Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches

The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/ susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes.We would like to acknowledge Dr. Agostinho Carvalho and Dr. Manuel Guerreiro (Hospital da Arrabida, Vila Nova de Gaia, Portugal) for the critical review and discussion of the manuscript and for the work support. This work was supported by FCT - Fundacao para a Ciencia e Tecnologia (PTDC/BIA-MIC/114116/2009). A.F., O.P. and B.S.M. have fellowships from FCT (SFRH/BD/51991/2012, SFRH/BD/52292/2013, and SFRH/BPD/90533/2012, respectively). M.M.A. was supported by CCDR-N (QREN) in the scope of the project "Integration of cutting-edge health science research and ground-breaking technologies for the development of new clinically useful therapies, tissue regeneration strategies, advanced prophylactic measures and diagnosis methods - (N-01-01-01-24-01-07) - RL5" (UMINHO/BI/245/2013)

Death due to bicycle accidents in the northeast region of Brazil

Objective: To evaluate the death prevalence due to bicycle accidents in the northeast region of Brazil between 2001 and 2010. Methodology: This study was conducted with a descriptive quantitative and analytical approach through secondary data. The sample consisted of all Death Certificates (DC) registered over the Mortality Information System (MIS) of the Unified Health System Data Base that reported bicycle accidents between 2001 and 2010. Descriptive measures were determined to all variables. The sociodemographic variables were intersected with the basic cause of death to search a statistical correlation. Results: Over the considered period of time, 2763 Death Certificates were brought up, where the deaths that occurred over the northeast region of Brazil were due to bicycle accidents, being evidenced a higher frequency to men, between 25-39 and 40-59 years old, with brown skin color, single and with 1-3 scholarity years. The victims mean age was 38,49 (DP = 18,322). Conclusion: The increase in the numbers of fatal bicycle accidents show that a restructuration of the traffic infrastructure is needed, an increase on the cycling paths offer and effective legal changes to the reduction of this kind of accident.Objetivo: Evaluar la prevalencia de la mortalidad por accidentes de bicicletas en el Nordeste entre 2001 y 2010. Metodología: Este estudio se realizó en un enfoque cuantitativo descriptivo y analítico a través de datos secundarios. La muestra estuvo constituida por todas las declaraciones de la Muerte (DO) registrados en el Sistema de Informaciones sobre Mortalidad (SIM), Base de datos del Sistema Nacional de Salud (DATASUS), quienes reportaron accidentes de bicicleta entre 2001 y 2010. Medidas descriptivas fueron determinadas para todas las variables. Las variables sociodemográficas se cruzaron con la causa básica de defunción en busca de correlación estadística. Resultados: En el período que se examina se plantearon 2.763 declaraciones de muertes en las que ocurrieron en el noreste de Brasil se debieron a accidentes de bicicleta, lo que evidencia una mayor frecuencia en el sexo masculino, entre los 25-59 años, marrón, único y escolaridad 1-3 años. La edad promedio de las víctimas era 38,49 años (DE = 18.322). Conclusiones: El aumento en el número de accidentes mortales con señales bicicleta a la necesaria mejora de la infraestructura de transporte, el aumento de la oferta de ciclos de punto y los cambios legales eficaces para reducir este tipo de accidentes

The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics.

ABSTRACT: A global genome database of all of Earth’s species diversity could be a treasure trove of scientific discoveries. However, regardless of the major advances in genome sequencing technologies, only a tiny fraction of species have genomic information available. To contribute to a more complete planetary genomic database, scientists and institutions across the world have united under the Earth BioGenome Project (EBP), which plans to sequence and assemble high-quality reference genomes for all ∼1.5 million recognized eukaryotic species through a stepwise phased approach. As the initiative transitions into Phase II, where 150,000 species are to be sequenced in just four years, worldwide participation in the project will be fundamental to success. As the European node of the EBP, the European Reference Genome Atlas (ERGA) seeks to implement a new decentralised, accessible, equitable and inclusive model for producing high-quality reference genomes, which will inform EBP as it scales. To embark on this mission, ERGA launched a Pilot Project to establish a network across Europe to develop and test the first infrastructure of its kind for the coordinated and distributed reference genome production on 98 European eukaryotic species from sample providers across 33 European countries. Here we outline the process and challenges faced during the development of a pilot infrastructure for the production of reference genome resources, and explore the effectiveness of this approach in terms of high-quality reference genome production, considering also equity and inclusion. The outcomes and lessons learned during this pilot provide a solid foundation for ERGA while offering key learnings to other transnational and national genomic resource projects.info:eu-repo/semantics/publishedVersio

Práticas artísticas no ensino básico e secundário

A matéria-prima de que trata esta revista é base de trabalho para um ensino artístico alargado, estendendo-se fora dos limites da aula, transgredindo os limites formais dos curricula, implicando património e riqueza cultural, sensibilizando para o imaterial, criando públicos apreciadores e também agentes criadores. É toda uma comunidade que se interliga através dos valores imateriais que sempre foram os da arte. A tarefa do educador é muito alargada: exige-se que esteja à altura deste desígnio humanista, que é também um desafio ao destino da humanidade: pela educação artística constroem-se futuros, e sem arte há intolerância, materialismo, indiferença, alienação, morte. Os tempos que se vivem são exigentes. As questões da pós modernidade estão muito acesas, desde as que nos obrigam ao desassossego, como a sustentabilidade e a poluição, como as que nos implicam politicamente, como a justiça, os direitos civis, a desigualdade. Tudo isto é matéria com a qual se amassa um barro que pode ser mais ou menos criativo: trata-se de extrair a matéria-prima com que se pode fazer os blocos que constroem o futuro. Aos profissionais da educação e do ensino, esta consciência, ao mesmo tempo desamparada – os cortes da economia neoliberal transformaram a arte em indústria, e a sua educação em criação de consumidores – e ao mesmo tempo vigilante e interventiva. Os artigos que responderam a esta chamada, respondem, cada um a seu modo, a este desassossego, a este desconforto, a este mal-estar contemporâneo. Dispuseram-se segundo uma sequência que se articula com base em temas afins que se podem descrever sucintamente: Todos os que participaram neste número mostraram a sua matéria-prima, a sua reação à falta que a arte nos faz. A chamada soa, e ressoa, e é necessário que seja por todos ouvida, em todos os países. É simples: as artes estão em perigo. Perigo porque há menos horas, menos professores, menos opções, menos conhecimento. As reduções no horário, a eliminação de disciplinas tão importantes como a história da arte, fazem de cada professor um agente da resistência, um ser mais implicado na sobrevivência da chama da criação. Matéria-prima: matéria para resgatar a verdade humana, a arte, a expressão mais valiosa da sua vaidade. Resgatar o homem que Michel Foucault (1988: 412) vê ameaçado, como um rosto na areia, desenhado à beira-mar.info:eu-repo/semantics/publishedVersio

Diretriz Brasileira sobre a Saúde Cardiovascular no Climatério e na Menopausa – 2024

Women, who represent approximately half of the global population according to estimates as of January 2024, may experience signs and symptoms of menopause for at least one-third of their lives, during which they have a higher risk of cardiovascular morbidity and mortality. The effects of menopausal hormone therapy (MHT) on the progression of atherosclerosis and cardiovascular disease (CVD) events vary depending on the age at which MHT is initiated and the time since menopause until its initiation. Beneficial effects on CVD outcomes and all-cause mortality have been observed when MHT was initiated before the age of 60 or within 10 years after menopause. The decision regarding the initiation, dose, regimen, and duration of MHT should be made individually after discussing the benefits and risks with each patient. For primary prevention of postmenopausal chronic conditions, the combined use of estrogen and progestogen is not recommended in asymptomatic women, nor is the use of estrogen alone in hysterectomized women. Hormone-dependent neoplasms contraindicate MHT. For the treatment of genitourinary syndrome of menopause, vaginal estrogen therapy may be used in patients with known cardiovascular risk factors or established CVD. For women with contraindications to MHT or who refuse it, non-hormonal therapies with proven efficacy (antidepressants, gabapentin, and fezolinetant) may improve vasomotor symptoms. Compounded hormonal implants, or "bioidentical" and "compounded" hormones, and "hormone modulation" are not recommended due to lack of scientific evidence of their effectiveness and safety.Mujeres, que representan aproximadamente la mitad de la población mundial según estimaciones de enero de 2024, pueden experimentar signos y síntomas de la menopausia durante al menos un tercio de sus vidas, durante los cuales tienen un mayor riesgo de morbilidad y mortalidad cardiovascular. Los efectos de la terapia hormonal de la menopausia (THM) en la progresión de la aterosclerosis y los eventos de enfermedad cardiovascular (ECV) varían según la edad en que se inicia la THM y el tiempo transcurrido desde la menopausia hasta su inicio. Se han observado efectos beneficiosos en los resultados de ECV y la mortalidad por todas las causas cuando la THM se inició antes de los 60 años o dentro de los 10 años posteriores a la menopausia. La decisión sobre la iniciación, dosis, régimen y duración de la THM debe tomarse individualmente después de discutir los beneficios y riesgos con cada paciente. Para la prevención primaria de condiciones crónicas en la posmenopausia, no se recomienda el uso combinado de estrógeno y progestágeno en mujeres asintomáticas, ni el uso de estrógeno solo en mujeres histerectomizadas. Las neoplasias dependientes de hormonas contraindican la THM. Para el tratamiento del síndrome genitourinario de la menopausia, se puede usar terapia estrogénica vaginal en pacientes con factores de riesgo cardiovascular conocidos o ECV establecida. Para mujeres con contraindicaciones a la THM o que la rechazan, las terapias no hormonales con eficacia demostrada (antidepresivos, gabapentina y fezolinetant) pueden mejorar los síntomas vasomotores. Los implantes hormonales compuestos, o hormonas "bioidénticas" y "compuestas", y la "modulación hormonal" no se recomiendan debido a la falta de evidencia científica sobre su efectividad y seguridad.As mulheres, que representam cerca de metade da população mundial segundo estimativas de janeiro de 2024, podem sofrer com sinais e sintomas da menopausa durante pelo menos um terço de suas vidas, quando apresentam maiores risco e morbimortalidade cardiovasculares. Os efeitos da terapia hormonal da menopausa (THM) na progressão de eventos de aterosclerose e doença cardiovascular (DCV) variam de acordo com a idade em que a THM é iniciada e o tempo desde a menopausa até esse início. Efeitos benéficos nos resultados de DCV e na mortalidade por todas as causas ocorreram quando a THM foi iniciada antes dos 60 anos de idade ou nos 10 anos que se seguiram à menopausa. A decisão sobre o início, a dose, o regime e a duração da THM deve ser tomada individualmente após discussão sobre benefícios e riscos com cada paciente. Para a prevenção primária de condições crônicas na pós-menopausa, não se recomendam o uso combinado de estrogênio e progestagênio em mulheres assintomáticas nem o uso de estrogênio sozinho em mulheres histerectomizadas. Neoplasias hormônio-dependentes contraindicam a THM. Para tratamento da síndrome geniturinária da menopausa, pode-se utilizar terapia estrogênica por via vaginal em pacientes com fatores de risco cardiovascular conhecidos ou DCV estabelecida. Para mulheres com contraindicação à THM ou que a recusam, terapias não hormonais com eficácia comprovada (antidepressivos, gabapentina e fezolinetante) podem melhorar os sintomas vasomotores. Os implantes hormonais manipulados, ou hormônios “bioidênticos” “manipulados”, e a ‘modulação hormonal’ não são recomendados pela falta de evidência científica de sua eficácia e segurança

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Splanchnic non-hepatic hemodynamics and metabolism during liver transplantation

Background/Aims: The aim of this study is to compare the splanchnic non-hepatic hemodynamics and the metabolic changes during orthotopic liver transplantation between the conventional with bypass and the piggyback methods. Methodology: A prospective, consecutive series of 59 primary transplants were analyzed. Oxygen consumption, glucose, potassium, and lactate metabolism were quantitatively estimated from blood samples from the radial artery and portal vein, collected up to 120 minutes after graft reperfusion. Mean arterial pressure, portal venous pressure, portal venous blood flow, and splanchnic vascular resistance were also measured or calculated at postreperfusion collection times. Results: There was a greater increase in portal venous blood flow (p=0.05) and lower splanchnic vascular resistance (p=0.04) in the piggyback group. Mean arterial pressure and portal venous pressure were similar for both groups. Oxygen, glucose and potassium consumption were higher in the piggyback group, but none of the metabolic parameters differed significantly between groups. Conclusions: In conclusion, the study detected a higher portal venous blood flow and a lower and splanchnic vascular resistance associated with the piggyback technique. After graft reperfusion, no difference in the splanchnic non-hepatic metabolic parameters was observed between the conventional with bypass and the piggyback methods of orthotopic liver transplantation