“HIIT the Inflammation”: Comparative Effects of Low-Volume Interval Training and Resistance Exercises on Inflammatory Indices in Obese Metabolic Syndrome Patients Undergoing Caloric Restriction

Exercise is a cornerstone in metabolic syndrome (MetS) treatment. However, the effects of low-volume exercise modalities on MetS-associated low-grade inflammation are unclear. A total of 106 MetS patients (53.7 ± 11.4 years) were randomized to low-volume high-intensity interval training (LOW-HIIT, 14 min/session), single-set resistance training (1-RT, ~15 min/session), whole-body electromyostimulation (WB-EMS, 20 min/session), three-set resistance training (3-RT, ~50 min/session), each performed 2 ×/week for 12 weeks, or a control group (CON). All groups received nutritional counseling for weight loss. Inflammatory and cardiometabolic indices were analyzed pre- and post-intervention. All groups significantly reduced body weight by an average of 3.6%. Only LOW-HIIT reduced C-reactive protein (CRP) (−1.6 mg/L, p = 0.001) and interleukin-6 (−1.1 pg/mL, p = 0.020). High-sensitivity CRP and lipopolysaccharide-binding protein decreased following LOW-HIIT (−1.4 mg/L, p = 0.001 and −2.1 ng/mL, p = 0.004) and 3-RT (−0.6 mg/L, p = 0.044 and −2.0 ng/mL, p < 0.001). MetS severity score improved with LOW-HIIT (−1.8 units, p < 0.001), 1-RT (−1.6 units, p = 0.005), and 3-RT (−2.3 units, p < 0.001). Despite similar effects on body weight, low-volume exercise modalities have different impact on inflammatory and cardiometabolic outcomes in MetS patients. LOW-HIIT has superior efficacy for improving inflammation compared to 1-RT and WB-EMS. Resistance-based exercise appears to require a higher volume to promote beneficial impact on inflammation.     

PIK3CA mutations in non-small cell lung cancer (NSCLC): Genetic heterogeneity,prognostic impact and incidence of prior malignancies

Background: Somatic mutations of the PIK3CA gene have been described in non-small cell lung cancer (NSCLC), but limited data is available on their biological relevance. This study was performed to characterize PIK3CA-mutated NSCLC clinically and genetically.Patients and methods: Tumor tissue collected consecutively from 1144 NSCLC patients within a molecular screening network between March 2010 and March 2012 was analyzed for PIK3CA mutations using dideoxy-sequencing and next-generation sequencing (NGS). Clinical, pathological, and genetic characteristics of PIK3CA-mutated patients are described and compared with a control group of PIK3CA-wildtype patients.Results: Among the total cohort of 1144 patients we identified 42 (3.7%) patients with PIK3CA mutations in exon 9 and exon 20. These mutations were found with a higher frequency in sqamous cell carcinoma (8.9%) compared to adenocarcinoma (2.9%, p<0.001). The most common PIK3CA mutation was exon 9 E545K. The majority of patients (57.1%) had additional oncogenic driver aberrations. With the exception of EGFR-mutated patients, non of the genetically defined subgroups in this cohort had a significantly better median overall survival. Further, PIK3CA-mutated patients had a significantly higher incidence of malignancy prior to lung cancer (p<0.001).Conclusion: PIK3CA-mutated NSCLC represents a clinically and genetically heterogeneous subgroup in adenocarcinomas as well as in squamous cell carcinomas with a higher prevalence of these mutations in sqamous cell carcinoma. PIK3CA mutations have no negative impact on survival after surgery or systemic therapy. However, PIK3CA mutated lung cancer frequently develops in patients with prior malignancies.     

Inhibitors of cytosolic phospholipase A2α with carbamate structure: synthesis,biological activity,metabolic stability,and bioavailability

Cytosolic phospholipase A₂α is a serine hydrolase involved in the generation of pro-inflammatory lipid mediators. Here, we describe structure–activity relationship studies on a series of carbamate-substituted indazole-5-carboxylic acid inhibitors of this enzyme. Bioavailability experiments in mice with 1-(3-(4-butylphenoxy)-2-{[(ethylthio)carbonyl]amino}propyl)indazole-5-carboxylic acid (14) revealed a high rate of glucuronidation and biliary excretion of this compound. Replacement of the rigid aromatic carboxylic acid system by a more flexible aliphatic one led to substances with a significantly increased in vitro stability against metabolic glucuronidation.