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Objectives: Increasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV-associated lymphoproliferative disease (EBV+ LPD). TNFRSF9 encodes a vital costimulatory molecule that enhances CD8+ T-cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from TNFRSF9 heterozygous mutations has been identified. Methods: Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous TNFRSF9 mutations [NM_001561.5: c.208 + 1->AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV+ LPD. Immunophenotyping and in vitro assays of lymphocyte function and NK cell activity were performed. Results: Biallelic TNFRSF9 mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8+ T cells from the patient had impaired activation, reduced expression/release of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV+ LPD. Conclusion: Our study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the TNFRSF9 gene plays a critical role in host immune responses to EBV infection.
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BACKGROUND: Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution. METHOD: We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T. RESULTS: Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T. CONCLUSION: CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.
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Leucemia Mieloide Aguda , Humanos , Decitabina/farmacologia , Aminopiridinas/metabolismo , Imunoterapia Adotiva , Linfócitos TRESUMO
Background: The aim of the present study was to investigate the association between alanine aminotransferase (ALT) levels at delivery and postpartum ALT flares among women with chronic hepatitis B (CHB). Methods: Pregnant women with CHB from November 2008 to November 2017 were included in this retrospective study. Multivariable logistic regression analysis and a generalized additive model were performed to determine both linear and nonlinear relationships between ALT levels at delivery and postpartum ALT flares. Stratification analysis was performed to test for effect modifications in subgroups. Results: A total of 2643 women were enrolled. Multivariable analysis indicated that ALT levels at delivery were positively associated with postpartum ALT flares (odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.02, P < 0.0001). When ALT levels were converted to a categorical variable, the ORs and 95% CIs in quartiles 3 and 4 versus quartile 1 were 2.26 (1.43-3.58) and 5.34 (3.48-8.22), respectively (P for trend < 0.001). When ALT levels were dichotomized into a categorical variable according to clinical cutoffs (40 U/L or 19 U/L), the ORs and 95% CIs were 3.06 (2.05-4.57) and 3.31 (2.53-4.35), respectively (P < 0.0001). The ALT level at delivery was also found to have a nonlinear relationship with postpartum ALT flares. The relationship followed an inverted U-shaped curve. Conclusions: The ALT level at delivery was positively correlated with postpartum ALT flares in women with CHB when the ALT level was less than 182.8 U/L. The ALT cutoff (19 U/L) at delivery was more sensitive to predict the risk of ALT flares postpartum.
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Hepatite B Crônica , Humanos , Feminino , Gravidez , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/tratamento farmacológico , Gestantes , Vírus da Hepatite B/genética , Estudos Retrospectivos , DNA Viral , Antígenos E da Hepatite B , Período Pós-Parto , Alanina Transaminase , Antivirais/uso terapêuticoRESUMO
BACKGROUND: CMV gastroenteritis is common in patients receiving allogeneic hematopoietic stem cell transplantation and it is difficult to distinguish from acute graft-versus-host disease (aGvHD), which has very similar symptoms but needs quite different treatment. CMV gastroenteritis is caused by local infection or reactivation of CMV in the gastrointestinal tract while aGvHD is due to immune rejection. The gold standard of diagnosis of CMV gastroenteritis and aGvHD is gastrointestinal biopsy under endoscopy, which is invasive and can potentially lead to severe side effects. Stool samples testing with quantitative polymerase chain reaction (qPCR) may be an alternative, while the application in trace level measurements and precision are not all satisfactory enough in reported research. METHODS: In this study, we designed a novel method that extracted the cell free DNA (cfDNA) from the fecal supernatant to perform digital PCR (dPCR) for the detection of CMV, analyzed the performance and compared it with the total DNA extracted by the current procedure. RESULTS: Twenty-two paired stool samples using two DNA extraction methods proved that the cfDNA extraction method had markedly higher DNA concentrations and control gene copy number, suggesting that cfDNA may be more informative and more useful for the detection of CMV DNA segment. The dPCR approach in detecting CMV DNA segment also exhibit good linearity (R2 = 0.997) and higher sensitivity (limit of detection at 50% was 3.534 copies/µL). Eighty-two stool samples from 44 immunocompromised patients were analyzed, CMV-positive rate was 28%, indicating that more than one-quarter of the gastrointestinal symptoms within these patients may be caused by CMV infection or reactivation. CONCLUSION: The combined results suggest that detection of CMV by dPCR in cfDNA of stool supernatant is a powerful method to identify CMV gastroenteritis and helps in clinical treatment decision making.
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Ácidos Nucleicos Livres , Infecções por Citomegalovirus , Enterite , Infecções por Enterovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Citomegalovirus/genética , Estudos Retrospectivos , Infecções por Citomegalovirus/diagnóstico , Doença Enxerto-Hospedeiro/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Reação em Cadeia da Polimerase , Infecções por Enterovirus/complicaçõesRESUMO
OBJECTIVE: Tenofovir disoproxil fumarate (TDF) use compared with telbivudine (LdT) use throughout pregnancy has not been adequately investigated. To compare the efficacy and safety of TDF and LdT for the prevention of mother-to-child transmission (MTCT) of hepatitis B from highly viremic mothers throughout pregnancy in real-world settings. STUDY DESIGN: This was a single-center, retrospective cohort study. From January 1, 2013, to December 31, 2018, we retrospectively enrolled 602 mothers with chronic hepatitis B (CHB) who received antiviral treatment throughout pregnancy at Beijing Ditan Hospital. A total of 562 mothers met the inclusion criteria, with 167 in the TDF group and 395 in the LdT group. Mothers and infants were followed for 28 weeks postpartum. The primary endpoint was the MTCT rate of HBV. The secondary endpoints were the safety profiles in mothers and infants. RESULTS: The MTCT rates were 0 % in both the TDF and LdT groups. The rates of neonatal congenital abnormalities were similar between the TDF and LdT groups (1.2 % vs 1.8 %, P = 0.896). There were no significant differences in perinatal complications between the two groups (all P > 0.05). There were also no significant differences in gestational age or infant height, weight, Apgar score. The level of HBV DNA at 28 weeks postpartum was an independent risk factor for postpartum alanine aminotransferase (ALT) flares (OR = 2.348, 95 % CI: 1.100-5.016, P = 0.027). CONCLUSION: TDF and LdT treatments throughout pregnancy in mothers with CHB were equally effective in preventing MTCT and safe.
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Hepatite B Crônica , Complicações Infecciosas na Gravidez , Antivirais/efeitos adversos , Estudos de Coortes , DNA Viral , Feminino , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/prevenção & controle , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/prevenção & controle , Estudos Retrospectivos , Telbivudina/uso terapêutico , Tenofovir/efeitos adversos , Carga ViralRESUMO
Different from canonical drugs, CAR T-cells are "living drugs", which derived from patient's own blood. Studies of the pharmacokinetics of CAR T-cells could improve our understanding of their efficacy, safety, optimal dosage, and other characterizes. We previously reported a phase I study of a novel fully human BCMA-targeting CAR (CT103A) in 18 patients with relapsed/refractory multiple myeloma. CT103A exhibited extraordinary persistence with low anti-drug antibody positivity. To figure out the pharmacokinetic characterizes and investigate the potential reason of CT103A's long-term persistence, we established a population pharmacokinetic (PopPK) model of CT103A based on 18 patients cohort by applying nonlinear mixed-effects modeling and analyzed the CAR T-cell clonal evolution. The results suggested that extramedullary spreading was found to impair Cmax and was therefore added as a covariate to the modified model. The model revealed tocilizumab and corticosteroids showed no impact on the CT103A expansion rate. No dominant clone existed in patients with persistently high peripheral CT103A by CAR integration sites analysis. Finally, patients with lower contraction rate constants and higher Cmax as well as memory CT103A fraction could achieve better clinical responses. Taken together, this study developed a PopPK model of a fully human anti-BCMA CAR T-cell therapy, and summarized its model characteristics. We suggested that the long-term persistence of CT103A was attributed to the memory CAR T-cell fraction but not the clonal evolution. This study will improve people's understanding of pharmacokinetics and PopPK of CAR T-cell immunotherapy.
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Small B-cell lymphoid neoplasms (SBCLNs) are a heterogeneous group of diseases characterized by malignant clonal proliferation of mature B-cells. However, the classification of SBCLNs remains a challenge, especially in cases where histopathological analysis is unavailable or those with atypical laboratory findings or equivocal pathologic data. In this study, gene expression profiling of 1039 samples from 27 gene expression omnibus (GEO) datasets was first investigated to select highly and differentially expressed genes among SBCLNs. Samples from 57 SBCLN cases and 102 nonmalignant control samples were used to train a classifier using the NanoString platform. The classifier was built by employing a cascade binary classification method based on the random forest algorithm with 35 refined gene signatures. Cases were successively classified as chronic lymphocytic leukemia/small lymphocytic lymphoma, conventional mantle cell lymphoma, follicular lymphoma, leukemic non-nodal mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, and other undetermined. The classifier algorithm was then validated using an independent cohort of 197 patients with SBCLNs. Under the distribution of our validation cohort, the overall sensitivity and specificity of proposed algorithm model were >95%, respectively, for all the cases with tumor cell content greater than 0.72. Combined with additional genetic aberrations including IGH-BCL2 translocation, MYD88 L265P mutation, and BRAF V600E mutation, the optimal sensitivity and specificity were respectively found at 0.88 and 0.98. In conclusion, the established algorithm demonstrated to be an effective and valuable ancillary diagnostic approach for the sub-classification and pathologic investigation of SBCLN in daily practice.
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Leucemia Linfocítica Crônica de Células B , Linfoma de Zona Marginal Tipo Células B , Linfoma de Célula do Manto , Macroglobulinemia de Waldenstrom , Adulto , Linfócitos B/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Fator 88 de Diferenciação Mieloide/genética , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/patologiaRESUMO
BACKGROUND: Entecavir (ETV) or adefovir dipivoxil (ADV) are not recommended during pregnancy because of embryotoxicity or teratogenicity found in animal studies; however, information on the safety of ETV or ADV in humans is limited. AIMS: The aim of this study was to investigate the safety of ETV or ADV in women with chronic hepatitis B (CHB). METHODS: We retrospectively enrolled 152 pregnant women with CHB who exposed to ETV or ADV in the first trimester of pregnancy. All the mothers were followed until postpartum 7 months. All newborns received immunoprophylaxis. The primary endpoint was the safety of mothers and infants. The secondary endpoint was the rate of mother-to-child transmission (MTCT) of hepatitis B virus (HBV). RESULTS: The pregnant women were divided into two groups. Group 1 included 20 pregnant women who became unplanned pregnancy with ETV or ADV treatment. All of them switched to TDF before 7 weeks of gestation. There were 20 women with 20 pregnancies and 18 live births. Group 2 included 132 with TDF before conception. There were 132 women with 141 pregnancies and 125 live births. The abortion rate of Group 1 was not higher than that in Group 2 (10.0 versus 10.6%, p = 1.000). The birth defect rate in Group 1 did not statistically differ from Group 2 (5.6 versus 4.8%, p = 1.000). There were no significant differences of gestational complications between the two groups. The rate of MTCT of HBV is 0%. CONCLUSIONS: Among infants exposed to ETV or ADV before conception, ETV or ADV was not associated with a higher risk for adverse birth outcomes.
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Hepatite B Crônica , Adenina/análogos & derivados , Antivirais/efeitos adversos , DNA Viral/uso terapêutico , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Guanina/análogos & derivados , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Organofosfonatos , Gravidez , Resultado da Gravidez/epidemiologia , Gestantes , Estudos Retrospectivos , Resultado do Tratamento , Carga ViralRESUMO
Acute leukemia with ambiguous lineage (ALAL) is a rare and highly aggressive malignancy with limited molecular characterization and therapeutic recommendations. In this study, we retrospectively analyzed 1635 acute leukemia cases in our center from January 2012 to June 2018. The diagnose of ALAL was based on either EGIL or 2016 WHO criteria, a total of 39 patients were included. Four patients diagnosed as acute undifferentiated leukemia (AUL) by both classification systems. Among the patients underwent high-throughput sequencing, 89.5% were detected at least one mutation and the median number of gene mutation was 3 (0-8) per sample. The most frequently mutated genes were NRAS (4, 21%), CEBPA (4, 21%), JAK3 (3, 16%), RUNX1 (3, 16%). The mutations detected in mixed-phenotype acute leukemia (MPAL) enriched in genes related to genomic stability and transcriptional regulation; while AUL cases frequently mutated in genes involved in signaling pathway. The survival analysis strongly suggested that mutation burden may play important roles to predict the clinical outcomes of ALAL. In addition, the patients excluded by WHO criteria had even worse clinical outcome than those included. The association of the genetic complexity of blast cells with the clinical outcomes and rationality of the diagnostic criteria of WHO system need to be evaluated by more large-scale prospective clinical studies.
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Instabilidade Genômica , Leucemia , Mutação , Proteínas de Neoplasias , Doença Aguda , Adolescente , Adulto , Feminino , Humanos , Leucemia/classificação , Leucemia/diagnóstico , Leucemia/genética , Leucemia/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prognóstico , Estudos RetrospectivosRESUMO
Epstein-Barr virus (EBV) T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells, including chronic active EBV infection of T/NK-cell type (CAEBV+T/NK), EBV-associated hemophagocytic lymphohistiocytosis (EBV+HLH), extranodal NK/T-cell lymphoma of nasal type (ENKTL), and aggressive NK-cell leukemia (ANKL). However, the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown. A total of 171 nonimmunosuppressed patients with EBV+T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed. The 94 gene variants, mostly located in UNC13D, LYST, ITK, and PRF1 genes were detected, and mutations covered 28/50 (56.00%) of CAEBV-T/NK, 31/51 (60.78%) of EBV+HLH, 13/28 (46.42%) of ENKTL, and 13/48 (27.09%) of ANKL. Most mutations represented monoallelic and missense. Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations (P=0.0284, P=0.0137). Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV+T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.
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Predisposição Genética para Doença , Herpesvirus Humano 4/patogenicidade , Transtornos Linfoproliferativos/genética , Proteínas de Neoplasias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China/epidemiologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Lactente , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linfócitos T/patologia , Linfócitos T/virologia , Adulto JovemAssuntos
Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Adolescente , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Criança , Pré-Escolar , Humanos , Imunoterapia Adotiva/efeitos adversos , Células Jurkat , Células K562 , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Resultado do TratamentoRESUMO
B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR-exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.
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Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Anticorpos de Cadeia Única/uso terapêutico , Adulto , Afibrinogenemia/etiologia , Idoso , Animais , Anticorpos Anti-Idiotípicos/biossíntese , Antineoplásicos/uso terapêutico , Antígeno de Maturação de Linfócitos B/imunologia , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Feminino , Doenças Hematológicas/etiologia , Humanos , Imunidade Humoral , Imunoterapia Adotiva/efeitos adversos , Leucemia Plasmocitária/etiologia , Leucemia Plasmocitária/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/imunologia , Indução de Remissão , Anticorpos de Cadeia Única/imunologia , TransgenesRESUMO
The CRISPR/Cas9 system is an efficient genome-editing system that has been successfully applied in the field of gene therapy. However, clinical applications of the CRISPR/Cas9 system are limited by the delivery method and safety concerns. Extracellular Vesicles (EVs) can be released from almost every type of cell, and they act as shuttles to convey molecules between cells. Here, we used EVs derived from epithelial cells as a biosafety delivery platform for the CRISPR/Cas9 system and modified the EVs with a chimeric-antigen receptor (CAR) to give them selective tropism to tumors. Compared to normal EVs, CAR-EVs accumulated in cancer tumors rapidly and released the CRISPR/Cas9 system targeting the MYC oncogene efficiently, both in vitro and in vivo. Taken together, the combination of EV and CAR was confirmed to be a novel strategy facilitating the use of natural gene therapy platforms in cancer treatment in this proof-of-concept research.
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Vesículas Extracelulares , Neoplasias , Receptores de Antígenos Quiméricos , Linfócitos B , Sistemas CRISPR-Cas , Edição de Genes , Humanos , Neoplasias/genética , Receptores de Antígenos Quiméricos/genética , TropismoRESUMO
Platelet transfusion is important in the prevention and treatment of bleeding in patients with acute myeloid leukemia (AML) after receiving intensive chemotherapy. However, platelet transfusion refractoriness (PTR) is an intractable clinical issue occurred in these patients. And its clinical and immunological features remain largely unknown. The potential causes and clinical features of PTR were retrospectively analyzed in 560 patients who were diagnosed as de novo AML in Tongji Hospital from June 2012 through June 2018. A high-throughput antibody screening for the detection of human leukocyte antigen (HLA) and its serotypes was performed in 133 newly diagnosed AML patients. PTR occurred in 11.8% of the de novo AML patients. The median age for patients with PTR was 46 years (range, 15-70). It frequently manifested in female patients and in patients with splenomegaly, M4 subtype, c-Kit gene mutation, and rearrangements of RUNX1-RUNX1T1 or CBFB-MYH11, commonly referred to as core binding factor AML (CBF-AML). Notably, CBF-AML was independently associated with the occurrence of PTR. PTR predominantly developed in patients who had CBF-AML (P < .001) and in patients who further had better minimal residual disease (MRD) reduction (≥3-log) before the second consolidation chemotherapy (P = .007). HLA-I antibodies were detected in the serum of 9.0% of AML patients and markedly enriched in patients with PTR (P < .001) and in patients with CBF-AML (P = .018). HLA-B was the most frequently identified serum epitope in PTR patients. Patients with CBF-AML had higher tendency to develop HLA-I antibodies and PTR, which depicted novel features of PTR in AML and might provide insights into its efficient managements.
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Leucemia Mieloide Aguda/terapia , Transfusão de Plaquetas/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: There are few large sample studies evaluating the safety and efficacy of lamivudine (LAM) or telbivudine (LdT) in preventing hepatitis B mother-to-child transmission (MTCT) in highly viremic mothers in the third trimester of pregnancy in real-world settings. The purpose of this study was to analyze a large sample size of HBV-infected mothers to better understand the safety and efficacy of LAM and LdT under the aforementioned criteria. METHODS: During the period of November 2008 to November 2017, we retrospectively enrolled mothers with HBV DNA > 1 × 106 IU/mL who received LAM or LdT during the third trimester of pregnancy and compared them to untreated mothers. All mothers were divided into the three following groups: the LAM group, the LdT group, and the control group. RESULTS: A total of 2624 HBV-infected mothers were enrolled in the study, with 363 in the LAM group, 1283 in the LdT group, and 978 in the control group. The MTCT rates were significantly lower in the LAM or LdT group than that in the control group (0.4% or 0.3% versus 9.0%, P < 0.001). Infants born to untreated mothers had a significantly higher risk of HBV infection (OR = 28.6, 95% CI: 10.4-78.7, P < 0.001). There were no significant differences in perinatal complications between the three groups (P > 0.05). There were also no differences for gestational age or infants' height, weight, Apgar scores, or birth defect rates. Postpartum discontinuation of antiviral therapy did not seem to increase the risk of postpartum alanine aminotransferase (ALT) flare. CONCLUSION: LAM or LdT treatment initiated in the third trimester for mothers with HBV DNA > 1 × 106 IU/mL was equally safe and effective in preventing MTCT.
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Hepatite B , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Lamivudina/administração & dosagem , Complicações Infecciosas na Gravidez/tratamento farmacológico , Telbivudina/administração & dosagem , Adulto , Feminino , Hepatite B/tratamento farmacológico , Hepatite B/transmissão , Humanos , Lamivudina/efeitos adversos , Gravidez , Estudos Retrospectivos , Telbivudina/efeitos adversosRESUMO
Background: The aim of this study was to describe biochemical, virological features and Mother-to child-transmission (MTCT) rate in chronic hepatitis B (CHB) women who stopped antiviral therapy before or in the early pregnancy. Methods: This was a single-center, retrospective study. Forty-three CHB women who stopped treatment before or in the early pregnancy and 103 CHB women with tenofovir disoproxil fumarate (TDF) treatment throughout pregnancy were enrolled. The virological and biochemical flares during pregnancy and postpartum period were studied. MTCT rates were also compared. Results: During pregnancy, ALT flares (43.9% vs 1.0%) and viral rebound (31.7% vs 0) were more common in women who stopped treatment (P<0.001). Postpartum ALT flares were less frequent in women with treatment than those stopped treatment (0 vs 6/35, P = 0.001). The birth defect rate in the mothers who stopped treatment did not statistically differ from that of mothers treated throughout pregnancy (4.9 % vs 3.9 %, P = 1.000). There were no significant differences of gestational complications between the two groups, except intrahepatic cholestasis of pregnancy (12.2% vs 0, P = 0.002). The rate of MTCT in mothers who discontinued treatment was higher (2.4% vs 0, P = 0.285), although there was no statistically significant. Conclusion: ALT flares were common in mothers who discontinued antiviral therapy. Thus, these pregnant women should be monitored closely. Cessation of treatment was not recommended although no hepatic failure was observed. Larger studies are needed to evaluate the safety of discontinuation before pregnancy.
Assuntos
Hepatite B Crônica/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Tenofovir/efeitos adversos , Adulto , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Antígenos E da Hepatite B , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/transmissão , Hepatite B Crônica/virologia , Humanos , Transmissão Vertical de Doenças Infecciosas , Período Pós-Parto/fisiologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Tenofovir/uso terapêutico , Carga Viral/genéticaRESUMO
BACKGROUND: Antiviral therapy throughout pregnancy in women with chronic hepatitis B (CHB) during pregnancy has been suggested; however, the data of tenofovir disoproxil fumarate (TDF) are limited. The aim of this study was to evaluate the safety and efficiency in women with CHB. METHODS: It was a single-center, retrospectively study. Eighty-one women received TDF 300 mg/day before pregnancy. Sixty-three women did not receive antiviral treatment. All infants in both groups received immunoprophylaxis. Mothers and infants were followed at least postpartum 7 months. The primary endpoint was the safety of mothers and infants. The secondary endpoints were mother-to-child transmission (MTCT) rate and hepatitis B virus (HBV) DNA suppression. RESULTS: TDF was well tolerated in the mothers. The rates of neonatal congenital abnormalities were similar between the two groups (3.7% or 3/81 versus 3.3% or 2/63, P = 1.000). There were also no significant differences in infant length and weight, Apgar score (1 minute), rate of low birth weight, gestational age, or rate of cesarean section between the two groups. TDF significantly reduced the viral load (3.4 ± 0.5 log IU/mL versus 6.3 ± 1.5 log IU/mL, P < 0.001) and the ALT levels (19.9 ± 10.2 versus 46.8 ± 44.8 U/L, P < 0.001) before delivery. At 7-month postpartum, the MTCT rate was 0% in the TDF-treated group when compared with 6.3% (4/63) in the untreated group (P = 0.035). CONCLUSION: TDF used throughout pregnancy can safely reduce the rate of MTCT.
Assuntos
Hepatite B Crônica , Complicações Infecciosas na Gravidez , Antivirais/efeitos adversos , Cesárea , DNA Viral , Feminino , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Mães , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estudos Retrospectivos , Tenofovir/efeitos adversos , Carga ViralRESUMO
Antigen-escape relapse has emerged as a major challenge for long-term disease control after CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. From March 2016 through January 2018, we conducted a pilot study in 89 patients who had refractory/relapsed B-cell malignancies, to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-specific, third-generation chimeric antigen receptor-engineered (CAR19/22) T cells. Among the 51 patients with acute lymphoblastic leukemia, the minimal residual disease-negative response rate was 96.0% (95% confidence interval [CI], 86.3-99.5). With a median follow-up of 16.7 months (range, 1.3-33.3), the median progression-free survival (PFS) was 13.6 months (95% CI, 6.5 to not reached [NR]), and the median overall survival (OS) was 31.0 months (95% CI, 10.6-NR). Among the 38 patients with non-Hodgkin lymphoma, the overall response rate was 72.2% (95% CI, 54.8-85.8), with a complete response rate of 50.0% (95% CI, 32.9-67.1). With a median follow-up of 14.4 months (range, 0.4-27.4), the median PFS was 9.9 months (95% CI, 3.3-NR), and the median OS was 18.0 months (95% CI, 6.1-NR). Antigen-loss relapse occurred in 1 patient during follow-up. High-grade cytokine release syndrome and neurotoxicity occurred in 22.4% and 1.12% patients, respectively. In all except 1, these effects were reversible. Our results indicated that sequential infusion of CAR19/22 T cell was safe and efficacious and may have reduced the rate of antigen-escape relapse in B-cell malignancies. This trial was registered at www.chictr.org.cn as #ChiCTR-OPN-16008526.
Assuntos
Antígenos CD19/imunologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Adolescente , Adulto , Idoso , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Terapia de Salvação , Taxa de Sobrevida , Linfócitos T/imunologia , Adulto JovemRESUMO
Background: DNA methyltransferase 3A (DNMT3A) plays a unique role in hematopoiesis and acute myeloid leukemia (AML) pathogenesis. While the influences of DNMT3A mutation subtypes are still under debate. Purpose: Exploration of the clinical and molecular differences between AML patients carrying DNMT3A R882 mutations and DNMT3A frameshift mutations. Methods: Next generation of sequencing (NGS) and clinical data of 118 AML patients in our center were analyzed and compared. NGS, mRNA and miRNA profiling and clinical data from 12 patients in TCGA database were integrative analyzed. Results: Among all patients enrolled, 113 patients were positive for the variants of interest. Overall, a total of 295 variants were discovered, among which 24 DNMT3A mutations were detected, including 1 non-sense, 20 missense, 3 frameshift mutations. And 7 DNMT3A R882 mutations (3 R882H, 2 R882C, and 2 R882P) were found. Clinical analysis from our cohort and TCGA database indicated that patients carrying DNMT3A R882 mutation exhibited significantly higher levels of peripheral blood hemoglobin and non-significantly inferior prognosis compared with patients with DNMT3A frameshift mutations. Integrative analysis indicated that miR-10b, miR-143, and miR-30a were significantly decreased in the DNMT3A R882 group. High miR-143 expression is significantly associated with better prognosis in AML patients with DNMT3A mutations. Conclusion: Different molecular and clinical characteristics existed between patients with DNMT3A variant subtypes. The distinct microRNA expression pattern for DNMT3A R882 AML patients might not only act as markers to predict disease prognosis, but also could be further investigated to develop novel therapeutic targets for patients with DNMT3A mutations.