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1.
BMC Cancer ; 21(1): 955, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433456

RESUMO

BACKGROUND: The improved prognosis of classic Hodgkin lymphoma (cHL) has been accompanied by elevated risks of non-cancer-specific death (non-CSD). The aim of this study was to verify the occurrence of non-CSD and its effect on rates of overall survival among adult patients with cHL. METHODS: To ensure sufficient follow-up time, we analyzed retrospective data from patients aged ≥20 years with cHL that was diagnosed between 1983 and 2005 in the Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was applied to analyze the non-CSD occurrence in relation to all factors. Using Fine-Gray's method, we calculated the cumulative incidences of CSD and non-CSD. Stacked cumulative incidence plots and ratio of non-CSD to all causes of death were applied to evaluate the effect of non-CSD on rates of overall survival. Finally, we analyzed long-term mortality through Cox proportional hazard regression analysis and competing risk regression analysis to emphasize a more appropriate model of survival for patients with cHL. RESULTS: Among the 18,518 patients included, there were 3768 cases of CSD (20.3%) and 3217 of non-CSD (17.4%). Older age, earlier period, male sex, unmarried status, mixed cellularity (MC) and lymphocyte-depletion (LD) histological subtype, and patients received radiotherapy (RT) only were associated with more non-CSD according to binary logistic analysis. The cumulative incidence of non-CSD exceeded CSD after approximately 280 months follow-up. The most common causes of non-CSDs were cardiovascular disease, subsequent primary neoplasms, infectious diseases, accidents, and suicide. In a Cox proportional hazards model, patients who were black, unmarried, at an advanced stage or underwent chemotherapy (CT) alone were at greater risk of mortality than were white patients, who were married, at an early stage, and underwent combined modality; these populations were also found to be at greater risk for CSD in a competing risk model, but the risk of non-CSD did not differ significantly according to race and marital status, patients with early-stage disease and who underwent RT only were found to be at higher risk of non-CSD instead. CONCLUSIONS: Lymphoma was the cause of death in most patients who died, but non-CSD was not unusual. Patients with cHL should be monitored closely for signs of cardiovascular disease and malignant tumors. Rates of overall survival of patients were diminished by non-CSD, and a competing risk model was more suitable for establishing the prognosis than was the Cox proportional hazards model.


Assuntos
Causas de Morte/tendências , Doença de Hodgkin/mortalidade , Programa de SEER/estatística & dados numéricos , Adulto , Terapia Combinada , Feminino , Seguimentos , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
2.
Bone Marrow Transplant ; 56(12): 2940-2947, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34433917

RESUMO

Between 2008 and 2019, 58,914 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) throughout China. In this report, we focus on 2019 data and describe current trends in HSCT in China. There was continued growth in transplant activity in China, with a rapid increase in haploidentical HSCT. In 2019, a total of 12,323 cases of HSCT were reported from 149 transplant teams, 78% (9597 cases) were allogeneic HSCTs. Haploidentical donor (HID) HSCT accounted for 60% (5771 cases) of allogeneic HSCT. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (AML) (37%) and acute lymphoblastic leukemia (ALL) (24%), and the largest proportion of non-malignant diseases comprised aplastic anemia (AA) (13%). Multiple stem cell source composed 70% of HID and 28% of MSD, which was typical in China. The BuCy based regimen (59%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu based regimen (23%) and TBI-based regimen (12%). This survey clearly shows comprehensive information about the current state and recent trends for HSCT in China. Further efforts should be made to obtain detailed information.

3.
Cell Transplant ; 30: 9636897211033778, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34269100

RESUMO

Acute graft-versus-host disease (aGVHD) is one of the most common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Janus kinase (JAK) inhibitors are considered as reliable and promising agents for patients with aGVHD. The prophylactic and therapeutic effects of SHR0302, a novel JAK inhibitor, were evaluated in aGVHD mouse models. The overall survival (OS), progression-free survival (PFS), bodyweight of mice, GVHD scores were observed and recorded. The bone marrow and spleen samples of diseased model mice or peripheral blood of patients were analyzed. SHR0302 could prevent and reverse aGVHD in mouse models with preserving graft-versus-tumor effect. Functionally, SHR0302 improved the OS and PFS, restored bodyweight, reduced GVHD scores, and reduced immune cells infiltrated in target tissues. SHR0302 treatment also enhanced the hematopoietic reconstruction compared to the control group. Mechanistically, our results suggested that SHR0302 could inhibit the activation of T cells and modulate the differentiation of helper T (Th) cells by reducing Th1 and increasing regulatory T (Treg) cells. In addition, SHR0302 decreased the expression of chemokine receptor CXCR3 on donor T cells and the secretion of cytokines or chemokines including interleukin (IL)-6, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), CXCL10, etc. thereby destroying the IFN-γ/CXCR3/CXCL10 axis which promotes the progression of GVHD. Besides, SHR0302 decreased the phosphorylation of JAK and its downstream STATs, AKT and ERK1/2, which ultimately regulated the activation, proliferation, and differentiation of lymphocytes. Experiments on primary cells from aGVHD patients also confirmed the results. In summary, our results indicated that JAK inhibitor SHR0302 might be used as a novel agent for patients with aGVHD.

4.
Respir Physiol Neurobiol ; 293: 103720, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34146730

RESUMO

The pathogenesis of obstructive sleep apnea (OSA) remains controversial. The role of anatomic stenosis is indisputable, and neural regulation of the upper airway remains to be elucidated. The upper airway maintains patency through the upper airway reflex. Lesions in any link of the reflex can increase the collapsibility of the upper airway. In this study, we investigated sensorimotor nerve lesions and their possible relationship with OSA. Tissue samples were obtained from the pharyngopalatine arch in 47 patients with OSA and 45 control participants to examine changes in the expression levels of myelin basic protein (MBP) and agrin through immunohistochemistry and western blotting. Downregulation of MBP in the mucosa reflects myelinated degeneration of mucosal sensory nerve axons, whereas upregulation of agrin in the neuromuscular junction reflects synaptic regeneration following denervation. The two neural factors correlate significantly with polysomnographic parameters, such as the apnea hypopnea index and lowest oxygen saturation. Our findings suggest that sensorimotor nerve damage in the upper airway of patients with OSA may be associated closely with the mechanism of OSA.

5.
Ann Hematol ; 100(9): 2363-2373, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33988738

RESUMO

With the dramatic improvements in outcomes following alternative donor hematopoietic stem cell transplantation (HSCT), interest in the use of alternative donors in severe aplastic anemia (SAA) is increasing. We conducted a multicenter prospective study to explore the efficiency and safety of upfront HSCT from a 6-8/8 HLA-matched unrelated donor (MUD) or 6-7/8 HLA-matched related donor (MRD) in acquired SAA patients under 40 years. Between August 2014 and July 2017, 115 patients were enrolled, including 48 (41.7%) patients receiving grafts from an 8/8 MUD, 25 (21.7%) from a 6-7/8 MRD, and 42 (36.5%) from a 6-7/8 MUD. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was higher in the 6-7/8 MUD group than in the 8/8 MUD group (42.9% vs. 12.8%, P=0.001). The corresponding incidence in the 6-7/8 MRD group was comparable to that in the 8/8 MUD group (21.7% vs. 12.8%, P=0.332). There was no significant difference in the incidence of chronic GVHD (24.3%, 13.6%, and 17.9%, P=0.676), graft failure (2.4%, 8.0%, and 6.3%, P=0.551), overall survival (85.7%, 96.0%, and 87.5%, P=0.424), and failure-free survival (83.3%, 88.0%, and 83.3%, P=0.885) among the three groups (6-7/8 MUD, 6-7/8 MRD, and 8/8 MUD). In multivariate analysis, conditioning regimen without low-dose irradiation or busulfan was associated with an inferior failure-free survival (HR=2.973, P=0.042). In conclusion, after an intensified conditioning regimen with additional low-dose irradiation or busulfan, the outcome of HSCT from a 6-7/8 MRD or 6-7/8 MUD is comparable to that from an 8/8 MUD.


Assuntos
Anemia Aplástica/terapia , Bussulfano/uso terapêutico , Antígenos HLA/análise , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Histocompatibilidade , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
6.
Bone Marrow Transplant ; 56(10): 2423-2431, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34035462

RESUMO

The standard regimens for graft-versus-host disease (GvHD) prophylaxis in matched unrelated donor (MUD) transplantation were based on antithymocyte globulin (ATG) in combination with calcineurin inhibitors (CNIs). To improve the efficiency of GvHD prophylaxis in MUD peripheral blood stem cell transplantation (MUD-PBSCT), 51 patients with hematological malignancies received a novel regimen for GvHD prophylaxis, which is composed of low dose of ATG (5 mg/kg) plus low-dose posttransplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy) combined with cyclosporine A (CsA) and mycophenolate mofetil (MMF). The cumulative incidences (CIs) of grades I-IV and II-IV acute GvHD (aGvHD) were 14.5% (95% CI, 9.4-19.6%) and 6.2% (95% CI, 2.8-9.6%) within 100 days after transplantation, respectively. The CI of mild-to-moderate chronic GvHD (cGvHD) within 1 year was 11.5% (95% CI, 6.6-16.4%). The 1-year probabilities of GvHD and relapse-free survival, relapse-free survival, and over survival were 70.6% (95% CI, 64.2-77.0%), 76.5% (95% CI, 70.6-82.4%), and 82.0% (95% CI, 76.5-87.5%), respectively. The CIs of CMV and EBV reactivation by day 180 were 10.4% (95% CI, 1.5-19.4%) and 8.3% (95% CI, 0.2-16.4%), respectively. The results suggested that low-dose ATG/PTCy combined with CsA/MMF as GvHD prophylaxis in MUD-PBSCT had promising activity.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Soro Antilinfocitário/uso terapêutico , Ciclofosfamida , Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Ácido Micofenólico , Recidiva Local de Neoplasia , Condicionamento Pré-Transplante , Doadores não Relacionados
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 603-609, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812438

RESUMO

OBJECTIVE: To establish a mouse mixed chimerism (MC) model of nonmyeloablative allogeneic bone marrow transplantation(allo-BMT) and explore its affecting factors. METHODS: The MC model was established by nonmyeloablative allo-BMT followed by high-dose post-transplant cyclophosphamide (PTCY). 123 mice in the experiments was retrospectively analyzed, and the factors related with the chimerism were explored with the univariate and multivariate logistic regression analysis. A multivariate linear regression was performed by R project to obtain a mathematical model for predicting the chimeric level with relevant affecting factors. RESULTS: The model presented mixed chimerism on day 14 after transplantation, and was characterized by a donor lymphocyte infusion (DLI) which significantly promoted donor engraftment on day 15, but transfplantation of PBS in control group was failed. Among 123 mice, 47 (38.21%) mice were MC, while 76 (61.79%) mice were non-MC in 123 mice, respectively; univariate analysis showed that the baseline body weight of mice (P=0.001, 17.84±1.19 g vs 18.50±0.94 g), total body irradiation(TBI,P=0.048) and the using of cyclophosphamide (P=0.16) were affected the chimeric state of mice, while the number of infusing cells and the time of detection showed no significant effects. Multivariate regression analysis showed that under certain conditions, the body weight of mice on day 0 was an independent factor affecting chimeric levels (OR=0.493, 95% CI 0.307-0.791, P=0.003). Through R project multiple linear regression, the math model was achieved, which was chimerism=6.09-12×weight(g)+80.03×TBI(Gy)-4.4×cell-counts (× 107) +0.38×CTX (mg/kg), R2=0.5841, P<0.001. CONCLUSION: The experiment presents a method for establishing a mixed chimeric mice model after non-myeloablative bone marrow transplantation and constructs a mathematical model with relevant factors affected chimerism status.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Transplante de Medula Óssea , Camundongos , Estudos Retrospectivos , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante Homólogo
8.
Biochem Biophys Res Commun ; 552: 157-163, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33744764

RESUMO

ß-Thalassemia is an autosomal recessive genetic disease caused by defects in the production of adult hemoglobin (HbA, α2ß2), which leads to an imbalance between α- and non-α-globin chains. Reactivation of γ-globin expression is an effective strategy to treat ß-thalassemia patients. Previously, it was demonstrated that hemoglobin subunit beta pseudogene 1 (HBBP1) is associated with elevated fetal hemoglobin (HbF, α2γ2) in ß-thalassemia patients. However, the mechanism underlying HBBP1-mediated HbF production is unknown. In this study, using bioinformatics analysis, we found that HBBP1 is involved in γ-globin production, and then preliminarily confirmed this finding in K562 cells. When HBBP1 was overexpressed, γ-globin expression was increased at the transcript and protein levels in HUDEP-2 cells. Next, we found that ETS transcription factor ELK1 (ELK1) binds to the HBBP1 proximal promoter and significantly promotes its activity. Moreover, the synthesis of γ-globin was enhanced when ELK1 was overexpressed in HUDEP-2 cells. Surprisingly, ELK1 also directly bound to and activated the γ-globin proximal promoter. Furthermore, we found that HBBP1 and ELK1 can interact with each other in HUDEP-2 cells. Collectively, these findings suggest that HBBP1 can induce γ-globin by enhancing ELK1 expression, providing some clues for γ-globin reactivation in ß-thalassemia.


Assuntos
Regulação da Expressão Gênica , RNA Longo não Codificante/genética , Talassemia beta/genética , Proteínas Elk-1 do Domínio ets/genética , gama-Globinas/genética , Diferenciação Celular/genética , Linhagem Celular , Células Precursoras Eritroides/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Células K562 , Interferência de RNA , Talassemia beta/metabolismo , Proteínas Elk-1 do Domínio ets/metabolismo , gama-Globinas/metabolismo
9.
Accid Anal Prev ; 153: 106035, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33607319

RESUMO

In the field of traffic safety, the occurrence of accidents remains a cause of concern for road regulators as well as users. Exploring risk factors inducing the accidents and quantifying the accident risk will not only benefit the prevention and control of traffic accidents but also assist in developing effective risk propagation model for road accidents. This study uses detailed accident record data to mine the risk factors affecting the occurrence of accidents, and quantify the accident risk under the combination of risk factors. First, by reviewing relevant literature and analyzing historical accident, we construct a multi-dimension characterization framework of risk factors with bi-level structure. The Human Factors Analysis and Classification System (HFACS) is applied to supplement and improve the framework. Next, under this framework, we identify the risk factors in traffic accident record, and analyze the statistical characteristics from the level of risk sources and risk characteristics. Then, the concept of accident liability weight is proposed to measure the impact of risk factors on accident occurrence. Through the liability affirmation of risk factors, the accident probability are updated. Last, we establish an accident risk quantify model (ARQM) based on the mean mutual information to compare the likelihood of accidents in different scenarios. In addition, we compare the accident probability and risk under equivalent liability and liability affirmation, as well as give some fundamental ideas regarding how to effectively prevent accidents.


Assuntos
Acidentes de Trânsito , Análise Fatorial , Humanos , Fatores de Risco
10.
Nat Commun ; 12(1): 20, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397932

RESUMO

Drug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Centrossomo/metabolismo , Recidiva Local de Neoplasia/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Instabilidade Cromossômica , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Humanos , Camundongos , Recidiva Local de Neoplasia/patologia , Fosforilação , Fosfosserina/metabolismo
12.
Adv Healthc Mater ; 9(20): e2001032, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32902190

RESUMO

Systemic antibiotic therapy is the main treatment for acute bacterial rhinosinusitis (ABRS). However, this treatment often causes side effects of dizziness, diarrhea, and drug resistance. In this study, a new polyethylene glycol hydrogel (PEG-H) treatment model is developed to achieve sustained release of drugs at the locality while avoiding those adverse effects. The PEG-H is composed of 4-arm-PEG-SH and silver ions through a high affinity and dynamic reversible coordination bond between the thiol and silver ion. In the initial test, PEG-H is loaded with Clarithromycin (CAM-Lips@Hydrogel) or Clarithromycin and Budesonide liposomes (CAM+BUD-Lips@Hydrogel). The results show that PEG-H maintains the characteristics of self-healing, biodegradability, moderate swelling rate, injectibility and sustained drug release. In in vivo studies, the hydrogel is injected into the maxillary sinus of ABRS rabbit models. In both a single or combined load, the hydrogel not only plays an effective role as an anti-bacterial, but also inhibits inflammatory response of local sinus mucosa. In addition, no other side effects are observed in the ABRS rabbit model through behavioral observation and drug sensitivity tests. Therefore, the injectable self-healing hydrogel with anti-bacterial and anti-inflammatory properties provides a new micro invasive therapeutic method for the clinical treatment of ABRS.


Assuntos
Hidrogéis , Polietilenoglicóis , Animais , Anti-Inflamatórios/farmacologia , Materiais Biocompatíveis , Liberação Controlada de Fármacos , Coelhos
13.
Front Oncol ; 10: 829, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32637351

RESUMO

Fms-like tyrosine kinase 3 (FLT3) mutation is one of the most common mutations in acute myeloid leukemia (AML). However, the effect of FLT3 mutation on survival is currently still controversial and the leukemogenic mechanisms are still under further investigation. The aim of our study is to identify differentially expressed genes (DEGs) in FLT3-mutant AML and to find crucial DEGs whose expression level is related to prognosis for further analysis. By mining the TCGA-LAML dataset, 619 differentially expressed lncRNAs (DElncRNAs) and 1,428 differentially expressed mRNAs (DEmRNAs) were identified between FLT3-mutant and FLT3-wildtype samples. Through weighted gene correlation network analysis (WGCNA) and the following Cox proportional hazards regression analysis, we constructed the prognostic risk models to identify the hub DElncRNAs and DEmRNAs associated with AML prognosis. The presence of both SH3TC2 divergent transcript (SH3TC2-DT) and SH3TC2 in respective prognostic risk models promotes us to further study the significance of this gene pair in AML. SH3TC2-DT and SH3TC2 were identified to be coordinately high expressed in FLT3-mutant AML samples. High expression of this gene pair was associated with poor survival. Using logistic regression analysis, we found that high SH3TC2-DT/SH3TC2 expression was associated with FLT3 mutation, high WBC count, and intermediate cytogenetic and molecular-genetic risk. AML with SH3TC2-DT/SH3TC2 high expression showed enrichment of transcripts associated with stemness, quiescence, and leukemogenesis. Our study suggests that the SH3TC2-DT/SH3TC2 gene pair may be a possible biomarker to further optimize AML prognosis and may function in stemness or quiescence of FLT3-mutant leukemic stem cells (LSCs).

14.
J Hematol Oncol ; 13(1): 42, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366260

RESUMO

BACKGROUND: Consolidative allogeneic hematopoietic stem cell transplantation is a controversial option for patients with relapsed/refractory acute lymphoblastic leukemia after chimeric antigen receptor T cell (CAR-T) therapy. We performed a multicenter retrospective study to assess whether patients can benefit from haploidentical hematopoietic stem cell transplantation after CAR-T therapy. METHODS: A total of 122 patients after CAR-T therapy were enrolled, including 67 patients without subsequent transplantation (non-transplant group) and 55 patients with subsequent haploidentical hematopoietic stem cell transplantation (transplant group). Long-term outcome was assessed, as was its association with baseline patient characteristics. RESULTS: Compared with the non-transplant group, transplantation recipients had a higher 2-year overall survival (OS; 77.0% versus 36.4%; P < 0.001) and leukemia-free survival (LFS; 65.6% versus 32.8%; P < 0.001). Multivariate analysis showed that minimal residual disease (MRD) positivity at transplantation is an independent factor associated with poor LFS (P = 0.005), OS (P = 0.035), and high cumulative incidence rate of relapse (P = 0.045). Pre-transplant MRD-negative recipients (MRD- group) had a lower cumulative incidence of relapse (17.3%) than those in the non-transplant group (67.2%; P < 0.001) and pre-transplant MRD-positive recipients (MRD+ group) (65.8%; P = 0.006). The cumulative incidence of relapse in MRD+ and non-transplant groups did not differ significantly (P = 0.139). The 2-year LFS in the non-transplant, MRD+, and MRD- groups was 32.8%, 27.6%, and 76.1%, respectively. The MRD- group had a higher LFS than the non-transplantation group (P < 0.001) and MRD+ group (P = 0.007), whereas the LFS in the MRD+ and non-transplant groups did not differ significantly (P = 0.305). The 2-year OS of the MRD- group was higher than that of the non-transplant group (83.3% versus 36.4%; P < 0.001) but did not differ from that of the MRD+ group (83.3% versus 62.7%; P = 0.069). The OS in the non-transplant and MRD+ groups did not differ significantly (P = 0.231). CONCLUSION: Haploidentical hematopoietic stem cell transplantation with pre-transplant MRD negativity after CAR-T therapy could greatly improve LFS and OS in patients with relapsed/refractory acute lymphoblastic leukemia. TRIAL REGISTRATION: The study was registered in the Chinese clinical trial registry (ChiCTR1900023957).


Assuntos
Recidiva Local de Neoplasia/terapia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Criança , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prognóstico , Estudos Retrospectivos , Transplante Haploidêntico , Resultado do Tratamento , Adulto Jovem
15.
J Leukoc Biol ; 107(5): 859-870, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32293060

RESUMO

The majority of acute myeloid leukemia (AML) patients will respond to standard chemotherapy, however, resistance is a prevalent problem contributing to incomplete responses, refractory disease, and ultimately patient death. Therefore, choosing more sensitive and effective chemotherapy regimens is of key clinical importance. In order to explore this issue, we investigated and optimized PharmaFlow, an automated flow cytometry method for evaluating the sensitivity of leukemia cells to multiple chemotherapeutic drugs ex vivo. We examined bone marrow samples from 38 Chinese AML patients and incubated them for 48 or 72 h with a panel of 7 single drugs and 6 combinations with cytarabine at different concentrations. Leukemic cell depletion was assessed by PharmaFlow and drug response parameter, called PharmaFlow score, was estimated using population pharmacodynamic models. We identified that most chemotherapeutic drugs and combinations could effectively eliminate pathological cells ex vivo. Estimated drug activities strongly correlated with the patients' duration to achieve clinical remission and PharmaFlow chemosensitivity measured ex vivo was highly predictive of the clinical outcome after chemotherapy. Applying a classification model, we determined a PharmaFlow score of 89.4 as the threshold to predict response to chemotherapy. Using this threshold, we found that in 84.2% of cases patient's cell response ex vivo predicted the observed clinical response and performed similarly or better than prognostic subgroups determined by cytogenetic characteristics. PharmaFlow has the potential to predict chemosensitivity for de novo, secondary and relapsed AML patients prior to treatment and may guide clinicians to tailor treatments and improve patient outcome.


Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Citometria de Fluxo/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Oncol Rep ; 43(1): 113-120, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789418

RESUMO

Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem in patients with chronic myelogenous leukemia (CML). Homoharringtonine (HHT) is an approved treatment for adult patients with chronic­ or accelerated­phase CML who are resistant to TKIs and other therapies; however, the underlying mechanisms remain unclear. In the present study, HHT treatment demonstrated induction of apoptosis in imatinib­resistant K562G cells by using MTS assay and western blotting, and BCR­ABL protein was reduced. CHX chase assay revealed that HHT induced degradation of the BCR­ABL protein, which could be reversed by autophagy lysosome inhibitors Baf­A1 and CQ. Next, HHT treatment confirmed the induction of autophagy in K562G cells, and silencing the key autophagic proteins ATG5 and Beclin­1 inhibited the degradation of the BCR­ABL protein and cytotoxicity. In addition, autophagic receptor p62/SQSTM1(p62) participated during the autophagic degradation of BCR­ABL induced by HHT, and this was confirmed by co­immunoprecipitation, in which HHT enhanced the ubiquitination of the BCR­ABL protein and promoted its binding to p62. In conclusion, HHT induced p62­mediated autophagy in imatinib­resistant CML K562G cells, thus promoting autophagic degradation of the BCR­ABL protein and providing a novel strategy for the treatment of TKI­resistant CML.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteínas de Fusão bcr-abl/química , Mepesuccinato de Omacetaxina/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas de Ligação a RNA/metabolismo , Autofagia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
17.
Ann Hematol ; 98(7): 1765-1773, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30993416

RESUMO

To investigate the effect of chronic graft-versus-host disease (cGVHD) on the outcomes of acute myeloid leukemia (AML) patients who relapsed after allogenic hematopoietic cell transplantation, we performed a retrospective analysis on 218 patients with a median follow-up of 21.4 (3.4-179.6) months. A total of 103 patients developed cGVHD, with a 2-year cumulative incidence of 48.9% (95% CI 42.1-55.7%). The estimated 3-year overall survival was 85.7% (95% CI 75.7-95.7%), 48.8% (95% CI 31.7-66.0%), and 54.1% (95% CI 44.3-63.8%) for patients with limited cGVHD, extensive cGVHD, and without cGVHD (P < 0.001). The 3-year event-free survival were 75.5% (95% CI 63.7-87.4%), 46.0% (95% CI 28.8-63.2%), and 45.0% (95% CI 35.6-54.4%) (P < 0.001), while the 3-year cumulative relapse rates were 22.8% (95% CI 11.0-34.6%), 11.6% (95% CI 5.3-22.6%), and 40.3% (95% CI 31.0-49.6%), respectively (P < 0.001). At the last evaluation, 62 patients relapsed with 17 patients having active cGVHD and 45 without. Compared to patients relapsing without cGVHD, patients who relapsed with cGVHD had a longer duration of remission and a better 2-year post-relapse survival [10.9 months (3.7-42.2) versus 4.4 months (2.2-28.3); P < 0.001]; [32.8% (95% CI 8.2-57.4%) versus 4.5% (95% CI 0-12.8%); P = 0.043]. For patients who relapsed with cGVHD, the remission rates were both 60% after salvage chemotherapy with or without donor lymphocyte infusion (P = 1.000). In conclusion, cGVHD may exert a stronger graft-versus-leukemia effect, which may decrease the post-transplantation relapse rate and may also benefit those patients who eventually relapsed after transplantation in terms of prolong post-relapse survival.


Assuntos
Doença Enxerto-Hospedeiro , Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transfusão de Linfócitos , Adolescente , Adulto , Doença Crônica , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Humanos , Incidência , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida
18.
Ann Hematol ; 98(4): 823-831, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30715566

RESUMO

To evaluate the strategy of using high-dose etoposide mobilization followed by autologous peripheral blood stem cell transplantation (APBSCT) in patients with diffuse large B cell lymphoma (DLBCL) refractory to rituximab-based chemotherapy. Forty patients with refractory DLBCL were treated with high-dose etoposide for stem cell mobilization. All patients were in progressive disease (PD) prior to mobilization and underwent high-dose chemotherapy followed by APBSCT. Successful PBSC mobilization was achieved in all patients. Twenty-three patients (57.5%) showed a clinical response to high-dose etoposide. After APBSCT, 17 patients (42.5%) achieved CR. The 2-year progression-free (PFS) and overall survival (OS) rate were higher in patients responding to high-dose etoposide (64.1% and 77.7%) compared to those without response (11.8% and 11.8%; P < 0.001 for both). The response to high-dose etoposide mobilization therapy was an independent prognostic factor for CR achievement, PFS and OS after APBSCT. High-dose etoposide mobilization chemotherapy followed by APBSCT could rescue a proportion of patients with refractory DLBCL who responded to etoposide mobilization regimen.


Assuntos
Etoposídeo/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B/terapia , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Autoenxertos , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Rituximab/administração & dosagem , Taxa de Sobrevida
19.
Blood Adv ; 3(4): 644-657, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30804018

RESUMO

Enhanced understanding of normal and malignant hematopoiesis pathways should facilitate the development of effective clinical treatment strategies for hematopoietic malignancies. Nuclear receptor corepressor 1 (NCoR1) has been implicated in transcriptional repression and embryonic organ development, but its role in hematopoiesis is yet to be fully elucidated. Here, we showed that hematopoietic-specific loss of NCoR1 leads to expansion of the hematopoietic stem cell (HSC) pool due to aberrant cell cycle entry of long-term HSCs under steady-state conditions. Moreover, NCoR1-deficient HSCs exhibited normal self-renewal capacity but severely impaired lymphoid-differentiation potential in competitive hematopoietic-reconstitution assays. Transcriptome analysis further revealed that several hematopoiesis-associated genes are regulated by NCoR1. In addition, NCoR1 deficiency in hematopoietic cells delayed the course of leukemia and promoted leukemia cell differentiation in an MLL-AF9-induced mouse model. NCoR1 and its partner, histone deacetylase 3, can modulate histone acetylation and gene transcription through binding the promoter regions of myeloid-differentiation genes. Our collective results support the critical involvement of NCoR1 in normal and malignant hematopoiesis in vivo.


Assuntos
Deleção de Genes , Hematopoese , Leucemia/genética , Correpressor 1 de Receptor Nuclear/genética , Animais , Proliferação de Células , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Leucemia/metabolismo , Leucemia/patologia , Leucopoese , Camundongos , Camundongos Endogâmicos C57BL , Correpressor 1 de Receptor Nuclear/metabolismo
20.
Bone Marrow Transplant ; 54(7): 1049-1057, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30446741

RESUMO

Nowadays, the most wildly used regimens for graft-versus-host disease (GvHD) prophylaxis in haplo-hematopoietic stem cell transplantation (Haplo-HSCT) are based on in vivo T-cell depletion (TCD) with anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy). To improve the efficiency of GvHD prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood (Haplo-PBSCT-Cord), a novel regimen, which is composed of low dose of ATG (5 mg/kg) and low-dose PTCy (50 mg/kg) for GvHD prophylaxis, was evaluated in a prospective phase II clinical trial (Clinicaltrials.org NCT03395860). Thirty-two patients diagnosed with hematological malignancies were enrolled in this trial. All patients received myeloablative conditioning regimens except for three patients. The cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD were 19.4% (95% CI, 5.5-33.3%) and 6.9% (95% CI, 0-16.3%) by day 100, respectively. The 1-year probability of relapse, disease free survival (DFS) and overall survival (OS) was 25.1% (95% CI, 7.3-42.9%), 59% (95% CI, 33.3-84.7%) and 78.4% (95% CI, 63-93.8%), respectively. The CIs of CMV and EBV reactivation by day 180 were 37.5% (95% CI, 19.8-55.2%) and 40.6% (95% CI, 22.6-58.6%), respectively. The results suggested that low-dose ATG with low-dose PTCy as GvHD prophylaxis in Haplo-PBSCT-Cord had promising activity.


Assuntos
Soro Antilinfocitário/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco de Sangue Periférico , Doadores não Relacionados , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida
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