Hilar Lo Común. Intervención cultural desde las grietas institucionales

El Proyecto de Intervención Cultural “Hilar - Lo Común”, propone fortalecer, mediante actividades artísticas, culinarias, manuales, entre otras, el entramado vincular de un grupo de mujeres que asisten a los espacios culturales provinciales: Alero La Esperanza y Alero Nahuel Huapi, pertenecientes al Ministerio de Cultura de Santa Fe, (descritos en detalle en el punto III) de la ciudad Villa Gdor. Gálvez, bajo la coordinación de docentes pertenecientes al Equipo de esa institución. A través del análisis institucional realizado, se ha podido leer que este recorte poblacional ha sido fundamental en la puesta en marcha de estos espacios culturales. Son las mujeres que han traído los primeros grupos de infancias a la oferta de talleres y a eventos artísticos y de a poco, se han animado a apuntarse como alumnas de propuestas para adultos/as. En esos espacios, han acrecentado vínculos afectivos, de confianza y de intercambio. Es por esto, que a través de lo arrojado en entrevistas, visitas, observación participante, se delinean nuevas propuestas que enriquezcan lo construído colectivamente, abra la comunicación y la escucha entre los actores y la institución y pueda replicarse en una instancia futura (o segunda etapa) a otros grupos intervinientes (usuarios) del espacio cultural, como también abrirse a otros escenarios posibles por fuera de la institución. La instancia protagónica es desde “la cocina” misma del grupo humano. Un develamiento “puertas adentro” para la circulación de la palabra, los intereses comunes e individuales, el encuentro de un espacio que aloje preguntas, consultas, saberes. Un ámbito donde aparezcan políticas del cuidado: físico, emocional, vincular. Ahora bien: ¿Por qué se cree necesario habilitar este espacio desde una intervención extranjera a la institución? Porque, como se develará en el diagnóstico institucional, se ha arribado al territorio (en su instancia de inauguración), con un boceto de agenda pedagógica - cultural cerrada, la cual hizo que, en ocasiones, se descuide el interés real de la vecindad en general y en la escucha atenta hacia este grupo de mujeres en particular. Si la debilidad del proyecto Alero, desde su concepción, fue y aún es una agenda cerrada de talleres y eventos, ya amasada en cuanto a paradigmas y recursos humanos, es posible que pequeñas intervenciones nuevas, con el sentido de la escucha territorial abierta y la participación democrática de grupo/s con pertenencia institucional construida, puedan viabilizar prácticas culturales empapadas de sentido identitario.Fil: Bellini, Elizabet Angela. Universidad Nacional de Rosari

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are two highly prevalent human diseases caused by excessive fat deposition in the liver. Although multiple approaches have been suggested, NAFLD/NASH remains an unmet clinical need. Here, we report the discovery of a novel class of hybrid molecules designed to function as cysteinyl leukotriene receptor 1 (CysLT1R) antagonists and G protein bile acid receptor 1 (GPBAR1/TGR5) agonists for the treatment of NAFLD/NASH. The most potent of these compounds generated by harnessing the scaffold of the previously described CystLT1R antagonists showed efficacy in reversing liver histopathology features in a preclinical model of NASH, reshaping the liver transcriptome and the lipid and energy metabolism in the liver and adipose tissues. In summary, the present study described a novel orally active dual CysLT1R antagonist/GPBAR1 agonist that effectively protects against the development of NAFLD/NASH, showing promise for further development

Comparação da cifose torácica entre o paciente com doença pulmonar obstrutiva crônica e o indivíduo saudável pelo método flexicurva

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction, air entrapment and pulmonary hyperinflation. These pathophysiological factors can compromise the diaphragmatic mobility, causing deformities in the thoracic cavity and consequently increasing the angle of the thoracic curvature. We compared the angle of the thoracic curvature between COPD patients and healthy individuals by the flexicurve method. Thirty-seven patients with COPD and 37 healthy individuals participated in the study. All subjects performed the following evaluations: anthropometry, spirometry, and measurement of the thoracic curvature angle. The data were analyzed and treated with descriptive analysis such as mean and standard deviation. The Shapiro-Wilk test was used to verify the normality of the data. The Student's t-test was used to compare the thoracic curvature angle of patients with COPD with healthy individuals. The significance level adopted was 5%. The mean age of the COPD group was 65.70±7.91 years, body mass index (BMI) of 26.73±5.34kg/m2, and FEV1(expected %) of 50.65±19.08, showing moderate obstruction degree. Healthy individuals showed an average of 7.27±62.49 years, BMI of 26.97±3.55kg/m² and FEV1(expected %) of 94.05±0 9.44. We did not observe any significant difference between patients with COPD and healthy individuals in the thoracic curvature angle: 56.67±11.31 and 55.42±9.61 degrees, respectively (p=0.61). The flexicurve method proved to be a useful and practical tool for assessing the thoracic kyphosis, and it also identified no difference between the thoracic curvature of COPD patients with moderate obstruction and of healthy individuals.La enfermedad pulmonar obstructiva crónica (EPOC) se caracteriza por la obstrucción del flujo de aire, aprisionamiento de aire e por la hiperinsuflación pulmonar. Estos factores fisiopatológicos pueden comprometer la movilidad diafragmática, causar deformidades en la caja torácica y consecuentemente aumentar el ángulo de la curvatura torácica. Se comparó el ángulo de la curvatura torácica entre pacientes con EPOC y de individuos sanos mediante el método flexicurva. Participaron del estudio 37 pacientes con EPOC y 37 individuos sanos. Todos los individuos realizaron las siguientes evaluaciones: antropometría, espirometría y medición del ángulo de la curvatura torácica. Los datos fueron analizados y tratados con análisis descriptivo como media y desviación estándar. Se utilizó la prueba de Shapiro-Wilk para comprobar la normalidad de los datos, y la prueba t de Student para comparar el ángulo de la curvatura torácica de los pacientes portadores de EPOC con los individuos sanos. El nivel de significancia adoptado fue del 5%. La edad promedio del grupo con EPOC fue 65,70±7,91 años, el índice de masa corporal (IMC), 26,73±5,34kg/m2, y VEF1 (% previsto), 50,65±19,08, presentando grado de obstrucción moderada. Los individuos sanos presentaron un promedio de 62,49±7,27 años, IMC de 26,97±3,55kg/m² y VEF1 (% previsto) de 94,05±9,44. No hubo diferencia significante entre los pacientes con EPOC y los pacientes sanos en el ángulo de la curvatura torácica: 56,67±11,31 y 55,42±9,61 grados, respectivamente (p=0,61). El método flexicurva ha mostrado ser una herramienta útil y práctica para evaluar la cifosis torácica, identificando que no hubo diferencia entre las curvaturas torácicas de los pacientes con EPOC con obstrucción moderada y de los individuos sanos.A doença pulmonar obstrutiva crônica (DPOC) é caracterizada pela obstrução do fluxo aéreo, aprisionamento de ar e pela hiperinsuflação pulmonar. Esses fatores fisiopatológicos podem comprometer a mobilidade diafragmática, causar deformidades na caixa torácica e consequentemente aumentar o ângulo da curvatura torácica. Comparamos o ângulo da curvatura torácica entre pacientes com DPOC e indivíduos saudáveis pelo método flexicurva. Participaram do estudo 37 pacientes com DPOC e 37 indivíduos saudáveis. Todos os indivíduos realizaram as seguintes avaliações: antropometria, espirometria e mensuração do ângulo da curvatura torácica. Os dados foram analisados e tratados com análise descritiva como média e desvio-padrão. O teste de Shapiro-Wilk foi utilizado para verificar a normalidade dos dados. O teste t de Student foi utilizado para comparar o ângulo da curvatura torácica dos pacientes portadores de DPOC com os indivíduos saudáveis. O nível de significância adotado foi de 5%. A média de idade do grupo com DPOC foi de 65,70±7,91 anos, o índice de massa corporal (IMC), 26,73±5,34kg/m2, e VEF1 (% previsto), 50,65±19,08, apresentando grau de obstrução moderada. Os indivíduos saudáveis apresentaram em média 62,49±7,27 anos, IMC de 26,97±3,55kg/m² e VEF1 (% previsto) de 94,05±9,44. Não houve diferença significante entre os pacientes com DPOC e os indivíduos saudáveis no ângulo da curvatura torácica: 56,67±11,31 e 55,42±9,61 graus, respectivamente (p=0,61). O método flexicurva mostrou-se uma ferramenta útil e prática para avaliar a cifose torácica, identificando que não houve diferença entre as curvaturas torácicas dos pacientes com DPOC com obstrução moderada e dos indivíduos saudáveis

Universal Newborn Screening for Congenital Cytomegalovirus Infection - From Infant to Maternal Infection: A Prospective Multicenter Study

Introduction: Most infants at risk for cytomegalovirus (CMV)-associated sensorineural hearing loss (SNHL) are unrecognized because of the absence of a universal neonatal CMV screening. The search of CMV-DNA by molecular methods in salivary swabs was demonstrated to be a reliable approach. This study describes the results obtained by carrying out a universal screening for congenital CMV (cCMV) infection including all live-born newborns in three Italian sites, as well as the therapeutic interventions and clinical outcome of the CMV-infected neonates. Moreover, CMV maternal infection's characteristics were evaluated. Methods: To confirm or exclude cCMV infection, a CMV-DNA-positive result on a first salivary swab was followed by repeated saliva and urine samples collected within 21 days of age. Breast milk samples were also collected. The search of CMV-DNA was performed with a single automated quantitative commercial real-time PCR assay, regardless of the type of samples used. Results: A total of 3,151 newborns were enrolled; 21 (0.66%) of them were congenitally infected (median saliva viral load at screening, 6.65 [range, 5.03-7.17] log10 IU/ml). Very low/low viral load in screening saliva samples (median value, 1.87 [range, 1.14-2.59] log10 IU/ml) was associated with false-positive results (n = 54; 1.7%). CMV-DNA was detected in almost half of the breast milk samples of mother-infant pairs with a false-positive result, suggesting that contamination from breast milk may not be the only explanation in the study population. cCMV infection confirmation with the search of CMV-DNA in a urine sample proved to be the gold standard strategy, since false-positive results were observed in 4/54 (7.5%) of the repeated saliva samples. Symptomatic cCMV infection was observed in 3/21 (14.3%) infants; notably, one (4.7%) developed moderate unilateral SNHL at 5 months after birth. Finally, two symptomatic cCMV infections were associated with primary maternal infection acquired in the first trimester of gestation; one newborn with severe cCMV symptoms was born to a mother with no CMV checkups in pregnancy. Conclusion: Without universal neonatal CMV screening, some infected infants who develop late neurological sequelae may not be recognized and, consequently, they are not able to benefit early from instrumental and therapeutic interventions to limit and/or treat CMV disease

The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer

Purpose: The gastric adenocarcinoma (GC) represents the third cause of cancer-related mortality worldwide, and available therapeutic options remain sub-optimal. The Fibroblast growth factor receptors (FGFRs) are oncogenic transmembrane tyrosine kinase receptors. FGFR inhibitors have been approved for the treatment of various cancers and a STAT3-dependent regulation of FGFR4 has been documented in the H.pylori infected intestinal GC. Therefore, the modulation of FGFR4 might be useful for the treatment of GC.MethodsTo investigate wich factors could modulate FGFR4 signalling in GC, we employed RNA-seq analysis on GC patients biopsies, human patients derived organoids (PDOs) and cancer cell lines.ResultsWe report that FGFR4 expression/function is regulated by the leukemia inhibitory factor (LIF) an IL-6 related oncogenic cytokine, in JAK1/STAT3 dependent manner. The transcriptomic analysis revealed a direct correlation between the expression of LIFR and FGFR4 in the tissue of an exploratory cohort of 31 GC and confirmed these findings by two external validation cohorts of GC. A LIFR inhibitor (LIR-201) abrogates STAT3 phosphorylation induced by LIF as well as recruitment of pSTAT3 to the promoter of FGFR4. Furthermore, inhibition of FGFR4 by roblitinib or siRNA abrogates STAT3 phosphorylation and oncogentic effects of LIF in GC cells, indicating that FGFR4 is a downstream target of LIF/LIFR complex. Treating cells with LIR-201 abrogates oncogenic potential of FGF19, the physiological ligand of FGFR4.ConclusionsTogether these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells

Self-perceived normality in defecation habits

Background: Available information on normal bowel habits was mainly gathered by means of telephone interviews or mailed questionnaires. Aims: We undertook a prospective study to evaluate the defecatory habits in subjects perceiving themselves as normal concerning this function. Subjects and Methods: A questionnaire (4-week diary with "yes-no" daily answers to six questions concerning bowel habits) was distributed to 204 subjects perceiving their defecation behaviour as normal. Results: The completed questionnaire was returned by 140 subjects. No significant differences were found between sexes or age groups for any variable, even though straining at stool and feeling of incomplete and/or difficult evacuation showed a trend to increase with age. No subject had less than three bowel movements per week or more than three per day. The percentage of symptoms linked to an abnormal defecatory behaviour was well below 10%. Fifty-five percent of subjects reported at least one parameter of abnormal functioning; the most frequent was straining at stool and the rarer was the manual manoeuvres to help defecation. Conclusions: In normal subjects the prevalence of symptoms considered in Rome II criteria as part of an abnormal defecatory behaviour (in more than 25% of defecations) is well below 10%, manual manoeuvres are almost never used to help defecation, and the frequency of defecations is at least three per week. © 2005 Editrice Gastroenterologica Italiana S.r.l

A straightforward multiparametric quality control protocol for proton magnetic resonance spectroscopy: Validation and comparison of various 1.5 T and 3 T clinical scanner systems

Purpose: The aim of this study was to propose and validate across various clinical scanner systems a straightforward multiparametric quality assurance procedure for proton magnetic resonance spectroscopy (MRS). Methods: Eighteen clinical 1.5 T and 3 T scanner systems for MRS, from 16 centres and 3 different manufacturers, were enrolled in the study. A standard spherical water phantom was employed by all centres. The acquisition protocol included 3 sets of single (isotropic) voxel (size 20 mm) PRESS acquisitions with unsuppressed water signal and acquisition voxel position at isocenter as well as off-center, repeated 4/5 times within approximately 2 months. Water peak linewidth (LW) and area under the water peak (AP) were estimated. Results: LW values [mean (standard deviation)] were 1.4 (1.0) Hz and 0.8 (0.3) Hz for 3 T and 1.5 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficient of variation of LW and AP for different spatial positions of acquisition voxel were 43% (20%) and 11% (11%), respectively. The mean (standard deviation) phantom T2 values were 1145 (50) ms and 1010 (95) ms for 1.5 T and 3 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficients of variation for repeated measurements of LW, AP and T2 were 25% (20%), 10% (14%) and 5% (2%), respectively. Conclusions: We proposed a straightforward multiparametric and not time consuming quality control protocol for MRS, which can be included in routine and periodic quality assurance procedures. The protocol has been validated and proven to be feasible in a multicentre comparison study of a fairly large number of clinical 1.5 T and 3 T scanner systems

Single-cell transcriptomics reveals shared immunosuppressive landscapes of mouse and human neuroblastoma

BACKGROUND High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies. METHODS We combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays. RESULTS We show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes. CONCLUSIONS Our study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and precious data resource to better understand the neuroblastoma ecosystem and suggest novel therapeutic strategies, targeting both tumor cells and components of the microenvironment

Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma

Noradrenergic and mesenchymal identities have been characterized in neuroblastoma cell lines according to their epigenetic landscapes and core regulatory circuitries. However, their relationship and relative contribution in patient tumors remain poorly defined. We now document spontaneous and reversible plasticity between the two identities, associated with epigenetic reprogramming, in several neuroblastoma models. Interestingly, xenografts with cells from each identity eventually harbor a noradrenergic phenotype suggesting that the microenvironment provides a powerful pressure towards this phenotype. Accordingly, such a noradrenergic cell identity is systematically observed in single-cell RNA-seq of 18 tumor biopsies and 15 PDX models. Yet, a subpopulation of these noradrenergic tumor cells presents with mesenchymal features that are shared with plasticity models, indicating that the plasticity described in these models has relevance in neuroblastoma patients. This work therefore emphasizes that intrinsic plasticity properties of neuroblastoma cells are dependent upon external cues of the environment to drive cell identity