Phase- and Stage-Related Proportions of T Cells Bearing the Transcription Factor FOXP3 Infiltrate Primary Melanoma

Although tumor-infiltrating lymphocytes (TILs) of primary cutaneous melanoma (PCM) include cytolytic T cells able to exert anti-PCM immunity, progression of PCM most frequently occurs, raising the hypothesis that the PCM microenvironment may also exert suppressive forces, for example, possibly developed by regulatory T (TREG) lymphocytes. The aim of this study was to investigate whether TILs of PCMs include lymphocytes bearing the transcription factor forkhead box protein P3 (FOXP3), which is the TREG lineage specification molecule in mice, and is debated to have a similar role in humans. Fourteen patients with PCM were selected, of which four had radial growth phase (RGP) stage I melanoma, five had vertical growth phase (VGP) stage I melanoma, and five had VGP stage III–IV melanoma. Formalin-fixed, paraffin-embedded sections were utilized for immunohistochemical single and double stainings. TILs of PCMs included FOXP3-bearing lymphocytes, which predominantly were CD20- and CD8-negative, but CD3-, CD4-, and CD25-positive, thus consistent with the standard immunophenotypical characteristics of “natural” TREG cells. Further, the proportions of FOXP3-bearing lymphocytes were higher in vertical than in RGP (P=0.001), as well as in late than in early melanoma stages (P<0.001). Should these FOXP3-bearing lymphocytes actually exert regulatory capabilities within the PCM microenvironment, they may suppress “in vivo” the local anti-PCM immune response, thus favoring melanoma progression

Enhanced Arteriogenesis and Wound Repair in Dystrophin-Deficient <i>mdx</i> Mice

Background— The absence of functional dystrophin in Duchenne muscular dystrophy (DMD) patients and in mdx mice results in progressive muscle degeneration associated with necrosis, fibrosis, and inflammation. Because vascular supply plays a key role in tissue repair, we examined whether new blood vessel development was altered in mdx mice. Methods and Results— In a model of hindlimb ischemia on femoral artery dissection, hindlimb perfusion, measured by laser Doppler imaging, was higher in mdx mice (0.67±0.26) than in wild-type (WT) mice (0.33±0.18, P <0.03). In keeping with these data, a significant increase in arteriole length density was found in mdx mice (13.6±8.4 mm/mm 3 ) compared with WT mice (7.8±4.6 mm/mm 3 , P <0.03). Conversely, no difference was observed in capillary density between mice of the 2 genotypes. The enhanced regenerative response was not limited to ischemic skeletal muscle, because in a wound-healing assay, mdx mice showed an accelerated wound closure rate compared with WT mice. Moreover, a vascularization assay in Matrigel plugs containing basic fibroblast growth factor injected subcutaneously revealed an increased length density of arterioles in mdx (46.9±14.7 mm/mm 3 ) versus WT mice (19.5±5.8 mm/mm 3 , P <0.001). Finally, serum derived from mdx mice sustained formation of endothelium-derived tubular structures in vitro more efficiently than WT serum. Conclusions— These results demonstrate that arteriogenesis is enhanced in mdx mice both after ischemia and skin wounding and in response to growth factors

High-Mobility Group Box 1 Protein in Human and Murine Skin: Involvement in Wound Healing

n/

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis

A REGIÃO DA BAIXADA LITORÂNEA DO RIO DE JANEIRO: INTERAÇÕES ENTRE O TURISMO E URBANIZAÇÃO

From 1970 with the construction of the bridge Rio - Niteroi, the region known as the Coastal Lowlands, located in the state of Rio de Janeiro, is experiencing a growing and continuing urbanization fostered mainly by increasing the number of vacation homes and by tourism. Attached to this process, there is the creation of spaces of contradictions, in order, the valuation of certain areas over others. The population of greater economic power occupies areas that have better urban infrastructure, while the less affluent classes end up occupying peripheral areas, often unhealthy and irregular. The sprawl of coastal areas and flood plains culminates in environmental degradation processes that contribute to the modification of the landscape in the region. Thus, this paper aims to study the spatio-temporal trajectory of the Coastal Lowlands, from their initial occupation until the current phase, in which tourism and summer are largely responsible for the socio-spatial transformations underway in the region.A partir de 1970, com a construção da ponte Rio - Niterói, a região conhecida como Baixada Litorânea, localizada no estado do Rio de Janeiro, tem passado por um crescente e contínuo processo de urbanização fomentado principalmente pelo aumento do número de casas de veraneio e pela atividade turística. Atrelado a este processo, observa-se, a criação de espaços de contradições, tendo em vista, a valorização de determinadas áreas em detrimento de outras. A população de maior poder econômico ocupa as áreas que possuem melhor infra-estrutura urbana, enquanto, as classes menos abastadas acabam por ocupar áreas periféricas, muitas vezes insalubres e irregulares. A ocupação desordenada de áreas costeiras e alagadiças culmina em processos de degradação ambiental que contribuem para a modificação da paisagem na região. Desta forma, o presente trabalho tem por objetivo estudar a trajetória espaço-temporal da Baixada Litorânea, desde seu processo inicial de ocupação até a fase atual, na qual o turismo e o veraneio são os grandes responsáveis pelas transformações sócio-espaciais em curso na região

Antioxidantes na lesão renal aguda induzida pela sepse: uma análise dos dados pré-clínicos / Antioxidants in the sepsis-induced acute kidney injury: a pre-clinical data analysis

Objetivo: Avaliar o uso de substâncias antioxidantes na lesão renal aguda induzida pela sepse em modelos pré-clínicos. Método: Trata-se de uma revisão integrativa da literatura, com adoção da estratégia PICO. Busca realizada nas bases de dados SCIELO, BVS e PUBMED, de artigos publicados entre janeiro de 2020 até 2010. Resultado: A busca retornou um total de 27 artigos, sendo mantido um total de 09 após aplicação dos critérios de inclusão e exclusão. A produção se concentrou respectivamente: 44% na China, 33% no Brasil, 11% na Turquia e 11% na Espanha; Oito artigos utilizaram a técnica de ligadura e punção do cécum e um a administração de lipopolissacarídeo; Foi avaliado um total de 11 substâncias antioxidantes nos nove artigos selecionados, apenas a N-Acetilcisteína  não comprovou efeito renoprotetor no modelo proposto. Conclusão: O uso de substâncias antioxidantes podem ser utilizadas como terapêutica para prevenção da lesão renal aguda induzida pela sepse agindo na via inflamatória da sepse, das onze substâncias compiladas neste trabalho apenas uma não conseguiu demonstrar o seu caráter renoprotetor, ainda são necessários mais estudos para saber eficácia e segurança em modelos clínicos

Fatores de risco para readmissão não planejada na unidade de terapia intensiva adulto / Risk factors for unplanned readmission in the adult intensive care unit

Objetivo: Identificar na literatura nacional e internacional os fatores de risco para readmissão não planejada em Unidade de Terapia Intensiva adulto (UTI). Método: Revisão integrativa de literatura nas bases de dados LILACS, SciELO, Medline e Cochrane, utilizando-se os descritores: patient readmission/readmissão do paciente/readmisión del paciente, intensive care units/unidades de terapia intensiva/unidades de cuidados intensivos e risk factors/fatores de risco/factores de riesgo, realizada entre agosto e setembro de 2019. Resultados: A partir da análise de 22 artigos, levantou-se os fatores de risco quanto a: dados sociodemográficos (idade avançada 45%, sexo masculino 27,2%), dados clínicos (comorbidades 59%, uso de ventilação mecânica 36.3%, alto índice de gravidade na admissão 27,2%, admissão por cirurgia de emergência 27,2% e alteração de exames laboratoriais 27,2%) e dados administrativos (ser proveniente da enfermaria 18,1% ). Conclusão: O conhecimento desses fatores de risco pode subsidiar o enfermeiro no compartilhamento do processo decisório de alta, visando melhores desfechos para o paciente e reduzindo custos hospitalares. Sugere-se, a partir desse levantamento, a elaboração de escala de predição de risco de readmissão em UTI que tenha sua eficácia e aplicabilidade testadas.

Prediction of early distant recurrence in upfront resectable pancreatic adenocarcinoma: A multidisciplinary, machine learning-based approach

Despite careful selection, the recurrence rate after upfront surgery for pancreatic adenocarcinoma can be very high. We aimed to construct and validate a model for the prediction of early distant recurrence (<12 months from index surgery) after upfront pancreaticoduodenectomy. After exclusions, 147 patients were retrospectively enrolled. Preoperative clinical and radiological (CT-based) data were systematically evaluated; moreover, 182 radiomics features (RFs) were extracted. Most significant RFs were selected using minimum redundancy, robustness against delineation uncertainty and an original machine learning bootstrap-based method. Patients were split into training (n = 94) and validation cohort (n = 53). Multivariable Cox regression analysis was first applied on the training cohort; the resulting prognostic index was then tested in the validation cohort. Clinical (serum level of CA19.9), radiological (necrosis), and radiomic (SurfAreaToVolumeRatio) features were significantly associated with the early resurge of distant recurrence. The model combining these three variables performed well in the training cohort (p = 0.0015,HR = 3.58,95%CI = 1.98–6.71) and was then confirmed in the validation cohort (p = 0.0178,HR = 5.06,95%CI = 1.75–14.58). The comparison of survival curves between low and high-risk patients showed a p-value <0.0001. Our model may help to better define resectability status, thus providing an actual aid for pancreatic adenocarcinoma patients’ management (upfront surgery vs. neoadjuvant chemotherapy). Independent validations are warranted