine sulfoxide reductase B2 (MsrB2) can reverse oxidation induced MetO in mitochondrial proteins, so we investigated its role in diabetic cardiomyopathy. We observed that DM-induced heart damage in diabetic mice model is characterized by increased ROS, increased protein MetO with mitochondria structural pathology, and cardiac fibrosis. In addition, MsrB2 was significantly increased in mouse DM cardiomyocytes, supporting the induction of a protective process. Further, MsrB2 directly induces Parkin and LC3 activation (mitophagy markers) in cardiomyocytes. In MsrB2, knockout mice displayed abnormal electrophysiological function, as determined by ECG analysis. Histological analysis confirmed increased cardiac fibrosis and disrupted cardiac tissue in MsrB2 knockout DM mice. We then corroborated our findings in human DM heart samples. Our study demonstrates that increased MsrB2 expression in the heart protects against diabetic cardiomyopathy.
Graphic Abstract
A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease
Authors: Galasko Douglas , Farlow Martin R. , Lucey Brendan P. , Honig Lawrence S. , Elbert Donald , Bateman Randall , Momper Jeremiah , Thomas Ronald G. , Rissman Robert A. , Pa Judy , Aslanyan Vahan , Balasubramanian Archana , West Tim , Maccecchini Maria , Feldman Howard H. 
Published: July 2024

Abstract
Background
Amyloid beta protein (Aβ) is a treatment target in Alzheimer’s Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.

Methods
Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21–23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.

Results
From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups.

Conclusions
Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.

Trial registration
NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).
Cost-effectiveness of immune checkpoint inhibitors as a first-line therapy for advanced hepatocellular carcinoma: a systematic review
Authors: Gong Hongyu , Ong Siew Chin , Li Fan , Shen Yan , Weng Zhiying , Zhao Keying , Jiang Zhengyou , Wang Meng 
Published: July 2024

AbstractSince 2017, immune checkpoint inhibitors (ICIs) have been available for the treatment of advanced hepatocellular carcinoma (HCC) or unresectable HCC, but their adoption into national medical insurance programs is still limited. Cost-effectiveness evidence can help to inform treatment decisions. This systematic review aimed to provide a critical summary of economic evaluations of ICIs as a treatment for advanced HCC and identify key drivers (PROSPERO 2023: CRD42023417391). The databases used included Scopus, Web of Science, PubMed, Embase, and Cochrane Central. Economic evaluations of ICIs for the treatment of advanced HCC were included. Studies were screened by two people. Of the 898 records identified, 17 articles were included. The current evidence showed that ICIs, including atezolizumab plus bevacizumab, sintilimab plus bevacizumab/bevacizumab biosimilar, nivolumab, camrelizumab plus rivoceranib, pembrolizumab plus lenvatinib, tislelizumab, durvalumab, and cabozantinib plus atezolizumab, are probably not cost-effective in comparison with tyrosine kinase inhibitors or other ICIs. The most influential parameters were price of anticancer drugs, hazard ratios for progression-free survival and overall survival, and utility for health statest. Our review demonstrated that ICIs were not a cost-effective intervention in advanced HCC. Although ICIs can significantly enhance the survival of patients with advanced HCC, decision-makers should consider the findings of economic evaluations and affordability before adoption of new therapies.
Discrepancies between self-reported medication in adherence and indirect measurement adherence among patients undergoing antiretroviral therapy: a systematic review
Authors: Liao Rujun , Tang Zihuan , Zhang Na , Hu Lin , Chang Zongqi , Ren Jiayi , Bai Xuefei , Shi Jinhong , Fan Sisi , Pei Rong , Du Liang , Zhang Tao 
Published: July 2024

Abstract
Background
Given the critical importance of medication adherence in HIV/AIDS treatment, this study aims to compare medication adherence measured by self-report (SR) and indirect measurement among antiretroviral therapy (ART) patients, exploring the differences of adherence results measured by different tools.

Methods
We systematically searched PubMed, Embase, and the Cochrane Library to identify all relevant literature published up to November 22, 2023, without language restrictions, reporting adherence to ART measured by both SR and indirect measurement methods, while also analyzing individual and group adherence separately. Discrepancies between SR and indirect measurement results were assessed using the Mann–Whitney U test or Wilcoxon signed-rank test, with correlations evaluated using the Pearson correlation coefficient. Following one-to-one comparisons, meta-epidemiological one-step analysis was conducted, and network meta-analysis techniques were applied to compare results obtained through specific adherence assessment tools reported in the identified articles.

Results
The analysis encompassed 65 original studies involving 13,667 HIV/AIDS patients, leading to 112 one-to-one comparisons between SR and indirect measurement tools. Statistically significant differences were observed between SR and indirect measurement tools regarding both individual and group adherence (P < 0.05), with Pearson correlation coefficients of 0.843 for individual adherence and 0.684 for group adherence. During meta-epidemiological one-step analysis, SR-measured adherence was determined to be 3.94% (95% CI: -4.48–13.44%) higher for individual adherence and 16.14% (95% CI: 0.81–18.84%) higher for group adherence compared to indirectly measured results. Subgroup analysis indicated that factors such as the year of reporting and geographic region appeared to influence the discrepancies between SR and indirect measurements. Furthermore, network meta-analysis revealed that for both individual and group adherence, the results obtained from most SR and indirect measurement tools were higher than those from electronic monitoring devices, with some demonstrating statistical significance (P < 0.05).

Conclusions
The findings underscored the complexity of accurately measuring medication adherence among ART patients. Significant variability was observed across studies, with self-report methods showing a significant tendency towards overestimation. Year of reporting, geographic region, and adherence measurement tools appeared to influence the differences between SR and indirect measurements. Future research should focus on developing and validating integrated adherence measurements that can combine SR data with indirect measures to achieve a more comprehensive understanding of adherence behaviors.

Graphical Abstract
Prognostic significance of troponin in patients with malignancy (NIHR Health Informatics Collaborative TROP-MALIGNANCY study)
Authors: Samuel Nathan A. , Roddick Alistair , Glampson Ben , Mulla Abdulrahim , Davies Jim , Papadimitriou Dimitri , Panoulas Vasileios , Mayer Erik , Woods Kerrie , Shah Anoop D. , Gautama Sanjay , Elliott Paul , Hemmingway Harry , Williams Bryan , Asselbergs Folkert W. , Melikian Narbeh , Kharbanda Rajesh , Shah Ajay M. , Perera Divaka , Patel Riyaz S. , Channon Keith M. , Mayet Jamil , Shah Anoop S. V. , Kaura Amit 
Published: July 2024

Abstract
Background
Cardiac troponin is commonly raised in patients presenting with malignancy. The prognostic significance of raised troponin in these patients is unclear.

Objectives
We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients with a routinely measured troponin and a primary diagnosis of malignancy.

Methods
We used the National Institute for Health Research (NIHR) Health Informatics Collaborative data of 5571 patients, who had troponin levels measured at 5 UK cardiac centres between 2010 and 2017 and had a primary diagnosis of malignancy. Patients were classified into solid tumour or haematological malignancy subgroups. Peak troponin levels were standardised as a multiple of each laboratory’s 99th -percentile upper limit of normal (xULN).

Results
4649 patients were diagnosed with solid tumours and 922 patients with haematological malignancies. Raised troponin was an independent predictor of mortality in all patients (Troponin > 10 vs. <1 adjusted HR 2.01, 95% CI 1.73 to 2.34), in solid tumours (HR 1.84, 95% CI 1.55 to 2.19), and in haematological malignancy (HR 2.72, 95% CI 1.99 to 3.72). There was a significant trend in increasing mortality risk across troponin categories in all three subgroups (p < 0.001).

Conclusion
Raised troponin level is associated with increased mortality in patients with a primary diagnosis of malignancy regardless of cancer subtype. Mortality risk is stable for patients with a troponin level below the ULN but increases as troponin level increases above the ULN in the absence of acute coronary syndrome.
Comparison of outcomes in kidney transplantations involving blood-related and non-blood-related living donors: a multicenter retrospective study by the Michinoku renal transplant network
Authors: Matsuura Tomohiko , Toyoshima Moe , Saitoh Mitsuru , Nishida Hayato , Hatakeyama Shingo , Maita Shinya , Murakami Reiichi , Sugimura Jun , Abe Takaya , Tomita Hirofumi , Saitoh Hisao , Tsuchiya Norihiko , Ohyama Chikara , Habuchi Tomonori , Obara Wataru 
Published: July 2024

Abstract
Background
This study aimed to compare the outcomes of living donor kidney transplantation with blood- and non-blood-related donors across multiple facilities. Previous reports comparing these outcomes have been single-center studies. As the donors were the recipients’ spouses in all cases with non-blood-related donors, we independently compared the outcomes of wife-to-husband (WTH) and husband-to-wife (HTW) transplantations. No previous multicenter studies have compared transplant outcomes between spouses in this manner.

Methods
This retrospective study used a shared database including 643 cases from 6 facilities that primarily used tacrolimus as a calcineurin inhibitor. We used propensity score matching to compare the outcomes of transplantations with blood- and non-blood-related donors and those of WTH and HTW transplantations.

Results
Of the 643 cases examined, 381 and 262 had blood- and non-blood-related donors, respectively. All non-blood-related donor cases had spouses as donors. After propensity score matching, 84 cases each were selected from the blood- and non-blood-related donor groups for comparison, with no significant intergroup difference in the time to graft loss. Among the 262 interspousal transplantations, 91 were HTW transplantations and 171 were WTH transplantations. Following propensity score matching, 58 cases each were selected from the WTH and HTW groups for comparison, with no significant intergroup difference in the time to graft loss.

Conclusions
In this large multicenter retrospective study, no significant differences were observed in the outcomes of transplantations with blood- and non-blood-related donors. Furthermore, no significant differences were observed in the outcomes of WTH and HTW cases. Many centers that use tacrolimus-based four-drug immunosuppressive therapy may have similar trends as those observed in this study, making our findings significant for planning transplantation involving kidneys donated from patients’ spouses.
Efficacy and safety of ruxolitinib in patients with lower risk myelofibrosis: A single-arm, exploratory and prospective study.
Authors: Hu Shiwei , Yang Xiudi , Tong Hongyan , Jin Jie , Huang Jian 
Published: July 2024

6573 Background: The COMFORT studies assessed the efficacy and safety of ruxolitinib in patients with intermediate-2 and high risk myelofibrosis (MF), and JUMP study has broadened the investigation including patients with intermediate-1 MF in the classification of DIPSS. However, there have been limited prospective studies evaluating the efficacy and safety of patients with low risk MF in the classification of more comprehensive scoring system. Here we present a single-arm, exploratory and prospective study to assess the efficacy and safety of ruxolitinib in patients with lower risk MF in China. Methods: Lower risk was defined as MIPSS-70 ≤ 3, MIPSS+V2.0 ≤ 3, DIPSS-Plus ≤ 1, DIPSS ≤ 2 or MYSEC-PM < 14 according to the expert guidelines. Patients aged ≥ 18 with overt primary myelofibrosis (overt-PMF), prefibrotic primary myelofibrosis (pre-PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF), classified as lower risk were enrolled. The primary endpoint was the proportion of patients with a spleen length reduction of ≥ 50% from baseline at week 48. Secondary endpoints included the best spleen response, the proportion of patients with a ≥ 50% reduction in Total Symptom Score (TSS50) and safety. Results: A total of 40 patients were enrolled in the lower risk group, including 7 pre-PMF, 17 overt-PMF, 8 PPV-MF, and 8 PET-MF patients. The median age was 62.0 years. 32 (80%) were JAK2V617F positive. 16 patients had next generation sequencing (NGS), the most frequent non-driver mutation was in TET2 (43.8%), followed by BCOR (12.5%). By week 48, 26 (65.0%) patients achieved a ≥ 50% decrease in palpable spleen length. 32 (80.0%) patients achieved a ≥ 50% reduction from baseline at any time. The median time to a spleen response was 4.3 weeks. The TSS50 rates at week 48 was 25%. No patients required red blood cell transfusion at baseline. And only 1 patient had a baseline hemoglobin (HB) <100 g/L, which remained stable during the follow-up process. The most common grade ≥ 3 hematological treatment emergent adverse events (TEAEs) were anemia (10.0%) and thrombocytopenia (2.5%). 6 (15.0%) and 15 (37.5%) patients experienced grade 1 or 2 anemia and thrombocytopenia, respectively. The mostly common non-hematological TEAEs was infection (12.5), including upper respiratory tract infection (7.5%), urinary infection (2.5%), fever (2.5%), predominantly of grade 1 or 2. Of note, 1 patient developed staphylococcal sepsis and 1 patient experienced acute renal failure. No one discontinued ruxolitinib treatment due to TEAEs. Conclusions: Ruxolitinib is an effective treatment for patients with intermediate-1 and low risk MF, resulting in improved spleen and symptom responses, along with fewer hematological and non-hematological TEAEs. This trial was registered as ChiCTR2200064250 at ClinicalTrials.gov . Clinical trial information: ChiCTR2200064250.