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Background: Although China accounts for 7.8% of worldwide new prostate cancer (PCa) cases and 14.5% of new deaths according to GLOBOCAN 2020, the risk of PCa associated with germline mutations is poorly defined, hampered in part by lack of nationwide evidence. Here, we sequenced 19 PCa predisposition genes in 1,836 Chinese patients with PCa and estimated disease risk associated with inherited mutations. Patients and Methods: Patients were recruited from 4 tertiary cancer centers (n=1,160) and a commercial laboratory (n=676). Germline DNA was sequenced using a multigene panel, and pathogenic/likely pathogenic (P/LP) mutation frequencies in patients with PCa were compared with populations from the gnomAD (Genome Aggregation Database) and ChinaMAP (China Metabolic Analytics Project) databases. Clinical characteristics and progression-free survival were assessed by mutation status. Results: Of 1,160 patients from hospitals, 89.7% had Gleason scores ≥8, and 65.6% had metastases. P/LP mutations were identified in 8.49% of Chinese patients with PCa. Association with PCa risk was significant for mutations in ATM (odds ratio [OR], 5.9; 95% CI, 3.1–11.1), BRCA2 (OR, 15.3; 95% CI, 10.0–23.2), MSH2 (OR, 15.8; 95% CI, 4.2–59.6), and PALB2 (OR, 5.9; 95% CI, 2.7–13.2). Compared with those without mutations, patients with mutations in ATM, BRCA2, MSH2, or PALB2 showed a poor outcome with treatment using androgen deprivation therapy and abiraterone (hazard ratio, 2.19 [95% CI, 1.34–3.58] and 2.47 [95% CI, 1.23–4.96], respectively) but similar benefit from docetaxel. Conclusions: The present multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.

Gao Liu,1,2 Jia Li,1,2 Cai-Yun Zhang,1,2 Dong-Yang Huang,3 Ji-Wei Xu1,2 1Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou, 514000, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, People’s Republic of China; 3Center for Molecular Biology, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of ChinaCorrespondence: Dong-Yang HuangCenter for Molecular Biology, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of ChinaEmail huangdy@stu.edu.cnJi-Wei XuDepartment of Hepatobiliary Surgery, Meizhou People’s Hospital, No. 38 Huangtang Road, Meizhou, 514000, People’s Republic of ChinaTel +86-13823832715Email javeeht@163.comIntroduction: One of the most common cancers is hepatocellular carcinoma (HCC), which is an aggressive cancer that is associated with high mortality. The expression and role of ARHGAP20 in HCC remain unclear.Materials and Methods: The expression and clinical role of ARHGAP20 were investigated using online databases and HCC samples from Meizhou People’s Hospital. Wound healing assays, transwell migration/invasion assays, and lung metastasis models were performed using nude mice. Gene set enrichment analyses were used to further explore the potential mechanisms.Results: Inspired by expression analyses of three different public databases (ie, TIMER, Oncomine, and HCCDB database), we confirmed that ARHGAP20 was downregulated in clinical HCC tumors compared with normal controls. ARHGAP20 expression inhibited HCC migration and invasion in vitro and in vivo. Based on GSEA results, we tested markers of the PI3K-AKT signaling pathway. Interestingly, while ARHGAP20 upregulation suppressed HCC migration/invasion and phosphorylation of AKT/PI3K molecules, exposure to the PI3K-AKT pathway agonist rhIGF-1 partially rescued these phenomena. ARHGAP20 also showed a close correlation with certain components in the HCC immune microenvironment. Furthermore, we revealed that downregulated ARHGAP20 was significantly correlated with larger tumor size and vascular invasion, and could be used as an adverse independent prognostic factor for HCC OS but not RFS.Conclusion: ARHGAP20 was identified for the first time as a tumor suppressor gene that could inhibit HCC progression by regulating the PI3K-AKT signaling pathway and the immune microenvironment in HCC.Keywords: HCC, ARHGAP20, progression, PI3K-AKT, immune microenvironment

At present, the deficiency of β-cell function is progressive in patients with type 2 diabetes mellitus. Exenatide cannot only control blood glucose well, but also promotes the regeneration and proliferation of islet β-cells and improves the function of β cells. However, it needs to be given twice a day, and there are many adverse reactions such as nausea. PEGylated exenatide (study code: PB-119) needs to be administered only once a week. The purpose of this experiment was to evaluate the safety, pharmacokinetics and pharmacodynamics of an escalating dose regimen of subcutaneous PEGylated exenatide injections in healthy subjects. Twelve healthy young adult subjects in each group received once-weekly subcutaneous injections of 165 μg, 330 μg, and 660 μg PEGylated exenatide for 6 weeks. Plasma drug concentration was determined in venous blood collected across selected time points. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, and electrocardiogram. Blood glucose, insulin, glucagon and C peptide were monitored at different time points to evaluate the pharmacodynamics of PEGylated exenatide. A total of 11, 10, and 12 subjects completed the study in 165 µg, 330 µg, and 660 µg dose groups, respectively. After 6 consecutive weeks of administration, the t1/2 in the 165 μg, 330 μg, and 660 µg dose groups was 55.67 ± 11.03 h, 56.99 ± 21.37 h, and 54.81 ± 13.87 h, respectively. The Cavg was 4.22 ± 0.78 ng/ml, 6.03 ± 1.43 ng/ml, and 10.50 ± 3.06 ng/ml, respectively. AUCss was 708.59 ± 131.87 h•ng/ml, 1012.63 ± 240.79 h•ng/ml, and 1763.81 ± 514.50 h•ng/ml, respectively. The accumulation index was 1.15 ± 0.07, 1.17 ± 0.11, and 1.14 ± 0.07. The CLss/F was 241.25 ± 51.13 ml/h, 341.53 ± 73.62 ml/h, and 450.06 ± 313.76 ml/h, respectively. A total of 10 of 36 (27.78%) subjects in the three dose groups developed specific antibodies after consecutive subcutaneous injections of PEGylated exenatide. The Cavg and Cmax were higher than those of antibody-negative subjects. Furthermore, in antibody-positive subjects, CLss/F, t1/2, AUCτ, accumulation index, MRT(0–inf) and other parameters were lower than those of antibody-negative subjects. In the 165 μg dose group, two subjects (16.67%) experienced 4 adverse events. In the 330 μg dose group, no subjects reported adverse events. In the 660 μg dose group, 8 subjects (66.67%) reported 16 adverse events, which were mostly gastrointestinal. There were no significant changes in the pharmacodynamic parameters except the glucagon level at day 36 in the 660 µg dose group, the 2h postprandial insulin and C peptide levels at day 36 and day 50 in the 165 μg dose group compared with baseline (− 1 day). A once-weekly subcutaneous injection of 165 µg and 330 µg PEGylated exenatide is safe. No significant effects on blood glucose or pancreatic hormone levels were observed in the subjects within these dose groups. The pharmacokinetic parameters of PEGylated exenatide may be affected by immunogenicity. The study is registered at clinicaltrials.gov (No. NCT03062774).

BACKGROUND Aortic dissection (AD) is a life-threatening condition with a high mortality rate without immediate medical attention. Early diagnosis and appropriate treatment are critical in treating patients with AD. In the emergency department, patients with AD commonly present with classic symptoms of unanticipated severe chest or back pain. However, it is worth noting that atypical symptoms of AD are easily misdiagnosed. CASE SUMMARY A 51-year-old woman was first diagnosed with scapulohumeral periarthritis due to left shoulder pain. After careful examination of her previous medical history and contrast-enhanced computed tomography angiography, the patient was diagnosed with a new type A AD after chronic type B dissection in the ascending aorta. The patient was successfully treated with surgical replacement of the dissected aortic arch and remains in good health. CONCLUSION New retrograde type A AD after chronic type B dissection is relatively rare. It is worth noting that a physician who has a patient with suspected AD should be vigilant. Both patient medical history and imaging tests are crucial for a more precise diagnosis.

Objective With the epidemic of coronavirus disease 2019 (COVID-19), the healthcare workers (HCWs) require proper respiratory personal protective equipment (rPPE) against viral respiratory infectious diseases (VRIDs). It is necessary to evaluate which type of mask and manner of wearing is the best suitable rPPE for preventing the VRID. Study design A Bayesian network meta-analysis was performed to comprehensively analyze the protective efficacy of various rPPE. Methods This network meta-analysis protocol was registered in an international prospective register of systematic reviews (CRD42020179489). Electronic databases were searched for cluster randomized control trials (RCTs) of comparing the effectiveness of rPPE and wearing manner in preventing HCWs from VRID. The primary outcome was the incidence of laboratory-confirmed viral respiratory infection reported as an odds ratio (OR) with the associated 95% credibility interval (CrI). The secondary outcome was the incidence of clinical respiratory illness (CRI) reported as an OR with the associated 95% CrI. Surface under the cumulative ranking curve analysis (SUCRA) provided a ranking of each rPPE according to the primary outcome and the secondary outcome as data supplement. Results Six studies encompassing 12,265 HCWs were included. In terms of the incidence of laboratory-confirmed viral respiratory infection, the continuous wearing of N95 respirators (network OR, 0.48; 95% CrI: 0.27 to 0.86; SUCRA score, 85.4) showed more effective than the control group. However, in terms of reducing the incidence of CRI, there was no rPPE showing superior protective effectiveness. Conclusions There are significant differences in preventive efficacy among current rPPE. Our result suggests that continuous wearing of N95 respirators on the whole shift can serve as the best preventive rPPE for HCWs from the VRID., Highlights • First network meta-analysis of respiratory personal protective equipment (rPPE). • Wearing manner is important for susceptible healthcare workers. • Continuous wearing of N95 respirators on the whole shift can serve as the best preventive rPPE for healthcare workers from the VRIDs.

Cancer stem cells (CSCs) have an established role in cancer progression and therapeutic resistance. The p63 proteins are important transcription factors which belong to the p53 family, but their function and mechanism in CSCs remain elusive. Here, we investigated the role of TAp63α in colorectal CSCs and the effects of sulforaphane on TAp63α. We found that TAp63α was upregulated in spheres with stem cell properties compared to the parental cells. Overexpression of TAp63α promoted self-renewal capacity and enhanced CSC markers expression in colorectal sphere-forming cells. Furthermore, we showed that TAp63α directly bound to the promoter region of Lgr5 to enhance its expression and activate its downstream β-catenin pathway. Functional experiments revealed that sulforaphane suppressed the stemness of colorectal CSCs both in vitro and in vivo. Upregulation of TAp63α attenuated the inhibitory effect of sulforaphane on colorectal CSCs, indicating the role of TAp63α in sulforaphane suppression of the stemness in colorectal cancer. The present study elucidated for the first time that TAp63α promoted CSCs through targeting Lgr5/β-catenin axis and participated in sulforaphane inhibition of the stem cell properties in colorectal cancer.

Background The purpose of this study was to investigate the safety, tolerability and pharmacokinetics of tetramethylpyrazine nitrone (TBN) in healthy Chinese volunteers. Methods A single-ascending-dose (SAD) study where 68 subjects were randomized to a single dose of placebo or TBN (50, 100, 200, 400, 700, 1,000, 1,400, or 1,800 mg) through IV infusion over 30 min. A multiple-ascending-dose (MAD) study where 24 subjects received TBN twice daily (with 12 hr interval) for total 6.5 days at doses of either 700 or 1,400 mg. Adverse events were recorded and pharmacokinetic samples were collected during the whole study period. Results No serious adverse events were found in the study. All of the observed adverse events, including increased white blood cell (4.4% subjects) and neutrophil counts (4.4% subjects), and decreased hemoglobin levels (4.2% subjects), were laboratory test abnormalities. All the adverse events were mild and tolerable, and returned to normal without any intervention. In the SAD study, linear Cmax values were observed in the dose interval of 50-1,800 mg. In the MAD study, the average steady-state concentrations (Cavg.ss ) of TBN in the 700 and 1,400 mg dose group were 2,407 and 5,837 ng/ml, respectively. No drug accumulation was observed in this study. Conclusions TBN is well tolerated in healthy volunteers. Linear Cmax values were observed in the interval of 50-1,800 mg, and target exposures of TBN were achieved without accumulation after twice daily administration to subjects. (This study has been registered at ChiCTR.org.cn. Identifier: ChiCTR1800016225 and ChiCTR1800019627.).

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.

Ent-kaur-15-en-17-al-18-oic acid (LL-3) was demonstrated that it can inhibit LPS-induced nitric oxide (NO) production and macrophage migration, maintain homeostasis of oxidative stress, including increased mitochondrial membrane potential (MMP), decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and maintenance of superoxide dismutase (SOD) and glutathione (GSH) activities and inhibit oxidative stress-induced P38 and nuclear factor κB (NF-κB) pathways to decrease inducible nitric oxide synthase (iNOS), cyclooxygense-2 (COX-2), and tumour necrosis factor (TNF)-α mRNA expressions without marked cytotoxicity. These findings revealed that LL-3 could serve as a candidate lead compound for further studying anti-inflammatory therapies.[Formula: see text].

Acute heart failure (AHF) is a severe complication after cardiac surgery with cardiopulmonary bypass (CPB). Although some AHF biomarkers have been used in clinic, they have limitations when applied in the prediction and diagnosis of AHF after cardiac surgery with CPB, and there are still no effective and specific biomarkers. We and other researchers have shown that circulating microparticles (MPs) increased in a variety of cardiovascular diseases. However, whether the concentration of circulating MPs could be a new biomarker for AHF after cardiac surgery remains unknown. Here, 90 patients undergoing cardiac surgery with CPB and 45 healthy subjects were enrolled. Patients were assigned into AHF (n=14) or non-AHF (n=76) group according to the diagnosis criteria of AHF. The concentrations of circulating MPs were determined before, as well as 12 h and 3 days after operation with nanoparticle tracking analysis technique. MPs concentrations in patients before surgery were significantly higher than those of healthy subjects. Plasma levels of MPs were significantly elevated at 12 h after surgery in patients with AHF, but not in those without AHF, and the circulating MPs concentrations at 12 h after surgery were higher in AHF group compared with non-AHF group. Logistic regression analysis indicated that MPs concentration at postoperative 12 h was an independent risk factor for AHF. The area under receiver operating characteristic curve for MPs concentration at postoperative 12 h was 0.81 and the best cut-off value is 5.20×108 particles mL-1 with a sensitivity of 93% and a specificity of 10%. These data suggested that the concentration of circulating MPs might be a new biomarker for the occurrence of AHF after cardiac surgery with CPB.

To evaluate the use of real-time shear wave elastography (SWE) in the assessment of renal elasticity and the efficacy of steroid treatment in adult idiopathic nephrotic syndrome (INS). This study included 120 patients with INS. Patients were divided into steroid-sensitive and steroid-resistant groups. Renal biopsy was performed. Thirty healthy subjects were recruited as controls. Young’s modulus (YM) of the renal parenchyma was measured by SWE. The YM values in each group were compared using glomerular sclerosis index (GI) and renal interstitial fibrosis (RIF). The YM values were significantly different between the INS and control groups, as well as between the steroid-sensitive and steroid-resistant groups (P

Exenatide promotes insulin secretion and inhibits postprandial glucagon secretion. Polyethylene glycolated exenatide injection (PB-119), a derivative obtained by modification of exenatide, is more stable in metabolic behavior than exenatide in vivo. Our study aimed to evaluate the safety, tolerability and pharmacokinetic characteristics of polyethylene glycolated exenatide as a single subcutaneous injection in healthy volunteers. Seventy subjects were randomly assigned to 8 incremental dosage groups (2, 5, 10, 25, 50, 100, 200 and 400 µg). The 2- to 50-µg groups had 8 subjects in each group (the ratio of test preparation to placebo was 3:1), and the 100- to 400-µg groups had 10 subjects in each group (the ratio of test preparation to placebo was 4:1). All the subjects received a single subcutaneous injection of polyethylene glycolated exenatide and placebo according to the dosage groups. The tolerability test was conducted in the 2- to 10-µg groups. The pharmacokinetic test was carried out in the 25- to 400-µg groups, and plasma samples were collected to determine the pharmacokinetics of polyethylene glycolated exenatide. After medication, the vital signs of the subjects were monitored, and laboratory tests and electrocardiogram tests were carried out regularly in all the subjects. All 70 subjects completed the experiment. Except for the 5-µg and 10-µg groups, the safety and tolerability tests showed no adverse reactions in the 2-µg to 50-µg groups. Several subjects in the 100-µg and 200-µg groups had tolerable gastrointestinal tract reactions, and all subjects in the 400-µg group experienced adverse reactions, mainly gastrointestinal tract reactions and liver dysfunction. The pharmacokinetics of polyethylene glycolated exenatide was studied in 36 subjects, which showed slow absorption, a mean peak time of 20–40 h, and a mean elimination half-life of 51–64 h. The administration of polyethylene glycolated exenatide injection at a single dose of 2–200 µg is safe and tolerable for healthy volunteers. Once-weekly polyethylene glycolated exenatide injection can be recommended. The study was registered at clinicaltrials.gov (No. NCT02084251).

Heparinase I (Hep I) specifically degrades heparin to oligosaccharide or unsaturated disaccharide and has been widely used in preparation of low molecular weight heparin (LMWH). In this wor...

In order to strengthen the prevention and management in the geriatric department during the pandemic of COVID-19 and to explore how to implement nursing measures to control the spread of COVID-19 to elderly patients, our geriatric department established a leading group for epidemic prevention to train the medical staffs, the patients and caregivers and implemented a set of measures such as controlling the source of infection, cutting off the transmission route, and rehabilitation nursing of Chinese medicine, thus achieved zero infection of medical staff and elderly patients.

Background: Femoral neck fractures are the worst consequence of osteoporosis (OP), and its early prevention and treatment have become a public health problem.This study aims to investigate the relationship of bone-related biomarkers,femoral neck bone mineral density (BMD) and maximum load (Lmax),selecting the indicator which can reflect femoral neck bone loss and reduced bone strength. Methods: A total of 108 patients were recruited from January 2017 to December 2019. Femoral neck BMD, femoral neck Lmaxand bone-related biomarkerswere all measured and analyzed.Results: The expression of femoral neck type I collagen (COL-I)were significantly decreased, whereas other markers were all significantly increased with the decreasing of femoral neck BMD and Lmax(Pindependent factorsof femoral neck BMD and Lmax, whereasCOL-I was independent factor affectingLmax(P< 0.05). Moreover, CTX was the independent risk factor of OPN and COL-I(PConclusions: Bone-related biomarkersdo reflect decreased femoral neck bone mass and bone strength. Of them, the CTX increases most significantly in the process of bone loss, and can be used as a surrogate markerof OPN and COL-I for bone loss and reduced bone strength.Early measurement of CTXcouldfacilitate the diagnosis of osteopenia and provide a theoretical basis for delaying the occurrence of femoral neck OP and fragility fractures.

STAT3 is constitutively activated in many malignant tumor types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor α (ERR-α) correlating with STAT3 was highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues, which was associated with both the pathologic stage and prognosis of patients with TNBC. In vitro studies showed that ERR-α promoted TNBC cell migration and invasion, which was regulated by STAT3. Phosphorylated STAT3 (p-STAT3, Tyr 705) could bind to the promotor of ERR-α, and activate its transcription, which was suggested by luciferase assay and chromatin immunoprecipitation assay. We also found that ERR-α was the key target gene regulated by STAT3 in promoting epithelial–mesenchymal transition (EMT), migration, and invasion. ERR-α upregulated the expression of ZEB1, N-cadherin, and vimentin while downregulated the expression of E-cadherin. Furthermore, in vivo studies showed that ERR-α could increase the metastasis ability of TNBC. Our finding demonstrated that ERR-α was a direct regulatory gene target of p-STAT3, which was enriched for processes involving invasion and metastasis in TNBC and provided insight into TNBC pathogenesis, as well as a potential therapeutic option against TNBC metastasis. Implications: Our research first showed that p-STAT3 (Tyr 705) could bind to the promotor region of ERR-α and promote EMT in TNBC by ZEB1 pathways, thus providing a potential clinical target for TNBC.

While hundreds of consistently altered metabolic genes had been identified in hepatocellular carcinoma (HCC), the prognostic role of them remains to be further elucidated. Messenger RNA expression profiles and clinicopathological data were downloaded from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma and GSE14520 data set from the Gene Expression Omnibus database. Univariate Cox regression analysis and lasso Cox regression model established a novel four-gene metabolic signature (including acetyl-CoA acetyltransferase 1, glutamic-oxaloacetic transaminase 2, phosphatidylserine synthase 2, and uridine-cytidine kinase 2) for HCC prognosis prediction. Patients in the high-risk group shown significantly poorer survival than patients in the low-risk group. The signature was significantly correlated with other negative prognostic factors such as higher α-fetoprotein. The signature was found to be an independent prognostic factor for HCC survival. Nomogram including the signature shown some clinical net benefit for overall survival prediction. Furthermore, gene set enrichment analyses revealed several significantly enriched pathways, which might help explain the underlying mechanisms. Our study identified a novel robust four-gene metabolic signature for HCC prognosis prediction. The signature might reflect the dysregulated metabolic microenvironment and provided potential biomarkers for metabolic therapy and treatment response prediction in HCC.

OBJECTIVE Fracture is a common consequence of osteoporosis and is associated with high morbidity and mortality. Recently, increasing evidence has suggested that polymorphisms in tumor necrosis factor-α (TNF-α) gene were associated with osteoporosis risk and bone mineral density (BMD), but results remain conflicting. We herein performed a meta-analysis based on evidence currently available from the literature to make a more precise estimation of these relationships. METHODS The PubMed, EMBASE, Cochrane Library, CNKI (China National Knowledge Infrastructure) and Wan Fang databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed and all available data were accumulated. The pooled odds ratios (ORs) or mean differences (MDs) and corresponding 95% confidence intervals (CIs) were applied to assess the strength of the relationships. RESULTS A total of 15 studies involving 5273 subjects were included in our meta-analysis. The GG genotype of TNF-α G308A was associated with an increased risk of osteoporosis under a mutant model (GG vs GA+AA: OR = 0.63, 95% CI: 0.51-0.77, P

Cysteine, a critical residue for catalytic process but also vulnerable to oxidative damage, was conventionally expressed as a buried catalytic site in most redox enzymes. In the present work, specific surface-exposed sites of a NADH oxidase from Lactobacillus rhamnosus (LrNox) were selected and mutated to cysteine to investigate its effects on catalytic function because LrNox has a buried catalytic cysteine but no surface-exposed one. The results showed that exception of the sites on dimer interface, the activities of LrNox mutants were improved to vary degrees when the polar uncharged and alanine residues were mutated to cysteine. But the cysteine mutations of polar charged and nonpolar residues except alanine showed obvious decline in catalytic activity. Substituting of Ala85 and Thr96 with other residues suggested that the cysteine mutation showed the highest activity. Structural analysis suggested that even a single cysteine mutation on the specific non-conserved surface area of LrNox could induce changes on the conformation of catalytic cysteine and lower the activation free energy to improve the catalytic activity.

Better understanding of esophageal precancerous lesions (EPL) can inform prevention strategies for esophageal squamous cell carcinoma (ESCC). Here, a cross-sectional epidemiologic study based on the Early Diagnosis and Early Treatment Project of Esophageal Cancer database from 2011 to 2017 was performed to fully investigate and characterize the epidemiology of EPL in rural Huai'an District. Data of 11,518 participants ages 35–75 years were collected through face-to-face interviews by questionnaire. Participants underwent a routine endoscopy examination, tissues were biopsied, and diagnosed according to the histologic criteria of dysplasia. Unconditional univariate and multivariate logistic regression analyses were performed to obtain crude and adjusted odds ratios and corresponding 95% confidence intervals, respectively. A total of 667 subjects were diagnosed with EPL. Factors associated with an increased risk of EPL included: drinking shallow well water and surface water, irregular diet, excessive smoking, exposure to secondhand smoke, consumption of corn, corn flour, pickled food, fried food, and hot food, and having a history of digestive system diseases. In addition, liquor use, but not other alcohol types, contributed to risk of EPL. Consumption of deep well water and vegetables, fruits, and animal livers were associated with lower EPL risk. This study suggested a completely distinct pattern that alcohol use plays only a minor role in EPL and excessive tobacco use shows a significant association in rural Huai'an District, while eating habits and environmental exposure may be the dominant factors. This work may be promising to provide scientific evidence to support primary prevention of ESCC in this region.

Withaminimas A-F (1-6), six new withaphysalin-type withanolides were isolated from the aerial parts of Physalis minima L.. The structures of these compounds were elucidated through a variety of spectroscopic techniques including HR-MS, NMR, and ECD. Compound 1 belongs to rare 18-norwithanolides, and 2-3 were 13/14-secowithanolides. According to the traditional usage of P. minima, inhibitory effects on nitric oxide (NO) production in lipopolysaccaride-activated RAW264.7 macrophages were evaluated, and compounds 1-4 exhibited significant inhibitory effects with IC50 values among 3.91-18.46 μmol·L-1.

A monocationic ZnII tetrahedral cluster, [Zn4L3(μ3-OH)]·NO3·1.25H2O (Zn4L3) based on a new salicylamide imine ligand H2L, H2L = 1-(2-hydroxy-3-methoxy-benzamido)-3-(2-hydroxy-3-methoxy-benzylideneamino)-propane, has been prepared. Single crystal X-ray analysis reveals that three deprotonated ligands L2– chelate three Zn(II) centres with their salicylamide moiety in such a way that the three salicylimine groups attached to the other side of the three chelates are converged to bind another Zn(II) centre to provide a tetrahedral cluster with two phenyl groups of the same ligand L2– being close enough to present a strong intramolecular π⋯π stacking effect. Fluorescence studies indicate that Zn4L3 is stable in water and exhibits highly sensitive and selective recognition of phosphates against other common anions including CO32–, HCO3–, NO3–, F−, Cl−, Br−, I−, HSO4–, SO42–, OAc−, BF4–, ClO4– and CF3SO3– in HEPES buffer solution (pH = 7.4) + DMSO (V : V = 1 : 9). The excellent sensing capability of Zn4L3 for phosphate against other common anions with a low detection limit of 0.15 μM renders it a candidate probe for phosphate detection. Furthermore, the observed fluorescence quenching responses of Zn4L3 towards phosphates were highly reversible. The possible sensing mechanisms for phosphate detection by Zn4L3 was investigated by means of 1H NMR, UV-Vis spectra and high-resolution ESI-MS spectra and the results indicate that phosphates could exclusively decompose Zn4L3 to release H2L in HEPES buffer solution (pH = 7.4) + DMSO (V : V = 1 : 9).

Protein therapeutics are increasingly used to treat various diseases, yet they often suffer from short serum half-lives. An emerging strategy to extend lifetime in vivo is to attach fatty acids onto proteins to increase their binding to human serum albumin (HSA). Herein, the genetic encoding of ϵ-N-heptanoyl-l-lysine (HepoK) is reported, which introduces a fatty-acid-containing amino acid into proteins with exquisite site-specificity and homogeneity, overcoming issues associated with existing chemical conjugation methods. The expression in E .coli and purification of HepoK-incorporated glucagon-like peptide-1 (GLP1) is demonstrated. GLP1(HepoK) showed stronger binding to HSA than GLP1(WT), without impairing the stimulation of the GLP1 receptor in cells. Moreover, GLP1(HepoK) decreased blood glucose level to the same level as GLP1(WT) in mice, showing longer-lasting effects than GLP1(WT). HepoK incorporation will also be useful for investigating the function of protein lipidation.

Peng Su,1,2 Jun-lin Zhou,2 Cai Yun,1 Feng Liu,1 Yi Zhang1 1Department of Orthopaedics, Teaching Hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing, People’s Republic of China; 2Department of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Jun-lin ZhouDepartment of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, 100020, People’s Republic of ChinaTel +86-13240718193Email zhoujunlin145@163.comObjective: This study aimed to directly and accurately measure the range of motion of the acromioclavicular joint through 3D reconstruction and image registration.Methods: Thirteen healthy volunteers participated in the study. Computerized tomography (CT) was used to measure the acromioclavicular joint in four different motion poses. The images were integrated using reconstruction and registration technology, and the rotation angle range of the acromioclavicular joint was measured using 3D reconstruction. The measurements were expressed by axial angle representation. The dominant and the non-dominant sides were compared, and the difference in the axial angle of the acromioclavicular joint was compared in different postures.Results: The difference between the dominant and non-dominant sides in acromioclavicular motion was not significant. In the sagittal motion of the upper limb, the rotation angle of the acromioclavicular joint was greatest in a resting horizontal position, with an average of 26.1°. In this position, 34.6% of flexion and extension movements of the upper limb were completed by the acromioclavicular joint, which was the highest level of engagement. The rotation angle was lowest in the resting posteroinferior position, with an average of 8.2°. In this position, 24.9% of the flexion and extension movements of the upper limb were completed by the acromioclavicular joint.Conclusion: Combining 3D reconstruction and image registration is a direct and accurate method of measuring the motion of the acromioclavicular joint. The rotational motions of the acromioclavicular joint are bilaterally symmetrical and can be used as a reference for comparative study. The maximum range of motion of the acromioclavicular joint during rotation was found in the resting horizontal position. The clinical examination and post-treatment evaluation of the acromioclavicular joint’s rotation function can therefore be targeted in this range.Keywords: image registration, axial angle representation, acromioclavicular joints

Background The cross-sectional area of three parallel screws might affect the stability of the internal fixation of femoral neck fractures. The screws fixed in the oblique-triangle configuration (OTC) were assumed to have a larger cross-sectional area, but the biomechanical stability has not yet been validated. In this study, finite element analyses were performed to compare the biomechanical properties of the internal fixation fixed by the OTC and the traditional Inverted Equilateral Triangle Configuration (IETC). Method Pauwels type III fracture was established on the three-dimensional femoral model and three cannulated screws with the OTC and traditional IETC methods were applied. The oblique-triangle configuration with the largest area inscribed the femoral neck isthmus by the three screws was determined, the area and circumference of the cross-section formed by the OTC and IETC model were compared. Stress, strain, and displacement peaks of the two configuration models under different loads were compared. Twelve pairs of nodes on the fracture ends were selected and the displacement of the fracture ends was evaluated through the displacement between these nodes. Results The area and circumference of the cross-section formed by the OTC were larger than those in the IETC model. The degree of stress dispersion around the screw holes in the OTC model was better than that of the IETC, but the stress distribution order of the three screws in the two models was consistent. The maximum stress, strain, displacement, and displacement of the fracture end in the OTC model were smaller than those in the IETC model. The stress, strain, displacement, and fracture end displacement peaks of the two fixed models gradually increase with the increase of loads. Conclusion The oblique-triangle configuration showed superior mechanical properties than the IETC in finite element analyses. This study suggests that when three screws are fixed in parallel method, the larger the cross-sectional area of the screw configuration, the better stability of the internal fixation might be obtained. Furthermore, the biomechanical properties of various spatial configurations and screw holes of the three parallel screws need to be considered before clinical practice.

Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). Qingre Huoxue treatment (Qingre Huoxue decoction (QRHXD)/Qingre Huoxue external preparation (QRHXEP)) is a therapeutic scheme of TCM for RA. To date, there have been few studies comparing the efficacy and safety of QRHXD and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for the treatment of active RA. This was investigated in a multicenter, double-blind, randomized controlled trial involving 468 Chinese patients with active RA [disease activity score (DAS)-28 > 3.2] treated with QRHXD/QRHXEP (TCM group), methotrexate plus hydroxychloroquine [Western medicine (WM) group], or both [integrative medicine (IM) group]. Patients were followed up for 24 weeks. The primary outcome measure was the change in DAS-28 from baseline to 24 weeks. The secondary outcome measures were treatment response rate according to American College of Rheumatology 20, 50, and 70% improvement criteria (ACR-20/50/70) and the rate of treatment-related adverse events (TRAEs). The trial was registered at ClinicalTrials.gov (NCT02551575). DAS-28 decreased in all three groups after treatment (p < 0.0001); the score was lowest in the TCM group (p < 0.05), while no difference was observed between the WM and IM groups (p > 0.05). At week 24, ACR-20 response was 73.04% with TCM, 80.17% with WM, and 73.95% with IM (based on the full analysis set [FAS], p > 0.05); ACR-50 responses were 40.87, 47.93, and 51.26%, respectively, (FAS, p > 0.05); and ACR-70 responses were 20.87, 22.31, and 25.21%, respectively, (FAS, p > 0.05). Thus, treatment efficacy was similar across groups based on ACR criteria. On the other hand, the rate of TRAEs was significantly lower in the TCM group compared to the other groups (p < 0.05). Thus, QRHXD/QRHXEP was effective in alleviating the symptoms of active RA—albeit to a lesser degree than csDMARDs—with fewer side effects. Importantly, combination with QRHXD enhanced the efficacy of csDMARDs. These results provide evidence that QRHXD can be used as an adjunct to csDMARDs for the management of RA, especially in patients who experience TRAEs with standard drugs.Clinical Trial Registration: ClinicalTrials.gov, identifier NCTNCT025515.

This research covers a multi-dimensional investigation into accessibility barriers in care services for older people with disabilities in rural China. In-depth interviews with 13 rural disabled older people in China were conducted using qualitative methods. Based on a welfare pluralism approach, the results showed that in comparison with urban areas, care services for disabled older populations in rural areas are more subject to social barriers. This can be seen in the limited state (lack of resources, rigorous eligibility qualifications, uneven distribution, and irregular implementation), the absent market (low levels of consumption, high cost pressures, self-exclusion, and traditional cultural constraints), absent NGOs and volunteers (difficulties in access for NGOs and volunteers outside the area and formation difficulties of local NGOs and volunteers), as well as low-quality care in households and communities (unprofessional care from the spouse, unsustainable care from children, and unavailable community-based care). A multi-subject support network should be established to remove accessibility barriers to care services for older people with disabilities in rural areas through active intervention and interaction. The results of the research provide insights that will aid in the formulation of future social care service plans and health policies for rural older people with disabilities.