Rare emergence of drug resistance in HIV-1 treatment -naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

Tenofovir alafenamide (TAF), a novel prodrug of the NtRTI tenofovir (TFV), delivers TFV-diphosphate (TFV-DP) to target cells more efficiently than the current prodrug, tenofovir disoproxil fumarate (TDF), with a 90% reduction in TFV plasma exposure. TAF, within the fixed dose combination of elvitegravir /cobicistat / emtricitabine (FTC)/TAF (E/C/F/TAF), has been evaluated in one Phase 2 and two Phase 3 randomized, double-blinded studies in HIV-infected treatment-naive patients, comparing E/C/F/TAF to E/C/F/TDF. In these studies, the TAF-containing group demonstrated non-inferior efficacy to the TDF-containing comparator group with 91.9% of E/C/F/TAF patients having <50 copies/mL of HIV-1 RNA at week 48. An integrated resistance analysis across these three studies was conducted, including HIV-1 genotypic analysis at screening, and genotypic/phenotypic analysis for patients with HIV-1 RNA >400 copies/mL at virologic failure. Pre-existing primary resistance-associated mutations (RAMs) were observed at screening among the 1903 randomized and treated patients: 7.5% had NRTI-RAMs, 18.2% had NNRTI-RAMs, and 3.4% had primary PI-RAMs. Pre-treatment RAMs did not influence treatment response at Week 48. In the E/C/F/TAF group, resistance development was rare; seven patients (0.7%, 7/978) developed NRTI-RAMs, five of whom (0.5%, 5/978) also developed primary INSTI-RAMs. In the E/C/F/TDF group, resistance development was also rare; seven patients (0.8%, 7/925) developed NRTI-RAMs, four of whom (0.4%, 4/925) also developed primary INSTI-RAMs. An additional analysis by deep sequencing in virologic failures revealed minimal differences compared to population sequencing. Overall, resistance development was rare in E/C/F/TAF-treated patients, and the pattern of emergent mutations was similar to E/C/F/TDF.     

Factors Related to Hepatocellular Carcinoma Recurrence After Liver Transplantation—A Brazilian Multicenter Study

Background

Liver transplantation (LT) is a curative treatment option for hepatocellular carcinoma (HCC); recurrent HCC after liver transplantation (HCC-R) is diagnosed in 9%–16%. The objective of this study was to evaluate which factors are associated with R-HCC after liver transplantation.

血清microRNA-184和microRNA-20a联合检测对胃癌的诊断价值

目的 探讨血清microRNA-184（miR-184）和microRNA-20a（miR-20a）联合检测对胃癌诊断的临床价值。方法 分别选取孝感中心医院332例及368例经病理确诊为慢性胃炎和胃癌的患者。采用荧光定量PCR检测所有患者血清miR-20a与miR-184的表达水平。绘制受试者工作特征（ROC）曲线,评价2种miRNA诊断胃癌的效能。根据ROC曲线确定这2种miRNA诊断胃癌的阈值,计算敏感性和特异性,并对比癌胚抗原（CEA）的测定结果。结果 慢性胃炎组患者血清miR-20a水平较胃癌组患者低（P <0.05）;慢性胃炎组患者血清miR-184水平较胃癌组患者高（P <0.05）。临床病理特征中,胃癌患者血清miR-20a表达水平与临床分期、淋巴结转移、饮酒史、年龄及性别差异无统计学意义（P >0.05）;胃癌患者血清miR-184表达水平与患者淋巴结转移、饮酒史、年龄及性别差异无统计学意义（P >0.05）,与肿瘤临床分期有差异（P <0.05）。Logistic回归分析结果显示,血清miR-20a［R=1.012（95% CI：1.697,6.875）］、miR-184［R=2.056（95% CI：0.417,0.722）］表达水平与胃癌的发生相关（P <0.05）。经ROC曲线分析表明,诊断胃癌采用血清miR-20a的临界值为4.24,曲线下面积（AUC）为0.762,特异性为71.7%,敏感性为79.4%;miR-184临界值为10.35,AUC为0.861,特异性为82.8%,敏感性为88.4%;CEA临界值为6 mg/ml,AUC为0.740,特异性为71.4%,敏感性为69.3%;血清miR-20a、miR-184联合诊断胃癌的AUC为0.908,特异性为87.6%,敏感性为84.7%。血清miR-184和miR-20a联合诊断胃癌的AUC、特异性及敏感性较3种单一检测方法大或高。结论 采用血清miR-20a和miR-184联合检测方法诊断胃癌,临床具有一定的应用价值。     

Peripheral antinociceptive effects of inhibitors of monoacylglycerol lipase in a rat model of inflammatory pain

BACKGROUND AND PURPOSE The endocannabinoid 2-arachidonoylglycerol (2-AG) is degraded primarily by monoacylglycerol lipase (MGL). We compared peripheral antinociceptive effects of JZL184, a novel irreversible MGL inhibitor, with the reversible MGL-preferring inhibitor URB602 and exogenous 2-AG in rats. EXPERIMENTAL APPROACH Nociception in the formalin test was assessed in groups receiving dorsal paw injections of vehicle, JZL184 (0.001-300 μg), URB602 (0.001-600 μg), 2-AG (ED(50)), 2-AG + JZL184 (at their ED(50)), 2-AG + URB602 (at their ED(50)), AM251 (80 μg), AM251 + JZL184 (10 μg), AM630 (25 μg) or AM630 + JZL184 (10 μg). Effects of MGL inhibitors on endocannabinoid accumulation and on activities of endocannabinoid-metabolizing enzymes were assessed. KEY RESULTS Intra-paw administration of JZL184, URB602 and 2-AG suppressed early and late phases of formalin pain. JZL184 and URB602 acted through a common mechanism. JZL184 (ED(50) Phase 1: 0.06 ± 0.028; Phase 2: 0.03 ± 0.011 μg) produced greater antinociception than URB602 (ED(50) Phase 1: 120 ± 51.3; Phase 2: 66 ± 23.9 μg) or 2-AG. Both MGL inhibitors produced additive antinociceptive effects when combined with 2-AG. Antinociceptive effects of JZL184, like those of URB602, were blocked by cannabinoid receptor 1 (CB(1)) and cannabinoid receptor 2 (CB(2)) antagonists. JZL184 suppressed MGL but not fatty-acid amide hydrolase or N-arachidonoyl-phosphatidylethanolamine phospholipase D activities ex vivo. URB602 increased hind paw 2-AG without altering anandamide levels. CONCLUSIONS AND IMPLICATIONS MGL inhibitors suppressed formalin-induced pain through peripheral CB(1) and CB(2) receptor mechanisms. MGL inhibition increased paw skin 2-AG accumulation to mediate these effects. MGL represents a target for the treatment of inflammatory pain.     

Survenue de cancers au cours de la sclérodermie systémique : facteurs de risque,impact sur la survie et revue de la littérature

IntroductionPatients with systemic sclerosis (SSc) have an increased risk of malignancy. In this study, we aimed to analyze the prevalence of cancer, the risk factors and the impact on overall survival.Patients and methodsWe analyzed clinical (history of cancer, toxic exposition, organ involvement), immunological and treatment data in a monocentric cohort of SSc patients followed between January 2004 and December 2017.ResultsTwo hundred and ten patients with SSc were included. During the follow-up, twenty-one patients (10 %) were diagnosed with malignancies. The underlying malignancies were breast adenocarcinoma (n = 6, 28%), lung cancer (n = 6, 28%), colorectal (colic adenocarcinoma, carcinoid tumor of the appendix), ovarian and cervix uteri, melanoma, kidney and papillary thyroid carcinoma (one of each). The median time between the first visit and the diagnosis of cancer was 4 [2–10] years. The overall survival in SSc patients with cancer was not significantly different from patients without cancer, with median survival during the first quartile (75%) at 12 years for patients with cancer and 11.6 years for those without cancer (P = 0.9). The history of renal scleroderma crisis (HR 10.99, IC95% [1.95–62.07]; P = 0.006) and the presence of anti-topoisomerase I antibodies (HR 5.5, IC95% [1.40–21.67]; P = 0.01) were associated with an increased risk of cancer, whereas the presence of gastroesophageal reflux was inversely associated with the cancer occurrence (HR 0.22, IC95% [0.056–0.867]; P = 0.03).ConclusionThe history of renal scleroderma crisis and the positivity of anti-topoisomerase I antibodies were associated with an increased risk of cancer in SSc patients in this monocentric study.