Preclinical Characterization and In Vivo Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein

The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2-a]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.     

A novel mutation of SETBP1 in atypical chronic myeloid leukemia transformed from acute myelomonocytic leukemia

To investigate an oncogenic mutation of SETBP1 in the evolution from acute myelomonocytic leukemia (M4) to secondary aCML. Clinical data and molecular studies were analyzed of paired aCML and 'normal'DNA from a case with M4. We identified a mutation in SETBP1 (encoding a p.Asp868Ala alteration). The analysis of paired sample indicated that SETBP1 mutation was acquired during leukemic evolution.     

Diagnostic value of radial endobronchial ultrasonographic features in predominant solid peripheral pulmonary lesions

BackgroundTransbronchial lung biopsy (TBLB) of peripheral pulmonary lesions (PPLs) is usually performed for a definite diagnosis. Radial probe endobronchial ultrasonography is often acknowledged as a good guidance method for TBLB as it can help physicians confirm the lesions’ position. It is also a non-invasive imaging diagnostic method. This clinical study was designed to evaluate the ability of radial endobronchial ultrasonography (R-EBUS) to differentiate benign from malignant predominant solid PPLs based on imaging features.MethodsPatients with predominant solid PPLs were enrolled in this study retrospectively. TBLB was performed using R-EBUS with or without other guidance techniques. One typical sonographic image and one video of each lesion were recorded for analysis. Six radial probe endobronchial ultrasonographic image features (size, shape, echogenicity, margin, blood vessel, and linear-discrete air bronchogram) were studied by ultrasonography specialists and physicians who were blinded to the final diagnosis. The sum score model of the combined predictive factors indicated the best diagnostic accuracies for predicting malignant PPLs. The model group results were used to establish the diagnostic standard for a verification group.ResultsA total of 303 patients were enrolled in the model group from July 2018 to July 2019 at the Shanghai Chest Hospital (214 with malignant and 89 with benign lesions). The mean lesion long axis on computed tomographic images was 34.39±13.79 mm. There were significant statistical differences between benign and malignant lesions in the long axis, short axis, shape, margin, blood vessel, and linear-discrete air bronchogram assessed by radial endobronchial ultrasound. Long axis, lobulation, distinct but not sharp margin, absence of blood vessel, and absence of linear-discrete air bronchogram were good predictive factors of malignant lesions. A sum score model value of 79.54% of these combined factors indicated the best diagnostic accuracy for predicting malignant lesions. Eighty-seven patients were enrolled in the verification group from August to October 2019. The sum score model showed a diagnostic accuracy of 82.76%.ConclusionsRadial endobronchial ultrasonographic features can differentiate malignant from benign lesions and thus have potential diagnosis value in predominant solid PPLs.     

多烯磷脂酰胆碱联合双环醇治疗胃癌化疗导致的药物性肝损伤患者疗效及其对血清细胞因子和氧化应激指标水平的影响

目的 探讨应用多烯磷脂酰胆碱联合双环醇治疗胃癌化疗所致的药物性肝损伤(DILI)患者疗效及其对血清细胞因子和氧化应激指标的影响。方法 2017年5月～2019年5月我院收治的胃癌根治术后患者78例,给予奥沙利铂、多西他赛和氟尿嘧啶化疗。在化疗过程中出现DILI患者40例,被随机分为对照组(n=19)和观察组(n=21),给予对照组患者多烯磷脂酰胆碱治疗,给予观察组多烯磷脂酰胆碱联合双环醇片治疗,两组均观察4周。采用ELISA法检测血清肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6),采用硫代巴比妥酸法检测血清丙二醛(MDA),采用黄嘌呤氧化法检测血清超氧化物歧化酶(SOD)。采用卡氏功能状态(KPS)量表评估患者生存质量。结果 在治疗4周末,观察组血清丙氨酸氨基转移酶(ALT)水平为(33.5±7.9)U/L,显著低于对照组【(42.4±8.8)U/L,P<0.05】,血清天冬氨酸氨基转移酶(AST)水平为(34.4±5.7)U/L,显著低于对照组【(39.4±6.2)U/L,P<0.05】,血清碱性磷酸酶(ALP)水平为(60.6±14.2)U/L,显著低于对照组【(75.3±16.6)U/L,P<0.05】,而KPS评分为(64.1±17.2)分,显著高于对照组【(48.3±14.5)分,P<0.05】;联合组肝功能复常率为81.0%,显著高于对照组的63.2%(P<0.05);观察组血清TNF-α水平为(15.2±2.1)mg/L,显著低于对照组【(21.4±3.6)mg/L,P<0.05】,血清IL-6水平为(28.1±4.5)pg/mL,显著低于对照组【(46.2±5.9)pg/mL,P<0.05】;血清MDA水平为(5.1±0.8)nmol/mL,显著低于对照组【(5.9±0.7)nmol/mL,P<0.05】,而血清SOD水平为(2.3±0.5)U/mL,显著高于对照组【(1.8±0.4)U/mL,P<0.05】。结论 联合应用多烯磷脂酰胆碱和双环醇片治疗化疗药导致的DILI患者能改善肝功能,可能与抑制了氧化应激反应,降低了血清细胞因子水平有关,值得进一步研究。     

Clinical report and analysis of 24 cases of multiple magnetic beads foreign body in gastrointestinal tract of children

Background/AimsThis study aimed to analyze the data of 24 cases of multiple perforation or obstruction of the digestive tract caused by accidental ingestion of magnetic beads, to improve the understanding of its harmfulness to children and explore the best treatment.Materials and MethodsIn total, 24 cases were collected and retrospectively analyzed. These patients were divided into two groups: perforation group and non-perforation group. The medical history, number of magnetic beads, white blood cell (WBC) count, and C-reactive protein (CRP) were analyzed.ResultsThere was no significant difference in age, gender, medical history, number of magnetic beads, and WBC count between the perforation group and non-perforation group, but there was a significant difference in CRP. After the diagnosis, 70% of the cases underwent laparotomy and perforation repair. All cases recovered smoothly after the operation, and no complications occurred during the follow-up.ConclusionThis study offers diagnosis and treatment methods for the perforation or obstruction of the digestive tract caused by accidental ingestion of magnetic beads and raises the awareness regarding the harmfulness of the presence of foreign bodies in the digestive tract.     

Seroprevalence of H7N9 infection among humans: A systematic review and meta‐analysis

In spring 2013, a novel avian‐origin influenza A (H7N9) virus emerged in mainland China. The burden of H7N9 infection was estimated based on systematic review and meta‐analysis. The systematic search for available literature was conducted using Chinese and English databases. We calculated the pooled seroprevalence of H7N9 infection and its 95% confidence interval by using Freeman‐Tukey double arcsine transformation. Out of 16 890 records found using Chinese and English databases, 54 articles were included in the meta‐analysis. These included studies of a total of 64 107 individuals. The pooled seroprevalence of H7N9 infection among humans was 0.122% (95% CI: 0.023, 0.275). In high‐risk populations, the highest pooled seroprevalence was observed among close contacts (1.075%, 95% CI: 0.000, 4.357). The seroprevalence among general population was (0.077%, 95% CI: 0.011, 0.180). Our study discovered that asymptomatic infection of H7N9 virus did occur, even if the seroprevalence among humans was low.