Mesenchymal Stromal Cell Senescence Induced by Dnmt3a -Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy.

Clonal hematopoiesis (CH) can predispose to blood cancers due to enhanced fitness of mutant hematopoietic stem and progenitor cells (HSPCs), but the mechanisms driving this progression are not understood. We hypothesized that malignant progression is related to microenvironment-remodelling properties of CH-mutant HSPCs. Single-cell transcriptomic profiling of the bone marrow microenvironment in Dnmt3a R878H/+ mice revealed signatures of cellular senescence in mesenchymal stromal cells (MSCs). Dnmt3a R878H/+ HSPCs caused MSCs to upregulate the senescence markers SA-ß-gal, BCL-2, BCL-xL, Cdkn1a (p21) and Cdkn2a (p16), ex vivo and in vivo . This effect was cell contact-independent and can be replicated by IL-6 or TNFα, which are produced by Dnmt3a R878H/+ HSPCs. Depletion of senescent MSCs in vivo reduced the fitness of Dnmt3a R878H/+ hematopoietic cells and the progression of CH to myeloid neoplasms using a sequentially inducible Dnmt3a ; Npm1 -mutant model. Thus, Dnmt3a -mutant HSPCs reprogram their microenvironment via senescence induction, creating a self-reinforcing niche favoring fitness and malignant progression. Statement of Significance: Mesenchymal stromal cell senescence induced by Dnmt3a -mutant hematopoietic stem and progenitor cells drives clonal hematopoiesis and initiation of hematologic malignancy.

A Modified Socket-Shield Technique: Simplifying the Root Sectioning Process.

Socket wall resorption leading to a loss of surrounding bone following tooth extraction has been documented in the dental literature. The use of various socket-shield techniques has been suggested as a solution to this issue. In these approaches, the tooth root is sectioned in two, and the coronal two-thirds of the buccal root is preserved in the socket. This allows the periodontium along with the bundle and buccal bone to remain intact, thus preventing or minimizing bone remodeling. According to the literature, this procedure is highly technique sensitive, especially when it comes to sectioning the root. Additionally, the procedure requires significant time, and several complications may occur, such as fenestration or luxation of the remaining root, requiring its complete extraction. This case report presents a modified socket-shield technique using a trephine bur guided by a computer-designed surgical guide to simplify root sectioning, thus reducing surgical time while increasing predictability of the outcome.

Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma.

Studies defining normal and disrupted human neural crest cell development have been challenging given its early timing and intricacy of development. Consequently, insight into the early disruptive events causing a neural crest related disease such as pediatric cancer neuroblastoma is limited. To overcome this problem, we developed an in vitro differentiation model to recapitulate the normal in vivo developmental process of the sympathoadrenal lineage which gives rise to neuroblastoma. We used human in vitro pluripotent stem cells and single-cell RNA sequencing to recapitulate the molecular events during sympathoadrenal development. We provide a detailed map of dynamically regulated transcriptomes during sympathoblast formation and illustrate the power of this model to study early events of the development of human neuroblastoma, identifying a distinct subpopulation of cell marked by SOX2 expression in developing sympathoblast obtained from patient derived iPSC cells harboring a germline activating mutation in the anaplastic lymphoma kinase (ALK) gene.

A role for astrocytic insulin-like growth factor I receptors in the response to ischemic insult.

Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults using tamoxifen-regulated Cre deletion of IGF-IR in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 (Iba 1) microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.

Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis.

Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH accelerated atherosclerosis, identifies IL-6-induced CSF1R expression as a critical mechanism and supports blockade of IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.

Immunogenicity of the hepatitis B vaccine adjuvanted with AS04C in patients with biological therapies.

BACKGROUND: Hepatitis B vaccination is necessary for patients with biologic therapies because of the immunomodulatory effect of these drugs. Due to the elevated use of these therapies in the latest years, the research for new vaccination regimens and the improvement of the current ones is essential. New adjuvants like AS04C might be a potential strategy to improve immune response. Hepatitis B vaccine adjuvanted with AS04C has not been studied in this population before. We analyzed the immunogenicity of an adjuvanted hepatitis B vaccine in patients with biologic therapies. Variables that might affect vaccine response were also evaluated. METHODS: Analytic observational retrospective cohort study performed between January 2016 and September 2018. 301 patients under biological treatment aged from 18 years were included. Patients received 4 doses of hepatitis B adjuvanted vaccine (Fendrix®) in a 0-1-2-6 month immunization schedule. Several sociodemographic, clinical and pharmacological variables were evaluated. The outcome variable was measured as the antibody titers (anti-HBs). The geometric mean of titers (GMT) as a measure for the central tendency was calculated from these values. RESULTS: The immunization schedule of the hepatitis B vaccine adjuvanted with AS04C demonstrated high levels of seroconversion with 82.1 % (95 % CI, 77.6-86.6) of vaccinated patients seroconverting after primary vaccination and achieving 89.0 % (95 % IC, 85.3-92.7) after the booster doses for non-responders. The use of corticosteroid therapy and high doses of them, age over 60 years and the main diagnosis were associated with lower seroconversion rates and lower anti-HBs titers. CONCLUSIONS: The hepatitis B vaccine adjuvanted with AS04C (Fendrix®) produces an adequate immune response in patients with autoimmune diseases and immunosuppressive and/or immunomodulating therapies. This immunization schedule is proposed as a very suitable and adapted option for the protection of patients with autoimmune diseases under active biological therapies.

Utilidad de la determinación del perfil de ácidos grasos / Usefulness of the determination of the fatty acids profile

Resumen Al tener en cuenta las consecuencias de los desequilibrios nutricionales en el desarrollo de las enfermedades, se considera importante determinar el perfil de ácidos grasos (AG) en dietas con distintas fuentes lipídicas y su impacto sobre los AG del suero de ratas. Se prepararon dietas con distintas fuentes lipídicas y completas en el resto de los nutrientes. Las fuentes lipídicas fueron: manteca, aceite de oliva, aceite de girasol alto oleico, aceite de girasol y aceite de soja (control). Los animales recibieron las dietas durante 10 días. Se determinó el perfil de AG de las dietas y del suero de las ratas por cromatografía gaseosa. Los cambios en el perfil de AG en suero se producen en función de la fuente lipídica aportada por la dieta. Por ende, es importante esta determinación como diagnóstico de la deficiencia de ácidos grasos esenciales, EPA y DHA, cuyas funciones son fundamentales para el funcionamiento del organismo.

Abstract Taking into account the consequences of nutritional imbalances in the development of diseases, it is considered important to determine the profile of fatty acids (FA) in diets with different lipid sources and their impact on serum FA of growing rats. Diets with different lipid sources and complete in the rest of the nutrients were prepared. The lipid sources used were butter, olive oil, high oleic sunflower oil, sunflower oil, and soybean oil (control). Animals were fed with experimental and control diets for 10 days. The FA profile of the diets and of rat serum was determined by gas chromatography (GC). Changes in FA profile in serum occur depending on the source of fat provided by the diet. Therefore, the determination of fatty acids is of utmost importance, as a diagnosis of the deficiency of essential fatty acids, EPA and DHA, whose functions are essential for the proper functioning of the body.

Resumo Tendo em conta as consequências dos desequilíbrios nutricionais no desenvolvimento das doenças, considera-se importante determinar o perfil de ácidos graxos (AG) em dietas com diferentes fontes lipídicas e o seu impacto nos AG do soro de ratos. Foram elaboradas dietas com diferentes fontes lipídicas e completas no restante dos nutrientes. As fontes lipídicas utilizadas foram: manteiga, azeite, óleo de girassol alto oleico, óleo de girassol e óleo de soja (controle). Os animais foram alimentados com dietas por 10 dias. O perfil de AG das dietas e o soro dos ratos foi determinado por cromatografia gasosa. Alterações no perfil de AG em soro ocorrem dependendo da fonte lipídica fornecida pela dieta. Por isso, esta determinação é de extrema importância, como diagnóstico da deficiência de ácidos graxos essenciais, EPA e DHA, cujas funções são essenciais para o funcionamento do organismo.

Reconstructing Peri-implant and Papillary Soft Tissue in the Esthetic Area Using Interdental Tissue, a Tuberosity Connective Tissue Graft, and a Tunneling Approach: A Case Report.

Long-term survival of dental implants in both fully and partially edentulous patients has been proven successful, as reported in the literature. However, maintenance of soft-tissue quality and volume is often difficult due to the multiple surgeries involved in implant placement and the physiological resorption of bone after tooth extraction. Soft-tissue augmentation is frequently necessary to improve soft-tissue contour and can be done simultaneously with implant or abutment placement or following the final insertion of the implant-supported prostheses. The purpose of this case report is to demonstrate a surgical procedure used to augment a peri-implant buccal soft-tissue defect using interdental palatal tissue from a pocket reduction procedure in combination with a distal wedge graft from the tuberosity as connective tissue utilizing a tunneling approach in the esthetic area. The implant restorations in the reported case were delivered 1 year prior to the soft-tissue reconstruction.

Patient-Related Risk Factors for Maxillary Sinus Augmentation Procedures: A Systematic Literature Review.

The posterior maxilla has traditionally presented a challenge for successful placement of dental implants due to a combination of poor bone quality, ridge atrophy, and pneumatization of the sinus floor following tooth extraction. However, with the successful and predictable surgical outcomes reported in the literature, more clinicians and patients are choosing an implant-supported restoration in the edentulous posterior maxilla. Consequently, sinus elevation and augmentation have gained more popularity. Extensive research has been conducted on types of bone graft materials and implants, less-invasive techniques to perform sinus augmentation, and timing for implant placement for sinus grafting. Despite the predictability of the techniques and biomaterials employed in sinus grafting procedures, intra- and postoperative complications are common. Much of the current literature discusses the local risk factors related to sinus augmentation, with few studies focusing on the patient-related risk factors. The purpose of this review is to identify, evaluate, and discuss the possible management of patient-related risk factors to allow for more predictable maxillary sinus floor augmentation outcomes.

Despedida silenciada: equipe médica, família, paciente: cúmplices da conspiração do silêncio / Silenced farewell: medical staff, family, patient: accomplices in the conspiracy of silence

A comunicação, mesmo ao fim da vida, é ferramenta importante. Ter informações sobre diagnóstico e prognóstico permite que pacientes e família vivenciem esse período de forma menos dolorosa. Quando se estabelece o pacto ou conspiração do silêncio, isso já não é possível. O pacto do silêncio é descrito como um acordo implícito ou explicito, por parte dos familiares, amigos e profissionais, de alterar a informação ao paciente com a finalidade de ocultar o diagnóstico ou a gravidade da situação. Esse tema é importante perante a incidência ainda elevada desse pacto na atualidade e pelas consequências dele. Este artigo teórico tem o objetivo de discorrer sobre este tema com base na pesquisa bibliográfica de estudos originais que apontam as causas, consequências e indicam possíveis estratégias de intervenções que estão sendo utilizadas para diminuir a incidência do pacto. Porém ainda são necessárias mais intervenções naquele sentido, pois, ainda hoje, se vivenciam mortes solitárias e despedidas silenciadas.

Communication, even at the end of life, is an important tool. Having information on diagnosis and prognosis lessens the pain for patients and their families. When we establish the pact or conspiracy of silence, this is no longer possible. The pact of silence is described as an implicit or explicit agreement on part of family members, friends and professionals. They agree to omit information from the patient in order to hide the diagnosis and/or the severity of the situation. This topic is important due to the high incidence of this pact today and the consequences of it. This theoretical paper aims to discuss this topic based on the bibliographical research of original studies that point to the causes and consequences and that indicate possible strategies of interventions that are being used to reduce the incidence of the pact. But there is still a need for more interventions because, even today, we experience lonely deaths and silent farewells.

Despedida silenciada: equipe médica, família, paciente – cúmplices da conspiração do silêncio / Silenced farewell: medical staff, family, patient –accomplices in the conspiracy of silence

A comunicação, mesmo ao fim da vida, é ferramenta importante. Ter informações sobre diagnóstico e prognóstico permite que pacientes e família vivenciem esse período de forma menos dolorosa. Quando se estabelece o pacto ou conspiração do silêncio, isso já não é possível. O pacto do silêncio é descrito como um acordo implícito ou explicito, por parte dos familiares, amigos e profissionais, de alterar a informação ao paciente com a finalidade de ocultar o diagnóstico ou a gravidade da situação. Esse tema é importante perante a incidência ainda elevada desse pacto na atualidade e pelas consequências dele. Este artigo teórico tem o objetivo de discorrer sobre este tema com base na pesquisa bibliográfica de estudos originais que apontam as causas, consequências e indicam possíveis estratégias de intervenções que estão sendo utilizadas para diminuir a incidência do pacto. Porém ainda são necessárias mais intervenções naquele sentido, pois, ainda hoje, se vivenciam mortes solitárias e despedidas silenciadas.(AU)

Communication, even at the end of life, is an important tool. Having information on diagnosis and prognosis lessens the pain for patients and their families. When we establish the pact or conspiracy of silence, this is no longer possible. The pact of silence is described as an implicit or explicit agreement on part of family members, friends and professionals. They agree to omit information from the patient in order to hide the diagnosis and/or the severity of the situation. This topic is important due to the high incidence of this pact today and the consequences of it. This theoretical paper aims to discuss this topic based on the bibliographical research of original studies that point to the causes and consequences and that indicate possible strategies of interventions that are being used to reduce the incidence of the pact. But there is still a need for more interventions because, even today, we experience lonely deaths and silent farewells.(AU)

Internação domiciliar: avaliações imperativas implicadas na função de cuidar / Home hospitalization: reviews imperative involved in the function of caring

Este artigo teórico está dividido em duas partes, a primeira utiliza a revisão de literatura como sua metodologia para discorrer sobre a internação domiciliar e os cuidados paliativos que tem como filosofia o cuidado humanizado ao paciente e família podendo ser integrado à internação domiciliar. A segunda parte apresenta artigos descritivos de programas de internação domiciliar em cuidados paliativos realizados em hospitais universitários. Esta modalidade de cuidado vem se expandindo e surge para proporcionar ambiente mais humanizado ao paciente, sendo necessária a inserção da família nos cuidados ao paciente. Os programas selecionados relatam a caracterização do atendimento, porém não salientam intervenções detalhadas junto aos familiares. São necessárias intervenções com foco em apoio às questões centrais da família e orientação em relação aos cuidados para não influenciar negativamente na evolução do paciente e para que o atendimento domiciliar seja realizado adequadamente. Este artigo se faz relevante para atualizar e ampliar o conhecimento sobre o tema, já que a revisão da literatura indica uma carência de estudos sobre internação domiciliar com abordagem em cuidados paliativos, além de mostrar as necessidades da família referidas em pesquisas recentes, para que se possa avalia-las antes de formular os planos de cuidados nesta modalidade em expansão.

This theoretical paper is divided into two parts, the first uses the literature review and methodology to discuss home care and palliative care philosophy that has as humanized care to the patient and family may be integrated in home care. The second part presents descriptive articles of home care programs in palliative care conducted in university hospitals. This type of care is expanding and appears to provide more humane environment for the patient; the family involvement in patient care is required. The selected programs report the characterization of service, but not emphasize detailed interventions with relatives. Interventions focusing on supporting the core issues of family and guidance regarding the care not to influence negatively on patient outcomes and for home care are required to be performed properly. This article is relevant for updating and expanding knowledge on the subject, since the literature indicates a lack of studies on home care with palliative care approach and to demonstrate the needs of the family referred to in recent research, for which can evaluate them before formulating care plans for expansion in this mode.

Internação domiciliar: avaliações imperativas implicadas na função de cuidar / Home hospitalization: reviews imperative involved in the function of caring

Este artigo teórico está dividido em duas partes, a primeira utiliza a revisão de literatura como sua metodologia para discorrer sobre a internação domiciliar e os cuidados paliativos que tem como filosofia o cuidado humanizado ao paciente e família podendo ser integrado à internação domiciliar. A segunda parte apresenta artigos descritivos de programas de internação domiciliar em cuidados paliativos realizados em hospitais universitários. Esta modalidade de cuidado vem se expandindo e surge para proporcionar ambiente mais humanizado ao paciente, sendo necessária a inserção da família nos cuidados ao paciente. Os programas selecionados relatam a caracterização do atendimento, porém não salientam intervenções detalhadas junto aos familiares. São necessárias intervenções com foco em apoio às questões centrais da família e orientação em relação aos cuidados para não influenciar negativamente na evolução do paciente e para que o atendimento domiciliar seja realizado adequadamente. Este artigo se faz relevante para atualizar e ampliar o conhecimento sobre o tema, já que a revisão da literatura indica uma carência de estudos sobre internação domiciliar com abordagem em cuidados paliativos, além de mostrar as necessidades da família referidas em pesquisas recentes, para que se possa avalia-las antes de formular os planos de cuidados nesta modalidade em expansão.(AU)

This theoretical paper is divided into two parts, the first uses the literature review and methodology to discuss home care and palliative care philosophy that has as humanized care to the patient and family may be integrated in home care. The second part presents descriptive articles of home care programs in palliative care conducted in university hospitals. This type of care is expanding and appears to provide more humane environment for the patient; the family involvement in patient care is required. The selected programs report the characterization of service, but not emphasize detailed interventions with relatives. Interventions focusing on supporting the core issues of family and guidance regarding the care not to influence negatively on patient outcomes and for home care are required to be performed properly. This article is relevant for updating and expanding knowledge on the subject, since the literature indicates a lack of studies on home care with palliative care approach and to demonstrate the needs of the family referred to in recent research, for which can evaluate them before formulating care plans for expansion in this mode.(AU)

Superposition of leprosy and other neglected tropical diseases in the state of Rio de Janeiro: a case series report.

This is a report on eight non-HIV infected leprosy patients presenting unusual co-infection with other, often neglected, tropical diseases, namely: American tegumentary leishmaniasis (ATL), sporotrichosis, and cryptococcosis. To the best of our knowledge, there have been very few ATL-leprosy co-infection reports in the literature to date and only one previous description of the coexistence of leprosy-cryptococcosis and leprosy-sporotricosis.

Hypoxia upregulates carcinoembryonic antigen expression in cancer cells.

Carcinoembryonic antigen (CEA, ceacam5) is an important tumor-associated antigen with reported roles, e.g., in immunological defense, cell adhesion, cell survival and metastasis. Its overexpression in cancer cells is known to involve transcriptional activation of the CEA gene, but the underlying molecular details remain unclear. Here, we show that hypoxia and intracellular alkalinization, 2 factors commonly found in solid tumors, increase CEA protein expression in breast (MCF-7) and colorectal (CaCo-2 and HT-29) cancer cells. The increase was comparable (2-3-fold) to that observed in colorectal carcinomas in vivo. CEA promoter analyses further revealed that this upregulation involves a known binding site for HIF-1 transcription factor (5'-ACGTG-3') within one of the CEA promoter's positive regulatory elements (the FP1 site; the E-box). Accordingly, deletion or targeted mutagenesis of this motif rendered the CEA promoter unresponsive to hypoxia. Our chromatin immunoprecipitation data confirmed that endogenous HIF-1alpha binds to the CEA promoter in hypoxic cells but not in normoxic cells. Moreover, overexpression of the hypoxia-inducible factor (HIF-1alpha) was sufficient to increase CEA protein expression in the cells. In contrast, c-Myc, which is known to bind to the overlapping E-box, did not potentiate HIF-1alpha-induced CEA expression. CEA overexpression in vivo was also found to coincide with the expression of carbonic anhydrase IX, a well-known hypoxia marker. Collectively, these results define CEA as a hypoxia-inducible protein and suggest an important role for the tumor microenvironmental factors in CEA overexpression during tumorigenesis.