Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induced a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to an erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated the MPN disease burden, including leukemic engraftment and splenomegaly, in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only for primary MPN samples harboring ASXL1 mutations. Last, treatment of CD34+ hematopoietic/stem progenitor cells with the PRMT6 inhibitor EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.

Técnica de Puckett en el tratamiento de mamas tuberosas con lipotransferencia complementaria / The Puckett Technique for Treating Tuberous Breasts with Complementary Lipotransfer

Introducción: La mama tuberosa es una anomalía congénita de la mama que se presenta en la pubertad y es relativamente frecuente. Objetivo: El objetivo de este artículo es dar a conocer el resultado estético del tratamiento quirúrgico de esta afección con la técnica de Pukett sin incluir el implante mamario, con lipotransferencia complementaria. Presentación del caso: Se presenta una paciente femenina, de 25 años de edad, con mama tuberosa grado 4. Se le realiza corrección con técnica de Pukett sin implantes mamarios y en su lugar se usa grasa autóloga. Luego de corregir las anomalías que conforman esta malformación se obtuvo una mama armoniosa sin complicaciones. Conclusión: La técnica de Pukett combinada con lipotransferencia ofrece resultados estéticos y estables en el tratamiento de la mama tuberosa(AU)

Introduction: Tuberous breast is a congenital breast anomaly that presents at puberty and is relatively frequent. Objective: The aim of this article is to report the aesthetic outcome after treating this condition surgically using the Puckett technique without breast implant, with complementary lipotransfer instead. Case presentation: The is presented of a 25-year-old female patient with grade-4 tuberous breast. She is performed a correction using the Puckett technique without breast implants; autologous fat is used instead. After correcting the anomalies that make up this malformation, a harmonious breast was obtained without complications. Conclusion: The Puckett technique combined with lipotransfer offers aesthetic and stable outcomes in the treatment of tuberous breast(AU)

High Incidence of Respiratory Syncytial Virus in Children with Community-Acquired Pneumonia from a City in the Brazilian Pre-Amazon Region.

INTRODUCTION: Although fewer children have been affected by the severe form of the coronavirus disease 2019 (COVID-19), community-acquired pneumonia (CAP) continues to be the leading global cause of child hospitalizations and deaths. AIM: This study investigated the incidence of respiratory syncytial virus (RSV) as well its subtypes (RSV A and B), adenovirus (ADV), rhinovirus (HRV), metapneumovirus (HMPV), coronavirus (NL63, OC43, 229E and HKU1), parainfluenza virus subtypes (PI1, PI2 and PI3), bocavirus and influenza A and B viruses (FluA and FluB) in children diagnosed with CAP during the COVID-19 pandemic. METHODS: A total of 200 children with clinically confirmed CAP were initially recruited, of whom 107 had negative qPCR results for SARS-CoV-2 and were included in this study. Viral subtypes were identified using a real-time polymerase chain reaction in the nasopharyngeal swab samples. RESULTS: Viruses were identified in 69.2% of the patients. RSV infections were the most frequently identified (65.4%), with type RSV B being the most prevalent (63.5%). In addition, HCoV 229E and HRV were detected in 6.5% and 3.7% of the patients, respectively. RSV type B was associated with severe acute respiratory infection (ARI) and a younger age (less than 24 months). CONCLUSIONS: New strategies for preventing and treating viral respiratory infections, particularly RSV infections, are necessary.

USB1 is a miRNA deadenylase that regulates hematopoietic development.

Mutations in the 3' to 5' RNA exonuclease USB1 cause hematopoietic failure in poikiloderma with neutropenia (PN). Although USB1 is known to regulate U6 small nuclear RNA maturation, the molecular mechanism underlying PN remains undetermined, as pre-mRNA splicing is unaffected in patients. We generated human embryonic stem cells harboring the PN-associated mutation c.531_delA in USB1 and show that this mutation impairs human hematopoiesis. Dysregulated microRNA (miRNA) levels in USB1 mutants during blood development contribute to hematopoietic failure, because of a failure to remove 3'-end adenylated tails added by PAPD5/7. Modulation of miRNA 3'-end adenylation through genetic or chemical inhibition of PAPD5/7 rescues hematopoiesis in USB1 mutants. This work shows that USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN.

Atrazine adsorption and desorption on functionalized montmorillonite: aluminum-pillared and lithium saturated.

Atrazine is an herbicide used worldwide, and it is considered a severe environmental contaminant. The present study aims to evaluate the atrazine adsorption in aqueous media in montmorillonite samples which were either in natural state or functionalized through saturation with lithium and pillarization with aluminum by different methods. Montmorillonite saturated with lithium adsorbed significantly more atrazine than the natural montmorillonite sample. Among the samples obtained through the three aluminum-pillarization methods, the mass percentage of adsorbed atrazine was very similar. However, the best combination was the aluminum-pillarization (due to the maintenance of the open interlayer region) and saturation with lithium (due to the significant reduction of the cation exchange capacity of the mineral), because both processes facilitate the interaction of atrazine with the montmorillonite. Another advantage was that the adsorption of atrazine in the pillared and lithium saturated samples had small desorption, which is desirable in the environmental perspective. It is recommended to build filters with aluminum-hydroxy pillared, lithium saturated montmorillonite as an alternative method to rapidly remove atrazine from aqueous media. In addition to the shorter production time, this process resulted in montmorillonite with high occupancy rate and stability of the aluminum-hydroxy pillars.

Nevo Melanocítico Congénito Gigante con hemangioma hepático asociado. Reporte de caso clínico. Revisión bibliográfica

El nevo melanocítico congénito gigante es una lesión pigmentada de gran tamaño presente al nacimiento. Su incidencia es de 1/1.000-500.000 recién nacidos. La localización más frecuente es el tronco posterior, la cara, el cuero cabelludo y las extremidades. El objetivo que buscamos con la presentación de este caso clínico es ofrecer una revisión actualizada sobre la evaluación al nacimiento, conducta y tratamiento a seguir por los neonatólogos y pediatra de atención primaria ante la inesperada presencia de las dermatopatías no tan frecuentes como la que nos ocupa. Se trata de un recién nacido que nace con un "nevo melanocítico congénito gigante" y que además se asocia con un hemangioma hepático diagnosticado en el ingreso. Valoramos la importancia de esta patología que radica en los problemas impactantes desde el punto de vista estético, quirúrgico y emocional que pueden originar en el paciente y sus familiares, además de la posible asociación con otras malformaciones del sistema nervioso central y en algunos de ellos, el riesgo de ser el origen de un melanoma.

The giant congenital melanocytic nevus is a large pigmented lesion present at birth. Its incidence is 1 / 1,000-500,000 newborns. The most frequent location is the posterior trunk, the face, the scalp and the extremities. We decided with the presentation of this clinical case to offer an updated review on the evaluation at birth, behavior and treatment to be followed by neonatologists, primary care pediatrician before the unexpected presence of dermatopathies not as frequent as the one we are dealing with today, the "nevus" giant congenital melanocytic ". The importance of this pathology lies in the impactful problems from the aesthetic, surgical and emotional point of view that can originate in the patient and their relatives, in addition to the possible association with other malformations of the central nervous system and in some of them, the risk of being the origin of a melanoma.

O nevo melanocítico congênito gigante é uma grande lesão pigmentada presente ao nascimento. Sua incidência é de 1/1.000-500.000 recém-nascidos. A localização mais frequente é o tronco posterior, face, couro cabeludo e extremidades. O objetivo que buscamos com a apresentação deste caso clínico é oferecer uma revisão atualizada sobre a avaliação ao nascimento, comportamento e tratamento a ser acompanhado por neonatologistas e pediatras da atenção primária na presença inesperada de dermatopatias não tão frequentes quanto a em questão. É um recém-nascido nascido com um "nevo melanocítico congênito gigante" e também está associado a um hemangioma hepático diagnosticado na admissão. Valorizamos a importância dessa patologia que reside nos problemas chocantes do ponto de vista estético, cirúrgico e emocional que podem se originar no paciente e em seus familiares, além da possível associação com outras malformações do sistema nervoso central e, em algumas de las, o risco de ser a origem do melanoma.

Produção científica brasileira sobre saúde da população negra: revisão de escopo rápida / Brazilian scientific production on the health of the black population: a rapid scoping review

Resumo O artigo apresenta uma prospecção da produção científica brasileira sobre a saúde da população negra (SPN) publicada em periódicos científicos. Trata-se de uma revisão de escopo rápida, combinada com análise temática e bibliométrica. As buscas foram realizadas em quatro bases indexadas. Foram selecionados 519 trabalhos em consonância com os eixos temáticos e subtemas estratégicos da Agenda de Prioridades de Pesquisa do Ministério da Saúde e das diretrizes da Política Nacional de Saúde Integral da População Negra. Os dados mostraram estudos publicados entre 1969 e 2022, a maioria deles com abordagem quantitativa. Entre os selecionados, 65 foram especificamente sobre a população negra e 54 sobre a população quilombola. A análise dos termos mais recorrentes nos títulos dos trabalhos selecionados mostrou que prevaleceram aspectos epidemiológicos e condições de saúde e doença. Observou-se limitações nos descritores de indexação hoje disponíveis, que não abrangem a terminologia mais adequada conceitualmente. O artigo contribui para consolidar o conhecimento sobre a produção científica relacionada com a SPN, subsidiando também a discussão em torno de uma agenda prioritária propositiva para pesquisas com vistas a aprimorar as políticas de saúde para essa população, superar o racismo e denunciar as violações de direitos.

Abstract The article presents a perspective on the Brazilian scientific production on the health of the black population (SPN) published in scientific journals. We performed a rapid scoping review combined with thematic and bibliometric analysis. Our search included four indexed databases. We retrieved 519 studies in line with the thematic axes and strategic underlying themes of the Agenda of Research Priorities of the Ministry of Health and the guidelines of the National Policy for the Comprehensive Health of the Black Population. The data mainly returned quantitative studies published from 1969 to 2022. Sixty-five of the selected studies were explicitly about the black population and 54 about the quilombola population. The analysis of the most recurrent terms in the titles of the selected studies evidenced that epidemiological aspects and health and disease conditions prevailed. We observed limitations in the currently available indexing descriptors, which do not cover the most conceptually appropriate terminology. This paper consolidates knowledge about the SPN-related scientific production. It supports the discussion on a propositional priority research agenda to improve health policies for this population, overcome racism, and denounce rights violations.

Advances in the recruitment and loyalty of blood donors: A critical outlook over the Brazilian scenario / Avanços no recrutamento e fidelização de doadores de sangue: um olhar crítico sobre o panorama brasileiro

The growing need for more stringent methods of safe blood transfusion has engendered blood banks in Brazil. The transfusion appears, then, as an alternative path for blood-related pathologies and their components. Followed by the enforcement of altruistic principles, blood donation has become resistant within society due to its myths and prejudices. Thus, the implementation of public policies became more evident in tracing the social profile of blood donors, and the public power started regulating, supervising and controlling the rational use of blood and blood products. This way, the indices of blood donation in the Unified Health System (SUS) result from various means of interaction with both the potential donor and with the loyal donor, through digital media, school lectures, symposia, congresses and visual media. This process hitched the recruitment to the peculiarities of potential donors, mostly promoted by Health professionals. There is a need to gradually increase such measures to facilitate the donation process, adapting it to the reality of these people, to amplify the number of loyal donors (AU)

A crescente necessidade de métodos mais rígidos de segurança na transfusão sanguínea engendrou os bancos de sangue no Brasil. A transfusão aparece, então, como via alternativa para tratamento de patologias relacionadas ao sangue e aos seus componentes. A partir da aplicação de princípios altruístas, a doação de sangue tornou-se mais resistente pela sociedade, devido aos mitos e preconceitos. A aplicação de políticas públicas, dessa forma, tornaram-se mais evidentes para traçar o perfil social do doador de sangue, e o poder público passou a regulamentar, fiscalizar e controlar o uso racional de hemoderivados e hemocomponentes. Nesse sentido, os índices de doação de sangue no Sistema Único de Saúde (SUS) são resultados de diversos meios de interação tanto com o potencial doador quanto com o fidelizado, por intermédio de mídias digitais, palestras em centros escolares, simpósios, congressos e meios audiovisuais. Esse processo atrelou o recrutamento às peculiaridades dos potenciais doadores, promovido principalmente pelos profissionais da saúde. Surge a necessidade de aumentar, cada vez mais, tais medidas de modo a facilitar e flexibilizar o processo de doação, adaptando-o, assim, à realidade dessas pessoas, para amplificar o número de doadores fidelizados (AU)

Antifungal and physicochemical properties of Ocimum essential oil loaded in poly(lactic acid) nanofibers.

Poly(lactic acid) (PLA) nanofibres containing different proportions of the essential oils from Ocimum basilicum L. and Ocimum gratissimum L. were prepared by solution blow spinning method. The essential oils were extracted by hydrodistillation and characterized by gas chromatography. MEV, contact angle, DSC and FTIR were used to characterize the nanofibres. The effect of bioative nanofibres on the growth of the fungus and on the production of ochratoxin A were evaluated using the fumigation test. Linalool, 1·8-cineole and camphor were the principal components of the essential oil from O. basilicum, and eugenol was the principal constituent in the oil from O. gratissimum. An increase in the average diameter of the nanofibres was observed with the addition of the essential oils. The essential oils acted as a plasticizer, resulting in a reduction in the crystallinity of the PLA. The encapsulation of essential oils in PLA nanofibres was verified by FTIR. An effective antifungal and antimicotoxygenic activity against Aspergillus ochraceus and Aspergillus westerdjikiae was observed for the bioative nanofibres. These results confirm the potential of PLA nanofibres containing the essential oils for the control of toxigenic fungi that cause the deterioration of food and are harmful to human health.

Atenção à Saúde Mental de crianças e adolescentes negros e o racismo / Atención a la salud mental de niños y adolescentes negros y el racismo / Mental health assistance for black children and adolescents and racism

O objetivo deste trabalho é identificar estratégias utilizadas por uma equipe de um Centro de Atenção Psicossocial Infantojuvenil (Capsij) na assistência a crianças e adolescentes pretos e pardos com problemas de saúde. Seus pressupostos apoiaram-se no vasto campo de estudos das relações raciais, paradigma pelo qual são feitas também as análises. Participaram 18 trabalhadores do Capsij - Brasilândia; as entrevistas foram guiadas por um questionário semiestruturado e a análise temática para interpretação dos dados foi organizado tendo raça/cor como categoria analítica. Os resultados mostram que cuidado a crianças e adolescentes que manifestam sofrimentos pela vivência do racismo, ou que o tem como uma dimensão importante, demanda do profissional espaços de sensibilização, informação e letramento para as formações raciais, assim como convoca a elaboração de estratégias de enfrentamento ao racismo institucional, sobretudo em perspectiva intersetorial.(AU)

Identificar estrategias utilizadas por un equipo de un Centro de Atención Psicosocial infantojuvenil (CAPSij) en la asistencia a niños y adolescentes negros y mulatos con problemas de salud. Las presuposiciones de este trabajo se apoyaron en el vasto campo de estudios de las relaciones raciales, paradigma a partir del cual se realizan también los análisis. Participaron 18 trabajadores del CAPSij - Brasilândia; las entrevistas fueron guiadas por un cuestionario semiestructurado y el análisis temático para la interpretación de los datos se estructuró teniendo raza/color como categoría analítica. Los resultados muestran que el cuidado a niños y adolescentes que manifiestan sufrimientos por la vivencia del racismo, o que lo tienen como una dimensión importante, demanda del profesional espacios de sensibilización, información y aprendizaje para las formaciones raciales, así como convoca la elaboración de estrategias de enfrentamiento al racismo institucional, sobre todo en perspectiva intersectorial.(AU)

The study aimed to identify strategies used by a team of a Psychosocial Care Center (CAPSij) to assist black and brown children and adolescents with health problems. The assumptions of the study were supported by the vast field of studies on race relations, the paradigm that also underpinned the analyses. Eighteen workers from the Brasilândia CAPSij were interviewed. The interviews were guided by a semi-structured questionnaire and the thematic analysis for data interpretation was structured having race/color as the analytical category. The results showed that the provision of care for children and adolescents who express suffering due to the experience of racism, or who have it as an important dimension, demands, of the professional, spaces for awareness, information and literacy regarding racial formations. In addition, it calls for the development of strategies to combat institutional racism, especially in an intersectoral perspective.(AU)

Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe.

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.

Antibacterial and Antifungal Activities and Toxicity of the Essential Oil from Callistemon viminalis Complexed with ß-Cyclodextrin.

The essential oil from Callistemon viminalis (EOC) is rich in monoterpenes, with a variety of biological properties: antibacterial, antifungal, insecticide, and antioxidant. Inclusion complexes (ICs) with cyclodextrins (CDs) is an alternative to prevent toxicity, improve the activity, and reduce the concentration to be used. Thus, the objective of this work was to prepare an IC (EOC/ß-CD) and evaluate the antibacterial, antifungal and phospholipase activities, as well as the toxicity. Antimicrobial activity used the agar diffusion test and antifungal activity the disc diffusion test. Toxicity tests were carried out using Lactuca sativa L. The inhibition of phospholipase activity using the venom of Bothrops atrox as an inducer was performed. Antibacterial and antifungal tests demonstrated a decrease in the minimum inhibitory concentration (MIC) of the IC. It was most significantly observed for the bacterium Listeria monocytogenes, for which there was a decrease in the MIC from 250 µg mL-1 to 62.5 µg mL-1 after complexation, and for the fungus Aspergillus flavus, with a decrease in MIC from 125 µg mL-1 to 62.5 µg mL-1 after complexation. Toxicity tests with Lactuca sativa showed a decrease in toxicity after complexation in all parameters analyzed, with no statistical difference from the negative control. Inhibition of phospholipase activity induced by Bothrops atrox venom was more expressive in the highest proportion studied (1:10 m:m), exerting 23% inhibition. The assays demonstrated that the complexation between the EOC and ß-CD is a promising alternative for use in different branches, especially in food industry, to fully exploit its application potential.

Aspectos clínico-epidemiológicos dos acidentes botrópicos notificados em um hospital de referência de Alagoas / Clinical-epidemiological aspects of bothropic accidents notified in an Alagoas reference hospital

RESUMO: Os acidentes ofídicos configuram um sério transtorno à saúde pública dos países tropicais, em razão da frequência com a qual se apresentam e da magnitude da morbimortalidade que acarretam. No Brasil, observa-se uma prevalência anual entre 19 e 22 mil desses acidentes, e, dentre os casos em que se há notificação da espécie, o gênero Bothrops é responsável por 80,50% dos casos. Objetivo: Descrever os aspectos clínico-epidemiológicos dos acidentes botrópicos notificados em um hospital de referência no estado de Alagoas. Métodos: Estudo observacional, descritivo do tipo transversal e retrospectivo, dos registros clínicos de pacientes internados no Hospital Escola Dr. Hélvio Auto, por acidentes botrópicos de 2010 a 2018. Resultados: A partir da investigação de 694 prontuários médicos, constatou-se a maior prevalência de acidentes no ano 2017. O perfil epidemiológico foi composto por indivíduos de sexo masculino, adultos, de etnia parda, de baixo nível de escolaridade, trabalhadores rurais, e caracterizado por ocorrer majoritariamente na mesorregião Leste Alagoano. Por sua vez, o perfil clínico caracterizou-se por apresentar como região anatômica mais acometida os membros inferiores, manifestações de dor e edema, gravidade leve a moderado e desfecho evolutivo satisfatório. Conclusões: A investigação realizada permitiu traçar o perfil clínico-epidemiológico dos acidentes botrópicos no estado de Alagoas, bem como identificou que o grupo social composto por trabalhadores rurais apresentou certa dificuldade de acesso ao atendimento hospitalar adequa-do em tempo hábil, o que determinou a incidência de casos de maior gravidade nessa população. (AU)

ABSTRACT: Ophidic accidents constitute serious public health in tropical countries, due to the frequency that these events occur and their relevant magnitude of morbidity and mortality. In Brazil, there is an annual prevalence between 19.000 and 22.000 of these accidents, and among the cases that notify the species, it is possible to verify that the Bothropsgenus is responsible for 80.50% of the cases. Objective: Describing the clinical and epidemiological aspects of bothropic accidents reported in a reference hospital in the state of Alagoas. Methods: Observational, descriptive cross-sectional, and retrospective study of the clinical records of patients admitted into the Escola Dr. Hélvio Auto Hospital for bothropic accidents from 2010 to 2018. Results: It shows that the year of 2017 was the most prevalent year of cases, through the investigation of 694 medical records. The epidemiological profile has been composed of male, adult, brown individuals, low education, rural workers, and characterized by occurring mostly in the Eastern Alagoas. Therefore, the clinical profile was characterized by the occurrence of the most affected anatomic region as lower limbs, manifestations of pain and edema, mild to moderate severity, and satisfactory clinical outcome. Conclusions: The investigation allowed to trace the clinical and epidemiological profile of bothropic accidents in the state of Alagoas, and also identify the social group composed of rural workers as the one with some demanding to access the hospital care accurately, and who was the population with the incidence of the highest severity. (AU)

Telomere Dysfunction Activates p53 and Represses HNF4α Expression Leading to Impaired Human Hepatocyte Development and Function.

BACKGROUND AND AIMS: Telomere attrition is a major risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo. APPROACH AND RESULTS: Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-regulation, immediately after endoderm differentiation and completely absent in in vitro-derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening prevents the up-regulation and activation of human hepatocyte nuclear factor 4 alpha (HNF4α) in a p53-dependent manner. Both reactivation of telomerase and silencing of p53 rescued hepatocyte formation in telomerase mutants. Likewise, the conditional expression (doxycycline-controlled) of HNF4α, even in cells that retained short telomeres, accrued DNA damage, and exhibited p53 stabilization, successfully restored hepatocyte formation from hESCS. CONCLUSIONS: Our data show that telomere dysfunction acts as a major regulator of HNF4α during hepatocyte development, pointing to a target in the treatment of liver disease in telomere-syndrome patients.

Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita.

Dyskeratosis congenita (DC) is a pediatric bone marrow failure syndrome caused by germline mutations in telomere biology genes. Mutations in DKC1 (the most commonly mutated gene in DC), the 3' region of TERC, and poly(A)-specific ribonuclease (PARN) cause reduced levels of the telomerase RNA component (TERC) by reducing its stability and accelerating TERC degradation. We have previously shown that depleting wild-type DKC1 levels by RNA interference or expression of the disease-associated A353V mutation in the DKC1 gene leads to decay of TERC, modulated by 3'-end oligoadenylation by noncanonical poly(A) polymerase 5 (PAPD5) followed by 3' to 5' degradation by EXOSC10. Furthermore, the constitutive genetic silencing of PAPD5 is sufficient to rescue TERC levels, restore telomerase function, and elongate telomeres in DKC1_A353V mutant human embryonic stem cells (hESCs). Here, we tested a novel PAPD5/7 inhibitor (RG7834), which was originally discovered in screens against hepatitis B viral loads in hepatic cells. We found that treatment with RG7834 rescues TERC levels, restores correct telomerase localization in DKC1 and PARN-depleted cells, and is sufficient to elongate telomeres in DKC1_A353V hESCs. Finally, treatment with RG7834 significantly improved definitive hematopoietic potential from DKC1_A353V hESCs, indicating that the chemical inhibition of PAPD5 is a potential therapy for patients with DC and reduced TERC levels.

Tumor propagating cells: drivers of tumor plasticity, heterogeneity, and recurrence.

Tumorigenesis is associated with the development of a highly variable pattern of cellular diversity, consequence of genetic and epigenetic diversification, followed by clonal selection and expansion. This process is shaped by the microenvironment and leads to intratumoral heterogeneity, which is characterized by differences between cancer cells in terms of gene expression, phenotypic markers, growth dynamics, and resistance to treatment. Another relevant aspect in intratumor heterogeneity is cell plasticity-the ability of a cell to switch to new identities. In this review, we focus on the mechanisms that regulate cancer cell plasticity within a tumor, and explore the concept of tumor propagating cells, or TPCs, a cancer cell able to propagate/phenocopy the parental tumor and recapitulate tumor heterogeneity. We discuss the influence of the microenvironment and driver mutations on TPCs formation and function, the existence of phenotypically distinct TPC clones within a tumor, the evolution of TPCs with disease progression, and their implications for therapy.

PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells.

Acute treatment with replication-stalling chemotherapeutics causes reversal of replication forks. BRCA proteins protect reversed forks from nucleolytic degradation, and their loss leads to chemosensitivity. Here, we show that fork degradation is no longer detectable in BRCA1-deficient cancer cells exposed to multiple cisplatin doses, mimicking a clinical treatment regimen. This effect depends on increased expression and chromatin loading of PRIMPOL and is regulated by ATR activity. Electron microscopy and single-molecule DNA fiber analyses reveal that PRIMPOL rescues fork degradation by reinitiating DNA synthesis past DNA lesions. PRIMPOL repriming leads to accumulation of ssDNA gaps while suppressing fork reversal. We propose that cells adapt to repeated cisplatin doses by activating PRIMPOL repriming under conditions that would otherwise promote pathological reversed fork degradation. This effect is generalizable to other conditions of impaired fork reversal (e.g., SMARCAL1 loss or PARP inhibition) and suggests a new strategy to modulate cisplatin chemosensitivity by targeting the PRIMPOL pathway.

Indicadores de monitoramento e avaliação da implementação da Política Nacional de Saúde Integral da População Negra / Indicators for monitoring and evaluating the implementation of the National Policy for the Integrative Health of the Black Population

Resumo O artigo apresenta a metodologia de construção de um painel de indicadores para monitoramento e avaliação da implementação da Política Nacional de Saúde Integral da População Negra (PNSIPN). A metodologia foi desenvolvida em quatro etapas: identificação do cenário, contexto da implementação, indicadores da PNSIPN e validação dos indicadores. Em todas as etapas participaram os proponentes da Política, burocratas de nível de rua, assessores técnicos dos colegiados de representação de gestores, representantes dos movimentos sociais, de associações e fóruns de patologias. Esses atores identificaram e pactuaram os indicadores do painel, categorizados em indicadores de enfrentamento ao racismo; indicadores das condições sociodemográficas segundo sexo, faixa etária e raça/cor; e indicadores de morbidade e mortalidade segundo sexo, faixa etária e raça/cor. O painel de indicadores para o monitoramento e análise da implementação da PNSIPN é viável e pode ser utilizado em nível municipal, estadual e federal, possivelmente subsidiando o processo de implementação e possibilitando o aprimoramento da gestão. A metodologia contribui para identificar indicadores de políticas públicas destinadas à garantia dos direitos humanos, da vigilância de direitos e da advocacy.

Abstract The article presents the methodology used in building a panel of indicators for monitoring and evaluating the implementation of the National Policy for the Integrative Health of the Black Population (PNSIPN). The methodology was developed in four stages: scenario identification, implementation context, PNSIPN indicators and validation of the indicators. The proponents of the policy, street-level bureaucrats, technical advisors of the collegiate representing the managers, representatives of social movements, of associations and forums of pathologies participated in every stage. Those actors identified and agreed on the panel's indicators, which have been categorized into indicators of coping with racism; indicators of sociodemographic conditions according to gender, age and race/color; and indicators of morbidity and mortality according to gender, age and race/color. The indicator panel for monitoring and evaluating the PNSIPN implementation is feasible and can be used at municipal, state and federal levels, possibly subsidizing the implementation process and enabling the improvement of management. The methodology contributes to the identification of indicators for public policies aimed at guaranteeing human rights, rights surveillance and advocacy.