Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

The Diagnostic Value of Liver Biopsy for Unexplained Liver Dysfunction: A Retrospective Study.

Objective: To analyse clinical manifestations of unexplained abnormal liver function and perform hepatobiliary histopathology procedures on patients to evaluate the value of liver biopsy in diagnosing the aetiology of unexplained abnormal liver function. Methods: A convenience sampling method was used to retrospectively collect the data of patients who were diagnosed with unexplained abnormal liver function and who received liver biopsy in the Pathology Department of Tianjin Second People's Hospital, China, between March 2022 and July 2023 to analyse liver pathology and clinical manifestations. Results: A total of 1302 patients were included in this study, which mainly included 11 diseases: autoimmune liver disease (74 cases, 5.68%), drug-induced liver injury (DILI) (204 cases, 15.67%), cancer (237 cases, 18.20%), non-alcoholic fatty liver disease (104 cases, 7.99%), non-alcoholic steatohepatitis (74 cases, 5.68%), viral hepatitis (490 cases, 37.63%), other types of hepatitis (30 cases, 2.30%), cholestatic liver disease (17 cases, 1.31%), alcoholic liver disease (15 cases, 1.15%), hepatic cyst (5 cases, 0.38%) and Gilbert syndrome (4 cases, 0.31%). The success rate of liver biopsy sampling was 100%, and (1.52 ± 0.130) tissue strips were sampled. The average operating time was 11.52 minutes. The percutaneous liver biopsy did not significantly increase short-term liver function index values (serum γ-glutamyl transpeptidase, total bilirubin, alanine transaminase, aspartate aminotransferase, alkaline phosphatase). Ninety-two patients had a small amount of liver subcapsular fluid, but there was no progress after medical treatment. Conclusion: Ultrasound-guided percutaneous liver biopsy has value in the diagnosis of unexplained abnormal liver function. Viral hepatitis, cancer and DILI are the most common causes of unexplained abnormal liver function. Liver biopsy does not aggravate the organic and functional impairment of the liver.

Noninvasive tests maintain high accuracy for advanced fibrosis in chronic hepatitis B patients with different nomenclatures of steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a new nomenclature proposed in 2023. We aimed to compare the diagnostic efficacy of noninvasive tests (NITs) for advanced fibrosis under different nomenclatures in patients with chronic hepatitis B (CHB). A total of 844 patients diagnosed with CHB and concurrent steatotic liver disease (SLD) by liver biopsy were retrospectively enrolled and divided into four groups. The performances of fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio index (GPRI), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM) were compared among the four groups. The four NITs showed similar diagnostic efficacy for nonalcoholic fatty liver disease (NAFLD), MASLD, and metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with CHB with advanced fibrosis. LSM showed the most stable accuracy for NAFLD (AUC = 0.842), MASLD (AUC = 0.846), and MAFLD (AUC = 0.863) compared with other NITs (p < 0.05). Among the four NITs, APRI (AUC = 0.841) and GPRI (AUC = 0.844) performed best in patients with CHB & MetALD (p < 0.05). The cutoff value for GPRI in patients with CHB & MetALD was higher than that in the other three groups, while further comparisons of NITs at different fibrosis stages showed that the median GPRI of CHB & MetALD (1.113) at F3-4 was higher than that in the CHB & MASLD group (0.508) (p < 0.05). Current NITs perform adequately in patients with CHB and SLD; however, alterations in cutoff values for CHB & MetALD need to be noted.

Aerosol liquid water in PM2.5 and its roles in secondary aerosol formation at a regional site of Yangtze River Delta.

Aerosol liquid water content (ALWC) plays an important role in secondary aerosol formation. In this study, a whole year field campaign was conducted at Shanxi in north Zhejiang Province during 2021. ALWC estimated by ISORROPIA-II was then investigated to explore its characteristics and relationship with secondary aerosols. ALWC exhibited a highest value in spring (66.38 µg/m3), followed by winter (45.08 µg/m3), summer (41.64 µg/m3), and autumn (35.01 µg/m3), respectively. It was supposed that the secondary inorganic aerosols (SIA) were facilitated under higher ALWC conditions (RH > 80%), while the secondary organic species tended to form under lower ALWC levels. Higher RH (> 80%) promoted the NO3- formation via gas-particle partitioning, while SO42- was generated at a relative lower RH (> 50%). The ALWC was more sensitive to NO3- (R = 0.94) than SO42- (R = 0.90). Thus, the self-amplifying processes between the ALWC and SIA enhanced the particle mass growth. The sensitivity of ALWC and OX (NO2 + O3) to secondary organic carbon (SOC) varied in different seasons at Shanxi, more sensitive to aqueous-phase reactions (daytime R = 0.84; nighttime R = 0.54) than photochemical oxidation (daytime R = 0.23; nighttime R = 0.41) in wintertime with a high level of OX (daytime: 130-140 µg/m3; nighttime: 100-140 µg/m3). The self-amplifying process of ALWC and SIA and the aqueous-phase formation of SOC will enhance aerosol formation, contributing to air pollution and reduction of visibility.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Associations between abdominal obesity indices and pathological features of non-alcoholic fatty liver disease: Chinese visceral adiposity index.

BACKGROUND AND AIM: Many abdominal obesity indices such as waist circumference (WC), lipid accumulation product (LAP), visceral obesity index (VAI), and Chinese VAI (CVAI) have been considered to be associated with the risk of non-alcoholic fatty liver disease (NAFLD), but the association between abdominal obesity indices and the pathological features of NAFLD is uncertain. This study aims to explore the associations between these indices and the pathological features of NAFLD. METHODS: A total of 147 patients with biopsy-confirmed NAFLD were enrolled in the final analysis. General information, biochemical tests, and pathological information of patients were collected. VAI, LAP, and CVAI were calculated. Spearman's correlation analysis and logistics regression analysis were applied to assess the relationship between abdominal obesity indices and the pathological features of NAFLD. Receiver operating characteristic curve analyses were used to assess the value of abdominal obesity indices in predicting liver fibrosis and non-alcoholic steatohepatitis. RESULTS: Non-alcoholic fatty liver disease activity score (NAS) ≥ 5 significantly correlated with WC, LAP, VAI, and CVAI both in univariate and multivariate analyses (P < 0.05). Fibrosis was significantly and positively correlated with WC, LAP, and CVAI (P < 0.05). After adjustment for potential confounders, fibrosis remained associated with CVAI (P < 0.05). CONCLUSION: CVAI is significantly associated with the pathological features of NAFLD, and CVAI shows the most superior efficacy in diagnosing fibrosis among these indices.

Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer.

Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient's condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.

Clinical efficacy and safety of tumor-specific individualized multi-target DC-CIK in the treatment of advanced non-small cell lung cancer / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：评价肿瘤特异性个体化多靶点树突状细胞-细胞因子诱导的杀伤细胞（DC-CIK）治疗晚期非小细胞肺癌（NSCLC）患者的临床疗效和安全性。方法：回顾性分析2019年10月1日至2022年10月31日东部战区总医院生物治疗科行肿瘤特异性个体化多靶点DC-CIK治疗晚期NSCLC患者的临床资料。统计NSCLC患者的临床疗效和不良反应，分析治疗前后血清中肿瘤标志物的变化，FCM检测患者治疗前后的淋巴细胞亚群和各种细胞因子的表达情况，用质谱仪检测治疗前后靶点的变化。结果: 共入组52例晚期NSCLC患者，其中女性21例、男性31例；年龄32~71岁，平均年龄（50.97±10.72）岁，中位年龄47.5岁。经DC-CIK治疗后，CR 0例，PR 0例，SD 27例，PD 25例。与治疗前比较，DC-CIK治疗后：（1）CEA和CYFRA21-1水平无显著改变，CA125水平显著低于治疗前（P<0.01）；（2）治疗后患者淋巴细胞亚群无显著变化；（3）治疗后患者外周血IL-2、IL-4、IFN-γ和TNF-α水平显著升高（均P<0.01），IL-6、IL-10及IL-17水平无明显变化；（4）治疗后靶点数下降明显。DC-CIK治疗过程中无严重不良反应发生。结论: 晚期NSCLC患者行肿瘤特异性个体化多靶点自体DC-CIK治疗是安全的，能使患者产生抗肿瘤免疫反应并得到一定的临床获益。

Particle Distribution and Heat Transfer of SiO2/Water Nanofluid in the Turbulent Tube Flow.

In order to clarify the effect of particle coagulation on the heat transfer properties, the governing equations of nanofluid together with the equation for nanoparticles in the SiO2/water nanofluid flowing through a turbulent tube are solved numerically in the range of Reynolds number 3000 ≤ Re ≤ 16,000 and particle volume fraction 0.005 ≤ φ ≤ 0.04. Some results are validated by comparing with the experimental results. The effect of particle convection, diffusion, and coagulation on the pressure drop ∆P, particle distribution, and heat transfer of nanofluid are analyzed. The main innovation is that it gives the effect of particle coagulation on the pressure drop, particle distribution, and heat transfer. The results showed that ∆P increases with the increase in Re and φ. When inlet velocity is small, the increase in ∆P caused by adding particles is relatively large, and ∆P increases most obviously compared with the case of pure water when the inlet velocity is 0.589 m/s and φ is 0.004. Particle number concentration M0 decreases along the flow direction, and M0 near the wall is decreased to the original 2% and decreased by about 90% in the central area. M0 increases with increasing Re but with decreasing φ, and basically presents a uniform distribution in the core area of the tube. The geometric mean diameter of particle GMD increases with increasing φ, but with decreasing Re. GMD is the minimum in the inlet area, and gradually increases along the flow direction. The geometric standard deviation of particle diameter GSD increases sharply at the inlet and decreases in the inlet area, remains almost unchanged in the whole tube, and finally decreases rapidly again at the outlet. The effects of Re and φ on the variation in GSD along the flow direction are insignificant. The values of convective heat transfer coefficient h and Nusselt number Nu are larger for nanofluids than that for pure water. h and Nu increase with the increase in Re and φ. Interestingly, the variation in φ from 0.005 to 0.04 has little effect on h and Nu.

Hepatic steatosis leads to overestimation of liver stiffness measurement in both chronic hepatitis B and metabolic-associated fatty liver disease patients.

BACKGROUND: The impact of hepatic steatosis on liver stiffness measurement (LSM) in both chronic hepatitis B(CHB) and metabolic-associated fatty liver disease (MAFLD) remains controversial. AIMS: To determine whether LSM is affected by hepatic steatosis in CHB-MAFLD. METHODS: Hepatic steatosis and liver fibrosis were assessed by histological and noninvasively methods. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance of LSM. RESULTS: The prevalence of MAFLD in CHB patients (n = 436)was 47.5% (n = 207). For patients with low amounts of fibrosis (F0-1 and F0-2), the median LSM was 8.8 kPa and 9.2 kPa in patients with moderate- severe steatosis,which was significantly higher than that in patients with none-mild steatosis (P < 0.05) . The positive predictive value(PPV) was lower for LSM identifying significant fibrosis (F ≥ 2) as well as severe fibrosis (F ≥ 3) in group which controlled attenuation parameter(CAP) ≥ 268 dB/m than its counterpart(68.2% vs 84.6% and 24.3% vs 45.0%). The AUROC of LSM detected F ≥ 2 was 0.833 at a cutoff of 8.8 kPa and 0.873 at a cutoff of 7.0 kPa in patients with CAP ≥ 268 and CAP < 268, respectively. CONCLUSIONS: The presence of moderate-severe steatosis, detected by histology or CAP, should be taken into account to avoid overestimation of LSM.

Numerical Study on the Coagulation and Breakage of Nanoparticles in the Two-Phase Flow around Cylinders.

The Reynolds averaged N-S equation and dynamic equation for nanoparticles are numerically solved in the two-phase flow around cylinders, and the distributions of the concentration M0 and geometric mean diameter dg of particles are given. Some of the results are validated by comparing with previous results. The effects of particle coagulation and breakage and the initial particle concentration m00 and size d0 on the particle distribution are analyzed. The results show that for the flow around a single cylinder, M0 is reduced along the flow direction. Placing a cylinder in a uniform flow will promote particle breakage. For the flow around multiple cylinders, the values of M0 behind the cylinders oscillate along the spanwise direction, and the wake region in the flow direction is shorter than that for the flow around a single cylinder. For the initial monodisperse particles, the values of dg increase along the flow direction and the effect of particle coagulation is larger than that of particle breakage. The values of dg fluctuate along the spanwise direction; the closer to the cylinders, the more frequent the fluctuations of dg values. For the initial polydisperse particles with d0 = 98 nm and geometric standard deviation σ = 1.65, the variations of dg values along the flow and spanwise directions show the same trend as for the initial monodisperse particles, although the differences are that the values of dg are almost the same for the cases with and without considering particle breakage, while the distribution of dg along the spanwise direction is flatter in the case with initial polydisperse particles.

A Novel Noninvasive Diagnostic Model of HBV-Related Inflammation in Chronic Hepatitis B Virus Infection Patients With Concurrent Nonalcoholic Fatty Liver Disease.

Background and Aims: Patients with chronic hepatitis B virus infection (CBI) with concurrent nonalcoholic fatty liver disease (NAFLD) is becoming increasingly common in clinical practice, and it is quite important to identify the etiology when hepatitis occurs. A noninvasive diagnostic model was constructed to identify patients who need antihepatitis B virus (HBV) therapies [histologic activity index (HAI) ≥ 4] in patients with CBI with concurrent NAFLD by analyzing clinical routine parameters. Approach and Results: In total, 303 out of 502 patients with CBI with concurrent NAFLD proven by liver biopsy from January 2017 to December 2020 in the Tianjin Second People's Hospital were enrolled and they were divided into the HBV-related inflammation (HBV-I) group (HAI ≥ 4,176 cases) and the non-HBV-I group (HAI < 4,127 cases) according to hepatic pathology. The univariate analysis and multivariate logistic regression analysis were performed on the two groups of patients, and then the HBV-I model of patients with CBI with concurrent NAFLD was constructed. The areas under receiver operating characteristic curves (AUROCs) were used to evaluate the parameters of the regression formula. Another 115 patients with CBI with concurrent NAFLD proven by liver biopsy from January 2021 to January 2022 were enrolled as the validation group. There were some statistical differences in demographic data, biochemical indicators, immune function, thyroid function, virology indicator, and blood routine indicators between the two groups (P < 0.05) and liver stiffness measurement (LSM) in the HBV-I group was significantly higher than those in the non-HBV-I group (P < 0.05). While controlled attenuation parameters (CAP) in the HBV-I group were lower than those in the non-HBV-I group (P < 0.05); (2) We developed a novel model by logistic regression analysis: HBV-I = -0.020 × CAP + 0.424 × LSM + 0.376 × lg (HBV DNA) + 0.049 × aspartate aminotransferase (AST) and the accuracy rate was 82.5%. The area under the receiver operating characteristic (AUROC) is 0.907, the cutoff value is 0.671, the sensitivity is 89.30%, the specificity is 77.80%, the positive predictive value is 90.34%, and the negative predictive value is 81.89%; (3) The AUROC of HBV-I in the validation group was 0.871 and the overall accuracy rate is 86.96%. Conclusion: Our novel model HBV-I [combining CAP, LSM, lg (HBV DNA), and AST] shows promising utility for predicting HBV-I in patients with CBI with concurrent NAFLD with high sensitivity, accuracy, and repeatability, which may contribute to clinical application.

Heat Transfer and Pressure Drop of Nanofluid with Rod-like Particles in Turbulent Flows through a Curved Pipe.

Pressure drop, heat transfer, and energy performance of ZnO/water nanofluid with rodlike particles flowing through a curved pipe are studied in the range of Reynolds number 5000 ≤ Re ≤ 30,000, particle volume concentration 0.1% ≤ Φ ≤ 5%, Schmidt number 104 ≤ Sc ≤ 3 × 105, particle aspect ratio 2 ≤ λ ≤ 14, and Dean number 5 × 103 ≤ De ≤ 1.5 × 104. The momentum and energy equations of nanofluid, together with the equation of particle number density for particles, are solved numerically. Some results are validated by comparing with the experimental results. The effect of Re, Φ, Sc, λ, and De on the friction factor f and Nusselt number Nu is analyzed. The results showed that the values of f are increased with increases in Φ, Sc, and De, and with decreases in Re and λ. The heat transfer performance is enhanced with increases in Re, Φ, λ, and De, and with decreases in Sc. The ratio of energy PEC for nanofluid to base fluid is increased with increases in Re, Φ, λ, and De, and with decreases in Sc. Finally, the formula of ratio of energy PEC for nanofluid to base fluid as a function of Re, Φ, Sc, λ, and De is derived based on the numerical data.

MicroRNA-494-3p Exacerbates Renal Epithelial Cell Dysfunction by Targeting SOCS6 under High Glucose Treatment.

BACKGROUND: Diabetic nephropathy is a common complication of the kidneys induced by diabetes and is the main cause of end-stage renal disease. MicroRNA-494-3p was reported to be upregulated in renal tissues collected from db/db mice, but its specific role in diabetic nephropathy was still unclear. This study aimed to explore the effect of miR-494-3p on renal fibrosis using an in vitro cell model of diabetic nephropathy. METHODS: After human renal tubular epithelial cells (HK-2) were treated with high glucose (HG), the viability and apoptosis of cells were examined by CCK-8 assays and flow cytometry analyses. Additionally, protein levels of fibronectin, collagen I, collagen III, collagen IV, and epithelial-mesenchymal transition (EMT) markers in HG-induced HK-2 cells were quantified by Western blotting. miR-494-3p expression in HK-2 cells was detected by reverse-transcription quantitative polymerase chain reaction. The binding relation between miR-494-3p and the messenger RNA suppressor of cytokine signaling 6 (SOCS6) was detected by luciferase reporter assays. RESULTS: HG reduced cell viability and enhanced cell apoptosis in a time- or concentration-dependent manner. Additionally, HG induced collagen accumulation and triggered the EMT process. miR-494-3p was upregulated in HG-treated HK-2 cells. miR-494-3p inhibition alleviated HG-induced cell dysfunction. Mechanistically, miR-494-3p bound with SOCS6 and negatively regulated SOCS6 expression. Moreover, silencing SOCS6 rescued the suppressive effect of miR-499-5p inhibition on HG-induced cell dysfunction. CONCLUSION: miR-494-3p aggravates renal fibrosis, EMT process, and cell apoptosis by targeting SOCS6, suggesting that the miR-494-3p/SOCS6 axis may become a potential strategy for the treatment of diabetic nephropathy.

Impact of hepatic steatosis on treatment response of autoimmune hepatitis: A retrospective multicentre analysis.

Background: There is a paucity of data on whether steatosis impacts autoimmune hepatitis (AIH) treatment response. We aimed to evaluate the influence of baseline steatosis on the biochemical response, fibrosis progression, and adverse longterm outcomes of AIH. Methods: Steatosis was diagnosed by a controlled attenuation parameter (CAP) ≥ 248 dB / m. Only patients who underwent immunosuppressive therapy with available liver histological material at diagnosis and qualified CAP within seven days of the liver biopsy were included. Univariate and multivariate analyses were subsequently conducted. Results: The multicentre and retrospective cohort enrolled 222 subjects (88.3% female, median age 54 years, median follow-up 48 months) in the final analysis, and 56 (25.2%) patients had hepatic steatosis. Diabetes, hypertension, and significant fibrosis at baseline were more common in the steatosis group than in the no steatosis group. After adjusting for confounding factors, hepatic steatosis was an independent predictor of insufficient biochemical response (OR: 8.07) and identified as an independent predictor of long-term adverse outcomes (HR: 4.07). By subgroup multivariate analysis (different degrees of steatosis, fibrosis, and prednisone dose), hepatic steatosis independently showed a relatively stable correlation with treatment response. Furthermore, in contrast to those without steatosis, a significant increase in liver stiffness (LS) was observed in patients with steatosis (4.1%/year vs. -16%/year, P < 0.001). Conclusions: Concomitant hepatic steatosis was significantly associated with poor response to treatment in AIH patients. Routine CAP measurements are therefore essential to guide the management of AIH.

Prophylactic and therapeutic effects of different doses of vitamin C on high-fat-diet-induced non-alcoholic fatty liver disease in mice.

Epidemiological studies support the association between inadequate vitamin C (Vc) intake and non-alcoholic fatty liver disease (NAFLD). However, the intervention dose of Vc, and the prophylactic and therapeutic effects on NAFLD are unclear. This study aimed to investigate the prophylactic and therapeutic effects of low (LVc), medium (MVc) and high (HVc) doses of Vc on NAFLD. C57BL/6 mice were randomly assigned to prophylactic groups (mice received a high-fat diet (HFD) concomitant with different doses of Vc) and therapeutic groups (HFD-induced NAFLD mice treated with different doses of Vc). Results showed that prophylactic LVc and MVc administration reduced the risk of NAFLD development in HFD-fed mice, as evidenced by significantly lowered body weight, perirenal adipose tissue mass, and steatosis, whereas prophylactic HVc administration did not prevent HFD-induced NAFLD development. Furthermore, therapeutic MVc administration significantly ameliorated HFD-induced increase in body weight, perirenal adipose tissue mass and steatosis, whereas therapeutic LVc and HVc administration did not ameliorate NAFLD symptoms. In fact, therapeutic HVc administration significantly increased body weight, perirenal adipose tissue mass, and lobular inflammation. Moreover, prophylactic LVc administration was more effective than therapeutic LVc administration as evidenced by significantly lower body weight, perirenal adipose tissue mass, steatosis, ballooned hepatocytes, and lobular inflammation in prophylactic LVc administration. The same trends were observed between prophylactic HVc administration and therapeutic HVc administration. In addition, all Vc-administered mice exhibited low blood glucose, triglycerides and homeostasis model assessment of insulin resistance values and high adiponectin levels compared to HFD-fed mice. Our study suggested that MVc was beneficial for HFD-induced NAFLD prophylaxis and therapy. LVc prevented HFD-induced NAFLD development, while HVc for NAFLD management was risky. This study offers valuable insight into the effect of various Vc doses on NAFLD management.

Comparison of diagnostic accuracy of 3 diagnostic criteria combined with refined pathological scoring system for drug-induced liver injury.

Drug-induced liver injury (DILI) is difficult in diagnose, criteria used now are mostly based on history review. We tried to evaluate the value of these criteria and histopathology features in DILI to perform a method diagnosing DILI more definitely.We enrolled 458 consecutive hospitalized DILI patients from January 1, 2012 to December 31, 2018, using Roussel-Uclaf Causality Assessment Method (RUCAM), Maria & Victorino scale (M&V), and Digestive Disease Week-Japan criterion (DDW-J) combined with refined pathological scoring system respectively to perform the evaluation.A total of 458 DILI patients were enrolled, the area under receiver operating characteristics (AUROC) of the 3 clinical diagnostic criteria were 0.730 (95% confidence interval [CI]: 0.667-0.793), 0.793 (95% CI: 0.740-0.847), and 0.764 (95% CI: 0.702-0.826) respectively. Three hundred two DILI patients' liver biopsies were included: steatosis in 204 cases (67.5%), cholestasis in 151 cases (50%), cell apoptosis in 139 cases (46%), eosinophil granulocyte infiltration in 131 cases (43.4%), central and/or portal phlebitis in 103 cases (34.1%), iron deposition in 90 cases (29.8%), and pigmented macrophages in 92 cases (30.5%). The AUROC of refined pathological scale combined with 3 criteria were 0.843 (95% CI: 0.747-0.914), 0.907 (95% CI: 0.822-0.960), and 0.881 (95% CI: 0.790-0.942) respectively. In hepatocellular type, the AUROCs were 0.894 (95% CI: 0.787-0.959), 0.960 (95% CI: 0.857-0.994), and 0.940 (95% CI: 0.847-0.985); in cholestatic type, the AUROCs were 0.750 (95% CI: 0.466-0.931), 0.500 (95% CI: 0.239-0.761), and 0.500 (95% CI: 0.239-0.761); in mixed type, the AUROCs were 0.786 (95% CI: 0.524-0.943), 0.869 (95% CI: 0.619-0.981), and 0.762 (95% CI: 0.498 to -0.930).Combined with pathological scale can significantly improve the accuracy of clinical diagnostic criteria, no matter in alone or combined condition, M&V might be more accurate in diagnosing DILI from suspected patients.

KIF15 Promotes Proliferation and Growth of Hepatocellular Carcinoma.

Liver cancer is thought as the most common human malignancy worldwide, and hepatocellular carcinoma (HCC) accounts for nearly 90% liver cancer. Due to its poor early diagnosis and limited treatment, HCC has therefore become the most lethal malignant cancers in the world. Recently, molecular targeted therapies showed great promise in the treatment of HCC, and novel molecular therapeutic targets is urgently needed. KIF15 is a microtubule-dependent motor protein involved in multiple cell processes, such as cell division. Additionally, KIF15 has been reported to participate in the growth of various types of tumors; however, the relation between KIF15 and HCC is unclear. Herein, our study investigated the possible role of KIF15 on the progression of HCC and found that KIF15 has high expression in tumor samples from HCC patients. KIF15 could play a critical role in the regulation of cell proliferation of HCC, which was proved by in vitro and in vivo assays. In conclusion, this study confirmed that KIF15 could be a novel therapeutic target for the treatment of HCC.

Short-term treatment efficacy of NK cells for ovarian cancer ascites / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the short-term clinical efficacy and safety of intraperitoneal perfusion of natural killer (NK) cells in the treatment of ovarian cancer with ascites. Methods: The clinical data of 15 ovarian cancer patients with ascites effusion, who received NK cell perfusion in the Qinhuai Medical District of the General Hospital of Eastern Theater Command from November 2016 to January 2019, were analyzed. The peripheral blood was collected to isolate the peripheral blood mononuclear cells, and to further obtain the NK cells after culture. NK cell suspension was intraperitoneally perfused into the abdominal cavity (no less than 2×109 cells/ time). The volume of peritoneal effusion, the level of serum tumor marker CA-125, the level of serum cytokines IL-2, INF-γ and TNF-α as well as the changes in peripheral blood lymphocyte subsets were detected before and after the treatment; Moreover, the clinical efficacy and adverse reactions were observed. Results: The effective rate of intraperitoneal perfusion of NK cells was 66.7%, and there were no obvious treatment-related adverse reactions. Compared with before treatment, the serum tumor marker CA-125 level significantly decreased after treatment (P<0.05), and the levels of IL-15, IFN-γ and TNF-α increased significantly (P<0.05 or P<0.01), while there was no significant changes in peripheral blood lymphocyte subsets (all P>0.05). Conclusion: Intraperitoneal infusion of NK cells in the treatment of ovarian cancer associated peritoneal effusion has a good short-term clinical efficacy with little adverse reactions, which is a promising method for the treatment of cancerous peritoneal effusion.