bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microsatellite instability-related prognostic risk score (MSI-pRS) defines a subset of lung squamous cell carcinoma (LUSC) patients with genomic instability and poor clinical outcome
Authors: Hu Zixin , Liu Zhening , Zheng Jiabin , Peng Yanmei , Lu Xingyu , Li Jia , Tan Kexin , Cui Huijuan 
Published: February 2023

Background: Lung squamous cell carcinoma (LUSC) shares less typical onco-drivers and target resistance, but a high overall mutation rate and marked genomic complexity. Mismatch repair (MMR) deficiency leads to microsatellite instability (MSI) and genomic instability. MSI is not an ideal option for prognosis of LUSC, whereas its function deserves exploration.Method: MSI status was classified by MMR proteins using unsupervised clustering in the TCGA–LUSC dataset. The MSI score of each sample was determined by gene set variation analysis. Intersections of the differential expression genes and differential methylation probes were classified into functional modules by weighted gene co-expression network analysis. Least absolute shrinkage and selection operator regression and stepwise gene selection were performed for model downscaling.Results: Compared with the MSI-low (MSI-L) phenotype, MSI-high (MSI-H) displayed higher genomic instability. The MSI score was decreased from MSI-H to normal samples (MSI-H &gt; MSI-L &gt; normal). A total of 843 genes activated by hypomethylation and 430 genes silenced by hypermethylation in MSI-H tumors were classified into six functional modules. CCDC68, LYSMD1, RPS7, and CDK20 were used to construct MSI-related prognostic risk score (MSI-pRS). Low MSI-pRS was a protective prognostic factor in all cohorts (HR = 0.46, 0.47, 0.37; p-value = 7.57e-06, 0.009, 0.021). The model contains tumor stage, age, and MSI-pRS that showed good discrimination and calibration. Decision curve analyses indicated that microsatellite instability-related prognostic risk score added extra value to the prognosis. A low MSI-pRS was negatively correlated with genomic instability. LUSC with low MSI-pRS was associated with increased genomic instability and cold immunophenotype.Conclusion: MSI-pRS is a promising prognostic biomarker in LUSC as the substitute of MSI. Moreover, we first declared that LYSMD1 contributed to genomic instability of LUSC. Our findings provided new insights in the biomarker finder of LUSC.
Prediction of early treatment response to the combination therapy of TACE plus lenvatinib and anti-PD-1 antibody immunotherapy for unresectable hepatocellular carcinoma: Multicenter retrospective study
Authors: Li Shuqun , Wu Junyi , Wu Jiayi , Fu Yangkai , Zeng Zhenxin , Li Yinan , Li Han , Liao Weijia , Yan Maolin 
Published: February 2023

Background and aimThe purpose of this study was to investigate and validate the efficacy of a nomogram model in predicting early objective response rate (ORR) in u-HCC patients receiving a combination of TACE, Lenvatinib, and anti-PD-1 antibody treatment after 3 months (triple therapy).MethodThis study included 169 u-HCC cases from five different hospitals. As training cohorts (n = 102), cases from two major centers were used, and external validation cohorts (n = 67) were drawn from the other three centers. The clinical data and contrast-enhanced MRI characteristics of patients were included in this retrospective study. For evaluating MRI treatment responses, the modified revaluation criteria in solid tumors (mRECIST) were used. Univariate and multivariate logistic regression analyses were used to select relevant variables and develop a nomogram model. Our as-constructed nomogram was highly consistent and clinically useful, as confirmed by the calibration curve and decision curve analysis (DCA); an independent external cohort also calibrated the nomogram.ResultsThe ORR was 60.9% and the risk of early ORR was independently predicted by AFP, portal vein tumor thrombus (PVTT), tumor number, and size in both the training (C-index = 0.853) and test (C-index = 0.800) cohorts. The calibration curve revealed that the nomogram-predicted values were consistent with the actual response rates in both cohorts. Furthermore, DCA indicated that our developed nomogram performed well in clinical settings.ConclusionThe nomogram model accurately predicts early ORR achieved by triple therapy in u-HCC patients, which aids in individual decision-making and modifying additional therapies for u-HCC cases.
An integrated co-expression network analysis reveals novel genetic biomarkers for immune cell infiltration in chronic kidney disease
Authors: Xia Jia , Hou Yutong , Cai Anxiang , Xu Yingjie , Yang Wen , Huang Masha , Mou Shan 
Published: February 2023

BackgroundChronic kidney disease (CKD) is characterized by persistent damage to kidney function or structure. Progression to end-stage leads to adverse effects on multiple systems. However, owing to its complex etiology and long-term cause, the molecular basis of CKD is not completely known.MethodsTo dissect the potential important molecules during the progression, based on CKD databases from Gene Expression Omnibus, we used weighted gene co-expression network analysis (WGCNA) to identify the key genes in kidney tissues and peripheral blood mononuclear cells (PBMC). Correlation analysis of these genes with clinical relevance was evaluated based on Nephroseq. Combined with a validation cohort and receiver operating characteristic curve (ROC), we found the candidate biomarkers. The immune cell infiltration of these biomarkers was evaluated. The expression of these biomarkers was further detected in folic acid-induced nephropathy (FAN) murine model and immunohistochemical staining.ResultsIn total, eight genes (CDCP1, CORO1C, DACH1, GSTA4, MAFB, TCF21, TGFBR3, and TGIF1) in kidney tissue and six genes (DDX17, KLF11, MAN1C1, POLR2K, ST14, and TRIM66) in PBMC were screened from co-expression network. Correlation analysis of these genes with serum creatinine levels and estimated glomerular filtration rate from Nephroseq showed a well clinical relevance. Validation cohort and ROC identified TCF21, DACH1 in kidney tissue and DDX17 in PBMC as biomarkers for the progression of CKD. Immune cell infiltration analysis revealed that DACH1 and TCF21 were correlated with eosinophil, activated CD8 T cell, activated CD4 T cell, while the DDX17 was correlated with neutrophil, type-2 T helper cell, type-1 T helper cell, mast cell, etc. FAN murine model and immunohistochemical staining confirmed that these three molecules can be used as genetic biomarkers to distinguish CKD patients from healthy people. Moreover, the increase of TCF21 in kidney tubules might play important role in the CKD progression.DiscussionWe identified three promising genetic biomarkers which could play important roles in the progression of CKD.
Relationships of ferroptosis-related genes with the pathogenesis in polycystic ovary syndrome
Authors: Lin Shuang , Jin Xin , Gu He , Bi Fangfang 
Published: February 2023

BackgroundNumerous studies have suggested that ferroptosis plays a significant role in the development of polycystic ovary syndrome (PCOS), but the mechanism remains unclear.MethodsIn this study, we explored the role of ferroptosis-related genes in the pathogenesis of PCOS using a comprehensive bioinformatics method. First, we downloaded several Gene Expression Omnibus (GEO) datasets and combined them into a meta-GEO dataset. Differential expression analysis was performed to screen for significant ferroptosis-related genes between the normal and PCOS samples. The least absolute shrinkage selection operator regression and support vector machine–recursive feature elimination were used to select the best signs to construct a PCOS diagnostic model. Receiver operating characteristic curve analysis and decision curve analysis were applied to test the performance of the model. Finally, a ceRNA network-related ferroptosis gene was constructed.ResultsFive genes, namely, NOX1, ACVR1B, PHF21A, FTL, and GALNT14, were identified from 10 differentially expressed ferroptosis-related genes to construct a PCOS diagnostic model. Finally, a ceRNA network including 117 lncRNAs, 67 miRNAs, and five ferroptosis-related genes was constructed.ConclusionOur study identified five ferroptosis-related genes that may be involved in the pathogenesis of PCOS, which may provide a novel perspective for the clinical diagnosis and treatment of PCOS.
Clinical outcomes of children and adolescents with sickle cell disease and COVID-19 infection: A year in review at a metropolitan tertiary pediatric hospital
Authors: Martin Olufunke Y. , Darbari Deepika S. , Margulies Stefanie , Nickel Robert S. , Leonard Alexis , Speller-Brown Barbara , Martin Brenda , Barber John R. , Webb Jennifer , Majumdar Suvankar , Sharron Matthew P. , Campbell Andrew D. 
Published: February 2023

BackgroundCOVID-19 was declared a global pandemic in March 2020. Early reports were primarily in adults, and sickle cell disease (SCD) was classified as a risk factor for severe COVID-19 disease. However, there are a limited number of primarily multi-center studies reporting on the clinical course of pediatric patients with SCD and COVID-19.MethodsWe conducted an observational study of all patients with SCD diagnosed with COVID-19 at our institution between March 31, 2020, and February 12, 2021. Demographic and clinical characteristics of this group were collected by retrospective chart review.ResultsA total of 55 patients were studied, including 38 children and 17 adolescents. Demographics, acute COVID-19 clinical presentation, respiratory support, laboratory findings, healthcare utilization, and SCD modifying therapies were comparable between the children and adolescents. Seventy-three percent (N = 40) of all patients required emergency department care or hospitalization. While 47% (N = 26) were hospitalized, only 5% (N = 3) of all patients required intensive care unit admission. Patients frequently had concurrent vaso-occlusive pain crisis (VOC) (N = 17, 43%) and acute chest syndrome (ACS) (N = 14, 35%). Those with ACS or an oxygen requirement had significantly higher white blood cell count, lower nadir hemoglobin, and higher D-dimers, supporting a pro-inflammatory and coagulopathic picture. Non-hospitalized patients were more likely to be on hydroxyurea than hospitalized patients (79 vs. 50%, p = 0.023).ConclusionChildren and adolescent patients with SCD and acute COVID-19 often present with ACS and VOC pain requiring hospital-level care. Hydroxyurea treatment appears to be protective. We observed no mortality despite variable morbidity.
Repetitive transcranial magnetic stimulation over the posterior parietal cortex improves functional recovery in nonresponsive patients: A crossover, randomized, double-blind, sham-controlled study
Authors: Xu Chengwei , Wu Wanchun , Zheng Xiaochun , Liang Qimei , Huang Xiyan , Zhong Haili , Xiao Qiuyi , Lan Yue , Bai Yang , Xie Qiuyou 
Published: February 2023

BackgroundRecent studies have shown that patients with disorders of consciousness (DoC) can benefit from repetitive transcranial magnetic stimulation (rTMS) therapy. The posterior parietal cortex (PPC) is becoming increasingly important in neuroscience research and clinical treatment for DoC as it plays a crucial role in the formation of human consciousness. However, the effect of rTMS on the PPC in improving consciousness recovery remains to be studied.MethodWe conducted a crossover, randomized, double-blind, sham-controlled clinical study to assess the efficacy and safety of 10 Hz rTMS over the left PPC in unresponsive patients. Twenty patients with unresponsive wakefulness syndrome were recruited. The participants were randomly divided into two groups: one group received active rTMS treatment for 10 consecutive days (n = 10) and the other group received sham treatment for the same period (n = 10). After a 10-day washout period, the groups crossed over and received the opposite treatment. The rTMS protocol involved the delivery of 2000 pulses/day at a frequency of 10 Hz, targeting the left PPC (P3 electrode sites) at 90% of the resting motor threshold. The primary outcome measure was the JFK Coma Recovery Scele-Revised (CRS-R), and evaluations were conducted blindly. EEG power spectrum assessments were also conducted simultaneously before and after each stage of the intervention.ResultrTMS-active treatment resulted in a significant improvement in the CRS-R total score (F = 8.443, p = 0.009) and the relative alpha power (F = 11.166, p = 0.004) compared to sham treatment. Furthermore, 8 out of 20 patients classified as rTMS responders showed improvement and evolved to a minimally conscious state (MCS) as a result of active rTMS. The relative alpha power also significantly improved in responders (F = 26.372, p = 0.002) but not in non-responders (F = 0.704, p = 0.421). No adverse effects related to rTMS were reported in the study.ConclusionsThis study suggests that 10 Hz rTMS over the left PPC can significantly improve functional recovery in unresponsive patients with DoC, with no reported side effects.Clinical trial registrationwww.ClinicalTrials.gov, identifier: NCT05187000.
Benchmarking performance of an automatic polysomnography scoring system in a population with suspected sleep disorders
Authors: Choo Bryan Peide , Mok Yingjuan , Oh Hong Choon , Patanaik Amiya , Kishan Kishan , Awasthi Animesh , Biju Siddharth , Bhattacharjee Soumya , Poh Yvonne , Wong Hang Siang 
Published: February 2023

AimThe current gold standard for measuring sleep disorders is polysomnography (PSG), which is manually scored by a sleep technologist. Scoring a PSG is time-consuming and tedious, with substantial inter-rater variability. A deep-learning-based sleep analysis software module can perform autoscoring of PSG. The primary objective of the study is to validate the accuracy and reliability of the autoscoring software. The secondary objective is to measure workflow improvements in terms of time and cost via a time motion study.MethodologyThe performance of an automatic PSG scoring software was benchmarked against the performance of two independent sleep technologists on PSG data collected from patients with suspected sleep disorders. The technologists at the hospital clinic and a third-party scoring company scored the PSG records independently. The scores were then compared between the technologists and the automatic scoring system. An observational study was also performed where the time taken for sleep technologists at the hospital clinic to manually score PSGs was tracked, along with the time taken by the automatic scoring software to assess for potential time savings.ResultsPearson's correlation between the manually scored apnea–hypopnea index (AHI) and the automatically scored AHI was 0.962, demonstrating a near-perfect agreement. The autoscoring system demonstrated similar results in sleep staging. The agreement between automatic staging and manual scoring was higher in terms of accuracy and Cohen's kappa than the agreement between experts. The autoscoring system took an average of 42.7 s to score each record compared with 4,243 s for manual scoring. Following a manual review of the auto scores, an average time savings of 38.6 min per PSG was observed, amounting to 0.25 full-time equivalent (FTE) savings per year.ConclusionThe findings indicate a potential for a reduction in the burden of manual scoring of PSGs by sleep technologists and may be of operational significance for sleep laboratories in the healthcare setting.
The potential antidepressant effect of antidiabetic agents: New insights from a pharmacovigilance study based on data from the reporting system databases FAERS and VigiBase
Authors: Battini Vera , Van Manen Robbert P. , Gringeri Michele , Mosini Giulia , Guarnieri Greta , Bombelli Anna , Pozzi Marco , Nobile Maria , Radice Sonia , Clementi Emilio , Carnovale Carla 
Published: February 2023

Background: Growing evidence supports a bidirectional association between diabetes and depression; promising but limited and conflicting data from human studies support the intriguing possibility that antidiabetic agents may be used to relieve effectively depressive symptoms in diabetic patients. We investigated the potential antidepressant effects of antidiabetic drugs in a high-scale population data from the two most important pharmacovigilance databases, i.e., the FDA Adverse Event Reporting System (FAERS) and the VigiBase.Material and methods: From the two primary cohorts of patients treated with antidepressants retrieved from FDA Adverse Event Reporting System and VigiBase we identified cases (depressed patients experiencing therapy failure) and non-cases (depressed patients experiencing any other adverse event). We then calculated the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Empirical Bayes Regression-Adjusted Mean (ERAM) for cases versus non-cases in relation with the concurrent exposure to at least one of the following antidiabetic agent: A10BA Biguanides; A10BB Sulfonylureas; A10BG Thiazolidinediones; A10BH DPP4-inhibitors; A10BJ GLP-1 analogues; A10BK SGLT2 inhibitors (i.e., those agents for which preliminary evidence from literature supports our pharmacological hypothesis).Results: For GLP-1 analogues, all the disproportionality scores showed values &lt;1, i.e., statistically significant, in both analyses [from the FAERS: ROR confidence interval of 0.546 (0.450–0.662); PRR (p-value) of 0.596 (0.000); EBGM (CI) of 0.488 (0.407–0.582); ERAM (CI) of 0.480 (0.398–0.569) and VigiBase: ROR (CI) of 0.717 (0.559–0.921); PRR (p-value) of 0.745 (0.033); EBGM (CI) of 0.586 (0.464–0.733); ERAM of (CI): 0.515 (0.403–0.639)]. Alongside GLP-1 analogues, DPP-4 Inhibitors and Sulfonylureas showed the greatest potential protective effect. With regard to specific antidiabetic agents, liraglutide and gliclazide were associated with a statistically significant decrease in all disproportionality scores, in both analyses.Conclusion: The findings of this study provide encouraging results, albeit preliminary, supporting the need for further clinical research for investigating repurposing of antidiabetic drugs for neuropsychiatric disorders.
Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity
Authors: Liu Zhihua , Feng Yu , Zhao Hang , Hu Jinping , Chen Yanmin , Liu Dongdong , Wang Hongliang , Zhu Xiangyang , Yang Hongzhen , Shen Zhufang , Xia Xuejun , Ye Jun , Liu Yuling 
Published: February 2023

Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from twigs of mulberry (Morus alba L., genus Morus in the Moraceae family) was approved by the National Medical Products Administration in 2020 for the treatment of type 2 diabetes mellitus. In addition to excellent hypoglycemic effect, increasing evidence has confirmed that SZ-A exerts multiple pharmacological effects, such as protecting pancreatic ß-cell function, stimulating adiponectin expression, and alleviating hepatic steatosis. Importantly, a specific distribution of SZ-A in target tissues following oral absorption into the blood is essential for the induction of multiple pharmacological effects. However, there is a lack of studies thoroughly exploring the pharmacokinetic profiles and tissue distribution of SZ-A following oral absorption into the blood, particularly dose-linear pharmacokinetics and target tissue distribution associated with glycolipid metabolic diseases. In the present study, we systematically investigated the pharmacokinetics and tissue distribution of SZ-A and its metabolites in human and rat liver microsomes, and rat plasma, as well as its effects on the activity of hepatic cytochrome P450 enzymes (CYP450s). The results revealed that SZ-A was rapidly absorbed into the blood, exhibited linear pharmacokinetic characteristics in the dose range of 25–200 mg/kg, and was broadly distributed in glycolipid metabolism-related tissues. The highest SZ-A concentrations were observed in the kidney, liver, and aortic vessels, followed by the brown and subcutaneous adipose tissues, and the heart, spleen, lung, muscle, pancreas, and brain. Except for the trace oxidation products produced by fagomine, other phase I or phase II metabolites were not detected. SZ-A had no inhibitory or activating effects on major CYP450s. Conclusively, SZ-A is rapidly and widely distributed in target tissues, with good metabolic stability and a low risk of triggering drug-drug interactions. This study provides a framework for deciphering the material basis of the multiple pharmacological functions of SZ-A, its rational clinical use, and the expansion of its indications.
Acute arterial stiffness responses to on-ball balance exercises in young and middle-aged adults: Role of posture and cumulative effects
Authors: Chen Wei , Miao Gaofan , Xv Yanfei , Zhou Zhixiong , Zhu Weili 
Published: February 2023

Objective: To examine the acute arterial stiffness changes after maintaining one bout of balance on Swiss ball using different postures in young and middle-aged adults, and to evaluate the cumulative exposure effects on arterial stiffness after multiple exercise bouts in middle-aged adults.Methods: Using crossover design, we first enrolled 22 young adults (24.0 ± 1.1 years) and randomized them to non-exercise control (CON), on-ball balance exercise trial lasting 1 × 5 min in kneeling posture (K1) and sitting posture (S1). In a following crossover experiment, 19 middle-aged adults (53.0 ± 4.7 years) were randomized to non-exercise control (CON), on-ball balance exercise trial lasting 1 × 5 min in kneeling posture (K1) and in sitting posture (S1), and on-ball balance exercise trial lasting 2 × 5 min in kneeling posture (K2) and in sitting posture (S2). Cardio-ankle vascular index (CAVI), an indicator of systemic arterial stiffness, was measured at baseline (BL), immediately after (0 min), and every 10 min after exercise. CAVI changes from BL in the same trial (⊿CAVI) were used for analysis.Results: In K1 trial, ⊿CAVI decreased significantly at 0 min (p &lt; 0.05) in both young and middle-aged adults; however in S1 trial, ⊿CAVI at 0 min increased significantly in young adults (p &lt; 0.05), with ⊿CAVI tending to increase in middle-aged adults. Bonferroni post-test revealed that at 0 min, ⊿CAVI of K1 in both young and middle-aged adults, and ⊿CAVI of S1 in young adults differed significantly from that of CON (p &lt; 0.05). In middle-aged adults, ⊿CAVI decreased significantly at 10 min compared to BL in K2 trial (p &lt; 0.05), and increased at 0 min compared to BL in S2 trial (p &lt; 0.05); however, difference compared to CON was not significant.Conclusion: Single on-ball balance bout in kneeling posture improved arterial stiffness transiently in both young and middle-aged adults; however, sitting posture elicited opposite changes, and this happened only in young adults. Multiple balance bouts resulted in no significant change in arterial stiffness in middle-aged adults.