Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib

BACKGROUND: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P =.013), Role Functioning (P =.004), and Fatigue (P <.001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P =.005). CONCLUSIONS: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society

Percentage of use of instruments in surgical procedures / Percentual de utilização de instrumentais em procedimentos cirúrgicos

Objective: to analyze the percentage of surgical instruments that make up the operating laparotomy box and are not used during surgeries. Method: descriptive, cross-sectional study with quantitative approach, which counted instrumental constituents of the exploratory laparotomy box used and not used during 13 surgeries performed in a period of 17 days, in a hospital in the interior of São Paulo. Results: in the 13 surgeries analyzed, a total of 1300 (100%) tweezers were obtained in the boxes, where 832 (64%) were not used and 468 (36%) were used. In surgical times, the highest number of use was 166 (35.5%) articles, for seizures and reparators. Conclusion: there were 64% of instruments not used in the analyzed surgeries. There is a need to implement management strategies that reduce the numbers found and, consequently, reduce expenses, to generate less waste and reduce failures in the management of material resources.Objetivo: analizar el porcentaje de instrumentos quirúrgicos que componen la caja de laparotomía quirúrgica y no se utilizan durante las cirugías. Método: estudio descriptivo, transversal con enfoque cuantitativo, que contó constituyentes instrumentales de la caja de laparotomía exploratoria utilizada y no utilizada durante 13 cirugías realizadas en un período de 17 días, en un hospital del interior de São Paulo. Resultados: en las 13 cirugías analizadas, se obtuvieron un total de 1300 (100%) pinzas en las cajas, donde no se utilizaron 832 (64%) y 468 (36%). En tiempos quirúrgicos, el mayor número de uso fue de 166 (35,5%) artículos, para convulsiones y reparadores. Conclusión: hubieran 64% de instrumentos no utilizados en las quirurgias analizadas. Es necesario implementar estrategias de gestión que reduzcan los números encontrados y, en consecuencia, reduzcan los gastos, para generar menos residuos y reducir las fallas en la gestión de los recursos materiales.Objetivo: analisar o percentual de instrumentais cirúrgicos que compõem a caixa de laparotomia exploradora e não são utilizados durante as cirurgias. Método: estudo descritivo, transversal com abordagem quantitativa, que contabilizou instrumentais constituintes da caixa de laparotomia exploradora utilizados e não utilizados durante 13 cirurgias realizadas em um período de 17 dias, em um hospital do interior paulista. Resultados: nas 13 cirurgias analisadas, obteve-se um total de 1300 (100%) pinças presentes nas caixas, onde 832 (64%) não foram utilizadas e 468 (36%) foram utilizadas. Nos tempos cirúrgicos, o maior número de uso foi de 166 (35,5%) artigos, para preensão e afastadores. Conclusão: houve 64% de instrumentais não utilizados nas cirurgias analisadas. Há necessidade de implementar estratégias gerenciais que reduzam os números encontrados e, consequentemente, reduzam gastos, para gerar menor desperdício e reduzir falhas no gerenciamento de recursos materiais.

Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a "real-life" setting. We retrospectively analyzed 163 patients receiving dasatinib (n= 95) or nilotinib (n= 68) as second-line therapy after imatinib. The two cohorts were comparable for disease's characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients. Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib. In a "real-life" setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation

Immunotherapy approaches to treat adult acute lymphoblastic leukemia

Recent developments in immunotherapy are improving treatment results of B-precursor acute lymphoblastic leukemia. This advancement is promoted by new monoclonal antibodies such as inotuzumab ozogamicin, ofatumumab and blinatumomab, by rituximab, and by genetically engineered chimeric antigen receptor-modified T-cells. These treatments, variously targeting CD22, CD20 and CD19 antigens, yield unprecedented high rates of hematologic and molecular remissions even when used in monotherapy and in chemo-resistant or post-transplantation relapsed patients. Beside the encouraging results in relapsed/refractory disease, these agents may open a totally new era in the frontline management of this illness, redefining treatment standards and options for different risk subsets and placing the achievement of a molecular remission at the forefront of treatment objectives. The ever increasing importance of modern immunotherapy in improving treatment design and therapeutic outcome is reviewed

The preservation and a risk plano of Unesco cultural heritage

WAR FREE WORLD HERITAGE LISTED CITIES project was designed and financed within the framework of the EU CIUDAD program. It is an international cooperation project focused on urban and regional planning for cities that are registered in the World Heritage List and located in critical areas being exposed to the threats of conflicts and natural hazards such as earthquakes or flood. As case studies, Risk Preparedness Plans and Risk Mitigation measures have been defined for Byblos (Lebanon) and Mtskheta (Georgia) in order to create the required conditions for both cities to be candidates for enhanced protection status to UNESCO and will be presented in this work, for applications to other UNESCO sites at risk

An European Project for the Preservation of UNESCO Cultural Heritage

Relazione sullo svolgimento del progetto ENPI CIUDAD "War Free World Heritage Listed Cities", volto a fornire alla città di Mtskheta (Georgia) gli strumenti per favorire una corretta gestione del sito UNESCO "Historical Buildings of Mtskheta" e permettere così l'uscita dalla lista del patrimonio a rischio e l'entrata nella lista del patrimonio a protezione rafforzata