Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations

Paixão pelo Exercício

A realização regular de exercício físico traz diversos benefícios à saúde física e psicológica dos praticantes, inclusive, podendo contribuir com seus níveis de bem-estar subjetivo. A paixão tem função fundamental no engajamento e manutenção destas práticas por longos períodos. Este estudo objetivou estimar evidências de validade da Escala de Paixão pelo Exercício com base na estrutura interna e relação com variáveis externas, afeto positivo e negativo. As análises fatoriais exploratória (amostra 1, N = 460 adultos da população geral praticantes de exercício físico) e confirmatória (amostra 2, N = 333 adultos da população geral praticantes de exercício físico) sugeriram adequação das duas dimensões da paixão, harmoniosa e obsessiva. A análise fatorial confirmatória multigrupo indicou a invariância forte do instrumento em função do sexo dos praticantes. Por meio da Modelagem de Equações Estruturais, verificou-se associação positiva da paixão harmoniosa com afeto positivo e associação negativa com afeto negativo experienciados durante a prática de exercício; em contraste, foi observada associação positiva entre paixão obsessiva e afeto negativo durante tal prática. Estes são indicativos de que não só a prática constante de atividades físicas impacta os níveis de felicidade dos sujeitos, mas também o tipo de relação que estabelecem com o exercício

Vivenciando a pandemia em uma unidade de saúde De Porto Alegre/RS: atendimento ao COVID-19 no primeiro trimestre de 2021 / Experiencing the pandemic in a healthcare facility in Porto Alegre/RS: COVID-19 care in the first quarter of 2021

O avanço da pandemia por COVID-19 exigiu uma reorganização na estrutura de atendimento dos serviços de saúde, principalmente, na atenção primária, que é umas das principais portas de entrada da rede assistencial. Este trabalho teve como objetivo relatar a trajetória crescente de atendimento dos usuários sintomáticos respiratórios, bem como seus contatos domiciliares e de trabalho, em uma unidade de saúde do município de Porto Alegre/RS no primeiro trimestre de 2021. Em janeiro de 2021, a unidade atendeu em média 19,75 (± 2,69) indivíduos com sintomas gripais, suspeitos e contactantes domiciliares ou de trabalho de pessoas infectadas pelo coronavírus, por semana. Durante o mês de fevereiro a média semanal foi de aproximadamente 21,75 (± 11,43) casos atendidos. Em março, a unidade teve a maior média semanal: 69 pessoas (± 19,71). A partir do dia 22/03/21 o número de atendimentos voltou a regredir, chegando a 42 atendimentos na semana. Espera-se, que com o decorrer da pandemia, a conscientização da população acerca das orientações de prevenção e importância da vacinação, a contaminação pelo SARS-CoV-2 seja abrandada, reduzindo a sobrecarga do sistema de saúde e da atenção primária, e consequentemente, refletindo em melhores resultados referentes ao cuidado em saúde da população

Enfisema pulmunar: aspectos fisiopatológicos e sua associação com o tabagismo

O tabagismo é um tema de preocupação global para a saúde, pois a inalação recorrente das substâncias tóxicas liberadas pelo cigarro é uma das principais causas de doenças pulmonares obstrutivas crônicas (DPOC). Nesse grupo de enfermidades, encontra-se o enfisema, patologia respiratória em que há redução da elasticidade do tecido pulmonar associada a destruição dos alvéolos, resultando em uma gradual perda da capacidade respiratória, sem que haja prognóstico de reversão ou melhora do quadro. Este artigo pretende fornecer uma revisão de literatura sobre a influência das toxinas do tabaco no desenvolvimento do enfisema pulmonar, bem como sua patogênese e epidemiologia. Portanto, foi realizada uma busca por artigos científicos nas bases de dados: US National Library of Medicine (PubMed), Scientific Electronic Library Online (SciELO), Medical Literature Analysis and Retrieval System Online (MEDLINE) e Literatura Latino-Americana em Ciências da Saúde (LILACS)

Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma

This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabine (2′-2′-difluorodeoxycitidine) infusion with circulating haemopoietic progenitor support and to evaluate the activity of the treatment. Secondary end points were pharmacokinetic of gemcitabine and difluorodeoxyuridina (dFdU) measured at first course and the activity andexpression profile of cytidine deaminase (CdA) on circulating mononuclear cells. Patients with advanced pancreatic carcinoma received escalating dose of gemcitabine 10 mg m−2 min−1 every 2 weeks with circulating haemopoietic progenitor support. First dose level was 3000 mg m−2 and the doses were increased by 500 mg m−2 until MTD. In all, 23 patients were enrolled. Toxicities were mild or moderate; the only patient treated at 7000 mg m−2 died because of toxicity; therefore; the MTD was established at 6500 mg m−2. The overall response rate was 22.2%. The AUC of gemcitabine showed a dose-dependent increase, while the AUC of dFdU reached a plateau at 4500 mg m−2. A significant relationship was found between the AUC of dFdU and CdA expression and activity (P<0.05). Moreover, progression rate and survival were significantly related to CdA expression and activity levels. The activity of high-dose gemcitabine is not superior to that reported with less intensive FDR schedules. The predictive role of CdA expression and activity on outcome deserves further investigation

Current status of haploidentical stem cell transplantation for leukemia

Haploidentical hematopoietic stem cell transplantation has made tremendous progress over the past 20 years and has become a feasible option for leukemia patients without a HLA identical sibling donor. The early complications of severe graft-versus-host disease (GVHD), graft failure and delayed engraftment, as well as disease recurrence have limited the use of this approach. Newer strategies have been applied and overcome some of the problems, including the use of T-cell depleted graft, "mega" dose of stem cells, intensive post-transplant immunosuppression and manipulation of the graft. These have decreased the transplant related mortality and GVHD associated with haploidentical transplantation, however, the major problems of disease relapse and infection, which related to late immune reconstitution, limit the development of haploidentical HSCT. Future challenges remain in improving post-transplant immune reconstitution and finding the best approach to reduce the incidence and severity of GVHD, while preserving graft-versus-leukemia effect to prevent the recurrence of underlying malignancy

Allogeneic hematopoietic stem cell transplantation in China: where we are and where to go

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective and sometimes the only curative therapy for patients with certain hematological diseases. Allo-HSCT has been practiced in China for approximately 30 years, and great improvements have been made within the past decade, particularly in fields such as the haploidentical HSCT system, strategies to overcome relapse and GVHD, and modified HSCT for elderly patients. This review will describe the current situation and provide a prospective of these unique aspects of Allo-HSCT in China

Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer