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Xi Chen,* Bei Feng,* Di-Qi Zhu, Yi-Wei Chen, Wei Ji, Tian-Ji Ji, Fen LiDepartment of Cardiology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China*These authors contributed equally to this workBackground: Electrospun gelatin/polycaprolactone (Gt/PCL) nanofibrous scaffolds loaded with graphene are novel nanomaterials with the uniquely strong property of electrical conductivity, which have been widely investigated for their potential applications in cardiovascular tissue engineering, including in bypass tracts for atrioventricular block.Purpose: Electrospun Gt/PCL/graphene nanofibrous mats were successfully produced. Scanning electron micrography showed that the fibers with graphene were smooth and homogeneous. In vitro, to determine the biocompatibility of the scaffolds, hybrid scaffolds with different fractions of graphene were seeded with neonatal rat ventricular myocytes. In vivo, Gt/PCL scaffolds with different concentrations of graphene were implanted into rats for 4, 8 and 12 weeks.Results: CCK-8 assays and histopathological staining (including DAPI, cTNT, and CX43) indicated that cells grew and survived well on the hybrid scaffolds if the mass fraction of graphene was lower than 0.5%. After implanting into rats for 4, 8 or 12 weeks, there was no gathering of inflammatory cells around the nanomaterials according to the HE staining results.Conclusion: The results indicate that Gt/PCL nanofibrous scaffolds loaded with graphene have favorable electrical conductivity and biological properties and may be suitable scaffolds for use in the treatment of atrioventricular block. These findings alleviate safety concerns and provide novel insights into the potential applications of Gt/PCL loaded with graphene, offering a solid foundation for comprehensive in vivo studies.Keywords: gelatin, polycaprolactone, graphene, electrical conductivity, toxicity, atrioventricular block

The objective of this study was to detect cerebral potentials elicited by proximal stimulation of the first sacral (S1) nerve root at the S1 dorsal foramen and to investigate latency and amplitude of the first cerebral potential. Tibial nerve SEP and S1 nerve root SEP were obtained from 20 healthy subjects and 5 patients with unilateral sciatic nerve or tibial nerve injury. Stimulation of the S1 nerve root was performed by a needle electrode via the S1 dorsal foramen. Cerebral potentials were recorded twice to document reproducibility. Latencies and amplitudes of the first cerebral potentials were recorded. Reproducible cerebral evoked potentials were recorded and P20s were identified in 36 of 40 limbs in the healthy subjects. The mean latency of P20 was 19.8 ± 1.6 ms. The mean amplitude of P20-N30 was 1.2 ± 0.9 μV. In the five patients, P40 of tibial nerve SEP was absent, while well-defined cerebral potentials of S1 nerve root SEP were recorded and P20 was identified from the involved side. This method may be useful in detecting S1 nerve root lesion and other disorders affecting the proximal portions of somatosensory pathway. Combined with tibial nerve SEP, it may provide useful information for diagnosis of lesions affecting the peripheral nerve versus the central portion of somatosensory pathway. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the clinical application value of the central venous-arterial carbon dioxide partial pressure difference (Pv-aCO2) in postoperative cognitive dysfunction(POCD) in patients with acute aortic dissection., Methods: A retrospective analysis was conducted on the general data of 236 patients. Blood gas samples were collected from the arterial and venous lines at various time points during the surgery, including before and after the initiation of cardiopulmonary bypass (CPB), immediately after CPB initiation, before and after deep hypothermic circulatory arrest, 30 min after rewarming, and 5 min before weaning from CPB. The partial PV-aCO2 was calculated. Based on the average PV-aCO2 value, patients were divided into an observation group (PV-aCO2 > 6 mmHg, n = 112) and a control group (PV-aCO2 < 6 mmHg, n = 124). The perioperative data and Mini-Mental State Examination (MMSE) scores were compared between the two groups to assess the incidence and severity of POCD. Additionally, the expression levels of peripheral serum S100β in the two groups were compared 6 h postoperatively., Results: The incidence of POCD was higher in the observation group compared to the control group, while MMSE scores and serum S100β levels were lower in the observation group. Additionally, the observation group patients with POCD had lower MMSE scores and serum S100β levels compared to the control group patients. In addition, logistic regression analysis revealed that advanced age, serum S100β levels, female gender, CPB time, unilateral brain perfusion time, hyperlipidemia, diabetes, and smoking history were all independent risk factors for postoperative POCD (all P < 0.05)., Conclusion: Pv-aCO2 can effectively reflect the intraoperative cerebral metabolic level in patients with acute aortic dissection and can serve as an intraoperative warning indicator for cognitive dysfunction. Its clinical recommendation for use is warranted., Competing Interests: Declarations. Human ethics and consent to participate declarations: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Risk estimation of intracranial aneurysm rupture is critical in determining treatment strategy. There is a scarcity of multicenter studies on the predictive power of clinical-radiomics models for aneurysm rupture. This study aims to develop a clinical-radiomics model and explore its additional value in the discrimination of aneurysm rupture., Methods: A total of 516 aneurysms, including 273 (52.9%) with ruptured aneurysms, were retrospectively enrolled from four hospitals between January 2019 and August 2020. Relevant clinical features were collected, and radiomic characteristics associated with aneurysm were extracted. Subsequently, three models, including a clinical model, a radiomics model, and a clinical-radiomics model were constructed using multivariate logistic regression analysis to effectively classify aneurysm rupture. The performance of models was analyzed through operating characteristic curves, decision curve, and calibration curves analysis. Different models' comparison used DeLong tests. To offer an understandable and intuitive scoring system for assessing rupture risk, we developed a comprehensive nomogram based on the developed model., Results: Three clinical risk factors and fourteen radiomics features were explored to establish three models. The area under the receiver operating curve (AUC) for the radiomics model was 0.775 (95% CI,0.719-0.830), 0.752 (95% CI,0.663-0.841), 0.747 (95% CI,0.658-0.835) in the training, internal and external test datasets, respectively. The AUC for clinical model was 0.802 (95% CI, 0.749-0.854), 0.736 (95% CI, 0.644-0.828), 0.789 (95% CI, 0.709-0.870) in these three sets, respectively. The clinical-radiomics model showed an AUC of 0.880 (95% CI,0.840-0.920), 0.807 (95% CI,0.728-0.887), 0.815 (95% CI,0.740-0.891) in three datasets respectively. Compared with the radiomics and clinical models, the clinical-radiomics model demonstrated better diagnostic performance (DeLong' test P < 0.05)., Conclusion: The clinical-radiomics model represents a promising approach for predicting rupture of intracranial aneurysms., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Jia et al.)

Aim: To evaluate the effects of bariatric arterial embolization (BAE) on gastric emptying of, and the glycaemic response to, an oral glucose load in an obese canine model with impaired glucose tolerance., Methods: Eleven male dogs were fed a high-fat, high-fructose diet for 7 weeks before receiving BAE, which involved selective embolization of the left gastric artery (n = 5; 14.9 ± 0.8 kg), or the sham (n = 6; 12.6 ± 0.8 kg) procedure. Postprocedural body weight was measured weekly for 4 weeks. Prior to and at 4 weeks postprocedure, a glucose solution containing 13 C-acetate was administered orally for evaluation of the gastric half-emptying time (T50) and the glycaemic response. The relationship between the changes in the blood glucose area under the curve over the first 60 minutes (AUC 0-60min ) and the T50 was also assessed., Results: At 4 weeks postprocedure, BAE reduced body weight (BAE vs. the sham procedure: -5.7% ± 0.9% vs. 3.5% ± 0.9%, P < .001), slowed gastric emptying (T50 at baseline vs. postprocedure: 75.5 ± 2.0 vs. 82.5 ± 1.8 minutes, P = .021 in the BAE group; 73.8 ± 1.8 vs. 74.3 ± 1.9 minutes in the sham group) and lowered the glycaemic response to oral glucose (AUC 0-60min at baseline vs. postprocedure: 99.2 ± 13.7 vs. 67.6 ± 9.8 mmol·min/L, P = .043 in the BAE group; 100.2 ± 13.4 vs. 103.9 ± 14.6 mmol·min/L in the sham group). The change in the glucose AUC 0-60min correlated inversely with that of the T50 (r = -0.711; P = .014)., Conclusions: In a canine model with impaired glucose tolerance, BAE, while reducing body weight, slowed gastric emptying and attenuated the glycaemic response to an oral glucose load., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background and Objective: To compare the efficacy of EUS-guided celiac plexus neurolysis (CPN) and celiac plexus irradiation with iodine-125 ( 125 I) seeds with absolute ethanol for relieving pain in patients with advanced pancreatic cancer., Methods: We retrospectively analyzed data of 81 patients with advanced pancreatic cancer who underwent EUS-CPN or EUS- 125 I implantation between January 2017 and December 2020. Postoperative pain was assessed using visual analog scale (VAS) scores; self-assessments of quality of life and the median survival time were compared between the 2 groups., Results: EUS-CPN and 125 I implantation were performed in 43 and 38 patients, respectively. Postoperative VAS scores were significantly lower than the preoperative levels in both groups. One week after the operation, 26 patients (60.5%) in the EUS-CPN group achieved partial pain relief, whereas no patients in the EUS- 125 I seed group experienced pain relief. However, after 4 weeks postoperatively, VAS scores had decreased, and the rate of partial pain relief was higher for EUS- 125 I seeds than for EUS-CPN. Self-assessments of quality of life were similar in both groups during the first 1 month after the procedure., Conclusions: Both EUS-CPN and EUS- 125 I seeds can safely and effectively relieve pain in patients with advanced pancreatic cancer. Although EUS- 125 I seeds take additional time to show effects, the extent and duration of pain relief are better compared with CPN, and interestingly, the median survival time was different., Competing Interests: Zhen-Dong Jin is an Associate Editor of the journal. This article was subject to the journal's standard procedures, with peer review handled independently of the editor and his research group., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Scholar Media Publishing.)

Refractive error is a common ophthalmic disease in children. It refers to the mismatch between the axial length and the refractive power that results in visual blur, which is usually driven by the interaction of genetic and environmental factors. The impacts of pregnancy and puerperium-related factors on refractive error in children have gradually gained attention. According to the different stages of pregnancy, this review summarizes the impacts of four aspects on refractive error in children, including lifestyle during pregnancy, complications and comorbidities during pregnancy, adverse pregnancy outcomes and other factors, which aims to provide perinatal healthcare clues for the prevention and control of refractive error in children, achieve prevention beforehand and reduce the public health burden of refractive error in children.

Aim: To evaluate the efficacy and safety of silicone oil (SO) as a corneal lubricant to improve visualization during vitrectomy., Methods: Patients who underwent vitreoretinal surgery were divided into two groups. Group 1 was operated on with initial SO (Oxane 5700) as a corneal lubricant. Group 2 was operated on with initial lactated ringer's solution (LRS) and then replaced with SO as required. Fundus clarity was scored during the surgery. Fluorescein staining was performed to determine the damage to corneal epithelium., Results: Totally 114 eyes of 114 patients were included. Single SO use maintained a clear cornea and provided excellent visualization of surgical image. In group 1, the fundus clarity was grade 3 in 41/45 eyes and grade 2 in 4/45 eyes. In group 2, corneal edema frequently occurred after initial LRS use. The fundus clarity was grade 3 in 19/69 eyes, 2 in 37/69 eyes and 1 in 13/69 eyes ( P <0.05). SO was applied in 29 eyes of initial LRS use with subsequent corneal edema, which eliminated the corneal edema in 26 eyes. Corneal fluorescein staining score in group 1 was 0 in 28 eyes, 1 in 11 eyes and 2 in 6 eyes, and 40, 20 and 9, respectively, in group 2 (all P >0.05)., Conclusion: The use of SO as a corneal lubricant is effective and safe for preserving and improving corneal clarity and providing clear surgical field during vitrectomy., (International Journal of Ophthalmology Press.)

The utilization of radiotherapy (RT) serves as the principal approach for managing nasopharyngeal carcinoma (NPC). Consequently, it is imperative to investigate the correlation between the radiation microenvironment and radiation resistance in NPC. PubMed and China National Knowledge Infrastructure (CNKI) databases were accessed to perform a search utilizing the English keywords "nasopharyngeal cancer", "radiotherapy", and "microenvironment". The search time spanned from the establishment of the database until January 20, 2023. A total of 82 articles were included. The post-radiation tumor microenvironment (TME), or the radiation microenvironment, includes several components, such as the radiation-immune microenvironment and the radiation-hypoxic microenvironment. The radiation-immune microenvironment includes various factors like immune cells, signaling molecules, and extracellular matrix. RT can reshape the TME, leading to immune responses with both cytotoxic effects (T cells, B cells, natural killer (NK) cells) and immune escape mechanisms (regulatory T cells (Tregs), macrophages). RT enhances immune responses through DNA release, type I interferons, and immune cell recruitment. Radiation-hypoxic microenvironment affects metabolism and molecular changes. RT-induced hypoxia causes vascular changes, fibrosis, and vessel compression, leading to tissue hypoxia. Hypoxia activates hypoxia-inducible factor (HIF)-1α/2α, promoting angiogenesis and glycolysis in tumor cells. TME changes due to hypoxia also involve immune suppressive cells like myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Tregs. The radiation microenvironment is involved in radiation resistance and holds a significant effect on the prognosis of patients with NPC. Exploring the radiation microenvironment provides new insights into RT and NPC research., Competing Interests: None to declare., (Copyright 2023, Zhu et al.)

Objective: To investigate the mechanism by which Chinese medicine Shengmai Yin (SMY) reverses epithelial-mesenchymal transition (EMT) through lipocalin-2 (LCN2) in nasopharyngeal carcinoma (NPC) cells CNE-2R., Methods: Morphological changes in EMT in CNE-2R cells were observed under a microscope, and the expressions of EMT markers were detected using quantitative real-time PCR (RT-qPCR) and Western blot assays. Through the Gene Expression Omnibus dataset and text mining, LCN2 was found to be highly related to radiation resistance and EMT in NPC. The expressions of LCN2 and EMT markers following SMY treatment (50 and 100 µ g/mL) were detected by RT-qPCR and Western blot assays in vitro. Cell proliferation, migration, and invasion abilities were measured using colony formation, wound healing, and transwell invasion assays, respectively. The inhibitory effect of SMY in vivo was determined by observing a zebrafish xenograft model with a fluorescent label., Results: The CNE-2R cells showed EMT transition and high expression of LCN2, and the use of SMY (5, 10 and 20 µ g/mL) reduced the expression of LCN2 and reversed the EMT in the CNE-2R cells. Compared to that of the CNE-2R group, the proliferation, migration, and invasion abilities of SMY high-concentration group were weakened (P<0.05). Moreover, SMY mediated tumor growth and metastasis in a dose-dependent manner in a zebrafish xenograft model, which was consistent with the in vitro results., Conclusions: SMY can reverse the EMT process of CNE-2R cells, which may be related to its inhibition of LCN2 expression. Therefore, LCN2 may be a potential diagnostic marker and therapeutic target in patients with NPC., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

The rising prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) poses a major challenge to global health. Existing therapeutic approaches have limitations, and there is a need for new, safe, and less invasive treatments. Interventional metabolic therapy is a new addition to the treatment arsenal for metabolic disorders. This review focuses on two interventional techniques: bariatric arterial embolization (BAE) and endovascular denervation (EDN). BAE involves embolizing specific arteries feeding ghrelin-producing cells to suppress appetite and promote weight loss. EDN targets nerves that regulate metabolic organs to improve glycemic control in T2DM patients. We describe the current state of these techniques, their mechanisms of action, and the available safety and effectiveness data. We also propose a new territory called "Interventional Metabology" to encompass these and other interventional approaches to treating metabolic disorders., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade., (© 2023 Wiley Periodicals LLC.)

Objective: To analyze correlation of occupational hydrogen fluoride exposure to low doses of bone metabolism index through occupational epidemiological investigation and benchmark dose calculation. Methods: In May 2021, using cluster sampling method, 237 workers exposed to hydrogen fluoride in a company were selected as the contact group, and 83 workers not exposed to hydrogen fluoride in an electronics production company were selected as the control group. The external exposure dose and urinary fluoride concentration, blood and urine biochemical indicators of the workers was measured.The relationship between external dose and internal dose of hydrogen fluoride was analyzed. The external dose, urinary fluoride was used as exposure biomarkers, while serum osteocalcin (BGP), serum alkaline phosphatase (AKP) and urinary hydroxyproline (HYP) were used as effect biomarkers for bone metabolism of hydrogen fluoride exposure. The benchmark dose calculation software (BMDS1.3.2) was used to calculate benchmark dose (BMD) . Results: Urine fluoride concentration in the contact group was correlated with creatinine-adjusted urine fluoride concentration ( r =0.69, P =0.001). There was no significant correlation between the external dose of hydrogen fluoride and urine fluoride in the contact group ( r =0.03, P =0.132). The concentrations of urine fluoride in the contact group and the control group were (0.81±0.61) and (0.45±0.14) mg/L, respectively, and the difference between the two groups was statistically significant ( t =5.01, P =0.025). Using BGP, AKP and HYP as effect indexes, the urinary BMDL-05 values were 1.28, 1.47 and 1.08 mg/L, respectively. Conclusion: Urinary fluoride can sensitively reflect the changes in the effect indexes of biochemical indexes of bone metabolism. BGP and HYP can be used as early sensitive effect indexes of occupational hydrogen fluoride exposure.

Objective: To analyze the clinical characteristics, diagnosis and treatment of anomalous aortic origin of a coronary artery (AAOCA) in children. Methods: There were 17 children diagnosed with AAOCA from January 2013 to January 2022 in Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine.Their clinical manifestations, laboratory and imaging data, treatment and prognosis were retrospectively analyzed. Results: These 17 children included 14 males and 3 females, with the age of (8.7±3.5) years. There were 4 anomalous left coronary artery (ALCA) and 13 anomalous right coronary artery (ARCA). Seven children presented with chest pain or chest pain after exercise, three patients presented with cardiac syncope, one complained chest tightness and weakness, and the other six patients had no specific symptoms. Cardiac syncope and chest tightness occurred in patients with ALCA. Fourteen children had the dangerous anatomical basis of myocardial ischemia caused by coronary artery compression or stenosis on imaging. Seven children had coronary artery repair, of whom two were ALCA and five were ARCA. One patient had received heart transplantation because of heart failure. The incidence of adverse cardiovascular events and poor prognosis in ALCA group was higher than that in ARCA group (4/4 vs. 0/13, P< 0.05). They were followed up in the outpatient department regularly for 6 (6, 12) months; except for the one who lost visit, the rest of the patients had a good prognosis. Conclusions: Cardiogenic syncope or cardiac insufficiency usually occurs in ALCA, and adverse cardiovascular events and poor prognosis are more common in ALCA than in ARCA. Early surgical treatment should be considered for children with ALCA and ARCA accompanied by myocardial ischemia.

Aim: To introduce a simple resistance controlled suprachoroidal space (SCS) injection technique using a disposable 30-gauge needle connected to a 1 mL syringe and evaluate the effectiveness and applicability of this technique in the treatment of macular edema., Methods: A total of 20 patients with various types of macular edema were subjected to a resistance controlled SCS injection of triamcinolone acetonide (TA) with a disposable 30-gauge needle connected to a 1 mL syringe. This technique allows the easy and smooth injection of the TA only once the tip of the needle reached the potential SCS which was indicated by the lower resistance on the plunger. The main outcome measures were anterior segment spectral-domain optical coherence tomography (AS-OCT) measurements post-operation immediately and central subfield thickness (CST), best-corrected visual acuity (BCVA), and intraocular pressure (IOP) measurements at 3mo post-operation., Results: AS-OCT examination showed the expansion of the SCS near the injection site immediately after SCS injection. At three months of follow-up, as compared to the baseline, the mean CST was significantly decreased from 535.0±157.24 to 319.55±127.30 µm ( P <0.001), the mean BCVA was significantly improved from 1.05±0.41 to 0.73±0.41 logMAR ( P <0.001), and the mean IOP was not significantly different, from 15.05±2.54 to 15.85±3.60 mm Hg ( P =0.185). Any complication related to the injection procedure including cataract, choroidal and retinal hemorrhage, retinal detachment, or endophthalmitis was not observed in this study., Conclusion: The simple and minimally invasive technique of SCS injection of TA with a disposable 30-gauge needle connected to a 1 mL syringe is useful and applicable for macular edema., (International Journal of Ophthalmology Press.)

Objectives: Spinal muscular atrophy with lower extremity predominance 1 (SMALED1) and Charcot-Marie-Tooth diseasetype 2O (CMT2O) are two kinds of hereditary neuromuscular diseases caused by DYNC1H1 mutations. In this study, we reported two patients with SMALED1 caused by DYNC1H1 mutations. The genotype-phenotype correlations were further analyzed by systematically reviewing previous relevant publications., Materials and Methods: Two patients' with SMALED1 and their parents' clinical data were collected, and detailed clinical examinations were performed. WES was then applied, which was confirmed by Sanger sequencing. PubMed, Web of Science, CNKI, and Wanfang Data were searched, and all publications that met the inclusion criteria were carefully screened. Any individual patient without a detailed description of clinical phenotypes was excluded., Results: The two patients manifested delayed motor milestones and muscle wasting of both lower extremities. The diagnosis was further confirmed as SMALED1. Genetic testing revealed heterozygous DYNC1H1 mutations c.1792C>T and c.790C>G; the latter is a novel dominant mutation. Genotype-phenotype analysis of DYNC1H1 variants and neuromuscular diseases revealed that mutations in the DYN1 region of DYNC1H1 protein were associated with a more severe phenotype, more complicated symptoms, and more CNS involvement than the DHC&#95;N1 region., Conclusion: Our study potentially expanded the knowledge of the phenotypic and genetic spectrum of neuromuscular diseases caused by DYNC1H1 mutations. The genotype-phenotype correlation may reflect the pathogenesis underlying the dyneinopathy caused by DYNC1H1 mutations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Dong, Zhu, Yang, Qian, Liu and Chen.)

Introduction: BRAF variants were reported resistant mechanisms to EGFR tyrosine kinase inhibitors (TKIs) in EGFR -mutant NSCLC. Nevertheless, characteristics and subsequent treatment strategies of such patients remain unclear., Methods: From October 2016 to May 2020, patients with advanced NSCLC for whom next-generation sequencing detected mutations of both BRAF and EGFR were retrospectively included. From June 2020 to January 2021, patients with EGFR -mutant NSCLC who acquired the BRAF V600E mutation after progression on osimertinib were prospectively enrolled to explore the efficacy and safety of EGFR plus BARF co-inhibition., Results: A total of 58 patients were retrospectively identified and five prospectively included. BRAF variants were acquired after a median time of 22.7 months from initial diagnosis. The frequency of variations in TP53 , PIK3CA , RB1 , MET , LRP1B , APC , CDKN2A , MYC , ERBB2 , and SMAD4 was all more than 10%; these mutations affected the cell cycle or p53 pathway and the EGFR downstream and bypass pathways. The median progression-free survival was 5.0 months for patients on chemotherapy and 2.1 months for those on TKIs not targeting both of EGFR and BRAF ( p  = 0.019). The median PFS was 7.8 months in five patients who received EGFR plus BRAF co-inhibitory drugs. RAS signaling was activated on disease progression., Conclusions: Variations in the EGFR downstream and bypass pathways were frequent in patients with dual mutations of EGFR and BRAF . The efficacies of TKIs not targeting both EGFR and BRAF were inferior to chemotherapy. EGFR plus BRAF co-inhibition improved efficacy. Such treatment strategies should be further explored., (© 2022 The Authors.)

Background: To analyze the relationship between V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) status and radioresistance in non-small cell lung cancer (NSCLC), we identified potential genotypic differences and pathways involved., Methods: We retrospectively analyzed epidermal growth factor receptor ( EGFR ) and KRAS status in patients undergoing definitive radiotherapy for NSCLC between 2004 and 2018. Cox proportional hazard models were used to evaluate local progression-free survival (LPFS). Using clonogenic survival and measurement of γH2AX foci, we analyzed the difference in radiosensitivity between NSCLC cell lines with different KRAS status. The Cancer Genome Atlas (TCGA) analysis was used to explore the potential pathways involved., Results: The results showed that of the 286 patients identified, 68 (24%) had local tumor progression (mean ± standard deviation (SD), 27 ± 17.4 months); of these patients, KRAS mutations were found in 14 (23%), and KRAS status was associated with LPFS. After adjusting for concurrent chemotherapy, gross tumor volume, and mutation status in multivariate analysis, KRAS mutation was associated with shorter LPFS (hazard ratio: 1.961; 95% confidence interval: 1.03 - 2.17; P = 0.032). KRAS mutation showed higher radioresistance in vitro . TCGA data showed that the ERK1/2 pathway, phosphatidylinositol I3 kinase (PI3K)/mTOR, p38 MAPK pathway, cell cycle checkpoint signaling, DNA damage, repair pathways, and EGFR/PKC/AKT pathway were differentially expressed in patients with KRAS mutations or cell lines compared with their expression in the wild-type group., Conclusions: Diverse analyses identified that KRAS mutation was associated with radioresistance in NSCLC. KRAS mutation status may be helpful as a biomarker of radioresistance and a potential target to increase radiosensitivity., Competing Interests: All authors have no conflict of interest to declare., (Copyright 2022, Zhu et al.)

Recently, creative deviance has been lauded to be an innovation-enhancing approach with applications in many new and high-tech domains. Previous study on antecedents to creative deviance remains scattered and vague. Our research conceptualizes creative deviance from the perspective of independent innovation and explores its antecedents, mechanisms, as well as conditions. Team authoritarian leadership is conceptualized as a contradictory unity as it mixes advantages and disadvantages. However, it is surprising to find that there are very few researches that have examined its relevant influence mechanisms and boundary conditions for authoritarian leadership. Contributing to an advanced understanding of authoritarian leadership in research and development teams, we investigated whether team authoritarian leadership is positively or negatively related to creative deviance. Drawing on social information processing theory and regulatory focus theory, we supposed that team authoritarian leadership facilitates creative deviance when the degree is low and inhibits it when the degree is high; dual occupational stress and prevention regulatory focus play mediation roles between team authoritarian leadership and creative deviance respectively, both variables play a chain mediation role in that relationship; and the mindfulness characteristic of an individual moderates the inverted-U team authoritarian leadership-creative deviance association, such that this association is weaker with low individual mindfulness. With two-phase questionnaire data collected from 433 members in 82 R&D teams of high-tech enterprises in electronic information technology, new material technology, new medical technology, resource and environment technology and advanced manufacturing technology randomly selected from five provinces in eastern China, these hypotheses are supported empirically. Overall, we find that, our study broadens antecedents and the relevant occurrence mechanisms of creative deviance when studied through a leadership management lens. Moreover, our research enriches the cognate studies on authoritarian leadership by empirically demonstrating that team authoritarian leadership may function as an double-edged sword of creative deviance in the R&D workplace. These above findings offer insightful thoughts to scholars in the field of authoritarian leadership and bring practical suggestions for team superiors who seek to implement best innovation practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Li, Zhu and Li.)

Engineered cartilage derived from mesenchymal stromal cells (MSCs) always fails to maintain the cartilaginous phenotype in the subcutaneous environment due to the ossification tendency. Vascular invasion is a prerequisite for endochondral ossification during the development of long bone. As an oral antitumor medicine, Inlyta (axitinib) possesses pronounced antiangiogenic activity, owing to the inactivation of the vascular endothelial growth factor (VEGF) signaling pathway. In this study, axitinib-loaded poly(ε-caprolactone) (PCL)/collagen nanofibrous membranes are fabricated by electrospinning for the first time. Rabbit-derived MSCs-engineered cartilage is encapsulated in the axitinib-loaded nanofibrous membrane and subcutaneously implanted into nude mice. The sustained and localized release of axitinib successfully inhibits vascular invasion, stabilizes cartilaginous phenotype, and helps cartilage maturation. RNA sequence further reveals that axitinib creates an avascular, hypoxic, and low immune response niche. Timp1 is remarkably upregulated in this niche, which probably plays a functional role in inhibiting the activity of matrix metalloproteinases and stabilizing the engineered cartilage. This study provides a novel strategy for stable subcutaneous chondrogenesis of mesenchymal stromal cells, which is also suitable for other medical applications, such as arthritis treatment, local treatment of tumors, and regeneration of other avascular tissues (cornea and tendon)., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

We constructed a radiomics-clinical model to predict intraventricular hemorrhage (IVH) growth after spontaneous intracerebral hematoma. The model was developed using a training cohort (N=626) and validated with an independent testing cohort (N=270). Radiomics features and clinical predictors were selected using the least absolute shrinkage and selection operator (LASSO) method and multivariate analysis. The radiomics score (Rad-score) was calculated through linear combination of selected features multiplied by their respective LASSO coefficients. The support vector machine (SVM) method was used to construct the model. IVH growth was experienced by 13.4% and 13.7% of patients in the training and testing cohorts, respectively. The Rad-score was associated with severe IVH and poor outcome. Independent predictors of IVH growth included hypercholesterolemia (odds ratio [OR], 0.12 [95%CI, 0.02-0.90]; p=0.039), baseline Graeb score (OR, 1.26 [95%CI, 1.16-1.36]; p<0.001), time to initial CT (OR, 0.70 [95%CI, 0.58-0.86]; p<0.001), international normalized ratio (OR, 4.27 [95%CI, 1.40, 13.0]; p=0.011), and Rad-score (OR, 2.3 [95%CI, 1.6-3.3]; p<0.001). In the training cohort, the model achieved an AUC of 0.78, sensitivity of 0.83, and specificity of 0.66. In the testing cohort, AUC, sensitivity, and specificity were 0.71, 0.81, and 0.64, respectively. This radiomics-clinical model thus has the potential to predict IVH growth.

Tao-He-Cheng-Qi decoction (THCQ) is an effective traditional Chinese medicine used to treat intracerebral hemorrhage (ICH). This study was performed to investigate the possible neuroprotective effect of THCQ decoction on secondary brain damage in rats with intracerebral hemorrhage and to elucidate the potential mechanism based on a metabolomics approach. Sprague-Dawley (SD) rats were randomly divided into five groups: the sham group, collagenase-induced ICH model group, THCQ low-dose (THCQ-L)-treated group, THCQ moderate-dose (THCQ-M)-treated group and THCQ high-dose (THCQ-H)-treated group. Following 3 days of treatment, behavioral changes and histopathological lesions in the brain were estimated. Untargeted metabolomics analysis with multivariate statistics was performed by using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-Q-Exactive Orbitrap MS). THCQ treatment at two dosages (5.64 and 11.27 g/kg·d) remarkably improved behavior ( p < 0.05), brain water content (BMC) and hemorheology ( p < 0.05) and improved brain nerve tissue pathology and inflammatory infiltration in ICH rats. Moreover, a metabolomic analysis demonstrated that the serum metabolic profiles of ICH patients were significantly different between the sham group and the ICH-induced model group. Twenty-seven biomarkers were identified that potentially predict the clinical benefits of THCQ decoction. Of these, 4 biomarkers were found to be THCQ-H group-specific, while others were shared between two clusters. These metabolites are mainly involved in amino acid metabolism and glutamate-mediated cell excitotoxicity, lipid metabolism-mediated oxidative stress, and mitochondrial dysfunction caused by energy metabolism disorders. In addition, a correlation analysis showed that the behavioral scores, brain water content and hemorheology were correlated with levels of serum metabolites derived from amino acid and lipid metabolism. In conclusion, the results indicate that THCQ decoction significantly attenuates ICH-induced secondary brain injury, which could be mediated by improving metabolic disorders in cerebral hemorrhage rats., Competing Interests: D-MS, MW, and D-QZ were employed by the company Guangdong Yifang Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Cai, Chen, Gang, Wei, Zhu, Li, Yang, Luo, Bi and Sun.)

Introduction: We studied the impact of vibratory stimulation on the electrophysiological features of digital sensory nerve action potential (SNAP)., Methods: The antidromic digit 3 SNAP was recorded in 19 healthy adults before, during, and after applying a vibration to either 3rd or 5th metacarpal phalangeal joint (MCPJ) at 60 Hz and amplitude of 2 mm. 100% supramaximal stimulus intensity was performed in 5 subjects (randomly selected from the 19 subjects) where the SNAP sizes were recorded., Results: The amplitude of digit 3 SNAP declined to 58.9 ± 8.6% when a vibration was applied to MCPJ digit 3. These impacts did not change by increasing the electrical stimulus intensity. The SNAP regained its baseline value immediately after the cessation of vibration stimulation. The magnitude of size reduction of digit 3 SNAP was less when vibration was moved to from MCPJ of digit 3 to MCPJ of digit 5. Discussion . The marked drop of the SNAP size during vibratory stimulation reflects the decreased responsiveness of A β afferents to electrical stimulation, which deserve further investigation in the study of focal vibration in neurorehabilitation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Dong Qing Zhu et al.)

To explore the molecular epidemiological status of human immunodeficiency virus type 1 (HIV-1) in Ganzhou, China, eight HIV-1-positive outpatients were recruited from July 5 to 21, 2018. Six HIV-1 near-full-length sequences were amplified and sequenced from the plasma samples that were collected before the patients' antiretroviral treatments. Phylogenetic and bootscan analyses revealed that one of the sequences was CRF01&#95;AE, one was CRF55&#95;01B, and two were CRF07&#95;BC. Notably, one of the sequences was a unique recombinant form, and one of them was a second-generation recombinant form of CRF07&#95;BC and subtype C. These results revealed that multiple HIV-1 subtypes are circulating in Ganzhou, China. Systematic surveys with large sample sizes are urgently needed to explore the exact molecular epidemiological characteristics and to trace the origins of HIV-1 in Ganzhou, China.

Objective: To investigate the application value of the technique of fracture body surface localization film combined with CT volume rendering in the selection of minimally invasive incision for internal fixation of rib fractures., Patients and Methods: Clinical data of 55 cases of patients who underwent internal fixation for rib fracture in our hospital from June 2019 to April 2020 were selected. The differences in the accuracy of preset incision, incision length, operation time, intraoperative blood loss, postoperative wound drainage, and postoperative pain score between the group with fracture body surface localization film combined with CT volume rendering (n=32) and the group with traditional localization method (n=23)., Results: Compared with traditional localization method, fracture body surface localization film combined with CT volume rendering could improve the accuracy of surgical incision, reduce the operation time, incision length, intraoperative blood loss, postoperative wound drainage, and postoperative pain score (p<0.05)., Conclusions: The application of fracture body surface localization film combined with CT volume rendering has obvious effects on the accurate selection of incision of rib fracture internal fixation, and it is an effective method that is worthy of promotion.

Objective: To analyze the indication, efficacy and complications of implantable cardioverter-defibrillator (ICD) implantation in children with severe tachycardia. Methods: The retrospective study collected the clinical data of 6 patients who accepted ICD implantation in Shanghai Children's Medical Center from January 2009 to January 2020. The etiologies of tachycardia, procedure of the ICD implantation and the operation associated complications were analyzed. Results: The 6 patients aged from 6 years and 5 months to 16 years and 2 months, and their weight were from 15.4 kg to 49.8 kg. Three patients were diagnosed with long QT syndrome, and the remaining three with catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and lethal cardiac channelopathy, respectively. All the patients suffered from drug-resistant ventricular tachycardia or ventricular vibration before the operation. After the ICD implantation, 3 patients had electric storm, which was alleviated after analgesics-sedatives treatment with chlorpromazine, dexmedetomidine or midazolam combined with fentanyl, as well as reset of the ICD parameters and support from psychological consultation. The other 3 patients did not undergo any complications as the above comprehensive strategies were given after the operation prophylactically. All patients continued anti-arrhythmic medicine after the operation and all survived at the end of the follow-up period lasted from 1 month to 7 years. Two patients had ventricular tachycardia (VT) and ventricular vibration, which were successfully recognized and defibrillated by ICD. Conclusions: ICD implantation is safe and effective in children and adolescent patients. The electric storm may happen after operation, which could be prevented by the comprehensive strategies including appropriate ICD parameter-setting, analgesics-sedatives treatment and psychological support.

Background and Objectives: During the coronavirus disease 2019 outbreak, the treatment of families with children on long-term KRT is challenging. This study was conducted to identify the current difficulties, worries regarding the next 2 months, and mental distress experienced by families with children on long-term KRT during the coronavirus disease 2019 outbreak and to deliver possible management approaches to ensure uninterrupted treatment for children on long-term KRT., Design, Setting, Participants, & Measurements: A multicenter online survey was conducted between February 10 and 15, 2020, among the families with children on long-term KRT from five major pediatric dialysis centers in mainland China. The primary caregivers of children currently on long-term KRT were eligible and included. Demographic information, severe acute respiratory syndrome coronavirus 2 infection status, current difficulties, and worries regarding the next 2 months were surveyed using a self-developed questionnaire. The Patient Health Questionnaire-9 and the General Anxiety Disorder Scale-7 were used to screen for depressive symptoms and anxiety, respectively., Results: Among the children in the 220 families included in data analysis, 113 (51%) children were on dialysis, and the other 107 (49%) had kidney transplants. No families reported confirmed or suspected cases of coronavirus disease 2019. Overall, 135 (61%) and 173 (79%) caregivers reported having difficulties now and having worries regarding the next 2 months, respectively. Dialysis supply shortage (dialysis group) and hard to have blood tests (kidney transplantation group) were most commonly reported. A total of 29 (13%) caregivers had depressive symptoms, and 24 (11%) had anxiety. After the survey, we offered online and offline interventions to address their problems. At the time of the submission of this paper, no treatment interruption had been reported., Conclusions: The coronavirus disease 2019 outbreak has had physical, mental, logistical, and financial effects on families with children on long-term KRT., (Copyright © 2020 by the American Society of Nephrology.)

Aim: The aim of this study is to characterize the effect of chemotherapy drug doxorubicin with neoadjuvant drug docetaxel for different molecular subtypes., Methods: A total of 83 patients with late-stage breast cancer were chosen to undergo treatment and compared to these patients to the combinational treatment to identify the molecular characteristics that can predict the responses., Results: Total response rate is 81.9% (68/83 patients). Among them, 7 patients show pathological complete response of 8.4%, 12 patients show clinical complete response of 14.5%, 49 patients show partial response of 59%, and 15 patients show stable disease of 18.1%. The comparison among different subtypes of breast cancer, including luminal A, luminal B, basal-like, and ERBB2 + subtypes, did not show statistical significant differences to the treatment of combinational treatment for the complete response rate, including pathological complete response and clinical complete response. Comparing with luminal A and luminal B subtypes, the ERBB2 + and basal-like subtypes have better complete response and response rate rates. The disease-free survival rate and overall survival rate at 29 months after treatment did not show statistical significant differences among different subtypes of patients with breast cancer., Conclusion: The molecular subtypes of breast cancer can predict responses to the combinational treatment of doxorubicin with docetaxel, and ERBB2 + and basal-like subtypes have better response rate and complete response rate. There is correlation of estrogen receptor and KI-67 level changes with response rate as well, where KI-67 high patients are more sensitive to the treatment.

Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1 H )-one ( 2a ) by C-ring expansion and isometric replacement of the A/B-ring, successively, aimed at finding new potential alternative drug candidates with different scaffold(s), high antitumor activity, and other improved properties to replace prior, once promising drug candidates that failed in further studies. Two series of new compounds 7 ( a-d ) and 13 ( a-j ) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds 13c , 13d , and 13e with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI 50 values (4.6-9.6 nM) in cellular assays, comparable to lead 2a , clinical drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, 13d showed better aqueous solubility than 2a and a similar log P value., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Renal cell carcinoma (RCC) is the most common malignancy involving the kidneys and a major cause of cancer mortality. The involvement of microRNA (miRNA) expression in the tumorigenesis and progression of RCC has been previously highlighted. Therefore, we conducted this study to investigate whether microRNA-363 (miR-363) affects the development of RCC via the Janus tyrosine kinases (JAK2)-signal transducers and activators of transcription (STAT) axis by targeting the growth hormone receptor (GHR), by observing the changes that occurred in the RCC and the normal adjacent tissues of patients with RCC. RCC cells were transfected with a series of miR-363 mimic, miR-363 inhibitor, or small interfering RNA against GHR to determine the influence of miR-363 on the expression of GHR and JAK2-STAT3 axis-related genes with the use of reverse transcription quantitative polymerase chain reaction and Western blot analysis. The angiogenesis, viability, invasion, and migration of cells were evaluated by means of in vitro angiogenesis, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT), wound-healing, and Transwell assays. The results revealed reduced miR-363 expression and elevated GHR expression in RCC. It was also found that miR-363 altered the activation of the JAK2-STAT3 axis through the inhibition of GHR. Cells treated with the miR-363 inhibitor presented with increased capillary vessels, cell viability, invasion, and migration, whereas it was on the contrary in the RCC cells with overexpressed miR-363. These results implicated that the overexpression of miR-363 could specifically bind to GHR to downregulate the expression of GHR, which, in turn, inactivates the JAK2-STAT3 axis, thereby influencing the angiogenesis, cell invasion, and migration abilities in RCC., (© 2018 Wiley Periodicals, Inc.)

Modern pharmacological studies have shown that Shengmai San has the effects of enhancing immunity and improving blood circulation, and Curcumae Longae Rhizoma(Jianghuang) has anti-inflammatory, anti-cancer, anti-oxidation and other functions. Shengmai San combined with Jianghuang is a new research direction in the study of anti-tumor of traditional Chinese medicines. The main treatment for nasopharyngeal carcinoma is radiation therapy, but radiation therapy can cause a variety of side effects, and it also changes the composition of the intestinal flora. In this study, the 16 s rDNA sequencing platform was used to perform macro-sequence sequencing of the intestinal flora samples of nude mice bearing the veins of Shengmai Jianghuang San, and then the results of intestinal flora data were analyzed to investigate the effect of Shengmai Jianghuang San on tumors. The results showed that Shengmai Jianghuang San combined with irradiation could enhance the therapeutic effect of tumor treatment. Radiation therapy would reduce the total number and diversity of intestinal flora in nude mice, and also change the structure of the flora. Shengmai Jianghuang San could protect the diversity of colonies, and also partially restore the colony imbalance caused by irradiation. This study provides a research idea for Shengmai Jianghuang San as a sensitizing adjuvant for radiotherapy of nasopharyngeal carcinoma.

Typical N-acetyl-D-neuraminic acid (Neu5Ac) production uses N-acetyl-D-glucosamine (GlcNAc) and excess pyruvate as substrates in the enzymatic or whole-cell biocatalysis process. In a previous study, a Neu5Ac-producing biocatalytic process via engineered Escherichia coli SA-05/pDTrc-AB/pCDF-pck-ppsA was constructed without exogenous pyruvate. In this study, glycerol was found to be a good energy source compared with glucose for the catalytic system with resting cells, and Neu5Ac production increased to 13.97 ± 0.27 g L -1 . In addition, a two-stage pH shift strategy was carried out, and the Neu5Ac yield was improved to 14.61 ± 0.31 g L -1 . The GlcNAc concentration for Neu5Ac production was optimized. Finally, an integrated strategy was developed for Neu5Ac production, and the Neu5Ac yield reached as high as 18.17 ± 0.27 g L -1 . These results provide a new biocatalysis technology for Neu5Ac production without exogenous pyruvate.

Gastric microbiota provides a biological barrier against the invasion of foreign pathogens from the oral cavity, playing a vital role in maintaining gastrointestinal health. Klebsiella spp. of oral origin causes various infections not only in gastrointestinal tract but also in other organs, with Klebsiella pneumoniae serotype K1 resulting in a liver abscess (KLA) through oral inoculation in mice. However, the relationship between gastric microbiota and the extra-gastrointestinal KLA infection is not clear. In our study, a 454 pyrosequencing analysis of the bacterial 16S rRNA gene shows that the composition of gastric mucosal microbiota in mice with or without KLA infection varies greatly after oral inoculation with K. pneumoniae serotype K1 isolate. Interestingly, only several bacteria taxa show a significant change in gastric mucosal microbiota of KLA mice, including the decreased abundance of Bacteroides, Alisptipes and increased abundance of Streptococcus . It is worth noting that the abundance of Klebsiella exhibits an obvious increase in KLA mice, which might be closely related to KLA infection. At the same time, the endogenous antibiotics, defensins, involved in the regulation of the bacterial microbiota also show an increase in stomach and intestine. All these findings indicate that liver abscess caused by K. pneumoniae oral inoculation has a close relationship with gastric microbiota, which might provide important information for future clinical treatment., Gastric microbiota provides a biological barrier against the invasion of foreign pathogens from the oral cavity, playing a vital role in maintaining gastrointestinal health. Klebsiella spp. of oral origin causes various infections not only in gastrointestinal tract but also in other organs, with Klebsiella pneumoniae serotype K1 resulting in a liver abscess (KLA) through oral inoculation in mice. However, the relationship between gastric microbiota and the extra-gastrointestinal KLA infection is not clear. In our study, a 454 pyrosequencing analysis of the bacterial 16S rRNA gene shows that the composition of gastric mucosal microbiota in mice with or without KLA infection varies greatly after oral inoculation with K. pneumoniae serotype K1 isolate. Interestingly, only several bacteria taxa show a significant change in gastric mucosal microbiota of KLA mice, including the decreased abundance of Bacteroides, Alisptipes and increased abundance of Streptococcus . It is worth noting that the abundance of Klebsiella exhibits an obvious increase in KLA mice, which might be closely related to KLA infection. At the same time, the endogenous antibiotics, defensins, involved in the regulation of the bacterial microbiota also show an increase in stomach and intestine. All these findings indicate that liver abscess caused by K. pneumoniae oral inoculation has a close relationship with gastric microbiota, which might provide important information for future clinical treatment.

ChlA-F is a novel conformation-derivative of Cheliensisin A, styryl-lactone isolates that show potent anti-tumor potential in vivo and vitro. However, the anti-cancer activity and its potential mechanisms underlying ChlA-F action have never been explored. In the present study, we evaluated the potency of ChlA-F on autophagy-mediated anchorage-independent growth inhibition in human high-grade invasive bladder cancer (BC) cells. We found that ChlA-F treatment significantly inhibited anchorage-independent growth of human BC cells by inducing autophagy in a Sestrin-2 (SESN2)-dependent fashion. Our results revealed that ChlA-F treatment specifically induced SESN2 expression via increasing its transcription and mRNA stability. On one hand, ChlA-F treatment markedly attenuated Dicer protein abundance, in turn abolishing miR-27a maturation and further relieving miR-27a binding directly to SESN2 mRNA 3'UTR, thereby promoting SESN2 mRNA stabilization. On the other hand, ChlA-F treatment promoted Sp1 abundance and consequently mediated SESN2 transcription. These results demonstrate that its activation of the autophagic pathway through specifically promoting SESN2 expression mediates the anti-cancer effect of ChlA-F, which offers insights into the novel anti-cancer effect of ChlA-F on BC, as well as providing therapeutic alternatives against human BC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study was designed to investigate the possible synergism of amlodipine and candesartan on the reduction of blood pressure (BP) in hypertensive rats. The end organ protection was also observed. In acute experiment, spontaneously hypertensive rats (SHRs) were treated with intragastric administration of amlodipine (0.5, 1, 2, 3 mg/kg), candesartan (1, 2, 3, 4, 6, 8 mg/kg), and 14 different combinations to find the possible ratio of synergistic interaction. In two kidneys, one clip (2K1C) rats, the effects of amlodipine (1 mg/kg), canderastan (2 mg/kg) and their combination on BP reduction were also observed. In chronic study, SHRs were treated with amlodipine (1 mg/kg), candesartan (2 mg/kg), and their combination for 5 months. Organ damage evaluation was performed after BP recording. The probability sum test (q test) was used to evaluate the synergistic action. There is a synergistic interaction between amlodipine and candesartan on BP reduction. The optimal dose ratio is 1:2. The synergistic effect was also confirmed by 2K1C hypertensive rats. In chronic study, this combination (1:2) possessed an obvious synergism on the reduction of BP and BP variability (BPV) and protection on end organs. Multiple regression analysis showed that heart and aortic hypertrophy indexes and glomerular damage parameters were positively related to BP and BPV. In conclusion, combination of amlodipine and candesartan exhibited a potent antihypertensive effect and possessed an obvious synergism on BP reduction and organ protection in hypertension. The optimal proportion was 1:2. BP and BPV reduction may both importantly contribute to end organ protection., (© 2017 John Wiley & Sons Australia, Ltd.)

Certain probiotic species of lactic acid bacteria, especially Lactobacillus plantarum, regulate bacteriocin synthesis through quorum sensing (QS) systems. In this study, we aimed to investigate the luxS-mediated molecular mechanisms of QS during bacteriocin synthesis by L. plantarum KLDS1.0391. In the absence of luxS, the 'spot-on-the-lawn' method showed that the bacteriocin production by L. plantarum KLDS1.0391 significantly decreased upon co-cultivation with L. helveticus KLDS1.9207 (P < 0.01) but did not change significantly when mono-cultivated. Furthermore, liquid chromatography-electrospray ionization tandem mass spectrometry analysis showed that, as a response to luxS deletion, L. plantarum KLDS1.0391 altered the expression level of proteins involved in carbohydrate metabolism, amino acid metabolism, fatty acid synthesis and metabolism, and the two-component regulatory system. In particular, the sensor histidine kinase AgrC (from the two-component system, LytTR family) was expressed differently between the luxS mutant and the wild-type strain during co-cultivation, whereas no significant differences in proteins related to bacteriocin biosynthesis were found upon mono-cultivation. In summary, we found that the production of bacteriocin was regulated by carbohydrate metabolism, amino acid metabolism, fatty acid synthesis and metabolism, and the two-component regulatory system. Furthermore, our results demonstrate the role of luxS-mediated molecular mechanisms in bacteriocin production.

We investigated the clinical significance of mechanical ventilation on ischemic-reperfusion injury caused by lung chest trauma as well as vascular endothelial growth factor (VEGF) expression levels in peripheral blood. Sixty-eight patients with severe chest trauma complicated with acute respiratory distress syndrome that were treated at our Tianjin Hospital from September 2013 to July 2016 were recruited. These patients were randomly and evenly divided into two groups, the research group and the control group. Thirty-four age and gender matched healthy people were selected as the normal group. Routine treatment was given to both the research and control groups, but mechanical ventilation was used in the research group. We detected pulmonary vascular resistance (PVR) and alveolar-arterial oxygen difference (AaDO 2 ) for patients in both groups before treatment, and after treatment for 1, 3, 6 and 12 h. We also tested PMN, superoxide dismutase (SOD), malondialdehyde (MDA), NO and Ang II value 30 min before and after treatment. We used the ELISA-test to detect VEGF expression levels in peripheral blood, followed by a statistical analysis. PVR levels of different time points in the research group were significantly lower than control group after treatment. The AaDO 2 value of the control group is much smaller than research group (P<0.5) after treatment for 1, 3 or 6 h. PMN count difference and MDA level in the research group is significantly lower than the control group after treatment for 30 min, but SOD and NO levels are much higher. Ang II levels of the research group in left atrial blood is significantly lower than control group (P<0.05). By comparing the hospitalization times, we found that patients in the research group have a shorter duration in hospital than the control group; differences are statistically significant (P<0.05). Additionally, compared to control group, research group VEGF expression levels in peripheral blood are significantly lower (P<0.05). Therefore, mechanical ventilation can reduce the high VEGF expression levels in serum caused by ischemic-reperfusion and can be used for clinical application.

Aim: To investigate the epidemiologic characteristics and outcomes of open globe injury in Shanghai., Methods: A retrospective study was conducted for 148 unilateral open globe injury cases presenting to a tertiary referral hospital of Shanghai. Electronic medical records were reviewed and phone surveys were conducted to collect and analyze 1) background of patient; 2) setting of injury and clinical signs at presentation; 3) treatment procedure and outcome; 4) quality of life after injury., Results: There were more male patients (77.03%) than females (22.97%), more temporary habitants (79.05%) than residents (20.95%). The subjects in this study presented a significantly lower constitutional status of education than that of the whole Shanghai population ( P <0.001). Occupational injury was the first cause of injuries (39.86%), followed by home accident (20.27%), road accident (16.89%), violent behavior (16.89%) and outdoor injury (6.08%). The 143 subjects (96.62%) were not wearing spectacles at the time of injury. Of all patients, 77 subjects (52.03%) had the outcome of no vision (including enucleation). The classification and regression tree (CART) prognosis presents 59.58% sensitivity to predict visual survival correctly and 80.19% specificity to predict no vision correctly. The patients whose injured eye had no vision reported more reduction of life quality., Conclusion: We found that male subject, temporary habitants, low educational status and no eyewear are risk factors of open globe injury in Shanghai. Occupational injury is the leading cause. CART analysis presents a certain agreement to the actual visual outcome. The injury imposes negative impact on quality of life especially in no vision cases. The education of eye protection may help to avoid the injury.

Stroke is a leading cause of mortality and disability worldwide. There is growing evidence that metformin (Met) has potent neuroprotective effects; however, its mechanisms remain unclear. We examined the role of the arterial baroreflex and cholinergic-α7 nicotinic acetylcholine receptor (α7nAChR) anti-inflammory pathway in the beneficial effects of Met against stroke. Stroke-prone spontaneously hypertensive rats (SHRSP) were used to observe stroke development indicated by lifespan of SHRSP and the ischemic injury induced by permanent middle cerebral artery occlusion (MCAO). Sinoaortic denervation was used to inactivate the arterial baroreflex. MCAO were also performed in α7nAChR knockout (KO) mice. Briefly, Met increased the life span of SHRSP and reduced the infarct area induced by MCAO. Met also improved the function of arterial baroreflex. The beneficial effects of Met on stroke were markedly attenuated by blunting the arterial baroreflex. Met up-regulated the expression of vesicular acetylcholine transporter (VAChT) and α7nAChR, down-regulated the level of pro-inflammtory cytokines in serum and peri-infarct of ischemic brain. Arterial baroreflex dysfunction decreased the expression of VAchT and α7nAChR, showed upward tendency in the level of pro-inflammtory cytokines. Most importantly, arterial baroreflex dysfunction nearly abolished such effect of Met on cholinergic signaling. In addition, the α7nAChR KO mice also had significantly worse ischemic damage induced by MCAO, and neuroprotection of Met disappeared in α7nAChR KO mice. In conclusion, Met improved the arterial baroreflex function, and then enhancing cholinergic anti-inflammatory pathway in an α7nAChR-dependent manner, thereby effectively prevent ischemic induced brain injury and delayed stroke onset in SHRSP., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The effectiveness of neoadjuvant chemoradiotherapy (NCRT) treatment for patients with esophageal carcinoma (EC) remains controversial. The aim of this study was to compare the effect of NCRT followed by surgery (NCRTS) with surgery alone (SA) for EC., Methods: The PubMed, EMBASE, and the Cochrane Library databases were electronically searched up to August 2015 for all the published studies that investigated EC patients receiving either NCRTS or SA, and the reference lists were also manually examined for the eligible studies. The risk ratio (RR) with 95% confidence intervals (CI s) as effective size was determined to assess the 1-, 3-, 5-year survival rates (SRs), postoperative morbidity, and postoperative mortality. Heterogeneity was determined using the Q-test. The Begg's test and Egger's test were used for assessing any potential publication bias., Results: Of 1120 identified studies, 16 eligible studies were included in this analysis (involving 2549 patients). Overall, the pooled results suggested that NCRTS was associated with significantly improved 1-year (RR: 1.07, 95% CI: 1.02-1.13), 3-year (RR: 1.26, 95% CI: 1.14-1.39), and 5-year (RR: 1.36, 95% CI: 1.18-1.56) SRs. However, the results also indicated that NCRTS had no or little effect on postoperative morbidity (RR: 0.93, 95% CI: 0.82-1.05) and postoperative mortality (RR: 1.17, 95% CI: 0.56-2.44)., Conclusions: Compared with SA, NCRTS can increase 1-, 3-, and 5-year SRs in patients with EC., Competing Interests: There are no conflicts of interest.

Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.

Background: Obesity is a growing global public health problem which requires all healthcare professionals to deliver weight management care within their roles., Aim: To describe nurses' perceived barriers, skills and practices regarding weight-related care and explore differences between English and Chinese nurses., Methods: A cross-sectional, self-administered questionnaire survey was distributed to 588 English nurses employed in a range of clinical settings and healthcare organizations and attending a large university in London (October-November 2010), and 519 Chinese nurses working in one of the largest hospitals in Shanghai, China (February-April 2011). Perceived barriers, skills and practices regarding weight-related care were measured. Data analysis was undertaken using responses from 399 English and 466 Chinese nurses., Results: English and Chinese nurses reported similar barriers to undertaking weight-related care practices which included two relatively new barriers, namely complex patients and the absence of clear practice guidelines. Both English and Chinese nurses reported being moderately skilled to perform weight-related care practices with the most mean skill scores at the moderate level. Up to 11-54% of the English nurses and 10-25% of the Chinese nurses reported providing recommended weight-related interventions for most of their patients. Generally, the English nurses reported more barriers, high-level skills and practices regarding weight-related care than the Chinese nurses., Limitations: The convenience samples and self-report data may have been sources of bias., Conclusions: A variety of barriers and limited skills may help explain the suboptimal weight-related practices among the nurses., Implications for Nursing and Health Policy: Skill development of pre-registration and qualified nurses is indicated as well as the development of the nurse role to include weight management care of obese patients. Evidence-based guidelines should be readily accessible to support the nurse role in weight-related care., (© 2015 International Council of Nurses.)

Thirteen new N-aryl 1,2,3,4-tetrahydroquinoline compounds (4a-f, 6a-c, and 8a-d) were synthesized and evaluated for antitumor activity and drug-like properties. Compound 4a exhibited high inhibitory potency with low nanomolar GI50 values of 16-20 nM in cellular assays, including excellent activity against the P-glycoprotein overexpressing cell line KBvin. Compound 4a inhibited colchicine binding to tubulin and tubulin assembly with an IC50 value of 0.85 μM, superior to the reference compound CA4 (1.2 μM) in the same assay. In addition, 4a also exhibited highly improved water solubility (75 μg/mL) and a suitable logP value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound 4a could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Resistance to chemotherapeutic drugs is a major obstacle in hepatocellular carcinoma (HCC) therapy. MicroRNA&mdash;145 (miR&mdash;145) has been shown to be down&mdash;regulated in several cancers and may be involved in the process of carcinogenesis. The present study aimed to evaluate the effects of miR&mdash;145 in adriamycin (ADM)&mdash;resistant human HCC cells. We found that miR&mdash;145 was significantly reduced in HepG2/ADM and HuH7/ADM cells compared with the chemosensitive parental cells. Up&mdash;regulation of miR&mdash;145 increased the ADM cytotoxicity in chemoresistant tumor cells. In addition, Smad3 was identi&#64257;ed as the target of miR&mdash;145 and miR&mdash;145 overexpression inhibited Smad3 expression both at the mRNA and protein levels. The luciferase reporter assay confirmed that Smad3 was a direct target of miR&mdash;145. Moreover, up&mdash;regulation of miR&mdash;145 suppressed Smad3 related EMT features as shown by increased expression of E&mdash;cadherin and reduced vimentin level in HepG2/ADM and HuH7/ADM cells. Our study demonstrated that miR&mdash;145 modulated both chemoresistance and EMT in HCC cells, and up&mdash;regulation of miR&mdash;145 might be a potential therapeutic strategy for treatment of chemoresistant HCC.

Lung cancer is one of the most common but serious cancers in the world. Both the X-ray repair cross-complementing group 1 (XRCC1) gene and the human multidrug resistance 1 (MDR1) gene are important candidate genes influencing the susceptibility to various diseases, including lung cancer. This study aimed to assess the correlation of genetic polymorphisms in XRCC1 and MDR1 with the susceptibility to lung cancer. In this study, a total of 320 lung cancer patients and 346 cancer-free controls in Chinese population were enrolled in this study. Data about the clinical characteristics and related risk factors of lung cancer were collected by questionnaires. The single-nucleotide polymorphisms (SNPs) of XRCC1 and MDR1 genes were genotyped by created restriction site-polymerase chain reaction method. Our data showed that the risk for lung cancer increased significantly among the variant Arg194Trp (C > T, rs1799782) and Arg399Gln (G > A, rs25487) of XRCC1, but there are no significant differences in the allelic and genotypic frequencies of c.1564A > T and c.3073A > C of MDR1 between lung cancer patients and cancer-free controls. In conclusion, these preliminary results suggest that the C > T, rs1799782 and C > T, rs25487 of XRCC1 genetic variants might be used as molecular markers for detecting lung cancer susceptibility.