Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN?) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [¹⁴C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [¹⁴C]-diclofenac was incubated with HRN? mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN? mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN? mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN? mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN? mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN? mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.     

Effects of ω-3 Fatty Acids and Catechins on Fatty Acid Synthase in the Prostate: A Randomized Controlled Trial

Animal and human studies suggest fish oil and green tea may have protective effect on prostate cancer. Fatty acid synthase (FAS) has been hypothesized to be linked to chemoprotective effects of both compounds. This study evaluated the independent and joint effects of fish oil (FO) and green tea supplement (epigallocatechin-3-gallate, EGCG) on FAS and Ki-67 levels in prostate tissue. Through a double-blinded, randomized controlled trial with 2 × 2 factorial design, 89 men scheduled for repeat prostate biopsy following an initial negative prostate biopsy were randomized into either FO alone (1.9 g DHA + EPA/day), EGCG alone (600 mg/day), a combination of FO and EGCG, or placebo. We used linear mixed-effects models to test the differences of prostate tissue FAS and Ki-67 by immunohistochemistry between pre- and post-intervention within each group, as well as between treatment groups. Results did not show significant difference among treatment groups in pre-to-post-intervention changes of FAS (P = 0.69) or Ki-67 (P = 0.26). Comparing placebo group with any of the treatment groups, we did not find significant difference in FAS or Ki-67 changes (all P > 0.05). Results indicate FO or EGCG supplementation for a short duration may not be sufficient to produce biologically meaningful changes in FAS or Ki-67 levels in prostate tissue.     

Trait modality distribution of aquatic macrofauna communities as explained by pesticides and water chemistry

Analyzing functional species’ characteristics (species traits) that represent physiological, life history and morphological characteristics of species help understanding the impacts of various stressors on aquatic communities at field conditions. This research aimed to study the combined effects of pesticides and other environmental factors (temperature, dissolved oxygen, dissolved organic carbon, floating macrophytes cover, phosphate, nitrite, and nitrate) on the trait modality distribution of aquatic macrofauna communities. To this purpose, a field inventory was performed in a flower bulb growing area of the Netherlands with significant variation in pesticides pressures. Macrofauna community composition, water chemistry parameters and pesticide concentrations in ditches next to flower bulb fields were determined. Trait modalities of nine traits (feeding mode, respiration mode, locomotion type, resistance form, reproduction mode, life stage, voltinism, saprobity, maximum body size) likely to indicate pesticides impacts were analyzed. According to a redundancy analysis, phosphate -and not pesticides- constituted the main factor structuring the trait modality distribution of aquatic macrofauna. The functional composition could be ascribed for 2–4 % to pesticides, and for 3–11 % to phosphate. The lack of trait responses to pesticides may indicate that species may have used alternative strategies to adapt to ambient pesticides stress. Biomass of animals exhibiting trait modalities related to feeding by predation and grazing, presence of diapause form or dormancy, reproduction by free clutches and ovoviviparity, life stage of larvae and pupa, was negatively correlated to the concentration of phosphate. Hence, despite the high pesticide pollution in the area, variation in nutrient-related stressors seems to be the dominant driver of the functional composition of aquatic macrofauna assembly in agricultural ditches.     

Psychomotor therapy targeting anger and aggressive behaviour in individuals with mild or borderline intellectual disabilities: A systematic review

Background: Poor anger regulation is considered a risk factor of aggression in individuals with mild or borderline intellectual disabilities. Psychomotor therapy (PMT) targets anger regulation through body- and movement-oriented interventions. This study aims to inform practitioners on efficacy and research-base of PMT in this population.

Method: This systematic review evaluated nine studies which met inclusion criteria in terms of participants, intervention procedures, outcomes and certainty of evidence.

Results: Seven studies revealed a substantial reduction of aggressive behaviour or anger. Certainty of evidence was rated inconclusive in most cases due to absence of experimental control.

Conclusions: We can conclude that body-oriented PMT, involving progressive relaxation and meditation procedure “Soles of the Feet”, is a promising approach. However, the paucity of studies and methodological limitations preclude classifying it as an evidence-based practice. This suggests stronger methodological research and research aimed at PMT’s mechanisms of action (e.g., improved interoceptive awareness) is warranted.     

Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function

Background

Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.

Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers