[A phase I study of subcutaneous envafolimab (KN035) monotherapy in Chinese patients with advanced solid tumors].

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

Medicolegal Identification of Medical Malpractices in Orthopaedic Surgery.

OBJECTIVES: To analyze the characteristics of medical malpractices in orthopaedic surgeries, to explore principles and methods in medical legal identification, and to provide basic data for uniform medicolegal standard for the future medical identification. METHODS: A retrospective analysis was conducted on 100 cases of medical malpractices in orthopaedic surgery, among the 364 cases archived in Medicolegal Expertise Center of Xi'an Jiaotong University during 2002-2015. RESULTS: In the 100 cases of orthopedic medical malpractices, with 104 hospitals involved in, 95 cases were judged with medical errors and the other 9 cases with no error. The top 3 reasons for errors were （1） inadequate observation or estimation of diseases （27.9%）, （2） intraoperative improper operation （17.3%）, and （3） delayed or missed diagnosis and treatment （12.5%）. The consequences of medical malpractices were mostly disability （61%）, followed by prolonged diseases （31%） and death （8%）. With regard to the causal relationship between medical errors and consequences, 95 cases （91.4%） were with causality and the other 9 cases （8.6%） with no causality. Specifically, 56 cases （53.9%） were with medical errors as the secondary causes accounting for 25% causative potency, and 20 cases （19.2%） were with medical errors as the major causes accounting for 75% causative potency. CONCLUSIONS: It is pivotally important for determining the causative potency of medical errors to analyse the causes of damages in orthopaedic surgery and to distinguish subjective factors from objective ones of medical errors.

Aspartate aminotransferase-to-platelet ratio predicts response to transarterial chemoembolisation and prognosis in hepatocellular carcinoma patients.

AIM: To evaluate the value of the aspartate aminotransferase-to-platelet ratio index (APRI) for hepatocellular carcinoma (HCC) patients who underwent transarterial chemoembolisation (TACE). MATERIALS AND METHODS: A total of 315 patients were enrolled, who were randomly divided into the training cohort (n=158) and the validation cohort (n=157). The optimal cut-off value of the APRI was determined using the X-tile software in the training cohort, and was validated in the validation cohort. Several serum-based markers, neutrophil-to-lymphocyte (N/L) and aspartate aminotransferase-to-alanine aminotransferase (AST/ALT) ratios were included to compare with the APRI. To predict individual survival rate, independent predictors were included to build a nomogram. RESULTS: Using the X-tile, a cut-off value of the APRI as 0.40 was yielded to distinguish patients with distinct outcomes in the training cohort, but failed for the N/L and ALT/AST ratios. In the training cohort, 66 patients with high APRI had poorer survival (p<0.001) than did 92 patients with low APRI. Using the same cut-off value of APRI, 61 patients with high APRI had poorer survival (p<0.001) than did 96 patients with low APRI in the validation cohort. Furthermore, a nomogram, including the APRI, TACE cycles, tumour size, and tumour number, was built based on the training cohort, and validated well in the validation cohort (concordance index [C-index] 0.713). CONCLUSION: The APRI is a promising marker to predict treatment response and outcome for HCC patients after TACE treatment.

VEGF, eNOS, and ABCB1 genetic polymorphisms may increase the risk of osteonecrosis of the femoral head.

We investigated the associations between vascular endothelial growth factors (VEGF), endothelial nitric oxide synthase (eNOS), and ATP-binding cassette subfamily B member 1 transporter (ABCB1) polymorphisms and the risk of osteonecrosis of the femoral head (ONFH). Published studies were reviewed and analyzed based on predefined selection criteria. The strength of the association between VEGF, eNOS, and ABCB1 polymorphisms and ONFH risk was evaluated based on the odds ratio with corresponding 95%CIs. Meta-analysis was performed using the Comprehensive Meta-analysis 2.0 software. A total of 135 relevant articles were retrieved, of which 10 studies met the selection criteria, and included a total of 1025 patients with ONFH and 1730 healthy controls. The meta-analysis study results revealed that the VEGF rs2010963 G>C polymorphism increased the risk of ONFH, while the VEGF rs2010963 G>C and ABCB1 rs1045642 C>T polymorphisms increased the risk of ONFH under the allele model. In conclusion, the VEGF, eNOS, and ABCB1 polymorphisms may contribute to ONFH, but further studies including larger sample sizes are needed to confirm the results.

Voluntary exercise protects against ulcerative colitis by up-regulating glucocorticoid-mediated PPAR-γ activity in the colon in mice.

AIM: Voluntary exercise has been shown to protect against the development of ulcerative colitis, but the mechanism is not fully understood. We hypothesized that prior voluntary exercise would attenuate colonic inflammation and ameliorate clinical symptoms in dextran sulphate sodium (DSS)-induced ulcerative colitis by increasing glucocorticoid production and up-regulating PPAR-γ activity in the colon. METHODS: Male C57Bl/6J mice were assigned to sedentary, exercise, exercise with PPAR-γ antagonist GW9662 or glucocorticoid synthesis inhibitor metyrapone. Following the completion of the 30 days' exercise training programme, they were treated with or without 2% DSS in drinking water for 5 days, followed by 5 days of regular water. RESULTS: Compared with sedentary mice, exercise mice exhibited improved clinical symptoms (weight loss and diarrhoea) and less inflammation (expression of pro-inflammatory cytokines and histological injury) in response to DSS, whereas these beneficial effects were abolished by both GW9662 and metyrapone treatment. Molecular studies revealed that exercise significantly increased the expression of PPAR-γ, augmented the expression of steroidogenic enzymes (CYP11A1 and CYP11B1) and elevated corticosterone levels in the colon. GW9662 treatment reversed the expression of PPAR-γ without altering the expression of steroidogenic enzymes and corticosterone secretion in the colon, while metyrapone treatment blocked glucocorticoid secretion and abrogated the increase in PPAR-γ expression in the colon. CONCLUSION: These findings suggest that prior voluntary exercise suppresses the expression of pro-inflammatory cytokines in the colon in response to inflammatory challenge by up-regulating glucocorticoid-mediated PPAR-γ activity, contributing to protection against the development of ulcerative colitis.

Inhibitory effects of estradiol on inward rectifier and delayed rectifier K+ currents in guinea pig ventricular myocytes.

AIM: To study the effects of estradiol (Est) on inward rectifier K+ (IK1) and delayed rectifier K+ (IK) channels in isolated guinea pig ventricular myocytes. METHODS: Using whole cell patch-clamp recording techniques. RESULTS: Est 10 mumol.L-1 and 100 mumol.L-1 decreased the action potential duration, APD50, from (474 +/- 71) ms to (330 +/- 75) ms and (229 +/- 67) ms (n = 7 cells of 7 guinea pigs, P < 0.05), respectively. Est 100 mumol.L-1 also decreased APD90 from (587 +/- 60) ms to (418 +/- 79) ms (n = 7, P < 0.05). Est inhibited IK tail current (IK.tail) concentration-dependently. IK.tail was depressed 53% (n = 5, P < 0.05) at 10 mumol.L-1 and 80% (n = 5, P < 0.01) at 100 mumol.L-1 compared with control. Est > or = 10 mumol.L-1 blocked IK1. The maximal inhibition of inward current of IK1 occurred at -100 mV test potential was 49% (n = 5, P < 0.01) and outward current of IK1 at -40 mV was 72% (n = 5, P < 0.01). The reverse potential shifted negatively, from -70 to -76 mV. CONCLUSION: Est possessed blocking effects on both IK1 and IK channels in guinea pig ventricular myocytes.

Effects of sex hormones on action potential and contraction of guinea pig papillary muscle.

AIM: To study the effects of sex hormones, estradiol (Est), progesterone (Pro) and testosterone (Tes) on the action potential (AP) and contraction of guinea pig papillary muscle. METHODS: Using conventional glass microelectrode and mechanical recording of myocardial contraction. RESULTS: Est slowed down the maximal rate of rise of phase 0 (Vmax) of AP at low concentration (1 mumol.L-1). At 10 mumol.L-1 and above, Est also prolonged AP duration (APD50 and APD90), effective refractory period (ERP) and decreased the maximal isometric tension (Pmax) and velocity of tension development (dT/dt) of contraction. Tes (100 mumol.L-1 - 1 mmol.L-1) prolonged APD90 and ERP with decreased Pmax and dT/dt. But Pro (1 mumol.L-1 - 1 mmol.L-1) had no effects on both AP and contraction. CONCLUSION: Est prolonged AP and depressed contraction of guinea pig papillary muscle.

Effects of sodium pentobarbital on electric and mechanical activities of guinea pig papillary muscle.

AIM: To study the effects of sodium pentobarbital (SP) on the action potential (AP) and contraction of guinea pig papillary muscle. METHODS: Using conventional glass microelectrode and mechanical recording of myocardium contraction. RESULTS: SP (> or = 10 mumol.L-1) prolonged the AP duration (APD) and effective refractory period (ERP), while amplitude (APA) and Vmax of phase 0 showed no changes. The effects of SP were abolished by pretreatment with cromakalim, an agonist of ATP-sensitive K+ channel. The maximal isometric tension (Pmax) and velocity of tension development (dT/dt) were decreased to 51% and 48% of control, respectively. The first postrest beat (B1) and second postrest beat (B2) were also depressed. CONCLUSION: SP affected the action potential by reducing activities of the K+ channels and reduced the contraction of guinea pig myocardium.

[Study on the relationship between congenital toxoplasmosis and monsters of cleft lip and palate accompanied by multiple malformation]

Toxoplasomsis is a zoonotic disease resulted from toxoplasma infection,This paper reports ten monsters that suffered from congenital cleft lip and palate accompanied antigens(RCEP,COA test) were positive.Toxoplasma antibodies (IHA,IFA,RIPEGA test) in mothers' serum were also positive.Microscopic examination revealed toxoplasma trophozoites and pseudocysts in the tissue of cleft lip and palate as well as viscera.In addition,We used SPA method to reveal toxoplasma in the tissue.We indicate that toxoplasma infection of pregnant women is one of the cause of monsters.It is the important biological factor and closely related to eugenics.Stomatologists must pay attention to this etiology.