bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of a prediction model for therapeutic response and prognosis based on chemokine signaling-related genes in stage I–III lung squamous cell carcinoma
Authors: Lai Jinzhi , Yang Shiyu , Chu Shuqiang , Xu Tianwen , Huang Jingshan 
Published: August 2022

Background: The chemokine signaling pathway plays an essential role in the development, progression, and immune surveillance of lung squamous cell carcinoma (LUSC). Our study aimed to systematically analyze chemokine signaling-related genes (CSRGs) in LUSC patients with stage I–III disease and develop a prediction model to predict the prognosis and therapeutic response.Methods: A total of 610 LUSC patients with stage I–III disease from three independent cohorts were included in our study. Least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox regression analyses were used to develop a CSRG-related signature. GSVA and GSEA were performed to identify potential biological pathways. The ESTIMATE algorithm, ssGSEA method, and CIBERSORT analyses were applied to explore the correlation between the CSRG signature and the tumor immune microenvironment. The TCIA database and pRRophetic algorithm were utilized to predict responses to immunochemotherapy and targeted therapy.Results: A signature based on three CSRGs (CCL15, CXCL7, and VAV2) was developed in the TCGA training set and validated in the TCGA testing set and GEO external validation sets. A Kaplan–Meier survival analysis revealed that patients in the high-risk group had significantly shorter survival than those in the low-risk group. A nomogram combined with clinical parameters was established for clinical OS prediction. The calibration and DCA curves confirmed that the prognostic nomogram had good discrimination and accuracy. An immune cell landscape analysis demonstrated that immune score and immune-related functions were abundant in the high-risk group. Interestingly, the proportion of CD8 T-cells was higher in the low-risk group than in the high-risk group. Immunotherapy response prediction indicated that patients in the high-risk group had a better response to CTLA-4 inhibitors. We also found that patients in the low-risk group were more sensitive to first-line chemotherapeutic treatment and EGFR tyrosine kinase inhibitors. In addition, the expression of genes in the CSRG signature was validated by qRT‒PCR in clinical tumor specimens.Conclusion: In the present study, we developed a CSRG-related signature that could predict the prognosis and sensitivity to immunochemotherapy and targeted therapy in LUSC patients with stage I–III disease. Our study provides an insight into the multifaceted role of the chemokine signaling pathway in LUSC and may help clinicians implement optimal individualized treatment for patients.
Cuproptosis scoring model predicts overall survival and assists in immunotherapeutic decision making in pancreatic carcinoma
Authors: Liu Tijun , Liu Qing , Wang Yongju , Yang Rong , Tian Fang 
Published: August 2022

Background: Cuproptosis is a newly identified form of non-apoptotic cell death that is associated with the progression and treatment responses in pancreatic adenocarcinoma (PAAD). However, its impact on oncology and tumor microenvironment (TME) remains unclear.Methods: Hub genes were identified using least absolute shrinkage and selection operator (LASSO) Cox regression for 25 newly reported cuproptosis-related regulators and subjected to stepwise regression to obtain cuproptosis-related score (CuRS). Additionally, the clinical significance, functional status, role on TME, and genomic variation of CuRS were further examined systematically.Results: A CuRS model incorporating TRAF2, TRADD, USP21, FAS, MLKL, TNFRSF10B, MAPK8, TRAF5, and RIPK3 was developed. The stability and accuracy of this risk model as an independent prognostic factor for PAAD were confirmed in the training and external validation cohorts. Patients in the high-CuRS group had “cold” tumors with active tumor proliferation and immunosuppression, whereas those in the low-CuRS group comprised “hot” tumors with active immune function and cell killing capacity. Additionally, patients in the high-CuRS group carried fewer genomic copy number variations (CNVs) and greater somatic mutations. Furthermore, patients in the low- and high-CuRS groups exhibited increased sensitivity to immunotherapy and chemotherapy, respectively.Conclusion: We developed and validated a robust CuRS model based on cuproptosis to assess patients’ prognoses and guide clinical decision-making. Overall, the findings of this study are expected to contribute to the comprehensive understanding of cuproptosis and facilitate precise treatment of PAAD.
Construction and verification of a novel hypoxia-related lncRNA signature related with survival outcomes and immune microenvironment of bladder urothelial carcinoma by weighted gene co-expression network analysis
Authors: Cai Dawei , Zhou Zhongbao , Wei Guangzhu , Wu Peishan , Kong Guangqi 
Published: August 2022

Background: Bladder urothelial carcinoma (BLCA) is a common malignant tumor with the greatest recurrence rate of any solid tumor. Hypoxia is crucial in the growth and immune escape of malignant tumors. To predict clinical outcomes and immunological microenvironment of patients with BLCA, a hypoxia-related long non-coding RNA (HRlncRNA) signature was established.Methods: The Cancer Genome Atlas (TCGA) provided us with the differentially expressed profile of HRlncRNAs as well as clinical data from patients with BLCA, and we used weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with malignancies.Results: Finally, Cox analysis revealed that HRlncRNAs, which comprised 13 lncRNAs, were implicated in the predictive signature. The training, testing, and overall cohorts of BLCA patients were divided into the low-risk group and high-risk group based on the median of the risk score. The Kaplan–Meier curves revealed that BLCA patients with a high-risk score had a poor prognosis, and the difference between subgroups was statistically significant. The receiver operating characteristic curves revealed that this signature outperformed other strategies in terms of predicting ability. Multivariate analysis revealed that the risk score was an independent prognostic index for overall survival (HR = 1.411; 1.259–1.582; p &lt; 0.001). Then, a nomogram with clinicopathological features and risk score was established. This signature could effectively enhance the capacity to predict survival, according to the calibration plots, stratification, and clinical analysis. The majority of Kyoto Encyclopedia of Genes and Genomes (KEGG) were WNT, MAPK, and ERBB signaling pathways. Two groups had different immune cell subtypes, immune checkpoints, immunotherapy response, and anti-tumor drug sensitivity, which might result in differing survival outcomes. We then validated the differential expression of signature-related genes between tumor and normal tissues using TCGA paired data.Conclusion: This prognostic signature based on 13 HRlncRNAs may become a novel and potential prognostic biomarker, providing more accurate clinical decision-making and effective treatment for BLCA patients.
Liver transplantation combined with tyrosine kinase inhibitors for the treatment of hepatic metastatic giant gastrointestinal stromal tumors: A case report and literature review
Authors: Qian Jun Lin , Hu Ze Min , He Kun , He Yong Zhu 
Published: August 2022

BackgroundSurgical resection combined with oral tyrosine kinase inhibitors(TKI) is the most effective treatment for gastrointestinal stromal tumor(GIST) liver metastases. Liver transplantation (LT) is the last resort for the treatment of terminal liver malignancy. Whether it can be a potential treatment option for liver metastases from unresectable GIST is worth exploring.Case presentationWe report a 38-year-old woman who underwent jejunal stromal tumor resection and TKI(imatinib) therapy 15 years ago for jejunal stromal tumor liver metastases. During the period from 2015 to 2018, the liver metastases continued to grow after the patient stopped taking imatinib voluntarily, and the patient subsequently underwent multiple interventional surgeries and drug treatments, which were still poorly curative. The tumor was deemed unresectable because it filled the entire liver, and the patient subsequently underwent LT and was treated with imatinib post-operatively, which resulted in no recurrence of the tumor within 18 months of follow-up.Literature reviewThere are few reports in the literature on LT for the treatment of liver metastases from GIST. A systematic review and summary of the current literature by literature search revealed that LT as a last resort for metastatic GIST of the liver remains a major challenge.ConclusionsLT combined with TKI-targeted therapy is a potential therapy worth exploring for patients with unresectable metastatic GIST.
The molecular subtypes of triple negative breast cancer were defined and a ligand-receptor pair score model was constructed by comprehensive analysis of ligand-receptor pairs
Authors: Pan Weijun , Song Kai , Zhang Yunli , Yang Ciqiu , Zhang Yi , Ji Fei , Zhang Junsheng , Shi Jian , Wang Kun 
Published: August 2022

BackgroundIntercellular communication mediated by ligand-receptor interactions in tumor microenvironment (TME) has a profound impact on tumor progression. This study aimed to explore the molecular subtypes mediated by ligand-receptor (LR) pairs in triple negative breast cancer (TNBC), identify the most important LR pairs to construct a prognostic risk model, and study their effect on TNBC immunotherapy.MethodsLR pairs subclasses of TNBC were categorized by consensus clustering based on LR Pairs in METABRIC dataset. Least absolute shrinkage and selection operator (LASSO) Cox regression and stepwise Akaike information criterion (stepAIC) were conducted to build a LR pairs score model. The relationship between LR pairs score and immune cell infiltration, stromal score and immune score associated with TME was analyzed, and the prediction of drug therapy and immunotherapy efficacy by LR pairs score was evaluated.ResultsAccording to the expression pattern of 145 TNBC prognostic LR pairs, the samples were divided into three subclasses with different survival outcomes, copy number variation (CNV), TME immune cell infiltration, stromal score and immune score. The LR pairs score model constructed in the METABRIC dataset was composed of four LR pairs, and its predictive significance for TNBC prognosis was verified in GSE58812 and GSE21653 cohorts. In addition, LR pairs score was negatively correlated with several immune pathways regulating immunity and immune score, and related to the sensitivity of anti-neoplastic drugs and the effect of anti-PD-L1 therapy.ConclusionOur study confirmed the impact of LR pairs on the molecular heterogeneity of TNBC, characterized three LR pairs subtypes with different survival outcomes and TME patterns, and proposed a LR pairs score system with predictive significance for TNBC prognosis and anti-PD-L1 therapeutic effect, which provides a potential evaluation scheme for TNBC management.
Improvement of an interobserver agreement of ARDS diagnosis by adding additional imaging and a confidence scale
Authors: Hagens Laura A. , Van der Ven Fleur L. I. M. , Heijnen Nanon F. L. , Smit Marry R. , Gietema Hester A. , Gerretsen Suzanne C. , Schultz Marcus J. , Bergmans Dennis C. J. J. , Schnabel Ronny M. , Bos Lieuwe D. J. 
Published: August 2022

Acute respiratory distress syndrome (ARDS) often is not recognized in clinical practice, largely due to variation in the interpretation of chest x-ray (CXR) leading to poor interobserver reliability. We hypothesized that the agreement in the interpretation of chest imaging for the diagnosis of ARDS in invasively ventilated intensive care unit patients between experts improves when using an 8-grade confidence scale compared to using a dichotomous assessment and that the agreement increases after adding chest computed tomography (CT) or lung ultrasound (LUS) to CXR. Three experts scored ARDS according to the Berlin definition based on case records from an observational cohort study using a dichotomous assessment and an 8-grade confidence scale. The intraclass correlation (ICC), imaging modality, and the scoring method were calculated per day and compared using bootstrapping. A consensus judgement on the presence of ARDS was based on the combined confidence grades of the experts, followed by a consensus meeting for conflicting scores. In total, 401 patients were included in the analysis. The best ICC was found using an 8-grade confidence scale for LUS (ICC: 0.49; 95%-CI: 0.29–0.63) and CT evaluation (ICC: 0.49; 95%-CI: 0.34–0.61). The ICC of CXR increased by 0.022 and of CT by 0.065 when 8-grade scoring was used instead of the dichotomous assessment. Adding information from LUS or chest CT increased the ICC by 0.25 when using the 8-grade confidence assessment. An agreement on the diagnosis of ARDS can increase substantially by adapting the scoring system from a dichotomous assessment to an 8-grade confidence scale and by adding additional imaging modalities such as LUS or chest CT. This suggests that a simple assessment of the diagnosis of ARDS with a chart review by one assessor is insufficient to define ARDS in future studies.Clinical trial registrationTrialregister.nl (identifier NL8226).
Combined proton radiography and irradiation for high-precision preclinical studies in small animals
Authors: Schneider Moritz , Bodenstein Elisabeth , Bock Johanna , Dietrich Antje , Gantz Sebastian , Heuchel Lena , Krause Mechthild , Lühr Armin , von Neubeck Cläre , Nexhipi Sindi , Schürer Michael , Tillner Falk , Beyreuther Elke , Suckert Theresa , Müller Johannes Richard 
Published: August 2022

Background and purposeProton therapy has become a popular treatment modality in the field of radiooncology due to higher spatial dose conformity compared to conventional radiotherapy, which holds the potential to spare normal tissue. Nevertheless, unresolved research questions, such as the much debated relative biological effectiveness (RBE) of protons, call for preclinical research, especially regarding in vivo studies. To mimic clinical workflows, high-precision small animal irradiation setups with image-guidance are needed.Material and methodsA preclinical experimental setup for small animal brain irradiation using proton radiographies was established to perform planning, repositioning, and irradiation of mice. The image quality of proton radiographies was optimized regarding the resolution, contrast-to-noise ratio (CNR), and minimal dose deposition in the animal. Subsequently, proof-of-concept histological analysis was conducted by staining for DNA double-strand breaks that were then correlated to the delivered dose.ResultsThe developed setup and workflow allow precise brain irradiation with a lateral target positioning accuracy of&lt;0.26mm for in vivo experiments at minimal imaging dose of&lt;23mGy per mouse. The custom-made software for image registration enables the fast and precise animal positioning at the beam with low observer-variability. DNA damage staining validated the successful positioning and irradiation of the mouse hippocampus.ConclusionProton radiography enables fast and effective high-precision lateral alignment of proton beam and target volume in mouse irradiation experiments with limited dose exposure. In the future, this will enable irradiation of larger animal cohorts as well as fractionated proton irradiation.
Myricitrin inhibits fibroblast-like synoviocyte-mediated rheumatoid synovial inflammation and joint destruction by targeting AIM2
Authors: Shen Chuyu , Xu Meilin , Xu Siqi , Zhang Shuoyang , Lin Wei , Li Hao , Zeng Shan , Qiu Qian , Liang Liuqin , Xiao Youjun , Xu Hanshi 
Published: August 2022

Objective: To explore the effect and underlying mechanism of Myricitrin (Myr) in regulating fibroblast-like synoviocyte (FLS)-mediated synovitis and joint destruction in RA.Methods: FLSs were isolated from synovial tissues from patients with RA. Gene expression was measured using quantitative RT-qPCR. Protein expression was detected by immunohistochemistry or Western blot. Cell apoptosis was performed by an Annexin-PI staining assay. EdU incorporation was used to assess the proliferation of RA FLS. Transwell assay was used to characterize the cell migration and invasion ability of RA FLS. The potential target of Myr was identified by RNA sequencing analysis. The in vivo effect of Myr was assessed in a collagen-induced arthritis (CIA) model.Results: Myr treatment inhibited the lamellipodia formation, migration, and invasion, but not the apoptosis and proliferation, of RA FLSs. Myr also reduced the expression of CCL2, IL-6, IL-8, MMP-1, MMP-3, and MMP-13 induced by TNF-α. The RNA-seq results indicated that AIM2 may be a target gene of Myr in RA FLSs. Furthermore, compared to healthy controls, AIM2 expression showed higher levels in synovial tissues and FLSs from RA patients. AIM2 knockdown also inhibited RA FLS migration, invasion, cytokine, and MMP expression. In addition, either Myr treatment or AIM2 knockdown reduced the phosphorylation of AKT induced by TNF-α stimulation. Importantly, Myr administration relieved arthritis symptoms and inhibited AIM2 expression in the synovium of CIA mice.Conclusion: Our results indicate that Myr exerts an anti-inflammatory and anti-invasion effect in RA FLSs and provide evidence of the therapeutic potential of Myr for RA.
Preclinical evidence and possible mechanisms of β-asarone for rats and mice with Alzheimer’s disease: A systematic review and meta-analysis
Authors: Du Xin-Yuan , Cao Yu-Shuang , Yang Juan , Guo Li-Chen , Zhang Tong , Yuan Qing , Chen Xi , Hu Li-min 
Published: August 2022

Background: Currently, there are many different drugs to improve Alzheimer’s disease (AD) from different pathways. As a supplement and alternative medicine, traditional Chinese medicine (TCM) targets multiple pathways which may be different from classical Western medicine, which may be orchestrated with Western medicine to materialize multiplying efficacy in AD patients.Objective: To investigate the therapeutic effect and assess the available preclinical evidence and possible mechanisms of β-asarone which was extracted from Acorus gramineus Soland (Araceae, AGS) for AD based on rat and mouse animal models.Methods: PubMed, Embase, Scopus, Cochrane Library, BIOSIS Previews, Web of Science, EBSCO, and Google Scholar were searched from inception to 5 May 2022. Rat and mouse experiments assessing the therapeutic effects of β-asarone for AD were included. Primary outcomes were neuroethology, including escape latency and times of crossing platform. Second outcomes were cell apoptosis, including Bax and Bcl-2. The weighted mean difference (WMD) was generated for continuous variables. The relative outcomes were analyzed with the aid of Get Data Graph Digitizer 2.26 and software STATA version 16.0 MP.Results: For the primary endpoint, compared with the modeling group, β-asarone significantly decreased the escape latency (WMD = -12.61, 95% CI: -18.66 to -6.57) and increased the times of crossing platform (WMD = 1.50, 95% CI: 0.31–2.70). For the secondary endpoint, β-asarone remarkably reduced the relative expression of the amyloid precursor protein (APP) (WMD = −2.25, 95% CI: −2.49 to −2.01), decreased the expression of the apoptosis-related protein, associated X protein (Bax) (WMD = −2.40, 95% CI: −3.51 to −1.29), lowered the expression of apoptosis-related protein, B-cell lymphoma-2 (Bcl-2) (WMD = 0.42, 95% CI: 0.38–0.46), and decreased the signal pathway-related proteins, phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) (WMD = −0.70, 95% CI: −0.93 to −0.47) over the control group.Conclusion: β-asarone spectacularly improved the learning ability and memory in rats and mice, which might be correlated with its potential neuroprotective effect through multiple signaling pathways.
Trends in orphan drug use and spending among children and adolescents during 2010–2020 in Korea
Authors: Oh Jung Yeon , Lee Jin Yong , Kim Dong-Sook 
Published: August 2022

Background: Since 2014 in Korea, the Ministry of Food and Drug Safety has designated orphan drugs (ODs) for the treatment of rare diseases. This study investigated the market share and 20 most frequently prescribed therapeutic subgroups of ODs among children and adolescents in Korea.Methods: This study referenced the Korean national health insurance database from January 2010 through December 2020. The outcome measures were the number of prescriptions and expenditures on ODs.Results: Among children aged 0–12 years, the number of patients using ODs increased from 11,264 in 2010 to 14,017 in 2020. Expenditures on ODs and their proportion of total pharmaceutical expenditures also tripled from 13.3 million USD (1.2%) in 2010 to 46.4 million USD (6.2%) in 2020. Among the overall population and adolescents aged 13–17 years, the percentage of total pharmaceutical expenditures for ODs increased from 0.4% in 2010 to 3.2% in 2020 and from 2.1% in 2010 to 11.2% in 2020, respectively. The highest numbers and drug costs of child patients were for H01 (pituitary and hypothalamic hormones and analogues, 44,839) and A16 (other alimentary tract and metabolism products, 160 million USD). The individual ODs with the highest drug costs were A16AB09 (idursulfase, 82.4 million USD) and M09AX07 (nusinersen, 36.2 million USD).Conclusion: Although the market size of ODs remained small in Korea, both the number of approved ODs and the proportion of total pharmaceutical expenditures for ODs have increased. Additional policies related to designation and reimbursement should be put in place to ensure timely access to ODs.