SKOR1 mediates FER kinase-dependent invasive growth of breast cancer cells.

High expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity of FER is essential for its oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MB-231 cells reduces migration and invasion, as well as metastasis when xenografted into a mouse model of breast cancer. Using the FERASKI system, we identified Ski family transcriptional corepressor 1 (SKOR1) as a direct FER kinase substrate. SKOR1 loss phenocopies FER inhibition, leading to impaired proliferation, migration and invasion, and inhibition of breast cancer growth and metastasis formation in mice. We show that SKOR1 Y234, a candidate FER phosphorylation site, is essential for FER-dependent tumor progression. Finally, our work suggests that the SKOR1 Y234 residue promotes Smad2/3 signaling through SKOR1 binding to Smad3. Our study thus identifies SKOR1 as a mediator of FER-dependent progression of high-risk breast cancers.

HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia.

Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.

A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion.

Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion.

FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer.

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.

Idiopathic Multicentric Hyaline Vascular-Type Castleman Disease.

Castleman disease is a rare lymphoproliferative disorder presenting with localized or disseminated lymphadenopathy and systemic symptoms. It can be categorized clinically as unicentric or multicentric, histopathologically as hyaline vascular, plasma cell, or mixed variant, and etiologically, considering the subtypes based on causative viral agents and associated syndromes. The multicentric type can mimic other haematological malignancies, ranging from asymptomatic to multiple organ involvement. Although its pathophysiology is not well known, the current approved treatments are directed towards interleukin-6, CD-20, and viral agents. The authors present an 82-year-old leucodermic man presented with a 2-week history of constitutional symptoms. Examination revealed pallor, hepatosplenomegaly, and palpable left axillary lymphadenopathy. Investigation showed anaemia, thrombocytopenia, polyclonal hypergammaglobulinemia, hypoalbuminemia, and high acute phase reactants, with image study revealing multiple axillary, mediastinal, inguinal, and pelvic lymphadenopathies. The lymph node biopsy was consistent with hyaline vascular-type Castleman disease without human herpersvirus-8 markers. He started prednisolone with initial improvement evolved poorly on a short term. Castleman disease has a broad spectrum of clinical manifestations, associations, and complications that bring a diagnostic challenge, requiring a multidisciplinary approach. Clinicians should be familiar with its features because proper diagnosis and aggressive targeted treatment are the pillars of proper management of these patients.

The GoodHope Ehlers Danlos Syndrome Clinic: development and implementation of the first interdisciplinary program for multi-system issues in connective tissue disorders at the Toronto General Hospital.

Ehlers-Danlos Syndrome (EDS) are a heterogeneous group of genetic connective tissue disorders, and typically manifests as weak joints that subluxate/dislocate, stretchy and/or fragile skin, organ/systems dysfunction, and significant widespread pain. Historically, this syndrome has been poorly understood and often overlooked. As a result, people living with EDS had difficulty obtaining an accurate diagnosis and appropriate treatment, leading to untold personal suffering as well as ineffective health care utilization. The GoodHope EDS clinic addresses systemic gaps in the diagnosis and treatment of EDS. This paper describes a leap forward-from lack of awareness, diagnosis, and treatment-to expert care that is tailored to meet the specific needs of patients with EDS. The GoodHope EDS clinic consists of experts from various medical specialties who work together to provide comprehensive care that addresses the multi-systemic nature of the syndrome. In addition, EDS-specific self-management programs have been developed that draw on exercise science, rehabilitation, and health psychology to improve physical and psychosocial wellbeing and overall quality of life. Embedded into the program are research initiatives to shed light on the clinical presentation, underlying mechanisms of pathophysiology, and syndrome management. We also lead regular educational activities for community health care providers to increase awareness and competence in the interprofessional management of EDS beyond our doors and throughout the province and country.

Adult patient perspectives on phenylketonuria care: Highlighting the need for dedicated adult management and services.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by an inability to metabolize the amino acid phenylalanine (Phe). If left untreated, an accumulation of Phe results in neurodevelopmental, neurological and psychological impairments. Advancements in detection and treatment of PKU have improved outcomes and life expectancy for these patients, emphasizing the need for life-long, specialized care. Due to the paucity of adult-focused PKU clinics, patients who are well into adulthood are still being treated in pediatric centers. This retrospective study evaluates the perceived expectations, benefits and challenges of 50 adult PKU patients (mean age 31.3 ± 10.4 years) transitioning from a pediatric to adult care setting using a transition questionnaire administered at the first clinic visit at the adult PKU care center. Patients reported a lack of access to adult resources and adult-specific PKU educational material in their pediatric PKU clinic. In contrast, the established relationships with the pediatric health care team and familiarity with treatment plans were aspects of pediatric care that patients enjoyed. The results from this study will contribute to the optimization of adult PKU patient care, establishment of strategies for transitioning adults with PKU and other metabolic disorders from pediatric to adult care, and support the need to establish adult-only PKU care facilities.

Identification of a Novel Mutation in a Family with Pseudohypoparathyroidism Type 1a.

INTRODUCTION: Pseudohypoparathyroidism type 1a is caused by GNAS mutations leading to target organ resistance to multiple hormones rather than parathyroid hormone, resulting not only in hypocalcemia, but also in Albright's hereditary osteodystrophy phenotype. MATERIALS AND METHODS: DNA sequencing of the GNAS gene identified a novel heterozygous mutation in peripheral blood leukocytes in the family presented in this case report. RESULTS: We present a case of a 25-year-old woman with pseudohypoparathyroidism type 1a admitted with seizures, whose family presents an autosomal dominant transmission of a novel heterozygous GNAS mutation (c.524_530+3del). CONCLUSION: Pseudohypoparathyroidism type 1a is mostly caused by inactivating GNAS mutations that have been gradually reported in the literature that lead to a typical and complex clinical phenotype and resistance to multiple hormones. The deletion caused by the mutation identified in the presented case has not been reported previously.

Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells.

Studies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. A careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies.

[The used of the nursing laboratory by nursing students]. / CARACTERÍSTICAS DO TREINAMENTO DE ESTUDANTES NO LABORATÓRIO DE ENFERMAGEM.

The authors describle the results of a small survey of the students' training for in the Nursing Laboratory of the School of Nursing the improvment of their psychomotor hability classroom laboratory. The students answered questions on the motivation for the use of the Laboratory, preferences for training alone or with classmates and for using the doll or a classmate to simulate the patient, the monitoring of a senior student, the bibliography used and the procedures selected for training.

GNAQ and BRAF mutations show differential activation of the mTOR pathway in human transformed cells.

Somatic mutations in GNAQ gene were described as being the main oncogenic activation in uveal melanomas, whereas mutations in BRAF gene have been described as a key genetic alteration that contributes to skin melanoma development. We have previously reported differential activation of the MAPK and AKT/mTOR signalling pathways in uveal and skin melanomas harbouring, respectively, GNAQ and BRAF mutations. The aim of this work was to compare the functional effect of GNAQ and BRAF mutations in mTOR and MAPK pathway activation, cell proliferation and apoptosis. In this work, we performed transient transfection of HEK293 cells with BRAF(WT), BRAF(V 600E), GNAQ(WT), GNAQ(Q209P) and GNAQ(Q209L) vectors. We treated melanoma cell lines displaying different BRAF and GNAQ mutational status with the mTOR inhibitor RAD001 and with the MEK1/2 inhibitor U0126 and evaluated the effects in the growth of the cell lines and in mTOR and MAPK pathway effectors expression. At variance with the significant increase in the level of pmTOR Ser2448 and pS6 Ser235/236 proteins observed in cells transfected with BRAF vectors, no significant alteration in mTOR pathway effectors was observed in cells transfected with the three GNAQ expressing vectors. Also, GNAQ overexpression enhances Stat3 activation, which might mediate GNAQ oncogenic effects. None of the vectors led to significant differences in proliferation or apoptosis in the transfected cell lines. Cell lines harbouring a BRAF mutation were more sensitive to RAD001 treatment. U0126 leads to the reduction of MAPK and mTOR pathways activation in all cell lines tested. Our results indicate that GNAQ and BRAF activation drive distinct intracellular signalling pathways that may be useful for therapeutic decisions in human melanomas.

Degradation pathway of pentachlorophenol by Mucor plumbeus involves phase II conjugation and oxidation-reduction reactions.

Environmental pollution by pentachlorophenol (PCP) is a critical concern worldwide and fungal bioremediation constitutes an elegant and environment-friendly solution. Mucorales from the Zygomycota phylum are often observed to be competitive in field conditions and Mucor plumbeus, in particular, can efficiently deplete PCP from media. The pathway for PCP degradation used by this fungus has not been investigated. In this study, PCP-derived metabolites were identified by liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, including tetra- and tri-chlorohydroquinones and phase II-conjugated metabolites. Amongst the latter are the previously reported glucose, sulfate and ribose conjugates, and identified for the first time in fungi sulfate-glucose conjugates. A PCP transformation pathway for M. plumbeus is proposed, which excludes the involvement of cytochrome P-450 and extracellular ligninolytic enzymes.

The effect of folate status on the uptake of physiologically relevant compounds by Caco-2 cells.

The aim of this work was to investigate the effect of folate status on the uptake of several physiologically relevant substances by Caco-2 cells. For this, Caco-2 cells cultured in high-folate conditions (HF) and low-folate conditions (LF) were compared. Growth rates of HF and LF Caco-2 cells were similar. However, proliferation rate of LF cells was greater than that of HF cells during the first 2days of culture and slightly smaller thereafter, viability of LF cells was greater than that of HF cells, and apoptosis index was similar in both cell cultures. We verified that in LF cells, comparatively to HF cells: (1) uptake of [3H]folic acid is upregulated, via an increase in the Vmax of uptake; (2) uptake of [3H]deoxy-glucose, [3H]O-methyl-glucose and [3H]1-methyl-4-phenylpyridinium (MPP+) is downregulated, via a decrease in the Vmax of uptake; additionally, a reduction in Km was observed for [3H]O-methyl-glucose; (3) uptake of [3H]5-hydroxytryptamine and [14C]butyrate is not changed; and (4) the steady-state mRNA levels of the folic acid transporters RFC (reduced folate carrier), PCFT (proton-coupled folate transporter) and FRalpha (folate receptor alpha), of the organic cation transporter OCT1 (organic cation transporter type 1), of the glucose transporter GLUT2 (facilitative glucose transporter type 2) and of the butyrate transporter MCT1 (monocarboxylate transporter type 1) were decreased. In conclusion, folate deficiency produces substrate-specific changes in the uptake of bioactive compounds by Caco-2 cells. Moreover, these changes are associated with alterations in the mRNA levels of specific transporters for these compounds.

Caracterização físico-química da mucilagem de inhame liofilizada / Physical and chemical characteristics of the mucilage of lyophilized yam

A mucilagem do inhame desempenha papel de interesse na indústria de alimentos em razão das suas propriedades como espessante, estabilizante e emulsificante. Neste estudo, objetivou-se caracterizar a mucilagem liofilizada do inhame por meio de análises físicas, químicas e reológicas. Foram determinados a composição centesimal, valor calórico, pH, acidez, sais minerais, vitamina C, açúcares totais, polifenóis, pectinametilesterase, poligalacturonase, termogravimétrica, análise térmica diferencial, calorimetria diferencial de varredura, espectroscopia infravermelho e viscosidade aparente. A mucilagem de inhame liofilizada apresentou elevados teores de proteína bruta e fibra alimentar e baixos teores de fração glicídica e de valor calórico. Quanto à análise termogravimétrica a mucilagem de inhame demonstrou maior perda de massa cerca de 60 por cento à temperatura média de 200º C, o que inviabiliza o seu uso acima desta temperatura.

The mucilage of yam is of interest in the food industry due to its properties as a thickener, stabilizer and emulsifier. The aim of this study was to characterize the freeze-dried mucilage of yam through physical analysis, chemical and rheological properties. The study measured the proximate composition, caloric value, pH, acidity, minerals, vitamin C, sugars, polyphenols, pectin methylesterase, polygalacturonase, thermogravimetric, differential thermal analysis, differential scanning calorimetry, infrared spectroscopy and viscosity. The lyophilized yam mucilage showed high levels of crude protein and dietary fiber content and low fraction of glucose and calories. A thermogravimetric analysis mucilage of the yam showed a higher weight loss (about 60 percent) at an average temperature of 200º C, thus precluding their use above this temperature.

O médico militar brasileiro e os desafios éticos da profissão / The Brazilian military medical and ethical challenges of the profession

Ethos refere-se ao modo de viver de indivíduos ou grupos e suas escolhas, nos relacionamentos entre si e o meio em que vivem. O médico militar no Brasil responde ao ethos profissional militar ou da Medicina conforme a forma de acesso ou opção pessoal de exercer suas atividades exclusivamente no meio militar. Tal fato sinaliza a coexistência de dois indivíduos, possuidores de ethos profissionais diferentes (médico, militar e médico militar) e diferenciados (forma de acesso e opção pessoal). A questão de estudo, o ethos profissional médico predomina sobre o ethos profissional militar nas atividades do médico militar brasileiro teve o objetivo de analisar o ethos médico no âmbito da estrutura militar brasileira, enquanto profissão, e seus desafios éticos. Os objetivos específicos foram: discutir aspectos sociológicos e éticos estruturantes da profissão, para identificar quem é o cliente do médico militar, qual a natureza de sua relação cliente-profissional; quais são os fins, os meios e as obrigações profissionais do médico militar brasileiro; abordar suas diretivas profissionais de caráter ético-profissional vigentes em nosso país; identificar os possíveis conflitos éticos enfrentados de sua carreira/cotidiano de suas atividades e perspectivas de quais serão as questões éticas a serem enfrentadas no futuro da profissão...

Ethos refers to people's way of life, or groups, in relationships with each other and with the environment in which they live. The military physician in Brazil responds to the professional military ethos or to the Medicine as the forms of access or the personal choice to exercise their activities exclusively in the military. There is a coexistence of two individuals, owners of different professionals ethos (physician, military and military physician) and differentiated (means of access and personal choice).The study question, a the professional medical ethos prevails over the professional military ethos of the Brazilian military physician, had the aim of analyzing the medical practice within the Brazilian military structure, while as profession, and its ethos faced of ethical challenges. The specific objectives are: discussing of the structural sociological and ethical aspects of the profession, to identify who is the military physician's customer, what is the type of its client-professional relationship; what are the purposes; and which are the means; and which are the Brazilian military doctor's professional obligations; approach to their professional policies, with ethical and professional concept, prevailing in our country; Identifying the potential ethical conflicts faced in their career/daily life of their activities and perspectives which are the ethical questions that will be faced in the professional's future...

Qualidade da carne de marreco pequim branco (Anas Platyrhynchos platyrhynchos L. 1758) comparado a frango de corte / Meat quality in white peking mallard (Anas Platyrhynchos platyrhynchos L. 1758 ) compared to broiler chicken

O total de 20 carcaças resfriadas (10 Marrecos Pequim Branco e 10 de frangos de corte) foi submetido às análises de composição centesimal, colesterol, cor (sistema CIE L*a*b*), perda de peso por cozimento (PPC) e força de cisalhamento (FC). A carne de marreco apresenta (P<0,05) menos umidade (71,77 e 74,53 por cento), do que a carne de frango (74,73 e 76,07 por cento). Quando comparados os cortes, o peito mostrou (P<0,05) médias mais elevadas de umidade e proteína, do que no corte perna. A carne de marreco mostra (P<0,05) luminosidade mais baixa (37,59 e 35,75) e maior teor de vermelho (18,48 a 20,67), do que a luminosidade (40,98 e 45,18) e o teor de vermelho (10,02 e 5,52) observado em frangos. A FC foi (P<0,05) mais elevada (4,90 kgf) em peito de marrecos, do que em peito de frango (2,63 kgf). A carne de Marreco Pequim Branco é mais escura e com vermelho mais intenso do que carne de frango de corte. Embora menos macia do que a carne de frango, a carne de marreco é considerada macia.

Twenty refrigerated carcasses (10 Peking mallard and 10 broiler chicken) were submitted to analyses of chemical composition, cholesterol, colour (CIE L*a*b* system), weight loss by cooking (PPC) and shear force (FC). Mallard meat had lower (P<0.05) humidity in both leg and breast (71.77 and 74.53 percent, respectively) when compared with chicken meat (74.73 and 76.07 percent, respectively). When different cuts were compared, the breast had a higher (P<0.05) humidity and protein content than the leg in both species. Mallard leg and breast had lower (P<0.05) lightness (37.59 and 35.75, respectively) and higher red content (18.48 and 20.67, respectively), than the lightness (40.98 and 45.18, respectively) and red content (10.02 and 5.52, respectively) observed in chicken. The FC was higher (P<0.05) in mallard breast (4.90 kgf) than in chicken breast (2.63 kgf). Meat from White Peking mallard is darker and with a stronger red pigment than meat from broiler chicken. Even though it is less tender than meat from broiler chicken, mallard meat still has an acceptable tenderness.

Condições de trabalho nos hospitais públicos de São Paulo: percepções e impressões do diretor de enfermagem / Working conditions in public hospitals in São Paulo: observations and impressions of the nursing director

Foram entrevistados 20 diretores de enfermagem em hospitais públicos na cidade de São Paulo, com o objetivo de levantar as percepções e as impressões desses responsáveis técnicos sobre as condições de trabalho oferecidas pela Secretaria de Estado da Saúde de São Paulo. Utilizamos escalas classificatórias e somatórias Likert para abordar o grau de satisfação com as condições de trabalho referenciadas por Berti et al. Na opinião desses responsáveis técnicos, 64,7 por cento desses hospitais apresentam condição suficientemente satisfatória de trabalho, 23,5 por cento condição satisfatória, 11,7 por cento não satisfatória e não houve instituição com condição de trabalho altamente satisfatória para assistencia de enfermagem.

Moradia e corporeidade em espaços lineares: um estudo sobre formas de subjetividade na favela / Dwelling, human corporeity in liminal spaces: a study about forms of subjectivity in a slum

Esta pesquisa aborda a construção e a revelação de formas de subjetividade em uma comunidade fronteiriça situada numa favela - espaço limiar, marcado pela instabilidade geográfica, social e existencial - de São Paulo. Realizou-se, por três anos, uma observação participante e foram colhidos depoimentos de quatro famílias focalizando-se a história do movimento comunitário e a transformação do espaço. Os resultados indicaram que os moradores da favela, migrantes nordestinos, habitam entre duas sociedades de referência: a comunidade natal e a de destino, vivendo numa espécie de "abismo" na sociedade de destino, excluídos de forma dominante de ocupação do espaço e incluídos em formas transitórias de ocupação dos espaços-entre. Além disso, constatou-se: formas híbridas de subjetividade que articulam experiências de enraizamento e desenraizamento, estratégias solidárias e perversas de inclusão; o importante papel da mulher nos movimentos de organização dos espaços públicos e privados e a pertinência da relação entre subjetividade, moradia e corporeidade.

The used of the nursing laboratory by nursing students / Características do treinamento de estudantes no laboratório de enfermagem

As autoras descrevem os resultados de um levantamento realizado em laboratório de enfermagem (LE), com a finalidade de verificar algumas características de treinamento de estudantes para a aquisição de habilidades psicomotoras. Os alunos responderam a um questionário com questões versando sobre a motivação para o uso do LE, preferencias quanto à companhia para o treinamento, à orientação, à forma de simular o cliente, ao auxílio provido por aluno monitor, às fases dos procedimentos treinados e ao êxito alcançado.

The authors describle the results of a small survey of the students' training for in the Nursing Laboratory of the School of Nursing the improvment of their psychomotor hability classroom laboratory. The students answered questions on the motivation for the use of the Laboratory, preferences for training alone or with classmates and for using the doll or a classmate to simulate the patient, the monitoring of a senior student, the bibliography used and the procedures selected for training.