bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pancreatic β-cells package double C2-like domain beta protein into extracellular vesicles via tandem C2 domains
Authors: Esparza Diana , Lima Carinna , Abuelreich Sarah , Ghaeli Ima , Hwang Jinhee , Oh Eunjin , Lenz Ayelet , Gu Angel , Jiang Nan , Kandeel Fouad , Thurmond Debbie C. , Jovanovic-Talisman Tijana 
Published: October 2024

IntroductionDouble C2-like domain beta (DOC2B) is a vesicle priming protein critical for glucose-stimulated insulin secretion in β-cells. Individuals with type 1 diabetes (T1D) have lower levels of DOC2B in their residual functional β-cell mass and platelets, a phenotype also observed in a mouse model of T1D. Thus, DOC2B levels could provide important information on β-cell dys(function).ObjectiveOur objective was to evaluate the DOC2B secretome of β-cells. In addition to soluble extracellular protein, we assessed DOC2B localized within membrane-delimited nanoparticles – extracellular vesicles (EVs). Moreover, in rat clonal β-cells, we probed domains required for DOC2B sorting into EVs.MethodUsing Single Extracellular VEsicle Nanoscopy, we quantified EVs derived from clonal β-cells (human EndoC-βH1, rat INS-1 832/13, and mouse MIN6); two other cell types known to regulate glucose homeostasis and functionally utilize DOC2B (skeletal muscle rat myotube L6-GLUT4myc and human neuronal-like SH-SY5Y cells); and human islets sourced from individuals with no diabetes (ND). EVs derived from ND human plasma, ND human islets, and cell lines were isolated with either size exclusion chromatography or differential centrifugation. Isolated EVs were comprehensively characterized using dotblots, transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting.ResultsDOC2B was present within EVs derived from ND human plasma, ND human islets, and INS-1 832/13 β-cells. Compared to neuronal-like SH-SY5Y cells and L6-GLUT4myc myotubes, clonal β-cells (EndoC-βH1, INS-1 832/13, and MIN6) produced significantly more EVs. DOC2B levels in EVs (over whole cell lysates) were higher in INS-1 832/13 β-cells compared to L6-GLUT4myc myotubes; SH-SY5Y neuronal-like cells did not release appreciable DOC2B. Mechanistically, we show that DOC2B was localized to the EV lumen; the tandem C2 domains were sufficient to confer sorting to INS-1 832/13 β-cell EVs.DiscussionClonal β-cells and ND human islets produce abundant EVs. In cell culture, appreciable DOC2B can be packaged into EVs, and a small fraction is excreted as a soluble protein. While DOC2B-laden EVs and soluble protein are present in ND plasma, further studies will be necessary to determine if DOC2B originating from β-cells significantly contributes to the plasma secretome.
Identification and validation of efferocytosis-related biomarkers for the diagnosis of metabolic dysfunction-associated steatohepatitis based on bioinformatics analysis and machine learning
Authors: Cao Chenghui , Liu Wenwu , Guo Xin , Weng Shuwei , Chen Yang , Luo Yonghong , Wang Shuai , Zhu Botao , Liu Yuxuan , Peng Daoquan 
Published: October 2024

BackgroundMetabolic dysfunction-associated steatohepatitis (MASH) is a highly prevalent liver disease globally, with a significant risk of progressing to cirrhosis and even liver cancer. Efferocytosis, a process implicated in a broad spectrum of chronic inflammatory disorders, has been reported to be associated with the pathogenesis of MASH; however, its precise role remains obscure. Thus, we aimed to identify and validate efferocytosis linked signatures for detection of MASH.MethodsWe retrieved gene expression patterns of MASH from the GEO database and then focused on assessing the differential expression of efferocytosis-related genes (EFRGs) between MASH and control groups. This analysis was followed by a series of in-depth investigations, including protein–protein interaction (PPI), correlation analysis, and functional enrichment analysis, to uncover the molecular interactions and pathways at play. To screen for biomarkers for diagnosis, we applied machine learning algorithm to identify hub genes and constructed a clinical predictive model. Additionally, we conducted immune infiltration and single-cell transcriptome analyses in both MASH and control samples, providing insights into the immune cell landscape and cellular heterogeneity in these conditions.ResultsThis research pinpointed 39 genes exhibiting a robust correlation with efferocytosis in MASH. Among these, five potential diagnostic biomarkers—TREM2, TIMD4, STAB1, C1QC, and DYNLT1—were screened using two distinct machine learning models. Subsequent external validation and animal experimentation validated the upregulation of TREM2 and downregulation of TIMD4 in MASH samples. Notably, both TREM2 and TIMD4 demonstrated area under the curve (AUC) values exceeding 0.9, underscoring their significant potential in facilitating the diagnosis of MASH.ConclusionOur study comprehensively elucidated the relationship between MASH and efferocytosis, constructing a favorable diagnostic model. Furthermore, we identified potential therapeutic targets for MASH treatment and offered novel insights into unraveling the underlying mechanisms of this disease.
Treatment and molecular analysis of bullous pemphigoid with tofacitinib: a case report and review of current literature
Authors: Li Xiang , Zhang Lian , Gu Hongzhi , He Wanzhen , Zhai Zhifang , Zhang Mingwang 
Published: October 2024

BackgroundBullous pemphigoid (BP) is a rare, life-threatening autoimmune blistering disease with pruritus and tension blisters/bullous as the main clinical manifestations. Glucocorticosteroids are the main therapeutic agents for it, but their efficacy is poor in some patients. Tofacitinib, a small molecule agent that inhibits JAK1/3, has shown incredible efficacy in a wide range of autoimmune diseases and maybe a new valuable treatment option for refractory BP.ObjectiveTo report a case of refractory BP successfully treated with tofacitinib, then explore the underlying mechanism behind the treatment, and finally review similarities to other cases reported in the literature.MethodsCase report and literature review of published cases of successful BP treatment with JAK inhibitors. The case report describes a 73-year-old male with refractory BP that was successfully managed with the combination therapy of tofacitinib and low-dose glucocorticoids for 28 weeks. Immunohistochemistry and RNA sequencing were performed to analyze the underlying mechanism of tofacitinib therapy. A systematic literature search was conducted to identify other cases of treatment with JAK inhibitors.ResultsThroughout the 28-week treatment period, the patient experienced clinical, autoantibody and histologic resolution. Immunohistochemical analysis showed tofacitinib significantly decreased the pSTAT3 and pSTAT6 levels in the skin lesions of this patient. RNA sequencing and immunohistochemical testing of lesion samples from other BP patients identified activation of the JAK-STAT signaling pathway. Literature review revealed 17 previously reported cases of BP treated with four kinds of JAK inhibitors successfully, including tofacitinib (10), baricitinib (1), upadacitinib (3) and abrocitinib (3).ConclusionsOur findings support the potential of tofacitinib as a safe and effective treatment option for BP. Larger studies are underway to better understand this efficacy and safety.
Bacterial profiles and their antibiotic susceptibility patterns in neonatal sepsis at the University of Gondar Comprehensive Specialized Hospital, Ethiopia
Authors: Deress Teshiwal , Belay Gizeaddis , Ayenew Getahun , Ferede Worku , Worku Minichile , Feleke Tigist , Mulu Meseret , Belay Solomon , Getie Michael 
Published: October 2024

BackgroundNeonatal sepsis is a major cause of morbidity and mortality worldwide. Understanding the bacterial profiles and antibiotic susceptibility patterns causing neonatal sepsis is crucial for guiding appropriate treatment, improving patient outcomes, and combating the emergence of antibiotic resistance. Despite its importance, data regarding neonatal sepsis in the study area is limited. Therefore, this study aimed to characterize the bacterial pathogens and identify associated factors among neonates with suspected sepsis at the University of Gondar Comprehensive Specialized Hospital, Ethiopia.MethodsA cross-sectional study was conducted by reviewing laboratory records of neonates admitted for suspected sepsis from January 2019 to December 2021. Data were checked for completeness and encoded in a spreadsheet program. Then, data were exported to STATA version 17 for analysis. Descriptive statistics such as frequency and percentage were computed. The association between neonatal sepsis and potential risk factors was assessed using Pearson’s chi-square test. A p-value of &lt; 0.05, was considered statistically significant.ResultsA total of 1,236 neonates were included. Of these, 96.2% (1,190/1,236) had a fever before admission. The prevalence of culture-confirmed sepsis was 25.4% (314/1,236). Bacterial pathogens accounted for 23% (284/1,236) of these isolates, with Gram-negative bacteria being more prevalent at 75.3% (214/284) than Gram-positive bacteria at 24.7% (70/284). The most frequently isolated bacterial pathogens were K. pneumoniae 38.7% (110/284) and S. aureus 13% (37/284). The isolates demonstrated a high resistance level to commonly used antibiotics, with 61.6% exhibiting multidrug resistance. K. pneumoniae showed the highest rate of multidrug resistance (90.9%). Neonatal sepsis was associated with several factors, including fever before and after admission, hypothermia, increased respiration, suspected pneumonia, and suspected meningitis.ConclusionThis study identified a high prevalence of culture-confirmed sepsis in neonates at UoGCSH, with Gram-negative bacteria, especially K. pneumoniae, dominating the isolated pathogens. The isolated bacteria exhibited alarming resistance to commonly used antibiotics, with a high proportion demonstrating multidrug resistance. Implementing effective antibiotic stewardship programs is crucial to optimize antibiotic use, reduce unnecessary prescriptions, and curb the spread of resistant strains.
Iron load in the normal aging brain measured with QSM and R2* at 7T: findings of the SENIOR cohort
Authors: Guevara Miguel , Roche Stéphane , Brochard Vincent , Cam Davy , Badagbon Jacques , Leprince Yann , Bottlaender Michel , Cointepas Yann , Mangin Jean-François , de Rochefort Ludovic , Vignaud Alexandre 
Published: October 2024

BackgroundIron accumulates in the brain during aging and is the focus of intensive research as an abnormal load, particularly in Deep Gray Matter (DGM), is related to neurodegeneration. Magnetic Resonance Imaging (MRI) metrics such as Quantitative Susceptibility Mapping (QSM) and apparent transverse relaxation rate R2* can be used to follow up iron in vivo. While the influence of age and sex on iron levels has already been reported, a careful consideration of neuronal risk factors, as well as for an enhanced sensitivity, is needed to define the normal evolution.MethodsQSM and R2* at ultra-high field MRI are used to study iron in DGM using a carefully-characterized cohort of the healthy aging brain (SENIOR). Seventy-seven cognitively healthy elders (from 54 to 78 y/o) with clinical, biology, genetics, and cardiovascular risk factors careful evaluation. Differences linked with age, sex, cardiovascular risk factors and weight are studied.ResultsAge and sex have an influence on the brain iron deposition measured by QSM and R2* in a context of normal aging, without appearance of a pathological neurodegenerative process. Iron deposition shows higher values in the caudate and the putamen in older participants. Female participants present a higher level of iron in the amygdala, and males in the thalamus. Female participants also present differences in the accumbens, caudate and hippocampus when evaluating the joint age and sex effect. Participants with higher cardiovascular risk factors showed higher values of the iron, even without any impairment in their cognitive capability. An overweight is related with a higher iron load in the putamen for QSM and R2* in female participants. We controlled that these modifications of iron deposition are not related to a specific profile in the genotype of ApoE loci.ConclusionsEstablishing baseline values of QSM and R2* as iron probes in the context of aging is essential to determine differences in the process of neurodegeneration. Age and sex of participants are important factors that affect brain iron normal values. On the other hand, the presence of cardiovascular risk factors, which can be associated with age related diseases, can also potentially be linked with the iron deposition in the brain.
The role of micronutrients and serum metabolites in intervertebral disk degeneration: insights from a Mendelian randomization study and mediation analysis
Authors: Jiang Nizhou , Wang Quanxiang , Jiang Jian , Li Lei 
Published: October 2024

BackgroundIntervertebral disk degeneration (IVDD) is a complex degenerative skeletal condition, potentially influenced by micronutrients and serum metabolites in its etiology. However, the exact causal relationship between these factors and IVDD remains ambiguous.MethodsThe research employed a Two-Sample Mendelian Randomization (2SMR) analysis to thoroughly evaluate the causal relationship between 15 micronutrients (consisting of 7 minerals and 8 vitamins) as exposure variables, 1,091 blood metabolites, and 309 metabolite ratios as intermediary factors, and IVDD as the outcome. Additionally, reverse MR analysis and mediation analysis were carried out to validate the reliability of the results and explore the underlying mechanism by which micronutrients influence the risk of IVDD by regulating metabolites.ResultsAmong the micronutrients examined, vitamin B12 exhibited a noteworthy negative correlation with the incidence of IVDD (OR: 0.752, 95% [CI]: 0.573–0.987, p = 0.040), indicating a potential reduction in IVDD risk with increased vitamin B12 consumption. Of the 1,091 blood metabolites and 309 metabolite ratios analyzed, 52 metabolites displayed significant associations with IVDD, primarily linked to amino acid, fatty acid, nucleotide, and sphingolipid metabolic pathways. Mediation analysis identified 4-acetaminophen sulfate as a potential mediator in the protective effect of vitamin B12 against IVDD.ConclusionThis study has shown that vitamin B12 may reduce the risk of IVDD and has identified 52 serum metabolites that are associated with IVDD. Furthermore, it proposes that 4-acetaminophen sulfate could serve as a potential mechanism by which vitamin B12 exerts its inhibitory effects on IVDD.
Joint association of serum sodium and frailty with mild cognitive impairment among hospitalized older adults with chronic diseases: a cross-sectional study
Authors: Hui Zhaozhao , Wang Lina , Deng Jing , Liu Feng , Cheng Liping , Li Yajing , Tian Yuxin , Ma Le , Liu Xiaohong 
Published: October 2024

BackgroundTo examine the associations of serum sodium and frailty with the risk of mild cognitive impairment (MCI) among hospitalized older adults with chronic diseases.MethodsA cross-sectional study was conducted in 403 hospitalized older adults with chronic diseases. Serum sodium concentration was assessed by the ion-selective electrode method, frailty status was evaluated by the FRAIL scale, and MCI was determined by the Montreal Cognitive Assessment (MoCA). Multiple logistic regression models were used to estimate the associations of serum sodium and frailty with MCI.ResultsParticipants with the lowest tertile of serum sodium had a higher risk of MCI than those in the middle tertile group (OR = 1.75, 95% CI: 1.01–3.04). Below 143 mmol/L, the risk of MCI was 1.38 (95% CI: 1.03–1.84) for per 1 SD decrease in serum sodium. Compared with the robust group, frailty was significantly associated with an increased risk of MCI (OR = 3.94, 95% CI: 1.92–8.10). Moreover, in comparison with participants with the middle tertile of serum sodium and who were robust/prefrail, those with frailty and either the lowest (OR = 5.53, 95% CI: 2.08–14.67) or the highest tertile of serum sodium (OR = 3.48, 95% CI: 1.20–10.05) had higher risks of MCI.ConclusionBoth lower and higher serum sodium impose a significantly higher risk for MCI in older adults with frailty. This could inform the design of clinical trials and the development of guidelines and recommendations for correcting serum sodium and frailty in hospitalized older adults with chronic diseases.
The potential role of next-generation sequencing in identifying MET amplification and disclosing resistance mechanisms in NSCLC patients with osimertinib resistance
Authors: Xiao Xiao , Xu Ren , Lu Jun , Xin Beibei , Wang Chenyang , Zhu Kexin , Zhang Hao , Chen Xinyu 
Published: October 2024

PurposesOsimertinib, one of the third-generation EGFR-tyrosine kinase inhibitors (TKIs) designed to target EGFR T790M mutation, significantly improves the prognosis of lung cancer. However, drug resistance still happens and MET amplification is responsible for one of the main causes. Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection, but fundamentally limited by observer subjectivity. Herein, we assessed the value of next-generation sequencing (NGS) method in MET amplification detection in non-small cell lung cancer (NSCLC), as well as revealed the mutation profiling of NSCLC patients with osimertinib resistance to provide some valuable clues to the mechanisms of resistance.MethodsA total of 317 cancer tissue samples from 317 NSCLC patients at time of progression following osimertinib were submitted to NGS and only 96 tissues were tested by FISH simultaneously. With FISH results as gold standard, enumeration algorithm was applied to establish the optimal model for identifying MET amplification using gene copy number (GCN) data.ResultsThe optimal model for identifying MET amplification was constructed based on the GCN of MET, BRAF, CDK6 and CYP3A4, which achieved a 74.0% overall agreement with FISH and performed well in identifying MET amplification except polysomy with a sensitivity of 85.7% and a specificity of 93.9%. The inconsistency between NGS and FISH occurred mainly in polysomy subtype, while MET GCN ≥ 5 could be reliably recognized by NGS. Moreover, the most frequently mutated genes in NSCLC patients with osimertinib resistance were EGFR (59.94%), followed by TP53 (43.85%), NRG1 (9.46%), PIK3CA (6.31%), and ATM (5.36%). The known resistance mechanisms, including MET amplification, EGFR (C797S, L718Q/R), TP53, CDK4, CDK6, CDKN2A, BRAF, KRAS, NRAS and PIK3CA mutations were also disclosed in our cohort.ConclusionsNGS assay can achieve a high concordance with FISH in MET amplification detection and has advantages in portraying various genetic alterations, which is of worthy in clinical promotion.
Proteomic study of medicinal mushroom extracts reveals antitumor mechanisms in an advanced colon cancer animal model via ribosomal biogenesis, translation, and metabolic pathways
Authors: Jakopovic Boris , Horvatić Anita , Baranasic Jurica , Car Iris , Oršolić Nada , Jakopovich Ivan , Sedić Mirela , Kraljević Pavelić Sandra 
Published: October 2024

IntroductionColorectal cancer ranks as the third most common cancer in both men and women, with approximately 35% of cases being stage IV metastatic at diagnosis. Even with treatment advancements, the survival rates for these patients remain suboptimal. There is a significant focus on developing multi-targeted therapies due to the common issue of drug resistance in standard and targeted cancer treatments. Medicinal mushrooms, both as single compounds and as complex extracts, have undergone extensive research. Numerous types of mushrooms have been shown to be safe, effective inhibitors of cancer pathways and strong enhancers of the immune system.MethodsIn this study, we performed both qualitative and quantitative proteomic analyses using tandem mass tags (TMT) on CT26 wild type (CT26. WT) colon cancer tissues from Balb/c mice, which were treated with a special blend of medicinal mushroom extracts, either alone or in combination with the chemotherapy drug 5-fluorouracil.ResultsThe results showed a notable increase in survival rates and indicated that medicinal mushroom preparation Agarikon Plus, both alone and combined with 5-fluorouracil or another medicinal mushroom preparation Agarikon.1, impedes multiple key processes in colorectal cancer progression. The analysis of differentially expressed proteins in treated groups was done by use of bioinformatics tools and a decrease in ribosomal biogenesis (e.g., RPS3) and translation processes (e.g., RPL14) as well as an increase in unfolded protein response (e.g., DNAJC3), lipid metabolism (e.g., ACOT7), and the tricarboxylic acid cycle (e.g., FH) were observed.ConclusionThe treatment induced various alterations of known biomarkers and protein clusters critical to the progression and prognosis of colorectal cancer, laying a promising foundation for further translational research on this treatment modality.
Near-infrared photoimmunotherapy in cancer treatment: a bibliometric and visual analysis
Authors: Tian Jinglin , Chen Chunbao , Du Xue , Wang Miao 
Published: October 2024

BackgroundNear-infrared photoimmunotherapy (NIR-PIT) is an emerging cancer treatment technology that combines the advantages of optical technology and immunotherapy to provide a highly effective, precise, and low side-effect treatment approach. The aim of this study is to visualize the scientific results and research trends of NIR-PIT based on bibliometric analysis methods.MethodsThe Web of Science Core Collection (WoSCC) database was searched in August 2024 for relevant publications in the field of NIR-PIT. Data were analyzed using mainly CiteSpace and R software for bibliometric and visual analysis of the country/region, authors, journals, references and keywords of the publications in the field.ResultsA total of 245 publications were retrieved, including articles (n = 173, 70.61%) and reviews (n = 72, 29.39%). The annual and cumulative number of publications increased every year. The highest number of publications was from the United States (149, 60.82%), followed by Japan (70, 28.57%) and China (33, 13.47%). The research institution with the highest number of publications was National Institutes of Health (NIH)-USA (114, 46.53%). Kobayashi H (109) was involved in the highest number of publications, Mitsunaga M (211) was the most frequently cited in total. CANCERS (17) was the most frequently published journal, and NAT MED (220) was the most frequently co-cited journal. The top 10 keywords include near-infrared photoimmunotherapy (166), photodynamic therapy (61), monoclonal antibody (58), in vivo (50), cancer (46), expression (31), breast cancer (27), enhanced permeability (24), antibody (23), growth factor receptor (16). Cluster analysis based on the co-occurrence of keywords resulted in 13 clusters, which identified the current research hotspots and future trends of NIR-PIT in cancer treatment.ConclusionThis study systematically investigated the research hotspots and development trends of NIR-PIT in cancer treatment through bibliometric and visual analysis. As an emerging strategy, the research on the application of NIR-PIT in cancer treatment has significantly increased in recent years, mainly focusing on the targeting, immune activation mechanism, and treatment efficacy in solid tumors has received extensive attention. Future studies may focus on improving the efficacy and safety of NIR-PIT in cancer treatment, as well as developing novel photosensitizers and combination therapeutic regimens, and exploring the efficacy of its application in a wide range of solid tumors, which will provide an important reference and guidance for the application of NIR-PIT in clinical translation.