Actionable Genetic Screens Unveil Targeting of AURKA, MEK, and Fatty Acid Metabolism as an Alternative Therapeutic Approach for Advanced Melanoma.

Despite the remarkable improvements achieved in the management of metastatic melanoma, there are still unmet clinical needs. A considerable fraction of patients does not respond to immune and/or targeted therapies owing to primary and acquired resistance, high-grade immune-related adverse events, and a lack of alternative treatment options. To design effective combination therapies, we set up a functional ex vivo preclinical assay on the basis of a drop-out genetic screen in metastatic melanoma patient-derived xenografts. We showed that this approach can be used to isolate actionable vulnerabilities predictive of drug efficacy. In particular, we highlighted that the dual targeting of AURKA and MAPK/extracellular signal-regulated kinase kinase employing the combination of alisertib and trametinib is highly effective in a cohort of metastatic melanoma patient-derived xenografts, both ex vivo and in vivo. Alisertib and trametinib combination therapy outperforms standard-of-care therapy in both BRAF-mutant patient-derived xenografts and targeted therapy-resistant models. Furthermore, alisertib and trametinib treatment modulates several critical cancer pathways, including an early metabolic reprogramming that leads to the transcriptional upregulation of the fatty acid oxidation pathway. This acquired trait unveiled an additional point of intervention for pharmacological targeting, and indeed, the triple combination of alisertib and trametinib with the fatty acid oxidation inhibitor etomoxir proved to be further beneficial, inducing tumor regression and remarkably prolonging the overall survival of the mice.

Is there a role for homeopathy in breast cancer surgery? A first randomized clinical trial on treatment with Arnica montana to reduce post-operative seroma and bleeding in patients undergoing total mastectomy.

AIM: This study aimed to evaluate the benefits of Arnica montana on post-operative blood loss and seroma production in women undergoing unilateral total mastectomy by administering Arnica Montana 1000 Korsakovian dilution (1000 K). MATERIALS AND METHODS: From 2012 to 2014, 53 women were randomly assigned to A. montana or placebo and were followed up for 5 days. The main end point was the reduction in blood and serum volumes collected in drainages. Secondary end points were duration of drainage, a self-evaluation of pain, and the presence of bruising or hematomas. RESULTS: The per-protocol analysis revealed a lower mean volume of blood and serum collected in drainages with A. montana (-94.40 ml; 95% confidence interval [CI]: 22.48-211.28; P = 0.11). A regression model including treatment, volume collected in the drainage on the day of surgery, and patient weight showed a statistically significant difference in favor of A. montana (-106.28 ml; 95% CI: 9.45-203.11; P = 0.03). Volumes collected on the day of surgery and the following days were significantly lower with A. montana at days 2 (P = 0.033) and 3 (P = 0.0223). Secondary end points have not revealed significant differences. CONCLUSIONS: A. montana 1000 K could reduce post-operative blood and seroma collection in women undergoing unilateral total mastectomy. Larger studies are needed with different dilutions of A. montana to further validate these data.

Active music therapy approach for stroke patients in the post-acute rehabilitation.

Guidelines in stroke rehabilitation recommend the use of a multidisciplinary approach. Different approaches and techniques with music are used in the stroke rehabilitation to improve motor and cognitive functions but also psychological outcomes. In this randomized controlled pilot trial, relational active music therapy approaches were tested in the post-acute phase of disease. Thirty-eight hospitalized patients with ischemic and hemorrhagic stroke were recruited and allocated in two groups. The experimental group underwent the standard of care (physiotherapy and occupational therapy daily sessions) and relational active music therapy treatments. The control group underwent the standard of care only. Motor functions and psychological aspects were assessed before and after treatments. Music therapy process was also evaluated using a specific rating scale. All groups showed a positive trend in quality of life, functional and disability levels, and gross mobility. The experimental group showed a decrease of anxiety and, in particular, of depression (p = 0.016). In addition, the strength of non-dominant hand (grip) significantly increased in the experimental group (p = 0.041). Music therapy assessment showed a significant improvement over time of non-verbal and sonorous-music relationships. Future studies, including a greater number of patients and follow-up evaluations, are needed to confirm promising results of this study.

The methyl-CpG binding protein MBD1 is required for PML-RARalpha function.

PML-RARalpha induces a block of hematopoietic differentiation and acute promyelocytic leukemia. This block is based on its capacity to inactivate target genes by recruiting histone deacetylase (HDAC) and DNA methyltransferase activities. Here we report that MBD1, a member of a conserved family of proteins able to bind methylated DNA, cooperates with PML-RARalpha in transcriptional repression and cellular transformation. PML-RARalpha recruits MBD1 to its target promoter through an HDAC3-mediated mechanism. Binding of HDAC3 and MBD1 is not confined to the promoter region but instead is spread over the locus. Knock-down of HDAC3 expression by RNA interference in acute promyelocytic leukemia cells alleviates PML-RAR-induced promoter silencing. We further demonstrate that retroviral expression of dominant-negative mutants of MBD1 in hematopoietic precursors compromises the ability of PML-RARalpha to block their differentiation and thus restored cell differentiation. Our results demonstrate that PML-RARalpha functions by recruiting an HDAC3-MBD1 complex that contributes to the establishment and maintenance of the silenced chromatin state.

Usefulness of BFB/EMG in facial palsy rehabilitation.

OBJECTIVE: To analyze and to compare the recovery and the development of synkinesis in patients with idiopathic facial palsy (Bell's palsy) following treatment with two methods of rehabilitation, kinesitherapy (KT) and biofeedback/EMG (BFB/EMG). STUDY DESIGN: Retrospective cases--series review. METHODS: Seventy-four patients with Bell' palsy were clinically evaluated within 1 month from onset of palsy and at 12 months after palsy (House scale and synkinesis evaluation). Electromyography (EMG) and Electroneurography (ENG) were performed about 4 weeks after palsy to better evaluate functional abnormalities due to facial nerve lesion. The patients followed two different protocols for rehabilitation: the first 32 patients were treated with therapeutic exercises performed by therapists (KT group), the latter 42 patients were treated using BFB/EMG methods (BFB group) with inhibition of synkinetic movement as the primary goal. RESULTS: KT and BFB patients were evaluated for clinical and neurophysiological characteristics before rehabilitative treatment. BFB patients showed better clinical recovery and minor synkinesis than KT patients. CONCLUSIONS: BFB/EMG seems to be more useful than KT in Bell's palsy treatment. This could be due to the fact that BFB/EMG gives more accurate information than KT on muscle activation with better modulation in voluntary recruitment of motor unit.