The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis

Chirurgia dei vasi dell\u2019arto inferiore.

Anatomia chirurgica, vie d'accesso e trattamento delle patologie ostruttive e dilatative dei vasi dell'arto inferiore

Can Open aortic repair (OAR) be competitive with evar using a mini-invasive surgical protocol?

Evar Trial 1 is a paradigmatic example of various studies which proved the advantages of Evar on OAR in the perioperative period. We present a retrospective study comparing EVAR with OAR when the OAR patients are managed using a global mini-invasive protocol. Our results show that, if this protocol is used, and an attentive patient\u2019s selection is respected, OAR appears comparable with Evar in the peri-operative period

Afatinib as second-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck : subgroup analyses of treatment adherence, safety and mode of afatinib administration in the LUX-Head and Neck 1 trial

Objectives: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis). Methods: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week). Results: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83\u201392% and 76\u201392% (of patients with data available) across all subgroups took 6580% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70\u201391%), rash/acne (72\u201384%), stomatitis (34\u201373%) with afatinib; and included stomatitis (39\u2013100%), fatigue (22\u201350%), nausea (19\u201336%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took 6580% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72\u20131.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%). Conclusion: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration