Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine

Journal of Neuro-Oncology - MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication...     

Associations between Dietary Patterns and Cardiometabolic Risk Factors—A Longitudinal Analysis among High-Risk Individuals for Diabetes in Kerala,India

The association between dietary patterns and cardiometabolic risk factors is not well understood among adults in India, particularly among those at high risk for diabetes. For this study, we analyzed the data of 1007 participants (age 30–60 years) from baseline and year one and two follow-ups from the Kerala Diabetes Prevention Program using multi-level mixed effects modelling. Dietary intake was measured using a quantitative food frequency questionnaire, and dietary patterns were identified using principal component analysis. Two dietary patterns were identified: a “snack-fruit” pattern (highly loaded with fats and oils, snacks, and fruits) and a “rice-meat-refined wheat” pattern (highly loaded with meat, rice, and refined wheat). The “snack-fruit” pattern was associated with increased triglycerides (mg/dL) (β = 6.76, 95% CI 2.63–10.89), while the “rice-meat-refined wheat” pattern was associated with elevated Hb1Ac (percentage) (β = 0.04, 95% CI 0.01, 0.07) and central obesity (OR 1.16, 95% CI 1.01, 1.34). These findings may help inform designing dietary interventions for the prevention of diabetes and improving cardiometabolic risk factors in high-diabetes-risk individuals in the Indian setting.     

Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia

Lipopolysaccharide (LPS) may play an important role in chronic diseases through the activation of inflammatory responses. The type of diet consumed is of major concern for the prevention and treatment of these diseases. Evidence from animal and human studies has shown that LPS can diffuse from the gut to the circulatory system in response to the intake of high amounts of fat. The method by which LPS move into the circulatory system is either through direct diffusion due to intestinal paracellular permeability or through absorption by enterocytes during chylomicron secretion. Considering the impact of metabolic diseases on public health and the association between these diseases and the levels of LPS in the circulatory system, this review will mainly discuss the current knowledge about high-fat diets and subclinical inflammation. It will also describe the new evidence that correlates gut microbiota, intestinal permeability and alkaline phosphatase activity with increased blood LPS levels and the biological effects of this increase, such as insulin resistance. Although the majority of the studies published so far have assessed the effects of dietary fat, additional studies are necessary to deepen the understanding of how the amount, the quality and the structure of the fat may affect endotoxaemia. The potential of food combinations to reduce the negative effects of fat intake should also be considered in future studies. In these studies, the effects of flavonoids, prebiotics and probiotics on endotoxaemia should be investigated. Thus, it is essential to identify dietetic strategies capable of minimising endotoxaemia and its postprandial inflammatory effects.     

Differences between Four Skinfold Calipers in the Assessment of Adipose Tissue in Young Adult Healthy Population

Background: The aim of this study was to analyze the validity of four different skinfold calipers, as well as to establish the differences between them in a healthy young adult population. Methods: The present study followed a cross-sectional design, including 138 participants, with 69 males (21.46 ± 2.52 years) and 69 females (22.19 ± 2.85 years). The measurement protocol included basic measurements of body mass and stretch stature and eight skinfolds with a Harpenden, Holtain, Slim Guide, and Lipowise. The ∑6 and ∑8 skinfolds and fat mass were calculated. The order in which the skinfold calipers were used was randomized. Results: No significant differences were found in either the Σ6 and Σ8 skinfolds or masses and fat percentages calculated with the skinfolds obtained with the different calipers (p > 0.05), and the inclusion of the covariates of sex, BMI, and hydration status of the participants showed no effect on the differences. The Bland–Altman test showed significant differences between the calipers (p < 0.001). Conclusion: It has been observed that the analyzed calipers have shown validity for the assessment of adiposity-related variables in a male and female sample of non-overweight, young healthy adults, but they are not interchangeable with each other when the assessment is meant to be compared over time or with other samples.     

Nonopioid perioperative analgesia in head and neck cancer surgery: A systematic review

ObjectiveManagement of postoperative pain after head and neck cancer surgery is a complex issue, requiring a careful balance of analgesic properties and side effects. The objective of this review is to discuss the efficacy and safety of multimodal analgesia (MMA) for these patients.MethodsPubmed, Cochrane, Embase, Scopus, and clinicaltrials.gov were systematically searched for all comparative studies of patients receiving MMA (nonsteroidal anti‐inflammatory drugs (NSAIDs), acetaminophen, anticonvulsants, local anesthetics, and corticosteroids) for head and neck cancer surgeries. The primary outcome was additional postoperative opioid usage, and secondary outcomes included subjective pain scores, complications, adverse effects, and 30‐day outcomes.ResultsA total of five studies representing 592 patients (MMA, n = 275; non‐MMA, n = 317) met inclusion criteria. The most commonly used agents were gabapentin, NSAIDs, and acetaminophen (n = 221), NSAIDs (n = 221), followed by corticosteroids (n = 35), dextromethorphan (n = 40), and local nerve block (n = 19). Four studies described a significant decrease in overall postoperative narcotic usage with two studies reporting a significant decrease in hospital time. Subjective pain scores widely varied with two studies reporting reduced pain at postoperative day 3. There were no differences in surgical outcomes, medical complications, adverse effects, or 30‐day mortality and readmission rates.ConclusionMMA is an increasingly popular strategy that may reduce dependence on opioids for the treatment of postoperative pain. A variety of regimens and protocols are available for providers to utilize in the appropriate head and neck cancer patient.     

Investigation of the in vitro and ex vivo acetylcholinesterase and antioxidant activities of traditionally used Lycopodium species from South America on alkaloid extracts

Ethnopharmacological relevance

The study was aimed at evaluating medicinal and therapeutic potentials of two Lycopodiaceae species, Lycopodium clavatum (L.) and Lycopodium thyoides (Humb. & Bonpl. ex Willd), both used in South American folk medicine for central nervous system conditions. Alkaloid extracts were evaluated for chemical characterization, acetylcholinesterase and antioxidant activities.

Materials and methods

The alkaloid extracts obtained by alkaline extraction were determined for each species by GC/MS examination. The evaluation of the anticholinesterase and the antioxidant activities of the extracts were tested by determining in vitro and ex vivo models. Effects on acetylcholinesterase (AChE) were tested in vitro using rat brain homogenates and ex vivo after a single administration (25, 10 and 1 mg/kg i.p.) of the alkaloid extracts in mice. The in vitro antioxidant effects were tested for the 2-deoxyribose degradation, nitric oxide (NO) interaction, 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging activity and total reactive antioxidant potential (TRAP). After an acute administration (25 and 10 mg/kg i.p.) of the extracts in middle-aged (12 months) mice, the antioxidant effects were estimated through the thiobarbituric acid reactive substances test (TBARS), and the antioxidant enzymes activities for catalase (CAT) and superoxide dismutase (SOD) were measured.

Results

AChE activity was inhibited in vitro by the alkaloid-enriched extracts of both Lycopodium species in a dose and time-dependent manner in rat cortex, striatum and hippocampus. A significant inhibition was also observed in areas of the brain after acute administration of extracts, as well as decreased lipid peroxidation and increased CAT activity in the cortex, hippocampus and cerebellum. A moderate antioxidant activity was observed in vitro for the extracts. Chemically, the main alkaloids found for the two species were lycopodine and acetyldihidrolycopodine.

Conclusion

This study showed that the biological properties of the folk medicinal plants Lycopodium clavatum and Lycopodium thyoides include AChE inhibitory activity and antioxidant effects, two possible mechanisms of action in Alzheimer's related processes.     

Systemic oxidative stress in children with cystic fibrosis with bacterial infection including Pseudomonas Aeruginosa

IntroductionOxidative stress (OS) occurs in cystic fibrosis (CF).ObjectiveThe objective of this work is to evaluate the influence of bacterial infection on biomarkers of OS (catalase [CAT], glutathione peroxidade [GPx], reduced glutathione [GSH]), markers of oxidative damage (protein carbonyls [PC], thiobarbituric acid reactive substances [TBARS]), together with the nutritional status and lung function in children with CF.MethodsCross‐sectional study including CF group (CFG, n = 55) and control group (CG, n = 31), median age: 3.89 and 4.62 years, respectively. CFG was distributed into CFG negative bacteriology (CFGB−, n = 27) or CFG positive bacteriology (CFGB+, n = 28), and CFG negative Pseudomonas aeruginosa (CFGPa−, n = 36) or CFG positive Pseudomonas aeruginosa (CFGPa+, n = 19).ResultsCompared with CG, CFG (P = .034) and CFGB+ (P = .042) had lower body mass index‐for‐age z‐score; forced expiratory volume in the first second was lower in CFGB+ and CFGPa+ (both P < .001). After adjusting for confounders and compared with CG: CFG showed higher TBARS (P ≤ .001) and PC (P = .048), and lower CAT (P = .004) and GPx (P = .003); the increase in PC levels was observed in CFGB+ (P = .011) and CFGPa+ (P = .001) but not in CFGB− (P = .510) and CFGPa− (P = .460).ConclusionsThese results indicate a systemic OS in children with CF. The presence of bacterial infection particularly Pseudomonas aeruginosa seems to be determinant to exacerbate the oxidative damage to proteins, in which PC may be a useful biomarker of OS in CF.