Maximizing Anticancer Response with MPS1 and CENPE Inhibition Alongside Apoptosis Induction.

Antimitotic compounds, targeting key spindle assembly checkpoint (SAC) components (e.g., MPS1, Aurora kinase B, PLK1, KLP1, CENPE), are potential alternatives to microtubule-targeting antimitotic agents (e.g., paclitaxel) to circumvent resistance and side effects associated with their use. They can be classified into mitotic blockers, causing SAC-induced mitotic arrest, or mitotic drivers, pushing cells through aberrant mitosis by overriding SAC. These drugs, although advancing to clinical trials, exhibit unsatisfactory cancer treatment outcomes as monotherapy, probably due to variable cell fate responses driven by cyclin B degradation and apoptosis signal accumulation networks. We investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic navitoclax in lung cancer cells treated with the selective CENPE inhibitor GSK923295 (mitotic blocker) or the MPS1 inhibitor BAY1217389 (mitotic driver). Our aim was to steer treated cancer cells towards cell death. BH3-mimetics, in combination with both mitotic blockers and drivers, induced substantial cell death, mainly through apoptosis, in 2D and 3D cultures. Crucially, these synergistic concentrations were less toxic to non-tumor cells. This highlights the significance of combining BH3-mimetics with antimitotics, either blockers or drivers, which have reached the clinical trial phase, to enhance their effectiveness.

Blockade of protease-activated receptor 2 attenuates allergenmediated acute lung inflammation and leukocyte recruitment in mice.

Protease-activated receptor (PAR)2 has been implicated in mediating allergic airway inflammation.We investigate the role of PAR2 in lung inflammation and neutrophil and eosinophil recruitment into the lungs in amousemodel of shortterm acute allergic inflammation. Allergic lung inflammation was induced in sensitized BALB/c mice through intranasal instillations of ovalbumin (OVA), and mice were pretreated with the PAR2 antagonist ENMD1068 or with the PAR2-activating peptide (PAR2-AP) 1 hour before each OVA challenge. Bronchoalveolar lavage fluid (BALF) was collected, and the lungs, trachea and lymph nodes were removed after the last challenge to analyze the airway inflammation. PAR2 blockade reduced OVA-induced eosinophil and neutrophil counts, CXCL1, CCL5, amphiregulin, and interleukin (IL)-6 and 13 levels.Moreover, PAR2 blockade reduced OVA-induced PAR2 expression in cells present in BALF 2 hour after OVA challenge, and PAR2-AP acted synergistically with OVA promoting eosinophil recruitment intoBALF and increased IL-4 and IL-13 levels in lymph nodes. Conversely, PAR2 blockade increased IL- 10 levels when compared with OVA-treated mice. Our results provide evidence for a mechanism by which PAR2 meditates acute lung inflammation triggered by multiple exposures to allergen through a modulatory role on cytokine production and vascular permeability implicated in the lung diseases such as asthma.

Caracterização da pressão da língua em idosos / Characterization of tongue pressure in the elderly

Objetivo Caracterizar a pressão da língua em idosos. Métodos Estudo transversal, com a participação de 45 idosos, de 61 a 96 anos, sendo 34 (75,6%) do gênero feminino e 11 (24,4%) do masculino, sem distúrbios neurológicos e cognitivos, sem histórico de câncer de cabeça e pescoço e de procedimento radioterápico. Consistiu na aplicação de questionário, com registro da presença ou ausência de queixa de problemas na deglutição, seguido da avaliação miofuncional orofacial, enfocando a mobilidade e tensão de língua. Para a mensuração da pressão da língua, foi utilizado o Iowa Oral Performance Instrument (IOPI). A análise dos dados foi descritiva, com nível de significância de 5%. Resultados A média do pico pressórico foi de 44,6 KPa (±16), com os valores mínimo e máximo entre 9 e 88 KPa. Houve correlação moderada negativa entre pico pressórico e idade. Os longevos apresentaram a menor média de pico pressórico e inferior ao padrão de normalidade. Houve diferença entre a média de pico pressórico e uso de próteses, tensão de língua e mobilidade de língua no estalo. Conclusão Houve diminuição moderada do pico pressórico da língua com o aumento da idade e redução pressórica com o decréscimo da tensão da língua e de sua mobilidade no estalo. Em contrapartida, os valores de pico foram maiores nos idosos que utilizam próteses dentárias, quando comparados aos que destas não fazem uso. .

Purpose To characterize tongue pressure in elderly individuals. Methods This was a cross-sectional study involving 45 individuals aged between 61 and 96 years old (34 [75.6%] women; 11 [24.4%] men) with no neurological or cognitive disorders, no history of head or neck cancer, and no history of radiotherapy. The subjects were surveyed with a questionnaire that recorded the presence or absence of complaints about swallowing problems and an orofacial myofunctional evaluation, which examined the movement and tension of the tongue. The Iowa Oral Performance Instrument (IOPI) was used to measure tongue pressure. The data analysis was descriptive, with significance set at the 5% level. Results The mean pressure peak was 44.6 kPa (±16), with minimum and maximum values of 9 and 88 kPa, respectively. Pressure peak and age were moderately and negatively correlated. The oldest subject had the lowest average pressure peak, which was less than the normal range. The mean pressure peak differed according to the use of dentures, tongue pressure, and tongue mobility during clicking. Conclusion The pressure peak and the pressure of the tongue decreased moderately with increasing age, decreasing tongue tension, and mobility during clicking. In contrast, the pressure peak values were higher in the elderly who used dentures than those who did not. .

Blockade of proteinase-activated receptor 4 inhibits neutrophil recruitment in experimental inflammation in mice.

OBJECTIVE AND DESIGN: The activation of proteinase-activated receptors (PARs) has been implicated in the development of important hallmarks of inflammation, including in vivo leukocyte recruitment; however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Here, we examined the effects of the PAR4 antagonist YPGKF-NH 2 (tcY-NH2) on neutrophil recruitment in experimentally induced inflammation. METHODS: BALB/c mice were intrapleurally injected with tcY-NH2 (40 ng/kg) prior to intrapleural injection of carrageenan (Cg) or neutrophil chemoattractant CXCL8; the number of infiltrating neutrophils was evaluated after 4 h, and KC production was assessed at different times after Cg injection. Neutrophil adhesion and rolling cells were studied using a brain circulation preparation 4 h after the Cg or CXCL8 challenge in tcY-NH2-treated mice. RESULTS: PAR4 blockade inhibited CXCL8- and Cg-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence. Surprisingly, PAR4 blockade increased the level of KC in response to carrageenan. CONCLUSION: These results demonstrated that PAR4 blockade impairs neutrophil migration in vivo, suggesting that PAR4 plays an important role in the regulation of inflammation, at least in part because of its ability to inhibit the actions of the neutrophil chemoattractant CXCL8.

X Encontro Nacional da Federação Brasileira de Epilepsia (Epibrasil): debates com autoridades federais, estaduais e municipais proporcionam avanços para tirar a epilepsia das sombras / first National Meeting of Associations and Support Groups of Epilepsy

Since the launch of the “Manifesto of Campinas”, in 2003, during the first National Meeting of Associations andSupport Groups of Epilepsy, organized and conducted by ASPE - Health Care of Patients with Epilepsy, official executor of theDemonstration Project on Epilepsy in Brazil (WHO-ILAE-IBE), associations of people with epilepsy have been organized byEpibrasil – the Brazilian Federation of Epilepsy, to demand public policies for integral attention to this huge number of people inneed of assistance in all spheres of their lives especially in the field of health, education, labor and social security. Objective: To reportthe highlights of the X National Meeting of the Brazilian Federation of Epilepsy, that happened on 16 and 17 March 2012, in BeloHorizonte - MG. Method: We used descriptive qualitative analysis of events. Results: The event was attended by representatives ofassociations of people with epilepsy from several Brazilian states, representatives of specialized agencies serving people with epilepsyin Minas Gerais, the Municipality of Belo Horizonte, the Legislative Assembly of Minas Gerais, the Chamber Federal Chamber ofProsecutors and the Federal University of Minas Gerais. The Meeting was organized by the Association of Epilepsy of of Minas Gerais- AMAE, Academic League of Epilepsy of the Federal University of Minas Gerais - LAE/UFMG and the Center for Neuroscienceof the UFMG - NNC. The following associations were present: ASPE, Apedf, Aspepb, MAPE, Apeeron, AMAE, AEPC, ARE,Apeeac, ASCAE, AFAG and LAE-UFMG...

Desde 2003, quando do lançamento do Manifesto de Campinas durante a realização do I Encontro Nacional deAssociações e Grupos de Apoio de Epilepsia, organizado e realizado pela ASPE - Assistência à Saúde de Pacientes com Epilepsia,executora oficial do Projeto Demonstrativo em Epilepsia no Brasil da OMS-ILAE-IBE, as associações de pessoas com epilepsia seorganizam, por meio da Epibrasil – Federação Brasileira de Epilepsia, para reivindicar políticas públicas para atenção integral a esteenorme contingente de pessoas que carece de atendimento em todas as esferas de suas vidas, especialmente no campo da saúde,da educação, do trabalho e da previdência social. Objetivo: Relatar os principais destaques do X Encontro Nacional da FederaçãoBrasileira de Epilepsia que aconteceu nos dias 16 e 17 de março de 2012, em Belo Horizonte – MG. Método: Foi utilizada análisequalitativa descritiva dos eventos. Resultados: O evento contou com a presença de representantes de associações de pessoas comepilepsia de vários estados brasileiros, de representantes dos serviços especializados que atendem pessoas com epilepsia em MinasGerais, da Câmara Municipal de Belo Horizonte, da Assembleia Legislativa de Minas Gerais, da Câmara Federal, do MinistérioPúblico e da Universidade Federal de Minas Gerais. A organização esteve a cargo da Associação Mineira de Epilepsia - AMAE, daLiga Acadêmica de Epilepsia da Universidade Federal de Minas Gerais – LAE/UFMG e do Núcleo de Neurociências da UFMG –NNC. Compareceram as seguintes associações: ASPE, Apedf, Aspepb, MAPE, Apeeron, AMAE, AAPE, ARE, Apeeac, ASCAE,AFAG e LAE-UFMG...(