Gene expression patterns of Sirtuin family members (SIRT1 TO SIRT7): Insights into pathogenesis and prognostic of Myelodysplastic neoplasm.

To assess and validate the gene expression profile of SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7) in relation to the pathogenesis and prognostic progression of Myelodysplastic neoplasm (MDS). Eighty bone marrow samples of patients with de novo MDS were diagnosed according to WHO 2022 and IPSS-R criteria. Ten bone marrow samples were obtained from elderly healthy volunteers and used as control samples. Gene expression levels of all SIRTs were assessed using RT-qPCR assays. Downregulation of SIRT2 (p = 0.009), SIRT3 (p = 0.048), SIRT4 (p = 0.049), SIRT5 (p = 0.046), SIRT6 (p = 0.043), and SIRT7 (p = 0.047) was identified in MDS patients compared to control individuals. Also, we identified that while SIRT2-7 genes are typically down-regulated in MDS patients compared to normal controls, there are relative expression variations among MDS patient subgroups. Specifically, SIRT4 (p = 0.029) showed increased expression in patients aged 60 or above, and both SIRT2 (p = 0.016) and SIRT3 (p = 0.036) were upregulated in patients with hemoglobin levels below 8 g/dL. SIRT2 (p = 0.045) and SIRT3 (p = 0.033) were highly expressed in patients with chromosomal abnormalities. Different SIRTs exhibited altered expression patterns concerning specific MDS clinical and prognostic characteristics. The downregulation in SIRTs genes (e.g., SIRT2 to SIRT7) expression in Brazilian MDS patients highlights their role in the disease's development. The upregulation of SIRT2 and SIRT3 in severe anemia patients suggests a potential link to manage iron overload-related complications in transfusion-dependent patients. Moreover, the association of SIRT2/SIRT3 with genomic instability and their role in MDS progression signify promising areas for future research and therapeutic targets. These findings underscore the importance of SIRT family in understanding and addressing MDS, offering novel clinical, prognostic, and therapeutic insights for patients with this condition.

Role of the STING pathway in myeloid neoplasms: a prospero-registered systematic review of principal hurdles of STING on the road to the clinical practice.

Myeloid neoplasms are a group of bone marrow diseases distinguished by disruptions in the molecular pathways that regulate the balance between hematopoietic stem cell (HSC) self-renewal and the generation of specialized cells. Cytokines and chemokines, two important components of the inflammatory process, also influence hematological differentiation. In this scenario, immunological dysregulation plays a pivotal role in the pathogenesis of bone marrow neoplasms. The STING pathway recognizes DNA fragments in the cell cytoplasm and triggers an immune response by type I interferons. The role of STING in cancer has not yet been established; however, both actions, as an oncogene or tumor suppressor, have been documented in other types of cancer. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42023407512) to discuss the role of STING pathway in the advancement of pathogenesis and/or prognosis for different myeloid neoplasms. In brief, scientific evidence supports investigations that primarily use cell lines from myeloid neoplasms, such as leukemia. More high-quality research and clinical trials are needed to understand the role of the STING pathway in the pathology of hematological malignancies. Finally, the STING pathway suggests being a promising therapeutic molecular target, particularly when combined with current drug therapies.

High PD-L1 expression is associated with unfavorable clinical features in myelodysplastic neoplasms.

INTRODUCTION: Immune checkpoints are regulators of the immune system response that allow self-tolerance. Molecules such as Programmed Cell Death Protein 1 (PD-1) and its Ligand (PD-L1) participate in the immune checkpoint by signaling co-inhibition of lymphocyte responses. In cancers, PD-L1 expression is associated with the immune evasion mechanism, which favors tumor growth. The use of anti-PD-1/PD-L1 drugs is already well described in solid tumors, but still not fully understood in hematologic malignancies. Myelodysplastic neoplasms (MDSs) are heterogeneous bone marrow disorders with an increased risk of progression to Acute Myeloid Leukemia (AML). The MDS affects hematopoietic stem cells and its pathogenesis is linked to genetic and epigenetic defects, in addition to immune dysregulation. The influence of the PD-L1 on the MDS remains unknown. METHODS: In this study, we evaluated the mRNA expression of the PD-L1 in 53 patients with MDS, classified according to the WHO 2016 Classification. RESULTS: Patients with dyserythropoiesis presented significantly higher PD-L1 expression than patients without dyserythropoiesis (p = 0.050). Patients classified as having MDS with an excess of blasts 2 (MDS-EB2) presented a significant upregulation in the mRNA expression of the PD-L1 compared to the MDS with an excess of blasts 1 (MDS-EB1) (p = 0.050). Furthermore, we detected three patients with very high levels of PD-L1 expression, being statistically classified as outliers. CONCLUSION: We suggested that the high expression of the PD-L1 is associated with a worse prognosis in the MDS and functional studies are necessary to evaluate the possible use of anti-PD-L1 therapies for high-risk MDS, such as the MDS-EBs.

The effect of wound electrical stimulation in venous leg ulcer healing-a systematic review.

OBJECTIVE: The benefit of using electric stimulation therapy (EST) to heal venous leg ulcers (VLUs) is not well established. The main aim of this systematic review was to evaluate the effects of ulcer EST in VLU healing. METHODS: A systematic search of the literature was conducted using the databases PubMed, Scopus, and Web of Science and included original studies that reported VLU healing after EST. The inclusion criteria were at least two surface electrodes placed on or near the wound or a planar probe covering the ulcer area to be treated. The Cochrane risk of bias tool for randomized control trials (RCTs) and Joanna Briggs Institute critical appraisal checklist for case series were used to evaluate the risk of bias. RESULTS: This review included eight RCTs and three case series involving a total of 724 limbs in 716 patients with VLUs. The mean patient age was 64.2 years (95% confidence interval, 62.3-66.2), and 46.2% (95% confidence interval, 41.2%-50.4%) were men. The active electrode was placed on the wound with the passive electrode placed on healthy skin (n = 6), the two electrodes were placed on either side of the wound edges (n = 4), or a planar probe was used (n = 1). The pulsed current was the most used waveform (n = 9). The change in the ulcer size was the main method used to determine ulcer healing (n = 8), followed by the ulcer healing rate (n = 6), exudate levels (n = 4), and the time to healing (n = 3). Five RCTs detected a statistically significant improvement in at least one VLU healing outcome, after EST compared with the control group. In two of these, EST was better than the control but only for patients who had not undergone surgical treatment of VLU. CONCLUSIONS: The findings from the present systematic review support the use of EST to accelerate wound healing of VLUs, especially for patients who are not surgical candidates. However, the significant variation in electric stimulation protocols represents an important limitation to its use and should be addressed in future studies.

Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic Syndrome.

Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p = 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p = 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p = 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p < 0.001, OR=9.05 × 10-10), and intermediate (p < 0.001, OR=3.08 × 10-10), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classified as good (p < 0.001, OR=4.03 × 10-13) and intermediate (p < 0.001, OR=2.54 × 10-13). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS.

Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic Syndrome

Abstract Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p= 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p= 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p= 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p< 0.001, OR=9.05 × 10−10), and intermediate (p< 0.001, OR=3.08 × 10−10), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classified as good (p< 0.001, OR=4.03 × 10−13) and intermediate (p< 0.001, OR=2.54 × 10−13). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS.

Global Proteomics Analysis of Bone Marrow: Establishing Talin-1 and Centrosomal Protein of 55 kDa as Potential Molecular Signatures for Myelodysplastic Syndromes.

Myelodysplastic syndrome (MDS) is a hematological disorder characterized by abnormal stem cell differentiation and a high risk of acute myeloid leukemia transformation. Treatment options for MDS are still limited, making the identification of molecular signatures for MDS progression a vital task. Thus, we evaluated the proteome of bone marrow plasma from patients (n = 28) diagnosed with MDS with ring sideroblasts (MDS-RS) and MDS with blasts in the bone marrow (MDS-EB) using label-free mass spectrometry. This strategy allowed the identification of 1,194 proteins in the bone marrow plasma samples. Polyubiquitin-C (UBC), moesin (MSN), and Talin-1 (TLN1) showed the highest abundances in MDS-EB, and centrosomal protein of 55 kDa (CEP55) showed the highest relative abundance in the bone marrow plasma of MDS-RS patients. In a follow-up, in the second phase of the study, expressions of UBC, MSN, TLN1, and CEP55 genes were evaluated in bone marrow mononuclear cells from 45 patients by using qPCR. This second cohort included only seven patients from the first study. CEP55, MSN, and UBC expressions were similar in mononuclear cells from MDS-RS and MDS-EB individuals. However, TLN1 gene expression was greater in mononuclear cells from MDS-RS (p = 0.049) as compared to MDS-EB patients. Irrespective of the MDS subtype, CEP55 expression was higher (p = 0.045) in MDS patients with abnormal karyotypes, while MSN, UBC, and TALIN1 transcripts were similar in MDS with normal vs. abnormal karyotypes. In conclusion, proteomic and gene expression approaches brought evidence of altered TLN1 and CEP55 expressions in cellular and non-cellular bone marrow compartments of patients with low-risk (MDS-RS) and high-risk (MDS-EB) MDSs and with normal vs. abnormal karyotypes. As MDS is characterized by disrupted apoptosis and chromosomal alterations, leading to mitotic slippage, TLN1 and CEP55 represent potential markers for MDS prognosis and/or targeted therapy.

Tissue methylation and demethylation influence translesion synthesis DNA polymerases (TLS) contributing to the genesis of chromosomal abnormalities in myelodysplastic syndrome.

AIMS: DNA methylation has its distribution influenced by DNA demethylation processes with the catalytic conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Myelodysplastic syndrome (MDS) has been associated with epigenetic dysregulation of genes related to DNA repair system, chronic immune response and cell cycle. METHODS: We evaluated the tissue DNA methylation/hydroxymethylation in bone marrow trephine biopsies of 73 patients with MDS, trying to correlate with the mRNA expression of 21 genes (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2, CDC20, AURKA, AURKB and TPX2). RESULTS: The M-score (5mC) was significantly higher in patients with chromosomal abnormalities than patients with normal karyotype (95% CI -27.127779 to -2.368020; p=0.022). We observed a higher 5mC/5hmC ratio in patients classified as high-risk subtypes compared with low-risk subtypes (95% CI -72.922115 to -1.855662; p=0.040) as well as patients with hypercellular bone marrow compared with patients with normocellular/hypocellular bone marrow (95% CI -69.189259 to -0.511828; p=0.047) and with the presence of dyserythropoiesis (95% CI 17.077703 to 51.331388; p=0.001). DNA pols with translesion activity are significantly influenced by methylation. As 5mC immunoexpression increases, the expressions of POLH (r=-0.816; r2 =0.665; p=0.000), POLQ (r=-0.790; r2=0.624; p=0.001), PCNA (r=-0.635; r2=0.403; p=0.020), POLK (r=-0.633; r2=0.400; p=0.036 and REV1 (r=-0.578; r2=0.334; p=0.049) decrease. CONCLUSIONS: Our results confirm that there is an imbalance in the DNA methylation in MDS, influencing the development of chromosomal abnormalities which may be associated with the low expression of DNA polymerases with translesion synthesis polymerases activity.

Lesão por pressão relacionada a dispositivos médicos: prevenção e fatores de risco associados / Lesión por presión relacionada con dispositivos médicos: prevención y factores de riesgo asociados / Pressure injury related to medical devices: prevention and associated risk factors

Introdução: A lesão por pressão é encontrada na pele ou tecido subjacente, geralmente sobre uma proeminênciaóssea, resultante da exposição à pressão ou forças de cisalhamento, possuindo fatores intrínsecos e extrínsecos: imobilidade, inconsciência, perda da continência urinária e fecal, deficiência nutricional, doenças crônico degenerativas, peso e relacionados a dispositivos médicos. Objetivo: Descrever a prevenção e fatores de risco para Lesão por pressão relacionadas à dispositivos médicos. Método: Revisão integrativa de literatura, entre 201 O a 2020 nas bases de dados LILACS, PubMed, Bdenf e site de busca Scielo. Resultados: Foram incluídos nove estudos, sendo: quatro (44,4%) publicações que descrevem os principais dispositivos relacionados a estas lesões. Conclusão: Foi descrito os fatores associados ao desenvolvimento de Lesões por Pressão Relacionadas a Dispositivos Médicos e como preveni-las, identificando quais os dispositivos de risco, e medidas de prevenção e tratamento, cuidados específicos e eficazes por meio dos profissionais de enfermagem na prevenção e tratamento(AU)

lntroduction: Pressure injury is found in the skin or underlying tissue, usually over a bony prominence, resulting fromexposure to pressure or shear forces, having intrinsic and extrinsic factors: immobility, unconsciousness, loss of urinary and fecal continence, nutritional deficiency, chronic degenerative diseases, weight and related to medical devices. Objective: To describe the prevention and risk factors for Pressure lnjury related to medical devices. Method: lntegrative literature review, between 201 O and 2020 in LILACS, PubMed, Bdenf and Scielo search engine databases. Results: Nine studies were included: four (44,4%) publications describing the main devices related to these injuries. Conclusion: The factors associated with the development of Pressure Injuries Related to Medical Devices and how to prevent them were described, identifying which are the risk devices, and prevention and treatment measures, specific and effective care through nursing professionals in prevention and treatment.(AU)

lntroducción: La lesión por presión se encuentra en la piei o tejido subyacente, generalmente sobre una prominenciaósea, como resultado de la exposición a fuerzas de presión o cizallamiento, teniendo factores intrínsecos y extrínsecos: inmovilidad, inconsciencia, pérdida de continencia urinaria y fecal, deficiencia nutricional, crónico degenerativo. enfermedades, peso y relacionados con dispositivos médicos. Objetivo: Describir la prevención y los factores de riesgo de las lesiones por presión relacionadas con los dispositivos médicos. Método: Revisión integrativa de la literatura, entre 201 O y 2020 en las bases de datos de los motores de búsqueda LILACS, PubMed, Bdenf y Scielo. Resultados: Se incluyeron nueve estudios: cuatro (44,4%) publicaciones que describen los principales dispositivos relacionados con estas lesiones. Conclusión: Se describieron los factores asociados ai desarrollo de Lesiones por Presión Relacionadas con Dispositivos Médicos y cómo prevenirias, identificando cuáles son los dispositivos de riesgo, y las medidas de prevención y tratamiento, atención específica y efectiva a través de profesionales de enfermería en prevención y tratamiento.(AU)

Diagnóstico e tratamento de úlcera hipertensiva de Martorell: artigo de revisão / Diagnóstico y tratamiento de la úlcera hipertensiva de Martorell: artículo de revisión / Diagnosis and treatment of Martorell's hypertensive ulcer: review article

Introdução: A úlcera hipertensiva de Martorell é uma ferida crônica, associada a hipertensão arterial sistêmica, dedifícil manejo clínico e subdiagnosticada. Objetivo: Investigar os métodos de diagnóstico e os tratamentos existentes para a UHM. Método: Estudo descritivo e qualitativo de revisão integrativa com a análise sistemática de referências bibliográficas nas bases de dados PubMed, SciELO, MEDLINE e LILACS no período de 2016 e 2021, e periódicos da CAPES. Resultados: Clinicamente o paciente apresenta uma ferida pequena, de forma arredondada, superficial, com margens necróticas e cianóticas e eritema perilesional eventual. Os pulsos distais usualmente estão presentes e há ausência de edema e varizes locais. De todos os sinais e sintomas relatados, destaca-se a dor, descrita como intensa e desproporcional à sua dimensão. Conclusão: O cerne ao diagnóstico é avaliação clínica e o tratamento é a normalização da pressão arterial sistêmica e curativos regulares e, uso de analgésicos, antibióticos e vasodilatadores periféricos.(AU)

lntroduction: Martorell's hypertensive ulcer is a chronic wound, associated with systemic hypertension withdifficult clinicai management and it is often underdiagnosed. Goal: To investigate the diagnostic method and current treatments for Martorell's hypertensive ulcer disease. Method: A descriptive and qualitative study of integrative literature review with a systematic analysis of bibliographic references from PubMed, SciELO, MEDLINE and LILACS databases, ranging from 2016 to 2021, as well as selected articles from CAPES journals. Results: patients usually present with a small, rounded and superficial wound with cyanotic and necrotic edges and occasional perilesional erythema. Distal pulses are usually present and there is an absence of edema and local varicose veins. From all the signs and symptoms reported by patients with this type of injury, it is possible to point out that the pain is intense and disproportionate to its dimension. Conclusion: The core of diagnosis is the clinicai evaluation and the treatment is controlled systemic blood pressure, regular bandages and, if needed, analgesics, antibiotics and peripheral vasodilators. (AU)

lntrodución: La úlcera hipertensiva de Martorell es una herida crónica, asociada a la hipertensión arterial sistémica,de difícil manejo clínico y muchas veces subdiagnosticada. Objetivo: Investigar los métodos de diagnóstico y tratamientos existentes para este tipo de lesión. Método: Se realizá un análisis sistemático de referencias bibliográficas en las bases de datas PubMed, SciELO, MEDLINE y LILACS en el período de publicación entre 2016 y 2021, además de artículos seleccionados de revistas CAPES. Resultados: Clínicamente el paciente suele presentarse con una pequena herida, redondeada, superficial, con márgenes necróticos y cianóticos con eritema perilesional ocasional. Los pulsos distales suelen estar presentes y hay ausencia de edema y venas varicosas locales. De todos los signos y síntomas reportados por los pacientes con este tipo de lesiones, se destaca el dolor, que se describe como intenso y desproporcionado con la zona de la herida y su tamafio. Conclusión: La base dei tratamiento es la normalización de la presión arterial sistémica y los apósitos regulares y, si necesario, analgésicos, antibióticos y vaso dilatadores periféricos(AU)

c 9253-6T > c REV3L: A novel marker of poor prognosis in Myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by dysplasias, ineffective hematopoiesis and risk of acute myeloid leukemia transformation. Approximately 90% of MDS patients present mutations in genes involved in various cell signaling pathways. Specialized DNA polymerases, such as POLN, POLI, POLK, POLQ, POLH, POLL and REV3L, insert a nucleotide opposite replication-blocking DNA lesions in an error-prone manner and, in this way, sometimes can actively promote the generation of mutation. For the best of our knowledge, has not been described the mutations of these genes in MDS. DNA target sequencing CDS regions of the REV3L gene was performed in a 58-year-old man diagnosed as High Risk Myelodysplastic Syndrome. The patient presented very low hemoglobin, increased number of blasts, karyotype:47,XY,+8[6]/47,XY,del(7)(q32),+8[7], no response to hypomethylating therapy (decitabine), all markers of poor prognosis. Target sequencing identified a mutation c.9253-6T>C REV3L (Substitution - intronic) with VAF (variant allele frequency) = 16% considered pathogenic according to Functional Analysis through. Hidden Markov Models (FATHMM). This is the first evidence of REV3L mutation in MDS and, of utmost importance, associated with poor prognosis.

Enfermeiro: ator no empreendedorismo social / Nurse: actor in social entrepreneurships

Introdução: O empreendedor social é um agente de mudanças que inspira outras pessoas a se engajarem em torno de uma causa comum e corrobora com a melhoria de ambientes onde os recursos são escassos. O enfermeiro realiza o empreendedorismo social, uma vez que busca soluções inovadoras e busca a sustentabilidade social. Objetivo: discutir o papel do Enfermeiro como ator no empreendorismo social. Método: Estudo descritivo e qualitativo de revisão integrativa de literatura nas bases de dados Pubmed, Lilacs, Scielo e indexador Spell, entre 2010 a 2020 sobre empreendedorismo social e enfermagem. Resultados: Foram encontradas vinte pesquisas, do qual 25% retrata as características empreendedoras de acadêmicos, docentes e enfermeiros; 25% aborda o empreendedorismo na formação dos enfermeiros; 15% dos estudos trazem informações nacionais e internacionais sobre a temática. Conclusão: É essencial discutir sobre o papel do enfermeiro enquanto empreendedor social, sua formação e atuação para seu empoderamento na assistência de saúde.(AU)

Introduction: The social entrepreneur is an agent of change that inspires others to engage around a common cause and supports the improvement of environments where resources are scarce. Nurses carry out social entrepreneurship, as they seek innovative solutions and seek social sustainability. Objective: to discuss the role of the nurse as an actor in social entrepreneurship. Method: Descriptive and qualitative study of an integrative literature review in Pubmed, Lilacs, Scielo and Spell indexer databases, between 2010 and 2020 on social entrepreneurship and nursing. Results: Twenty researches were found, of which 25% portray the entrepreneurial characteristics of academics, teachers and nurses; 25% addresses entrepreneurship in the training of nurses; 15% of the studies bring national and international information on the subject. Conclusion: It is essential to discuss the role of nurses as social entrepreneurs, their training and performance for their empowerment in health care.(AU)

El emprendedor social es un agente de cambio que inspira a otras personas a involucrarse en una causa común. El enfermero realiza emprendimiento social al buscar soluciones innovadoras y la sostenibilidad social. Objetivo: discutir el rol del enfermero como actor en el emprendimiento social. Método: Estudio descriptivo y cualitativo de revisión integradora de literatura sobre emprendimiento social y enfermería en las bases de datos Pubmed, Lilacs, Scielo y Spell index, entre 2010 y 2020. Resultados: Se encontraron veinte encuestas, de las cuales el 25% retrata las características emprendedoras de académicos, docentes y enfermeros; El 25% aborda el espíritu empresarial en la formación de enfermeros; El 15% de los estudios aportan información nacional e internacional sobre el tema. Conclusión: Discutir sobre el rol del enfermero como emprendedor social, su formación y desempeño para que estos profesionales se empoderen en el cuidado de la salud.(AU)

Educação continuada e metodologias ativas em cursos a distância em enfermagem: revisão integrativa da literatura / Continuing education and active methodologies in distance courses in nursing: integrative literature review / Educación continua y metodologías activas en cursos de enfermería a distancia: una revisión integradora de la literatura

Objetivo: Verificar e discutir as metodologias ativas de ensino adotadas na educação de enfermeiros em cursos à distância. Método: A pesquisa foi aprovada pelo Comitê de Ética em Pesquisa da Universidade Federal de São Paulo. Realizou-se revisão integrativa da literatura em bases de dados utilizando os seguintes descritores e suas combinações: Educação a Distância, Enfermagem e Metodologias ativas. Resultados: Observou-se que 33,3% dos estudos promoviam aprendizagem por meio de ambiente virtual de aprendizagem, 30,3% usavam o formato e-learning e 12,1% utilizavam método híbrido. Considerações finais: As metodologias ativas de ensino têm sido empregadas em cursos de capacitação de profissionais de saúde, inclusive enfermagem, e têm contribuído positivamente na qualidade da assistência prestada aos pacientes. (AU)

Objective: To verify and discuss the active teaching methodologies adopted in the education of nurses in distance learning courses. Method: The research was approved by the Research Ethics Committee of the Federal University of São Paulo. An integrative literature review was carried out on databases using the following descriptors and their combinations: Distance Education, Nursing and Active Methodologies. Results: It was observed that 33,3% of the studies promoted learning through a virtual learning environment, 30,3% used the e-learning format and 12.1% used a hybrid method. Conclusion: Active teaching methodologies have been used in training courses for health professionals, including nursing, and have contributed positively to the quality of care provided to patients.(AU)

Objetivo: Verificar y discutir las metodologías activas de enseñanza utilizadas en los cursos de educación a distancia para la educación en enfermería. Métodos: El estudio fue aprobado por el Comité de Ética en Investigación de la Universidad Federal de São Paulo. Se realizó una revisión bibliográfica integradora utilizando los siguientes descriptores y sus combinaciones: educación a distancia, enfermería y metodologías activas. Resultados: Se observó que el 33,3% de los estudios promovió el aprendizaje a través del entorno de aprendizaje virtual, el 30,3% utilizó el formato de aprendizaje electrónico y el 12,1% utilizó el método híbrido. Consideraciones finales: Se han empleado metodologías de Aprendizaje Activo en cursos de capacitación para profesionales de la salud, incluida la enfermería, que han contribuido positivamente a la calidad de la atención brindada a los pacientes.(AU)

Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer-A Clinicopathological Series.

BACKGROUND: Glycogen Synthase Kinase-3 beta (GSK-3ß) regulates diverse cell functions including metabolic activity, signaling and structural proteins. GSK-3ß phosphorylates target pro-oncogenes and regulates programmed cell death-ligand 1 (PD-L1). This study investigated the correlation between GSK-3ß expression and clinically relevant molecular features of lung adenocarcinoma (PDL1 score, PTEN expression and driver mutations). METHODS: We evaluated 95 lung cancer specimens from biopsies and surgical resections. Immunohistochemistry was performed to analyze the expression of GSK-3ß, PTEN, and PDL1. Epidemiological data, molecular characteristics and staging were evaluated from medical records. The histologic classification was performed by an experienced pulmonary pathologist. RESULTS: Most patients were female (52.6%) and the majority had a positive smoking history. The median age was 68.3 years, with individuals over 60 years accounting for 82.1%. The predominant histological subtype was adenocarcinoma (69.5%), followed by squamous cell carcinoma (20.0%). GSK-3ß expression in tumors was cytoplasmic with a dotted pattern and perinuclear concentration, with associated membranous staining. Seven (7.3%) tumors had associated nuclear expression localization. Seventy-seven patients (81.1%) had advanced clinical-stage tumors. GSK-3ß was positive in 75 tumors (78%) and GSK3-positive tumors tended to be diagnosed at advanced stages. Among stage III/IV tumors, 84% showed GSK3 positivity (p= 0.007). We identified a statistically significant association between GSK-3ß and PTEN in the qualitative analysis (p 0.021); and when comparing PTEN to GSK-3ß intensity 2+ (p 0.001) or 3+ expression (> 50%) - p 0.013. GSK-3ß positive tumors with a high histological score had a worse overall survival. CONCLUSION: We identified the histological patterns of GSK-3ß expression and evaluated its potential as marker for overall survival, establishing a simple histological score to measure the evaluated status in resected tissues. The use of GSK-3ß expression as an immune response biomarker remains a challenge. Future studies will seek to explain the role of its interaction with PTEN.

ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis.

Toll-like receptors are mutated or overexpressed in up to 50% of patients with myelodysplastic syndrome (MDS). Endogenous retroviruses (ERV) trigger TLR3 leading to interferon regulatory genes (IRFs) activation. We evaluated if the ERVs-TLR3-IRF axis activation would be linked to MDS pathogenesis and we also conducted a detailed cancer analysis of the ERVs, TLR3 and IRFs gene expression in 30 cancer types using GEPIA database. Seventy-nine bone marrow samples from patients with MDS were evaluated for cytogenetics and quantitative real­time PCR of TLR3, ERVK6, ERVW-1, ERV3-1, IRF3 and IRF7. Patients with dyserythropoiesis showed higher TLR3 (p = 0.035), ERVK6 (p = 0.001), ERVW1 (p = 0.045) and ERV3-1 (p = 0.016) expression than patients without dyserythropoiesis. Upregulation of Interferon Regulatory Factors, IRF3 and IRF7, was associated with poor prognostic markers in MDS such as > 10% of blasts (p = 0.003-IRF3; p = 0.009-IRF7), low platelets count (< 50.000/mm3) (p = 0.001-IRF3; p = 0.021-IRF7), transfusion dependence (p = 0.014-IRF3) and chromosomal abnormalities (p = 0.036-IRF7). We found strong correlations between ERVK6-ERVW1 (r = 0.800; r2 = 0.640; p = 0.000), ERVW1-ERV3-1 (r = 0.715; r2 = 0.511; p = 0.000), and IRF7-IRF3 (r = 0.567; r2 = 0.321; p = 0.000) and moderate correlation between ERVK6-ERV3-1(r = 0.485; r2 = 0.235; p = 0.000), ERVW1-IRF7 (r = 0.389; r2 = 0.151; p = 0.001), ERVW1-IRF3 (r = 0.357; r2 = 0.127; p = 0.004), ERV3-1-IRF7 (r = 0.314; r2 = 0.098; p = 0.009), and ERV3-1-IRF3 (r = 0.324; r2 = 0.104; p = 0.007). Using GEPIA Database in 30 cancer types, we detected a typical pattern of upregulation as here presented in MDS. We suggest TLR3 activation by ERVs is linked to MDS pathogenesis leading to bone marrow failure. Abnormal double-stranded RNA (dsRNA) expression of Endogenous Retroviruses (ERV) triggers TLR3 hyperactivation. This induces IRF3, IRF7, and NF-kB to translocate to the nucleus and activate transcription of IFNα/ß which binds to the type I-IFN receptor promoting interferon response. Thus, just as TLR4 induces a crucial myeloid shift, the ERVs-TLR3 axis may play an important role in establishing one of the most striking characteristics in MDS, dyserythropoiesis.

Qualidade de vida e autoestima de pacientes com úlcera venosa / Quality of life and self-esteem of patients with venous ulcer / Calidad de vida y autoestima de pacientes con úlcera venosa

Objetivo: Avaliar a qualidade de vida e autoestima de pacientes com úlcera venosa. Método: Estudo primário, exploratório, observacional, transversal e descritivo realizado com 75 pacientes atendidos na Atenção Primária de Conselheiro Lafaiete-MG no período de dezembro de 2018 a maio de 2019 com a aplicação da Escala de autoestima de Rosenberg e o questionário de qualidade de vida SF-36. Resultados: O gênero feminino foi mais prevalente (60%), idade média de 68,9 anos e predomínio de doenças crônico-degenerativas. O levantamento das médias da Escala de Autoestima de Rosenberg teve maiores pontuações foram relacionadas ao gênero feminino, raça branca, aposentados, tabagistas, etilistas, com HAS e DM. Conclusão: A presença de úlcera venosa interferiu negativamente na autoestima de ambos os gêneros, entretanto o gênero masculino apresenta melhores escores quando comparados ao gênero feminino.(AU)

To assess the quality of life and self-esteem of patients suffering from venous ulcer. Method: Cross-sectional study regarding 75 patients, seen in the family health units in the Conselheiro Lafaiete municipality-MG. The individual basic care registration form, Rosenberg's self-esteem scale and the SF-36 quality of life survey were utilized for the data gathering. Results: Attested female predominance(60%), with a median age of 68,9 years. The Rosenberg's self-esteem scale attested an average of 9,7, the greatest average of the SF-36 test was 57,7. The Overall Health Status variable indicated the highest score among those evaluated, correlating to improvement, while the Physical Aspect corresponded to worsening, especially when associated with the female sex and the presence of comorbid conditions. Conclusion: The presence of venous ulcers interfered the self-esteem of both genders.(AU)

Objetivo: Evaluar la calidad de vida y la autoestima de pacientes con úlceras venosas. Método: Estudio primario, exploratorio, observacional, transversal y descriptivo realizado con 75 pacientes atendidos en la Atención Primaria de Conselheiro Lafaiete-MG entre diciembre 2018 y mayo 2019 con la aplicación de la escala de autoestima de Rosenberg y el cuestionario de calidad de vida SF-36. Resultados: el sexo femenino tuvo mayor prevalencia (60%), con edad promedia de 68,9 años y predominio de enfermedades crónico-degenerativas. Los promedios de la escala de Rosenberg con mayor puntuación fueron los relacionados al género femenino, de raza blanca, jubilados, fumadores, usuarios de bebidas alcohólicas, con HSA y DM. Conclusión: la presencia de úlceras venosas interfirió negativamente en la autoestima de ambos sexos, sin embargo, el sexo masculino presenta mejores puntajes cuando comparados al sexo femenino.(AU)

c.9253-6T>c REV3L: A novel marker of poor prognosis in Myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by dysplasias, ineffective hematopoiesis and risk of acute myeloid leukemia transformation. Approximately 90% of MDS patients present mutations in genes involved in various cell signaling pathways. Specialized DNA polymerases, such as POLN, POLI, POLK, POLQ, POLH, POLL and REV3L, insert a nucleotide opposite replication-blocking DNA lesions in an error-prone manner and, in this way, sometimes can actively promote the generation of mutation. For the best of our knowledge, has not been described the mutations of these genes in MDS. DNA target sequencing CDS regions of the REV3L gene was performed in a 58-year-old man diagnosed as High Risk Myelodysplastic Syndrome. The patient presented very low hemoglobin, increased number of blasts, karyotype:47,XY,+8[6]/47,XY,del(7)(q32),+8[7], no response to hypomethylating therapy (decitabine), all markers of poor prognosis. Target sequencing identified a mutation c.9253-6T>C REV3L (Substitution - intronic) with VAF (variant allele frequency)=16% considered pathogenic according to Functional Analysis through. Hidden Markov Models (FATHMM). This is the first evidence of REV3L mutation in MDS and, of utmost importance, associated with poor prognosis.

Chromosomal abnormalities and dysregulated DNA repair gene expression in farmers exposed to pesticides.

Exposure to pesticides is considered a major factor underlying increased risk of hematological disorders in agricultural workers due to its carcinogenic potential. However, genotoxic impact of pesticides in DNA integrity of bone marrow stem cells (BMSC) of farmers exposed is not yet well known. We evaluated presence of chromosomal abnormalities (CA) and mRNA expression of DNA repair targets (ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6, LIG4, CSA, CSB, XPA, XPC, XPG) in 90 bone marrow samples of farmers divided into three groups: commercial farming (CF), family farming (FF) and organic farming (OF). Our results showed that farmers in CF (72.7 %) and FF (27.3 %) groups had significantly higher values of CA when compared to OF group (0.0 %; p = 0.003). CF showed lower XPG (p = 0.008), CSA (p < 0.001), ATM (p = 0.036) and LIG4 (p = 0.004) mRNA expression than OF. FF presented lower XPG (p = 0.012) and LIG4 (p = 0.004) expression than OF. CF + FF individual with ≥12 years of exposure to pesticides showed decreased mRNA expression of XPC (p = 0.001), XPG (p = 0.010), CSB (p = 0.05), ATM (p = 0.030) and LIG4 (p = 0.044) than those who have been exposed for <12 years. CF + FF with CA showed a lower expression of BRCA2 when compared to CF + FF group without CA (p = 0.007). These results highlight that genotoxic exposure to pesticides negatively affects expression profile of important DNA repair genes in BMSC, favoring irreparable chromosomal lesions.

Can synthetic lethality approach be used with DNA repair genes for primary and secondary MDS?

Cancer-specific defects in DNA repair pathways create the opportunity to employ synthetic lethality approach. Recently, GEMA (gene expression and mutation analysis) approach detected insufficient expression of BRCA or NHEJ (non-homologous end joining) to predict PARP inhibitors response. We evaluated a possible role of DNA repair pathways using gene expression of single-strand break (XPA, XPC, XPG/ERCC5, CSA/ERCC8, and CSB/ERCC6) and double-strand break (ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6, LIG4) in 92 patients with myelodysplastic syndrome (73 de novo, 9 therapy-related (t-MDS). Therapy-related MDS (t-MDS) demonstrated a significant downregulation of axis BRCA1-BRCA2-RAD51 comparing to normal controls (p = 0.048, p = 0.001, p = 0.001). XRCC6 showed significantly low expression in de novo MDS comparing to controls (p = 0.039) and for patients who presented chromosomal abnormalities (p = 0.047). Downregulation of LIG4 was consistently associated with poor prognostic markers in de novo MDS (hemoglobin < 8 g/dL (p = 0.040), neutrophils < 800/mm3 (p < 0.001), patients with excess of blasts (p = 0.001), very high (p = 0.002)/high IPSS-R (p = 0.043) and AML transformation (p < 0.001). We also performed an evaluation of GEPIA Database in 30 cancer types and detected a typical pattern of downregulation as here presented in primary or secondary MDS. All these results suggest synthetic lethality approach can be tested with DNA repair genes (beyond that of BRCA1/2 status) for de novo and therapy-related myelodysplastic syndrome and may encourage clinical trials evaluating the use of PARP1 inhibitors in MDS.