bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exome sequencing link mutation in RGPD4 with systemic sclerosis-associated interstitial lung disease and the low level of testosterone—an exploration study
Authors: Wang Na , Zhang Qian , Sun Wei , Yang Xiaoyu , Huang Hui , Xu Zuojun 
Published: September 2022

BackgroundInterstitial lung disease (ILD) is the most common and potentially most devastating manifestation of SSc in pulmonary involvement. However, the mechanism for systemic sclerosis-associated ILD (SSc-ILD) is unclear. This work aims to explore the potential candidates for SSc-ILD upon whole exome sequencing (WES) and attempts to analyze the possible pathogenesis of SSc-ILD from the perspective of the genetic level.MaterialsVariants were confirmed by whole exome sequencing (WES), and SKAT analysis was employed to explore the most differential variants. Targeted variants were performed in biological functions, associated with clinical manifestations, and the probable change of downstream.ResultsBy WES and SKAT analysis of SSc with and without ILD, only the variants of RGPD4 achieved statistical power (P &lt; 2.51 × 10-6, P-FDR = 0.025, OR = 15.95). A total of 20 rare functional variants (missense, truncating, splicing) were tested for the RGPD4 gene, and five truncating and damaging missense variants were identified. Carriers showed the older inclusion age (P = 0.02) and the higher frequency use of prednisone (P=0.02) compared to the non-carriers. Further analysis illustrated that carriers showed lower levels of TES in comparison to non-carriers but did not reach statistical difference (P = 0.08). In bivariate correlation analysis, we analyzed the relationship between the mutant status of RGPD4 and the levels of sex hormones after adjusting for age confounders. Only the level of TES showed a negative correlation with the mutant status (B = -0.509, P = 0.037).ConclusionThe variants of RGPD4 might contribute to the ILD development of SSc and might also be a causative factor of lower TES among SSc-ILD, which provided insight to a better understanding of pathobiology of SSc-ILD, and androgen hormone supplement might be a therapeutic target in this debilitating disease.
A comprehensive role evaluation and mechanism exploration of POGLUT2 in pan-cancer
Authors: Xu Xianyun , Xie Guangming , Xie Mingfeng , Liu Qian 
Published: September 2022

ObjectiveTo evaluate the role of POGLUT2 in pan-cancer through bioinformatics analysis and experimental verification.MethodsExpression, gene mutation and amplification, methylation, and copy number alteration (CNA) of POGLUT2 were evaluated using The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) databases. Moreover, POGLUT2 on survival and disease progression in pan-cancer was performed using TCGA data. Immune infiltration and tumor microenvironment evaluations were assessed by ImmuneScore, ImmuCellAI, and TIMER databases. POGLUT2 correlated drug resistance analysis was performed using the GDSC2 database. Furthermore, POGLUT2 knockdown of breast cancer cells was established, followed by in vitro biological function assays and in vivo tumor growth study. The mechanisms of POGLUT2 in breast cancer were briefly evaluated via its connection with Notch signaling.ResultsIncreased levels of POGLUT2 were found in multiple types of cancer tissues and cell lines. Moreover, increased gene mutation and amplification, methylation, and CNA of POGLUT2 were found in several types of cancers. POGLUT2 was mainly expressed in stromal cells as verified by StromalScore, ESTIMATEScore, ImmuneScore, and Tumor purity, and POGLUT2 was positively correlated with cancer-associated fibroblasts, macrophages, monocytes, and neutrophils in the tumor microenvironment. In vitro and in vivo results showed that POGLUT2 knockdown could delay tumor growth and progression. Notch signaling components were related to the function of POGLUT2.ConclusionsIncreased levels of POGLUT2 could result in the dysregulated immune cell infiltration and tumor microenvironment and showed a significant regulatory effect on the progression of breast cancer through Notch-related signaling.
Identification of an amino acid metabolism-associated gene signature predicting the prognosis and immune therapy response of clear cell renal cell carcinoma
Authors: Zhang Fan , Lin Junyu , Zhu Daiwen , Tang Yongquan , Lu Yiping , Liu Zhihong , Wang Xianding 
Published: September 2022

BackgroundThe upregulation of amino acid metabolism is an essential form of metabolic reprogramming in cancer. Here, we developed an amino acid metabolism signature to predict prognosis and anti-PD-1 therapy response in clear cell renal cell carcinoma (ccRCC).MethodsAccording to the amino acid metabolism-associated gene sets contained in the Molecular Signature Database, consensus clustering was performed to divide patients into two clusters. An amino acid metabolism-associated signature was identified and verified. Immune cell infiltrates and their corresponding signature risk scores were investigated. Two independent cohorts of clinical trials were analyzed to explore the correspondence between the signature risk score and the immune therapy response.ResultsTwo clusters with different amino acid metabolic levels were identified by consensus clustering. The patients in the two clusters differed in overall survival, progression-free survival, amino acid metabolic status, and tumor microenvironment. We identified a signature containing eight amino acid metabolism-associated genes that could accurately predict the prognosis of patients with ccRCC. The signature risk score was positively correlated with infiltration of M1 macrophages, CD8+ T cells, and regulatory T cells, whereas it was negatively correlated with infiltration of neutrophils, NK cells, and CD4+ T cells. Patients with lower risk scores had better overall survival but worse responses to nivolumab.ConclusionAmino acid metabolic status is closely correlated with tumor microenvironment, response to checkpoint blockade therapy, and prognosis in patients with ccRCC. The established amino acid metabolism-associated gene signature can predict both survival and anti-PD-1 therapy response in patients with ccRCC.
Dual-layer dual-energy CT for improving differential diagnosis of squamous cell carcinoma from adenocarcinoma at gastroesophageal junction
Authors: Wu Meihong , Sheng Mao , Li Ruomei , Zhang Xinna , Chen Xingbiao , Liu Yin , Liu Bin , Yu Yongqiang , Li Xiaohu 
Published: September 2022

ObjectiveTo examine the clinical values of dual-energy CT parameters derived from dual-layer spectral detector CT (SDCT) in the differential diagnosis of squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the gastroesophageal junction (GEJ).MethodsTotally 66 patients with SCC and AC of the GEJ confirmed by pathological analysis were retrospectively enrolled, and underwent dual-phase contrast-enhancement chest CT with SDCT. Plain CT value, CT attenuation enhancement (△CT), iodine concentration (IC), spectral slope (λHU), effective atomic number (Zeff) and 40keV CT value (CT40keV) of the lesion in the arterial phase (AP) and venous phase (VP) were assessed. Multivariate logistic regression analysis was performed to evaluate the diagnostic efficacies of different combinations of dual-energy CT parameters. Receiver operating characteristic (ROC) curves were used to analyze the accuracy of dual-energy CT parameters and Delong test was used to compare AUCs.ResultsIC, λHU, Zeff and CT40keV in AP and VP and △CT in VP were significantly higher in the AC group than those in the SCC group (all P&lt;0.05). ROC curve analysis showed that IC, λHU, Zeff and CT40keV in VP had high diagnostic performances, with AUCs of 0.74, 0.74, 0.79 and 0.78, respectively. Logistic regression showed the combination of ICVP, λHU VP, CT40keV VP and Zeff VP had the highest AUC (0.84), with a threshold of 0.40, sensitivity and specificity in distinguishing SCC and AC were 93.1% and 73.0%, respectively. Delong test showed that the AUC of △CTVP was lower than other AUCs of dual-energy CT parameters.ConclusionDual-energy CT parameters derived from SDCT provide added value in the differential diagnosis of SCC and AC of the GEJ, especially the combination of IC, λHU, CT40keV and Zeff in VP.Advances in knowledgeDual-energy CT parameters derived from dual-layer spectral detector CT provide added value to differentiate AC from SCC at the GEJ, especially the combination of effective atomic number, spectral slope, iodine concentration and 40keV CT value in VP.
Machine learning models predict lymph node metastasis in patients with stage T1-T2 esophageal squamous cell carcinoma
Authors: Li Dong-lin , Zhang Lin , Yan Hao-ji , Zheng Yin-bin , Guo Xiao-guang , Tang Sheng-jie , Hu Hai-yang , Yan Hang , Qin Chao , Zhang Jun , Guo Hai-yang , Zhou Hai-ning , Tian Dong 
Published: September 2022

BackgroundFor patients with stage T1-T2 esophageal squamous cell carcinoma (ESCC), accurately predicting lymph node metastasis (LNM) remains challenging. We aimed to investigate the performance of machine learning (ML) models for predicting LNM in patients with stage T1-T2 ESCC.MethodsPatients with T1-T2 ESCC at three centers between January 2014 and December 2019 were included in this retrospective study and divided into training and external test sets. All patients underwent esophagectomy and were pathologically examined to determine the LNM status. Thirty-six ML models were developed using six modeling algorithms and six feature selection techniques. The optimal model was determined by the bootstrap method. An external test set was used to further assess the model’s generalizability and effectiveness. To evaluate prediction performance, the area under the receiver operating characteristic curve (AUC) was applied.ResultsOf the 1097 included patients, 294 (26.8%) had LNM. The ML models based on clinical features showed good predictive performance for LNM status, with a median bootstrapped AUC of 0.659 (range: 0.592, 0.715). The optimal model using the naive Bayes algorithm with feature selection by determination coefficient had the highest AUC of 0.715 (95% CI: 0.671, 0.763). In the external test set, the optimal ML model achieved an AUC of 0.752 (95% CI: 0.674, 0.829), which was superior to that of T stage (0.624, 95% CI: 0.547, 0.701).ConclusionsML models provide good LNM prediction value for stage T1-T2 ESCC patients, and the naive Bayes algorithm with feature selection by determination coefficient performed best.
Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in children with leukemia/lymphoma: A retrospective case series
Authors: Zhang Yucai , Zhou Yiping , Shi Jingyi , Shan Yijun , Sun Ting , Wang Chunxia , Shao Jingbo , Cui Yun 
Published: September 2022

ObjectiveThe cancer patients with severe acute respiratory distress syndrome (ARDS) benefit from extracorporeal membrane oxygenation (ECMO) remains unanswered. We analyzed clinical characteristics and outcomes of pediatric patients with leukemia/lymphoma who developed ARDS and treated with ECMO.MethodsPediatric leukemia or lymphoma patients with ARDS who underwent ECMO between August 2017 and December 2021 were retrospectively analyzed in a tertiary pediatric intensive care unit (PICU).ResultsSeven patients with median age 53 (IQR 42–117) months and 4 males were included. Six cases of leukemia [5 of acute lymphocytic leukemia (ALL) and 1 of acute myelogenous leukemia (AML, M5)] and 1 of non-Hodgkin lymphoma with severe ARDS received ECMO on chemotherapy period. The etiology of ARDS is community or chemotherapy-associated bacterial or/and fungal or viral infection. All the patients received chemotherapy in the 2 weeks prior to ECMO and five were neutropenic at initial ECMO. Six cases underwent veno-arterial ECMO (VA ECMO) and 1 for veno-venous ECMO (VV-ECMO). The median duration of ECMO support was 122 (IQR 56–166) hours. Overall, 42.9% (three of seven) survived to hospital discharge and 6 months survival rate was 28.6% (two of seven). Bleeding was the main ECMO-associated complication occurring in 7 patients, followed by nosocomial infection in 4 cases. All the patients required vasopressor support, and 6 received continuous renal replacement therapy (CRRT).ConclusionOur experiences suggest that rescue ECMO provides a selective treatment strategy in childhood hematologic malignancies with severe ARDS.
Cross-sectional study of the prevalence of prescription opioids misuse in French patients with chronic non-cancer pain: An update with the French version of the POMI scale
Authors: Kerckhove Nicolas , Delage Noémie , Bertin Célian , Kuhn Emmanuelle , Cantagrel Nathalie , Vigneau Caroline , Delorme Jessica , Lambert Céline , Pereira Bruno , Chenaf Chouki , Authier Nicolas ,   Poma Network
Published: September 2022

Public health issues related to chronic pain management and the risks of opioid misuse and abuse remain a challenge for practitioners. Data on the prevalence of disorders related to the use of prescribed opioids in patients suffering from chronic pain remains rather patchy, in particular because of the absence of a gold standard for their clinical assessment. We estimated the prevalence of prescription opioid misuse (POM), using a specific and validated opioid misuse scale (POMI-5F scale), in adults with chronic non-cancer pain. Nine-hundred-fifty-one (951) patients with opioids prescription and followed-up in pain clinics and addictology centers for chronic non-cancer pain (CNCP) completed the survey interview. The results suggest that 44.4% of participants have POM, accompanied by overuse (42.5%), use of opioids for effects other than analgesia (30.9%), withdrawal syndrome (65.7%), and craving (6.9%). The motivations cited for POM, apart from pain relief, were to calm down, relax and improve mood. POM was shown to be related to male sex (OR 1.52), young age (OR 2.21) and the presence of nociplastic pain (OR 1.62) of severe intensity (OR 2.31), codeine use (OR 1.72) and co-prescription of benzodiazepines (OR 1.59). Finally, despite the presence of three subgroups of misusers, no factor was associated with the intensity of misuse, reinforcing the view that distinguishing between strong and weak opioids is not appropriate in the context of use disorder. Almost half of patients with CNCP misuse their prescribed opioid. Practitioners should be attentive of profiles of patients at risk of POM, such as young, male patients suffering from severe nociplastic pain, receiving prescription for codeine and a co-prescription for benzodiazepine. We encourage French-speaking practitioners to use the POMI-5F scale to assess the presence of POM in their patients receiving opioid-based therapy.Clinical Trial Registrationclinicaltrials.gov, identifier NCT03195374
A high throughput method for Monitoring of Sorafenib, regorafenib, cabozantinib and their metabolites with UPLC-MS/MS in rat plasma
Authors: Gu Er-Min , Liu Ya-Nan , Pan Lvjun , Hu Yingying , Ye Xuemei , Luo Pingping 
Published: September 2022

As multi-targeted tyrosine kinase inhibitors, sorafenib, regorafenib and cabozantinib are widely used in hepatocellular carcinoma (HCC) for systemic therapies with anti-proliferative and anti-angiogenic effects. Nevertheless, adverse effects or insufficient efficacy appear frequently due to the plasma concentration with individual variability of these drugs. To ensure the curative effect and safety by therapeutic drug monitoring (TDM), this study developed a high throughput method to quantify sorafenib, regorafenib, cabozantinib and their active metabolites in plasma simultaneously. The chromatographic separation analysis achievement was performed on a Waters-ACQUITY UPLC BEH C18 column by UPLC-MS/MS system using a gradient elution of solvent A (acetonitrile) and solvent B (water with 0.1% formic acid) in 3.0 min. This method presented satisfactory results of specificity, precision (the intra-day coefficient of variation was between 2.5% and 6.6%, and the inter-day coefficient of variation was between 4.0% and 11.1%) and accuracy (within ±15% for intra-day and inter-day), as well as the stability under certain conditions, the matrix effect in plasma, and extraction recovery (75.6%–94.4%). The linearity of each analyte in the proper concentration scope indicated excellent. This study strictly complied with the performance rules of assay validation in biological medium proposed by FDA and was successfully applied to the pharmacokinetic study in rats. Thus, it would be an advantageous option to research the relationship between concentration-efficacy and concentration-toxic in HCC patients who were supposed to take these medications.
Virtual screening and activity evaluation of multitargeting inhibitors for idiopathic pulmonary fibrosis
Authors: Wang Rui , Xu Jian , Yan Rong , Liu Huanbin , Zhao Jingxin , Xie Yuan , Deng Wenbin , Liao Weiping , Nie Yichu 
Published: September 2022

Transforming growth factor β receptor (TGF-β1R) and receptor tyrosine kinases (RTKs), such as VEGFRs, PDGFRs and FGFRs are considered important therapeutic targets in blocking myofibroblast migration and activation of idiopathic pulmonary fibrosis (IPF). To screen and design innovative prodrug to simultaneously target these four classes of receptors, we proposed an approach based on network pharmacology combining virtual screening and machine learning activity prediction, followed by efficient in vitro and in vivo models to evaluate drug activity. We first constructed Collagen1A2-A549 cells with type I collagen as the main biomarker and evaluated the activity of compounds to inhibit collagen expression at the cellular level. The data from the first round of Collagen1A2-A549 cell screening were substituted into the machine learning model, and the model was optimized accordingly. As a result, the false positive rate of the model was reduced from 85.0% to 66.7%, and two prospective compounds, Z103080500 and Z104578368, were finally selected. Collagen levels were reduced effectively by both Z103080500 (67.88% reduction) and Z104578368 (69.54% reduction). Moreover, these two compounds showed low cellular cytotoxicity. Subsequently, the effect of Z103080500 and Z104578368 was evaluated in a bleomycin-induced C57BL/6 mouse IPF model. These results showed that 50 mg/kg Z103080500 and Z104578368 could effectively reduce the number of inflammatory cells and the expression level of α-SMA. Meanwhile, Z103080500 and Z104578368 reduced the expression of major markers and inflammatory factors of IPF, such as collagen, IFN-γ, IL-17 and HYP, indicating that these screened Z103080500 and Z104578368 effectively delayed lung tissue inflammation and had a potential therapeutic effect on IPF. Our findings demonstrate that a screening and evaluation model for prodrug against IPF has been successfully established. It is of great significance to further modify these compounds to enhance their potency and activity.
Caloric restriction prevents obesity- and intermittent hypoxia-induced cardiac remodeling in leptin-deficient ob/ob mice
Authors: Jones Aaron A. , Framnes-DeBoer Sarah N. , Shipp Arianne , Arble Deanna M. 
Published: September 2022

Background: Intermittent hypoxia (IH), a key characteristic of obstructive sleep apnea, is independently associated with cardiometabolic impairment. While endogenous leptin levels may provide cardioprotective effects against hypoxia, leptin resistance is common among obese individuals presenting with obstructive sleep apnea.Methods: Here, we assessed left ventricle (LV) function using M-mode echocardiography in lean wild-type, calorically-restricted ob/ob, and obese ob/ob mice before and after 6 days of IH to determine how obesity and intermittent hypoxia interact to affect cardiac function independent of leptin signaling.Results: Calorically-restricting ob/ob mice for 4 weeks prior to IH exposure prevented weight gain (−2.1 ± 1.4 g) compared to free-fed ob/ob mice (8.7 ± 1.1 g). Free-fed ob/ob mice exhibited increased LV mass (0.713 ± 0.008 g) relative to wild-type mice (0.685 ± 0.004 g) and increased posterior wall thickness (0.089 ± 0.006 cm) relative to calorically-restricted ob/ob mice (0.072 ± 0.004 cm). Following 6 days of IH, free-fed ob/ob mice exhibited increases in cardiac output (44.81 ± 2.97 pre-IH vs. 57.14 ± 3.09 ml/min post-IH), LV diameter (0.400 ± 0.007 pre-IH vs. 0.428 ± 0.009 cm post-IH) and end diastolic volume (0.160 ± 0.007 pre-IH vs. 0.195 ± 0.012 ml post-IH) that were not detected in wild-type or calorically-restricted ob/ob mice.Conclusion: Caloric restriction can prevent obesity-induced LV hypertrophy and protect against acute IH-induced cardiac remodeling independent of leptin signaling. These findings may have clinical implications for obstructive sleep apnea.
Assessing the effects of artificial gravity in an analog of long-duration spaceflight: The protocol and implementation of the AGBRESA bed rest study
Authors: Clément Gilles , Rittweger Jörn , Nitsche Andrea , Doering Wolfgang , Frings-Meuthen Petra , Hand Olga , Frett Timo , Noppe Alexandra , Paulke Freia , Lecheler Leopold , Jordan Jens , Stern Claudia , Mulder Edwin 
Published: September 2022

A comprehensive strategy is required to mitigate risks to astronauts’ health, well-being, and performance. This strategy includes developing countermeasures to prevent or reduce adverse responses to the stressors astronauts encounter during spaceflight, such as weightlessness. Because artificial gravity (AG) by centrifugation simultaneously affects all physiological systems, AG could mitigate the effects of weightlessness in multiple systems. In 2019, NASA and the German Aerospace Center conducted a 60-days Artificial Gravity Bed Rest Study with the European Space Agency (AGBRESA). The objectives of this study were to 1) determine if 30 min of AG daily is protective during head down bed rest, and 2) compare the protective effects of a single daily bout (30 min) of AG versus multiple daily bouts (6 × 5 min) of AG (1 Gz at the center of mass) on physiological functions that are affected by weightlessness and by head-down tilt bed rest. The AGBRESA study involved a comprehensive suite of standard and innovative technologies to characterize changes in a broad spectrum of physiological systems. The current article is intended to provide a detailed overview of the methods used during AGBRESA.