Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

Serotonin transporter-linked polymorphic region genotypes in relation to stress conditions among patients with papillary thyroid carcinoma.

The serotonin-transporter-linked polymorphic region (5-HTTLPR) gene has been reported to predispose individuals experiencing trauma to affective disorders such as anxiety and depression. We hypothesized that SS genotype of 5-HTTLPR gene would induce stress conditions and poor prognosis of papillary thyroid carcinoma (PTC). The study enrolled 287 patients with or without post-traumatic stress disorder (PTSD) following surgical treatment of PTC with their baseline characteristics collected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was conducted to detect genotype frequency. Five self-rating scales, including Impact of Event Scale-Revised Edition (IES-R), MedicaI Coping Modes Questionnaire (MCMO), Hamilton Depression Scale (HAMD), Social Support Rating Scale (SSRS) and Stressful Life Events (SLEs), were used for depressive state assessment. Survival situations were observed through 15-year follow-up visits one time every six months. Survival rate was calculated using Life Table. Logistic regression analysis was used to analyze factors related to prognosis of PTC. Increased SS genotype and decreased LL genotypes were found in patients with PTSD. PTSD is associated with high stress, and inter-group analysis revealed that patients carrying SS genotype exhibited a high stress condition. PTSD and SS genotype correlated to large tumor size, advanced clinical stage, lymph node metastasis, and decreased 10-year and 15-year survival rate. As for patients carrying the same genotype, those suffering from PTSD showed poorer survival. Also, 5-HTTPRL, MCMQ score (confrontation/avoidance/surrender), HAMD score, SSRS total score, SLEs score, tumor size, clinical stage, and lymph node metastasis were relevant factors for prognosis of PTC. The results demonstrate SS genotype of the 5-HTTPRL gene as a contributor of high stress among patients with PTC. Thus, 5-HTTPRL and stress conditions represent potential investigative focus targets for prognosis of PTC.

Betulinic acid prevents high glucose­induced expression of extracellular matrix protein in cardiac fibroblasts by inhibiting the TGF­ß1/Smad signaling pathway.

The proliferation and differentiation of cardiac fibroblasts (CFs) is central to cardiac fibrosis. Betulinic acid (BA) is an active compound isolated from the bark of the birch tree Betula spp. (Betulaceae) and has been shown to attenuate hepatic fibrosis. However, the effect of BA on the high glucose­induced fibrosis response in CFs remains to be elucidated, therefore, the present study investigated the effect of BA on high glucose­induced CFs and examined the possible mechanism underlying the effect of BA on CF transdifferentiation. CFs were pre­incubated with various concentrations of BA for 24 h and then stimulated with high glucose (25 mM) for various times. Cell proliferation was evaluated using an MTT assay. The mRNA expression levels of α­smooth muscle actin (SMA) and transforming growth factor (TGF)­ß1 were determined using reverse transcription­quantitative polymerase chain reaction analysis. The protein expression levels of α­SMA, collagen I, collagen III, fibronectin, TGF­ß1, small mothers against decapentaplegic (Smad)2/3, phosphorylated (p)­Smad2 and p­Smad3 and were detected using western blot analysis. The data revealed that BA attenuated the CF proliferation and myofibroblast differentiation induced by high glucose. In addition, BA inhibited the expression of extracellular matrix (ECM) in the CFs induced by high glucose. It was also found that BA inhibited the high glucose­induced phosphorylation of Smad2/3 in the CFs. Taken together, BA suppressed the high glucose­induced increase in the proliferation of CFs and expression of ECM via inhibition of the TGF­ß1/Smad signaling pathway. Thus, BA may offer therapeutic potential towards the treatment of cardiac fibrosis.

A CONSORT-compliant, randomized, double-blind, placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that can progress to cirrhosis and liver failure. Anthocyanin, a member of the flavonoid family, has been shown to ameliorate NAFLD-associated pathologies in rodents.The aim of this CONSORT-compliant pilot study is to evaluate the effects of anthocyanin supplementation on insulin resistance and liver injury biomarkers in patients with NAFLD.A total of 74 subjects with NAFLD were divided into 2 groups in this double-blind, randomized study. Patients received either purified anthocyanin (320 mg/d) derived from bilberry and black currant or placebo for 12 weeks. Diet, physical activity, anthropometric parameters, glucose tolerance, and a set of biomarkers related to NAFLD were evaluated before and after intervention.No significant differences were observed in nutrient intake, physical activity, anthropometric parameters, or plasma lipid profile between patients receiving anthocyanin or placebo. Compared to controls, the anthocyanin group exhibited significant decreases (P < 0.05, all comparisons) in plasma alanine aminotransferase (-19.1% vs 3.1%), cytokeratin-18 M30 fragment (-8.8% vs 5.6%) and myeloperoxidase (-75.0% vs -44.8%). Significant decreases from baseline in fasting blood glucose and homeostasis model assessment for insulin resistance were observed in the anthocyanin group; however, these differences were not significant relative to placebo controls. In addition, the oral glucose tolerance test indicated that anthocyanin supplementation significantly decreased the 2-hour loading glucose level compared to control (-18.7% vs -3.8%, P = 0.02).A 12-week supplement of purified anthocyanin improved insulin resistance, indicators of liver injury, and clinical evolution in NAFLD patients. Further studies are warranted to determine the clinical applications of anthocyanin in NAFLD.This trial was registered at clinicaltrials.gov as NCT01940263.