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2.
Theranostics ; 11(16): 7879-7895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335970

RESUMO

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.


Assuntos
Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Timosina/farmacologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , China , Modelos Animais de Doenças , Células Endoteliais/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Regeneração , Transplante de Células-Tronco/métodos , Suínos , Timosina/metabolismo , Timosina/fisiologia
3.
Exp Anim ; 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34135271

RESUMO

Transverse aortic constriction (TAC) has been widely used to study cardiac hypertrophy, fibrosis, diastolic dysfunction, and heart failure in rodents. Few studies have been reported in preclinical animal models. The similar physiology and anatomy between non-human primates (NHPs) and humans make NHPs valuable models for disease modeling and testing of drugs and devices. In the current study, we aimed to establish a TAC model in NHPs and characterize the structural and functional profiles of the heart after TAC. A non-absorbable suture was placed around the aorta between the brachiocephalic artery and left common carotid artery to create TAC. NHPs were divided into 2 groups according to pressure gradient (PG): the Mild Group (PG=31.01 ± 12.40 mmHg, n=3) and the Moderate Group (PG=53.00 ± 9.37 mmHg, n=4). At 4 weeks after TAC, animals in both TAC groups developed cardiac hypertrophy: enlarged myocytes and increased wall thickness of the left ventricular (LV) anterior wall. Although both TAC groups had normal systolic function that was similar to a Sham Group, the Moderate Group showed diastolic dysfunction that was associated with more severe cardiac fibrosis, as evidenced by a reduced A wave velocity, large E wave velocity/A wave velocity ratio, and short isovolumic relaxation time corrected by heart rate. Furthermore, no LV arrhythmia was observed in either animal group after TAC. A diastolic dysfunction model with cardiac hypertrophy and fibrosis was successfully developed in NHPs.

4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 98-103, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33554804

RESUMO

OBJECTIVE: To evaluate the prognostic value of GELTAMO-IPI for patients with diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 238 newly diagnosed DLBCL patients treated in Shanxi Cancer Hospital from September 2011 to March 2016 were collected retrospectively, the risk stratification and prognostic evaluation of the patients were analyzed according to GELTAMO-IPI. Progression-free survival (PFS) and overall survival (OS) of the patients were analyzed by the Kaplan-Meier method, COX regression analysis was used to compare the risk of death and progress in each risk group. Harrell's C statistics was used to compare the prognostic stratification ability of each model. RESULTS: The 3-year OS rate statistics showed that both IPI and GELTAMO-IPI could distinguish low risk group and Low-intermediate risk group, but the prognosis stratification ability of IPI was better (IPI: HR=5.085, P<0.05; GELTAMO-IPI; HR=4.639, P>0.05). GELTAMO-IPI could distinguish High-intermediate risk group from high risk group (GELTAMO-IPI: HR=2.966, P<0.05; 3 years OS rate was 34.5%), but the ability of IPI to identify high risk groups was weak (3 years OS>50%). The results of Harrell's C statistics showed the C-index of IPI and GELTAMO-IPI was 0.687 and 0.721 (P<0.001); the C-index of the predicted PFS was 0.672 and 0.700 (P<0.001). It was suggested that the prognostic stratification ability of GELTAM0-IPI be superior to that of IPI, R-IPI, NCCN-IPI. CONCLUSION: GELTAMO-IPI can make a clear distinction between DLBCL patients with different prognosis, especially for high-risk patients, and the prognostic stratification ability of GELTAMO-IPI is significantly better than that of IPI.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Fatores de Risco
5.
Ann Transl Med ; 8(18): 1158, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33241007

RESUMO

Background: To evaluate the role of high-resolution computed tomography (HRCT) in the diagnosis of 2019 novel coronavirus (2019-nCoV) pneumonia and to provide experience in the early detection and diagnosis of 2019-nCoV pneumonia. Methods: Seventy-two patients confirmed to be infected with 2019-nCoV from multiple medical centers in western China were retrospectively analyzed, including epidemiologic characteristics, clinical manifestations, laboratory findings and HRCT chest features. Results: All patients had lung parenchymal abnormalities on HRCT scans, which were mostly multifocal in both lungs and asymmetric in all patients, and were mostly in the peripheral or subpleural lung regions in 52 patients (72.22%), in the central lung regions in 16 patients (22.22%), and in both lungs with "white lung" manifestations in 4 patients (5.56%). Subpleural multifocal consolidation was a predominant abnormality in 38 patients (52.78%). Ground-glass opacity was seen in 34 patients (47.22%). Interlobular septal thickening was found in 18 patients, 8 of whom had only generally mild thickening with no zonal predominance. Reticulation was seen in 8 patients (11.11%), and was mild and randomly distributed. In addition, both lungs of 28 patients had 2 or 3 CT imaging features. Out of these 72 patients, 36 were diagnosed as early stage, 32 patients as progressive stage, and 4 patient as severe stage pneumonia. Moreover, the diagnostic accuracy of HRCT features combined with epidemiological history was not significantly different from the detection of viral nucleic acid (all P >0.05). Conclusions: The HRCT features of 2019-nCoV pneumonia are characteristic to a certain degree, which when combined with epidemiological history yield high clinical value in the early detection and diagnosis of 2019-nCoV pneumonia.

6.
J Clin Pathol ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020176

RESUMO

AIMS: A growing research demonstrated that YAP1 played important roles in gliomagenesis. We explored the expression of YAP1 and STAT3, the relationship between them and the effect of YAP1, STAT3 on prognosis in glioma. METHODS: Expression of YAP1, p-YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 in 141 cases of low-grade gliomas (LGG) and 74 cases of high-grade gliomas (HGG) of surgical specimens were measured by immunohistochemistry. Pearson's X2 test was used to determine the correlation between immunohistochemical expressions and clinicopathological parameters. Pearson's or Spearman correlation test was used to determine the association between these proteins expression. Survival analysis was used to investigate the effect of these proteins on prognosis. RESULTS: High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in HGG compared with LGG (p=0.000). High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in 63.5%, 59.5%, 66.2% and 31.1% cases of HGG, respectively. YAP1 expression was associated to tumour location, Ki-67 and P53, STAT3 expression was related with Ki-67 and P53, and the expression of pSTAT3-S727 was associated with Ki-67. There was a significantly positive correlation between YAP1 and pSTAT3-S727 (p<0.0001; r=0.5663). Survival analysis revealed that patients with YAP1 and pSTAT3-S727 coexpression had worse overall survival (OS) and progression-free survival (PFS) (p<0.0001). Tumour grade, age, Ki-67 and YAP1 expression were independent prognostic factors for OS. In LGG group, both YAP1 and pSTAT3-S727 expressions were negative correlation with IDH1 mutation, YAP1 and pSTAT3-S727 coexpression showed worse OS and PFS of glioma patients. CONCLUSION: Our research showed that YAP1 and STAT3 were significantly activated in HGG compared with LGG. YAP1 significantly correlated with pSTAT3-S727 in glioma, YAP1 and pSTAT3-S727 coexpression may serve as a reliable prognostic biomarker and therapeutic target for glioma.

7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1563-1569, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067955

RESUMO

OBJECTIVE: To explore the influence of lymphocyte / monocyte ratio (LMR), LMR/lactate dehydrogenase (LDH) ratio on the prognosis of patients with diffuse large B-cell lymphoma. METHODS: Clinical data of 107 newly diagnosed patients with DLBCL, including age, sex, stage, B symptoms, IPI score, ECOG score, absolute lymphocyte count, absolute value of monocytes, the ratio of lymphocyte to monocyte(LMR), LDH, LMR/LDH, and SUVmax detected by FDG-PET/CT were analyzed. The best cut-off points of LMR and LMR/LDH were determined by receiver operating characteristics (ROC) curve; the chi-square test was used to analyze the correlation of clinical factors with LMR and LMR/LDH; Spearman correlation analysis was used to determine the correlation between serum LDH level and SUVmax; the Kaplan-Meier protocol was used to compare the overall survival (OS) rate and progression-free survival (PFS) rate between LMR and LMR/LDH groups; the Cox proportional risk model was used to carry out the multivariate analysis of prognostic factors. RESULTS: The optimal limit value for LMR and LMR/LDH (%) determined by ROC curve was 2.535 (P<0.05) and 0.35% (P<0.01) respectively. Patients with an LMR<2.535 had a higher incidence of advanced Ann Arbor stage, B symptoms, higher IPI score, higher ECOG score, and elevated LDH level, while patients with LMR/LDH 0.35% had the same trend as patients with LMR <2.535. A significant positive correlation between serum LDH and SUVmax was observed by Spearman correlation analysis (P<0.001). K-M survival analysis showed that the PFS rate and OS rate in high LMR group were significantly better than that in the low LMR group (P<0.05). K-M analysis showed that the PFS rate and OS rate in high LMR/LDH group were statistical significantly better than that in low LMR/LDH group (P<0.05). Multivariate COX analysis showed that the predictive value in LMR/LDH was much better than single LMR, which may be an independent prognostic factor for patients with DLBCL. CONCLUSION: At the initial diagnosis, high LMR/LDH suggests that DLBCL patient is a better prognosis.


Assuntos
L-Lactato Desidrogenase , Monócitos , Humanos , Contagem de Leucócitos , Linfócitos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Estudos Retrospectivos
8.
Pathol Res Pract ; 216(11): 153187, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32919304

RESUMO

Hub proteins related with Hippo signal pathway in glioma were investigated using proteomics methods (Tandem Mass Tag, TMT) to determine the differentially expressed proteins in glioblastoma (GBM). Ingenuity Pathway Analysis (IPA) was performed to complement proteomic findings by identifying the top canonical pathways as well as to suggest novel proteins for the targeted therapy of glioma. A total of 222 formalin-fixed paraffin-embedded (FFPE) glioma tissue samples were used to verify the expression of protein phosphatase 1γ (PP1γ), Yes-associated protein 1 (YAP1), and SOX2 via immunohistochemistry. Bioinformatics analysis revealed these proteins as crucial in the Hippo signaling pathway in GBM. Spearman correlation was performed to analyze the relationship of these three proteins, and survival analysis was conducted to investigate their effects on prognosis. Among the 5808 proteins identified by TMT with the standard of P-value < 0.05 and fold change (FC) of>1.2 or <0.83, 1398 upregulated and 1060 downregulated differentially expressed proteins were found. IPA revealed that the Hippo signaling was activated in the top 10 canonical pathways, and PP1γ was activated in the Hippo signaling. Immunohistochemistry analysis indicated that PP1γ, YAP1, and SOX2 were highly and positively expressed in glioma. PP1γ expression was related to WHO grade (p = 0.003) and ki-67 expression (p = 0.012). Low PP1γ expression was associated with IDH1-mut in low-grade glioma (LGG; WHO grades II and III) (p = 0.037). PP1γ was positively correlated with YAP1 (p < 0.001; r = 0.259) and SOX2 (p = 0.009; r = 0.175). In survival analysis, age, WHO grade, ki-67 expression, and PP1γ expression independently predicted a short OS in total cohort (p < 0.05). Therefore, PP1γ is a hub protein associated with Hippo signal pathway in glioma, and its expression indicates poor prognosis in patients with glioma. Therefore, PP1γ may be a promising prognostic biomarker and a therapeutic target in glioma.

9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 657-663, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204914

RESUMO

OBJECTIVE: To study the instability of mitochondrial DNA(mt DNA) D-loop region genes in patients with Leukemia. METHODS: The HV-1 and HV-2 regions of D-loop region in 24 patients with leukemia were amplificated and sequenced, then their results were compared with revised Cambridge reference sequence (rCRS) and Databank mtDB. The mutation rate was detected by SPSS 22.0 statistics software. RESULTS: The total mutation rate in patients was 95.83% (23/24), the detection showed 82 mutated genes, out of which 47 (57.32%) mutated genes located in HV-1 region, 35 (42.68%) mutated genes in HV-2 region. The comparison showed that the mutation rate in untreated (UT) group and treated (T) group of AML patients was (2.37±0.82)×10-3 and (4.76±2.45)×10-3 respectively(P<0.01), the mutation rate in PR and CR groups of treated AML patients was (5.10±2.56)×10-3 and (4.51±2.51)×10-3 respectively (P<0.05), the comparison among M3 group showed that the mutation rates in UT, PR and CR groups were (2.55±0.63)×10-3, (5.37±3.41)×10-3 and (3.71±1.65)×10-3 respectively (P>0.05). CONCLUSION: The more high mutation rate and many kinds of mutation types exist in D-loop region, suggesting that the genes in D-loop region display the more strong instability, the chemotherapy may aggravate the instability of genes in D-loop region.


Assuntos
DNA Mitocondrial , Leucemia , Humanos , Mitocôndrias , Mutação , Taxa de Mutação
10.
Lancet Haematol ; 6(6): e328-e337, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31126528

RESUMO

BACKGROUND: Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. METHODS: In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology-Oncology Programs Evaluation System in China. Young patients (16-60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61-80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1-5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01852435. FINDINGS: From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6-77·6) and in the R-CEOP70 group was 72·4% ([66·5-77·5]; HR 1·00 [0·73-1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1-93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7-82·3]; 0·44 [0·25-0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4-83·7%]; 0·49 [0·27-0·86]; p=0·017). Grade 3-4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. INTERPRETATION: R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.


Assuntos
Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neutropenia/etiologia , Modelos de Riscos Proporcionais , Rituximab/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto Jovem
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 580-584, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998174

RESUMO

OBJECTIVE: To investigate the injury effect of anti-donor specific antibody (DSA) on human umbilical vein enolothelial cells (HUVEC) in NK-mediated antibody-dependent cell cytotoxity (ADCC). METHODS: The peripheral blood of 10 healthy donors was colleced for allo-HSCT of AML patients diagnosed in Department of Hemology of the Tumor Hospital affiliated to Shanxi Medical University, then the peripheral blood NK cells were isolated and used as the effector cells; the HUVEC of passages 9-6 were selected and co-cultured with DSA, then the DSA-binding HUVEC were used as the target cells (CDH group), while the DSA-unbinding HUVEC were used as negative control (UDH group). After co-culture of effecor cells with target cells, the expression of IFN-γ was detected by flow cytometry and the HUVEC activity was detected by using MTT method, so as to indirectily reflect the injury effect of DSA-mediated ADCC on endothelial cells. RESULTS: With the increase of effector-target (E:T) ratio, the activity of HUVEC decreased, the expression level of IFN-γ increased. Under the some effector-target ratio (1∶1, 10∶1, 20∶1), the activity of HUVEC in CDH group was significantly lower than that of UDH group, and the expression of IFN-γ was significantly higher than that of the UDH group (P<0.05). CONCLUSION: DSA can damage vascular endothelial cells through the ADCC effect mediated by NK cells.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Células Endoteliais , Células Matadoras Naturais , Anticorpos Monoclonais , Citometria de Fluxo , Humanos
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(5): 1378-1383, 2018 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30295254

RESUMO

OBJECTIVE: To investigate the diagnosis and treatment of patients with T-lymphoblastic lymphoma(T-LBL)combined with acute myeloid leukemia(AML). METHODS: The clinical features of 4 patients with T-LBL combined with AML were retrospectively analyzed, Among them the case 1 and 2 were synchronous occurrence,and case 3 and 4 were sequentially occurred. Especially for former 2 patients,the dliagnosis differentiated from the involved lymph node of AML is important. RESULTS: The biopsies, immunohistochemical(IHC)test and T-cell receptor(TCR)gene rearrangement of the lymph node have been re-evaluated in our institulion. The diagnosis of T-LBL was confirmed. The diagnosis of AML was based on morphology,cytochemistry,immunophenotypy,karyotype and fusion gene of cells. The biphenotypic and bilineal types were found by flow cytometriy(FCM). The diagnosis of mixed acute leukemin(MAL)was confirmed. All the patients received chemotherapy,all of which died from leukemia. The survivnl duration was 2 to 5 months from the diagnosis of AML. CONCLUSION: T-LBL combined with AML is an aggressive disease with am unfarourable prognosis, The new therapies should be designed to treat these rare cases.


Assuntos
Leucemia Linfoide , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos
13.
Circulation ; 138(24): 2798-2808, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30030417

RESUMO

BACKGROUND: The adult mammalian heart has limited ability to repair itself after injury. Zebrafish, newts, and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown whether hearts of young large mammals can regenerate. METHODS: We examined the regenerative capacity of the pig heart in neonatal animals (ages 2, 3, or 14 days postnatal) after myocardial infarction or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry, and Western blotting were performed to study cell proliferation, sarcomere dynamics, and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. RESULTS: After myocardial infarction, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day-old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls, and did not recover function. Genome-wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day-old animals that was absent in 2-day-old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the myocardial infarction showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. CONCLUSIONS: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.


Assuntos
Coração/fisiologia , Infarto do Miocárdio/patologia , Animais , Animais Recém-Nascidos , Citocinese/genética , Ecocardiografia , Fibrose , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Regeneração , Suínos , Troponina I/análise , Função Ventricular Esquerda
14.
Chin Med J (Engl) ; 131(15): 1767-1775, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30058572

RESUMO

Background: Prospective real-life data on the safety and effectiveness of rituximab in Chinese patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) are limited. This real-world study aimed to evaluate long-term safety and effectiveness outcomes of rituximab plus chemotherapy (R-chemo) as first-line treatment in Chinese patients with DLBCL or FL. Hepatitis B virus (HBV) reactivation management was also investigated. Methods: A prospective, multicenter, single-arm, noninterventional study of previously untreated CD20-positive DLBCL or FL patients receiving first-line R-chemo treatment at 24 centers in China was conducted between January 17, 2011 and October 31, 2016. Enrolled patients underwent safety and effectiveness assessments after the last rituximab dose and were followed up for 3 years. Effectiveness endpoints included progression-free survival (PFS) and overall survival (OS). Safety endpoints were adverse events (AEs), serious AEs, drug-related AEs, and AEs of special interest. We also reported data on the incidence of HBV reactivation. Results: In total, 283 previously untreated CD20-positive DLBCL and 31 FL patients from 24 centers were enrolled. Three-year PFS was 59% (95% confidence interval [CI]: 50-67%) for DLBCL patients and 46% (95% CI: 20-69%) for FL patients. For DLBCL patients, multivariate analyses showed that PFS was not associated with international prognostic index, tumor maximum diameter, HBV infection status, or number of rituximab treatment cycles, and OS was only associated with age >60 years (P < 0.05). R-chemo was well tolerated. The incidence of HBV reactivation in hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/hepatitis B core antibody-positive patients was 13% (3/24) and 4% (3/69), respectively. Conclusions: R-chemo is effective and safe in real-world clinical practice as first-line treatment for DLBCL and FL in China, and that HBV reactivation during R-chemo is manageable with preventive measures and treatment. Trial Registration: ClinicalTrials.gov, NCT01340443; https://clinicaltrials.gov/ct2/show/NCT01340443.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , China , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vincristina/administração & dosagem
15.
Cell Death Dis ; 9(3): 278, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449539

RESUMO

Tumor metastasis is the leading cause of death in patients with advanced gastric cancer (GC). Limited therapeutic regimens are available for this condition, which is associated with a poor prognosis, and the mechanisms underlying tumor metastasis remain unclear. In the present study, increased histone methyltransferase G9A expression in GC tissues correlated with advanced stage and shorter overall survival, and in vitro and in vivo experiments revealed that G9A promoted tumor invasion and metastasis. Moreover, we observed that Reg IV induced G9A via the p-ERK/p-SP1 pathway. SP1 directly binds the G9A promoter and enhances G9A expression, and upregulated G9A then forms a transcriptional activator complex with P300 and GR, thereby promoting ITGB3 expression induced by dexamethasone (DEX) and contributing to GC metastasis. However, the G9A-mediated increase in ITGB3 expression was not dependent on the SET domain and methyltransferase activity of G9A. This study demonstrates that G9A is an independent prognostic marker and promotes metastasis in GC, thus suggesting that it may be a tumor biomarker and potential therapeutic target in GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Integrina beta3/metabolismo , Neoplasias Peritoneais/enzimologia , Neoplasias Gástricas/enzimologia , Animais , Sítios de Ligação , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proteína p300 Associada a E1A/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Integrina beta3/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Domínios PR-SET , Proteínas Associadas a Pancreatite/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Fosforilação , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais , Fator de Transcrição Sp1/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Regulação para Cima
16.
Cancer Lett ; 408: 10-21, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28843497

RESUMO

Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) regulate gene and protein expression by exerting an influence on transcriptional and post-transcriptional processes. Here, we report that the lncRNA UCA1 increases the metastatic ability of gastric cancer (GC) cells by regulating GRK2 protein stability by promoting Cbl-c-mediated GRK2 ubiquitination and degradation. This process then activates the ERK-MMP9 signalling pathway. Furthermore, we demonstrate that GRK2 is downregulated in GC cells and that silencing of GRK2 might cause similar phenotypic changes and signalling pathway activation as those induced by elevated UCA1 in GC cells. Our results suggest that UCA1 might function as a mediator of protein ubiquitination and may be a promising molecular target for GC therapy.


Assuntos
Movimento Celular , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Animais , Apoptose , Proliferação de Células , Quinase 2 de Receptor Acoplado a Proteína G/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteólise , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Adolesc ; 59: 35-44, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28554076

RESUMO

Western Studies show that father involvement is predictive of adolescent development; however, there are few studies that demonstrate this relationship in Chinese cultures, including Taiwan. The purpose of this study is to examine the impact of father involvement on adolescents' development in areas of academic achievement, self-esteem, internalizing, and externalizing behaviors in Taiwan. This study utilized dyadic data of 1043 10th graders from wave 5 of a longitudinal study on adolescent development in Taiwan. The study utilized student reports of father involvement, child academic achievement, externalizing behaviors, internalizing behaviors, and self-esteem. Structural equation modeling results indicate father involvement significantly predicts child academic achievement, externalizing behaviors, internalizing behaviors, and self-esteem. Gender analysis shows that male adolescents exhibited more externalizing behaviors, whereas female adolescents exhibited more internalizing behaviors. The findings of this study provide evidence that father involvement is important for the overall wellbeing of adolescents in Chinese cultures.


Assuntos
Desenvolvimento do Adolescente , Poder Familiar/psicologia , Comportamento Paterno , Autoimagem , Sucesso Acadêmico , Adolescente , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores Sexuais , Taiwan
18.
J Transl Med ; 15(1): 52, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28241766

RESUMO

BACKGROUND: Gastric cancer (GC) is one of the most malignant tumors and the second leading cause of cancer-related deaths in the world. Luteolin, a flavonoid present in many fruits and green plants, suppresses cancer progression. The effects of luteolin on GC cells and their underlying mechanisms remain unclear. METHODS: Effects of luteolin on cell proliferation, migration, invasion, and apoptosis were examined in vitro and in vivo by cell counting kit-8 (CCK-8), transwell assays, and flow cytometry, respectively. Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blots were performed to evaluate Notch1 signaling and activation of epithelial-mesenchymal transition (EMT) in GC cells treated with or without luteolin. Immunohistochemistry was performed to examine proliferation and Notch1 expression in xenograft tumors. RESULTS: Luteolin significantly inhibited cell proliferation, invasion, and migration in a dose-dependent and time-dependent manner and promoted cell apoptosis. Luteolin reversed EMT by shrinking the cytoskeleton and by inducing the expression of epithelial biomarker E-cadherin and downregulating the mesenchymal biomarkers N-cadherin, vimentin and Snail. Furthermore, Notch1 signaling was inhibited by luteolin, and downregulation of Notch1 had similar effects as luteolin treatment on cell proliferation, migration, and apoptosis. In addition, luteolin suppressed tumor growth in vivo. A higher expression of Notch1 correlated with a poor overall survival and a poor time to first progression. Furthermore, co-immunoprecipitation analysis revealed that activated Notch1 and ß-catenin formed a complex and regulated cell proliferation, migration, and invasion. CONCLUSIONS: In this study, GC progression was inhibited by luteolin through suppressing Notch1 signaling and reversing EMT, suggesting that luteolin may serve as an effective anti-tumor drug in GC treatment.


Assuntos
Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Luteolina/uso terapêutico , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Luteolina/química , Luteolina/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Invasividade Neoplásica , Prognóstico , Ensaio Tumoral de Célula-Tronco
19.
PLoS One ; 11(9): e0162611, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27622506

RESUMO

BACKGROUND: Diabetes is a major global public health problem driven by a high prevalence of metabolic risk factors. OBJECTIVE: To describe the differences of metabolic risk factors of type 2 diabetes, as well as glycemic control and complicated diabetic complications between rural and urban Uygur residents in Xinjiang Uygur Autonomous Region of China. METHODS: This comparative cross-sectional study, conducted among 2879 urban and 918 rural participants in Xinjiang, China, assessed the metabolic risk factors of diabetes and related complications differences between urban and rural settlements. RESULTS: Compared to rural areas, urban participants had higher education level and more average income, little physical activity, less triglycerides and higher HDL-c (p < 0.05 respectively). Differences in metabolic risk factors by urban/rural residence included overweight or obesity, triglycerides (≥1.71mmol/l), HDL-c (< 1.04 mmol/l), alcohol intake, and physical inactivity (p < 0.01 respectively). There was significant difference regarding the prevalence of HbA1c >8% (48.1% versus 54.5%, p = 0.019) between rural and urban diabetic participants. No significant difference in the prevalence of type 2 diabetic complications between urban and rural participants (74.9% versus 72.2%; p = 0.263) was detected. Compared to rural participants, the most prevalent modifiable risk factors associated with diabetic complications in urban participants were obesity (BMI ≥ 28 Kg/m2), HDL-c (< 1.04 mmol/l), physical inactivity and irregular eating habits (p = 0.035, p = 0.001, p < 0.001, and p = 0.013, respectively). CONCLUSIONS: Urban settlers were significantly more likely to have metabolic risk factors highlighting the need for public health efforts to improve health outcomes for these vulnerable populations. Diabetes related complications risk factors were prevalent amongst rural and urban diabetes settlers.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Adulto , Idoso , Índice de Massa Corporal , China , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , População Rural , População Urbana , Adulto Jovem
20.
Mol Oncol ; 10(9): 1473-1484, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27590684

RESUMO

Biglycan (BGN) is an important component of the extracellular matrix (ECM) that is implicated in a variety of human cancers. In our previous study, we reported that BGN was overexpressed in gastric cancer (GC) tissues and promoted cancer metastasis. Moreover, the tubular formation capacity in HUVECs was promoted by stimulation with culture media from BGN-overexpressing GC cells, but the exact underlying mechanism is still unknown. The purpose of this study was to determine the role and molecular mechanism of BGN in VEGF expression in endothelial cells. We found that BGN stimulation of endothelial cells increased the interaction between NF-kB and the HIF-1α promoter, leading to enhanced promoter activity and increased HIF-1α mRNA levels, as well as augmented HIF-1 activity that resulted in VEGF expression. All of this was dependent on the interaction of BGN with its receptors, TLR2 and TLR4. Moreover, we found that BGN enhanced endothelial cell migration and proliferation, as well as tube formation, in a TLR signaling pathway-dependent manner. In addition, endothelial cell-derived VEGF in turn was found to act on GC cells and promotes their migration. The combined findings of our current and previous studies suggest that BGN secreted from GC cells into the tumor stroma promotes GC development, as well as its progression, potentially through the chronic activation of tumor angiogenesis.


Assuntos
Biglicano/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Modelos Biológicos , NF-kappa B/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
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