Low affective temperament consistency during development: Results from a large retrospective study.

BACKGROUND: Temperament is still regarded as a stable part of personality, an "endophenotype" developed early in life. However, how frequently temperament traits can change throughout life is not clear. The aim of this study was to investigate affective temperament changes from late childhood to adolescence and from late adolescence to adulthood. METHODS: We used data from a cross-sectional web-based survey collected from the Brazilian Internet Study on Temperament and Psychopathology. We used the Affective and Emotional Composite Temperament Scale questionnaire to assess temperament at time of participation, and at age of 10-12 and 18 years, retrospectively, dividing affective temperaments into four major groups: internalized, externalized, stable and unstable. The final sample consisted of 36,255 participants from 24 to 40 years of age (71.9% women). RESULTS: Most of the sample (66.2%) changed to a different affective temperament group at adulthood. We found a significant decrease in internalized temperaments from 10-12 to 18 years of age (34.5% to 25.0% in women and 31.8% to 26.7% in men), parallel with an increase of externalized temperaments (14.1% to 20.3% in women and 17.3% to 19.6% in men). From 18 years of age to adult life, stable temperaments decreased slightly in frequency (37.9% to 32.5% in women and 38.6% to 36.8% in men), while unstable types increased (16.9% to 24.0% in women and 15.3% to 18.4% in men). LIMITATIONS: The retrospective design and self-reported evaluation may bias self-perception. CONCLUSIONS: Affective temperaments often change over time, contrary to the classic view of temperament as a consistent phenotype.

Biomarcadores preditivos em imuno-oncologia / Predictive biomarkers in immune oncology

Introdução: Os inibidores de checkpoint imunológico são drogas promissoras do campo da imunoterapia oncológica moderna. Entretanto, somete um grupo selecionado de pacientes apresenta benefício com tais terapias. Contudo, temse procurado por biomarcadores preditivos que possam auxiliar na tomada de decisão terapêutica. Os biomarcadores mais estudados são a expressão de PD-L1, a carga de mutação somática tumoral, e a presença de defeito nos genes do mismatch-repair do DNA ou de alta instabilidade microsatélite (MMRd/MSI-H). Métodos: Foram revisados os ensaios clínicos que dão suporte as evidências atuais para utilização dos inibidores de checkpoint imunológico na prática clínica. Resultados: A testagem de PD-L1 como biomarcador preditivo só é recomendada para o uso de Pembrolizumab no câncer de pulmão, e não se demonstrou papel preditivo para a expressão de PD-L1 no câncer colorretal e urotelial. Nas demais neoplasias a maior expressão de PD-L1 costuma se relacionar com aumento nas taxas de resposta e sobrevida, embora mesmo pacientes PD-L1 negativos se beneficiem das terapias anti-PD-1/ PD-L1. Apenas os estudos com Atezolizumab no câncer urotelial avaliaram a carga de mutação somática como biomarcador independente, que esteve relacionada com maior taxa de resposta objetiva e maior sobrevida global. O papel da imunoterapia no tratamento dos tumores MMRd/MSI-H ainda está sendo investigado, mas as evidências até então a apontam como uma opção terapêutica promissora para esse grupo de pacientes. Conclusão: Com exceção do câncer de pulmão, não há evidência para a testagem de PD-L1 como biomarcador na prática clínica. A avaliação da carga de mutação somática como biomarcador preditivo ainda é experimental. As evidências atuais sugerem que os pacientes portadores de neoplasias MMRd/MSI-H são candidatos ao tratamento com inibidores de checkpoint imunológico.

Introduction: The immune checkpoint inhibitors are promising drugs in the field of cancer immunotherapy. However, a selected population will derive benefit from this treatment strategy. Predictive biomarkers have been investigated in order to guide decisions making process. The three most studied biomarkers are the PD-L1 expression, the mutational load and the presence of DNA mismatch-repair defects or high microsatellite instability. Methods: The clinical trials that support the current recommendations for immune checkpoint inhibitors therapy were reviewed. Results: Testing for PD-L1 is only recommended prior to Pembrolizumab therapy in lung cancer, and the PD-L1 expression was not shown to be a predictive factor in urothelial and colorectal cancer. In other neoplasias, although the higher PD-L1 expression was likely to improve response or survival rates with PD-1/PD-L1 blockade, even the PD-L1 negative patients might benefit from these drugs. Only the clinical trials with Atezolizumab in urothelial cancer reported the higher somatic mutational load as independent predictive biomarker, and it was associated with higher response rates and longer overall survival. The role of immunotherapy in the treatment of MMR-d/MSI-H tumors is still being investigated, but the evidence so far support that it might be a promising therapeutical option for this subset of patients. Conclusions: Exception for lung cancer, testing for PD-L1 expression is not recommended in the clinical practice. Evaluating for somatic mutational burden is still experimental. The current evidence suggests that the patients with MMR-d/MSI-H tumors are candidates for immune checkpoint inhibition therapy.

Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors.

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5µg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1µg/side) or MPH+SCH23390 (1.5µg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both ß-adrenergic and D1/D5 dopaminergic receptors.