bluuebunny/crossref_metadata_2025_split huggingface dataset:
m7G-Associated subtypes, tumor microenvironment, and validation of prognostic signature in lung adenocarcinoma
Authors: Wang Guangyao , Zhao Mei , Li Jiao , Li Guosheng , Zheng Fukui , Xu Guanglan , Hong Xiaohua 
Published: August 2022

Background: 7-Methylguanosine (m7G) is an important posttranscriptional modification that regulates gene expression and is involved in tumorigenesis and development. Tumor microenvironment has been proven to be highly involved in tumor progression and prognosis. However, how m7G-associated genes affect the tumor microenvironment of patients with lung adenocarcinoma (LUAD) remains to be further clarified.Methods: The genetic alterations of m7G-associated genes and their associations with the prognosis and tumor microenvironment in LUAD patients were systemically analyzed. An m7G-Riskscore was established and analyzed for its performance in disease prognosis and association with patient response to immunotherapy. Expression of the model genes at the protein level was investigated through ex vivo experiments. A nomogram was finally obtained based on the m7G-Riskscore and several significant clinical pathological features.Results: m7G-Associated genes were obtained from five LUAD datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases, and their expression pattern was determined. Based on the m7G-associated genes, three LUAD clusters were defined. The differentially expressed genes from the three clusters were screened and used to further divide the LUAD patients into two gene clusters. It was demonstrated that the alterations of m7G-associated genes were associated with the clinical pathological features, prognosis, and tumor immune infiltration in LUAD patients. An m7G-Riskscore including CAND1, RRM2, and SLC2A1 was obtained with robust and accurate prognostic performance. WB and cell immunofluorescence also showed significant dysregulation of CAND1, RRM2, and SLC2A1 in LUAD. In addition, a nomogram was established to improve the clinical feasibility of the m7G-Riskscore. Correlation analysis revealed that patients with a lower m7G-Riskscore had higher immune and stromal scores, responded well to chemotherapeutics and multiple targeted drugs, and survived longer. Patients with a higher m7G-Riskscore tended to suffer from a higher tumor mutation burden. Furthermore, the m7G-Riskscore exhibited significant associations with immune cell infiltration and cancer stemness.Conclusion: This study systemically analyzed m7G-associated genes and identified their potential role in tumor microenvironment and prognosis in patients with LUAD. The findings of the present study may help better understand LUAD from the m7G perspective and also provide a new thought toward the prognosis and treatment of LUAD.
Dynamic change of IDO1 activity predicts survival in patients with unresectable stage III NSCLC and chemoradiotherapy
Authors: Wu Linfang , Wang Daquan , Chen Yanhua , Qian Mingmin , Xu Xin , Zhang Tao , Bi Nan , Wang Luhua 
Published: August 2022

ObjectiveHigh activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T-cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.Materials and methodsSystemic IDO1 activity was calculated by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. The dynamic change of IDO1 activity was followed in 24 patients by measuring the Kyn : Trp ratio before, during, and after RT administration.ResultsIn 24 patients with dynamic tracking of plasma IDO1 activity, there were no significant alterations observed among the three time points (Friedman test, p = 0.13). The changing pattern of the Kyn : Trp ratio was divided into four groups: decreased consistently during RT, first increased, then decreased, increased consistently, first decreased then increased. Patients whose Kyn : Trp ratio kept decreasing or first increased then decreased were defined as the good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p = 0.04; p = 0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than the bad-change group (p = 0.01, HR = 0.22). In 113 stage III NSCLC patients with pre-radiation Kyn : Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p = 0.079).ConclusionFavorable change in IDO1 activity during RT was associated with superior OS, PFS, and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.
Increased intrathecal neurofilament light and immunoglobulin M predict severe disability in relapsing-remitting multiple sclerosis
Authors: Rosenstein Igal , Rasch Sofia , Axelsson Markus , Novakova Lenka , Blennow Kaj , Zetterberg Henrik , Lycke Jan 
Published: August 2022

BackgroundEmerging evidence supports that determination of intrathecal immunoglobulin M (IgM) synthesis (ITMS) and neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) may be clinically useful as disease severity biomarkers in relapsing-remitting multiple sclerosis (RRMS).MethodsMonocentric observational longitudinal cohort study in which prospectively collected data were retrospectively retrieved. Included were patients with RRMS (n=457) who had a diagnostic investigation including analysis of ITMS and CSF neurofilament light (cNfL). ITMS was calculated with the linear index formula, the intrathecal fraction of IgM according to Reiber (IgMIF), and by qualitative determination of oligoclonal IgM bands (OCMB). Univariable and multivariable models were performed to predict Evidence of Disease Activity-3 (EDA-3) status within 24 months from onset, and the risk of Expanded Disability Status Score (EDSS) ≥3 and ≥6.ResultsAll investigated methods to calculate ITMS significantly predicted evidence of disease activity (EDA-3) within 24 months. IgMIF&gt;0% showed the strongest association with EDA-3 status (adjusted hazard ratio [aHR] 3.7, 95%CI 2.7-5, p&lt;0.001). Combining IgM-index&gt;0.1 or OCMB with increased cNfL were strong predictors of EDSS≥3 (for cNfL+/IgM-index+: aHR 4.6, 95%CI 2.6-8.2, p&lt;0.001) and EDSS≥6 (aHR 8.2, 95%CI 2.3-30, p&lt;0.001).ConclusionsIn a real-world setting, ITMS was a useful biomarker in early RRMS to predict disabling MS and its prognostic value was even stronger in combination with cNfL. Our data suggest that determination of ITMS and cNfL should be included in the diagnostic work-up of RRMS for prognostic purposes and in decisions of disease-modifying therapy.
Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy
Authors: Su Bing-Nan , Shen Ren-Juan , Liu Zhuo-Lin , Li Yang , Jin Zi-Bing 
Published: August 2022

PurposeMutation in the USH2A gene is the most common cause of inherited retinal dystrophy (IRD), including non-syndromic retinitis pigmentosa (RP) and Usher syndrome II (USH2). Gene editing and therapy targeting USH2A, especially the hotspot region, would benefit a large proportion of IRD patients. In this study, we comprehensively analyzed the genetic spectrum of the USH2A gene, aiming to identify global hot spot mutations in USH2A-related IRDs and differences in hot spot regions across continents.Materials and methodsA retrospective USH2A-related IRD study was conducted, including our IRD cohort, and reported USH2A studies worldwide.ResultsA total of 3,972 mutated USH2A alleles of approximately 1,935 patients were collected from 33 cohort studies worldwide, containing 102 alleles of 51 patients in our IRD cohort. Mutations in exon 13 were the most common, reaching 18.4% globally and a higher frequency of 22% in America, 19.2% in Europe, and a lower 12% in East Asia. Pathogenic mutations that affected 10 of the 72 exons of USH2A, exon 2, exon 13, exon 41–43, exon 50, exon 54, exon 57, exon 61, and exon 63 in total were responsible for half of global USH2A mutant alleles. With base editors including adenine base editor (ABE), cytidine base editor (CBE), and glycosylase base editor (GBE), 76.3% of single nucleotide variations (SNVs) and 58% of all mutations in USH2A are correctable. Meantime, four novel pathogenic mutations were revealed in our IRD cohort, p. (Val1130Cysfs*72), p. (Ala2139fs*14), p. (Gly4139Arg), and p. (Val4166Cysfs*7).ConclusionIn this study, we revealed four novel mutations, expanding the spectrum of USH2A mutations, and importantly presented global hotspot exons and mutations of USH2A as well as the proportion of SNVs that can be restored by different base editors, providing a perspective for exploring high-efficiency and broader-reaching gene editing and gene therapies.
Association of sleep duration with chronic constipation among adult men and women: Findings from the National Health and Nutrition Examination Survey (2005–2010)
Authors: Yang Shuai , Li Shou-Zhen , Guo Fu-Zheng , Zhou Dong-Xu , Sun Xiao-Feng , Tai Jian-Dong 
Published: August 2022

BackgroundPrevious studies suggested that unhealthy sleep patterns were closely associated with gastrointestinal diseases, but the impact of unhealthy sleep duration on chronic constipation has not been well studied until now. In this study, we aim to explore the association between sleep duration and constipation among males and females.MethodsWe utilized the US National Health and Nutrition Examination Surveys data from 2005 to 2010, and adults (≥20 years old) who completed the sleep and bowel health questionnaires were enrolled in this observational study. Sleep duration was categorized into four groups: very short sleep (&lt;5 h/night), short sleep (5–6 h/night), normal sleep (7–8 h/night), and long sleep (≥9 h/night). Chronic constipation was defined as Bristol Stool Scale Type 1(separate hard lumps, like nuts) or Type 2(sausage-like but lumpy). Controlling demographic, lifestyle, and dietary factors, the logistic regression model in Generalized Linear Model (GLM) function was used to estimate the correlation of sleep duration with constipation among men and women.ResultsOf the 11,785 individuals (51.2% males and 48.8% females), 4.3% of men and 10.2% of women had constipation, respectively. More than half of patients with constipation did not adopt the recommended sleep duration. Compared with normal individuals, male participants with constipation had a higher proportion of shorter sleep duration (41.0 vs. 32.3% in the short sleep group and 6.3 vs. 4.7% in the very short sleep group), and female individuals with constipation had a higher proportion of long sleep duration (12.7 vs. 8.2%). After covariates adjustment, men with short sleep duration (5–6 h/night) correlated with increased odds for constipation (OR:1.54, 95%CI:1.05–2.25), and women with long sleep duration (≥9 h/night) linked to the higher constipation risk (OR:1.58, 95%CI:1.10–2.29). Excessive sleep duration in males or insufficient sleep duration in females was neither linked to increased nor decreased constipation risk.ConclusionsIn this observational study of a nationally representative sample of adults, we demonstrate a differential impact of unhealthy sleep duration on constipation among men and women. Short sleep duration poses a higher risk of constipation in men, and excessive sleep duration correlates with higher constipation risk in women.
Connectomic disturbances underlying insomnia disorder and predictors of treatment response
Authors: Lu Qian , Zhang Wentong , Yan Hailang , Mansouri Negar , Tanglay Onur , Osipowicz Karol , Joyce Angus W. , Young Isabella M. , Zhang Xia , Doyen Stephane , Sughrue Michael E. , He Chuan 
Published: August 2022

ObjectiveDespite its prevalence, insomnia disorder (ID) remains poorly understood. In this study, we used machine learning to analyze the functional connectivity (FC) disturbances underlying ID, and identify potential predictors of treatment response through recurrent transcranial magnetic stimulation (rTMS) and pharmacotherapy.Materials and methods51 adult patients with chronic insomnia and 42 healthy age and education matched controls underwent baseline anatomical T1 magnetic resonance imaging (MRI), resting-stage functional MRI (rsfMRI), and diffusion weighted imaging (DWI). Imaging was repeated for 24 ID patients following four weeks of treatment with pharmacotherapy, with or without rTMS. A recently developed machine learning technique, Hollow Tree Super (HoTS) was used to classify subjects into ID and control groups based on their FC, and derive network and parcel-based FC features contributing to each model. The number of FC anomalies within each network was also compared between responders and non-responders using median absolute deviation at baseline and follow-up.ResultsSubjects were classified into ID and control with an area under the receiver operating characteristic curve (AUC-ROC) of 0.828. Baseline FC anomaly counts were higher in responders than non-responders. Response as measured by the Insomnia Severity Index (ISI) was associated with a decrease in anomaly counts across all networks, while all networks showed an increase in anomaly counts when response was measured using the Pittsburgh Sleep Quality Index. Overall, responders also showed greater change in all networks, with the Default Mode Network demonstrating the greatest change.ConclusionMachine learning analysis into the functional connectome in ID may provide useful insight into diagnostic and therapeutic targets.
Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation
Authors: Hu Meixin , Li Huiping , Huang Zhuxi , Li Dongyun , Xu Ying , Xu Qiong , Chen Bo , Wang Yi , Deng Jingxin , Zhu Ming , Feng Weijun , Xu Xiu 
Published: August 2022

BackgroundMutations in the STAMBP gene, which encodes a deubiquitinating isopeptidase called STAM-binding protein, are related to global developmental delay, microcephaly, and capillary malformation. Owing to the limited number of reported cases, the functional and phenotypic characteristics of STAMBP variants require further elucidation.Materials and methodsWhole exome sequencing was performed on a patient presenting with a neurodevelopmental disorder. Novel compound heterozygous mutations in STAMBP [c.843_844del (p.C282Wfs*11) and c.920G &gt; A (p.G307E)] were identified and validated using Sanger sequencing. A 3D human cortical organoid model was used to investigate the function of STAMBP and the pathogenicity of the novel mutation (c.920G &gt; A, p.G307E).ResultsThe patient was presented with global developmental delay, autism spectrum disorder, microcephaly, epilepsy, and dysmorphic facial features but without apparent capillary malformation on the skin and organs. Cortical organoids with STAMBP knockout (KO) showed significantly lower proliferation of neural stem cells (NSCs), leading to smaller organoids that are characteristic of microcephaly. Furthermore, STAMBP disruption did not affect apoptosis in early cortical organoids. After re-expressing wild-type STAMBP, STAMBPG307E, and STAMBPT313I (a known pathogenic mutation) within STAMBP KO organoids, only STAMBPWT rescued the impaired proliferation of STAMBP deficient organoids, but not STAMBPG307E and STAMBPT313I.ConclusionOur findings demonstrate that the clinical phenotype of STAMBP mutations is highly variable, and patients with different STAMBP mutations show differences in the severity of symptoms. The STAMBP missense mutation identified here is a novel pathogenic mutation that impairs the proliferation of NSCs in human brain development.
Nomogram individually predicts the risk for distant metastasis and prognosis value in female differentiated thyroid cancer patients: A SEER-based study
Authors: Wang Wenlong , Shen Cong , Yang Zhi 
Published: August 2022

ObjectiveDistant metastasis (DM) is an important prognostic factor in differentiated thyroid cancer (DTC) and determines the course of treatment. This study aimed to establish a predictive nomogram model that could individually estimate the risk of DM and analyze the prognosis of female DTC patients (FDTCs).Materials and methodsA total of 26,998 FDTCs were retrospectively searched from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2018 and randomly divided into validation and training cohorts. Univariate and multivariate analyses were performed to screen for prognostic factors and construct a prediction nomogram. The performance of the nomogram was assessed by the area under the receiver operating characteristic curve (AUC), concordance index (C-index), and a calibration curve. The overall survival (OS) and cancer-specific survival (CSS) were evaluated by Kaplan–Meier (K-M) analysis.ResultsA total of 263 (0.97%) FDTCs were reported to have DM. K-M analysis showed the association of multiple-organ metastases and brain involvement with lower survival rates (P &lt; 0.001) in patients. Tumor size, age at diagnosis, thyroidectomy, N1 stage, T3–4 stage, and pathological type were independent predictive factors of DM in FDTCs (all P &lt; 0.001). Similarly, age at diagnosis, Black, DM, T3–4 stage, thyroidectomy, and lung metastasis were determined as independent prognostic factors for FDTCs (all P &lt; 0.001). Several predictive nomograms were established based on the above factors. The C-index, AUC, and calibration curves demonstrated a good performance of these nomogram models.ConclusionOur study was successful in establishing and validating nomograms that could predict DM, as well as CSS and OS in individual patients with FDTC based on a large study cohort. These nomograms could enable surgeons to perform individualized survival evaluation and risk stratification for FDTCs.
Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children’s Leukemia Group
Authors: Xu Lu-Hong , Geng Xu , Liao Ning , Yang Li-Hua , Mai Hui-Rong , Wan Wu-Qing , Huang Li-Bin , Zheng Min-Cui , Tian Chuan , Chen Hui-Qin , Chen Qi-Wen , Long Xing-Jiang , Zhen Zi-Jun , Liu Ri-Yang , Li Qiao-Ru , Wu Bei-Yan , Wang Li-Na , Kong Xian-Ling , Chen Guo-Hua , Fang Jian-Pei , Li Yang 
Published: August 2022

ObjectivesThe prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children’s Leukemia Group (SCCLG).MethodsA total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction.ResultsThe frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P &lt;0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016).ConclusionCNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.
The decreased connectivity in middle temporal gyrus can be used as a potential neuroimaging biomarker for left temporal lobe epilepsy
Authors: Wu Jinlong , Wu Jun , Guo Ruimin , Chu Linkang , Li Jun , Zhang Sheng , Ren Hongwei 
Published: August 2022

ObjectiveWe aimed to explore voxel-mirrored homotopic connectivity (VMHC) abnormalities between the two brain hemispheres in left temporal lobe epilepsy (lTLE) patients and to determine whether these alterations could be leveraged to guide lTLE diagnosis.Materials and methodsFifty-eight lTLE patients and sixty healthy controls (HCs) matched in age, sex, and education level were recruited to receive resting state functional magnetic resonance imaging (rs-fMRI) scan. Then VHMC analyses of bilateral brain regions were conducted based on the results of these rs-fMRI scans. The resultant imaging data were further analyzed using support vector machine (SVM) methods.ResultsCompared to HCs, patients with lTLE exhibited decreased VMHC values in the bilateral middle temporal gyrus (MTG) and middle cingulum gyrus (MCG), while no brain regions in these patients exhibited increased VMHC values. SVM analyses revealed the diagnostic accuracy of reduced bilateral MTG VMHC values to be 75.42% (89/118) when differentiating between lTLE patients and HCs, with respective sensitivity and specificity values of 74.14% (43/58) and 76.67% (46/60).ConclusionPatients with lTLE exhibit abnormal VMHC values corresponding to the impairment of functional coordination between homotopic regions of the brain. These altered MTG VMHC values may also offer value as a robust neuroimaging biomarker that can guide lTLE patient diagnosis.
The coronavirus pandemic: Psychosocial burden, risk-perception, and attitudes in the Austrian population and its relation to media consumption
Authors: Schabus Manuel , Eigl Esther-Sevil , Widauer Sebastian Stefan 
Published: August 2022

Objective:The aim was to assess the psychosocial burden, risk-perception and attitudes regarding the coronavirus pandemic among the Austrian population after the second infection wave in Austria.MethodsA self-designed questionnaire was available online from 17th January to 19th February 2021. Knowledge, attitudes, fears, and psychosocial burdens were collected in a comprehensive convenience sample of 3,848 adults from the Austrian general population.Results67.2% reported their greatest fear was that a close relative could be infected; the fear of dying from COVID-19 oneself, however, was mentioned least frequently (15.2%). Isolation from family and friends (78%), homeschooling for parents (68.4%), and economic consequences (67.7%) were perceived as most stressful factors during the pandemic. Personal risk for COVID-19-associated (ICU) hospitalization was overestimated 3- to 97-fold depending on age group. Depending on the media mainly consumed, the sample could be divided into two subsamples whose estimates were remarkably opposite to each other, with regular public media users overestimating hospitalization risk substantially more.ConclusionThe results show a high degree of psychosocial burden in the Austrian population and emphasize the need for more objective risk communication in order to counteract individually perceived risk and consequently anxiety. Altogether data call for a stronger focus and immediate action for supporting mental well-being and general health in the aftermath of the coronavirus pandemic.