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p27Kip1 is a key cell cycle gatekeeper governing the timing of Cyclin-dependent kinase (CDK) activation/inactivation and, consequently, cell proliferation. Structurally, the protein is largely unfolded, a feature that strongly increases its plasticity and interactors and enhances the number of regulated cellular processes. p27Kip1, like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27Kip1 for specific interactions/functions. Several germline or somatic CDKN1B (the p27Kip1 encoding gene) mutations have been demonstrated to be associated with multiple endocrine neoplasia type 4 (MEN4), hairy cell leukemia, small-intestine neuroendocrine tumors, and breast and prostate cancers. Here, we analyzed the effect of four CDKN1B missense and nonsense mutations found in patients affected by MEN4 or cancers, namely, c.349C>T, p.P117S; c.397C>A, p.P133T; c.487C>T, p.Q163*; and c.511G>T, p.E171*. By transfecting breast cancer cell lines, we observed increased growth and cell motility for all the investigated mutants compared to wild-type p27Kip1 transfected cells. Furthermore, we discovered that the mutant forms exhibited altered phosphorylation on key residues and different localization or degradation mechanisms in comparison to the wild-type protein and suggested a possible region as crucial for the lysosome-dependent degradation of the protein. Finally, the loss of p27Kip1 ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27Kip1 forms exhibited with Cyclin/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT.

Background Most studies that follow up hepatectomy cases are limited in scope to an investigation of mortality and morbidity rates or the costs and length of hospital stay. In this study the authors aimed to characterize the quality of life and to evaluate mortality and its determinants after hepatectomy. Methods This prospective study was carried in a Post-Anaesthesia Care Unit (PACU) over 15 months, and 70 patients submitted to hepatectomy were enrolled. Demographic and peri-operative characteristics were evaluated for associations with mortality. At admission and 6 months after discharge, patients completed a Short Form-36 questionnaire (SF-36) and have their independence in Activities of Daily Living (ADL) was evaluated. Binary and multiple logistic regression analyses were used to evaluate of associations with mortality, and the Wilcoxon signed rank test was used to compare SF-36 scores before and after 6 months after hepatectomy. Results The mortality rate was 19% at 6 months. Multivariate analysis identified postoperative delirium as an independent determinant for mortality. Six months after discharge, 46% patients stated that their health in general was better or much better than that 1 year previously. Six months after hepatectomy, patients had worse scores in the physical function domain of SF-36; however, scores for all the other domains did not differ. At this time point, patients were more dependent in instrumental ADL than before surgery (32% versus 7%, p = 0.027). Conclusion This study identified postoperative delirium as an independent risk factor for mortality 6 months after hepatectomy. After 6 months, survivors were more dependent in instrumental ADL tasks and had worse scores in the physical function domain of SF-36.

p27 is a key cell cycle gatekeeper governing the timing of Cyclin-dependent kinase (CDK) activation/inactivation and, consequently, cell proliferation. Structurally, the protein is largely unfolded, a feature that strongly increases its plasticity and interactors and enhances the number of regulated cellular processes. p27 , like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27 for specific interactions/functions. Several germline or somatic (the p27 encoding gene) mutations have been demonstrated to be associated with multiple endocrine neoplasia type 4 (MEN4), hairy cell leukemia, small-intestine neuroendocrine tumors, and breast and prostate cancers. Here, we analyzed the effect of four missense and nonsense mutations found in patients affected by MEN4 or cancers, namely, c.349C>T, p.P117S; c.397C>A, p.P133T; c.487C>T, p.Q163*; and c.511G>T, p.E171*. By transfecting breast cancer cell lines, we observed increased growth and cell motility for all the investigated mutants compared to wild-type p27 transfected cells. Furthermore, we discovered that the mutant forms exhibited altered phosphorylation on key residues and different localization or degradation mechanisms in comparison to the wild-type protein and suggested a possible region as crucial for the lysosome-dependent degradation of the protein. Finally, the loss of p27 ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27 forms exhibited with Cyclin/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT.

A wide range of strategies and assistive systems support individuals with communication disabilities, with hightech Augmentative and Alternative Communication (AAC) systems emerging as valuable contemporary tools. Assessing high-tech AAC systems is intricate and time-consuming due to numerous contributing factors. While various guidelines, decision trees, scales, and matrices exist for assessment and intervention, they are not specifically designed for real-time evaluation of high-tech AAC devices. A major challenge is the lack of a comprehensive, standardized protocol tailored for evaluating high-tech AAC systems in people with communication disabilities. To address this, we combined the knowledge of existing literature with the collective expertise of a multidisciplinary, multicenter team specializing in AAC. This collaboration led to the development of an assessment tool within a multicenter framework. The goal was to create a detailed, replicable, and versatile framework for evaluating and designing high-tech AAC systems for adults with communication disabilities, which can be easily implemented and adapted by AAC teams across various healthcare settings.

O Estágio Profissionalizante integrado no 6º ano do Mestrado Integrado em Medicina da Faculdade de Ciências Médicas | NOVA Medical School é constituído por 6 estágios parcelares que passo a citar pela ordem de concretização: Ginecologia e Obstetrícia, Saúde Mental, Medicina Geral e Familiar, Pediatria, Cirurgia Geral e Medicina Interna. O último ano letivo representa o encerramento do meu percurso como aluna, sendo um ano que mistura nostalgia com a realização pessoal e profissional, uma vez que permite a aplicação de todo o conhecimento adquirido durante o curso e a aproximação à realidade da profissão.

A menopausa caracteriza-se por ocorrer 12 meses após o último período menstrual e marca o término dos ciclos menstruais. Com o envelhecimento, os folículos ovários esgotam-se progressivamente e, consequentemente, ocorre uma diminuição da produção de estrogénio. A menopausa definitiva é precedida pela pré-menopausa, na qual as mulheres podem vivenciar menstruações regulares, acompanhadas de algumas flutuações hormonais. Seguidamente, as mulheres entram na perimenopausa, período que pode ter um intervalo de tempo entre os 3 e os 12 meses, marcado por irregularidades nas menstruações. Nesta monografia, serão abordadas as manifestações clínicas subjacentes a esta fase, tais como os sintomas vasomotores, irregularidades menstruais, sintomas urogenitais, distúrbios do sono, transtornos de humor e depressivos, consequências metabólicas e cardiovasculares e a osteoporose. Será também explicado em detalhe o papel do controle endócrino do sistema reprodutor feminino tal como as opções de tratamento dos sintomas, nomeadamente, opções hormonais como não hormonais. Por fim, será elencado o papel do farmacêutico no aconselhamento e acompanhamento das mulheres neste período tão desafiador.

Tau tubulin kinase 2 (TTBK2) is a ubiquitous serine-threonine protein kinase implicated in diverse cellular processes, including microtubule regulation, ciliogenesis, synaptic signaling, and the phosphorylation of key proteins like TDP-43. Despite its relevance, many aspects of TTBK2 function in both physiological and pathological conditions remain poorly understood. Truncating variants in TTBK2 gene cause s pinocerebellar ataxia type 11 (SCA11), a rare form of autosomal dominant cerebellar ataxia. However, the functional consequences and pathogenic potential of missense variants have yet to be elucidated. In this study, we developed a CRISPR/Cas9 knock-in cell model harboring a missense variant in TTBK2 kinase domain (NM_173500.4:c.625 C > T; p.Leu209Phe) to evaluate its impact on TTBK2 expression, associated protein levels, and phosphoproteomic profiles. TTBK2 missense variant (TTBK2-L209F) was associated with reduced TTBK2 protein levels, altered levels of cytoskeleton-related proteins, and impaired kinase activity, namely toward TDP-43. Phosphoproteomic analyses identified dysregulation in pathways linked to gene regulation, protein degradation, cytoskeletal organization, and TGF-β signaling. These findings provide valuable insights into the biological roles of TTBK2 in cellular signaling. Moreover, this study underscores the importance of functional studies to better understand the consequences of TTBK2 missense variants, particularly those affecting the kinase domain, and their potential contribution to disease.

Conjugated donor–acceptor (D-A) copolymers are widely used in optoelectronic devices due to their influence on the resulting properties. This study focuses on the synthesis and characterization of the conjugated D-A copolymer constructed with fluorene and di-2-thienyl-2,1,3-benzothiadiazole units, resulting in Poly[2,7-(9,9-dioctyl-fluorene)-alt-5,5-(4,7-di(2-thienyl)-2,1,3-benzothiadiazole)] (PFDTBT). The synthesis associated with reaction times of 48 and 24 h, the latter incorporating the phase-transfer catalyst Aliquat 336, was investigated. The modified conditions produced copolymers with higher molar masses (Mw > 20,000 g/mol), improved thermal stability and red emission at 649 nm. Furthermore, the resulting D-A copolymers exhibited uniform morphology with low surface roughness (P2—Ra: 0.77 nm). These improved properties highlight the potential of D-A copolymers based on PFDTBT for various optoelectronic applications, including photovoltaics, light-emitting devices, transistors and biological markers in the form of quantum dots.

BackgroundLocally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.MethodsWe undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion.ResultsDespite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product.ConclusionsThese data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.