IRF2 loss is associated with reduced MHC I pathway transcripts in subsets of most human cancers and causes resistance to checkpoint immunotherapy in human and mouse melanomas.

Background In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms. Methods Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo. Results Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI. Conclusions Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics.

Analysis of the evolution of competences in the clinical practice of the nursing degree / Análise da evolução de competências da prática clínica no curso de enfermagem / Análisis de la evolución de las competencias en la práctica clínica del grado en enfermeira

Objective: to analyze the student's progression in the acquisition of specific and transversal competences in relation to the competence dimensions. Method: the cross-sectional descriptive study was carried out in the clinical practice subjects included in the Nursing Degree. We included 323 students and we contemplated the development of competences through an ad-hoc questionnaire with 4 dimensions: delivery and care management, therapeutic communication, professional development and care management. Results: the academic results between the practice of the second and third year showed an improvement in care provision and therapeutic communication skills (Clinical Placements I: 12%-29%; Clinical Placements II: 32%-47%) and worsened in professional development and care management (Clinical Placements I: 44%-38%; Clinical Placements II: 44%-26%). Conclusion: the correlations between these two years were high in all the dimensions analyzed. The evaluation of competence progression in the context of clinical practice in nursing university studies allows us to optimize these practices to the maximum and establish professional profiles with a greater degree of adaptation to the professional future.

Objetivo: analisar a progressão de estudantes na aquisição de competências específicas e transversais em relação às dimensões de competência. Método: este estudo transversal descritivo foi realizado no contexto das disciplinas de prática clínica do curso de enfermagem. O desenvolvimento de competências de 323 alunos foi analisado usando um questionário ad-hoc com quatro dimensões: provisão e gerenciamento do cuidado; comunicação terapêutica; desenvolvimento profissional; e gerenciamento do cuidado. Resultados: os resultados acadêmicos obtidos no segundo e terceiro anos apresentaram melhora nas habilidades referentes à provisão do cuidado e comunicação terapêutica (Práticas Clínicas I: 12%-29%; Práticas Clínicas II: 32%-47%) e uma piora no desenvolvimento profissional e gerenciamento do cuidado (Práticas Clínicas I: 44%-38%; Práticas Clínicas II: 44%-26%). Conclusão: as correlações entre estes dois anos foram altas em todas as dimensões analisadas. A avaliação da progressão de competências no contexto da prática clínica do curso de enfermagem nos permite otimizar estas práticas ao máximo e estabelecer perfis profissionais com maior grau de adaptação para o futuro profissional.

Objetivo: analizar la progresión del alumno en la adquisición de competencias específicas y transversales en relación con las dimensiones de competencia. Método: el estudio descriptivo transversal se realizó en los sujetos de práctica clínica incluidos en la licenciatura de Enfermería. Incluimos 323 estudiantes y contemplamos el desarrollo de competencias a través de un cuestionario ad hoc con 4 dimensiones: suministro y gestión del cuidado; comunicación terapéutica; desarrollo profesional; y, gestión del cuidado. Resultados: los resultados académicos entre la práctica del segundo y tercer año mostraron una mejora en la provisión del cuidado y en las habilidades de comunicación terapéutica: (Colocaciones clínicas I: 12% -29%; Colocaciones clínicas II: 32% -47%) y empeoraron en el desarrollo profesional y en la gestión del cuidado (Colocaciones clínicas I: 44%-38%; Colocaciones clínicas II: 44%-26%). Conclusión: las correlaciones entre estos dos años fueron altas en todas las dimensiones analizadas. La evaluación de la progresión de competencias, en el contexto de la práctica clínica, en los estudios universitarios de enfermería, nos permite optimizar estas prácticas al máximo y establecer perfiles profesionales con un mayor grado de adaptación al futuro profesional.

Compliance to treatment in diabetic pa tients from Bucaramanga, Colombia: a cross sectional study / Adherencia al tratamiento en pacientes diabéticos de Bucaramanga, Colombia: estudio de corte transversal

Objective: this study is aimed to evaluate knowledge about the disease, some behavioral habits and the level of compliance to pharmacological treatment, in a sample of diabetic patients, attending at hospital institution in the city of Bucaramanga (Colombia), during 2016. Diabetes mellitus is a chronic disease whose prevalence is increasing significantly in developing countries. Materials and Methods: cross sectional, descriptive study; a sample of 411 diabetic, aged over 35 years, who consulted at cardiovascular risk program, answered in the period between January and December 2016, a self-administered questionnaire that included the instruments IMEVID, Berbés and modified SMMS; Additionally, sociodemographic variables such as age, sex, stratum, education, were included. Results: 90% had a low socioeconomic status and 82.7% only reached primary studies or less. High Pharmacological adherence was observed in only 3.65%, medium adherence in 87.83% and low at 8.52%. Mean level of knowledge about diabetes was 13.32; Almost half (46.72%) scored below the average; Mean of glycosylated hemoglobin was 7.93%; 34.8% scored above this value. 18.7% have an inadequate lifestyle (IMEVID score <60). Low adherence found associated with: alcohol intake, IMEVID score <60, Ask more after eating, have a job and don't use insulin. Conclusion: it is necessary to esta-blish learning strategies and methodologies of motivation and training for diabetic patients, to improve quality of life and knowledge of the diabetes and, in this way,optimize the prognosis of the disease..(AU)

Objetivo: el estudio se propone evaluar el conocimiento sobre la enfermedad, algunos hábitos de comportamiento y el nivel de cumplimiento con el tratamiento farmacológico en una muestra de pacientes diabéticos que asistieron a una institución hospitalaria en la ciudad de Bucaramanga (Colombia) durante el 2016. La diabetes mellitus es una enfermedad crónica, su prevalencia está aumentando significativamente en los países en desarrollo. Materiales y Métodos: estudio de corte transversal, descriptivo; una muestra de 411 diabéticos, mayores de 35 años, que consultaron al programa de riesgo cardiovascular, respondieron en el período comprendido entre enero a diciembre de 2016, un cuestionario autoadministrado que incluía los instrumentos IMEVID, Berbés y SMMS modificado; Adicionalmente, se incluyeron variables sociodemográficas como edad, sexo, estrato, educación. Resultados: el 90% tenía un estatus socioeconómico bajo y el 82.7% solo alcanzó estudios primarios o menos. Se observó una alta adherencia farmacológica en solo el 3,65%, una adherencia media en el 87,83% y una baja en el 8,52%. El nivel medio de conocimiento sobre la diabetes fue de 13.32; Casi la mitad (46.72%) puntuó por debajo del promedio; La media de hemoglobina glicosilada fue de 7.93%; El 34.8% puntuó por encima de este valor. El 18.7% tiene un estilo de vida inadecuado (puntuación IMEVID <60). Se encontró que la baja adherencia estaba asociada con: consumo de alcohol, puntaje IMEVID <60, pedir más después de comer, tener un trabajo y no usar insulina. Conclusión: es necesario establecer estrategias de aprendizaje y metodologías de motivación y entrenamiento a los pacientes diabéticos, para mejorar la calidad de vida y el conocimiento de la diabetes, y de esta manera, optimizar el pronóstico de la enfermedad..(AU)

The Wilms' tumor suppressor gene regulates pancreas homeostasis and repair.

The Wilms' tumor suppressor gene (Wt1) encodes a zinc finger transcription factor that plays an essential role in the development of kidneys, gonads, spleen, adrenals and heart. Recent findings suggest that WT1 could also be playing physiological roles in adults. Systemic deletion of WT1 in mice provokes a severe deterioration of the exocrine pancreas, with mesothelial disruption, E-cadherin downregulation, disorganization of acinar architecture and accumulation of ascitic transudate. Despite this extensive damage, pancreatic stellate cells do not become activated and lose their canonical markers. We observed that pharmacological induction of pancreatitis in normal mice provokes de novo expression of WT1 in pancreatic stellate cells, concomitant with their activation. When pancreatitis was induced in mice after WT1 ablation, pancreatic stellate cells expressed WT1 and became activated, leading to a partial rescue of the acinar structure and the quiescent pancreatic stellate cell population after recovery from pancreatitis. We propose that WT1 modulates through the RALDH2/retinoic acid axis the restabilization of a part of the pancreatic stellate cell population and, indirectly, the repair of the pancreatic architecture, since quiescent pancreatic stellate cells are required for pancreas stability and repair. Thus, we suggest that WT1 plays novel and essential roles for the homeostasis of the adult pancreas and, through its upregulation in pancreatic stellate cells after a damage, for pancreatic regeneration. Due to the growing importance of the pancreatic stellate cells in physiological and pathophysiological conditions, these novel roles can be of translational relevance.

Identifying Coordination and Continuity of Care Indicators for Population-Based Cancer Screening Programs: A Delphi Study.

BACKGROUND: Continuity of care and care coordination are critical issues in virtually all healthcare systems. European guidelines for the quality of screening programs for breast and colorectal cancer describe process, structure, and outcome indicators, but none specifically evaluate coordination and continuity of care during the cancer screening process. OBJECTIVE: The aim of this study was to identify indicators reflecting care coordination and continuity in population-based breast and colorectal cancer screening program. METHODS: A two-round Delphi study was conducted in a sample of 30 cancer screening nurses to identify quality indicators. RESULTS: The final Delphi consensus resulted in six core indicators for the cancer screening program: adequacy of the referral of the target population from the screening program to other health services, waiting time for referral to other health services, understanding of the screening program by professionals involved in the process, effective information flow between professionals involved in the process, participants' perception of the screening program, and, finally, participants' understanding of information about the program. CONCLUSION: The evaluation of indicators is crucial for quality improvement and should allow a measuring system to be established that would allow a comparison of outcomes for all population-based cancer screening programs.

Role of the Wilms' tumor suppressor gene Wt1 in pancreatic development.

The Wilms tumor suppressor gene (Wt1) encodes a transcription factor involved in the development of a number of organs, but the role played by Wt1 in pancreatic development is unknown. The pancreas contains a population of pancreatic stellate cells (PSC) very important for pancreatic physiology. We described elsewhere that hepatic stellate cells originate from the WT1-expressing liver mesothelium. Thus, we checked if the origin of PSCs was similar. WT1 expression is restricted to the pancreatic mesothelium. Between embryonic day (E) 10.5 and E15.5, this mesothelium gives rise to mesenchymal cells that contribute to a major part of the PSC and other cell types including endothelial cells. Most WT1 systemic mutants show abnormal localization of the dorsal pancreas within the mesentery and intestinal malrotation by E14.0. Embryos with conditional deletion of WT1 between E9.5 and E12.5 showed normal dorsal pancreatic bud and intestine, but the number of acini in the ventral bud was reduced approximately 30% by E16.5. Proliferation of acinar cells was reduced in WT1 systemic mutants, but pancreatic differentiation was not impaired. Thus, mesothelial-derived cells constitute an important subpopulation of pancreatic mesodermal cells. WT1 expression is not essential for pancreas development, although it influences intestinal rotation and correct localization of the dorsal pancreas within the mesogastrium. Developmental Dynamics 247:924-933, 2018. © 2018 Wiley Periodicals, Inc.

A population of hematopoietic stem cells derives from GATA4-expressing progenitors located in the placenta and lateral mesoderm of mice.

GATA transcription factors are expressed in the mesoderm and endoderm during development. GATA1-3, but not GATA4, are critically involved in hematopoiesis. An enhancer (G2) of the mouse Gata4 gene directs its expression throughout the lateral mesoderm and the allantois, beginning at embryonic day 7.5, becoming restricted to the septum transversum by embryonic day 10.5, and disappearing by midgestation. We have studied the developmental fate of the G2-Gata4 cell lineage using a G2-Gata4Cre;R26REYFP mouse line. We found a substantial number of YFP+ hematopoietic cells of lymphoid, myeloid and erythroid lineages in embryos. Fetal CD41+/cKit+/CD34+ and Lin-/cKit+/CD31+ YFP+ hematopoietic progenitors were much more abundant in the placenta than in the aorta-gonad-mesonephros area. They were clonogenic in the MethoCult assay and fully reconstituted hematopoiesis in myeloablated mice. YFP+ cells represented about 20% of the hematopoietic system of adult mice. Adult YFP+ hematopoietic stem cells constituted a long-term repopulating, transplantable population. Thus, a lineage of adult hematopoietic stem cells is characterized by the expression of GATA4 in their embryonic progenitors and probably by its extraembryonic (placental) origin, although GATA4 appeared not to be required for hematopoietic stem cell differentiation. Both lineages basically showed similar physiological behavior in normal mice, but clinically relevant properties of this particular hematopoietic stem cell population should be checked in physiopathological conditions.

Surveillance nursing diagnoses, ongoing assessment and outcomes on in-patients who suffered a cardiorespiratory arrest / Diagnósticos de enfermagem de vigilância, avaliação contínua e resultados em pacientes que sofreram uma parada cardiorrespiratória / Diagnósticos enfermeros de vigilancia, evaluación en curso y resultados en pacientes hospitalizados que sufrieron paro cardiorrespiratorio

ABSTRACT Objective The purposes of this study were to examine the frequency of surveillance-oriented nursing diagnoses and interventions documented in the electronic care plans of patients who experienced a cardiac arrest during hospitalization, and to observe whether differences exist in terms of patients' profiles, surveillance measurements and outcomes. Method A descriptive, observational, retrospective, cross-sectional design, randomly including data from electronic documentation of patients who experienced a cardiac arrest during hospitalization in any of the 107 adult wards of eight acute care facilities. Descriptive statistics were used for data analysis. Two-tailed p-values are reported. Results Almost 60% of the analyzed patients' e-charts had surveillance nursing diagnoses charted in the electronic care plans. Significant differences were found for patients who had these diagnoses documented and those who had not in terms of frequency of vital signs measurements and final outcomes. Conclusion Surveillance nursing diagnoses may play a significant role in preventing acute deterioration of adult in-patients in the acute care setting.

RESUMO Objetivo Determinar a frequência de registro eletrônico de diagnósticos e intervenções de vigilância no plano de cuidados para pacientes que sofreram uma parada cardíaca durante a admissão e avaliar se existem diferenças com base no perfil do paciente, medidas de monitoramento e resultados. Método Estudo descritivo, observacional, retrospectivo, transversal, que incluiu dados dos registros eletrônicos de pacientes internados em uma das 107 unidades de oito hospitais de cuidados agudos. Para análise dos dados foram utilizados estatísticos descritivos. Os valores de p foram relatados em dois ramos. Resultados Foram obtidos dados de 492 documentos de enfermagem de pacientes que sofreram uma parada cardíaca. Quase 60% dos prontuários eletrônicos incluídos na análise continham um ou mais diagnósticos de vigilância. Diferenças significativas foram encontradas entre os pacientes com e sem registro desses diagnósticos, no que se refere à frequência das medições dos sinais vitais e aos resultados finais. Conclusão Os diagnósticos de vigilância podem desempenhar um papel importante na prevenção de deterioração aguda em pacientes adultos hospitalizados.

RESUMEN Objetivo Los objetivos de este estudio fueron examinar la frecuencia de los diagnósticos enfermeros basados en la vigilancia y las intervenciones documentadas en los planes de asistencia mediante sistema informático de pacientes que pasaron por paro cardiaco durante estancia hospitalaria y observar si existen diferencias en términos de perfil de los pacientes, medidas de vigilancia y resultados. Método Descriptivo, observacional, retrospectivo, transversal, randomizado, incluyendo datos de documentación informática de pacientes que pasaron por paro cardiaco durante estancia hospitalaria en cualquiera de las 107 alas adultas de las ocho instalaciones de cuidados intensivos. Las estadísticas descriptivas fueron utilizadas para los análisis de datos. Valores P bilaterales fueron relatados. Resultados Casi el 60% del los pacientes analizados por la gráfica electrónica tuvieron diagnóticos enfermeros de vigilancia representados en los planes de cuidados informatizados. Fueron encontradas diferencias significativas en pacientes que tuvieron dichos diagnósticos documentados y los que no los tuvieron en términos de frecuencia de mediciones de señales vitales y resultados finales. Conclusión Los diagnósticos enfermeros de vigilancia pueden jugar un rol significativo en la prevención del deterioro agudo de pacientes adultos hospitalizados en las unidades de cuidados intensivos.

Conditional deletion of WT1 in the septum transversum mesenchyme causes congenital diaphragmatic hernia in mice.

Congenital diaphragmatic hernia (CDH) is a severe birth defect. Wt1-null mouse embryos develop CDH but the mechanisms regulated by WT1 are unknown. We have generated a murine model with conditional deletion of WT1 in the lateral plate mesoderm, using the G2 enhancer of the Gata4 gene as a driver. 80% of G2-Gata4(Cre);Wt1(fl/fl) embryos developed typical Bochdalek-type CDH. We show that the posthepatic mesenchymal plate coelomic epithelium gives rise to a mesenchyme that populates the pleuroperitoneal folds isolating the pleural cavities before the migration of the somitic myoblasts. This process fails when Wt1 is deleted from this area. Mutant embryos show Raldh2 downregulation in the lateral mesoderm, but not in the intermediate mesoderm. The mutant phenotype was partially rescued by retinoic acid treatment of the pregnant females. Replacement of intermediate by lateral mesoderm recapitulates the evolutionary origin of the diaphragm in mammals. CDH might thus be viewed as an evolutionary atavism.

Coelomic epithelium-derived cells in visceral morphogenesis.

Coelomic cavities of vertebrates are lined by a mesothelium which develops from the lateral plate mesoderm. During development, the coelomic epithelium is a highly active cell layer, which locally is able to supply mesenchymal cells that contribute to the mesodermal elements of many organs and provide signals which are necessary for their development. The relevance of this process of mesenchymal cell supply to the developing organs is becoming clearer because genetic lineage tracing techniques have been developed in recent years. Body wall, heart, liver, lungs, gonads, and gastrointestinal tract are populated by cells derived from the coelomic epithelium which contribute to their connective and vascular tissues, and sometimes to specialized cell types such as the stellate cells of the liver, the Cajal interstitial cells of the gut or the Sertoli cells of the testicle. In this review we collect information about the contribution of coelomic epithelium derived cells to visceral development, their developmental fates and signaling functions. The common features displayed by all these processes suggest that the epithelial-mesenchymal transition of the embryonic coelomic epithelium is an underestimated but key event of vertebrate development, and probably it is shared by all the coelomate metazoans.