Avaliação dos efeitos modulatórios da hematopoese no envelhecimento: Papel das células tronco mesenquimais medulares / Evaluation of the modulatory effects of hematopoiesis during aging: Role of bone marrow mesenchymal stem cells

O envelhecimento é um processo fisiológico que traz consigo uma série de alterações no organismo que se estendem até o nível molecular. Diante disto, este é um processo complexo que afeta diversos tecidos, sendo um deles o hematopoético, local onde, através de interações da Célula Tronco Hematopoética (CTH) com o ambiente ao seu redor, incluindo a Célula Tronco Mesenquimal (CTM), ocorre a hematopoese. Embora já sejam descritas na literatura algumas alterações na medula óssea consequentes do envelhecimento, os mecanismos por trás de tais mudanças permanecem elusivas, principalmente no âmbito das interações celulares ocorrentes na medula óssea. Portanto, este trabalho buscou investigar como o envelhecimento afeta a regulação hematopoética no contexto de sua relação com as CTM medulares. Para esta pesquisa, foram utilizados camundongos machos isogênicos da linhagem C57BL/6, dividindoos em grupos conforme sua idade: jovens (3 ­ 5 meses) e idosos (18 ­ 19 meses). Foi realizada a caracterização do modelo através de aspectos físicos como consumo proteico, variação de peso, entre outros, seguido de avaliação bioquímica e hematológica. Adicionalmente, foram coletadas células medulares e, posteriormente, realizado o isolamento das CTMs. Para estudar a relação destas células com a hematopoese, foram realizados ensaios in vitro utilizando a linhagem celular leucêmica C1498 (TIB-49™, ATCC®) mantidas em contato com o sobrenadante das CTMs isoladas. Quanto aos parâmetros bioquímicos, os animais idosos apresentaram menores níveis de albumina, aspartato alanina transferase (ALT) e de triglicerídeos quando comparados aos animais jovens. Contrariamente, os animais idosos apresentaram um maior nível de colesterol. Na avaliação hematológica, foi constatado pelo hemograma que os animais idosos apresentaram valores comparáveis aos animais jovens, todavia, o mielograma mostrou menor celularidade geral, seguido de menor número de células da linhagem eritroide e maior número de precursores granulocíticos. Através da imunofenotipagem, foi revelado um maior número de CTHs e de precursores grânulosmonocíticos na medula de animais idosos quando comparado aos jovens, e uma menor frequência de progenitores linfoides. Na imunofenotipagem de sangue periférico de animais idosos houve uma redução no número de linfócitos B e de eritrócitos, e aumento na população de células natural killers. Na imunofenotipagem de CTMs, o marcador CD73 apresentou menor expressão nos animais idosos. Avaliando o secretoma destas células estromais, foram encontrados no sobrenadante de CTMs de animais idosos aumentos significativos nas concentrações de CXCL12 e SCF e redução de IL-11. No âmbito molecular, as CTMs de animais idosos apresentaram aumento na expressão de Akt1, Nos e Ppar-γ, e redução na expressão de Csf3 e Cdh2. Adicionalmente, quando comparado a ação das CTMs de animais idosos em relação as CTMs de animais jovens, observou-se que CTMs de animais idosos foram capazes de aumentar a expressão de Sox2, Pou5f1 e Nanog e diminuir a expressão de Cdkn1a de células da linhagem C1498. O sobrenadante de CTMs de animais idosos também resultou na maior proliferação e migração de células da linhagem C1498. Portanto, levando em consideração a importância das CTMs sobre a regulação do sistema hematopoético, pode-se concluir que, no envelhecimento, as CTMs criam um ambiente propício para a proliferação celular no qual a manutenção da pluripotência é estimulada, o que pode acarretar em uma desregulação do sítio hematopoético quando habitado por células malignas

Aging is a physiological process in which occurs a series of alterations in an organism that extend to a molecular level. It is a complex process that affects various tissues, one of them being the bone marrow, wherethrough the interactions of the hematopoietic stem cell (CTH) with its surrounding environment, including with the mesenchymal stem cell (CTM), hematopoiesis takes place. Although some aging-associated alterations in the bone marrow can be found described in the literature, the mechanisms behind said changes remain elusive, especially when regarding the cellular interactions present inside the bone marrow. Therefore, this research aimed to investigate how aging affects the regulation of hematopoiesis in the context of its interactions with bone marrow-derived CTMs. For this investigation, male isogenic C57BL/6 mice were used as animal models. These were separated in two groups according to their age: young (3 ­ 5 months) and aged (18 ­ 19 months). The animal models were characterized by their physical properties such as protein intake and weight variation, followed by biochemical and hematological evaluation. Bone marrow cells were obtained and identified through immunophenotyping, thus isolating different cell populations, including the CTMs. To study the relationship between these cells and hematopoiesis, in vitro assays were conducted utilizing the leukemic cell lineage C1498 (TIB-49™, ATCC®) maintained in contact with the supernatant of isolated CTMs. By their biochemical profile, aged mice showed lower levels of albumin, alanine-aspartate transferase (ALT) and triglycerides compared to the young group. In contrast, aged mice had a higher cholesterol level. Hematological evaluation by total blood count showed similar results between the two groups, however, the myelogram revealed that the aged animals had lower cellularity, with less frequent cells from the erythroid lineage, with an increase in granulocytic precursors. Through immunophenotyping, it was also revealed that aged mice have higher numbers of hematopoietic stem cells, while also being noted a reduced population of lymphoid progenitors. An increase in the granulomonocytic progenitors was also found. Immunophenotyping peripheral blood cells of aged mice revealed reduced numbers of B lymphocytes and erythrocytes, and an increased natural killer cell population. Additionally, the cell surface marker CD73 was found to be less expressed in aged mice CTMs. The secretome of these stromal cells obtained from aged mice showed higher levels of CXCL12 and SCF, and lower levels of IL-11when compared to the young counterparts. At a molecular level, CTMs obtained from aged mice expressed more Akt1, Nos and Ppar-γ, while the expression of Csf3 and Cdh2 was reduced. Additionally, when comparing the effects of aged mice CTMs with young mice CTMs, it was observed that the first expressed were capable of increasing the expression of Sox2, Pou5f1 and Nanog, while decreasing Cdkn1a expression in the C1498 cell lineage. The supernatant obtained from aged mice also favored the proliferation and cell migration of the C1498 cell line. Thus, considering the importance that CTMs have over the hematopoietic system, we can conclude that, in aging, CTMs create a special environment which favors cell proliferation and maintenance of pluripotency, which can result in a dysregulation of the hematopoietic tissue when malignant cells are present

Effect of clonal hematopoiesis in remission on hematopoiesis recovery in patients with NPM1 mutated acute myeloid leukemia after chemotherapy / 中华血液学杂志

Objective: To investigate the effect of clonal hematopoiesis (CH) in remission on hematopoiesis recovery in patients with NPM1 mutated acute myeloid leukemia (AML) after chemotherapy. Methods: Retrospective analysis was performed on 86 patients with NPM1(mut) AML newly diagnosed and treated in the First Affiliated Hospital of Soochow University between July 2016 and June 2019. Their clinical data and NGS test results at diagnosis were analyzed. Moreover, bone marrow samples in remission were tested using Sanger sequencing. The log-rank test was used to analyze the difference in hematopoietic recovery, and Cox proportional hazard models were used to analyze the prognostic factors affecting hematopoietic recovery. Results: The median age of the 86 NPM1(mut) AML patients was 50 years (15-69 years). There were 39 males and 47 females. Forty-one patients were induced with intensity chemotherapy ("7 + 3"), whereas 45 patients were treated with low-dose cytarabine-based induction chemotherapy. At diagnosis, The most common mutations in the patients were FLT3, DNMT3A, TET2, and IDH1/IDH2 mutations. CH-associated mutations persisted in 21 patients during remission, and the mutations were DNMT3A, TET2, ASXL1, and IDH1/IDH2. The recovery time of neutrophils in patients with CH-associated mutations in remission was consistent with that in patients without CH in remission (P=0.282) but the recovery time of platelets in patients with CH in remission was significantly longer[26 (95% CI 21-32) days vs 25 (95% CI 23-26) days, P=0.032]. Furthermore, univariate analysis indicated that age, induced chemotherapy program, and CH in remission were risk factors for platelet recovery, whereas multivariate analysis indicated that induced chemotherapy program and CH in remission were independent risk factors for platelet recovery (HR=0.454, P=0.001 and HR=0.520, P=0.027, respectively) . Conclusion: CH in remission delays the hematopoietic recovery of patients with NPM1(mut) AML after chemotherapy.

Advances in the study of congenital immune mechanisms mediated by modifiable cardiovascular risk factors for atherosclerosis / 中国胸心血管外科临床杂志

@#Obesity, sleep disorders, psychological stress, sedentary are modifiable cardiovascular risk factors. There is growing evidence that these risk factors may accelerate the chronic inflammatory process of atherosclerosis and lead to myocardial infarction. Studies on the role of immune cells and their related immune mechanisms in atherosclerosis have shown that the above modifiable risk factors can affect the hematopoiesis of the bone marrow system, affect the production of immune cells and phenotypes, and then affect the progress of atherosclerosis. This review will focus on the effects of modifiable cardiovascular risk factors on the progression of atherosclerosis through the role of the innate immune system.

Research Progress on Gene Mutation and CHIP in Pathogenesis of MDS --Review / 中国实验血液学杂志

With the development of molecular biology techniques, the people's understanding of myelodysplastic syndromes (MDS) has greatly improved, a heterogeneous hematopoietic pre-malignant disorder of the stem cells. Gene mutations include RNA splicing, DNA methylation, chromosome modification, transcription factors, signal transduction kinases, RAS pathways, cohesion complexes, DNA repair, etc. Gene mutation is the determinant of diagnostic typing and therapeutic efficacy of MDS. The new concepts of CHIP and ICUS have aroused people's attention to the elderly patients with clonal hematopoiesis and non-clonal cytopenia but without MDS characteristics, who have the possibility of high-risk transformation to MDS and leukemia. In order to better understand the pathogenesis of MDS, the significance of gene mutations, CHIP and ICUS in the diagnosis and prognosis of MDS were reviewed in this paper.

Mielolipoma suprarrenal, revisión de literatura en México a propósito de dos casos / Adrenal myelolipoma, review of the literature in Mexico apropos of two cases

Introducción: los mielolipomas suprarrenales (ML) son neoplasias benignas poco frecuentes constituidas por tejido adiposo y mieloide. Clínicamente asintomáticas, suelen ser diagnosticados incidentalmente. En México existen solo 32 casos publicados de ML, presentándose en pacientes de entre 37 a 65 años, siendo la relación hombre-mujer 1:1.1, el síntoma más comúnmente reportado es dolor abdominal inespecífico, y la cirugía abierta es el principal abordaje quirúrgico empleado en nuestro país (89%). Caso clínico: presentamos una recopilación de la literatura actual sobre ML en México, además de dos casos clínicos de pacientes con ML: un hombre de 67 años con enfermedad diverticular y una mujer de 40 años con dolor en hipocondrio; en ambos se realizó resección tumoral, midiendo 9.5 cm y 13.3 cm, respectivamente. Conclusiones: presentamos dos casos nuevos en nuestro país que corresponden a incidentalomas. En ambos casos la cirugía se realizó para confirmar el diagnóstico, así como para prevenir posibles complicaciones.

Background: Adrenal myelolipomas (ML) are rare benign neoplasms compound of adipose and myeloid tissue. Clinically they are usually asymptomatic, being diagnosed generally by incident. In Mexico, there are only 32 published cases of ML, these occur between 37 and 65 years, with the male-female ratio being 1:1.1, clinically they present with abdominal or lumbar pain, open surgery being the main surgical approach (89%). Clinical case: We made a literature review of ML in Mexico and present two clinical cases: a 67-year-old man in followup for diverticular disease and a 40-year-old woman with pain in the left upper quadrant. In both cases, tumor resection was performed measuring 9.5 cm and 13.3 cm long respectively. Conclusions: We present two new cases in our country that correspond to incidentalomas. In both cases, surgery was performed to confirm the diagnosis, as well as to prevent possible complications

The muddled pancytopenia

Pancytopenia always remains a challenge for its detailed diagnostics evaluation, ranging from megaloblastic anemia to marrow aplasia and leukemia. Here, we report the case scenario of a 70-year-old male who presented with pancytopenia and his elaborated diagnostics approach, concluding the diagnosis of myelofibrosis with positive W515L. This case illustrates the uniqueness of establishing the diagnosis of myelofibrosis.

Research Progress of Clonal Hematopoiesis of Indeterminate Potential in Multiple Myeloma --Review / 中国实验血液学杂志

With the progress of medical technology, cloning hematopoietic was found to be widely exist in normal people. Because of its clinical significance and prognosis is unclear, it is named clonal hematopoiesis of indeterminate potential(CHIP), which has been detected in blood diseases such as myelodysplastic syndrome and lymphoma, and proven to be related to poor prognosis. Recently, CHIP has been also detected in patients with multiple myeloma (MM). In this article, the definition and influencing factors of CHIP, clinical significance, prognosis and treatment in MM were reviewed.

Clonal hematopoiesis of indeterminate potential and aging / 中华老年医学杂志

Clonal hematopoiesis with indeterminant potential(CHIP)is defined as the proportion of detectable clonal hematopoietic cells in peripheral blood exceeding 2% and without confirmed hematologic malignancy.CHIP could increase the risk of malignant diseases through changes in DNA damage response, transcriptional programming and epigenetic modification.The incidence of malignant tumors in the blood system is significantly higher in the CHIP patients than healthy person.In addition, CHIP represents a negative factor associated with aging.Recent studies have found that the incidences of infections, anemia, heart failure, thrombotic events, and tumors of the blood system in CHIP carriers were significantly increased.Starting with the epigenetic modifications, phenotypic changes and inflammatory mechanisms of CHIP-related gene mutations, this paper discussed the mechanisms of CHIP-related diseases and possible intervention aimed at aging.

Effect of donor clonal hematopoiesis on allogeneic hematopoietic stem cell transplantation / 白血病·淋巴瘤

Clonal hematopoiesis (CH) refers to the clonal expansion of hematopoietic stem/progenitor cells in some individuals with normal blood indexes. The incidence of CH increases with age, reflecting the decline of the hematopoietic and potential clonal evolution to a certain extent. In recent years, an increasing number of studies have shown that donor CH is an unfavorable factor affecting transplantation, graft-versus-host disease and donor cell leukemia after allogeneic hematopoietic stem cell transplantation. Emphasis on and identification of donor CH can optimize donor selection and help transplant patients benefit more. This article introduces the relevant research progress in combination with the content of the 63rd American Society of Hematology Annual Meeting.

Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis

Aging-elevated DNMT3A R882H-driven clonal hematopoiesis (CH) is a risk factor for myeloid malignancies remission and overall survival. Although some studies were conducted to investigate this phenomenon, the exact mechanism is still under debate. In this study, we observed that DNMT3A R878H bone marrow cells (human allele: DNMT3A R882H) displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult. DNMT3A R878H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation, especially TNFα insults. Mechanistically, we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNFα insults. Briefly, we elucidated the molecular mechanism driving DNMT3A R878H-based clonal hematopoiesis, which raises clinical value for treating DNMT3A R882H-driven clonal hematopoiesis and myeloid malignancies with aging.

Panax notoginseng saponins regulates hematopoietic function of bone marrow in aplastic anemia mice via TLR4/TLR2-NF-kB pathway / 中国药理学通报

Aim To explore the effects of Panax notog- inseng saponins( PNS) on hematopoietic functions anrl regulation on the TLR4/TLR2-NF-kB signaling path¬way in immune-mediated aplastic anemia ( AA ) C57 mice.Methods C57BL/6 mice were randomly divid¬ed into control group, total body irradiation group ( TBI) , model group, cyclosporine treatment group, PNS low-dose group, medium-dose group and high-dose group.The immune-mediated A A mice model was es¬tablished by total body irradiation with 5.0 Gy X-ray and mixed lymphocyte infusion.The body weight was measured, the spleen and thymus index was calculated , bone marrow pathology, the levels of peripheral blood triline cells,bone marrow nucleated cells( BMCs) and the levels of serum TNF-cx , 1L-2 , 1L-10 were detected, and the expression of CD1 lc and proteins related to the TLR4/TLR2-N F- k B pathway were detected 15 days later.Results Compared with control group, body weight, thymus index, the number of peripheral blood triline cells, BMCs and serum 1L-10 levels of the mice in model group significantly decreased ( P < 0.05 ) , while spleen index, the serum TNF-a, IL-2 levels and the protein expression of CD 11 c, TLR4, TLR2 , MvD88 , Akt and NF-kB in hone marrow significantly increased ( P <0.05).Compared with model group, after PNS treatment, hodv weight, thymus index, the number of peripheral blood triline cells, BMCs and serum IL-10 levels increased.Spleen index,serum TNF-cx,lL-2 lev¬els and the expression of CD11 c, TLR4, TLR2, NF-kB and Akt in bone marrow decreased, and the therapeutic effect was not dose-dependent.There was no signifi¬cant change in the expression of MvD88 and MAPK proteins.Conclusions PNS can improve AA bone marrow injury, regulate immune disoders and promote hematopoiesis, which may be related to the regulation of the number of DCs and the TLH4/TLH2 - Akt- NF-kB pathway in bone marrow.

Hematopoyesis Clonal de Potencial Indeterminado (HCPI): más allá de un modelo de campo de cancerización / Clonal hematopoiesis of indeterminate potential (CHIP): Beyond a model of field cancerization

Resumen La Hematopoyesis Clonal de Potencial Indeterminado (HCPI), más conocida como CHIP por sus siglas en inglés, se define como la expansión clonal de Células Madre Hematopoyéticas (CMHs) que albergan una o más mutaciones somáticas (en la mayoría de los casos una sola mutación) sin un cáncer hematológico subyacente ni evidencia morfológica definitiva de displasia, con una frecuencia alélica mayor al 2%. Los individuos con HCPI progresan a malignidad a una tasa de cerca del 0.5% a 1% por año, convirtiéndose así en un modelo de campo de cancerización. Sin embargo, sus implicaciones van más allá debido a que se ha encontrado asociación con enfermedades inflamatorias crónicas, como enfermedad cardiovascular ateroesclerótica, diabetes y enfermedades autoinmunes. Además, es considerado un factor predictivo en pacientes con cáncer hematolológico y no hematológico que reciben quimioterapia y radioterapia.

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of hematopoietic stem cells harboring one or more somatic mutations. These patients do not have underlying hematologic neoplasia, myelodysplasia, or dysplasia, but can progress to a malignant state at a rate of 0.5 to 1% per year. CHIP could be used as a model of field cancerization, since it has been associated with chronic inflammatory diseases, arteriosclerosis, diabetes, and autoimmune conditions. CHIP is also considered a predictive factor in hematological and non-hematological cancer patients receiving chemotherapy and radiotherapy.

Características morfológicas de las médulas óseas en pacientes con infección por Sars-Cov2 del Hospital 2 de Mayo, Perú / Morphological characteristics of bone marrows in patients with SARS-CoV-2 infection from Hospital 2 de Mayo, Peru

Introducción: Se ha descrito que, a nivel medular, el SARS-COV2 puede comprometer la hematopoyesis, manifestándose con citopenias y solo se cuenta con estudios realizados en autopsias. Objetivo: describir las características morfológicas de las médulas óseas de los pacientes hospitalizados por neumonía por COVID-19 en el Hospital Nacional "Dos de Mayo". Material y métodos: Estudio observacional transversal retrospectivo llevado a cabo en pacientes mayores de 18 años con diagnóstico confirmado de COVID-19 mediante prueba rápida o molecular y se excluyeron a aquellos con historia clínica incompleta, ilegible o extraviada y/o neumonía bacteriana o fúngica. Los hallazgos de las lecturas de las médulas óseas fueron confirmados por un hematólogo entrenado, recabándose datos como: Hemosiderina, celularidad, relación mielo/eritroide, serie mieloide, megacariocítica y células plasmáticas. Se utilizó estadística descriptiva basada en frecuencias y porcentajes para las variables cualitativas y media y desviación estándar para las variables cuantitativas. Resultados: Se incluyeron a un total de 30 pacientes. Los hallazgos medulares más frecuentes fueron: macrófagos con citofagocitosis 87% (n=26), hiperplasia con detención en la maduración de los progenitores mieloides en el 70% (n=21). El 87% (n=26) de las muestras presentó eosinofilia. En el 57% (n=17) de las muestras se observó ninguna o poca evidencia de formación plaquetaria. En el 40% (n=12) se encontró 6% de células plasmáticas. Conclusión: Los pacientes con infección por SARS-COV2, presentan alteraciones medulares entre los que destacan: la citofagocitosis con hiperplasia y detención de la maduración en la serie mieloide, poca o nula producción plaquetaria en los megacariocitos y eosinofilia.

Background: At the spinal level, SARS-CoV2 can compromise hematopoiesis, manifesting itself with cytopenias and there are only studies carried out in autopsies. Objective: to describe the morphological characteristics of the bone marrow of patients hospitalized for pneumonia due toCOVID-19 at the Hospital Nacional "Dos de Mayo". The study: Retrospective cross-sectional study carried out in patients diagnosed with COVID-19. The bone marrow readings were confirmed by atrained hematologist. Descriptive statistics were used for the quantitative and qualitative variables. Findings: 30 patients were included. The most frequent findings were: macrophages with cytophagocytosis (87%), hyperplasia with arrest in the maturation of myeloid progenitors (70%). 87% of the samples presented eosinophilia. Little or no evidence of platelet formation was observed in 57% of the samples. In 40%, 6% of plasma cells were found. Conclusion: SARS-CoV2 infection can generate spinal cord disorders.

Anemia sideroblástica una enfermedad infrecuente de causas múltiples / Sideroblastic anemia, a rare disease of multiple causes

Introducción: La anemia sideroblástica es un trastorno hematológico que altera el proceso de la hematopoyesis, en la cual se ve afectada en mayor proporción la línea eritroide. Además, se presentan alteraciones en la síntesis del grupo hemo por disfunción mitocondrial en las células de la médula ósea. Objetivo: Indagar sobre la anemia sideroblástica, sus variables y los diferentes tipos de presentación que puede tener esta enfermedad. Métodos: Se llevó a cabo una revisión de la literatura en las bases de datos MEDLINE, EMBASE, Lilacs y ScienceDirect, con los descriptores: anemia sideroblástica, hematopoyesis, anomalías congénitas y 5-aminolevulinato sintetasa, en español e inglés. Se seleccionaron 26 artículos relacionados. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: Es una enfermedad de origen congénito o secundario a otros procesos como el consumo de alcohol o inducido por algunos medicamentos. Se presenta con poca frecuencia y, en su mayoría, el diagnóstico se hace mediante estudios de laboratorio, como extendido de sangre periférica, estudio de médula ósea, a los que se les pueden aplicar diversas tinciones, realizar secuenciación o incluso realizar reacción en cadena de polimerasa. Conclusión: La anemia sideroblástica es una enfermedad puede relacionarse con otras alteraciones hematológicas que modifican el metabolismo del hierro. El tratamiento curativo es la trasfusión de hemocomponentes y debe hacerse un enfoque individualizado de cada paciente según el tipo de anemia sideroblástica(AU)

Introduction: Sideroblastic anemia is a hematological disorder that alters the hematopoiesis process. This condition affects, to a great extent, the erythroid line. In addition, alterations occur in the synthesis of the heme group due to mitochondrial dysfunction in the bone marrow cells. Objective: To investigate sideroblastic anemia, its variables and the different types of presentation of this disease. Methods: A literature review was carried out in the MEDLINE, EMBASE, Lilacs and ScienceDirect databases, using the descriptors anemia sideroblástica [sideroblastic anemia], hematopoyesis [hematopoiesis], anomalías congénitas [congenital anomalies] and 5-aminolevulinato sintetasa [5-aminolevulinate synthetase], in Spanish and English. Twety-six articles related to the topic were selected. An analysis and summary of the revised bibliography was carried out. Information analysis and synthesis: It is a disease of congenital origin or secondary to other processes such as alcohol consumption or induced by some medications. It occurs infrequently and its diagnosis is mostly made through laboratory studies, such as peripheral blood smear and bone marrow study, to which various stains can be applied, as well as sequencing or even polymerase chain reaction. Conclusion: Sideroblastic anemia is a disease that can be related to other hematological alterations that modify iron metabolism. The curative treatment is the transfusion of blood components. An individualized approach should be used according to the type of sideroblastic anemia(AU)

Dyskeratosis congenita

Dyskeratosis congenita (DC) is a genetic syndrome with progressive multisystem involvement classically characterized by the clinical triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Frequent complications are bone marrow failure, increased rate of malignancy, lung and liver diseases. DC results from an anomalous progressive shortening of telomeres resulting in DNA replication problems inducing replicative senescence. We report a death due to DC in a 16-year-old male with bone marrow failure and multiple organ dysfunction. At autopsy, nail dystrophy and skin hypopigmentation were observed. Gross and microscopic examinations of the internal organs showed cardiac hypertrophy, multiple lung consolidations and prominent interstitial fibrosis, liver cirrhosis, and fibrosis. Multiple foci of extramedullary hematopoiesis were identified, including on the epidural surface of the dura, that is an infrequent location, mimicking a focal area of epidural hemorrhage. Only a few autopsy studies about DC are reported in the literature. Further research should be done to understand the pathophysiology of the disease and its complications.

Transplantation of human umbilical cord blood mesenchymal stem cells in the repair of hematopoietic injury in bone marrow / 中国组织工程研究

BACKGROUND: A large number of studies mainly concern the proliferation effect of mesenchymal stem cells on hematopoietic stem cells in vitro and that bone marrow mesenchymal stem cell transplantation can reduce the death of hematopoietic cells caused by irradiation, increase the survival of bone marrow cells and repair hematopoiesis, while few of them investigate the repair of human umbilical cord blood mesenchymal stem cells transplantation on bone marrow hematopoiesis injury. OBJECTIVE: To explore the repair of hematopoietic microenvironment of bone marrow by human umbilical cord blood mesenchymal stem cells. METHODS: Male BALB/c mice were randomly divided into three groups. The mice in experimental group and control group were irradiated with total dose of 6-Gy X-ray to establish a mouse model of bone marrow hematopoietic injury. The normal group contained untreated normal mice. In the experimental group, CM-DiL labeled human umbilical cord blood mesenchymal stem cells were injected into the tail vein of each mouse at 5×106 (0.2 mL). The control group and the normal group received normal saline 0.2 mL through the tail vein. The peripheral blood hematology and bone marrow hematopoietic microenvironment repair were observed at 1, 5, 7, 14 and 21 days after cell transplantation. RESULTS AND CONCLUSION: Peripheral blood condition: At 1, 5 and 7 days after transplantation, the leucocyte, platelet, erythrocyte count and hemoglobin concentration in the experimental group and control group decreased progressively compared with the normal group. The most obvious decrease occurred on day 7. The trilineage recovered on day 14 after transplantation, basically returned to normal on day 21 after transplantation. Compared with the experimental group, the decrease of the trilineage in the control group was more obvious. The recovery was obvious faster in the experimental group than in the control group on day 14 after transplantation. Bone marrow smears: Bone marrow smears showed that the hematopoietic function was inhibited in the experimental group and the control group at 1, 5, 7, and 14 days after transplantation, especially on day 7. Bone marrow proliferation recovered on day 14 after transplantation. It was better in the experimental group than in the control group. On day 21 after transplantation, the hematopoietic function of bone marrow of mice in the experimental group and the control group recovered, and there was no difference between the experimental group and the control group compared with the normal group. Bone marrow pathological section: Bone marrow pathological sections showed that at 1, 5, 7, and 14 days after transplantation, the hematopoietic function of bone marrow in the experimental group and the control group was inhibited. On day 14 after transplantation, the bone marrow hematopoietic function of the experimental group and the control group began to recover, but the bone marrow proliferation of the experimental group was better than that of the control group. On day 21 after transplantation, there was no difference in the bone marrow proliferation between the experimental and the control groups and the normal group. The results suggested that human umbilical cord blood mesenchymal stem cells can promote the recovery of hematopoietic function of bone marrow.

Clinico-Hematological Profile of Aplastic Anemia in Southern Odisha: An Institutional Study

Introduction: Aplastic anemia is a potentially life-threateningfailure of hematopoiesis, characterized by pancytopenia andhypocellular bone marrow. Aplastic anemia if untreated resultsin very high mortality. Early diagnosis of Aplastic anemias isessential for appropriate management of the patient.Aims and Objectives: The aim of the study was to assess theprevalence of the condition in southern odisha admitted to thisinstitute and to study the clinico-hematological profile for theassessment of severity by using the modified Camitta criteriaaiding in their management protocol.Materials and Methods: This study was carried outprospectively in the Department of Pathology, MKCGMedical College & Hospital during the period of June 2017 toMay 2019. A detailed clinical history, physical examination,Complete Blood Count, CPS, Reticulocyte count, Bone marrowaspiration and Biopsy were performed in each case and theobservations were evaluated using simple and basic statisticaltools.Results: There are 63 diagnosed cases of aplastic anemiaduring the study period. Out of 63 cases 36 cases are male(57.14 %) and 27 cases are female (42.86 %) indicating a malepreponderance of this disease and male to female ratio is 1.3:1. We also found that, Aplastic anemia has a bi modal agedistribution. Fever, generalized weakness and bleeding due tothrombocytopenia are commonest clinical manifestations. All63 cases are sub categorized into 38 Non severe cases (60.32%), 17 severe cases (26.98 %) and 8 cases are very severe(12.70 %).Conclusion: A good knowledge on clinical and hematologicalparameters will certainly aid in early diagnosis of Aplasticanemia and sub-categorization for treatment. But in adeveloping country financial constraints and lack of awarenessforms a major drawback in patient management. So earlydiagnosis of Aplastic Anemia reduce the treatment cost as wellas will decrease mortality.

El caseinato de sodio y la caseína α inhiben la proliferación de la línea celular mieloide de ratón 32D clone 3 (32Dcl3) mediante el TNF-α / Sodium caseinate and alfa-casein inhibit proliferation of the mouse myeloid cell line 32D clone 3 (32Dcl3) via TNF-α

Resumen Introducción. Se ha demostrado que el caseinato de sodio y sus componentes (caseínas α, β y κ) inhiben la proliferación de la línea celular hematopoyética de ratón 32D clone 3 (32Dcl3) e inducen su diferenciación hacia macrófagos. Se sabe que la caseína α induce la producción de IL-1β y que esta última citocina inhibe la proliferación celular mediante la producción del factor de necrosis tumoral alfa (TNF-α), pero se desconoce si el caseinato de sodio y las caseínas inducen la producción de TNF y si este es el responsable de la inhibición de la proliferación. Objetivo. Evaluar si el caseinato de sodio y las caseínas α, β y κ inhiben la proliferación de la línea celular 32Dcl3 mediante la producción de TNF-α. Materiales y métodos. Se usaron diferentes concentraciones de caseinato de sodio y de las caseínas α, β y κ en las células 32Dcl3. Posteriormente, se evaluaron la viabilidad celular mediante una prueba con el MTT [3-(4,5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol], la inducción de apoptosis con la citometría de flujo y la síntesis del TNF-α con el ELISA. Además, se hicieron pruebas de neutralización con anti-TNF-α en células 32Dcl3 tratadas con caseinato de sodio y caseína α, y se evaluó la proliferación celular. Resultados. Se encontró que el caseinato de sodio y las caseínas α, β y κ reducían la proliferación de la línea celular 32Dcl3 sin afectar la viabilidad, y que solo el caseinato y la caseína α inducían la apoptosis y la liberación al medio de TNF-α. La proliferación de células 32Dcl3 tratadas con caseinato y caseína α se restableció al usar anticuerpos anti-TNF-α. Conclusión. El TNF-α fue el principal responsable de la inhibición de la proliferación en las células 32Dcl3 tratadas con caseinato de sodio o caseína α.

Abstract Introduction: Sodium caseinate (CS) and its components (alpha-casein, beta-casein, and kappa-casein) have been shown to inhibit the proliferation of the mouse hematopoietic 32D clone 3 (32Dcl3) cell line and induce its differentiation into macrophages. It is well-known that alpha-casein induces IL-1β production and that this cytokine inhibits the proliferation via the production of tumor necrosis factor alpha (TNF-alpha), but it is not known if CS and the caseins inhibit the proliferation via TNF-alpha production. Objective: To evaluate if CS and alpha-casein, beta-casein and kappa-casein inhibit the proliferation on 32Dcl3 cell line via TNF-alpha. Materials and methods: We used different concentrations of CS, alpha-casein, beta-casein and kappa-casein in 32Dcl3 cells to evaluate cell proliferation. We assessed cell viability by MTT, induction to apoptosis by flow cytometry, and TNF-alpha synthesis by ELISA. Additionally, we performed anti-TNF-alpha neutralization assays on 32Dcl3 cells treated with CS and alpha-casein and we evaluated proliferation. Results: The results showed that CS, alpha-casein, beta-casein, and kappa-casein reduced proliferation of the 32Dcl3 cell line without affecting the viability and that only CS and alpha-casein induced apoptosis and the release of TNF-alpha. The 32Dcl3 cells treated with CS and alpha-casein reestablished their proliferation by using anti-TNF-alpha antibodies. Conclusion: TNF-alpha was the main responsible for the inhibition of proliferation in 32Dcl3 cells treated with CS or alpha-casein.

Progress of clonal hematopoiesis of indeterminate potential / 白血病·淋巴瘤

Clonal hematopoiesis is a common aging_associated biological state. The incidence of malignant neoplasms for the patients with clonal hematopoiesis of indeterminate potential (CHIP) is 0.5%-1% every year. Potential factors of clonal progression in hematopoietic cells have been summarized, including disordered endogenous immunity caused by the augmentation of proliferative pressure, chromosomal instability caused by telomeres short; the amplification of clonal stem cells, acquisition of new mutations, and aging_associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program and epigenetic alterations while failing to support healthy hematopoiesis. CHIP is a vascular risk factor driven by interactions between clonal monocytes_macrophages and the endothelium, as well as a neoplastic progression risk factor driven by the acquisition of additional somatic mutations in the context of many other influences on hematopoiesis and clonal balance. Strategies to reduce the clonal burden associated with CHIP and to inhibit the key inflammatory pathways leading to atherosclerosis could improve the prognosis of the patients.

Protein malnutrition effects of perivascular bone marrow microenvironment on the regulation of hematopoiesis / Efeitos da desnutrição proteica sobre o microambiente perivascular medular na regulação da hematopoese

Protein malnutrition (PM) causes anemia and leukopenia by reduction of hematopoietic precursors and impaired production of mediators that induce hematopoiesis, as well as structural and ultrastructural changes in the bone marrow (BM) extracellular matrix. Hematopoiesis occurs in the bone marrow (BM) in distinct regions called niches, which modulate the processes of differentiation, proliferation and self-renewal of the hematopoietic stem cell (HSC). The perivascular niche, composed mainly by mesenchymal stem cells (MSC) and endothelial cells (EC), is the major modulator of HSC and its function extends to the migration of mature hematopoietic cells into the peripheral blood through the production of cytokines and growth factors. Thus, our hypothesis is that PM changes the perivascular niche and our objective is to evaluate whether PM affects the modulatory capacity of MSC and EC on hematopoiesis. C57BL/6 male mice were divided into Control and Malnourished groups, which received for 5 weeks, respectively, a normal protein diet (12% casein) and a low protein diet (2% casein). After this period, animals were euthanized, nutritional and hematological evaluations were performed, featuring the PM. We performed leukemic myelo-monoblasts cells transplantation and observed that these cells have a lower proliferation rate and are rather in the cell cycle G0/G1 phases in malnourished mice, indicating that the BM microenvironment is compromised in PM. MSC were isolated, characterized and differentiated in vitro into EC cells, which were evidenced by CD31 and CD144 markers. We performed the quantification of HSC and hematopoietic progenitors, as well as some regulators of proliferation and differentiation, ex vivo and after cultures with MSC or EC. We observed that PM reduces HSC and hematopoietic progenitors ex vivo. In PM, MSC promote increase in HSC and suppress hematopoietic differentiation, whereas ECs induce cell cycle arrest. Additionally, we verified that PM affects granulopoesis by decreasing the expression of G-CSFr in granule-monocytic progenitors. Thus, we conclude that PD compromises hematopoiesis due to intrinsic alterations in HSC, as well as alterations in the medullary perivascular niche

A desnutrição proteica (DP) provoca anemia e leucopenia decorrente da redução de precursores hematopoéticos e comprometimento da produção de mediadores indutores da hematopoese. A hematopoese ocorre na medula óssea (MO) em regiões distintas chamadas de nichos, que modulam os processos de diferenciação, proliferação e auto renovação da célula tronco hematopoiética (CTH). O microambiente perivascular, composto principalmente por células tronco mesenquimais (CTM) e células endoteliais (CE), é o principal modulador das CTH e sua função se estende até a migração das células hematopoiéticas maduras para o sangue periférico, através da produção de citocinas e fatores de crescimento. Dessa forma, nossa hipótese é que a DP altera o microambiente perivascular e objetivamos avaliar se a DP afeta a capacidade modulatória das CTM e CE sobre a hematopoese. Utilizamos camundongos C57BL/6 machos, divididos em grupos Controle e Desnutrido, sendo que o grupo Controle recebeu ração normoproteica (12% caseína) e o grupo Desnutrido recebeu ração hipoproteica (2% caseína), ambos durante 5 semanas. Após este período, os animais foram eutanasiados, foi realizada a avaliação nutricional e hematológica, caracterizando a DP. Realizamos transplantes de mielomonoblastos leucêmicos e observamos que estas células apresentam menor taxa de proliferação e se encontram em maior quantidade nas fases G0/G1 do ciclo celular em camundongos desnutridos, indicando que o microambiente medular está comprometido. Isolamos CTM, que foram caracterizadas e diferenciadas in vitro em CE, o que foi evidenciado pelos marcadores CD31 e CD144. Quantificamos CTH e progenitores hematopoéticos, bem como reguladores de proliferação e diferenciação, ex vivo e após culturas com CTM ou CE. Observamos que a DP reduz CTH e progenitores hematopoéticos ex vivo. Na DP, as CTM promovem incremento de CTH e suprimem a diferenciação hematopoética, enquanto que as CE induzem parada no ciclo celular. Adicionalmente, observamos que a DP afeta a granulopoese por diminuição da expressão de G-CSFr nos progenitores grânulo-monocíticos. Dessa forma, concluímos que a DP compromete a hematopoese por alterações intrínsecas na CTH, como também por alterações ocasionadas no microambiente perivascular medular