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.

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.

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.

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.

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.

Percepção corporal em pré-adolescentes e adolescentes com sobrepeso e obesidade: uma análise junguiana / Body perception in pre-adolescents and adolescents with overweight and obesity: a junguian análisis

O enfrentamento da obesidade demanda suporte psicossocial frente à prevalência de psicopatologias associadas ao viés do peso na adolescência. Analisou-se percepção corporal em 63 sujeitos, 37 meninos e 26 meninas, de 9 a 14 anos, de Monteiro Lobato, São Paulo, por meio do Desenho de Percepção Corporal. Avaliaram-se correlações entre consciência, persona corporal, sexo, idade e IMC por Qui-quadrado. Resultados: IMC influencia na percepção do Contorno Corporal. Sexo e idade influenciam na integração. Meninas e meninos pré-adolescentes obesos apresentaram, respectivamente, alteração limítrofe na percepção de Contorno e Postura Corporal. Para a psicologia junguiana, a obesidade na adolescência ativa conflitos inconscientes, altera o equilíbrio do ego, reforça o isolamento e realimenta a crise identitária. Percepção corporal, tema pouco explorado, demanda pesquisa, amostra ampliada e validação de instrumentos para estudo da obesidade na adolescência.

The confrontation of obesity demands psychosocial support in face of the high prevalence of psychopathologies associated with weight bias in adolescence. Body perception was analyzed in 63 subjects, 37 boys and 26 girls from 9 to 14 years old from Monteiro Lobato, São Paulo, through the Body Perception Drawing. The evaluation was based on body conscience and persona, correlated to sex, age and BMI via Chi-Square. Results: BMI influences the perception of Body Contour. Sex and age influence Integration. Obese pre-adolescent girls and boys presented borderline alteration in the Contour and Body Posture perception, respectively. For jungian psychology, obesity in adolescence activates unconscious conflicts, alters the ego balance, reinforces isolation and feeds the identity crisis. Body perception, an unexplored topic demands for research and validation of instruments for the understanding of obesity in adolescence.

Hacer frente a la obesidad requiere apoyo psicosocial en vista de la prevalencia de psicopatologías asociadas con el peso en la adolescencia. La percepción corporal se analizó en 63 sujetos, 37 niños y 26 niñas, de 9 a 14 años, de Monteiro Lobato, São Paulo, a través del Dibujo de Percepción Corporal. Se evaluaron las correlaciones entre Consciencia, Persona del cuerpo, Sexo, Edad e IMC por Chi-Square. Resultados: el IMC influye en la Percepción del contorno corporal. El género y la edad influyen en la integración. Niñas y niños obesos pre-adolescentes, respectivamente, presentaron cambios limítrofes en la percepción del contorno y la postura corporal. Para la psicología junguiana, la obesidad en la adolescencia activa conflictos inconscientes, altera el equilibrio del ego, refuerza el aislamiento y alimenta la crisis de identidad. La percepción corporal exige investigación, muestra ampliada y validación de instrumentos para el estudio de la obesidad en la adolescencia.

Tomada de decisão em epidemias e pandemias: reflexões éticas para profissionais da saúde no Brasil

O foco do presente capítulo é discutir as questões ético-legais envolvidas no rastreamento de casos, manejo, oferta de cuidado e tomada de decisão pelos profissionais e autoridades sanitárias em situações emergenciais de saúde, no contexto de epidemias e pandemias, tendo como fio condutor a doença pelo vírus ebola. Buscamos identificar os valores, princípios éticos e jurídicos envolvidos (AU)

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.

Participação social e regionalização: construção de um diálogo territorializado / Social participation and regionalization: the construction of a territorialized dialog

O artigo aborda a participação social em articulação com a regionalização da saúde no âmbito do SUS, com o objetivo de discutir de que forma tem se estruturado o diálogo entre os diversos atores das instâncias políticas e socioambientais do controle social. A coerência entre as expectativas veiculadas por estas políticas e sua operacionalização no plano territorial será analisada, por método compreensivo-racional, contrapondo as esperanças projectuais e os princípios subjacentes às dinâmicas de ordenamento da atenção à saúde em redes e de organização dos conselhos e movimentos sociais de saúde, através do estudo de caso do município de Jacareí. Discutiu-se a fragmentação socioambiental das paisagens, identidades e formas associativas vinculadas ao atravessamento pelo fenômeno da globalização; a precarização dos mecanismos formais de participação social e a não potencialização pela regionalização da saúde. Conclui-se que há significativos desajustes entre as esperanças projectuais das políticas de participação social e regionalização da saúde e o atendimento efetivo destas expectativas e se propôs formas de planejamento e gestão interativas, norteadas pela construção de modalidades dialógicas e territorializadas de interação social entre os diversos atores sociais do cenário da saúde.

Participação e movimentos sociais em saúde: esvaziamento ou desarticulação? / Participation and social movements in health: emptying or disarticulation?

Esse artigo problematiza a temática da participação no âmbito dos movimentos sociais em saúde...

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.

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...

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.

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.

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.