bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell RNA sequencing depicts metabolic changes in children with aplastic anemia
Authors: Zhou Qin , Huang Lifen , Liu Yong , Huang Junbin , Wen Luping , Yang Jing , Liang Jintang , Chen Yun , Chen Chun 
Published: March 2023

IntroductionAplastic anemia (AA) is a bone marrow hematopoietic failure syndrome mediated by immune cells. The mechanism of this immune disorder is not well understood and therapeutic strategies still need to be improved.MethodsStudies have found that abnormalities in metabolisms promote the survival of AA cells. In recent years, an increasing number of studies have reported the immunosuppressive therapy for the treatment of AA. In this study, we analyzed the transcriptome of AA from peripheral blood compared with healthy donors by single-cell sequencing and identified the affected metabolic pathways including lysine degradation. We demonstrated that the metabolic abnormalities of T lymphocytes mainly focus on glycolysis/gluconeogenesis. In addition, the metabolic abnormalities of natural killer cells concentrated in oxidative phosphorylation.ResultsThe key genes involved in abnormal metabolic processes were Neustein neurotrophic factor (NENF), inositol polyphosphate-4-phosphatase type II B (INPP4B), aldo-keto reductase family 1, member C3 (AKR1C3), and carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2 (CHST2) by differential gene expression analysis.DiscussionMolecule interaction analysis showed that tumor necrosis factor superfamily, member 12 (TNFSM12) in tumor necrosis factor (TNF) signaling was broadly activated in AA. In conclusion, we suppose that the treatment of the immune cells’ abnormal metabolic pathway may contribute to the development of novel strategies to treat AA.
Clinicopathological characteristics and prognosis of early-stage HER2 low-expression breast cancer: A single-center retrospective study
Authors: Liu Chang-Gen , Li Yi-Fan , Ma Tian-Yi , Lv Meng , Lv Zhi-Dong , Wang Yuan-Yuan , Liu Xiang-Ping , Mao Yan , Wang Hai-Bo 
Published: March 2023

BackgroundOwing to the emergence of drugs targeting human epidermal growth factor receptor 2 (HER2), remarkable prognostic enhancement has been seen for patients with HER2-positive breast carcinoma. However, anti-HER2 medicines are applicable merely to individuals with HER2-positive tumors, and the benefit for those with low HER2 expression is unclear. The DESTINY-Breast04 phase III and RC48 clinical trial results showed the benefit of antibody-drug couples for low HER2-expressing individuals with breast carcinoma, challenging the traditional dichotomy between HER2-negative and -positive tumors. Hence, the purposes of the present work are to explore the clinicopathological traits and prognostic differences in the HER2-low expression Chinese population with early-stage breast carcinoma.MethodsData from the database of the Breast Center of the Affiliated Hospital of Qingdao University were collected from January 2008 to December 2017. We screened a total of 4,598 patients, of which 2,837 had HER2-0 tumors and 1,761 had HER2-low tumors. Additionally, clinicopathological characteristics, survival, and prognostic information were obtained. Difference comparisons were made between HER2-0 and HER2-low groups regarding the clinical traits and outcomes.ResultsWe enrolled 4598 patients, with the HR-positive subjects suffering from HER2-low breast carcinoma higher in proportion than the HR-negative patients. In contrast to HER2-0 tumors, the HER2-low tumors were linked to an older median age at diagnosis, T1 tumors, N1 stage, a higher Ki-67 index, as well as inferior histological grade. Insignificant inter-group difference was noted regarding overall survival (OS), although the HER2–0 group exhibited better disease-free survival (DFS) than the HER2-low group for the entire (P = 0.003), lymph node-negative (P = 0.009) and HR-positive (P = 0.007) populations. According to the multivariate regression finding, low HER2 expression was an inferior DFS prognostic factor in the HER2-negative population with early-stage breast cancer (HR,1.33;95% CI, 1.06-1.66; P = 0.013).ConclusionThe clinical traits of the HER2-low carcinomas differed from those of HER2–0 tumors. Despite the insignificant inter-group difference in OS, the differences in DFS were found for the overall, lymph node-negative and HR-positive subjects, suggesting the possibility of HER2-low as an inferior prognostic factor for disease progression in early-stage breast cancer.
Comprehensive analysis of the expression and prognosis for RAI2: A promising biomarker in breast cancer
Authors: Jiao Ying , Li Shiyu , Gong Juejun , Zheng Kun , Xie Ya 
Published: March 2023

IntroductionRetinoic acid-induced 2 (RAI2) was initially related to cell differentiation and induced by retinoic acid. RAI2 has been identified as an emerging tumor suppressor in breast cancer and colorectal cancer.MethodsIn this study, we performed systematic analyses of RAI2 in breast cancer. Meta-analysis and Kaplan-Meier survival curves were applied to identify the survival prediction potential of RAI2. Moreover, the association between RAI2 expression and the abundance of six tumor-infiltrating immune cells was investigated by TIMER, including B cells, CD8+ T cells, CD4+ T cells, B cells, dendritic cells, neutrophils, and macrophages. The expression profiles of high and low RAI2 mRNA levels in GSE7390 were compared to identify differentially expressed genes (DEGs) and the biological function of these DEGs was analyzed by R software, which was further proved in GSE7390.ResultsOur results showed that the normal tissues had more RAI2 expression than breast cancer tissues. Patients with high RAI2 expression were related to a favorable prognosis and more immune infiltrates. A total of 209 DEGs and 182 DEGs were identified between the expression profiles of high and low RAI2 mRNA levels in the GSE7390 and GSE21653 databases, respectively. Furthermore, Gene Ontology (GO) enrichment indicated that these DEGs from two datasets were both mainly distributed in “biological processes” (BP), including “organelle fission” and “nuclear division”. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis demonstrated that these DEGs from two datasets were both significantly enriched in the “cell cycle”. Common hub genes between the DEGs in GSE7390 and GSE21653 were negatively associated with RAI2 expression, including CCNA2, MAD2L1, MELK, CDC20, and CCNB2.DiscussionsThese results above suggested that RAI2 might play a pivotal role in preventing the initiation and progression of breast cancer. The present study may contribute to understanding the molecular mechanisms of RAI2 and enriching biomarkers to predict patient prognosis in breast cancer.
RETRACTED: A novel therapeutic strategy of combined camrelizumab and apatinib for the treatment of advanced hepatocellular carcinoma
Authors: Yang Qing , Li Gengyu , Wu Xiaoqiu , Lin Haiying , Wu Wanrui , Xie Xiangpang , Zhu Yu , Cai Wei , Shi Changsheng , Zhuo Shengye 
Published: March 2023

Methods83 patients with hepatocellular carcinoma (HCC) admitted to the interventional oncology department were randomly divided into two groups. Apatinib and camrelizumab were administered to 42 patients in group A, whereas sorafenib was administered to 41 patients in group B for three months. The clinical efficacy was evaluated in terms of objective response rate (ORR), and disease control rate (DCR). Certain tumor markers like alpha-fetoprotein (AFP), carbohydrate antigen 199 (CA199), carcinoembryonic antigen (CEA), hypoxia-inducible factor (HIF-1), immune function T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+) were determined before and after treatment. The serum levels of vascular endothelial growth factor (VEGF), osteopontin (OPN), aspartate aminotransferase (AST), and epidermal growth factor 7 (EGF7)] were observed. The survival time between the two groups was compared, such as progression-free survival (PFS) and median survival (MS). Finally, the toxicity and side effects data were also obtained.ResultsThe ORR and DCR of group A were 69.05% and 88.10%, respectively, which were significantly higher (P&lt;0.05) than group B (ORR=53.66% and DCR=70.73%). After treatment, the AFP, CA199, CEA, and HIF-1 levels of both groups decreased significantly (P&lt;0.05), and the respective biomarker levels of group A were lower than those of group B (P&lt;0.05). Following treatment, CD3+, CD4+, CD4+/CD8+ index in group A significantly increased (P&lt;0.05) while CD8+ level was significantly decreased (P&lt;0.05). Compared to group B, a significant increase was observed in group A’s CD3+, CD4+, and CD4+/CD8+ index. There were no significant changes in CD3+, CD4+, CD8+, CD4+/CD8+ indexes before and after treatment in group B (P&gt;0.05). The serum level of VEGF, OPN, EGF-7 and AST indexes of group A&amp;B were decreased significantly (P&lt;0.05). Compared with group B, the VEGF, OPN, EGF7 and AST indexes of group A were significantly reduced (P&lt;0.05). PFS and MS in group A were significantly higher than in group B (P&lt;0.05). There was no significant difference between groups A and B in terms of toxicity and adverse effects (P&gt;0.05).ConclusionIn treating HCC, combining apatinib and camrelizumab can reduce tumor markers, enhance the immune system and curative effect, and prolong patient survival. The underline mechanism is related to the down-regulation of VEGF, OPN and HIF-1 indexes.
Multimodality MRI radiomics analysis of TP53 mutations in triple negative breast cancer
Authors: Sun Kun , Zhu Hong , Chai Weimin , Yan Fuhua 
Published: March 2023

ObjectivesTo explore the value of T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) radiomics features reflecting TP53 mutations in patients with triple negative breast cancer (TNBC).Study designThis retrospective study enrolled 91 patients with TNBC with TP53 testing (64 patients in the training cohort and 27 patients in the validation cohort). A total of 2832 radiomics features were extracted from the first phase of dynamic contrast-enhanced T1WI, T2WI and ADC maps. Analysis of variance (ANOVA) and the Kruskal-Wallis-test were used for feature selection. Then, linear discriminant analysis (LDA), multilayer perceptron (MLP), logistic regression (LR), LR with LASSO, decision tree (DT), naïve Bayes (NB), random forest (RF), and support vector machine (SVM) models were used for classification.ResultsThe validation AUCs of the eight classifiers ranged from 0.74 (NB) to 0.85 (SVM). SVM attained the highest AUC (0.85) and diagnostic accuracy (0.82) of all tested models. The top 3 ranking features in the SVM model were T1-square-first order-skewness (coefficient: 1.735), T2-wavelet-LHH-GLCM-joint energy, and T2-wavelet-LHH-GLCM-inverse difference moment (coefficient: -0.654, -0.634).ConclusionsRadiomics-based analysis with the SVM model is recommended for the detection of TP53 mutations in TNBC. Furthermore, T1WI- and T2WI-related features could be used as noninvasive biomarkers for predicting TP53 mutations.
HPV genotyping of cervical histologic specimens of 61, 422 patients from the largest women hospital in China
Authors: Zhong Fangfang , Li Zaibo , Sun Yihua , Xiao Yaoxing , Li Juan , Zhou Xianrong , Cong Qing , Sui Long , Tao Xiang , Zhao Chengquan 
Published: March 2023

ObjectivesWe investigated HPV genotypes in a large cohort of patients with definitive cervical histologic diagnosis.MethodsHPV testing was performed by real-time PCR assay, including 18 high-risk HPV (hrHPV) and 3 low-risk HPV (lrHPV). Totally 61,422 patients with documented HPV genotyping results within 6 months before cervical histologic diagnoses were included.ResultsHrHPV positive rate was 55.1% among all tested cases with the highest in adenosquamous carcinoma (94.1%), followed by squamous cell carcinoma (SCC) (93.7%), cervical intraepithelial neoplasia 2/3 (CIN2/3) (92.8%). HrHPV positive rates were significantly higher in high-grade squamous lesions than in those in glandular lesions. HPV16 was the most common genotype followed by HPV52 and HPV58 in CIN2/3. The most frequent hrHPV genotype in adenocarcinoma in situ (AIS) was HPV18, followed by HPV16, HPV45 and HPV52. In SCC cases, HPV16 was the most common type followed by HPV58, HPV52, HPV18 and HPV33. However, HPV18 showed significantly higher prevalence in adenocarcinoma and adenosquamous carcinoma than in that in SCC. Theoretically, the protective rates of 2/4-valent and 9-valent vaccine were 69.1% and 85.8% for cervical cancers.ConclusionsThe prevalence of HPV genotypes in Chinese population was different from that in Western population. Some hrHPV types were identified in cervical precancerous lesions and cancers, which are not included in current HPV vaccines. These data provide baseline knowledge for future HPV vaccine development.
Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model
Authors: Morales-Cano Daniel , Izquierdo-García Jose Luis , Barreira Bianca , Esquivel-Ruiz Sergio , Callejo Maria , Pandolfi Rachele , Villa-Valverde Palmira , Rodríguez Ignacio , Cogolludo Angel , Ruiz-Cabello Jesus , Perez-Vizcaino Francisco , Moreno Laura 
Published: March 2023

Background: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit.Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20 mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3 mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3 mg/kg/day), or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods.Results:In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA.Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH.
An updated review on phytochemistry and molecular targets of Withania somnifera (L.) Dunal (Ashwagandha)
Authors: Bashir Arsalan , Nabi Masarat , Tabassum Nahida , Afzal Suhaib , Ayoub Mehrose 
Published: March 2023

Withania somnifera (L.) Dunal belongs to the nightshade family Solanaceae and is commonly known as Ashwagandha. It is pharmacologically a significant medicinal plant of the Indian sub-continent, used in Ayurvedic and indigenous systems of medicine for more than 3,000 years. It is a rich reservoir of pharmaceutically bioactive constituents known as withanolides (a group of 300 naturally occurring C-28 steroidal lactones with an ergostane-based skeleton). Most of the biological activities of W. somnifera have been attributed to two key withanolides, namely, withaferin-A and withanolide-D. In addition, bioactive constituents such as withanosides, sitoindosides, steroidal lactones, and alkaloids are also present with a broad spectrum of therapeutic potential. Several research groups worldwide have discovered various molecular targets of W. somnifera, such as inhibiting the activation of nuclear factor kappa-B and promoting apoptosis of cancer cells. It also enhances dopaminergic D2 receptor activity (relief in Parkinson’s disease). The active principles such as sitoindosides VII-X and withaferin-A possess free radical properties. Withanolide-D increases the radio sensitivity of human cancer cells via inhibiting deoxyribonucleic acid (DNA) damage to non-homologous end-joining repair (NHEJ) pathways. Withanolide-V may serve as a potential inhibitor against the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to combat COVID. The molecular docking studies revealed that the withanolide-A inhibits acetyl-cholinesterase in the brain, which could be a potential drug to treat Alzheimer’s disease. Besides, withanolide-A reduces the expression of the N-methyl-D-aspartate (NMDA) receptor, which is responsible for memory loss in epileptic rats. This review demonstrates that W. somnifera is a rich source of withanolides and other bioactive constituents, which can be used as a safe drug for various chronic diseases due to the minimal side effects in various pre-clinical studies. These results are interesting and signify that more clinical trials should be conducted to prove the efficacy and other potential therapeutic effects in human settings.
Ginkgo biloba extract EGb 761® improves cognition and overall condition after ischemic stroke: Results from a pilot randomized trial
Authors: Cui Mei , You Tongyao , Zhao Yuwu , Liu Ruozhuo , Guan Yangtai , Liu Jianren , Liu Xueyuan , Wang Xin , Dong Qiang 
Published: March 2023

Background: Patients who experienced an ischemic stroke are at risk for cognitive impairment. Quantified Ginkgo biloba extract EGb 761® has been used to treat cognitive dysfunction, functional impairment and neuropsychiatric symptoms in mild cognitive impairment and dementia.Objectives: To assess the cognitive-related effects of EGb 761® treatment in patients after acute ischemic stroke, as well as the feasibility of patient selection and outcome measures.Methods: We conducted a randomized, multicentric, open-label trial at 7 centers in China. Patients scoring 20 or lower on the National Institutes of Health Stroke Scale were enrolled between 7 and 14 days after stroke onset and randomly assigned to receive 240 mg per day of EGb 761® or no additional therapy for 24 weeks in a 1:1 ratio. Both groups received standard treatments for the prevention of recurrent stroke during the trial. General cognitive function and a battery of cognitive tests for sub-domains were evaluated at 24 weeks. All patients were monitored for adverse events.Results: 201 patients ≥50 years old were included, with 100 assigned to the EGb 761® group and 101 to the reference group. The mean change from baseline on the global cognitive function as assessed by the Montreal Cognitive Assessment score was 2.92 in the EGb 761® group and 1.33 in the reference group (between-group difference: 1.59 points; 95% confidence interval [CI], 0.51 to 2.67; p &lt; 0.005). For cognitive domains, EGb 761® showed greater effects on the Hopkins Verbal Learning Test Total Recall (EGb 761® change 1.40 vs. reference −0.49) and Form 1 of the Shape Trail Test (EGb 761® change −38.2 vs. reference −15.6). Potentially EGb 761®-related adverse events occurred in no more than 3% of patients.Conclusion: Over the 24-week period, EGb 761® treatment improved overall cognitive performance among patients with mild to moderate ischemic stroke. Our findings provide valuable recommendations for the design of future trials, including the criteria for patient selection.Clinical Trial Registration:www.isrctn.com, identifier ISRCTN11815543.
Effects of various interventions on non-alcoholic fatty liver disease (NAFLD): A systematic review and network meta-analysis
Authors: Wang Xinchen , Jin Xiaoqian , Li Hancheng , Zhang Xianyu , Chen Xi , Lu Kuan , Chu Chenliang 
Published: March 2023

Background: With the increasing prevalence of obesity and metabolic syndrome, the incidence of non-alcoholic fatty liver disease (NAFLD) is also increasing. In the next decade, NAFLD may become the main cause of liver transplantation. Therefore, the choice of treatment plan is particularly important. The purpose of this study was to compare several interventions in the treatment of NAFLD to provide some reference for clinicians in selecting treatment methods.Methods: We searched Public Medicine (PubMed), Medline, Excerpta Medica Database (Embase), and Cochrane Library from January 2013 to January 2023 to identify randomized controlled trials (RCTs) published in English. The network meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Forty-three studies accounting for a total of 2,969 patients were included, and alanine aminotransferase (ALT), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) were selected as outcome measures for analysis and comparison.Results: We evaluated the results of drug, diet, and lifestyle interventions between the intervention and control groups. Curcumin (CUN) and probiotics (PTC) were selected for medication, the Mediterranean diet (MDED) was selected for special diet (SPD), and various kinds of exercise and lifestyle advice were selected for lifestyle interventions (LFT). The SUCRA was used to rank interventions according to the effect on ALT indicators (SUCRA: PTC 80.3%, SPD 65.2%, LFT 61.4%, PLB 32.8%, CUN 10.2%), TC indicators (SUCRA: PTC 89.4%, SPD 64%, CUN 34%, LFT 36.6%, PLB 17%), and LDL indicators (SUCRA: PTC 84.2%, CUN 69.5%, LFT 51.7%, PLB 30.1%, SPD 14.5%). The pairwise meta-analysis results showed that MDED was significantly better than NT in improving ALT [SMD 1.99, 95% CI (0.38, 3.60)]. In terms of improving TC and LDL, ATS was significantly better than NT [SMD 0.19, 95% CI (0.03, 0.36)] [SMD 0.18, 95% CI (0.01, 0.35)].Conclusion: Our study showed that PTC is most likely to be the most effective treatment for improving NAFLD indicators. Professional advice on diet or exercise was more effective in treating NAFLD than no intervention.