Towards a therapy for mitochondrial disease: an update

Preclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field.Our work is supported by MRC (grants: MC_UU_00015/5 and MC_EX_MR/P007031/1) and ERC (grant FP7-322424

Target Therapy in Platinum-Refractory/Resistant Ovarian Cancer: From Preclinical Findings to Current Clinical Practice

Epithelial ovarian cancer (EOC) is the sixth most common malignancy in women. Ovarian tumors consist of several clinical and pathological entities that share an anatomic site. The gold standard treatment, both in front-line and in adjuvant setting, is represented by carboplatin/paclitaxel combination. Conversely, the second-line treatment is not well defined. The response to platinum is the major prognostic factor for survival. In this review we discuss the current views on platinum-refractory/resistant patient treatment only, which includes patients progressing or relapsing within 6 months from the last platinum-based course. Concerning this subgroup, the activity of several conventional drugs was confirmed in different trials without a significant impact in terms of overall survival. In the last years particular emphasis was given to targeted anti-angiogenetic therapy which produced a survival improvement with an acceptable toxicity profile. New “ad hoc” approaches, with a major attention to outcome-predictive factors, are eagerly awaited

Transcription Factor EB Controls Metabolic Flexibility during Exercise

The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism

Amino function and side chain modifications of amino acids, and synthesis of thrombin inhibiting peptides

Dottorato di Ricerca in Metodologie per lo Sviluppo di Molecole di Interesse Farmacologico, Ciclo XXI, a.a. 2008Università della Calabri

Pharmacological targeting of the \uce 2-amyloid precursor protein intracellular domain

Amyloid precursor protein (APP) intracellular domain (AICD) is a product of APP processing with transcriptional modulation activity, whose overexpression causes various Alzheimer's disease (AD)-related dysfunctions. Here we report that 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid) (CHF5074), a compound that favorably affects neurodegeneration, neuroinflammation and memory deficit in transgenic mouse models of AD, interacts with the AICD and impairs its nuclear activity. In neuroglioma-APPswe cells, CHF5074 shifted APP cleavage from A\u3b242 to the less toxic A\u3b238 peptide without affecting APP-C-terminal fragment, nor APP levels. As revealed by photoaffinity labeling, CHF5074 does not interact with \u3b3-secretase, but binds to the AICD and lowers its nuclear translocation. In vivo treatment with CHF5074 reduced AICD occupancy as well as histone H3 acetylation levels and transcriptional output of the AICD-target gene KAI1. The data provide new mechanistic insights on this compound, which is under clinical investigation for AD treatment/prevention, as well as on the contribution of the AICD to AD pathology

Preferences of Patients with Advanced Colorectal Cancer for Treatment with Oral or Intravenous Chemotherapy

Background: In recent years, patient-reported outcomes such as health-related quality of life have become important areas of clinician focus in general cancer management. Patients' preferences for, and/or satisfaction with, oral versus intravenous (IV) chemotherapy schedules may have a major impact on such outcomes. Objective: To evaluate preferences for oral or IV chemotherapy in patients with advanced colorectal cancer. Methods: A multicenter, randomized, crossover trial was conducted in 12 hospitals in Southern Italy, in which 22 patients with advanced colorectal cancer received one cycle of oral capecitabine +- irinotecan or oxaliplatin, followed by one cycle of an IV de Gramont or similar regimen (arm A), or the same regimens in reverse order (arm B). Patients were aged 50-70 years and 21% had a higher level of education (graduate or similar). Patients received oral capecitabine 3500 mg/m2/day for 7 days (+- irinotecan 180 mg/m2 or oxaliplatin 85 mg/m2 on day 1 only), followed by an IV de Gramont regimen +- irinotecan (FOLFIRI) or oxaliplatin (FOLFOX); or the two schedules administered in reverse order. The main outcome measure was patients' preferences for oral versus IV chemotherapy, as determined by a pre- and post-treatment therapy preference questionnaire (TPQ). Results: Before treatment, 75% of patients preferred oral therapy. Characteristics that patients considered to be important were that treatment should not interfere with daily activities (100% of patients) and should not cause fatigue (95%), diarrhea (76%), or painful mouth ulcers (76%); other factors considered important were the risk of infection and nausea (90%), and that treatment could be administered at home (65%). After receiving both chemotherapy schedules, only 45% of patients preferred oral therapy, while 55% preferred IV therapy. Among the latter, the most important characteristics influencing treatment choice were less nausea (66%), fewer mood effects (65%), the safety of hospital IV treatment (62%), less interference with family relationships (55%), less vomiting (55%), less interference with daily activities (50%), and less diarrhea (50%). Although the order in which patients received therapy did not influence treatment preference, significantly fewer patients with a lower rather than higher educational level preferred oral therapy (47% vs 80%; chi-square test = 9.9; p_=_0.002). Conclusion: These results suggest that there may be a correlation between educational level and the preference of patients with advanced colorectal cancer for oral or IV chemotherapy. DOI: 10.2165/1312067-200801030-00005Adverse-drug-reactions, Antineoplastics, Colorectal-cancer, Intravenous, Oral, Patient-preference