BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.

BACKGROUND: Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) and/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis. METHODS: To unveil BUB1B as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes. RESULTS: Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B variants lead to decreased BubR1 expression and/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies. CONCLUSIONS: Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.

The convergence between defence and care in mammals.

The motivations to protect oneself and others have often been seen as conflicting. Here, we discuss recent evidence that self-defensive mechanisms may in fact be recruited to enable the helping of others. In some instances, the defensive response to a threat may even be more decisive in promoting helping than the response to a conspecific's distress (as predicted by empathy-altruism models). In light of this evidence, we propose that neural mechanisms implicated in self-defence may have been repurposed through evolution to enable the protection of others, and that defence and care may be convergent rather than conflicting functions. Finally, we present and discuss a working model of the shared brain mechanisms implicated in defence of both self and others.

Viability Study of Serra da Estrela Dog Wool to Produce Green Composites.

The environmental emergency has alerted consumers and industries to choose products derived from renewable sources over petroleum derivatives. Natural fibers of plant origin for reinforcing composite materials dominate the field of research aiming to replace synthetic fibers. The field of application of green dog wool composite materials needs to be reinforced and proven, as the industry is looking for more sustainable solutions and on the other hand this type of raw material (pet grooming waste) tends to grow. Hence, in the present work, the feasibility of applying natural fibers of dog origin (mainly composed by keratin) in green composites was studied. The green composites were developed using chemically treated dog wool of the breed Serra da Estrela (with NaOH and PVA) as reinforcement and a green epoxy resin as a matrix. The chemical treatments aimed to improve adhesion between fibers and matrix. The fibers' composition was determined using X-ray Diffraction (X-RD). Their morphology was determined using a scanning electron microscope (SEM). The wettability of the fiber was also evaluated qualitatively by analyzing drops of resin placed on the fibers treated with the different treatments. The mechanical properties of the composites were also studied through mechanical tensile, flexural, and relaxation tests. Overall, the best results were obtained for the dog wool fibers without treatment. The tensile and flexural strength of this biocomposite were 11 MPa and 26.8 MPa, respectively, while the tensile and flexural elastic modulus were 555 MPa and 1100 MPa, respectively. It was also possible to verify that the PVA treatment caused degradation of the fiber, resulting in a decrease in mechanical tensile strength of approximately 42.7%, 59.7% in flexural strength and approximately 59% of the stress after 120 min of relaxation when compared to fiber made from untreated dog wool. On the other hand, the NaOH treatment worked as a fiber wash process, removing waxes and fats naturally present on the fiber surface.

Temporal Analysis of Pharmaceuticals as Emerging Contaminants in Surface Water and Wastewater Samples: A Case Study.

Pharmaceuticals in the environment are a global concern, with studies in all continents highlighting their widespread occurrence and potential ecological impacts, revealing their presence, fate, and associated risks in aquatic ecosystems. Despite typically occurring at low concentrations (ranging from ng/L to µg/L), advancements in analytical methods and more sensitive equipment have enabled the detection of a higher number of pharmaceuticals. In this study, surface and wastewater samples were extracted using solid phase extraction and analyzed using ultra-high-performance liquid chromatography with tandem mass spectrometry. Among the therapeutic classes investigated, nonsteroidal anti-inflammatory drugs/analgesics, antibiotics, and psychiatric drugs showed a higher number of detected pharmaceuticals. Concentrations ranged from below method detection limit (

Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia.

Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.

Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect.

Advanced urothelial bladder cancer (UBC) patients are tagged by a dismal prognosis and high mortality rates, mostly due to their poor response to standard-of-care platinum-based therapy. Mediators of chemoresistance are not fully elucidated. This work aimed to study the metabolic profile of advanced UBC, in the context of cisplatin resistance. Three isogenic pairs of parental cell lines (T24, HT1376 and KU1919) and the matching cisplatin-resistant (R) sublines were used. A set of functional assays was used to perform a metabolic screening on the cells. In comparison to the parental sublines, a tendency was observed towards an exacerbated glycolytic metabolism in the cisplatin-resistant T24 and HT1376 cells; this glycolytic phenotype was particularly evident for the HT1376/HT1376R pair, for which the cisplatin resistance ratio was higher. HT1376R cells showed decreased basal respiration and oxygen consumption associated with ATP production; in accordance, the extracellular acidification rate was also higher in the resistant subline. Glycolytic rate assay confirmed that these cells presented higher basal glycolysis, with an increase in proton efflux. While the results of real-time metabolomics seem to substantiate the manifestation of the Warburg phenotype in HT1376R cells, a shift towards distinct metabolic pathways involving lactate uptake, lipid biosynthesis and glutamate metabolism occurred with time. On the other hand, KU1919R cells seem to engage in a metabolic rewiring, recovering their preference for oxidative phosphorylation. In conclusion, cisplatin-resistant UBC cells seem to display deep metabolic alterations surpassing the Warburg effect, which likely depend on the molecular signature of each cell line.

High preseason temperature variability drives convergence of xylem phenology in the Northern Hemisphere conifers.

Wood growth is key to understanding the feedback of forest ecosystems to the ongoing climate warming. An increase in spatial synchrony (i.e., coincident changes in distant populations) of spring phenology is one of the most prominent climate responses of forest trees. However, whether temperature variability contributes to an increase in the spatial synchrony of spring phenology and its underlying mechanisms remains largely unknown. Here, we analyzed an extensive dataset of xylem phenology observations of 20 conifer species from 75 sites over the Northern Hemisphere. Along the gradient of increase in temperature variability in the 75 sites, we observed a convergence in the onset of cell enlargement roughly toward the 5th of June, with a convergence in the onset of cell wall thickening toward the summer solstice. The increase in rainfall since the 5th of June is favorable for cell division and expansion, and as the most hours of sunlight are received around the summer solstice, it allows the optimization of carbon assimilation for cell wall thickening. Hence, the convergences can be considered as the result of matching xylem phenological activities to favorable conditions in regions with high temperature variability. Yet, forest trees relying on such consistent seasonal cues for xylem growth could constrain their ability to respond to climate warming, with consequences for the potential growing season length and, ultimately, forest productivity and survival in the future.

A Straining Heart: Transthyretin Amyloidosis as a Cause of Heart Failure.

Cardiac amyloidosis is a disease caused by the deposition of amyloid fibrils in the extracellular space of the heart, most often by immunoglobulin light chains or by transthyretin. It is often underdiagnosed because the signs and symptoms are nonspecific or due to the false perception that the diagnosis always requires an endomyocardial biopsy. Transthyretin amyloidosis is being increasingly recognized as a cause of heart failure, particularly in patients with heart failure with preserved ejection fraction (HFpEF). We present the clinical case of an 86-year-old man whose diagnosis was based on signs and symptoms compatible with cardiac amyloidosis and in which imaging performed a preponderant role. This case reminds clinicians to consider the diagnosis in older patients with HFpEF, left ventricular hypertrophy and rhythm disturbances. It highlights the importance of evaluating global longitudinal strain (GLS) in a standard echocardiographic evaluation.

Eletrólitos séricos e prognóstico em doentes submetidos a gastrostomia endoscópica / Serum electrolytes and outcome in patients undergoing endoscopic gastrostomy

ABSTRACT BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is a gold standard for long term enteral feeding. Neurologic dysphagia and head/neck cancer are the most common indications for PEG as they can lead to protein-energy malnutrition and serum electrolyte abnormalities, with potential negative impact on metabolic balance. Refeeding syndrome may also be related with severe electrolyte changes in PEG-fed patients and contribute to poor prognosis. OBJECTIVE: This study aims to evaluate the changes in serum concentrations of the main electrolytes and its possible association with the outcome. METHODS: Retrospective study of patients followed in our Artificial Nutrition Clinic, submitted to PEG from 2010 to 2016, having head/neck cancer or neurologic dysphagia, who died under PEG feeding. Serum electrolytes (sodium, potassium, chlorine, magnesium, calcium and phosphorus) were evaluated immediately before the gastrostomy procedure. Survival after PEG until death was recorded in months. RESULTS: We evaluated 101 patients, 59 with electrolyte alterations at the moment of the gastrostomy. Sodium was altered in 32 (31.7%), magnesium in 21 (20.8%), chlorine in 21 (20.8%), potassium in 14 (13.8%), calcium in 11 (10.9 %) and phosphorus in 11 (10.9%). The survival of patients with low sodium (<135 mmol/L) was significantly lower when compared to patients with normal/high values, 2.76 months vs 7.80 months, respectively (P=0.007). CONCLUSION: Changes in serum electrolytes of patients undergoing PEG were very common. More than half showed at least one abnormality, at the time of the procedure. The most frequent was hyponatremia, which was associated with significantly shorter survival, probably reflecting severe systemic metabolic distress.

RESUMO CONTEXTO: A gastrostomia endoscópica percutânea (PEG) é a via de eleição preferencial para a nutrição entérica de longa duração. A disfagia neurológica e as neoplasias cervico-faciais constituem as principais indicações para PEG por poderem conduzir a desnutrição energético-proteica e alterações hidroeletrolíticas, com potencial impacto negativo no equilíbrio metabólico. A síndrome de realimentação pode também estar associada a alterações hidroeletrolíticas graves em doentes alimentados por PEG e contribuir para um mau prognóstico. OBJETIVO: Avaliar as alterações das concentrações séricas dos principais eletrólitos e a eventual associação entre os valores séricos alterados e o prognóstico dos doentes gastrostomizados. Métodos - Estudo retrospetivo realizado em doentes seguidos na Consulta de Nutrição Artificial do Hospital Garcia de Orta, propostos e submetidos a PEG, de 2010 a 2016 e que faleceram sob nutrição por PEG. Consideraram-se os valores séricos dos iões em estudo avaliados imediatamente antes do procedimento endoscópico de gastrostomia, obtidos por consulta do processo clínico. A sobrevida, após a realização da PEG até à morte foi registrada em meses. RESULTADOS: Avaliaram-se 101 doentes. A sobrevida média pós-gastrostomia foi 6,55 meses. Destes, 59 apresentaram alterações de alguns iões no momento da realização da PEG. O sódio estava alterado em 31 (30,6%), magnésio em 20 (19,8%), cloro em 19 (18,8%), potássio em 14 (13,8%), cálcio em 10 (9,9%) e o fósforo em 9 (8,9%). Quando comparada a sobrevida dos doentes com valores de sódio baixo (<135 mmol/L) com a dos doentes com valores normais/elevados, esta foi 2,76 meses vs 7,80 meses, respectivamente (P=0,007). CONCLUSÃO: As alterações dos eletrólitos séricos nos doentes submetidos a PEG foram muito frequentes, com mais de metade dos doentes a apresentarem pelo menos uma alteração aquando da realização do procedimento. A alteração mais frequente foi a hiponatrémia, associando-se a pior prognóstico com sobrevida significativamente mais curta, refletindo provavelmente um grave compromisso metabólico sistêmico.

Promoção da segurança do doente crítico: práticas terapêuticas farmacológicas numa unidade de cuidados intensivos / Promoting safety of the critically ill patient: pharmacological therapeutic practices in an intensive care unit

O presente relatório intitulado "Promoção da Segurança do Doente Crítico ­ Práticas Terapêuticas Farmacológicas numa Unidade de Cuidados Intensivos" surge da realização de um estágio que decorreu na Unidade de Cuidados Intensivos Polivalente (UCIP) do Hospital de Braga (HB), no âmbito do Estágio do Mestrado em Enfermagem da Pessoa em Situação Crítica, da Escola Superior de Enfermagem da Universidade do Minho em parceria com a Escola Superior de Enfermagem da Universidade de Trás ­ os ­ Montes e Alto Douro. A realização deste relatório permite não só descrever e refletir acerca das atividades desenvolvidas ao longo do estágio, mas também apresentar uma proposta de intervenção tendo em vista a mudança de atitudes e de práticas clínicas por parte dos Enfermeiros que trabalham na unidade de cuidados intensivos, cuja meta é a garantia da segurança do doente e da qualidade dos cuidados prestados ao doente. Falar em segurança e qualidade é nos dias de hoje uma obrigatoriedade, dada a complexidade das práticas clínicas. A prática clínica, com o seu cariz multidisciplinar, faz-se dentro de uma rede de fatores humanos e organizacionais que fazem dela uma atividade de risco. No caso particular da UCIP onde foi realizado o estágio algumas práticas utilizadas pelos enfermeiros, no que diz respeito à preparação e administração da terapêutica farmacológica, levantam algumas dúvidas quanto à sua eficácia em termos de segurança do doente e qualidade de cuidados. O presente relatório pretende, por um lado, elucidar sobre a existência de práticas clínicas suscetíveis de levarem à ocorrência de erros, e por outro, apresentar uma proposta de alteração de comportamentos de risco observados ao longo do estágio. Tendo como referência a metodologia de Trabalho de Projeto foram realizadas entrevistas a treze enfermeiros da referida unidade, bem como, a observação direta das diferentes práticas clínicas lá executadas. Os discursos recolhidos foram submetidos à análise de conteúdo com o intuito de perceber a perspetiva de cada um dos entrevistados face ao tema exposto. O resultado da análise evidencia que a maioria dos enfermeiros desvaloriza a necessidade de mudança sobre as suas rotinas diárias no que concerne à preparação e administração da medicação, por considerarem que esta é uma prática correta e que dificilmente leva a ocorrência de erros. Por outro lado, estes profissionais não evidenciaram uma cultura de declaração do erro, que pode acontecer, por mais pequeno que seja. Conclui-se que sendo a segurança do doente um tema transversal nos diversos contextos de saúde, particularmente em Unidades de Cuidados Intensivos Polivalentes, pela sua complexidade tecnológica, a sua abordagem torna-se de interesse para as equipas de profissionais e para os gestores das organizações de saúde, capazes de garantirem que as práticas terapêuticas possam ser refletidas, melhoradas e praticadas em segurança.

The present report, entitled "Promoção da Segurança do Doente Crítico ­ Práticas Terapêuticas Farmacológicas numa Unidade de Cuidados Intensivos", follows the internship in the Intensive Care Unit (ICU) from Braga's Hospital, in the context of the Internship of the Masters in Nursing in Critical Situation Person of the Superior School of Nursing from Minho's University in partnership with the Superior School of Nursing from Trás-os-Montes and Alto Douro. The realization of this report does not only allows to describe and reflect on the activities developed throughout the internship, as well as to present an intervention proposal for a change of attitudes and clinical practices made by nurses working in the ICU, all of this to ensure the safety and quality of care provided to the patient. Speaking of safety and quality is nowadays mandatory given the complexity of clinical practice. Clinical practice with its multidisciplinary nature, is carried out within a network of human, team and organizational factors that makes it a risky activity. In the particular case of the ICU from the hospital where the internship occurred, some of the practices used by nurses, with regard to the preparation and administration of drug therapy, raises some doubts as to its effectiveness in terms of patient safety and quality care. This report is intended, in one hand, to elucidate on the existence of clinical practices susceptible to the occurrence of errors, and on the other hand to make a proposal for changing risk behaviors observed throughout the internship. Having as reference the project work methodology, interviews were conducted to thirteen nurses from the ICU, as well as direct observation of the different clinical practices performed there. The speeches collected were subjected to content analysis in order to understand the perspective of each one of the interviewed regarding the exposed theme. The analysis results show that most of the nurses devalues the need for change on their daily routines with regard to the preparation and administration of medication, considering that this is a correct practice and that hardly leads to errors. On the other hand, such professionals have not yet evidenced error reporting culture, which may happen, however small they may be. It is concluded that being patient safety a theme in different health contexts, particularly in Multipurpose Intensive Care Units, for its technological complexity, its approach becomes of interest to professional teams and managers of health organizations, able to ensure that the therapeutic practices can be reflected, enhanced and practiced safely.