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1.
Cell Mol Immunol ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017718

RESUMO

Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

2.
Signal Transduct Target Ther ; 6(1): 401, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34848680

RESUMO

Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

3.
Br J Haematol ; 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34741461

RESUMO

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P < 0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P = 0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

5.
Int J Med Sci ; 18(15): 3498-3505, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522176

RESUMO

Sox transcription factors play many diverse roles during development, including regulating stem cell states, directing differentiation, and influencing the local chromatin landscape. Sox10 has been implicated in the control of stem/progenitor activity and epithelial-mesenchymal transition, yet it has not been studied in relation to the hair follicle cycle or hair follicle stem cell (HFSC) control. To elucidate the role of Sox10 in hair follicle cycle control, we performed immunohistochemical and immunofluorescence analysis of its expression during hair morphogenesis, the postnatal hair cycle, and the depilation-induced murine hair follicle cycle. During hair follicle morphogenesis, Sox10 was expressed in the hair germ and peg. In telogen, we detected nuclear Sox10 in the hair bulge and germ cell cap, where HFSCs reside, while in anagen and catagen, Sox10 was detected in the epithelial portion, such as the strands of keratinocytes, the outer root sheath (ORS) in anagen, and the regressed epithelial strand of hair follicle in catagen. These results suggest that Sox10 may be involved in early hair follicle morphogenesis and postnatal follicular cycling.

7.
Int J Ophthalmol ; 14(9): 1334-1344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540608

RESUMO

AIM: To illustrate the underlying mechanism how prominin-1 (also known as Prom1) mutation contribute to progressive photoreceptor degeneration. METHODS: A CRISPR-mediated Prom1 knockout (Prom1-KO) mice model in the C57BL/6 was generated and the photoreceptor degeneration phenotypes by means of structural and functional tests were demonstrated. Immunohistochemistry and immunoblot analysis were performed to reveal the localization and quantity of related outer segment (OS) proteins. RESULTS: The Prom1-KO mice developed the photoreceptor degeneration phenotype including the decreased outer nuclear layer (ONL) thickness and compromised electroretinogram amplitude. Immunohistochemistry analysis revealed impaired trafficking of photoreceptor OS proteins. Immunoblot data demonstrated decreased photoreceptor OS proteins. CONCLUSION: Prom1 deprivation causes progressive photoreceptor degeneration. Prom1 is essential for maintaining normal trafficking and normal quantity of photoreceptor OS proteins. The new light is shed on the pathogenic mechanism underlying photoreceptor degeneration caused by Prom1 mutation.

8.
Int J Ophthalmol ; 14(8): 1160-1167, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34414078

RESUMO

AIM: To explore an xeno-free and defined coating substrate suitable for the culture of H9 human embryonic stem cell-derived retinal pigment epithelial (hES-RPE) cells in vitro, and compare the behaviors and functions of hES-RPE cells on two culture substrates, laminin521 (LN-521) and truncated recombinant human vitronectin (VTN-N). METHODS: hES-RPE cells were used in the experiment. The abilities of LN-521 and VTN-N at different concentrations to adhere to hES-RPE cells were compared with a high-content imaging system. Quantitative real-time polymerase chain reaction was used to evaluate RPE-specific gene expression levels midway (day 10) and at the end (day 20) of the time course. Cell polarity was observed by immunofluorescent staining for apical and basal markers of the RPE. The phagocytic ability of hES-RPE cells was identified by flow cytometry and immunofluorescence. RESULTS: The cell adhesion assay showed that the ability of LN-521 to adhere to hES-RPE cells was dose-dependent. With increasing coating concentration, an increasing number of cells attached to the surface of LN-521-coated wells. In contrast, VTN-N presented a strong adhesive ability even at a low concentration. The optimal concentration of LN-521 and VTN-N required to coat and adhesion to hES-RPE cells were 2 and 0.25 µg/cm2, respectively. Furthermore, both LN-521 and VTN-N could facilitate adoption of the desired cobblestone cellular morphology with tight junction and showed polarity by the hES-RPE cells. However, hES-RPE cells cultivated in VTN-N had a greater phagocytic ability, and it took less time for these hES-RPE cells to mature. CONCLUSION: VTN-N is a more suitable coating substrate for cultivating hES-RPE cells.

9.
Bone Marrow Transplant ; 56(11): 2723-2731, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34239051

RESUMO

The objective of this study was to compare clinical outcomes between noninherited maternal antigen (NIMA)-mismatched and noninherited paternal antigen (NIPA)-mismatched haploidentical hematopoietic stem cell transplantation (haplo-HSCT) among patients with hematological malignancies and perform a subgroup analysis. We retrospectively analyzed 378 patients with hematological malignancies who received haplo-HSCT from NIMA-mismatched (n = 201) and NIPA-mismatched (n = 177) donors between January 2012 and December 2017. The cumulative incidence of 100-d grades II-IV acute graft-versus-host disease (aGVHD) (19.2% vs. 32.8%, P = 0.003) was significantly lower in NIMA mismatch. Multivariate analysis showed that NIMA mismatch was associated with lower incidence of grades II-IV aGVHD and better overall survival (OS) and disease-free survival (DFS). According to the subgroup analysis, the clinical outcomes of older and/or female NIMA mismatches were comparable to those of younger and/or male NIPA mismatches with respect to grades II-IV aGVHD, chronic GVHD (cGVHD), nonrelapse mortality (NRM), relapse, DFS, and OS. In conclusion, this study confirmed the NIMA effect on aGVHD and demonstrated that NIMA mismatch was associated with better survival. In the NIMA mismatch context, donor age and sex did not seem to influence haplo-HSCT, which provides a basis for the selection of sibling donors.

11.
Transplant Cell Ther ; 27(10): 870.e1-870.e7, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34229053

RESUMO

Late-onset severe pneumonia (LOSP) is defined as severe pneumonia developing during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because of the high mortality in patients with LOSP, it is important to identify prognostic factors. In this study, we aimed to develop a risk score system with broad applicability that can help predict the risk of LOSP-associated mortality. We retrospectively analyzed 100 patients with LOSP after allo-HSCT between June 2009 and July 2017. The assessment variables included immune, nutritional, and metabolic parameters at the onset of LOSP. Of these 100 patients, 45 (45%) eventually died, and 55 (55%) were positive for organisms, most commonly viruses. In the multivariate analysis, higher monocyte count (≥0.20 × 109/L versus <0.20 × 109/L; P = .001), higher albumin level (≥30.5 g/L versus <30.5 g/L; P = .044), lower lactic dehydrogenase level (<250 U/L versus ≥250 U/L; P = .008) and lower blood urea nitrogen concentration (<7.2 mmol/L versus ≥7.2 mmol/L; P = .026) at the onset of LOSP were significantly associated with better 60-day survival. A risk score system based on the foregoing results showed that the probability of 60-day survival decreased with increasing risk factors, from 96.3% in the low-risk group to 49.1% in the intermediate-risk group and 12.5% in the high-risk group. Our results indicate that this scoring system using 4 variables can stratify patients with different probabilities of survival after LOSP, which suggests that patients' immune, nutritional, and metabolic status are crucial factors in determining outcome.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Pneumonia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pneumonia/diagnóstico , Prognóstico , Estudos Retrospectivos , Transplante Homólogo
12.
Curr Med Sci ; 41(3): 443-453, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34185250

RESUMO

We performed a retrospective analysis to investigate dynamic peri-hematopoietic stem cell transplantation (HSCT) minimal/measurable residual disease (MRD) on outcomes in patients with T-cell acute lymphoblastic leukemia (T-ALL). A total of 271 patients were enrolled and classified into three groups: unchanged negative MRD pre- and post-HSCT group (group A), post-MRD non-increase group (group B), and post-MRD increase group (group C). The patients in group B and group C experienced a higher cumulative incidence of relapse (CIR) (42% vs. 71% vs. 16%, P<0.001) and lower leukemia-free survival (LFS) (46% vs. 21% vs. 70%, P<0.001) and overall survival (OS) (50% vs. 28% vs. 72%, P<0.001) than in group A, but there was no significant difference in non-relapse mortality (NRM) among three groups (14% vs. 12% vs. 8%, P=0.752). Multivariate analysis showed that dynamic peri-HSCT MRD was associated with CIR (HR=2.392, 95% CI, 1.816-3.151, P<0.001), LFS (HR=1.964, 95% CI, 1.546-2.496, P<0.001) and OS (HR=1.731, 95% CI, 1.348-2.222, P<0.001). We also established a risk scoring system based on dynamic peri-HSCT MRD combined with remission status pre-HSCT and onset of chronic graft-versus-host disease (GVHD). This risk scoring system could better distinguish CIR (c=0.730) than that for pre-HSCT MRD (c=0.562), post-HSCT MRD (c=0.616) and pre- and post-MRD dynamics (c=0.648). Our results confirm the outcome predictive value of dynamic peri-HSCT MRD either alone or in combination with other variables for patients with T-ALL.

13.
Front Med (Lausanne) ; 8: 604085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34150785

RESUMO

Graft failure (GF) is a fatal complication of allogeneic stem cell transplantation, especially after haploidentical transplantation. The mortality of GF is nearly 100% without an effective salvage method. A second transplantation is usually necessary to save the patient's life. However, there is no standardized regimen, and the outcome is usually disappointing. We report on a prospective single-center study using a reduced-intensity conditioning regimen with different haploidentical donors (HIDs). Patients with GF after the first transplantation were enrolled in a prospective single-arm clinical trial (ClinicalTrials.Gov ID: NCT03717545) at the Peking University Institute of Hematology. The conditioning regimen consisted of fludarabine (30 mg/m2) (days-6 to-2) and cyclophosphamide (1,000 mg/m2/day) (days-5 to-4). Patients underwent a second transplant from a different HID using a granulocyte colony-stimulating factor primed bone marrow and peripheral blood stem cells. The primary outcome was neutrophil engraftment at day 28. The secondary outcomes included platelet engraftment at day 100, transplant-related mortality (TRM) at day 30, TRM at day 100, and overall survival (OS) at 1 year. From March 2018 to June 2020, 13 patients were enrolled in this clinical trial. Of the 13 patients, five had acute myeloid leukemia, five had acute lymphoblastic leukemia, two had myelodysplastic syndromes, and one had a non-Hodgkin lymphoma. The median age at first transplantation was 38 years (range, 8-55 years). As for the first transplantation, 11 patients underwent haploidentical transplantations and two underwent unrelated donor transplantations. At the time of GF, three patients had complete donor chimerism, five had mixed chimerism, and five had complete recipient chimerism. The median time from the first transplantation to the second transplantation was 49 (range 35-120) days. The medians of infused cell doses were as follows: mononuclear cells 7.93 (5.95-12.51) × 108/kg and CD34 + cells 2.28 (0.75-5.57) × 106/kg. All 13 patients achieved neutrophil engraftment after the second transplantation, with a median engraftment time of 11 (range 10-20) days after transplantation. The platelet engraftment rate on day 100 after transplantation was 76.9%. The TRMs at day 30, day 100, and 1-year were 0, 0, and 23.1%, respectively. The OS and disease-free survival at 1-year were 56.6 and 48.4%, respectively. For patients with GF after first transplantation, a second transplantation using a fludarabine/cyclophosphamide regimen from a different HID was a promising salvage option. Further investigation is needed to confirm the suitability of this method.

14.
Front Physiol ; 12: 653601, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177611

RESUMO

Aims: We examined the change in endogenous hydrogen sulfide (H2S) production and its role in sepsis-induced myocardial dysfunction (SIMD). Results: Significant elevations in plasma cardiac troponin I (cTnI), creatine kinase (CK), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) were noted in SIMD patients, whereas left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and plasma H2S were significantly decreased relative to those in the controls. Plasma H2S was linearly related to LVEF and LVFS. Subsequently, an SIMD model was developed in mice by injecting lipopolysaccharide (LPS), and NaHS, an H2S donor, was used to elucidate the pathophysiological role of H2S. The mice showed decreased ventricular function and increased levels of TNF-α, IL-1ß, cTnI, and CK after LPS injections. Toll-like receptor (TLR) 4 protein and endoplasmic reticulum stress (ERS) proteins were over expressed in the SIMD mice. All of the parameters above showed more noticeable variations in cystathionine γ-lyase knockout mice relative to those in wild type mice. The administration of NaHS could improve ventricular function and attenuate inflammation and ERS in the heart. Conclusion: Overall, these findings indicated that endogenous H2S deficiency contributed to SIMD and exogenous H2S ameliorated sepsis-induced myocardial dysfunction by suppressing inflammation and ERS via inhibition of the TLR4 pathway.

15.
Nat Commun ; 12(1): 2672, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976130

RESUMO

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.


Assuntos
Antígenos B7/metabolismo , Fucosiltransferases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antígenos B7/genética , Linhagem Celular Tumoral , Feminino , Fucose/metabolismo , Fucosiltransferases/genética , Técnicas de Inativação de Genes , Glicosilação , Células HEK293 , Humanos , Imunidade , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos SCID , Polissacarídeos/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Autophagy ; : 1-18, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33977871

RESUMO

Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer.Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol 3-kinase UPS: ubiquitin-proteasome system.

17.
Bone Marrow Transplant ; 56(9): 2097-2107, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33846561

RESUMO

Diffuse alveolar haemorrhage (DAH) is a life-threatening pulmonary complication occurring after allogeneic haematopoietic stem cell transplantation (allo-HSCT) without an explicit aetiology or a standard treatment. This study aimed to explore the occurrence and prognosis of DAH after allo-HSCT, in addition to comparing discrepancies in the incidence, clinical characteristics and outcomes of DAH between patients undergoing haploidentical HSCT (HID-HSCT) and matched related donor HSCT (MRD-HSCT). We retrospectively evaluated 92 consecutive patients among 3987 patients with a confirmed diagnosis of DAH following allo-HSCT (HID: 71 patients, MRD: 21 patients). The incidence of DAH after allo-HSCT was 2.3%, 2.4% after HID-HSCT and 2.0% after MRD-HSCT (P = 0.501). The prognosis of patients with DAH after transplantation is extremely poor. The duration of DAH was 7.5 days (range, 1-48 days). The probabilities of overall survival (OS) were significantly different between patients with and without DAH within 2 years after transplantation (P < 0.001). According to the Cox regression analysis, a significant independent risk factor for the occurrence of DAH was delayed platelet engraftment (P < 0.001), and a high D-dimer level (>500 ng/ml) was a significant risk factor for the poor prognosis of DAH. HID-HSCT is similar to MRD-HSCT in terms of the outcomes of DAH.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemorragia/etiologia , Humanos , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos
18.
Oncogene ; 40(13): 2422-2436, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664452

RESUMO

Polycomb repressor complex 1 (PRC1) is linked to the regulation of gene expression and histone ubiquitylation conformation, which contributes to carcinogenesis. However, the upstream regulators of PRC1 biogenesis machinery remain obscure. Here, we report that the polycomb group-related mammalian gene Mel18 is a target of the protein kinase AKT. AKT phosphorylates Mel18 at T334 to disrupt the interaction between Mel18 and other PRC1 members, leading to attenuated PRC1-dependent ubiquitylation of histone H2A at Lys119. As such, PRC1 target genes, many of which are known oncogenes, are derepressed upon T334-Mel18 phosphorylation, which promotes malignant behaviours, including cell proliferation, tumour formation, migration and invasion, bone and brain metastatic lesion formation. Notably, a positive correlation between AKT activity and pT334-Mel18 is observed, and prognostic models based on p-AKT and pT334-Mel18 that predicted overall survival and distant metastasis-free survival in breast cancer patients are established. These findings have implications for understanding the role of AKT and its associated proteins in chromatin ubiquitylation, and also indicate the AKT-Mel18-H2AK119ub axis as a novel prognostic biomarker and therapeutic target for cancer patients.


Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Proliferação de Células , Cromatina , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Histonas/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Ubiquitinação/genética
19.
Chin Med J (Engl) ; 134(10): 1199-1208, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33734137

RESUMO

BACKGROUND: For patients with B cell acute lymphocytic leukemia (B-ALL) who underwent allogeneic stem cell transplantation (allo-SCT), many variables have been demonstrated to be associated with leukemia relapse. In this study, we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT. METHODS: A total of 477 patients with B-ALL who underwent allo-SCT at Peking University People's Hospital from December 2010 to December 2015 were enrolled in this retrospective study. We aimed to evaluate the factors associated with transplant outcomes after allo-SCT, and establish a risk score to identify patients with different probabilities of relapse. The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables. RESULTS: All patients achieved neutrophil engraftment, and 95.4% of patients achieved platelet engraftment. The 5-year cumulative incidence of relapse (CIR), overall survival (OS), leukemia-free survival (LFS), and non-relapse mortality were 20.7%, 70.4%, 65.6%, and 13.9%, respectively. Multivariate analysis showed that patients with positive post-transplantation minimal residual disease (MRD), transplanted beyond the first complete remission (≥CR2), and without chronic graft-versus-host disease (cGVHD) had higher CIR (P  < 0.001, P = 0.004, and P  < 0.001, respectively) and worse LFS (P  < 0.001, P = 0.017, and P  < 0.001, respectively), and OS (P  < 0.001, P = 0.009, and P  < 0.001, respectively) than patients without MRD after transplantation, transplanted in CR1, and with cGVHD. A risk score for predicting relapse was formulated with the three above variables. The 5-year relapse rates were 6.3%, 16.6%, 55.9%, and 81.8% for patients with scores of 0, 1, 2, and 3 (P  < 0.001), respectively, while the 5-year LFS and OS values decreased with increasing risk score. CONCLUSION: This new risk score system might stratify patients with different risks of relapse, which could guide treatment.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfócitos B , Humanos , Recidiva , Estudos Retrospectivos , Fatores de Risco , Transplante de Células-Tronco
20.
Front Oncol ; 11: 639502, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33718234

RESUMO

Objective: Haploidentical stem cell transplantation (haplo-SCT) has demonstrated encouraging results in younger patients. There is also an increasing need for haplo-SCT in older patients. However, the high risk of treatment-related mortality (TRM) in older patients is still a major concern. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-SCT in older patients. Method: This prospective, single-arm clinical trial was performed at Peking University Institute of Hematology, China. Patients were enrolled if they were (1) diagnosed with acute leukemia or MDS; (2) without MSD and MUD, and with HID available; and (3) age ≥55 years. The Bu/Flu/Cy/ATG regimen consisted of the following agents: Ara-C (2 g/m2/day, injected i.v.) on days-10 and-9; BU (9.6 mg/kg, injected i.v. in 12 doses) on days-8,-7, and-6; Flu (30 mg/m2/day, injected i.v.) from day-6 to day-2; Cy (1 g/m2/day, injected i.v.) on days-5 and-4; semustine (250 mg/m2, orally) on day-3 and antithymocyte globulin (ATG) [2.5 mg/kg/day, rabbit, SangStat (Lyon, France)] on days-5,-4,-3, and-2. The primary endpoint was 1-year TRM. Results: From April 1, 2018 to April 10, 2020, a total of 50 patients were enrolled. All patients achieved neutrophil engraftment with complete donor chimerism. The cumulative incidence of grade 2-4 aGVHD at day-100 was 22.0%. The cumulative incidences of CMV viremia and EBV viremia on day 100 were 68.0 and 20.0%, respectively. The cumulative incidence of TRM at 1-year was 23.3%. and the cumulative incidence of relapse (CIR) at 1 year after transplantation was 16.5%. The overall survival (OS) and leukemia-free survival (LFS) at 1 year were 63.5 and 60.2%, respectively. The outcomes were also comparable with patients who received Bu/Cy/ATG regimen using a propensity score matching method. Conclusions: In conclusion, this study suggested that a novel conditioning regimen followed by haploidentical HSCT might be a promising option for older patients. The study was registered as a clinical trial. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03412409.

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