bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary microcephaly gene CENPE is a novel biomarker and potential therapeutic target for non-WNT/non-SHH medulloblastoma
Authors: Fang Huangyi , Zhang Yusong , Lin Chengyin , Sun Zhenkai , Wen Wei , Sheng Hansong , Lin Jian 
Published: August 2023

BackgroundNon-WNT/non-SHH medulloblastoma (MB) is one of the subtypes with the highest genetic heterogeneity in MB, and its current treatment strategies have unsatisfactory results and significant side effects. As a member of the centromere protein (CENP) family, centromeric protein E (CENPE) is a microtubule plus-end-directed kinetochore protein. Heterozygous mutations in CENPE can leads to primary microcephaly syndrome. It has been reported that CENPE is upregulated in MB, but its role in MB development is still unknown.MethodsWe downloaded the relevant RNA seq data and matched clinical information from the GEO database. Bioinformatics analysis includes differential gene expression analysis, Kaplan-Meier survival analysis, nomogram analysis, ROC curve analysis, immune cell infiltration analysis, and gene function enrichment analysis. Moreover, the effects of CENPE expression on cell proliferation, cell cycle, and p53 signaling pathway of non-WNT/non-SHH MB were validated using CENPE specific siRNA in vitro experiments.ResultsCompared with normal tissues, CENPE was highly expressed in MB tissues and served as an independent prognostic factor for survival in non-WNT/non-SHH MB patients. The nomogram analysis and ROC curve further confirmed these findings. At the same time, immune cell infiltration analysis showed that CENPE may participate in the immune response and tumor microenvironment (TME) of non-WNT/non-SHH MB. In addition, gene enrichment analysis showed that CENPE was closely related to the cell cycle and p53 pathway in non-WNT/non-SHH MB. In vitro experimental validation showed that knockdown of CENPE inhibited cell proliferation by activating the p53 signaling pathway and blocking the cell cycle.ConclusionThe expression of CENPE in non-WNT/non-SHH MB was positively correlated with poor prognosis. CENPE may affect tumor progression by regulating cell cycle, p53 pathway, and immune infiltration. Hence, CENPE is highly likely a novel biomarker and potential therapeutic target for non-WNT/non-SHH MB.
A meta-analysis of the Zilongjin tablets for non-small cell lung cancer and its network pharmacology of action against NSCLC and COVID-19
Authors: Yang Wuxia , Zhang Yichao , Gao Jing , Hu Pengcheng , Yang Yanjie , Xu Xiaoqing 
Published: August 2023

ObjectiveTo objectively evaluate the efficacy of the Zilongjin tablets in non-small cell lung cancer (NSCLC) and to explore its potential mechanism of action against NSCLC and COVID-19 based on network pharmacology.MethodsThe database was searched for randomized controlled trials (RCTs) of the Zilongjin tablets for NSCLC published up to 22 August 2022. The quality of included trials was assessed using Cochrane standard guidelines, and a meta-analysis was performed using Rev Man 5.3. Gene targets for intersections of NSCLC and COVID-19 (the NC) and drugs were obtained from the TCMSP database, HERB database, GeneCards database, and the NCBI database for network pharmacology research.ResultsMeta-analysis included 14 articles with 2,430 patients. The meta-analysis showed that the Zilongjin tablets combined with conventional chemotherapy were significantly more effective than chemotherapy alone in the treatment of NSCLC. A total of 29 drug-disease intersecting targets were identified in the network pharmacology. The “ingredient-target-pathway” diagram component-target-pathway network contained 119 nodes and 429 edges, with the majority of targets associated with inflammatory responses.ConclusionThe efficacy and quality of life of the Zilongjin tablets combined conventional chemotherapy for NSCLC were significantly better than chemotherapy alone, alleviating various adverse effects. At the same time, the Zilongjin tablets may modulate the inflammatory response to alleviate NSCLC and COVID-19.
Deep convolutional neural network for rib fracture recognition on chest radiographs
Authors: Huang Shu-Tien , Liu Liong-Rung , Chiu Hung-Wen , Huang Ming-Yuan , Tsai Ming-Feng 
Published: August 2023

IntroductionRib fractures are a prevalent injury among trauma patients, and accurate and timely diagnosis is crucial to mitigate associated risks. Unfortunately, missed rib fractures are common, leading to heightened morbidity and mortality rates. While more sensitive imaging modalities exist, their practicality is limited due to cost and radiation exposure. Point of care ultrasound offers an alternative but has drawbacks in terms of procedural time and operator expertise. Therefore, this study aims to explore the potential of deep convolutional neural networks (DCNNs) in identifying rib fractures on chest radiographs.MethodsWe assembled a comprehensive retrospective dataset of chest radiographs with formal image reports documenting rib fractures from a single medical center over the last five years. The DCNN models were trained using 2000 region-of-interest (ROI) slices for each category, which included fractured ribs, non-fractured ribs, and background regions. To optimize training of the deep learning models (DLMs), the images were segmented into pixel dimensions of 128 × 128.ResultsThe trained DCNN models demonstrated remarkable validation accuracies. Specifically, AlexNet achieved 92.6%, GoogLeNet achieved 92.2%, EfficientNetb3 achieved 92.3%, DenseNet201 achieved 92.4%, and MobileNetV2 achieved 91.2%.DiscussionBy integrating DCNN models capable of rib fracture recognition into clinical decision support systems, the incidence of missed rib fracture diagnoses can be significantly reduced, resulting in tangible decreases in morbidity and mortality rates among trauma patients. This innovative approach holds the potential to revolutionize the diagnosis and treatment of chest trauma, ultimately leading to improved clinical outcomes for individuals affected by these injuries. The utilization of DCNNs in rib fracture detection on chest radiographs addresses the limitations of other imaging modalities, offering a promising and practical solution to improve patient care and management.
Effect of smoking on the development of chronic obstructive pulmonary disease in young individuals: a nationwide cohort study
Authors: Chung Chiwook , Lee Kyu Na , Han Kyungdo , Shin Dong Wook , Lee Sei Won 
Published: August 2023

BackgroundCigarette smoking is an important risk factor for developing chronic obstructive pulmonary disease (COPD). However, the effect of smoking on the development of COPD in young individuals remains unclear. We aimed to evaluate the effect of smoking on COPD development in young individuals.MethodsUsing the Korean National Health Information Database, we screened individuals aged 20–39 years who participated in the national health check-up between 2009 and 2012. We defined physician-diagnosed COPD based on health insurance claims and searched the database until December 2019. We identified 6,307,576 eligible individuals, and 13,789 had newly developed COPD. We used multivariate Cox proportional hazards models to estimate the adjusted hazard ratio (aHR) of risk factors for COPD.ResultsThe incidence rate for developing COPD was 0.26/1000 person-year. The risk of developing COPD was significantly higher in current smokers [aHR 1.46, 95% confidence interval (CI) 1.39–1.53] and former smokers (aHR 1.21, 95% CI 1.14–1.29) than in non-smokers. Furthermore, the risk increased with increasing smoking amounts (≥20 pack-years, aHR 2.24; 10–20 pack-years, aHR 1.55; &lt;10 pack-years, aHR 1.27). Female participants had a higher relative risk of developing COPD due to smoking, compared with their male counterparts.ConclusionCigarette smoking increased the risk of developing COPD in young individuals. Current and heavy smokers had higher risks of developing COPD than non-smokers. Female smokers were more likely to develop COPD than male smokers.
A decentralized, prospective, observational study to collect real-world data from patients with myasthenia gravis using smartphones
Authors: Steyaert Sandra , Lootus Meelis , Sarabu Chethan , Framroze Zeenia , Dickinson Harriet , Lewis Emily , Steels Jean-Christophe , Rinaldo Francesca 
Published: August 2023

IntroductionWe conducted a 3-month, prospective study in a population of patients with Myasthenia Gravis (MG), utilizing a fully decentralized approach for recruitment and monitoring (ClinicalTrials.gov Identifier: NCT04590716). The study objectives were to assess the feasibility of collecting real-world data through a smartphone-based research platform, in order to characterize symptom involvement during MG exacerbations.MethodsPrimary data collection included daily electronically recorded patient-reported outcomes (ePROs) on the presence of MG symptoms, the level of symptom severity (using the MG-Activities of Daily Living assessment, MG-ADL), and exacerbation status. Participants were also given the option to contribute data on their physical activity levels from their own wearable devices.ResultsThe study enrolled and onboarded 113 participants across 37 US states, and 73% (N= 82) completed the study. The mean age of participants was 53.6 years, 60% were female. Participants were representative of a moderate to severe MG phenotype, with frequent exacerbations, high symptom burden and multiple comorbidities. 55% of participants (N=45) reported MG exacerbations during the study, with an average of 6.3 exacerbation days per participant. Median average MG-ADL scores for participants during self-reported exacerbation and non-exacerbation periods were 7 (interquartile range 4-9, range 1-19) and 0.3 (interquartile range 0-0.8, range 0-9), respectively. Analyses examining relationships between patient-reported and patient-generated health data streams and exacerbation status demonstrated concordance between self-reported MG-ADL scores and exacerbation status, and identified features that may be used to understand and predict the onset of MG symptom exacerbations, including: 1.) dynamic changes in day-to-day symptom reporting and severity 2.) daily step counts as a measure of physical activity and 3.) clinical characteristics of the patient, including the amount of time since their initial diagnosis and their active medications related to MG treatment. Finally, application of unsupervised machine learning methods identified unique clusters of exacerbation subtypes, each with their own specific representation of symptoms and symptom severity.ConclusionWhile these symptom signatures require further study and validation, our results suggest that digital phenotyping, characterized by increased multidimensionality and frequency of the data collection, holds promise for furthering our understanding of clinically significant exacerbations and reimagining the approach to treating MG as a heterogeneous condition.
Interferon-induced transmembrane protein 3 in the hippocampus: a potential novel target for the therapeutic effects of recombinant human brain natriuretic peptide on sepsis-associated encephalopathy
Authors: Li Nan , Ma Rui-Hang , Zhang Er-Fei , Ge Feng , Fang De-Yu , Zhang Jing , Zhang Yan-Ning , Gao Yan , Hou Li-Chao , Jin Hong-Xu 
Published: August 2023

ObjectiveThis study aims to explore whether interferon-induced transmembrane protein 3 (IFITM3) is involved in recombinant human brain natriuretic peptide (rhBNP)-mediated effects on sepsis-induced cognitive dysfunction in mice.MethodsThe cellular localization and expression level of IFITM3 in the hippocampus were detected. The IFITM3 overexpression was achieved using an intracranial stereotactic system to inject an adeno-associated virus into the hippocampal CA1 region of mice. Field experiments, an elevated plus maze, and conditioned fear memory tests assessed the cognitive impairment in rhBNP-treated septic mice. Finally, in the hippocampus of septic mice, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining and Immunoblot were used to detect changes in the protein expression of cleaved Caspase-8 and cleaved Caspase-3 in apoptosis-related pathways, and toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) p65 in inflammatory pathways.ResultsFourteen days after cecal ligation and puncture (CLP) surgery, IFITM3 localized in the plasma membrane and cytoplasm of the astrocytes in the hippocampus of septic mice, partially attached to the perivascular and neuronal surfaces, but not expressed in the microglia. The expression of IFITM3 was increased in the astrocytes and neurons in the hippocampus of septic mice, which was selectively inhibited by the administration of rhBNP. Overexpression of IFITM3 resulted in elevated anxiety levels and long-term learning and memory dysfunction, completely abolished the therapeutic effect of rhBNP on cognitive impairment in septic mice, and induced an increase in the number of neuronal apoptosis in the hippocampal CA1 region. The expression levels of cleaved Caspase-3 and cleaved Caspase-8 proteins were significantly increased in the hippocampus, but the expression levels of TLR4 and NF-κB p65 were not increased.ConclusionThe activation of IFITM3 may be a potential new target for treating sepsis-associated encephalopathy (SAE), and it may be one of the key anti-apoptotic mechanisms in rhBNP exerting its therapeutic effect, providing new insight into the clinical treatment of SAE patients.
Alterations of PAC-based resting state networks in Parkinson’s disease are partially alleviated by levodopa medication
Authors: Mertiens Sean , Sure Matthias , Schnitzler Alfons , Florin Esther 
Published: August 2023

IntroductionParkinson’s disease (PD) is a neurodegenerative disorder affecting the whole brain, leading to several motor and non-motor symptoms. In the past, it has been shown that PD alters resting state networks (RSN) in the brain. These networks are usually derived from fMRI BOLD signals. This study investigated RSN changes in PD patients based on maximum phase-amplitude coupling (PAC) throughout the cortex. We also tested the hypothesis that levodopa medication shifts network activity back toward a healthy state.MethodsWe recorded 23 PD patients and 24 healthy age-matched participants for 30 min at rest with magnetoencephalography (MEG). PD patients were measured once in the dopaminergic medication ON and once in the medication OFF state. A T1-MRI brain scan was acquired from each participant for source reconstruction. After correcting the data for artifacts and performing source reconstruction using a linearly constrained minimum variance beamformer, we extracted visual, sensorimotor (SMN), and frontal RSNs based on PAC.ResultsWe found significant changes in all networks between healthy participants and PD patients in the medication OFF state. Levodopa had a significant effect on the SMN but not on the other networks. There was no significant change in the optimal PAC coupling frequencies between healthy participants and PD patients.DiscussionOur results suggest that RSNs, based on PAC in different parts of the cortex, are altered in PD patients. Furthermore, levodopa significantly affects the SMN, reflecting the clinical alleviation of motor symptoms and leading to a network normalization compared to healthy controls.
Association of CCL4 rs10491121 and rs1634507 gene polymorphisms with cancer susceptibility: trial sequential analysis and meta-analysis
Authors: Yang Changsen , Song Tiangang , Mo Yajie , Wu Peixuan , Tian Haokun , Wen Lequan , Gao Yun 
Published: August 2023

BackgroundAlthough numerous case-control studies have explored the association between CC cytokine ligand-4 (CCL4) expression and cancer susceptibility, their results have been conflicting. This study aimed to determine the still-unknown connection of CCL4 rs10491121 and rs163450 polymorphisms with cancer susceptibility.MethodsSeveral databases, such as Web of Science, PubMed, and EMBASE, were searched for papers published since the creation of the database until November 2, 2022. Using RevMan 5.4 and StataMP 17 softwares, meta-analysis and subgroup analysis were performed after article screening and data extraction. For sensitivity analyses, one-by-one exclusion method was used, and then, the comprehensive effect was estimated and compared with that before exclusion. Trial sequential analysis (TSA)was performed using TSA 0.9.5.10 beta software.ResultsSeven case-control studies encompassing 3559 cases and 4231 controls were included. The P value was greater than 0.05 for all models, indicating the absence of an evident relationship of CCL4 gene rs10491121 and rs1634507 polymorphisms with cancer susceptibility. However, in the subgroup analysis of rs10491121, the P values in all models studied by us except GA vs. AA were &lt;0.05 considering the Chinese subgroup, suggesting that the G allele is a risk factor for cancer in the Chinese population. Besides, in the subgroup analysis of rs1634507 considering oral cancer, the co-dominant model GG vs. TT, dominant model GG + GT vs. TT, and allele model G vs. T groups showed OR &lt; 1 and P &lt; 0.05, indicating that the G allele was a protective factor of oral cancer. However, for other cancer types, all the models studied by us except GG vs. GT showed OR &gt; 1 and P &lt; 0.05, indicating that the G allele was a risk factor for these other cancers. Despite the statistically significant results, sensitivity analysis had some stability limitations, and TSA results suggested the possibility of false positives.ConclusionFor rs10491121, we identified an association between the G allele and increased cancer risk in the Chinese population. For rs1634507, the G allele was not found to be associated with reduced risk of oral cancer and increased risk of other cancers studied by us.
TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck
Authors: Rubió-Casadevall Jordi , Cirauqui Cirauqui Beatriz , Martinez Trufero Javier , Plana Serrahima Maria , García Castaño Almudena , Carral Maseda Alberto , Iglesias Docampo Lara , Pérez Segura Pedro , Ceballos Lenza Isaac , Gutiérrez Calderón Vanesa , Fuster Salvà José , Pena Álvarez Carolina , Hernandez Irene , del Barco Morillo Edel , Chaves Conde Manuel , Martínez Galán Joaquina , Durán Sánchez Marisa , Quiroga Vanesa , Ortega Eugenia , Mesia Ricard 
Published: August 2023

ObjectivesThe aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy.Materials and methodsThis retrospective, non-interventional study involved 16 centers in Spain. Inclusion criteria were to have started receiving ERBITAX regimen from January 2012 to December 2018; histologically confirmed SCCHN including oral cavity, oropharynx, hypopharynx, and larynx; age ≥18 years; and platinum (PT) chemotherapy ineligibility due to performance status, comorbidities, high accumulated dose of PT, or PT refractoriness.ResultsA total of 531 patients from 16 hospitals in Spain were enrolled. The median age was 66 years, 82.7% were male, and 83.5% were current/former smokers. Patients were ineligible to receive PT due to ECOG 2 (50.3%), comorbidities (32%), PT cumulative dose ≥ 225 mg/m2 (10.5%), or PT refractoriness (7.2%). Response rate was 37.7%. Median duration of response was 5.6 months (95% CI: 4.4–6.6). With a median follow-up of 8.7 months (95% CI: 7.7–10.2), median PFS and OS were 4.5 months (95% CI: 3.9–5.0) and 8.9 months (95% CI: 7.8–10.3), respectively. Patients treated with immunotherapy after ERBITAX had better OS with a median of 29.8 months compared to 13.8 months for those who received other treatments. The most common grade ≥ 3 toxicities were acne-like rash in 36 patients (6.8%) and oral mucositis in 8 patients (1.5%). Five (0.9%) patients experienced grade ≥ 3 febrile neutropenia.ConclusionThis study confirms the real-world efficacy and tolerability of ERBITAX as first-line treatment in recurrent/metastatic SCCHN when PT is not feasible. Immunotherapy after treatment with ERBITAX showed remarkable promising survival, despite potential selection bias.
AI-powered discovery of a novel p53-Y220C reactivator
Authors: Zhou Shan , Chai Dafei , Wang Xu , Neeli Praveen , Yu Xinfang , Davtyan Aram , Young Ken , Li Yong 
Published: August 2023

IntroductionThe p53-Y220C mutation is one of the most common mutations that play a major role in cancer progression.MethodsIn this study, we applied artificial intelligence (AI)-powered virtual screening to identify small-molecule compounds that specifically restore the wild-type p53 conformation from p53-Y220C. From 10 million compounds, the AI algorithm selected a chemically diverse set of 83 high-scoring hits, which were subjected to several experimental assays using cell lines with different p53 mutations.ResultsWe identified one compound, H3, that preferentially killed cells with the p53-Y220C mutation compared to cells with other p53 mutations. H3 increased the amount of folded mutant protein with wild-type p53 conformation, restored its transcriptional functions, and caused cell cycle arrest and apoptosis. Furthermore, H3 reduced tumorigenesis in a mouse xenograft model with p53-Y220C-positive cells.ConclusionAI enabled the discovery of the H3 compound that selectively reactivates the p53-Y220C mutant and inhibits tumor development in mice.
Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood
Authors: Uria-Oficialdegui M. L. , Navarro S. , Murillo-Sanjuan L. , Rodriguez-Vigil C. , Benitez-Carbante M. I. , Blazquez-Goñi C. , Salinas J. A. , Diaz-de-Heredia C. 
Published: August 2023

BackgroundDyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer. The main objective of this study is to describe the natural history of DC through a cohort of patients diagnosed in childhood and followed up for a long period of time.Material and methodsMulticenter, retrospective, longitudinal study conducted in patients followed up to 24 years since being diagnosed in childhood (between 1998 and 2020).ResultsFourteen patients were diagnosed with DC between the ages of 3 and 17 years (median, 8.5 years). They all had hematologic manifestations at diagnosis, and nine developed mucocutaneous manifestations during the first decade of life. Seven presented severe DC variants. All developed non-hematologic manifestations during follow-up. Mutations were identified in 12 patients. Thirteen progressed to bone marrow failure at a median age of 8 years [range, 3–18 years], and eight received a hematopoietic stem cell transplant. Median follow-up time was 9 years [range, 2–24 years]. Six patients died, the median age was 13 years [range, 6–24 years]. As of November 2022, eight patients were still alive, with a median age of 18 years [range, 6–32 years]. None of them have developed myeloblastic syndrome or cancer.ConclusionsDC was associated with high morbidity and mortality in our series. Hematologic manifestations appeared early and consistently. Non-hematologic manifestations developed progressively. No patient developed cancer possibly due to their young age. Due to the complexity of the disease multidisciplinary follow-up and adequate transition to adult care are essential.