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Acquired pure red cell aplasia (PRCA) is anemia associated with the absence of erythroblasts and is characterized by persistent and easy recurrence. However, the underlying mechanisms of acquired PRCA remain obscure, and the role of gene mutations in the pathogenesis of acquired PRCA is not fully characterized. In the present study, we detected thirty newly diagnosed patients with acquired PRCA using whole exome sequencing, and a potential role for STK10 in acquired PRCA was uncovered. The mRNA levels of STK10 in three patients with STK10 mutations were decreased. These three patients had a poor response to immunosuppressive therapy and two died in the follow-up period. Here we report that knockdown of STK10 inhibits erythroid differentiation and promotes apoptosis of K562 cells. We show that knockdown of STK10 resulted in inhibition of ribosome biogenesis and reduced ribosome levels in K562 cells. We also show that the p53 signaling pathway is activated by knockdown of STK10. Our results imply that ribosome biogenesis downregulation together with pathological p53 activation prevents normal erythropoiesis. Our study uncovers a new pathophysiological mechanism leading to acquired PRCA driven by STK10 mutations.
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Eritropoese , Mutação , Proteínas Serina-Treonina Quinases , Aplasia Pura de Série Vermelha , Ribossomos , Humanos , Eritropoese/genética , Aplasia Pura de Série Vermelha/genética , Proteínas Serina-Treonina Quinases/genética , Células K562 , Masculino , Feminino , Ribossomos/metabolismo , Ribossomos/genética , Pessoa de Meia-Idade , Idoso , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Técnicas de Silenciamento de Genes , AdultoRESUMO
PURPOSE: To investigate the efficacy and safety of concentrated growth factor fibrin (CGF) for the extraction of mandibular third molars. PATIENTS AND METHODS: This was a randomized, double-blind, and controlled clinical study. Patients who underwent mandibular impacted tooth extraction were randomly divided into 2 groups. In the CGF group, the tooth extraction fossa was utilized to place CGF gel. In the control group, the fossa was filled with serum. The visual analogue scale (VAS), reductions in swelling and trismus, incidence of postoperative dry socket, distal periodontal depth and bone regeneration of the second molar, and bone density (BMD) of the extraction fossa at 24 weeks were evaluated. RESULTS: One hundred eighteen patients were enrolled in this study. There was no significant difference in baseline clinical characteristics between the 2 groups. The pain score of the CGF group was significantly lower than that of the control group at 2, 24, and 48 hours after operation. There was no significant difference in the reduction in swelling or trismus between the 2 groups. There were no cases of dry socket in the CGF group and 3 cases of dry socket in the control group. The periodontal probing depth and bone regeneration of the second molar when the socket was implanted with CGF were better than those that healed naturally (P < .05). The bone mineral density of each group was significantly increased at 24 weeks but was significantly different between groups (P < .05). CONCLUSION: CGF can effectively reduce reactive tooth extraction pain and help avoid dry sockets. It can promote periodontal tissue and bone healing in distal and extracted sockets.
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Dente Serotino , Dente Impactado , Fibrina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Dente Molar/cirurgia , Dente Serotino/cirurgia , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Extração Dentária/efeitos adversos , Dente Impactado/complicações , Dente Impactado/cirurgiaRESUMO
Acquired pure red cell aplasia (PRCA) is a disorder characterized by normocytic anemia associated with reticulocytopenia and an absence of erythroblasts. The gene mutation profile in acquired PRCA is not defined yet. In this study, we aimed to identify the gene mutation spectrum of patients with acquired PRCA and the correlation between gene mutations and response to immunosuppressive therapy (IST). Thirty newly diagnosed acquired PRCA patients were enrolled in this study, and then whole-exome sequencing were performed among these patients and a panel with 93 candidate genes which associated with other bone marrow failure for the following analysis. Subsequently patients were treated with IST for at least 2 years. When treated with IST, there were thirteen complete response, ten partial response (ORR 76.7%), and seven no response at a medium of 8 (6-10) months. Totally twenty-three mutations in fifteen genes were detected in sixteen patients (53%). The mutated genes were associated with transcription, signal transduction, and epigenetic regulation pathways. The most frequent transitions in the point mutations were C > T. Age, gender, hemoglobin level at diagnosis, and gene mutation or not did not influence the response to IST. However, although patients with BCOR or BCORL1 mutations had a similar response to IST compared with those without mutation (P = 0.235), they had a better response than those with other gene mutations (P = 0.0193). In conclusion, patients with acquired PRCA may have clonal gene mutations. The patients with BCOR and BCORL1 mutations may suggest a better response to IST compared with those with other mutations.
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Mutação , Proteínas Proto-Oncogênicas/genética , Aplasia Pura de Série Vermelha/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Aplasia Pura de Série Vermelha/metabolismo , Aplasia Pura de Série Vermelha/terapia , Proteínas Repressoras/metabolismoRESUMO
PURPOSE: We investigated the promoting effect of concentrated growth factor (CGF) fibrin on the repair of jaw bone defects. PATIENTS AND METHODS: We designed a clinical trial composed of patients with jaw defects. Forty patients were divided into the test and control groups. CGF fibrin combined with Bio-Oss bone powder (Giestlich Pharma, Wolhusen, Switzerland) was used in the test group. Bio-Oss bone powder alone was used in the control group. The concentration of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-ß in the red blood cell (RBC) layer and CGF gel was measured. At different time points before and after surgery, the serum bone alkaline phosphatase (BAP), osteocalcin, and bone mineral density levels were measured. Regular examinations and computed tomography scans were also performed in the follow-up period. RESULTS: The CGF fibrin available for clinical use was obtained by centrifugation. One day after preparation by centrifugation, the VEGF and TGF-ß concentration in the CGF gel was 2.57-fold and 3.4-fold greater than the concentration in the RBC layer, respectively. The BAP and osteocalcin levels increased at 1 and 12 weeks postoperatively in both groups. Furthermore, the BAP and osteocalcin levels in the test group were significantly greater than those in the control group at 1 and 12 weeks postoperatively (P < .05 for all). The bone mineral density in the bone defect area of the test group was also significantly greater than that of the control group at 6 months postoperatively (P < .05). Evaluation of the regular radiographic scans revealed that the effects in the test group were better than those in the control group. CONCLUSIONS: CGF fibrin could promote new bone formation in jaw defects, with benefit to the healing of bone tissue and, thus, is a promising bone repair material.
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Fibrina , Arcada Osseodentária/patologia , Fator A de Crescimento do Endotélio Vascular , Resinas Acrílicas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Procedimentos Cirúrgicos Ortognáticos , SuíçaRESUMO
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disease with thrombosis as a major complication. The mechanism of thrombosis and related risk factors in PNH patients are still not well characterized. We retrospectively enrolled 99 patients with newly diagnosed PNH at our institute from 2011 to 2016. According to binary logistic regression model analysis, we first identified four baseline clinical risk factors which may be associated with incidence of thrombosis in the PNH cohort, including PNH clone sizes (fluorescent aerolysin of neutrophil) ≤ 80 (OR 1.056, 95%CI 1.016-1.097, P = 0.005), hemoglobin ≤ 75 g/L (OR 4.202, 95%CI 0.984-17.954, P = 0.053), platelet > 100 × 109/L (OR 6.547, 95%CI 1.490-28.767, P = 0.013) and rs495828 = G (OR 5.243, 95%CI 1.314-20.916, P = 0.019). These independent risk factors were combined together to develop a risk model to evaluate thrombosis risk (AUC = 0.756, 95%CI 0.607-0.905, P < 0.001). Our risk model revealed a higher cumulative incidence of thrombosis and an earlier thrombosis events in PNH patients with high risk (risk score ≥ 23) compared with those with low risk (risk score < 23, P < 0.001 and P = 0.043, respectively). Although with some limitations, we set up a prediction model for thrombosis risk in patients with PNH for the first time, but it needed to be verified in a prospective study with larger patients and longer follow-up time in the future.
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Hemoglobinúria Paroxística , Modelos Biológicos , Trombose , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Trombose/sangue , Trombose/epidemiologia , Trombose/etiologiaRESUMO
The authors determined an error in the affiliation section; it was captured as Department of Hematology, Peking Union Hospital, CAMS & PUMC, Beijing 100,730, China. The correct affiliation should be Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
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Acquired pure red cell aplasia (aPRCA) is a kind of anemia characterized by severe reticulocytopenia and obvious bone marrow erythroblastic cells decreased. Some patients are refractory or intolerant to the first-line therapy (cyclosporine A with/without steroids). The effects of the second-line therapy are not satisfactory and sometimes not available. In this study, we analyzed the efficacy and side effect of sirolimus on refractory/relapsed aPRCA and investigated the possible mechanism of sirolimus on immune regulation. Twenty-one patients with refractory/relapsed aPRCA were enrolled in this study and were administered with sirolimus. Totally, 76.2% of patients responded to the sirolimus with 42.9% complete response during the experimental period. The median time for reaction was 4 months. Side effects were tolerable including infections; mild oral mucositis; sinus tachycardia, the increase of creatinine, transaminase, triglyceride, or cholesterol; and thrombocytopenia. Most patients stayed in remission or remained stable during the follow-up period. Early drug withdrawal may lead to quick relapse. Compared with healthy control, Treg levels in patients with aPRCA reduced significantly before sirolimus but recovered after successful treatment. Level of Treg cells correlated with hemoglobin level after effective sirolimus treatment. Thus, sirolimus was effective and tolerable for refractory/relapsed aPRCA. Effective sirolimus treatment may lead to the upregulation of Treg cells which may partly explain the underlying mechanism.
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Aplasia Pura de Série Vermelha/tratamento farmacológico , Aplasia Pura de Série Vermelha/imunologia , Sirolimo/administração & dosagem , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Aplasia Pura de Série Vermelha/patologia , Indução de Remissão , Sirolimo/efeitos adversos , Linfócitos T Reguladores/patologiaRESUMO
BACKGROUND: This study focuses on the iron overload (IOL) of patients with transfused aplastic anemia (AA) or a low/intermediate-1 risk of myelodysplastic syndrome (MDS). METHODS: Ninety-two AA or MDS patients with IOL were prospectively recruited. Clinical data were collected every 6 months, and organ magnetic resonance imaging T2* values were collected annually. Patients with IOL were chelated. RESULTS: Serum ferritin was correlated with liver T2* and pancreatic T2* in the AA and MDS groups. Transfusion amounts were correlated with serum ferritin values, liver T2*, and pancreatic T2* in the AA group. At the 6-month and 1-year evaluations, patients with sufficient chelation experienced significant decreases in serum ferritin, and those with decreased serum ferritin experienced an obvious increase in hemoglobin. At their 1-year-follow-up, patients with adequate chelation showed significant increases in hepatic T2*, cardiac T2*, and left ventricular ejection fraction (LVEF). Patients with decreased serum ferritin (including those without chelation) experienced an increase in hemoglobin, hepatic T2*, cardiac T2*, and LVEF. CONCLUSION: The transfusion amount was more reliable at predicting IOL in patients with AA than in those with MDS. Adequate iron chelation can decrease serum ferritin levels and may improve hepatic T2*, cardiac T2*, and LVEF levels. A decrease in serum ferritin, even in the absence of chelation, may also benefit patients.
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Anemia Aplástica/complicações , Anemia Aplástica/diagnóstico , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/diagnóstico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/terapia , Transfusão de Sangue , Feminino , Ferritinas/sangue , Seguimentos , Hemoglobinas/análise , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Estudos Prospectivos , Risco , Função Ventricular Esquerda , Adulto JovemRESUMO
Corona virus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the whole world. Acquired thrombotic thrombocytopenic purpura (TTP) has been reported after administration of mRNA- or adenoviral vector-based COVID-19 vaccines, including Ad26.COV2-S, BNT162b2, mRNA-1273, and ChAdOx1 nCov-19. However, whether inactivated vaccines, such as CoronaVac, could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are unknown. In this study, two cases were reported. Both cases developed TTP after the second CoronaVac vaccination shot, but not the first. They demonstrated symptoms of fever, neurological abnormalities, renal dysfunction, thrombocytopenia, and hemolysis. Both patients achieved complete remission through several sessions of plasma exchanges and immune suppression. The incidence of TTP in Nanjing area was analyzed. The number of patients with TTP was 12 in 2019, 6 in 2020, 16 in 2021, and 19 in 2022. To the authors' knowledge, this report is the first report of TTP associated with inactivated COVID-19 vaccine (CoronaVac). The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based ones. Timely plasma exchange is a vital treatment for CoronaVac-related TTP, similar to activated vaccine-related TTP.
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Venetoclax combined with hypomethylating agents such as azacitidine and decitabine is the standard regime for the elderly patient with acute myeloid leukemia (AML) unfit for intensive induction therapy. However, many patients struggle with finances and forgo treatments due to the high costs of venetoclax. In this study, we performed the regime with azacitidine, low-dose venetoclax, and grapefruit juice on an unfit AML patient with TP53 mutation. The peak venetoclax concentration (Cmax) and side effects on the patient were also monitored. The patient achieved complete remission with the venetoclax Cmax within the effective concentration range (1,000-3,000 ng/ml) and maintained durable remission until recently. Febrile neutropenia, thrombocytopenia, and pneumonia appeared during the first cycle and were recovered by stimulating agents and antibiotic treatment. This improvement combination approach by drug-food interaction may enlighten other similarly patients with AML, especially those in low-middle income countries.
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Donor cell-derived leukemia (DCL) is a special type of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with DCL generally have a poor prognosis due to resistance to conventional chemotherapy. Here, we report a case of donor cell-derived acute lymphoblastic leukemia after umbilical cord blood transplantation. The patient didn't respond to induction chemotherapy. She then received anti-CD19 CAR-T cell therapy and achieved MRD-negative complete remission (CR). However, MRD levels rose from negative to 0.05% at 5 months after CAR-T cell therapy. Higher MRD levels were significantly associated with an increased risk of leukemia recurrence. Afterward, preemptive interferon-α treatment was administrated to prevent disease recurrence. To date, the patient has maintained MRD-negative CR for 41 months. Our results suggested that anti-CD19 CAR-T cells followed by interferon-α therapy are effective in treating donor cell-derived acute lymphoblastic leukemia. This report provides a novel strategy for the treatment of DCL.
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Introduction: The hematological manifestations of corona virus disease 2019 (COVID-19) can confound the diagnosis and therapy of other diseases. In this paper, we firstly reported a case of chronic myeloid leukemia (CML) of delayed diagnosis and intolerance to tyrosine kinase inhibitors (TKIs) concurrent with COVID-19. Case Presentation: A 56-year-old female was diagnosed as COVID-19 with no obvious leukocytosis [white blood cell (WBC), ≤17 × 109/L] or splenomegaly until ablation of the virus. Bone marrow aspiration was conducted to establish the diagnosis of CML. She accepted an adjusted dosage of imatinib initially and had to suspend it after myelosuppression (day 41). After hematopoietic therapy, imatinib was given again (day 62), but she was still non-tolerant, and nilotinib at 150 mg twice a day was prescribed from day 214. At just about 4 weeks later, nilotinib was discontinued due to myelosuppression. Then, it was reduced to 150 mg per day and was re-initiated (day 349), but she was still non-tolerant to it. Similarly, from day 398, flumatinib at 200 mg per day was tried, but she was non-tolerant. Her white blood cell or platelet count fluctuated markedly with poor therapeutic response. Considering that she was relatively tolerant and responsive to imatinib, the medication was re-initiated at 200 mg and reduced to 100 mg per day. Her follow-up revealed stable WBC and PLT counts. The latest BCR-ABL-210/ABL was decreased to 0.68% at about 6 months after imatinib was re-initiated, which means an improved response. Conclusion: The offset effect between CML and SARS-CoV-2 infection was supposed to be the underlying mechanism for the absence of leukocytosis or splenomegaly. The impact of immune network by SARS-CoV-2 preserved and disrupted the patient's response to TKIs despite the virus' ablation. We suggest that a continued elevation of basophils may be a useful indicator for CML concurrent with COVID-19, and individualized treatment with adjusted dosage and suitable type of TKIs should be considered to improve the patient's health outcome.
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Conventional antiplatelet agents indiscriminately inhibit both thrombosis and hemostasis, and the increased bleeding risk thus hampers their use at more aggressive dosages to achieve adequate effect. Blocking integrin αIIbß3 outside-in signaling by separating the ß3/Src interaction, yet to be proven in vivo, may nonetheless resolve this dilemma. Identification of a specific druggable target for this strategy remains a fundamental challenge as Src SH3 is known to be responsible for binding to not only integrin ß3 but also the proteins containing the PXXP motif. In vitro and in vivo mutational analyses show that the residues, especially E97, in the RT loop of Src SH3 are critical for interacting with ß3. DCDBS84, a small molecule resulting from structure-based virtual screening, is structurally validated to be directed toward the projected target. It specifically disrupts ß3/Src interaction without affecting canonical PXXP binding and thus inhibits the outside-in signaling-regulated platelet functions. Treatment of mice with DCDBS84 causes a profound inhibition of thrombosis, equivalent to that induced by extremely high doses of αIIbß3 antagonist, but does not compromise primary hemostasis. Specific targets are revealed for a preferential inhibition of thrombosis that may lead to new classes of potent antithrombotics without hemorrhagic side effects.
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Plaquetas , Trombose , Animais , Plaquetas/metabolismo , Hemostasia/fisiologia , Integrina beta3/química , Integrina beta3/metabolismo , Camundongos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombose/metabolismo , Trombose/prevenção & controleRESUMO
Background: T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) expresses on leukemic stem and progenitor populations of non-M3 acute myeloid leukemia (AML) as well as T lymphocytes. TIM-3 is thought to be involved in the self-renewal of leukemic stem cells and the immune escape of AML cells, however its correlation with AML prognosis is still controversial and worthy of further investigation. Methods: we simultaneously assessed TIM-3 expression levels of leukemic blasts and T lymphocytes in the bone marrow of de novo AML patients using flow cytometry. The correlations of TIM-3 expression between leukemic blasts and T lymphocytes and the correlations of TIM-3 expression with various patient parameters were analyzed. In addition, the Cancer Genome Atlas (TCGA) data of AML patients were acquired and analyzed to verify the results. Results: TIM-3 expression of CD34+ leukemic blasts (R2 = 0.95, p<0.0001) and CD34+CD38- leukemic stem cells (R2 = 0.75, p<0.0001) were significantly and positively correlated with that of the whole population of leukemic blasts. In addition, TIM-3 expression level of leukemic blasts correlated significantly and positively with that of CD8+ (R2 = 0.44, p<0.0001) and CD4+ (R2 = 0.16, p=0.0181) lymphocytes, and higher TIM-3 expression of leukemic blasts was significantly associated with a greater proportion of peripheral CD8+ T lymphocytes (R2 = 0.24, p=0.0092), indicating that TIM-3 on leukemic blasts might alter adaptive immunity of AML patients. Regarding clinical data, the presence of core binding factor (CBF) translocations was significantly correlated with higher TIM-3 expression of leukemic blasts (CBF versus non-CBF, median 22.78% versus 1.28%, p=0.0012), while TIM-3 expression levels of leukemic blasts were not significantly associated with the remission status after induction chemotherapy (p=0.9799), overall survival (p=0.4201) or event-free survival (p=0.9873). Similar to our results, TCGA data showed that patients with CBF translocations had significantly higher mRNA expression level of HAVCR2 (the gene encoding TIM-3) (median, 9.81 versus 8.69, p<0.0001), and as all patients in the cohort were divided into two groups based on the median HAVCR2 expression level, 5-year overall survivals were not significantly different (low versus high, 24.95% versus 24.54%, p=0.6660). Conclusion: TIM-3 expression level on AML blasts correlates with presence of CBF translocations rather than clinical outcomes.
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Background: Stanozolol and danazol are widely used in the treatment of aplastic anemia; however, their mechanisms of action are unclear. Methods: Bone marrow mononuclear cells from 10 patients newly diagnosed with aplastic anemia and 10 healthy volunteers were collected and cultured together with stanozolol, danazol, or blank control separately for marrow colony assays. K562 cell lines that had been incubated with stanozolol, danazol, or blank control were tested for erythroid or megakaryocytic differentiation. Meanwhile, CB6F1/Crl mice were injected with 1 × 106 C57BL/6 donor-originated lymphocytes after irradiation with 5 Gy total body irradiation to establish a model for immune-mediated bone marrow failure (aplastic anemia mouse model). Mice with aplastic anemia were treated with cyclosporin A monotherapy, cyclosporin A in combination with stanozolol, and cyclosporin A in combination with danazol for 30 days. Peripheral blood cell counts once a week and bone marrow colony assays at the end of 1 month were performed. The proportion of T cell subsets, level of inflammatory factors, erythropoietin, and thrombopoietin were detected before and after treatment. The levels of erythropoietin receptors on bone marrow mononuclear cells after treatment were tested using western blotting. Results: In the ex vivo experiments, the number of burst-forming units-erythroid; colony-forming units-granulocyte and macrophage; and colony-forming units-granulocyte, erythrocyte, monocyte, and megakaryocyte in the patients with aplastic anemia were significantly lower than that in the normal controls (P < 0.05). However, the number of colonies and mean fluorescence intensity of CD235a or CD41 expression in the harvested cultured cells were not significantly different among the different treatment groups in the patients with aplastic anemia, normal controls, and K562 cell lines. These results show that stanozolol and danazol produce no direct hematopoiesis-stimulating effects on progenitor cells. In the in vivo experiment, the mice with aplastic anemia treated with cyclosporin A and danazol exhibited the most rapid recovery of platelet; the platelet count returned to normal levels after 3 weeks of treatment, which was at least 1 week earlier than in the other groups. In contrast, mice treated with cyclosporin A and stanozolol exhibited the highest hemoglobin level at the end of treatment (P < 0.05). Bone marrow colony assays at 30 days showed that the number of burst-forming units-erythroid was the highest in mice treated with cyclosporin A and stanozolol, while the number of colony-forming units-granulocyte and macrophage was the highest in those treated with cyclosporin A and danazol. Compared to cyclosporin A monotherapy, additional stanozolol and danazol can both increase the level of regulatory T cells and upregulate interleukin-10, inhibiting the expression of tumor necrosis factor-α (P < 0.05). However, IL-2 was more effectively reduced by danazol than by stanozolol (P < 0.05). The cyclosporin A- and stanozolol-treated mice showed higher serum erythropoietin (corrected by hemoglobin level) and higher erythropoietin receptor levels in bone marrow mononuclear cells than the other groups (P < 0.05). Conclusions: Neither stanozolol nor danazol directly stimulated hematopoiesis in vitro. However, in vivo, stanozolol may exhibit an advantage in improving erythropoiesis, while danazol may induce stronger effects on platelets. Both danazol and stanozolol exhibited immunosuppressive roles. Stanozolol could enhance the secretion of erythropoietin and expression of erythropoietin receptor in bone marrow mononuclear cells.
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Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable clinical efficacy in treatment of many malignancies especially for B-cell hematologic malignancies. However, the application of CAR-T cells is hampered by potentially adverse events, of which cytokine release syndrome (CRS) is one of the severest and the most studied. Local cytokine-release syndrome (L-CRS) at particular parts of the body has been reported once in a while in B-cell lymphoma or other compartmental tumors. The underlying mechanism of L-CRS is not well understood and the existing reports attempting to illustrate it only involve compartmental tumors, some of which even indicated L-CRS only happens in compartmental tumors. Acute lymphoblastic leukemia (ALL) is systemic and our center treated a B-cell ALL patient who exhibited life threatening dyspnea, L-CRS was under suspicion and the patient was successfully rescued with treatment algorithm of CRS. The case is the firstly reported L-CRS related to systemic malignancies and we tentatively propose a model to illustrate the occurrence and development of L-CRS of systemic malignancies inspired by the case and literature, with emphasis on the new recognition of L-CRS.
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Síndrome da Liberação de Citocina/etiologia , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Receptores de Antígenos Quiméricos/imunologiaRESUMO
INTRODUCTION: Decitabine-based chemotherapy regimens have shown efficacy in the treatment of elderly patients with acute myeloid leukemia (AML). However, it remains unclear whether any molecular alteration is correlated with the therapeutic effect of such treatment regimens. METHODS: Gene mutations were detected using next-generation sequencing, and their impact on survival was investigated in elderly AML patients receiving decitabine-based chemotherapy. RESULTS: A higher incidence of gene mutations was identified in elderly AML patients than in the younger cohorts. Elderly patients more frequently carried DNMT3A, IDH2, ASXL1, TET2, RUNX1, CEBPA single mutation (CEBPAsingle-mut ), and TP53 mutations. Survival analysis showed that DNMT3A, FLT3-ITD, and TP53 mutations were associated with inferior overall survival (OS) and event-free survival (EFS) in younger AML patients receiving standard treatment. However, in elderly patients treated with decitabine-based chemotherapy, FLT3-ITD, and ASXL1 mutations, but not DNMT3A and TP53 mutations, were associated with poor OS and EFS. Moreover, contrary to CEBPA double mutation (CEBPAdouble-mut ), CEBPAsingle-mut was identified as an unfavorable prognostic factor. CONCLUSION: This study comprehensively analyzed the prognostic implications of gene mutations in elderly AML patients under decitabine-based treatment modality. Identification of genetic biomarkers to predict the subgroup of elderly AML patients who can benefit from decitabine-based regimens might have an immediate clinical utility to optimize the treatment of elderly AML patients.
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Decitabina/administração & dosagem , Leucemia Mieloide Aguda , Mutação , Proteínas de Neoplasias/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbß3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbß3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbß3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbß3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbß3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbß3 in particular. Integrin αIIbß3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbß3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbß3 and its signaling pathways.
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Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Abciximab/farmacologia , Sequência de Aminoácidos , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Eptifibatida/farmacologia , Humanos , Terapia de Alvo Molecular , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/agonistas , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Transdução de Sinais , Tirofibana/farmacologiaRESUMO
Congenital sideroblastic anemia (CSA) is a series of rare, heterogeneous disorders, characterized by iron overload in the mitochondria of erythroblasts and ringed sideroblasts in bone marrow. In recent years, rapid development of next-generation sequencing technology brings great advance in understanding of genetic and pathophysiologic features of CSA. Based on the pathophysiology of mitochondrial iron metabolism, causative genes of CSA can be divided into three subtypes: heme biosynthesis related; ironsulfur cluster biosynthesis and transportation related; and mitochondrial respiratory chain synthesis related. Patients with CSA present various clinical manifestation due to relevant mutation gene and require different treatment strategies. The recognition of the causative genes and evolution of pathogenicity is critical. In this review, we summarize the recent progress in mutation genes of CSA, and its potential role in the pathogenesis, diagnosis and treatment.