Antitumor activity of a small-molecule inhibitor of the histone kinase Haspin

The approval of histone deacetylase inhibitors for treatment of lymphoma subtypes has positioned histone modifications as potential targets for the development of new classes of anticancer drugs. Histones also undergo phosphorylation events, and Haspin is a protein kinase the only known target of which is phosphorylation of histone H3 at Thr3 residue (H3T3ph), which is necessary for mitosis progression. Mitotic kinases can be blocked by small drugs and several clinical trials are underway with these agents. As occurs with Aurora kinase inhibitors, Haspin might be an optimal candidate for the pharmacological development of these compounds. A high-throughput screening for Haspin inhibitors identified the CHR-6494 compound as being one promising such agent. We demonstrate that CHR-6494 reduces H3T3ph levels in a dose-dependent manner and causes a mitotic catastrophe characterized by metaphase misalignment, spindle abnormalities and centrosome amplification. From the cellular standpoint, the identified small-molecule Haspin inhibitor causes arrest in G2/M and subsequently apoptosis. Importantly, ex vivo assays also demonstrate its anti-angiogenetic features; in vivo, it shows antitumor potential in xenografted nude mice without any observed toxicity. Thus, CHR-6494 is a first-in-class Haspin inhibitor with a wide spectrum of anticancer effects that merits further preclinical research as a new member of the family of mitotic kinase inhibitors

A Modern View on the Red Sea Rift: Tectonics, Volcanism and Salt Blankets

Continental rifting and ocean basin formation can be observed at the present day in the Red Sea, which is used as the modern analogue for the formation of mid-ocean ridges. Competing theories for how spreading begins—either by quasi-instantaneous formation of a whole spreading segment or by initiation of spreading at multiple discrete “nodes” separated by thinned continental lithosphere—have been put forward based, until recently, on the observations that many seafloor features and geophysical anomalies (gravity, magnetics) along the axis of the Red Sea appeared anomalous compared to ancient and modern examples of ocean basins in other parts of the world. The latest research shows, however, that most of the differences between the Red Sea Rift (RSR) and other (ultra)slow-spreading mid-ocean ridges can be related to its relatively young age and the presence and movement of giant submarine salt flows that blanket large portions of the rift valley. In addition, the geophysical data that was previously used to support the presence of continental crust between the axial basins with outcropping oceanic crust (formerly named “spreading nodes”) can be equally well explained by processes related to the sedimentary blanketing and hydrothermal alteration. The observed spreading nodes are not separated from one another by tectonic boundaries but rather represent “windows” onto a continuous spreading axis which is locally inundated and masked by massive slumping of sediments or evaporites from the rift flanks. Volcanic and tectonic morphologies are comparable to those observed along slow and ultra-slow spreading ridges elsewhere and regional systematics of volcanic occurrences are related to variations in volcanic activity and mantle heat flow. Melt-salt interaction due to salt flows, that locally cover the active spreading segments, and the absence of large detachment faults as a result of the nearby Afar plume are unique features of the RSR. The differences and anomalies seen in the Red Sea still may be applicable to all young oceanic rifts, associated with plumes and/or evaporites, which makes the Red Sea a unique but highly relevant type example for the initiation of slow rifting and seafloor spreading and one of the most interesting targets for future ocean research

Trauma & the reproductive lifecycle in women Trauma e o ciclo reprodutivo feminino

Women are at significantly higher risk for developing post-traumatic stress disorder (PTSD) than men, resulting in increased psychosocial burden and healthcare related costs. Recent research has shown complex interactions between the impact of traumatic experiences, and the reproductive lifecycle in women. For example, women suffering from premenstrual dysphoric disorder (PMDD) who also report a history of sexual or physical abuse are more likely to present with different neuroendocrine reactivity to stressors, when compared to premenstrual dysphoric disorder subjects without prior history of trauma or abuse or non-premenstrual dysphoric disorder subjects. In addition, women with a history of abuse or trauma may experience re-emergence of symptoms during pregnancy. Lastly, females who experience miscarriage may present with even higher prevalence rates of post-traumatic stress disorder symptoms. In this manuscript we examine the existing data on gender differences in post-traumatic stress disorder, with particular focus on psychological and physiological factors that might be relevant to the development of symptoms after exposure to traumatic events associated with the reproductive life cycle. Current options available for the treatment of such symptoms, including group and counselling therapies and debriefing are critically reviewed.<br>Mulheres estão sujeitas a um maior risco para o desenvolvimento de transtorno de estresse pós-traumático (TEPT) do que os homens, o que acarreta prejuízos e custos significativos do ponto de vista psicossocial e de saúde pública. Estudos recentes mostram interações complexas entre o impacto de experiências traumáticas e o ciclo reprodutivo feminino. Por exemplo, mulheres com transtorno disfórico pré-menstrual (TDPM), que também relatam histórico de trauma ou abuso físico, estão mais sujeitas a apresentar uma resposta neuroendócrina diferenciada após exposição a um fator ou evento estressante, quando comparadas a mulheres com TDPM e sem história de abuso ou mulheres sem TDPM. Além disso, mulheres com histórico de trauma ou abuso podem apresentar recidiva de sintomas durante a gravidez. Por fim, aquelas que sofrem abortamento estão mais sujeitas ao desenvolvimento de sintomas do transtorno de estresse pós-traumático. Neste artigo, examinamos os dados existentes sobre diferenças de gênero e transtorno de estresse pós-traumático, com enfoque especial nos fatores psicológicos e fisiológicos mais relevantes para o surgimento de sintomas após exposição a eventos traumáticos relacionados ao ciclo reprodutivo feminino. Opções terapêuticas existentes são criticamente revistas, incluído terapias de aconselhamento e a técnica de debriefing psicológico