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1.
Ther Adv Hematol ; 13: 20406207221095226, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35510211

RESUMO

Background: The responses of intravenous immunoglobulin (IVIg) or corticosteroids as the initial treatment on pregnancy with ITP were unsatisfactory. This study aimed to assess the safety and effectiveness of prednisone plus IVIg versus prednisone or IVIg in pregnant patients with immune thrombocytopenia (ITP). Methods: Between 1 January 2010 and 31 December 2020, 970 pregnancies diagnosed with ITP at 19 collaborative centers in China were reviewed in this observational study. A total of 513 pregnancies (52.89%) received no intervention. Concerning the remaining pregnancies, 151 (33.04%) pregnancies received an initial treatment of prednisone plus IVIg, 105 (22.98%) pregnancies received IVIg alone, and 172 (37.64%) pregnancies only received prednisone. Results: Regarding the maternal response to the initial treatment, no differences were found among the three treatment groups (41.1% for prednisone plus IVIg, 33.1% for prednisone, and 38.1% for IVIg). However, a significant difference was observed in the time to response between the prednisone plus IVIg group (4.39 ± 2.54 days) and prednisone group (7.29 ± 5.01 days; p < 0.001), and between the IVIg group (6.71 ± 4.85 days) and prednisone group (p < 0.001). The median prednisone duration in the monotherapy group was 27 days (range, 8-195 days), whereas that in the combination group was 14 days (range, 6-85 days). No significant differences were found among these three treatment groups in neonatal outcomes, particularly concerning the neonatal platelet counts. The time to response in the combination treatment group was shorter than prednisone monotherapy. The duration of prednisone application in combination group was shorter than prednisone monotherapy. The combined therapy showed a lower predelivery platelet transfusion rate than IVIg alone. Conclusion: These findings suggest that prednisone plus IVIg may represent a potential combination therapy for pregnant patients with ITP.

2.
J Viral Hepat ; 29(5): 306-316, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35152507

RESUMO

Patients with hepatitis B-related cirrhosis complicated with thrombocytopenia have a higher risk of bleeding, which may lead to higher mortality. We aimed to explore the efficacy and safety of recombinant human thrombopoietin (rhTPO) in the treatment of hepatitis B-related cirrhosis complicated with severe thrombocytopenia. Patients with hepatitis B-related compensated liver cirrhosis complicated with severe thrombocytopenia were divided into four groups according to the treatment method for thrombocytopenia. Platelet counts, the appearance of bleeding symptoms and adverse events were evaluated during the observation period. Also during the observational period, the platelet counts in the prednisone group, rhTPO group and prednisone plus rhTPO group were higher than those in the no treatment group. Patients without splenomegaly reacted better to rhTPO. Fewer bleeding events of grade 2 or worse were observed in the three treatment groups compared to the no treatment group. The platelet counts at baseline and treatment with rhTPO and/or prednisone were factors associated with bleeding events of grade 2 or worse in multivariate analysis. There could be a potential advantage for the use of rhTPO plus prednisone based on higher platelet counts and fewer bleeding events. Treatment with rhTPO was more effective in patients without splenomegaly.


Assuntos
Hepatite B , Trombocitopenia , Hepatite B/complicações , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Contagem de Plaquetas , Prednisona , Proteínas Recombinantes/efeitos adversos , Esplenomegalia/complicações , Trombocitopenia/complicações , Trombocitopenia/tratamento farmacológico , Trombopoetina/efeitos adversos
3.
Blood ; 139(3): 333-342, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-34665865

RESUMO

The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA, and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07-0.36). Sustained response (SR), defined as maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04-0.35). The 2 most common adverse events (AEs) for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288.


Assuntos
Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Rituximab/uso terapêutico , Tretinoína/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Antineoplásicos/administração & dosagem , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva , Rituximab/administração & dosagem , Prevenção Secundária , Tretinoína/administração & dosagem
4.
Blood Adv ; 5(24): 5479-5489, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34507352

RESUMO

Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information on markers for early prognostication remains limited, and no predictive tools for TA-TMA are available. We attempted to develop and validate a prognostic model for TA-TMA. A total of 507 patients who developed TA-TMA following allo-HSCT were retrospectively identified and separated into a derivation cohort and a validation cohort, according to the time of transplantation, to perform external temporal validation. Patient age (odds ratio [OR], 2.371; 95% confidence interval [CI], 1.264-4.445), anemia (OR, 2.836; 95% CI, 1.566-5.138), severe thrombocytopenia (OR, 3.871; 95% CI, 2.156-6.950), elevated total bilirubin (OR, 2.716; 95% CI, 1.489-4.955), and proteinuria (OR, 2.289; 95% CI, 1.257-4.168) were identified as independent prognostic factors for the 6-month outcome of TA-TMA. A risk score model termed BATAP (Bilirubin, Age, Thrombocytopenia, Anemia, Proteinuria) was constructed according to the regression coefficients. The validated c-statistic was 0.816 (95%, CI, 0.766-0.867) and 0.756 (95% CI, 0.696-0.817) for the internal and external validation, respectively. Calibration plots indicated that the model-predicted probabilities correlated well with the actual observed frequencies. This predictive model may facilitate the prognostication of TA-TMA and contribute to the early identification of high-risk patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Microangiopatias Trombóticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia
5.
Transplant Cell Ther ; 27(3): 253.e1-253.e9, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781524

RESUMO

Acute cholecystitis (AC) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, only limited information is available on its clinical features, outcomes, and risk management strategies. This retrospective, nested, case-control study included 6701 patients undergoing allo-HSCT at our center from January 2004 to June 2019. In total, 72 patients (1.1%) were diagnosed with AC; among these, acute acalculous cholecystitis had a slightly higher prevalence (42 patients, 58.3%). Patients with moderate and severe AC exhibited remarkably worse overall survival (P = .001) and non-relapse mortality (P = .011) than others. Survival of haploidentical HSCT recipients with AC was comparable to that for patients with human leukocyte antigen (HLA)-identical donors. Age ≥ 18 years, antecedent stage II to IV acute graft-versus-host disease, and total parenteral nutrition were identified as potential risk factors for AC following allo-HSCT, while haploidentical transplantations were not more susceptible to AC than HLA-identical HSCT. Based on these criteria, a risk score model was developed and validated to estimate the probability of AC following allo-HSCT. The model separates all patients into low-, intermediate-, and high-risk groups and thereby provides a basis for early detection of this complication in the management of allo-HSCT.


Assuntos
Colecistite Aguda , Transplante de Células-Tronco Hematopoéticas , Adolescente , Estudos de Casos e Controles , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Fatores de Risco
6.
J Cell Physiol ; 236(9): 6726-6741, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33611789

RESUMO

Thrombocytopenia is a common complication of human cytomegalovirus (HCMV) infection in immunocompromised hosts, which contributes to poor prognosis even in patients receiving antiviral treatment. Here, we investigated the megakaryo/thrombopoiesis process, including the involvement of the c-Mpl/IEX-1 pathway, after HCMV infection, identified receptors mediating the interaction between megakaryocytes (MKs) and HCMV, and explored novel therapeutic targets. Our data shows that HCMV directly infects megakaryocytes in patients with HCMV DNAemia and influences megakaryopoiesis via the c-Mpl/IEX-1 pathway throughout megakaryocyte maturation, apoptosis, and platelet generation in vivo and in vitro. After treatment with inhibitors of PDGFRα and αvß3, the HCMV infection rate in MKs was significantly reduced, suggesting that IMC-3G3 and anti-αvß3 are potential therapeutic alternatives for viral infection. In summary, our study proposes a possible mechanism and potential treatments for thrombocytopenia caused by HCMV infection and other viral diseases associated with abnormal hemostasis.


Assuntos
Citomegalovirus/fisiologia , Transplante de Células-Tronco Hematopoéticas , Integrina alfaVbeta3/metabolismo , Megacariócitos/virologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Trombopoetina/metabolismo , Transdução de Sinais , Trombopoese , Adolescente , Adulto , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Criança , Citomegalovirus/ultraestrutura , Infecções por Citomegalovirus/patologia , Regulação para Baixo , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Ploidias , Fatores de Risco , Receptor 2 Toll-Like/metabolismo , Transplante Homólogo , Adulto Jovem
7.
Am J Hematol ; 96(5): 561-570, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33606900

RESUMO

Globally, postpartum hemorrhage (PPH) is the leading cause of maternal death. Women with immune thrombocytopenia (ITP) are at increased risk of developing PPH. Early identification of PPH helps to prevent adverse outcomes, but is underused because clinicians do not have a tool to predict PPH for women with ITP. We therefore conducted a nationwide multicenter retrospective study to develop and validate a prediction model of PPH in patients with ITP. We included 432 pregnant women (677 pregnancies) with primary ITP from 18 academic tertiary centers in China from January 2008 to August 2018. A total of 157 (23.2%) pregnancies experienced PPH. The derivation cohort included 450 pregnancies. For the validation cohort, we included 117 pregnancies in the temporal validation cohort and 110 pregnancies in the geographical validation cohort. We assessed 25 clinical parameters as candidate predictors and used multivariable logistic regression to develop our prediction model. The final model included seven variables and was named MONITOR (maternal complication, WHO bleeding score, antepartum platelet transfusion, placental abnormalities, platelet count, previous uterine surgery, and primiparity). We established an easy-to-use risk heatmap and risk score of PPH based on the seven risk factors. We externally validated this model using both a temporal validation cohort and a geographical validation cohort. The MONITOR model had an AUC of 0.868 (95% CI 0.828-0.909) in internal validation, 0.869 (95% CI 0.802-0.937) in the temporal validation, and 0.811 (95% CI 0.713-0.908) in the geographical validation. Calibration plots demonstrated good agreement between MONITOR-predicted probability and actual observation in both internal validation and external validation. Therefore, we developed and validated a very accurate prediction model for PPH. We hope that the model will contribute to more precise clinical care, decreased adverse outcomes, and better health care resource allocation.


Assuntos
Hemorragia Pós-Parto/etiologia , Complicações Hematológicas na Gravidez , Púrpura Trombocitopênica Idiopática/complicações , Adulto , Área Sob a Curva , China/epidemiologia , Estudos de Coortes , Suscetibilidade a Doenças , Registros Eletrônicos de Saúde , Feminino , Seguimentos , Previsões , Geografia Médica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Recém-Nascido , Modelos Logísticos , Modelos Teóricos , Hemorragia Pós-Parto/epidemiologia , Hemorragia Pós-Parto/prevenção & controle , Prednisona/uso terapêutico , Gravidez , Resultado da Gravidez , Prognóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/terapia , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária/estatística & dados numéricos
8.
Ann Hematol ; 100(2): 505-516, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33389025

RESUMO

We performed a nested case-control study to investigate the incidence, treatment, and prognosis of central nervous system (CNS) relapse after allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) and compared the outcomes of patients with CNS relapse following haploidentical donor (HID) HSCT versus identical sibling donor (ISD) HSCT. A total of 37 patients (HID-HSCT, 24; ISD-HSCT, 13) developed CNS relapse after transplantation between January 2009 and January 2019, with an incidence of 1.81%. The median time from transplantation to CNS relapse was 239 days. Pre-HSCT CNS involvement (HR 6.940, 95% CI 3.146-15.306, p < .001) was an independent risk factor for CNS relapse after allo-HSCT for AML. The 3-year overall survival (OS) for patients with CNS relapse was 60.3 ± 8.8%, which was significantly lower than that in the controls (81.5 ± 4.5%, p = .003). The incidence of CNS relapse was 1.64% for patients who received HID-HSCT and 2.55% for those who received ISD-HSCT (p = .193). There was no significant difference in OS between the HID-HSCT and ISD-HSCT subgroups among the patients with CNS relapse. In conclusion, CNS relapse is a rare but serious complication after allo-HSCT for AML, and the incidence and outcomes of patients with CNS relapse are comparable following HID-HSCT and ISD-HSCT.


Assuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Aloenxertos , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/terapia , Criança , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Taxa de Sobrevida
9.
Ann Hematol ; 99(11): 2659-2670, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32734550

RESUMO

Cytomegalovirus (CMV) can cause end-organ diseases including pneumonia, gastroenteritis, retinitis, and encephalitis in hematopoietic stem cell transplantation recipients. Potential differences among different CMV diseases remain uncertain. This study aimed to compare the clinical characteristics, risk factors, and mortality among different CMV diseases. A retrospective nested case-control study was performed based on a cohort of 3862 patients who underwent haploidentical hematopoietic stem cell transplantation at a single-center. CMV diseases occurred in 113 (2.92%) of 3862 haplo-HSCT recipients, including probable CMV pneumonia (CMVP, n = 34), proven CMV gastroenteritis (CMVG, n = 34), CMV retinitis (CMVR, n = 31), probable CMV encephalitis (CMVE, n = 7), and disseminated CMV disease (Di-CMVD, n = 7). Most (91.2%) cases of CMVG developed within 100 days, while most (90.3%) cases of CMVR were late onset. Refractory CMV infection and CMV viral load at different levels were associated with an increased risk of CMVP, CMVG, and CMVR. Compared with patients without CMV diseases, significantly higher non-relapse mortality at 1 year after transplantation was observed in patients with CMVP and CMVR, rather than CMVG. Patients with CMVP, Di-CMVD, and CMVE had higher overall mortality after diagnosis than that of patients with CMVG and CMVR (61.7%, 57.1%, 40.0% vs 27.7%, 18.6%, P = 0.001). In conclusion, the onset time, viral dynamics, and mortality differ among different CMV diseases. The mortality of CMV diseases remains high, especially for CMVP, Di-CMVD, and CMVE.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/terapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo
10.
Thromb Res ; 194: 168-175, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788111

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is regarded as a curative therapy for majority of hematologic malignancies and some non-malignant hematologic diseases. Venous thromboembolism (VTE) has become increasingly recognized as a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES: To show the characteristics of VTE after haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) and make comparisons with matched related donor HSCT (MRD-HSCT). PATIENTS/METHODS: A retrospective nested case-control study design was used, cases with VTE and matched controls were selected, with 3534 patients underwent HID-HSCT and 1289 underwent MRD-HSCT. RESULTS: During follow-up, 114 patients with VTE were identified. The incidence of VTE in HID-HSCT group was similar to that of MRD-HSCT group (2.4% versus 2.3%, P = 0.92). In HID-HSCT group, VTE occurred at a median time of 92.5 days, which was earlier than MRD-HSCT group (243.5 days). For HID-HSCT, advanced disease status, cardiovascular risk factors, acute graft-versus-host disease (aGVHD), and relapse were the independent risk factors for VTE. For MRD-HSCT, cardiovascular risk factors, aGVHD, and relapse were associated with VTE. Overall survival (OS) of patients following HID-HSCT and MRD-HSCT were similar, but the OS in patients with VTE was significantly lower than patients without VTE. CONCLUSIONS: There was no statistical difference in the incidence of VTE after HID-HSCT compared with MRD-HSCT. The development of VTE adversely impacted the OS after allo-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Tromboembolia Venosa , Estudos de Casos e Controles , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Recidiva Local de Neoplasia , Estudos Retrospectivos , Irmãos , Tromboembolia Venosa/etiologia
11.
Blood Adv ; 3(9): 1416-1428, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31053569

RESUMO

Impaired megakaryocyte (MK) maturation and reduced platelet production are important causes of immune thrombocytopenia (ITP). However, MK distribution and bone marrow (BM) niche alteration in ITP are unclear. To investigate the maturation and distribution of MKs in the BM niche and examine the components of BM niche regulation of MK migration, BM and peripheral blood were obtained from 30 ITP patients and 28 healthy donors. Nestin+ mesenchymal stem cells (MSCs) and CD41+ MKs were sorted by fluorescence-activated cell sorting. The components of the BM niche and related signaling were analyzed via immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, reverse transcription polymerase chain reaction, and western blot analysis. The number of MKs in the BM vascular niche was reduced in ITP. Moreover, the concentrations of CXCL12 and CXCR4+ MKs in the BM were decreased in ITP. Further investigation demonstrated that nestin+ MSCs and CXCL12 messenger RNA (mRNA) in nestin+ MSCs were both reduced whereas the apoptosis of nestin+ MSCs was significantly increased in ITP. Sympathetic nerves, Schwann cells, the proportion of ß3-adrenoreceptor (ß3-AR)+ nestin+ MSCs, and ß3-AR mRNA in nestin+ MSCs were all markedly reduced in ITP. Moreover, matrix metalloproteinase 9, vascular endothelial growth factor (VEGF), and VEGF receptor 1 were significantly reduced in ITP. Our data show that impaired MK distribution mediated by an abnormal CXCL12/CXCR4 axis is partially involved in reduced platelet production in ITP. Moreover, sympathetic neuropathy and nestin+ MSC apoptosis may have an effect on the alterations of BM CXCL12 in ITP.


Assuntos
Megacariócitos/citologia , Células-Tronco Mesenquimais/metabolismo , Nestina/metabolismo , Púrpura Trombocitopênica Idiopática/patologia , Adulto , Medula Óssea/metabolismo , Medula Óssea/patologia , Estudos de Casos e Controles , Quimiocina CXCL12/metabolismo , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Megacariócitos/metabolismo , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
Biol Blood Marrow Transplant ; 25(8): 1629-1636, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31048087

RESUMO

Immune-mediated neuropathies (IMNs) following hematopoietic stem cell transplantation have been described recently, which, excluding Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, may present with atypical patterns. This retrospective, nested, case-control study reviewed data from 3858 patients who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) during the past 10 years at a single center, and 40 patients (1.04%) with IMN following haplo-HSCT were identified. Chronic graft-versus-host disease (cGVHD) (P = .043) and cytomegalovirus (CMV) viremia (P = .035) were recognized as independent risk factors for the development of IMN after haplo-HSCT. There were no significant differences in overall survival (P = .619), disease-free survival (P = .609), nonrelapse mortality (P = .87), or the incidence of relapse (P = .583) between patients with and without IMN after haplo-HSCT. However, patients with post-transplant IMN were at higher risk of developing cGVHD (P = .012) than patients who did not develop IMN. Twenty-four of the 40 patients with IMN (60%) attained neurologic improvement after treatments including vitamins B1 and B12 and/or immunomodulatory agents. However, 19 (47.5%) patients still had persistent motor/sensory deficits despite receiving timely treatment. More studies are needed to help develop standardized diagnostic and therapeutic strategies for patients with post-transplant IMN.


Assuntos
Doença Enxerto-Hospedeiro , Síndrome de Guillain-Barré , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos/administração & dosagem , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Tiamina/administração & dosagem , Vitamina B 12/administração & dosagem , Adolescente , Adulto , Aloenxertos , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/mortalidade , Humanos , Incidência , Masculino , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/etiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/mortalidade , Fatores de Risco , Taxa de Sobrevida
13.
Cancer Lett ; 442: 193-201, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429106

RESUMO

ADAM28 has been shown to relate with tumor proliferation and prognosis. The expression of ADAM28 is up-regulated in acute myeloid leukemia (AML). However, the mechanism by which ADAM28 regulates the leukemic cell and the prognostic relevance with AML remain unknown. Here, we found that the expression level of ADAM28 was significantly elevated in AML patients suffering a relapse compared with those remaining in complete remission (CR). ADAM28 promoted the proliferation, migration and invasion in leukemic cells in vitro. Additionally, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. In a xenotransplantation mouse model, knockout of ADAM28 alleviated HL-60 cells growth and dissemination. The cumulative incidence of relapse (CIR) was significantly higher in patients with high ADAM28 expression. When separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR in the favorable and intermediate-risk group but not in poor-risk group. Taken together, these data suggest a pivotal role for ADAM28 in regulating the proliferation and invasion of leukemic cells and in the prediction of relapse in AML patients.


Assuntos
Proteínas ADAM/metabolismo , Movimento Celular , Proliferação de Células , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Leucemia Mieloide Aguda/enzimologia , Proteínas ADAM/genética , Animais , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Prognóstico , Proteólise , Recidiva , Transdução de Sinais , Células THP-1 , Fatores de Tempo , Carga Tumoral , Células Tumorais Cultivadas
14.
Funct Integr Genomics ; 18(3): 287-299, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29442265

RESUMO

Our understanding of the pathogenesis of immune thrombocytopenia (ITP) remains limited due to the complexity and heterogeneity of the disease. Recently, we observed that bone marrow mesenchymal stem cells (MSCs) derived from ITP patients exhibited growth defects and functional abnormalities that might be involved in the breakdown of self-tolerance. However, the underlying mechanism remains unclear. In this study, we profiled the expression of both mRNAs and miRNAs by utilizing the microarray technique and deciphered the mechanism underlying the impairment of MSCs derived from ITP patients (MSC-ITP). In total, we identified 740 genes and 32 miRNAs that were differentially expressed between ITP patients and controls. A compromised unfolded protein response (UPR) and decreased DNA transcription were shown to be significantly related to MSC-ITP. The interaction of miRNA with mRNA suggested that the cellular stress response, the UPR, and DNA transcription may be involved in the defects observed in MSC-ITP. Key differentially expressed genes were further validated by RT-PCR. Our results highlight that defects in the cellular stress response, as shown by a compromised UPR and differential DNA transcription, play key roles in causing the abnormalities observed in MSC-ITP. These data might contribute to a better understanding of the abnormal bone marrow niche and provide new insights into the pathogenesis of ITP.


Assuntos
MicroRNAs/genética , Púrpura Trombocitopênica Idiopática/genética , RNA Mensageiro/genética , Resposta a Proteínas não Dobradas/genética , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo
15.
Br J Haematol ; 180(3): 395-411, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29327472

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disease. Mesenchymal stem cells (MSCs) play important roles in the physiology and homeostasis of the haematopoietic system, including supporting megakaryocytic differentiation from CD34+ haematopoietic progenitor cells. Tumour necrosis factor alpha-induced protein 3 (TNFAIP3, also termed A20) plays a key role in terminating NF-κB signalling. Human genetic studies showed that the polymorphisms of the TNFAIP3 gene may contribute to ITP susceptibility. In this study, we showed a significant decrease in TNFAIP3 and increase in NF-κB/SMAD7 in ITP-MSCs. In co-cultures with CD34+ cells, NF-κB was overexpressed in MSCs from healthy controls (HC-MSCs) after transfection with NFKBIA (IκB)-specific short hairpin (sh)RNAs, resulting in MSC deficiency and a reduction in megakaryocytic differentiation and thrombopoiesis. Knockdown of TNFAIP3 expression using TNFAIP3-specific shRNAs in HC-MSCs affected megakaryocytopoiesis. However, IKBKB knockdown corrected megakaryocytopoiesis inhibition in the ITP-MSCs by decreasing NF-κB expression. Amplified TNFAIP3 expression in ITP-MSCs by TNFAIP3 cDNA can facilitate megakaryocyte differentiation. shRNA-mediated knockdown of SMAD7 expression rescued the impaired MSC function in ITP patients. Therefore, we demonstrate that a pathological reduction in TNFAIP3 levels induced NF-κB/SMAD7 pathway activation, causing a deficiency in MSCs in ITP patients. The ability of ITP-MSCs to support megakaryocytic differentiation and thrombopoiesis of CD34+ cells was impaired.


Assuntos
Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Trombopoese , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores , Medula Óssea/patologia , Estudos de Casos e Controles , Diferenciação Celular , Ensaio de Unidades Formadoras de Colônias , Citocinas/biossíntese , Expressão Gênica , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia , Modelos Biológicos , NF-kappa B/genética , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Trombopoese/efeitos dos fármacos , Trombopoese/genética , Fator de Crescimento Transformador beta/metabolismo , Tretinoína/farmacologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
16.
Eur J Haematol ; 100(2): 171-181, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29114931

RESUMO

OBJECTIVES: To explore the possible risk factors for the occurrence and mortality of thrombotic microangiopathy (TMA) with concomitant acute graft-vs-host disease (aGVHD) and to investigate outcomes and treatments of this disorder after allo-HSCT. METHODS: Fifty cases diagnosed with TMA with concomitant aGVHD and 150 controls were identified from a cohort composed of 3992 patients who underwent allo-HSCT from 2008 to 2016. RESULTS: Grade III-IV aGVHD (P = .000), acute kidney injury (AKI) (P = .033), and hypertension (P = .028) were significant independent risk factors associated with the occurrence of TMA with concomitant aGVHD. A haptoglobin level below normal (P = .013), a maximum volume of diarrhea >2500 mL/d (P = .015), and bloody diarrhea (P = .049) were significant markers for death in both univariate and multivariate analyses. Patients diagnosed with TMA with concomitant aGVHD had a lower overall survival (OS), a higher non-relapse mortality (NRM), but a lower risk of relapse. CONCLUSIONS: Thrombotic microangiopathy with concomitant aGVHD is a significant complication after allo-HSCT, with a worse outcome, including significantly lower OS and higher NRM. There are specific risk factors associated with occurrence and mortality of this complication.


Assuntos
Gastroenteropatias/epidemiologia , Gastroenteropatias/etiologia , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologia , Doença Aguda , Adolescente , Adulto , Criança , Feminino , Seguimentos , Gastroenteropatias/diagnóstico , Gastroenteropatias/terapia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/terapia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
17.
Int J Infect Dis ; 65: 81-84, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29031606

RESUMO

Noroviruses are a common cause of acute gastroenteritis outbreaks in institutions including schools and kindergartens around the world. An outbreak caused by GII.P16-GII.2 norovirus in a kindergarten in Lianyungang, Jiangsu Province, China is reported here. An epidemiological investigation was conducted, and pathogen detection was performed. The descriptive analysis indicated that this outbreak in middle class 1 had a point source. Twenty cases of acute gastroenteritis occurred in this class within a period of 8.5h; the attack rate was 52.6% (20/38). Airborne transmission via the air conditioning unit in a confined restroom could have played a critical role in this outbreak. Sequence analysis of GII-positive samples confirmed that the norovirus GII.P16-GII.2 variant was the etiological agent of this outbreak.


Assuntos
Ar Condicionado , Infecções por Caliciviridae/epidemiologia , Infecções por Caliciviridae/transmissão , Surtos de Doenças , Gastroenterite/epidemiologia , Norovirus/isolamento & purificação , Doença Aguda , Poluição do Ar em Ambientes Fechados , Infecções por Caliciviridae/diagnóstico , Pré-Escolar , China/epidemiologia , Fezes/virologia , Feminino , Gastroenterite/diagnóstico , Gastroenterite/virologia , Humanos , Incidência , Masculino , Instituições Acadêmicas , Manejo de Espécimes
18.
Stem Cells Dev ; 26(22): 1648-1661, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28946811

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disease in which dendritic cells (DCs) play a crucial role in the breakdown of self-tolerance. Studies have identified the function of mesenchymal stem cells (MSCs) in promoting the development of regulatory DCs (regDCs). Our previous work revealed that MSCs in ITP exerted senescence, apoptosis, and impaired immunosuppressive effects on T and B cells. However, it is unclear whether the effects of MSCs on regDC induction are altered in ITP. Our data demonstrated that MSCs in ITP were impaired in inhibiting CD1a+ DC and CD14+ DC differentiation from CD34+ hematopoietic progenitor cells (CD34+ HPCs). DCs differentiated with MSCs in ITP exhibited an increased expression of costimulatory molecules CD80/CD86 and secretion of proinflammatory interleukin-12 (IL-12). Accordingly, the tolerogenic characteristics were deficient in DCs induced by MSCs in ITP. DCs differentiated with MSCs in ITP exhibited an impaired ability to inhibit CD3+ T cell proliferation, to suppress T helper (Th)1 cell differentiation, and to induce anergic and regulatory T cells (Tregs). The expression of Notch signaling components was measured in MSCs in ITP. Reduced expression of the ligand Jagged-1, the receptor Notch-1 intracellular domain (NICD-1), and the target gene Hes-1 was identified in MSCs in ITP. The addition of biologically active Jagged-1 to CD34+ HPCs was observed to promote regDC differentiation. When cultured on Jagged-1-coated plates, MSCs in ITP showed an enhancement of the Notch-1 pathway activation, Jagged-1 expression, and the function in inducing regDCs. Pretreatment with all-trans retinoic acid (ATRA) was found to partially restore the capacity of MSCs in both ITP patients and healthy controls in inducing CD34+-derived regDCs. Our data elucidated that MSCs in ITP were impaired in inducing CD34+-regDCs, associated with the Notch-1/Jagged-1 signaling pathway. ATRA could partially correct the impairment of MSCs, suggesting that ATRA could serve as a potential therapeutic alternative for ITP.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proteína Jagged-1/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Receptores Notch/metabolismo , Tretinoína/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Humanos , Células-Tronco Mesenquimais/citologia , Trombocitopenia/metabolismo
19.
Eur J Obstet Gynecol Reprod Biol ; 210: 370-375, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28157643

RESUMO

OBJECTIVES: Ectopic pregnancies are among the leading causes of maternal morbidity and mortality in both developed and emerging nations, but tests for early, accurate, and convenient detection are lacking. STUDY DESIGN: Between January 2013 and February 2015, 504 women with tubal pregnancy were prospectively recruited, and their clinical characteristics were recorded. Samples of peritoneal fluid were collected by culdocentesis, and venous blood was drawn from the antecubital vein. In samples from each source, levels of the following biochemical markers were measured: cancer antigen 125 (CA125), human chorionic gonadotropin (hCG), progesterone, vascular endothelial growth factor, and creatine kinase. RESULTS: The ratios of biochemical markers in the peritoneal fluid and in the blood (Rp/v) were calculated. The median of Rp/v-CA125 and Rp/v-hCG were significantly lower in the ruptured ectopic pregnancy group than in the unruptured group. The optimal cutoff value to detect ectopic pregnancy rupture was 401.5U/mL as the upper limit for peritoneal CA125, with a sensitivity of 93.5% and specificity of 74.2%. The optimal cutoff value was 18.7 as the upper limit in the peritoneal fluid/blood ratio (Rp/v) of CA125, with a sensitivity of 77.5% and specificity of 68.4%. CONCLUSIONS: In countries with poor access to laparoscopy, culdocentesis is useful. In this study, culdocentesis provided additional information for management of abdominal pain when laparoscopy is not available. The authors propose Rp/v cutoff values that can be used conveniently and quickly to diagnose ruptured ectopic pregnancies and bleeding, enabling rapid and appropriate therapeutic responses.


Assuntos
Líquido Ascítico/química , Biomarcadores/sangue , Gravidez Tubária/sangue , Adulto , Antígeno Ca-125/sangue , Gonadotropina Coriônica/sangue , Creatina Quinase/sangue , Feminino , Humanos , Proteínas de Membrana/sangue , Paracentese , Gravidez , Gravidez Tubária/diagnóstico , Progesterona/sangue , Estudos Prospectivos , Ruptura Espontânea/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
20.
Sci Rep ; 7: 41404, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112250

RESUMO

3ß-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.


Assuntos
Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Endométrio/anormalidades , Insulina/efeitos adversos , Proteínas do Tecido Nervoso/biossíntese , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/biossíntese , Regulação para Cima/genética , Doenças Uterinas/enzimologia , Idoso , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Endométrio/enzimologia , Endométrio/patologia , Indução Enzimática/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Acetato de Medroxiprogesterona/farmacologia , Acetato de Medroxiprogesterona/uso terapêutico , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Prognóstico , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Fator de Transcrição STAT3/metabolismo , Regulação para Cima/efeitos dos fármacos , Doenças Uterinas/genética , Doenças Uterinas/patologia
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