Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target?

Although the prognosis of patients with localized prostate cancer is good after surgery, with a favorable response to androgen deprivation therapy, about one third of them invariably relapse, and progress to castration-resistant prostate cancer. Overall, prostate cancer therapies remain scarcely effective, thus it is mandatory to devise alternative treatments enhancing the efficacy of surgical castration and hormone administration. Dysregulation of the phosphoinositide 3-kinase pathway has attracted growing attention in prostate cancer due to the highly frequent association of epigenetic and post-translational modifications as well as to genetic alterations of both phosphoinositide 3-kinase and PTEN to onset and/or progression of this malignancy, and to resistance to canonical androgen-deprivation therapy. Here we provide a summary of the biological functions of the major players of this cascade and their deregulation in prostate cancer, summarizing the results of preclinical and clinical studies with PI3K signaling inhibitors and the reasons of failure independent from genomic changes

Valores de referência para plumbemia em população urbana

INTRODUCTION: The lead reference values for blood used in Brazil come from studies conducted in other countries, where socioeconomic, clinical, nutritional and occupational conditions are significantly different. In order to guarantee an accurate biomonitoring of the population which is occupationally exposed to lead, a major health concern of the studied community, reference values for individuals who are not occupationally exposed and who live in the southern region of the city were established. MATERIAL AND METHOD: The sample was composed of 206 subjects of at least 15 years of age. Various strategies were employed to assure good-quality sampling. Subjects who presented values outside clinical or laboratory norms were excluded, as well as those whose specific activities might interfere with the results. RESULTS: Lead reference values for blood were found to be from 2.40 to 16.6 µg.dL-1, obtained by the interval ; ± 2s (where ; is the mean and s is the standard deviation form observed values) and the median was 7.9 µg.dL-1.INTRODUÇÃO: Os valores de referência utilizados no Brasil, para chumbo em sangue, advêm de estudos realizados em outros países onde as condições socioeconômicas, clínicas, nutricionais e ocupacionais diferem bastante das brasileiras. Para garantir uma correta biomonitorização da população ocupacionalmente exposta ao chumbo, um dos principais problemas identificados no município estudado, foram estabelecidos valores de referência na população não exposta ocupacionalmente da região sul do município. MATERIAL E MÉTODO: Diferentes estratégias foram utilizadas para assegurar a qualidade de amostragem, que foi dimensionada em 206 sujeitos acima de 15 anos. Sujeitos que apresentaram valores clínicos e laboratoriais fora da faixa de normalidade foram excluídos, bem como os que apresentaram atividades específicas que pudessem interferir nos valores de plumbemia. RESULTADOS: Foram encontrados valores de referência para chumbo em sangue de 2,4 a 16,6 mg.dL-1, obtidos através do intervalo ; ± 2s (onde ; é o valor médio e s é o desvio-padrão dos valores observados) e mediana = 7,9 µg.dL-1

Avaliação de espécies vegetais no controle de Meloidogyne incognita.

Avaliou-se, sob condições de telado, em vasos contendo solo infestado com Meloidogyne incognita sp., o efeito nematicida dos seguintes extratos e pôs vegetais: extrato etanólico de Cassia occidentalis (suspensao aquosa 4%), extrato etanólico de Chenopodium ambrosioides (suspensa o aquosa 2 e 4%), extrato clorofórmico de Ageratum conyzoides (suspensão aquosa 2 e 4%) e os respectivos pós das duas ultimas plantas em concentração de 6% (p/v), comparando-se com o efeito nematicida de Furadan 350 F a 1 e 4% do principio ativo e testemunha contendo apenas solo infestado. Foram feitas 5 repeticoes por tratamento e o delineamento experimental foi inteiramente casualizado. A avaliação constou de contagem do numero total de galhas do sistema radicular de tomateiros transplantados para os vasos, 35 dias apos o transplante. Os tratamentos que tiveram porcentagens de redução acima de 50%, em relação a testemunha, foram: extrato etanolítico de C. occidentalis (56,9%), extrato cloroformico de A. conyzoides 4% (57,5%), pó de A. conyzoides (59,6%), Furadan 350 F 4% P.A. (72,1%), extrato etanolíco de C. ambrosioides 4% (85%) e po de C. ambrosioides (100%)

Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: still a potential druggable target?

Although the prognosis of patients with localized prostate cancer is good after surgery, with a favorable response to androgen deprivation therapy, about one third of them invariably relapse, and progress to castration-resistant prostate cancer. Overall, prostate cancer therapies remain scarcely effective, thus it is mandatory to devise alternative treatments enhancing the efficacy of surgical castration and hormone administration. Dysregulation of the phosphoinositide 3-kinase pathway has attracted growing attention in prostate cancer due to the highly frequent association of epigenetic and post-translational modifications as well as to genetic alterations of both phosphoinositide 3-kinase and PTEN to onset and/or progression of this malignancy, and to resistance to canonical androgen-deprivation therapy.Here we provide a summary of the biological functions of the major players of this cascade and their deregulation in prostate cancer, summarizing the results of preclinical and clinical studies with PI3K signaling inhibitors and the reasons of failure independent from genomic changes

Influence of climate cycles on grapevine domestication and ancient migrations in Eurasia

The objective of this work is to investigate the Holocenic climate cycles that may have influenced the domestication of grapevine in the Subcaucasian area and its subsequent spread in Eurasia. The analysis covered the longitudinal belt ranging from the Iberian Peninsula to Japan, seen as the preferential pathway for the Holocenic spread of grapevine and many other crops in Eurasia. Spectral analysis was considered as the criterion of investigation and the Holocenic cycles were analyzed considering different geochemical and biological proxies, of which seven are directly referred to vine. In this context the relation of the abovementioned proxies with spectral peaks of possible causal factors like Solar activity (SA), North Atlantic oceanic factors (Atlantic Multidecadal Oscillation - AMO and North Atlantic Oscillation - NAO), and subtropical oceanic factors (El Nino Southern Oscillation - ENSO) was also analyzed. In order to acquire a sufficiently wide number of proxies sensitive to the causal factors, we referred to a latitudinal belt wider than the one colonized by vine, also acquiring proxy from the Scandinavian area, notoriously susceptible to North Atlantic forcings. The analysis of the proxy spectral peaks, considering 20 classes with a 50-years step in the 0\u20131000 years range, showed that the 50% of the classes have a higher frequency of peaks at East than West, the 20% a higher frequency at West than East and the 10% an equal frequency, showing the efficiency of the propagation of Western signals towards the center of Eurasia. The search of the causal factors spectral peaks in the proxy series showed that AMO, NAO and SA acted with a certain regularity on the entire belt investigated both latitudinally and longitudinally, while spectral peaks linked to ENSO underwent a considerable attenuation moving northward. Finally, the specific analysis on viticultural proxies showed common peaks with causal factors

Human Neuromuscular Junction on a Chip: Impact of Amniotic Fluid Stem Cell Extracellular Vesicles on Muscle Atrophy and NMJ Integrity

Neuromuscular junctions (NMJs) are specialized synapses, crucial for the communication between spinal motor neurons (MNs) and skeletal muscle. NMJs become vulnerable in degenerative diseases, such as muscle atrophy, where the crosstalk between the different cell populations fails, and the regenerative ability of the entire tissue is hampered. How skeletal muscle sends retrograde signals to MNs through NMJs represents an intriguing field of research, and the role of oxidative stress and its sources remain poorly understood. Recent works demonstrate the myofiber regeneration potential of stem cells, including amniotic fluid stem cells (AFSC), and secreted extracellular vesicles (EVs) as cell-free therapy. To study NMJ perturbations during muscle atrophy, we generated an MN/myotube co-culture system through XonaTM microfluidic devices, and muscle atrophy was induced in vitro by Dexamethasone (Dexa). After atrophy induction, we treated muscle and MN compartments with AFSC-derived EVs (AFSC-EVs) to investigate their regenerative and anti-oxidative potential in counteracting NMJ alterations. We found that the presence of EVs reduced morphological and functional in vitro defects induced by Dexa. Interestingly, oxidative stress, occurring in atrophic myotubes and thus involving neurites as well, was prevented by EV treatment. Here, we provided and validated a fluidically isolated system represented by microfluidic devices for studying human MN and myotube interactions in healthy and Dexa-induced atrophic conditions—allowing the isolation of subcellular compartments for region-specific analyses—and demonstrated the efficacy of AFSC-EVs in counteracting NMJ perturbations