CHEK2 germline variants identified in familial nonmedullary thyroid cancer lead to impaired protein structure and function.

Approximately 5 to 15% of nonmedullary thyroid cancers (NMTC) present in a familial form (familial nonmedullary thyroid cancers [FNMTC]). The genetic basis of FNMTC remains largely unknown, representing a limitation for diagnostic and clinical management. Recently, germline mutations in DNA repair-related genes have been described in cases with thyroid cancer (TC), suggesting a role in FNMTC etiology. Here, two FNMTC families were studied, each with two members affected with TC. Ninety-four hereditary cancer predisposition genes were analyzed through next-generation sequencing, revealing two germline CHEK2 missense variants (c.962A > C, p.E321A and c.470T > C, p.I157T), which segregated with TC in each FNMTC family. p.E321A, located in the CHK2 protein kinase domain, is a rare variant, previously unreported in the literature. Conversely, p.I157T, located in CHK2 forkhead-associated domain, has been extensively described, having conflicting interpretations of pathogenicity. CHK2 proteins (WT and variants) were characterized using biophysical methods, molecular dynamics simulations, and immunohistochemistry. Overall, biophysical characterization of these CHK2 variants showed that they have compromised structural and conformational stability and impaired kinase activity, compared to the WT protein. CHK2 appears to aggregate into amyloid-like fibrils in vitro, which opens future perspectives toward positioning CHK2 in cancer pathophysiology. CHK2 variants exhibited higher propensity for this conformational change, also displaying higher expression in thyroid tumors. The present findings support the utility of complementary biophysical and in silico approaches toward understanding the impact of genetic variants in protein structure and function, improving the current knowledge on CHEK2 variants' role in FNMTC genetic basis, with prospective clinical translation.

Mitochondrial targets in hyperammonemia: Addressing urea cycle function to improve drug therapies.

The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage. This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD+ levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.

Implications of the COVID-19 Pandemic on the Family Structural Dimensions: A Correlational Study.

The COVID-19 pandemic caused changes in the families' social support network, employment status, and family income, which are the focus of attention of family health nurses. This study aims to describe the pandemic's repercussions in the areas of attention of the structural dimension of families according to the Dynamic Model of Family Assessment and Intervention, as perceived by Portuguese families, and to relate the changes in their employment status according to the variables of the structural dimension. A quantitative, descriptive, and correlational study was conducted using snowball sampling. A questionnaire of sociodemographic characterization and assessment of the family structural dimension according to the model's operational matrix was applied to 235 family members. Changes were found in their employment status; family income; intensity and frequency of contact with family, friends, and coworkers; frequency of contact with educational/health/religious institutions and community groups; cultural activities; and housing comfort conditions such as the use of heating/air conditioning, gas, and water consumption. Changes in employment status were related to family income, interaction with friends, frequency of cultural activities, and use of air conditioning and heating. Knowing the implications of the pandemic on the family's structural dimension results in a nursing intervention more focused on family needs.

The platelet-to-lymphocyte ratio as an indirect outcome predictor in primary hypertension: a retrospective study.

Background: Nondipper hypertensive patients have higher levels of platelet-to-lymphocyte ratio, a new studied inflammatory biomarker in primary hypertension. Furthermore, these patients have a higher risk of cardiovascular morbidity and mortality. This study aimed to assess the relationship between platelet-to-lymphocyte ratio and hypertensive pattern (dipper vs nondipper) and the association between the hypertensive pattern and major adverse cardiovascular events. Methods: A retrospective analysis was performed. One hundred fifty-three patients were included and classified as dipper or nondipper according to 24-hour ambulatory blood pressure measurements. Platelet-to-lymphocyte ratio was calculated based on complete blood count data. Results: The dipper group included 109 patients, and the nondipper group included 44 patients. Nondipper patients have 2.11 more risk of presenting a higher platelet-to-lymphocyte ratio than dipper individuals (odds ratio [OR] = 2.11; 95% CI, 1.220-3.664; P = .007). Nondipper patients also registered earlier cardiovascular events, such as acute myocardial infarction and stroke (P < .001). Conclusions: Nondipper hypertensive individuals registered higher levels of platelet-to-lymphocyte ratio and earlier cardiovascular events than dipper patients. Therefore, platelet-to-lymphocyte ratio could be used as an indirect predictor of cardiovascular risk in primary hypertension and contribute to optimize preventive strategies.

Physical Examination of Potential Deceased Organ and Tissue Donors: An Overview of the European Landscape.

Physical examination (PE) of donors is essential to identify potential risks to the safety and efficacy of donated organs and tissues and is mandatory in the EU. However, no detailed guidance is available as to how PE should be performed. Health authorities (HA) and health professionals (HP) in member states of the European Committee on Organ Transplantation of the Council of Europe (CD-P-TO) and observer countries completed surveys relating to the regulatory requirements for PE and the professional practice of PE in their countries for organ and tissue donors. The HA survey addressed regulatory aspects, and the HP survey addressed professional practices, training, and respondents' opinions on the value of PE. These surveys revealed significant inter-country variation in the regulatory approach to PE and the performance of PE by professionals. Most respondents opined that PE was important and yielded valuable information in identifying contraindications to donation. There is no consensus at a regulatory or professional level as to how PE should be performed on organ and tissue donors. There is a requirement for agreed best practice guidelines in this area.

Genomic and ecological factors shaping specialism and generalism across an entire subphylum.

Organisms exhibit extensive variation in ecological niche breadth, from very narrow (specialists) to very broad (generalists). Paradigms proposed to explain this variation either invoke trade-offs between performance efficiency and breadth or underlying intrinsic or extrinsic factors. We assembled genomic (1,154 yeast strains from 1,049 species), metabolic (quantitative measures of growth of 843 species in 24 conditions), and ecological (environmental ontology of 1,088 species) data from nearly all known species of the ancient fungal subphylum Saccharomycotina to examine niche breadth evolution. We found large interspecific differences in carbon breadth stem from intrinsic differences in genes encoding specific metabolic pathways but no evidence of trade-offs and a limited role of extrinsic ecological factors. These comprehensive data argue that intrinsic factors driving microbial niche breadth variation.

Venous thromboembolism-related genetic determinant F11 rs4253417 is a potential prognostic factor in ischaemic stroke.

Ischaemic stroke (IS) and venous thromboembolism (VTE) are two forms of thromboembolism that, although distinct, seem to share numerous risk factors. Concerning genetic risk factors, while many VTE genetic markers have been reported, inclusively by genome-wide association studies (GWAS), the identification and validation of genetic determinants underlying IS pathogenesis have been challenging. Considering that IS and VTE shared biological pathways and aetiological factors, the severity of IS might be also influenced by VTE-related genetic variants. Thus, the present study was designed to analyse the impact of six VTE GWAS-identified genetic variants on the clinical outcome of 363 acute IS patients. Results revealed that the single-nucleotide polymorphism (SNP) F11 rs4253417 was an independent predictor of the 5-year risk of death among patients with total anterior circulation infarct (TACI). Namely, the ones carrying the SNP C allele presented a fourfold increase in the 5-year risk of death compared to TT genotype carriers (CC/CT vs. TT; adjusted HR, 4.240; 95% CI, 1.260-14.270; P = 0.020). This SNP is known to be associated with coagulation factor XI (FXI) levels, thus with implications in haemostasis and inflammation. As such, F11 rs4253417 might be a promising prognostic biomarker among TACI patients to aid in clinical decision-making. However, additional investigation is required to confirm the study's results and dissect the underlying mechanisms.

Impact of the COVID-19 pandemic on the mental and physical health and overall wellbeing of university students in Portugal.

Throughout the pandemic of COVID-19 caused by SARS-CoV-2, university students were considered a vulnerable risk group for mental health impairment and wellbeing deterioration. This study aimed at evaluating the pandemic's impact on the physical and mental health and wellbeing among students of a Portuguese university. This cross-sectional study included 913 participants and ran from June to October 2020. Data collected included sociodemographics, three mental health self-report questionnaires (Depression Anxiety Stress Scale, Eating Disorder Examination Questionnaire and Brief COPE) and lifestyle practices (eating and sleeping patterns, media, and entertainment habits) during the first months of the pandemic, which included a 72-day full national lockdown. Descriptive and correlational statistical analysis were conducted. Students' food habits changed during the pandemic, namely on the consumption of snacks and fast food and, overall, less balanced meals became more prevalent. Additionally, almost 70% of the students reported Body Mass Index changes, while 59% went through sleep pattern changes-these were more pronounced in women and younger students. Over half (67%) of the inquirees exhibited an increase in their stress, depression, and generalized anxiety symptoms. Also, the study demonstrates that students' lifestyles trended negatively during the pandemic and highlights how important regular psychological, health monitoring and emotional support is, amongst this somehow overlooked population throughout the pandemic. Universities should provide support to overcome challenges in future stressful situations. This study might have an impact on how universities and higher education systems approach their students in terms of mental and physical health monitoring and promotion in future situations, non-related with COVID. Moreover, it has a large sample of students well characterized in terms of mental and physical health, which might be of interest for future comparison with other worldwide group of students throughout stressful situations, such as tragic events, wars, pandemics.

A glimpse at an early stage of microbe domestication revealed in the variable genome of Torulaspora delbrueckii, an emergent industrial yeast.

Microbe domestication has a major applied relevance but is still poorly understood from an evolutionary perspective. The yeast Torulaspora delbrueckii is gaining importance for biotechnology but little is known about its population structure, variation in gene content or possible domestication routes. Here, we show that T. delbrueckii is composed of five major clades. Among the three European clades, a lineage associated with the wild arboreal niche is sister to the two other lineages that are linked to anthropic environments, one to wine fermentations and the other to diverse sources including dairy products and bread dough (Mix-Anthropic clade). Using 64 genomes we assembled the pangenome and the variable genome of T. delbrueckii. A comparison with Saccharomyces cerevisiae indicated that the weight of the variable genome in the pangenome of T. delbrueckii is considerably smaller. An association of gene content and ecology supported the hypothesis that the Mix-Anthropic clade has the most specialized genome and indicated that some of the exclusive genes were implicated in galactose and maltose utilization. More detailed analyses traced the acquisition of a cluster of GAL genes in strains associated with dairy products and the expansion and functional diversification of MAL genes in strains isolated from bread dough. In contrast to S. cerevisiae, domestication in T. delbrueckii is not primarily driven by alcoholic fermentation but rather by adaptation to dairy and bread-production niches. This study expands our views on the processes of microbe domestication and on the trajectories leading to adaptation to anthropic niches.

Metodologias pedagógicas em enfermagem de saúde familiar: protocolo de scoping review / Pedagogical Methodologies in Family Health Nursing: Scoping Review Protocol Aim

Objetivo: Mapear as metodologias pedagógicas utilizadas no ensino de enfermagem de saúde familiar. Mais especificamente, pretende-se dar resposta às seguintes questões: 1) Quais as metodologias pedagógicas utilizadas no Ensino de Enfermagem de saúde familiar? 2) Em que nível de ensino são utilizadas referidas metodologias pedagógicas? 3) Em que contexto são utilizadas referidas metodologias pedagógicas? Metodologia: Scoping Review orientada pela metodologia proposta pelo Joanna Briggs Institute para a realização de Scoping Reviews. Na pesquisa e identificação dos estudos, serão usadas as bases de dados eletrónicas MEDLINE (via Pubmed), CINAHL Complete (via EBSCOhost), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scielo, Scopus. Adicionalmente, a pesquisa de estudos não publicados incluirá o Repositório Científico de Acesso Aberto de Portugal (RCAAP) e o OpenGrey. A estratégia de pesquisa abrangerá todos os artigos publicados em português, espanhol, francês e inglês, sem limite temporal. Resultados: Os dados serão apresentados em formato narrativo, com recurso a tabelas, alinhadas com o objetivo, foco e questão de revisão. O mapeamento da evidência disponível sobre metodologias pedagógicas em enfermagem de saúde familiar contribuirá para a disseminação da evidência disponível sobre o tema e permitirá identificar lacunas na literatura. Conclusão: Espera-se que a presente scoping review contribua para a análise crítica das metodologias pedagógicas em enfermagem de saúde familiar, dado o potencial impacto destas no desenvolvimento de competências dos estudantes de enfermagem.

Objetivo: Mapear las metodologías pedagógicas utilizadas en la enseñanza de la enfermería de la salud familiar. Más específicamente, se pretende dar respuesta a las siguientes preguntas: 1) ¿Cuáles son las metodologías pedagógicas utilizadas en la enseñanza de la enfermería de la familia? 2) ¿En qué nivel de enseñanza se utilizan estas metodologías pedagógicas? 3) ¿En qué contexto se utilizan estas metodologías pedagógicas? Método: Scoping review, orientada por la metodología propuesta por el Joanna Briggs Institute para la realización de scoping reviews. En la estrategia de investigación e identificación de estudios, se utilizarán las bases de datos electrónicas CINAHL Complete (vía EBSCOhost), MEDLINE (vía Pubmed), Registro Cochrane Central de Ensayos Controlados, Base de Datos Cochrane de Revisiones Sistemáticas, Scielo e Scopus. A su vez, la búsqueda de estudios inéditos incluirá el Repositorio Científico de Acceso Abierto de Portugal (RCAAP) y OpenGrey. La estrategia de búsqueda incluirá todos los artículos publicados en portugués, español, francés e inglés, sin límite de tiempo. Resultados: Los datos se presentarán en formato narrativo, utilizando tablas, alineados con el objetivo, enfoque y pregunta de revisión. El mapeo de la evidencia disponible sobre metodologías pedagógicas en enfermería de la familia contribuirá para la difusión de la evidencia disponible sobre el tema y permitirá identificar lagunas en la literatura. Conclusión: Se espera que la revisión contribuya al análisis crítico de las metodologías pedagógicas en enfermería de salud familiar, dado su potencial impacto en el desarrollo de habilidades del estudiantado de enfermería.

Aim: To map the pedagogical methodologies used in the teaching of family health nursing. More specifically, this study intends to answer the following questions: 1) What are the pedagogical methodologies used in family nursing education? 2) At what level of education are such pedagogical methodologies used? 3) In what context are such pedagogical methodologies used? Method: A scoping review will be conducted using the Joanna Briggs Institute's methodology for conducting Scoping Reviews. For the research strategy and identification of studies, the following electronic databases will be consulted MEDLINE (via Pubmed), CINAHL Complete (via EBSCOhost), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scielo, and Scopus. In addition, the search for unpublished studies will include the Scientific Repository for Open Access of Portugal (RCAAP), and OpenGrey. The research strategy will include all articles published in Portuguese, Spanish, French and English with a time limit. Results: Following the objective, focus and research questions, the data will be presented in a narrative format, using tables. The mapping of the available evidence on pedagogical methodologies in family nursing will contribute to the dissemination of the available evidence on this subject matter and will ease the identification of the literature. Conclusion: It is expected that this scoping review will contribute to the critical analysis of pedagogical methodologies in family health nursing given their potential impact on the development of skills of nursing students.

Metodologias pedagógicas em enfermagem de saúde familiar: Scoping review / Pedagogical methodologies in family health nursing: Scoping review / Metodologías pedagógicas en enfermería de salud familiar: Scoping review

Resumo Contexto: As metodologias pedagógicas adotadas são um fator importante na aquisição e desenvolvimento de competências dos estudantes de enfermagem. Não obstante, as metodologias pedagógicas utilizadas no ensino de enfermagem de saúde familiar encontram-se dispersas na literatura. Objetivo: Mapear as metodologias pedagógicas utilizadas no ensino de enfermagem de saúde familiar. Método de revisão sistemática: Scoping review com base nos princípios preconizados pelo Joanna Briggs Institute. Dois revisores independentes realizaram a análise de relevância dos artigos, a extração e síntese dos dados. Apresentação e interpretação dos resultados: Dois estudos foram incluídos na revisão. Foram utilizadas como metodologias pedagógicas o debriefing estruturado e a narração dialógica. Ambos os estudos foram implementados em estudantes da graduação de enfermagem. Um dos estudos foi realizado unicamente em contexto de laboratório e outro, adicionalmente, em contexto real. Conclusão: As metodologias pedagógicas e os contextos de implementação diferem entre os estudos. Mais estudos devem ser realizados no âmbito das metodologias pedagógicas em enfermagem de saúde familiar.

Abstract Background: Pedagogical methodologies are a critical factor in nursing students' acquisition and development of skills. Nevertheless, the pedagogical methodologies used in family health nursing education are scattered in the literature. Objective: To map the pedagogical methodologies used in family health nursing education. Review method: Scoping review based on the principles advocated by the Joanna Briggs Institute. Two independent reviewers appraised the articles and extracted and synthesized data. Presentation and interpretation of results: Two studies were included in this review. Structured debriefing and dialogical narrative were used as pedagogical strategies. Both studies were implemented on undergraduate nursing students. One of the studies was conducted in a laboratory setting and the other in a laboratory setting and a real-life environment. Conclusion: Pedagogical methodologies and implementation contexts differ across studies. Further studies should be conducted on the pedagogical strategies used in family health nursing.

Resumen Contexto: Las metodologías pedagógicas adoptadas son un factor importante en la adquisición y el desarrollo de las competencias de los estudiantes de enfermería. Sin embargo, las metodologías pedagógicas utilizadas en la enseñanza de enfermería de salud familiar están dispersas en la literatura. Objetivo: Mapear las metodologías pedagógicas utilizadas en la enseñanza de enfermería de salud familiar. Método de revisión sistemática: Revisión de alcance (scoping review) basada en los principios recomendados por el Joanna Briggs Institute. Dos revisores independientes realizaron el análisis de la relevancia de los artículos, la extracción de datos y la síntesis. Presentación e interpretación de los resultados: Se incluyeron dos estudios en la revisión. Se utilizaron como metodologías pedagógicas el debriefing estructurado y la narración dialógica. Ambos estudios se llevaron a cabo en estudiantes de enfermería de primer ciclo. Uno de los estudios se realizó únicamente en un entorno de laboratorio y el otro, además, en un contexto real. Conclusión: Las metodologías pedagógicas y los contextos de aplicación difieren entre los estudios. Deberían realizarse más estudios en el ámbito de las metodologías pedagógicas en enfermería de salud familiar.

REATIVA: An Efficient Health Promotion Program during Retirement Transition.

Retirement is a major life transition in adulthood that can cause vulnerability in individuals and their families. REATIVA is a face-to-face health intervention program that aims to promote the perception of self-efficacy and facilitate the transition to retirement of individuals and families. This article presents the efficiency of this program. A quasi-experimental study was conducted on 56 new retirees and families enrolled in the Portuguese National Health Service. The efficiency of the program was evaluated with the General Self-Efficacy (GSE) scale, which assesses self-efficacy, and the Retirement Adaptation Perception (EPFAR) scale, which assesses the perception of adaptation to retirement. The data were processed in IBM SPSS 27 software. An average positive change was found regarding the GSE and EPFAR in all participants of the REATIVA program. Notably, the MANOVA test with Greenhouse-Geisser correction revealed a significant effect of the program over time in the EPFAR scale (F = 17.405, p = 0.001; η2 = 0.554; PO = 0.982). The REATIVA program was found to be efficient in the promotion of individual and family health during the transition to retirement as an active and healthy aging process. New methodologies and intervention strategies were identified that could improve the efficacy of the program; namely, the involvement of more family members and using a blended approach.

Multi-Targeting Approach in Glioblastoma Using Computer-Assisted Drug Discovery Tools to Overcome the Blood-Brain Barrier and Target EGFR/PI3Kp110ß Signaling.

The epidermal growth factor receptor (EGFR) is upregulated in glioblastoma, becoming an attractive therapeutic target. However, activation of compensatory pathways generates inputs to downstream PI3Kp110ß signaling, leading to anti-EGFR therapeutic resistance. Moreover, the blood-brain barrier (BBB) limits drugs' brain penetration. We aimed to discover EGFR/PI3Kp110ß pathway inhibitors for a multi-targeting approach, with favorable ADMET and BBB-permeant properties. We used quantitative structure-activity relationship models and structure-based virtual screening, and assessed ADMET properties, to identify BBB-permeant drug candidates. Predictions were validated in in vitro models of the human BBB and BBB-glioma co-cultures. The results disclosed 27 molecules (18 EGFR, 6 PI3Kp110ß, and 3 dual inhibitors) for biological validation, performed in two glioblastoma cell lines (U87MG and U87MG overexpressing EGFR). Six molecules (two EGFR, two PI3Kp110ß, and two dual inhibitors) decreased cell viability by 40-99%, with the greatest effect observed for the dual inhibitors. The glioma cytotoxicity was confirmed by analysis of targets' downregulation and increased apoptosis (15-85%). Safety to BBB endothelial cells was confirmed for three of those molecules (one EGFR and two PI3Kp110ß inhibitors). These molecules crossed the endothelial monolayer in the BBB in vitro model and in the BBB-glioblastoma co-culture system. These results revealed novel drug candidates for glioblastoma treatment.

Quercetin Liposomal Nanoformulation for Ischemia and Reperfusion Injury Treatment.

Ischemia and reperfusion injury (IRI) is a common complication caused by inflammation and oxidative stress resulting from liver surgery. Current therapeutic strategies do not present the desirable efficacy, and severe side effects can occur. To overcome these drawbacks, new therapeutic alternatives are necessary. Drug delivery nanosystems have been explored due to their capacity to improve the therapeutic index of conventional drugs. Within nanocarriers, liposomes are one of the most successful, with several formulations currently in the market. As improved therapeutic outcomes have been demonstrated by using liposomes as drug carriers, this nanosystem was used to deliver quercetin, a flavonoid with anti-inflammatory and antioxidant properties, in hepatic IRI treatment. In the present work, a stable quercetin liposomal formulation was developed and characterized. Additionally, an in vitro model of ischemia and reperfusion was developed with a hypoxia chamber, where the anti-inflammatory potential of liposomal quercetin was evaluated, revealing the downregulation of pro-inflammatory markers. The anti-inflammatory effect of quercetin liposomes was also assessed in vivo in a rat model of hepatic IRI, in which a decrease in inflammation markers and enhanced recovery were observed. These results demonstrate that quercetin liposomes may provide a significant tool for addressing the current bottlenecks in hepatic IRI treatment.

Antagonist G-targeted liposomes for improved delivery of anticancer drugs in small cell lung carcinoma.

Ligand-mediated targeted liposomes have the potential to increase therapeutic efficacy of anticancer drugs. This work aimed to evaluate the ability of antagonist G, a peptide targeting agent capable of blocking the action of multiple neuropeptides, to selectivity improve targeting and internalization of liposomal formulations (long circulating liposomes, LCL, and stabilized antisense lipid particles containing ionizable amino lipid, SALP) to H69 and H82 small cell lung carcinoma (SCLC) cell lines. Antagonist G-targeted LCL and SALP were prepared by two different methods (either by direct covalent linkage at activated PEG grafted onto the liposomal surface or by post-insertion of DSPE-PEG-antagonist-G-conjugates into pre-formed liposomes). Association of the liposomal formulations with target SCLC cells was studied by fluorescence microscopy using fluorescence-labelled liposomes and confirmed quantitatively with [3H]-CHE-labelled liposomes. An antisense oligodeoxynucleotide against the overexpressed oncogene c-myc(as(c-myc)) was efficiently loaded into SALP formulations, the encapsulation efficiency decreased due to the inclusion of the targeting ligand. Also, liposome size was affected by as(c-myc) physical chemical properties. The amount of antagonist G linked to the surface of the liposomal formulations was dependent on the coupling method and lipid composition used. Covalent attachment of antagonist G increased liposomes cellular association and internalization via receptor-mediated and clathrin-dependent endocytosis, as assessed in SCLC cell lines. Biodistribution studies in healthy mice revealed a preferential lung accumulation of antagonist G-targeted SALP as compared to the non-targeted counterpart. Lung levels of the former were up to 3-fold higher 24 h after administration, highlighting their potential to be used as delivery vectors for SCLC treatment.

Acquired Hemophilia A associated with bullous pemphigoid: A rare combination.

Acquired Hemophilia A (AHA) is a rare autoimmune disorder, caused by the development of circulating autoantibodies against coagulation factor VIII (FVIII). AHA is associated with bullous pemphigoid in 2% of patients. We report a case of a 74-year-old man admitted with anemia and a tense subcutaneous and muscular hematoma in the right thigh. Blood analysis confirmed AHA. The patient had a recent diagnosis of bullous pemphigoid. Response to bypass agents and corticosteroids was good with bleeding control and normalization of FVIII and negative autoantibodies, respectively. In a 3-month follow-up period after tapering and stopping prednisolone, a relapse occurred, and immunosuppression was reinitiated. An early diagnosis and effective treatment in AHA are essential to reduce morbimortality. A careful tapering of immunosuppression is important to minimize FVIII inhibitor recurrence, as observed in this case.

Manganese(I) tricarbonyl complexes as potential anticancer agents.

The antiproliferative activity of [Mn(CO)3(N^N)Br] (N^N = phendione 1, bipy 3) and of the two newly synthesized Mn complexes [Mn(CO)3(acridine)(phendione)]OTf (2) and [Mn(CO)3(di-triazole)Br] (4) has been evaluated by MTS against three tumor cell lines A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), HCT116doxR (colorectal carcinoma resistant to doxorubicin), and in human dermal fibroblasts. The antiproliferative assay showed a dose-dependent effect higher in complex 1 and 2 with a selectivity toward ovarian carcinoma cell line 21 times higher than in human fibroblasts. Exposure of A2780 cells to IC50 concentrations of complex 1 and 2 led to an increase of reactive oxygen species that led to the activation of cell death mechanisms, namely via intrinsic apoptosis for 2 and autophagy and extrinsic apoptosis for 1. Both complexes do not target DNA or interfere with cell cycle progression but are able to potentiate cell migration and neovascularization (for 2) an indicative that their application might be directed for initial tumor stages to avoid tumor invasion and metastization and opening a new avenue for complex 2 application in regenerative medicine. Interestingly, both complexes do not show toxicity in both in vivo models (CAM and zebrafish).

Phaffia brasiliana sp. nov., a yeast species isolated from soil in a Cerrado-Atlantic Rain Forest ecotone site in Brazil.

During studies of yeasts associated with soil in a Cerrado-Atlantic Rain Forest ecotone site in Brazil, three orange-pigmented yeast strains were isolated from samples collected in Minas Gerais state, Brazil. Molecular analyses combining the 26S rRNA gene (D1/D2 domains) and the internal transcribed spacer (ITS) sequences as well as whole-genome sequence data showed that these strains could not be ascribed to any known species in the basidiomycetous genus Phaffia, and thus they are considered to represent a novel species for which the name Phaffia brasiliana sp. nov. is proposed. The holotype is CBS 16121T and the MycoBank number is MB 839315. The occurrence of P. brasiliana in a tropical region is unique for the genus, since all other species occur in temperate regions. Two factors appear to contribute to the distribution of the novel taxon: first, the region where it was found has relatively moderate temperature ranges and, second, an adaptation to grow or withstand temperatures higher than those of the other species in the genus seems to be in place.