bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endogenous TRAIL-R4 critically impacts apoptotic and non-apoptotic TRAIL-induced signaling in cancer cells
Authors: Rambow Anna-Christina , Aschenbach Insa , Hagelund Sofie , Tawfik Doaa , Gundlach Jan-Paul , Weiße Sebastian , Maass Nicolai , Trauzold Anna 
Published: September 2022

Binding of TRAIL to its death domain-containing receptors TRAIL-R1 and TRAIL-R2 can induce cell death and/or pro-inflammatory signaling. The importance of TRAIL and TRAIL-R1/R2 in tumor immune surveillance and cancer biology has meanwhile been well documented. In addition, TRAIL has been shown to preferentially kill tumor cells, raising hope for the development of targeted anti-cancer therapies. Apart from death-inducing receptors, TRAIL also binds to TRAIL-R3 and TRAIL-R4. Whereas TRAIL-R3 is lacking an intracellular domain entirely, TRAIL-R4 contains a truncated death domain but still a signaling-competent intracellular part. It is assumed that these receptors have anti-apoptotic, yet still not well understood regulatory functions.To analyze the significance of the endogenous levels of TRAIL-R4 for TRAIL-induced signaling in cancer cells, we stably knocked down this receptor in Colo357 and MDA-MB-231 cells and analyzed the activation of apoptotic and non-apoptotic pathways in response to treatment with TRAIL.We found that TRAIL-R4 affects a plethora of signaling pathways, partly in an opposite way. While knockdown of TRAIL-R4 in Colo357 strongly increased apoptosis and reduced clonogenic survival, it inhibited cell death and improved clonogenic survival of MDA-MB-231 cells after TRAIL treatment. Furthermore, TRAIL-R4 turned out to be an important regulator of the expression of a variety of anti-apoptotic proteins in MDA-MB-231 cells since TRAIL-R4-KD reduced the cellular levels of FLIPs, XIAP and cIAP2 but upregulated the levels of Bcl-xL. By inhibiting Bcl-xL with Navitoclax, we could finally show that this protein mainly accounts for the acquired resistance of MDA-MB-231 TRAIL-R4-KD cells to TRAIL-induced apoptosis. Analyses of non-apoptotic signaling pathways revealed that in both cell lines TRAIL-R4-KD resulted in a constitutively increased activity of AKT and ERK, while it reduced AKT activity after TRAIL treatment. Furthermore, TRAIL-R4-KD potentiated TRAIL-induced activation of ERK and p38 in Colo357, and NF-κB in MDA-MB-231 cells. Importantly, in both cell lines the activity of AKT, ERK, p38 and NF-κB after TRAIL treatment was higher in TRAIL-R4-KD cells than in respective control cells.Thus, our data provide evidence for the important regulatory functions of endogenous TRAIL-R4 in cancer cells and improve our understanding of the very complex human TRAIL/TRAIL-R system.
Electrochemical behavior of Mg electrode in sodium salt electrolyte system
Authors: Zhang Yu , Zhu Qingguang , Su Chang , Li Chao 
Published: September 2022

A suitable electrolyte is crucial to enhancing the electrochemical performance of magnesium (Mg) batteries. Here, the influence of Na2SiO3 on the electrochemical behavior of AZ31B Mg alloy in the Na2SO4-NaNO3 composite electrolyte was investigated. The results revealed that the activation potential of the AZ31B Mg alloy first represented a negative shift and then a positive shift with the increase in Na2SiO3. The most negative activation potential (−1.51 V) and the lowest polarization (−3.20 V) were found when 6 mM of Na2SiO3 was added; no discharge hysteresis was observed, and the polarization resistance value (R1) was 3,806 Ω. After 24 h immersion in the composite electrolyte with Na2SiO3, more and wider cracks appeared on the alloy surface, where a thick, dense film was formed, showing excellent discharge performance and corrosion resistance.
Simplification of ankle-brachial-index measurement using Doppler-waveform classification in symptomatic patients suspected of lower extremity artery disease
Authors: Métairie Antoine , Tollenaere Quentin , Lanéelle Damien , Le Faucheur Alexis , Le Pabic Estelle , Omarjee Loukman , Mahé Guillaume 
Published: September 2022

ObjectivesAnkle-brachial index (ABI) is commonly used for screening lower extremity peripheral artery disease (PAD) according to the international guidelines. Arterial Doppler waveform recordings is a tool to diagnose and assess PAD severity. We hypothesized that ABI measurement could be simplified by measuring only the pressure where the best arterial flow is recorded. The aim of this study was to evaluate the concordance between ABI performed according to the American Heart Association guidelines (AHA-ABI) and ABI measured according to best arterial waveform (FLOW-ABI).DesignThis was a monocentric cross-sectional study.MethodsWe included patients with exertional limb symptoms suspected of PAD. Arterial Doppler waveforms and ABI were acquired on both lower extremities at the pedis and tibial posterior arteries. Each arterial waveform was classified using the Saint-Bonnet classification. Concordances were analyzed with the kappa coefficient (confidence interval 95%). Exercise PAD study was registered n° NCT03186391.ResultsIn total, one hundred and eighty-eight patients (62+/−12 years and 26.8+/−4.5 kg/m2) with exertional limb symptoms were included from May 2016 to June 2019. On each extremity, FLOW-ABI had excellent concordance for the diagnosis of PAD with the AHA-ABI with a kappa of 0.95 (95% CI: 0.90, 0.99) in the right extremity and 0.91 (95% CI: 0.86, 0.97) in the left extremity.ConclusionThere is almost perfect concordance between AHA-ABI and FLOW-ABI. Thus, ABI can be simplified into five pressure measurements instead of seven in patient suspected of PAD with exertional limb symptoms. The question remains in patients with chronic limb ischemia.
Hemodynamic effects and tolerance of dobutamine for myocardial dysfunction during septic shock: An observational multicenter prospective echocardiographic study
Authors: Razazi Keyvan , Labbé Vincent , Laine Laurent , Bedet Alexandre , Carteaux Guillaume , de Prost Nicolas , Boissier Florence , Bagate Francois , Mekontso Dessap Armand 
Published: September 2022

BackgroundThe role of dobutamine during septic shock resuscitation is still controversial.MethodsThe aim of this prospective multicentre study was to comprehensively characterize the hemodynamic response of septic shock patients with systolic myocardial dysfunction to incremental doses of dobutamine (0, 5, 10, and 15 μg/kg/min).ResultsThirty two patients were included in three centers. Dobutamine significantly increased contractility indices of both ventricles [crude and afterload-adjusted left ventricular (LV) ejection fraction, global LV longitudinal peak systolic strain, tissue Doppler peak systolic wave at mitral and tricuspid lateral annulus, and tricuspid annular plane excursion) as well as global function indices (stroke volume and cardiac index) and diastolic function (increased e' and decreased E/e' ratio at lateral mitral annulus). Dobutamine also induced a significant decrease in arterial pressure and cardiac afterload indices (effective arterial elastance, systemic vascular resistance and diastolic shock index). Oxygen transport, oxygen consumption and carbon dioxide production all increased with dobutamine, without change in the respiratory quotient or lactate. Dobutamine was discontinued for poor tolerance in a majority of patients (n = 21, 66%) at any dose and half of patients (n = 15, 47%) at low-dose (5 μg/kg/min). Poor tolerance to low-dose dobutamine was more frequent in case of acidosis, was associated with lower vasopressor-free days and survival at day-14.ConclusionIn patients with septic myocardial dysfunction, dobutamine induced an overall improvement of echocardiographic parameters of diastolic and systolic function, but was poorly tolerated in nearly two thirds of patients, with worsening vasoplegia. Patients with severe acidosis seemed to have a worse response to dobutamine.
Effect of itraconazole on the safety and pharmacokinetics of antitumor SHR6390
Authors: Lv Xiaozhi , Wu Junyan , Yao Herui , Ye Suiwen , Zhang Nan 
Published: September 2022

The experimental drug SHR6390 has anti-tumor activity as a cyclin dependent kinase 4/6 inhibitor and is metabolized primarily by the cytochrome P450 3A4 enzyme. Therefore, The purpose of this trial was to evaluate the safety and pharmacokinetics of SHR6390, a potent cytochrome P450 3A4 inhibitor, in healthy Chinese subjects. In this trial study, 18 subjects received a single oral dose of SHR6390 50 mg on day 1, multiple doses of 200 mg itraconazole on days 12–24 for 13 days, and a single oral dose of SHR6390 50 mg on day 15. After coadministration with itraconazole, the maximum plasma concentration (Cmax) of SHR6390 increased by 70.7% (from 14.3 ng/ml to 24.5 ng/ml), and the area under the time curve from 0 to T (AUC0-T) increased by 110.8% from 468 h∙ng/mL to 988 h∙ng/mL. The area under the concentration-time curve extrapolated to ∞(AUC0-∞) increases from 509 H∙ng/mL to 1,040 h∙ng/mL, an increase of 105.1%. Oral gap (CL/F) decreased (47.9 L/h and 98.3 L/h) and apparent volume of distribution (Vz/F) decreased (4190 L and 5890 L). According to common terminology criteria, 15 32 adverse events were reported in 18 subjects (AEs) (27 SHR6390-related AEs and 15 Itraconazole-related AEs), AEs were all Class 1 adverse events. Overall, co-administration of Itraconazole increased the plasma exposure of SHR6390 in healthy subjects. Both SHR6390 alone and co-administration of Itraconazole showed acceptable safety profiles, which warrants further investigation. The experimental drug SHR-6390 of this clinical trial has been applied for registration, which is classified as Chemical drugs Class 1. The study drug SHR6390 registration number:ClinicalTrials.gov Identifier: NCT04423601 (https://clinicaltrials.gov/)
Antihypertensive treatment improves glycemic control in patients with newly diagnosed type 2 diabetes mellitus: A prospective cohort study
Authors: Li Jung-Chi , Cheng Po-Chung , Huang Chien-Nin , Jian Li-Fen , Wu Ying-Syuan , Lin Chih-Li 
Published: September 2022

BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder involving progressive pancreatic dysfunction. A substantial proportion of patients with T2DM cannot achieve euglycemia despite pharmacologic therapy. Preceding clinical studies have shown that hypertension contributes to glucose dysregulation, and investigators in this study hypothesized that antihypertensive treatment may improve glycemic control in patients with T2DM.MethodsThis prospective cohort study investigates the effect of adding the antihypertensive drug Amlodipine to standard diabetes therapy on serum glycosylated hemoglobin A1c (HbA1c) and lipid profile in patients with newly diagnosed T2DM. The study enrolled a total of 168 participants with newly diagnosed T2DM.ResultsRecipients of additional antihypertensive drug Amlodipine demonstrated significantly lower serum HbA1c (6.62% vs. 7.01%, P = 0.01), systolic blood pressure (132 mm Hg vs. 143 mm Hg, P &lt; 0.001), and diastolic blood pressure (78.9 mm Hg vs. 86.0 mm Hg, P &lt;0.001) compared to recipients of standard diabetes therapy after 24 weeks.ConclusionAntihypertensive treatment with Amlodipine in addition to standard diabetes therapy improves glycemic control in patients with T2DM and may be an appropriate option in people with diabetes and concomitant hypertension to help maintain euglycemia.
Living birth following preimplantation genetic testing for monogenic disorders to prevent low-level germline mosaicism related Nicolaides–Baraitser syndrome
Authors: Pan Jiexue , Li Jie , Chen Songchang , Xu Chenming , Huang Hefeng , Jin Li 
Published: September 2022

Objective: Paternal sperm mosaicism has few consequences for fathers for mutations being restricted to sperm. However, it could potentially underlie severe sporadic disease in their offspring. Here, we present a live birth of a female infant from a father with low-level sperm DNA mosaicism achieved via preimplantation genetic testing for monogenic disorders (PGT-M).Methods: A couple with the father carrying sperm DNA mosaicism received standard in vitro fertilization treatment, with intracytoplasmic sperm injection, embryo biopsy, polymerase chain reaction, and DNA analysis. Only one unaffected embryo was transferred to the uterine cavity. Amniocentesis was performed at the 16th week of gestation by copy-number variation-sequencing, karyotyping, and Sanger sequencing.Results: Eight surviving embryos were biopsied during the blastocyst stage. Karyomapping and Sanger sequencing were applied to detect the euploidy and paternal mutation. After performing PGT-M, followed by successful pregnancy, the prenatal genetic diagnoses revealed that the fetus was unaffected, and one healthy girl was born.Conclusion: This is the first reported live birth with unaffected children achieved via PGT for a low-level germline mosaicism father. It not only opens the possibility of preventing the recurrent monogenic disease of children among gonadal mosaicism families but also alerts clinicians to consider gonadal mosaicism as the source of DMNs.
Intrahepatic activated leukocyte cell adhesion molecule induces CD6highCD4+ T cell infiltration in autoimmune hepatitis
Authors: Qian Qiwei , Cui Nana , Huang Bingyuan , Zhao Yudong , Liu Qiaoyan , Hu Mingli , Li Bo , Wang Qixia , Miao Qi , You Zhengrui , Ma Xiong , Tang Ruqi 
Published: September 2022

Background and objectivesAutoimmune hepatitis (AIH) is characterized by the expansion and accumulation of pathogenic T cells in liver. Although CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are involved in the evolution of multiple inflammatory diseases, their roles in the pathogenesis of AIH remain unknown. Herein, we aimed to investigate ALCAM-CD6 axis in AIH development.MethodsImmunohistochemistry was performed to examine hepatic expression of CD6 and ALCAM. The concentration of serum ALCAM was evaluated by ELISA. The phenotypes of liver infiltrating T cells were determined by flow cytometry. Primary human CD4+T cells were used for functional studies.ResultsOur data showed that patients with AIH exhibited significantly higher expression of CD6 in the liver as compared to primary biliary cholangitis (PBC), chronic hepatitis B (CHB), non-alcoholic liver disease (NAFLD), and healthy controls (HC). In addition, hepatic CD6 expression was strongly correlated with disease severity of AIH. CD6 was mainly expressed on CD4+T cells in the liver and intrahepatic CD6highCD4+T cells demonstrated stronger proinflammatory response and proliferation features than CD6lowcounterparts in both AIH and HC. ALCAM, the ligand of CD6, was highly expressed in the hepatocytes of AIH and serum ALCAM was strongly associated with clinical indices of AIH. Interestingly, close spatial location between CD6+CD4+T cells and ALCAM+hepatocytes was observed. Finally, we found that CD6highCD4+T cells showed enhanced capacity of trans-endothelial migrationin vitro, which could be promoted by recombinant ALCAM.ConclusionsOur study found that ALCAM-CD6 axis was upregulated in the AIH liver, suggesting a potential target for alleviating AIH.
Critical reflection on required service to the community propels prospective medical students toward higher empathy, compassion, and bias mitigation but are these gains sustainable?
Authors: Van Winkle Lon J. , Thornock Bradley O. , Schwartz Brian D. , Horst Alexis , Fisher Jensen A. , Michels Nicole 
Published: September 2022

PurposeWe observed increased cognitive empathy and reflective capacity scores when prospective medical students wrote critical reflections on mandatory team service-learning in a Medical Humanities course, but these findings did not include a control group. Here we compare these survey results in similar courses with and without required service-learning.MethodsForty-three prospective medical students completed a Medical Humanities course requiring critical reflection on team service-learning. In comparison, 32 students finished a similar course in which service to the community was not mandatory. Before starting the courses, students completed reliable surveys of their cognitive empathy and reflective capacity, and more than 93% of the students completed the same surveys after finishing the courses.ResultsStudents' cognitive empathy and reflective capacity scores increased significantly when service-learning was required, but the scores did not increase significantly when service to the community was not required. The effect size for the empathy increase was of crucial practical importance (r = 0.50), whereas it was of moderate practical importance for the increase in reflective capacity (r = 0.34).ConclusionsThese and prior findings strongly support the conclusion that students' critical reflection on mandatory team service-learning fosters development of their cognitive empathy and reflective capacity. We present a model program to incorporate critical reflection on service to the community throughout the curricula of all healthcare professions trainees.
Comparing the effectiveness and safety of Dinoprostone vaginal insert and double-balloon catheter as cervical ripening treatments in Chinese patients
Authors: Yan Jinjing , Yin Baomin , Lv Hanghang 
Published: September 2022

BackgroundThis retrospective study was to compare the effectiveness and safety of Dinoprostone vaginal insert vs. double-balloon catheter as cervical ripening agents for labor induction.MethodsPregnant women with Bishop score &lt;7, who received either Dinoprostone vaginal insert 10 mg or Cook's double-balloon catheter for labor induction, were studied. The primary outcome was the rate of vaginal delivery within 48 h; the secondary outcomes were the proportion of women undergoing cesarean section, labor duration, oxytocin administration, changes in Bishop score, complications during labor, and maternal/neonatal outcomes.ResultsOne hundred and eighty-two women were included in Dinoprostone group, and 199 women were in double-balloon catheter group. The rate of vaginal delivery within 48 h was significantly higher in Dinoprostone group than that in double-balloon catheter group (90.11% vs. 75.38%, P = 0.0002). There were 18 cesarean section deliveries (9.89%) in Dinoprostone group and 49 cesarean section deliveries (24.62%) in double-balloon catheter group, with significant differences between two groups (P = 0.0002). The duration of labor was higher in Dinoprostone group, while the augmentation with oxytocin was significantly lower in Dinoprostone group than in double-balloon catheter group (all P &lt; 0.0001). The incidence of chorioamnionitis was significantly higher in double-balloon catheter group as compared with Dinoprostone group (0 vs. 12, P = 0.0005), while neonatal outcomes were similar in two groups.ConclusionDinoprostone vaginal insert as cervical ripening agent is more effective for labor induction and with lower risks of chorioamnionitis as compared with double balloon catheter in Chinese populations.
Point-of-care ultrasound of peripheral nerves in the diagnosis of Hansen's disease neuropathy
Authors: Voltan Glauber , Filho Fred Bernards , Leite Marcel Nani , De Paula Natália Aparecida , Santana Jaci Maria , Silva Claudia Maria Lincoln , Barreto Josafá Gonçalves , Da Silva Moises Batista , Conde Guilherme , Salgado Claudio Guedes , Frade Marco Andrey Cipriani 
Published: September 2022

IntroductionHansen's disease (HD) is the most common cause of treatable peripheral neuropathy in the world that may or may not involve skin manifestations, and physical examination based on simplified neurologic evaluation is a subjective and inaccurate procedure. High-resolution ultrasound (HRUS) can be used to evaluate peripheral nerves and is a validated technique of good reproducibility, permitting a detailed and precise examination.ObjectivesWe proposed to establish objective criteria for absolute values of the measurement of the CSA of peripheral nerves and their indices of the ΔCSA and ΔTpT in the diagnosis of Hansen's disease neuropathy as compared with healthy voluntaries.Materials and methodsIn municipalities from different regions of Brazil, we randomly selected 234 volunteer Brazilian patients diagnosed with leprosy to be submitted to peripheral nerve echography and compared with 49 healthy Brazilian volunteers.ResultsHansen Disease assessed by high resolution ultrasound is a primarily neural disease that leads to multiple hypertrophic mononeuropathy characterized by CSA values exceeding normal limits (Med CT = 10.2 mm2; UT = 9.8 mm2; UPT = 9.3 mm2; CFFH = 18.3 mm2; T = 9.6 mm2), and the pattern of asymmetry (ΔCSA&gt;2.5 mm2with RR 13) and focality (ΔTPT &gt; 2.5 mm2with RR 6.4) of this thickening has higher sensitivity (76,1%) and specificity (87,8 %) for its early diagnosis that laboratory tests. Analyzing each subject, the percentage of thickened nerves detected among the total number of nerves assessed was higher among patients with HD than among healthy individuals (p&lt; 0.0001). Individuals with two or more thickened nerves were at 24.1 times higher relative risk (95% CI: 6.74–88.98) of HD.
Fc receptor-like 5 gene polymorphisms and mRNA expression are associated with liver fibrosis in chronic hepatitis B
Authors: Yang Jiajia , Gu Juan , Wang Hongmei , Shi Jiayin , Lu Lingyun , She Wanxian , Wang Ying 
Published: September 2022

Objective: To investigate the associations of Fc receptor-like 5 (FCRL5) gene polymorphisms and mRNA expression with liver fibrosis in chronic hepatitis B (CHB).Methods: A total of 114 CHB patients with liver fibrosis and 120 CHB patients without liver fibrosis were selected for this study. The gender, age, body mass index (BMI), alanine transaminase (ALT) value, aspartate aminotransferase (AST) value, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis index based on 4 factors (FIB-4) were recorded. Two polymorphisms of the FCRL5 gene (rs6427384 and rs6692977) were genotyped. The mRNA expression level of FCRL5 in peripheral blood monocytes was determined.Results: ALT, AST, APRI, and FIB-4 in patients with fibrosis were significantly higher than those in non-fibrosis patients. There was statistically significant difference between fibrosis and non-fibrosis groups in the genotype distribution (χ2 = 7.805, p = 0.020) and allele frequencies (χ2 = 13.252, p &lt; 0.001) at FCRL5 rs6692977. When compared with CC genotype, the genotype CT or TT at rs6692977 was significantly associated with a increased risk of liver fibrosis in CHB patients (CT vs. CC: OR = 1.921, 95% CI = 1.093–3.375, p = 0.023; TT vs. CC: OR = 2.598, 95% CI = 1.067–6.324, p = 0.031). The mRNA relative expression levels of FCRL5 in patients with liver fibrosis were significantly higher than those in the non-fibrosis group (t = 13.456, p &lt; 0.001). The fibrosis patients carried TT or CT genotype of rs6692977 had significantly higher FCRL5 mRNA expression levels than those carried CC genotype (t = 2.859, p = 0.005). The mRNA expression levels of FCRL5, APRI, and FIB-4 index showed predictive efficacy in liver fibrosis with cut-off values of 0.75 (AUC = 0.896, 95% CI = 0.856–0.935), 0.45 (AUC = 0.852, 95% CI = 0.802–0.902) and 1.84 (AUC = 0.765, 95% CI = 0.703–0.826), respectively.Conclusion: FCRL5 gene rs6692977 polymorphisms and mRNA expression levels are associated with liver fibrosis in CHB patients.