bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kanamycin-Mediated Conformational Dynamics of Escherichia coli Outer Membrane Protein TolC
Authors: Pattanayak Biraja S. , Dehury Budheswar , Priyadarshinee Mamali , Jha Suman , Beuria Tushar K. , Soren Dhananjay , Mallick Bairagi C. 
Published: April 2021

TolC is a member of the outer membrane efflux proteins (OEPs) family and acts as an exit duct to export proteins, antibiotics, and substrate molecules across the Escherichia coli cell membrane. Export of these molecules is evidenced to be brought about through the reversible interactions and binding of substrate-specific drug molecules or antibiotics with TolC and by being open for transport, which afterward leads to cross-resistance. Hence, the binding of kanamycin with TolC was monitored through molecular docking (MD), the structural fluctuations and conformational changes to the atomic level. The results were further supported from the steady-state fluorescence binding and isothermal titration calorimetry (ITC) studies. Binding of kanamycin with TolC resulted in a concentration dependent fluorescence intensity quenching with 7 nm blue shift. ITC binding data maintains a single binding site endothermic energetic curve with binding parameters indicating an entropy driven binding process. The confirmational changes resulting from this binding were monitored by a circular dichroism (CD) study, and the results showed insignificant changes in the α-helix and β-sheets secondary structure contents, but the tertiary structure shows inclusive changes in the presence of kanamycin. The experimental data substaintially correlates the RMSD, Rg, and RMSF results. The resulting conformational changes of the TolC-kanamycin complexation was stabilized through H-bonding and other interactions.
Development and Validation of a Nomogram Based on Motoric Cognitive Risk Syndrome for Cognitive Impairment
Authors: Liu Yong , Wei Kai , Cao Xinyi , Jiang Lijuan , Gu Nannan , Feng Lei , Li Chunbo 
Published: April 2021

ObjectiveTo develop and validate a prediction nomogram based on motoric cognitive risk syndrome for cognitive impairment in healthy older adults.MethodsUsing two longitudinal cohorts of participants (aged ≥ 60 years) with 4-year follow-up, we developed (n = 1,177) and validated (n = 2,076) a prediction nomogram. LASSO (least absolute shrinkage and selection operator) regression model and multivariable Cox regression analysis were used for variable selection and for developing the prediction model, respectively. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness.ResultsThe individualized prediction nomogram was assessed based on the following: motoric cognitive risk syndrome, education, gender, baseline cognition, and age. The model showed good discrimination [Harrell’s concordance index (C-index) of 0.814; 95% confidence interval, 0.782–0.835] and good calibration. Comparable results were also seen in the validation cohort, which includes good discrimination (C-index, 0.772; 95% confidence interval, 0.776–0.818) and good calibration. Decision curve analysis demonstrated that the prediction nomogram was clinically useful.ConclusionThis prediction nomogram provides a practical tool with all necessary predictors, which are accessible to practitioners. It can be used to estimate the risk of cognitive impairment in healthy older adults.
Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis
Authors: Chen Shixue , Zhang Zhibo , Zheng Xuan , Tao Haitao , Zhang Sujie , Ma Junxun , Liu Zhefeng , Wang Jinliang , Qian Yuanyu , Cui Pengfei , Huang Di , Huang Ziwei , Wu Zhaozhen , Hu Yi 
Published: April 2021

BackgroundImmune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens.MethodsPublished articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata.ResultsA total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09–24.03), a median TTR of 2.05 months (m) (95%CI: 1.85–2.26), and a median DOR of 10.65 m (95%CI: 7.78–13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02–57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47–21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56–22.94]), while I+C (8.09 m [95%CI: 6.86–9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60–17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations.ConclusionsPD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.
RETRACTED: Circular RNA hsa_circ_0013958 Functions as an Oncogenic Gene Through Modulating miR-532-3p/WEE1 Axis in Hepatocellular Carcinoma
Authors: Ma Tao , Ma Yue , Du Yongjun , Wei Zhongheng , Wang Jianchu , Jun Yufu , Xiao Fenqiang 
Published: April 2021

Backgroundcirc0013958 was identified as a biomarker, which can be used for the diagnosis and screening of lung cancer. However, the role of circ0013958 in hepatocellular carcinoma (HCC) remains unclear.MethodsIn our study, quantitative real-time polymerase chain reaction was performed to determine the levels of circ0013958 in HCC tissues and cell lines. EdU, CCK-8, transwell, flow cytometry and tumorigenesis assays were applied to assess the functions of circ0013958 in HCC in vitro and in vivo. Western blot assay was to detect the expression of WEE1. Luciferase reporter assay, bioinformatics analysis and rescue experiments were used to examine the interaction among circ0013958, miR-532-3p and WEE1.ResultsIt revealed that circ0013958 was significantly up-regulated in HCC, which was positively correlated with poor prognosis of HCC patients. Circ0013958 promoted HCC cell proliferation and invasion, inhibited cell apoptosis in vitro, and promoted tumorigenesis in vivo. Circ0013958 acted as a miR-532-3p sponge to regulate WEE1 expression, thus promoting the progression of HCC.ConclusionsCirc0013958 promotes HCC progression through miR-532-3p/WEE1 axis. Circ0013958 may serve as a potential diagnostic biomarker and therapeutic target of HCC.
Preoperative Assessment for Event-Free Survival With Hepatoblastoma in Pediatric Patients by Developing a CT-Based Radiomics Model
Authors: Jiang Yi , Sun Jingjing , Xia Yuwei , Cheng Yan , Xie Linjun , Guo Xia , Guo Yingkun 
Published: April 2021

Objective: To explore a CT-based radiomics model for preoperative prediction of event-free survival (EFS) in patients with hepatoblastoma and to compare its performance with that of a clinicopathologic model.Patients and Methods: Eighty-eight patients with histologically confirmed hepatoblastoma (mean age: 2.28 ± 2.72 years) were recruited from two institutions between 2002 and 2019 for this retrospective study. They were divided into a training cohort (65 patients from institution A) and a validation cohort (23 patients from institution B). Radiomics features were extracted manually from pretreatment CT images in the portal venous (PV) phase. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied to construct a “radiomics signature” and radiomics score (Rad-score) for EFS prediction. Then, a nomogram incorporating the Rad-score, updated staging system, and significant variables of clinicopathologic risk (age, alpha-fetoprotein (AFP) level, histology subtype, tumor diameter) as the radiomic model, clinicopathologic model, and combined clinicopathologic-radiomic model were built for EFS estimation in the training cohort, the performance of which was assessed in an external-validation cohort with respect to clinical usefulness, discrimination, and calibration.Results: Nine survival-relevant features were selected for a radiomics signature and Rad-score building. Multivariable analysis revealed that histology subtype (P = 0.01), PV (P = 0.001) invasion, and metastasis (P = 0.047) were independent risk factors of EFS. Patients were divided into low- and high-risk groups based on the Rad-score with a cutoff of 0.08 according to survival outcome. The radiomics signature-incorporated nomogram showed good performance (P &lt; 0.001) for EFS estimation (C-Index: 0.810; 95% CI: 0.738–0.882), which was comparable with that of the clinicopathological model for EFS estimation (C-Index: 0.81 vs. 0.85). The radiomics-based nomogram failed to show incremental prognostic value compared with that using the clinicopathologic model. The combined model (radiomics signature plus clinicopathologic parameters) showed significant improvement in the discriminatory accuracy, along with good calibration and greater net clinical benefit, of EFS (C-Index: 0.88; 95% CI: 0.829–0.933).Conclusion: The radiomics signature can be used as a prognostic indicator for EFS in patients with hepatoblastoma. A combination of the radiomics signature and clinicopathologic risk factors showed better performance in terms of EFS prediction in patients with hepatoblastoma, which enabled precise clinical decision-making.
Clinicopathological Features and Prognoses in Patients With Brain Metastases From Small-Cell Esophageal Carcinoma: A Retrospective Analysis of 18 Patients
Authors: Jiao Wenpeng , Lin Chi , Xiao Linlin , Zhang Xinyuan , Hu Mengzhu , Zhao Min , Wang Jun 
Published: April 2021

Objective: This study aims to examine the clinical characteristics of patients with brain metastases (BM) from small-cell esophageal carcinoma (SCEC) and to explore the association of the corresponding factors with overall survival (OS).Methods: The data of 18 patients with brain metastases from SCEC, diagnosed from January 1, 2006, to December 31, 2018, in the Fourth Hospital of Hebei Medical University were analyzed retrospectively.Results: The 18 patients who were included in this study accounted for 6.7% of the patients with SCEC diagnosed from 2006 to 2018. Of the 18 patients, 8 (44.4%) were females. For the entire cohort, the median OS was 7 months, the 1-year OS was 22.2%, and the 2-year OS was 0%. For patients who received whole-brain radiotherapy (WBRT) and for those who did not (13 vs. 5), the median OS was 11.9 and 3 months, respectively, and the 1-year OS was 30.8 and 0%, respectively. When comparing diagnosis-specific Graded Prognostic Assessment (DS-GPA) scores of patients with BM from SCEC ranging from 2.5 to 4 and from 0 to 2, the median OS was 13.1 and 4 months, respectively, and the 1-year OS was 57.1 and 0%, respectively. In the univariable regression, patients who received WBRT had improved OS compared to those who did not (HR = 0.249, p = 0.018), and patients with a DS-GPA score of 2.5–4 were associated with improved OS compared with patients with a DS-GPA score of 0–2 (HR = 0.050, p = 0.005).Conclusion: The incidence of brain metastases in patients with SCEC is low, but the prognosis in those patients is very poor. The DS-GPA score may be a prognostic factor of patients with BM from SCEC. Brain radiotherapy could improve the survival of these patients.
Cardioprotective Roles of β-Hydroxybutyrate Against Doxorubicin Induced Cardiotoxicity
Authors: Liu Yihai , Wei Xuan , Wu Mingyue , Xu Jiamin , Xu Biao , Kang Lina 
Published: April 2021

Background: β-Hydroxybutyrate (BHB) is produced by fatty acid oxidation in the liver under the fasting state and confirmed to play a cardioprotective role in ischemia and hypertensive settings. Doxorubicin (DOX) is an effective chemotherapeutic drug, but limited by serious irreversible cardiotoxicity. However, whether BHB can protect from DOX-induced cardiotoxicity remains unknown.Methods and Results: C57BL/6 mice were intraperitoneally injected with DOX to induce cardiac toxicity and intragastrically administered into BHB for treatment. They were randomly divided into three groups, namely a sham group (Sham), a doxorubicin group (DOX), and a doxorubicin+β-Hydroxybutyrate group (DOX + BHB). Echocardiography and pathological staining were performed to evaluate cardiac function and fibrosis. H9c2 cardiomyocyte was treated with DOX or BHB for in vitro experiments. Cell apoptosis and ROS were determined by flow cytometry. BHB significantly restored DOX-induced cardiac function decline and partially prevented cardiac reverse remodeling, characterized by increased cell size and decreased fibrosis. In vitro, BHB treatment decreased cellular injury and apoptosis. Also, BHB alleviated oxidative stress level and increased mitochondrial membrane potential.Conclusion: Our results suggested that BHB could protected from DOX-induced cardiotoxicity by inhibiting cell apoptosis and oxidative stress and maintaining mitochondrial membrane integrity.
The Relationship Between Working Alliance and Symptom Improvement in Cognitive Therapy for Posttraumatic Stress Disorder
Authors: Beierl Esther T. , Murray Hannah , Wiedemann Milan , Warnock-Parkes Emma , Wild Jennifer , Stott Richard , Grey Nick , Clark David M. , Ehlers Anke 
Published: April 2021

Background: Working alliance has been shown to predict outcome of psychological treatments in multiple studies. Conversely, changes in outcome scores have also been found to predict working alliance ratings.Objective: To assess the temporal relationships between working alliance and outcome in 230 patients receiving trauma-focused cognitive behavioral treatment for posttraumatic stress disorder (PTSD).Methods: Ratings of working alliance were made by both the patient and therapist after sessions 1, 3, and 5 of a course of Cognitive Therapy for PTSD (CT-PTSD). Autoregressive, cross-lagged panel models were used to examine whether working alliance predicted PTSD symptom severity at the next assessment point and vice versa. Linear regressions tested the relationship between alliance and treatment outcome.Results: Both patients' and therapists' working alliance ratings after session 1 predicted PTSD symptom scores at the end of treatment, controlling for baseline scores. At each assessment point, higher therapist working alliance was associated with lower PTSD symptoms. Crossed-lagged associations were found for therapist-rated alliance, but not for patient-rated alliance: higher therapists' alliance ratings predicted lower PTSD symptom scores at the next assessment point. Similarly, lower PTSD symptoms predicted higher therapist working alliance ratings at the next assessment point. Ruminative thinking was negatively related to therapists' alliance ratings.Conclusions: Working alliance at the start of treatment predicted treatment outcome in patients receiving CT-PTSD and may be an important factor in setting the necessary conditions for effective treatment. For therapists, there was a reciprocal relationship between working alliance and PTSD symptom change in their patients during treatment, suggesting that their alliance ratings predicted symptom change, but were also influenced by patients' symptom change.
INDEED–Utilization and Cross-Sectoral Patterns of Care for Patients Admitted to Emergency Departments in Germany: Rationale and Study Design
Authors: Fischer-Rosinský Antje , Slagman Anna , King Ryan , Reinhold Thomas , Schenk Liane , Greiner Felix , von Stillfried Dominik , Zimmermann Grit , Lüpkes Christian , Günster Christian , Baier Natalie , Henschke Cornelia , Roll Stephanie , Keil Thomas , Möckel Martin 
Published: April 2021

Introduction: The crowding of emergency departments (ED) has been a growing problem for years, putting the care of critically ill patients increasingly at risk. The INDEED project's overall aim is to get a better understanding of ED utilization and to evaluate corresponding primary health care use patterns before and after an ED visit while driving forward processes and methods of cross-sectoral data merging. We aim to identify adequate utilization of EDs and potentially avoidable patient contacts as well as subgroups and clusters of patients with similar care profiles.Methods: INDEED is a joint endeavor bringing together research institutions and hospitals with EDs in Germany. It is headed by the Charité–Universitätsmedizin Berlin, collaborating with Otto von Guericke University Magdeburg, Technische Universität Berlin, the Central Research Institute of Ambulatory/Outpatient Health Care in Germany (Zi), and the AOK Research Institute as part of the Federal Association of AOK, as well as experts in the technological, legal, and regulatory aspects of medical research (TMF). The Institute for Information Technology (OFFIS) was involved as the trusted third party of the project. INDEED is a retrospective study of approximately 400,000 adult patients with statutory health insurance who visited the ED of one of 16 participating hospitals in 2016. The routine hospital data contain information about treatment in the ED and, if applicable, about the subsequent hospital stay. After merging the patients' hospital data from 2016 with their outpatient billing data from 2 years before to 1 year after the ED visit (years 2014–2017), a harmonized dataset will be generated for data analyses. Due to the complex data protection challenges involved, first results will be available in 2021.Discussion: INDEED will provide knowledge on extracting and harmonizing large scale data from varying routine ED and hospital information systems in Germany. Merging these data with the corresponding outpatient care data of patients offers the opportunity to characterize the patient's treatment in outpatient care before and after ED use. With this knowledge, appropriate interventions may be developed to ensure adequate patient care and to avoid adverse events such as ED crowding.
Notch1 Deficiency Induces Tumor Cell Accumulation Inside the Bronchiolar Lumen and Increases TAZ Expression in an Autochthonous KrasLSL-G12V Driven Lung Cancer Mouse Model
Authors: Meder Lydia , Florin Alexandra , Ozretić Luka , Nill Marieke , Koker Mirjam , Meemboor Sonja , Radtke Freddy , Diehl Linda , Ullrich Roland T. , Odenthal Margarete , Büttner Reinhard , Heukamp Lukas C. 
Published: April 2021

Purpose: Abrogation of Notch signaling, which is pivotal for lung development and pulmonary epithelial cell fate decisions was shown to be involved in the aggressiveness and the differentiation of lung carcinomas. Additionally, the transcription factors YAP and TAZ which are involved in the Hippo pathway, were recently shown to be tightly linked with Notch signaling and to regulate the cell fate in epidermal stem cells. Thus, we aim to elucidate the effects of conditional Notch1 deficiency on carcinogenesis and TAZ expression in lung cancer.Methods: We investigated the effect of conditional Cre-recombinase mediated Notch1 knock-out on lung cancer cells in vivo using an autochthonous mouse model of lung adenocarcinomas driven by KrasLSL-G12V and comprehensive immunohistochemical analysis. In addition, we analyzed clinical samples and human lung cancer cell lines for TAZ expression and supported our findings by publicly available data from The Cancer Genome Atlas (TCGA).Results: In mice, we found induction of papillary adenocarcinomas and protrusions of tumor cells from the bronchiolar lining upon Notch1 deficiency. Moreover, the mutated Kras driven lung tumors with deleted Notch1 showed increased TAZ expression and focal nuclear translocation which was frequently observed in human pulmonary adenocarcinomas and squamous cell carcinomas of the lung, but not in small cell lung carcinomas. In addition, we used data from TCGA to show that putative inactivating NOTCH1 mutations co-occur with KRAS mutations and genomic amplifications in lung adenocarcinomas.Conclusion: Our in vivo study provides evidence that Notch1 deficiency in mutated Kras driven lung carcinomas contributes to lung carcinogenesis in a subgroup of patients by increasing TAZ expression who might benefit from TAZ signaling blockade.
EVALUASI EFEKTIVITAS SISTEM PENGENDALIAN INTERN PIUTANG PADA PERGURUAN TINGGI NEGERI (SUATU STUDI KASUS)
Authors: Hastuti Hastuti , Burhany Dian Imanina , Rufaedah Yanti Rufaedah , Mai Muhammad Umar , Rochendi Hendi Rochendi 
Published: April 2021

This study aims to evaluate the extent to which the internal control system for non-tax state revenue receivables (PNBP) at a vocational college in Bandung has been running effectively, considering the value of the receivables always increases from year to year. This study uses a combined analysis method, namely quantitative and qualitative descriptive and operationalized research variables with reference to the elements of the COSO internal control system adopted in Government Regulation Number 60 of 2008 concerning SPIP (Government Internal Control System) and adapted to the research objectives. The research data consists of primary data and secondary data collected through questionnaires, interviews, observation and documentation. The data analysis used the analysis of the results of the questionnaire on 5 sub variables and 47 indicators of internal control. The research findings show that the overall internal control system for PNBP accounts is still ineffective with an effectiveness score of 0.3821. Because 4 of the 5 control components, namely the control environment, risk assessment, control activities as well as information and communication are still not effective. Meanwhile, one component of control, namely monitoring, is said to be quite effective. Increasing the effectiveness of the implementation of the internal control system for PNBP receivables is expected to be able to improve the performance of the financial department or the organization as a whole by increasing the collectability of PNBP receivables.

Keywords: Effectiveness, Internal Control System, Non-Tax State Revenue Receivables (PNBP)
Nazib Zhiganov Between the Official Ideology and New Music
Authors: Шатрашанова Мария Викторовна 
Published: April 2021

В статье рассматривается личность одного из ведущих татарских композиторов XX века - Назиба Гаязовича Жиганова. Актуальнейшей проблемой, с которой столкнулся композитор, было применение западных техник композиции в творчестве авторов из национальных республик. На сегодняшний день существует представление о Жиганове как о человеке консервативных взглядов, отрицавшем западные новации. Однако композитор был чутким музыкантом, выступавшим за обновление национального языка и обладавшим умением увидеть позитивные стороны новой музыки.
The main theme of this article is personality of Nazib Gayazovich Zhiganov who was one of the leading tatar composers in the 20 century. The problem of using of avant-garde techniques by national composers was one of the most important in Zhiganov leader and composer activity. For today he is more famous as a conservative person who denied modern achievement of foreign music. However, Zhiganov was a responsive musician who supported national music changings and could detect the positive qualities of avant-garde music.