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Find video protocols related to scientific articles indexed in Pubmed.
Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma patients.
Histopathology
PUBLISHED: 10-17-2014
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CD155 is an important ligand in triggering tumor rejection by immune cells. However, the expression of CD155 and its clinical significance in hepatocellular carcinoma (HCC) remains unknown.
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Immunosuppression for 6-8 weeks after modified donor lymphocyte infusion reduced acute graft-versus-host disease without influencing graft-versus-leukemia effect in haploidentical transplant.
Chin. Med. J.
PUBLISHED: 10-16-2014
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In haploidentical hematopoietic stem cell transplantation (HSCT), the duration of graft-versus-host disease (GVHD) prophylaxis after modified donor lymphocyte infusion (DLI) was the only risk factor of DLI-associated grades 3-4 acute GVHD. However, the successful application of modified DLI depended not only on the reduction of severe GVHD, but also on the preservation of graft-versus-leukemia (GVL) effect. Therefore, this study was performed to compare the impact of prophylaxis for 6-8 weeks and prophylaxis for <6 weeks on GVL effect after modified DLI in haploidentical HSCT.
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Negative association of donor age with CD34(+) cell dose in mixture allografts of G-CSF-primed bone marrow and G-CSF-mobilized peripheral blood harvests.
Chin. Med. J.
PUBLISHED: 10-16-2014
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The effects of donor characteristics on CD34(+) cell dose remain controversial. Recently, we developed a novel haploidentical transplant protocol, in which mixture allografts of granulocyte colony-stimulating factor (G-CSF)-primed bone marrow (G-BM) and G-CSF-mobilized peripheral blood (G-PB) were used. The aim of this study was to investigate the effects of donor characteristics on CD34(+) cell dose in mixture allografts of G-BM and G-PB.
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[The risk factors of post-transplant lymphoproliferative disorders following haploidentical hematopoietic stem cell transplantation].
Zhonghua Nei Ke Za Zhi
PUBLISHED: 09-30-2014
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Post-transplant lymphoproliferative disorder (PTLD) occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare but severe. Risk factors including pre-HSCT exposure variables, conditioning regimens, transplant-related complications, and post-HSCT immune reconstitution were investigated in the development of PTLD after allo-HSCT.
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[Efficacy and safety of intravenous itraconazole in different antifungal strategies for patients undergoing intensive chemotherapy or hematopoietic stem cell transplantation].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 08-26-2014
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To explore the efficacy and safety of intravenous itraconazole for patients undergoing intensive chemotherapy or hematopoietic stem cell transplantation in different strategies.
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[Second transplantation for 22 patients with graft failure after first allogeneic stem cell transplantation].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 08-26-2014
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To improve the understanding of treatment for graft failure by analyzing the efficacy of second transplantation for graft failure after first allogeneic stem cell transplantation (allo-HSCT).
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Improved response rates with bortezomib in relapsed or refractory multiple myeloma: an observational study in chinese patients.
Adv Ther
PUBLISHED: 07-24-2014
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Bortezomib, a novel proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma (MM). Efficacy and safety of bortezomib is well known; however, it was necessary to validate the data in patients with different ethnic backgrounds. The efficacy and safety of bortezomib was assessed in patients from China with relapsed/refractory MM in a real-world scenario.
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Invasive fungal infection in patients receiving chemotherapy for hematological malignancy: a multicenter, prospective, observational study in China.
Tumour Biol.
PUBLISHED: 07-24-2014
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This stud y examined the epidemiology, risk factors, management, and outcome of invasive fungal infection (IFI) in patients receiving chemotherapy for hematological malignancy in China. IFI risk factors were analyzed using univariate analysis and multivariate logistic regression. In total, 4,192 patients receiving 4,889 chemotherapy courses were enrolled [mean age 40.7 years, 58.4 % male, 16.9 % children (<18 years)]. The most common hematological diseases were acute myeloid leukemia (AML, 28.5 %), non-Hodgkin lymphoma (NHL, 26.3 %), and acute lymphoblastic leukemia (ALL, 20.2 %). Severe neutropenia (absolute neutrophil count [ANC] <500/mm(3)) occurred after one third (1,633/4,889, 33.4 %) of chemotherapy courses. Incidence of proven/probable IFI was 2.1 % per chemotherapy course and higher in patients with myelodysplastic syndrome (MDS, 4.94 %), acute hyperleukocytic leukemia (AHL, 4.76 %), AML (3.83 %), or induction chemotherapy. Risk factors included ANC <500/mm(3) [odds ratio (OR) 3.60], AML or MDS (OR 1.97), induction chemotherapy (OR 2.58), previous IFI (OR 3.08), and being male (OR 1.74). Antifungal agents, prescribed in one quarter (1,211/4,889, 24.8 %) of chemotherapy courses, included primary/secondary prophylaxis (n?=?827, 16.9 %) and/or treatment (n?=?655, 13.4 %; 86.9 % triazoles), which was empirical (84.3 %), pre-emptive (8.6 %), or targeted (7.1 %). Overall mortality following each chemotherapy course (1.5 %) increased in proven/probable (11.7 %) and possible IFI (8.2 %). In summary, IFI was more common in MDS, AHL, AML, or induction chemotherapy, and substantially increased mortality. Neutropenic patients receiving induction chemotherapy for AML or MDS and those with previous IFI were at particular risk. Antifungal prophylaxis showed an independent protective effect but was not commonly used, even in high-risk patients. By contrast, empiric antifungals were widely used.
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Interferon ?: the salvage therapy for patients with unsatisfactory response to minimal residual disease-directed modified donor lymphocyte infusion.
Chin. Med. J.
PUBLISHED: 07-22-2014
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Minimal residual disease (MRD)-directedmodified donor lymphocyte infusion (mDLI) is used to treat relapse after hematopoietic stem cell transplantation (HSCT). For patients who experience an unsatisfactory response tomDLI, relapse is usually inevitable. Therefore, we sought to evaluate the efficacy ofinterferon ? therapy in these patients.
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Bortezomib improves progression-free survival in multiple myeloma patients overexpressing preferentially expressed antigen of melanoma.
Chin. Med. J.
PUBLISHED: 05-06-2014
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Significant efforts have been made to identify factors that differentiate patients treated with novel therapies, such as bortezomib in multiple myeloma (MM). The exact expression pattern and prognostic value of the cancer/testis antigen preferentially expressed antigen of melanoma (PRAME) in MM are unknown and were explored in this study.
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[The clinical analysis of allogeneic hematopoietic stem cell transplantation from human leukocyte antigen-identical siblings in 95 patients with myelodysplastic syndrome].
Zhonghua Nei Ke Za Zhi
PUBLISHED: 04-29-2014
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To evaluate the efficacy and optimize the timing of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from human leukocyte antigen (HLA)-identical siblings for myelodysplastic syndrome (MDS).
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Phenotypic transition of corpus cavernosum smooth muscle cells subjected to hypoxia.
Cell Tissue Res.
PUBLISHED: 04-22-2014
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Corpora cavernosum smooth muscle cells (CCSMCs) have been shown to play a critical role in the male erectile response and are involved in the pathogenesis of multiple causes of erectile dysfunction (ED). To investigate the underlying mechanisms, we studied the changes that CCSMCs undergo under hypoxic conditions in vitro. The identified and characterized CCSMCs were exposed to hypoxia for 48 h and its phenotypic changes were examined by light and electron microscopy, MTS assay and flow cytometry. The mRNA and protein levels of TGF-?1 and type I/III collagen, as well as CCSMC phenotype marker proteins and their transcriptional factors, were assessed by qPCR, immunofluorescence analysis and western blotting. Our results showed that CCSMCs became hypertrophic with loss of myofilament bundles and formation of an extensive rough endoplasmic reticulum (RER) under hypoxic conditions, with inhibited cell proliferation and enhanced cell apoptosis. This was accompanied by the increased synthesis of TGF-?1 and types I and III collagen. Moreover, smooth muscle cell phenotypic markers were also affected by hypoxic conditions, as indicated by the decrease in ?-SMA, desmin and CNN1 expression and the increase in vimentin expression. These changes corresponded to changes in associated transcriptional factors, such as the increase in Elk-1 and KLF-4 expression and decrease in Myocd expression. In addition, a HIF-1? knockdown effectively reversed the hypoxia-induced CCSMC phenotype, whereas its overexpression induced the dedifferentiation phenotype. These results indicate that CCSMCs undergo a phenotypic transition under hypoxic conditions.
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Low expression of CD112 is associated with poor overall survival in patients with hepatocellular carcinoma.
Hum. Pathol.
PUBLISHED: 03-31-2014
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CD112 as an important ligand of CD226 can stimulate the natural killer (NK) cell-mediated target cell lysis. Previous studies have reported that CD112 is involved in cancer initiation and progression. However, its expression and clinical significance in hepatocellular carcinoma (HCC) have never been investigated. In this study, we used immunohistochemistry to examine CD112 expression in cancer and pericancer tissues from 159 HCC cases. Western blot and immunofluorescence were used to detect CD112 expression in HCC cell lines. ?(2) Test was used to assess the association of CD112 expression with clinicopathological characteristics, whereas Kaplan-Meier survival function and Cox proportional hazards regression model were used to explore the association between CD112 expression and clinical outcome of patients with HCC. Overall, CD112 expression was significantly reduced in HCC tissues when compared with adjacent pericancer liver tissues (P < .001). Western blot and immunofluorescence analyses showed that most HCC cell lines had low CD112 expression level. Furthermore, low CD112 expression was significantly associated with high serum ?-fetoprotein level (P = .004) in patients with HCC. Kaplan-Meier analysis showed that patients with low CD112 expression had poorer postsurgery overall survival than those with high CD112 expression (log-rank P = .045). In conclusion, our findings demonstrate that the down-regulation of CD112 may be an important mechanism through which HCC cells evade the natural killer cell-mediated immunosurveillance, and thus, CD112 may be a useful biomarker to assess the immunologic niche of HCC.
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Functional polymorphisms in the NPAS2 gene are associated with overall survival in transcatheter arterial chemoembolization-treated hepatocellular carcinoma patients.
Cancer Sci.
PUBLISHED: 03-31-2014
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The functional abnormality of circadian regulation genes is involved in the development and progression of hepatocellular carcinoma (HCC). However, the association between functional single nucleotide polymorphisms (SNPs) in circadian gene NPAS2 and the overall survival of HCC patients treated with transcatheter arterial chemoembolization (TACE) has never been investigated. Six functional SNPs in the NPAS2 gene were genotyped using the Sequenom iPLEX genotyping system in a cohort of 448 unresectable Chinese patients with HCC treated with TACE. Multivariate Cox proportional hazards model and Kaplan-Meier curves were used for the prognosis analysis. We found that two SNPs, rs1053096 and rs2305160, in the NPAS2 gene showed significant associations with overall death risk in HCC patients in the recessive model (hazard ratio [HR] = 1.48; 95% confidence interval [CI], 1.13-1.94; P = 0.004) and in the dominant model (HR = 1.63; 95% CI, 1.29-2.07; P < 0.001), respectively. Moreover, we observed a cumulative effect of these two SNPs on HCC overall survival, indicating a significant trend of increasing death risk with increasing number of unfavorable genotypes (P for trend < 0.001). Compared with the patients without any unfavorable genotypes, the HRs for patients with one and two unfavorable genotypes were 1.41 (95% CI, 1.10-1.82; P = 0.007) and 2.09 (95% CI, 1.46-2.97, P < 0.001), respectively. The haplotype and diplotype analyses further characterized the association between NPAS2 genotype and survival of HCC patients. Our results for the first time suggest that NPAS2 gene polymorphisms may serve as an independent prognostic marker for HCC patients treated with TACE.
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[A comparison of clinical characteristics and prognosis of adult acute graft-versus-host disease between human leukocyte antigen- identical and -mismatched allogeneic hematopoietic stem cell transplantation].
Zhonghua Nei Ke Za Zhi
PUBLISHED: 03-29-2014
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To compare the clinical characteristics and prognosis of acute graft-versus-host disease (aGVHD) between patients undergoing human leukocyte antigen (HLA)-identical and HLA-mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT).
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Genetic variants in genes of tricarboxylic Acid cycle key enzymes predict postsurgical overall survival of patients with hepatocellular carcinoma.
Ann. Surg. Oncol.
PUBLISHED: 03-28-2014
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Metabolic reprogramming is a hallmark of cancer, including the alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes. However, the significance of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes has not been investigated in hepatocellular carcinoma (HCC).
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Cryo-electron microscopy study of insect cell-expressed enterovirus 71 and coxsackievirus a16 virus-like particles provides a structural basis for vaccine development.
J. Virol.
PUBLISHED: 03-26-2014
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Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two most common etiological agents responsible for the epidemics of hand, foot, and mouth disease (HFMD), a childhood illness with occasional severe neurological complications. A number of vaccine candidates against EV71 or CA16 have been reported; however, no vaccine is currently available for clinical use. Here, we generated a secreted version of EV71 and CA16 virus-like particles (VLPs) using a baculovirus-insect cell expression system and reconstructed the three-dimensional (3D) structures of both VLPs by cryo-electron microscopy (cryo-EM) single-particle analysis at 5.2-? and 5.5-? resolutions, respectively. The reconstruction results showed that the cryo-EM structures of EV71 and CA16 VLPs highly resemble the recently published crystal structures for EV71 natural empty particles and CA16 135S-like expanded particles, respectively. Our cryo-EM analysis also revealed that the majority of previously identified linear neutralizing epitopes are well preserved on the surface of EV71 and CA16 VLPs. In addition, both VLPs were able to induce efficiently neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71- and CA16-associated HFMD.
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[A multicenter study on the validation of conversion factor for the conversion of BCR-ABL (P210) transcript levels to the international scale in chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 03-11-2014
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To validate the conversion factor(CF)for the conversion of BCR-ABL (P210) transcript levels to the international scale in chronic myeloid leukemia (CML).
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[Molecular response and prognostic factors of patients with Philadelphia chromosome/BCR-ABL-positive acute lymphoblastic leukemia treated by imatinib with chemotherapy].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 03-11-2014
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To evaluate the molecular response and prognostic factors of patients with Philadelphia chromosome/BCR-ABL-positive acute lymphoblastic leukaemia (Ph? ALL) treated by imatinib with chemotherapy.
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[Comparison of simultaneous bone marrow cytogenetic and peripheral blood molecular responses in chronic myeloid leukemia].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 03-11-2014
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Compare the correlation and the concordance of simultaneous bone marrow cytogenetic and peripheral blood molecular responses in patients with chronic myeloid leukemia (CML) during tyrosine kinase inhibitor (TKI) treatment.
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[Analysis of risk factors for secondary cytopenia after allogeneic hematopoietic stem cell transplantation].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 03-08-2014
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To investigate the incidence and risk factors for secondary cytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
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Association of leukocyte mitochondrial DNA content with glioma risk: evidence from a Chinese case-control study.
BMC Cancer
PUBLISHED: 02-11-2014
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Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) content may be implicated in the tumorigenesis of several malignancies. However, the association between mtDNA content in peripheral blood lymphocytes (PBLs) and glioma risk has not been investigated.
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Total body irradiation and cyclophosphamide plus antithymocyte globulin regimen is well tolerated and promotes stable engraftment as a preparative regimen before T cell-replete haploidentical transplantation for acute leukemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-08-2014
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We compared total body irradiation (TBI, 700 cGy)/cyclophosphamide (Cy, 3.6 g/m(2))/simustine (250 mg/m(2)) plus antithymocyte globulin (ATG) (TBI/Cy plus ATG) with cytarabine (8 g/m(2))/i.v. busulfan (Bu, 9.6 mg/kg)/Cy (3.6 g/m(2))/simustine (250 mg/m(2)) plus ATG (modified Bu/Cy plus ATG) as preparative therapy in T cell-replete haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for acute leukemia. From August 2009 to August 2013, 38 consecutive patients using TBI/Cy plus ATG regimen for T cell-replete haplo-HSCT (TBI group) at our center were eligible, which contained 28 high-risk and 10 standard-risk patients. A nested case-control study was designed. Seventy-seven patients using modified Bu/Cy plus ATG regimen (Bu group) were randomly selected in a 1 to 3:1 ratio matching for age, disease and status, year of HSCT (±2 years), and length of follow-up. Only 1 graft failure occurred in the TBI group. The incidence and time of neutrophil and platelet engraftment were comparable between the 2 groups. Severe grades III/IV graft-versus-host disease was observed in 13.4% of Bu group and only 2.6% of TBI group (P = .083). More toxicity of the liver (37.7% versus 10.5%; P = .002) and more hemorrhagic cystitis occurred in the Bu group (49.3% versus 23.7%, P = .008). Diarrhea was more common in the TBI group (44.7% versus 22.1%; P = .031). No significant differences were found in the 2-year incidences of relapse (26.5% for TBI group versus 32.3% for Bu group, P = .742), 1-year transplant-related mortality (12.6% versus 16.2%, P = .862), 2-year overall survival (60.2% versus 57.0%, P = .937), and 2-year incidence of disease-free survival (57.9% versus 56.6%, P = .845) between the 2 groups. We conclude that the TBI/Cy plus ATG regimen seems to be feasible in T cell-replete haplo-HSCT, which promotes stable engraftment and a lower incidence of liver toxicity and hemorrhagic cystitis. However, longer follow-up is necessary to determine the late relapse rate and late toxicity.
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Identification of the active sites in the methyltransferases of a transcribing dsRNA virus.
J. Mol. Biol.
PUBLISHED: 01-23-2014
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Many double-stranded RNA (dsRNA) viruses are capable of transcribing and capping RNA within a stable icosahedral viral capsid. The turret of turreted dsRNA viruses belonging to the family Reoviridae is formed by five copies of the turret protein, which contains domains with both 7-N-methyltransferase and 2'-O-methyltransferase activities, and serves to catalyze the methylation reactions during RNA capping. Cypovirus of the family Reoviridae provides a good model system for studying the methylation reactions in dsRNA viruses. Here, we present the structure of a transcribing cypovirus to a resolution of ~3.8Å by cryo-electron microscopy. The binding sites for both S-adenosyl-L-methionine and RNA in the two methyltransferases of the turret were identified. Structural analysis of the turret in complex with RNA revealed a pathway through which the RNA molecule reaches the active sites of the two methyltransferases before it is released into the cytoplasm. The pathway shows that RNA capping reactions occur in the active sites of different turret protein monomers, suggesting that RNA capping requires concerted efforts by at least three turret protein monomers. Thus, the turret structure provides novel insights into the precise mechanisms of RNA methylation.
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Neutropenia and invasive fungal infection in patients with hematological malignancies treated with chemotherapy: a multicenter, prospective, non-interventional study in China.
Tumour Biol.
PUBLISHED: 01-13-2014
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In this study, we explored the relationship between neutropenia (absolute neutrophil count (ANC) <1,500/mm(3)) and invasive fungal infection (IFI) in Chinese patients who had hematological malignancies treated with chemotherapy. We conducted a multicenter, prospective, non-interventional study of consecutive patients with hematological malignancies undergoing chemotherapy in China and determined clinical characteristics of patients who developed neutropenia and IFI. The results indicated that for the 2,177 neutropenic patients, 88 (4.0 %) were diagnosed with IFI. We found that a high risk of IFI (P<0.05) is associated with male gender, non-remission of the primary disease, use of two or more broad-spectrum antibiotics, treatment with parenteral nutrition, presence of cardiovascular disease, history of IFI, and neutropenia. When the ANC was less than 1,000, 1,000?500, 500?100, and <100/mm(3), the incidence of IFI was 0.5, 5.2, 3.9, and 4.7 %, respectively (ANC>1,000/mm(3) versus other groups, P<0.001). When the ANC was less than 1,000, 500, or 100/mm(3) for 10 days or more, the incidence of IFI was 3.2 versus 6.1 % (P=0.0052), 3.5 versus 7.1 % (P=0.0021), and 3.1 versus 10.0 % (P<0.001). When the ANC was less than 100/mm(3), taking antifungal prophylaxis reduced the incidence of IFI (P<0.05). The IFI-attributable mortality rate was 11.7 %. In conclusion, Chinese patients with IFI, severe and prolonged neutropenia increases the incidence of IFI. The incidence of IFI associated with neutropenia was reduced when antifungal prophylaxis was given. IFI was associated with a significantly increased high mortality rate in hematological malignancy patients with neutropenia.
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Direct ChIP-bisulfite sequencing reveals a role of H3K27me3 mediating aberrant hypermethylation of promoter CpG islands in cancer cells.
Genomics
PUBLISHED: 01-07-2014
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The model describing that aberrant CpG island (CGI) methylation leads to repression of tumour suppressor genes in cancers has been influential, but it remains unclear how such aberrancy is induced. Recent studies provided clues indicating that promoter hypermethylation in cancers might be associated with PRC target genes. Here, we used ChIP-BS-seq to examine methylation of the DNA fragments precipitated by the antibodies to both H3K27me3 and H3K4me3 histone modifications. We showed that, for a set of genes highly enriched with H3K27me3 both in cancer and normal cells, CGI promoters were aberrantly hypermethylated only in cancer cells in comparison with normal cells. In contrast, such aberrant CGI hypermethylation in cancer promoters that were deficient of H3K27me3 was not notable. Furthermore, we confirmed that these genes were consistently hypermethylated in TCGA primary cancer cells. These works support the association between H3K27me3 and DNA methylation marks for specific cancer genes and will spur future work on combined histone and DNA methylation that could define cancer's epigenetic abnormalities.
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Cryo-EM structures of two bovine adenovirus type 3 intermediates.
Virology
PUBLISHED: 01-03-2014
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Adenoviruses (Ads) infect hosts from all vertebrate species and have been investigated as vaccine vectors. We report here near-atomic structures of two bovine Ad type 3 (BAd3) intermediates obtained by cryo-electron microscopy. A comparison between the two intermediate structures reveals that the differences are localized in the fivefold vertex region, while their facet structures are identical. The overall facet structure of BAd3 exhibits a similar structure to human Ads; however, BAd3 protein IX has a unique conformation. Mass spectrometry and cryo-electron tomography analyses indicate that one intermediate structure represents the stage during DNA encapsidation, whilst the other intermediate structure represents a later stage. These results also suggest that cleavage of precursor protein VI occurs during, rather than after, the DNA encapsidation process. Overall, our results provide insights into the mechanism of Ad assembly, and allow the first structural comparison between human and nonhuman Ads at backbone level.
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Genetic variants in the EPCAM gene is associated with the prognosis of transarterial chemoembolization treated hepatocellular carcinoma with portal vein tumor thrombus.
PLoS ONE
PUBLISHED: 01-01-2014
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The epithelial cell adhesion molecule (EPCAM) is involved in the tumorigenesis and progression of many malignancies, including hepatocellular carcinoma (HCC). Single nucleotide polymorphisms (SNPs) of EPCAM have been reported to be with the risk and prognosis of several malignancies. However, the association of SNPs in EPCAM gene with the prognosis of HCC patients has never been investigated. In this study, two functional SNPs (rs1126497 and rs1421) in the EPCAM gene were selected and genotyped in a cohort of 448 unresectable Chinese HCC patients treated by TACE. The association of the two SNPs with the overall survival (OS) of patients was assessed by univariate and multivariate Cox proportional hazards model and Kaplan-Meier curve. Our data showed that there was no significant association between either SNP and OS of patients. However, in the stratified analysis, the variant-containing genotypes (WV+VV) of SNP rs1126497 exhibited a significant association with poorer OS in HCC patients who had portal vein tumor thrombus (PVTT) in multivariate analysis of Cox proportional hazard model (hazard ratio, 1.71; 95% confidence interval, 1.16-2.53, P?=?0.007), and in Kaplan-Meier curve analysis (P?=?0.023), comparing to those carrying wild-type genotype. Our results suggest that SNP rs1126497 in the EPCAM gene may serve as an independent prognosis biomarker for unresectable HCC patient with PVTT, which warranted further validating investigation.
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Association between leukocyte telomere length and glioma risk: a case-control study.
Neuro-oncology
PUBLISHED: 12-22-2013
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BackgroundCompelling epidemiological evidence indicates that alterations of telomere length are associated with risks of many malignancies in a tumor-specific manner, such as lung cancer, breast cancer, and non-Hodgkins lymphoma. However, the association between leukocyte telomere length and glioma risk has not been investigated.MethodsRelative telomere length (RTL) of peripheral blood leukocytes from 467 glioma patients and 467 healthy controls, matched by age and sex, was measured using the real-time PCR-based method in a case-control study. An unconditional multivariate logistic regression model was applied to estimate the association between RTL and glioma risk.ResultsGlioma patients showed notably longer RTL than controls (median, 0.555 vs 0.444; P > .04). RTL was negatively correlated with age in both cases (? = -0.430; P < .001) and controls (? = -0.388; P < .001). After adjusting for age, sex, smoking status and family history of cancer, multivariate logistic regression analysis showed that there was a U-shaped association between RTL and glioma risk (P for nonlinearity <.001). Compared with individuals in the second tertile of RTL, the odds ratios (95% CI) for participants in the first and third tertiles were 2.16 (range, 1.52-3.09) and 3.51 (range, 2.45-5.00), respectively. Stratified analysis showed that the association between RTL and glioma risk was not modulated by major host characteristics.ConclusionsOur study demonstrates for the first time that either shorter or longer RTL in peripheral blood leukocytes is associated with increased glioma risk, which warrants further investigation in the future.
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Two potential calmodulin-binding sequences in the ryanodine receptor contribute to a mobile, intra-subunit calmodulin-binding domain.
J. Cell. Sci.
PUBLISHED: 07-18-2013
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Calmodulin (CaM), a 16 kDa ubiquitous calcium-sensing protein, is known to bind tightly to the calcium release channel/ryanodine receptor (RyR), and modulate RyR function. CaM binding studies using RyR fragments or synthetic peptides have revealed the presence of multiple, potential CaM-binding regions in the primary sequence of RyR. In the present study, we inserted GFP into two of these proposed CaM-binding sequences and mapped them onto the three-dimensional structure of intact cardiac RyR2 by cryo-electron microscopy. Interestingly, we found that the two potential CaM-binding regions encompassing, Arg3595 and Lys4269, respectively, are in close proximity and are adjacent to the previously mapped CaM-binding sites. To monitor the conformational dynamics of these CaM-binding regions, we generated a fluorescence resonance energy transfer (FRET) pair, a dual CFP- and YFP-labeled RyR2 (RyR2R3595-CFP/K4269-YFP) with CFP inserted after Arg3595 and YFP inserted after Lys4269. We transfected HEK293 cells with the RyR2R3595-CFP/K4269-YFP cDNA, and examined their FRET signal in live cells. We detected significant FRET signals in transfected cells that are sensitive to the channel activator caffeine, suggesting that caffeine is able to induce conformational changes in these CaM-binding regions. Importantly, no significant FRET signals were detected in cells co-transfected with cDNAs encoding the single CFP (RyR2R3595-CFP) and single YFP (RyR2K4269-YFP) insertions, indicating that the FRET signal stemmed from the interaction between R3595-CFP and K4269-YFP that are in the same RyR subunit. These observations suggest that multiple regions in the RyR2 sequence may contribute to an intra-subunit CaM-binding pocket that undergoes conformational changes during channel gating.
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Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation.
Transplantation
PUBLISHED: 07-12-2013
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Epstein-Barr virus (EBV) infection may result in a spectrum of diseases in recipients of transplant. The aim of this study is to investigate the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT).
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High-throughput sequencing of methylated cytosine enriched by modification-dependent restriction endonuclease MspJI.
BMC Genet.
PUBLISHED: 06-13-2013
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As a well-known epigenomic modification, DNA methylation is found to be common in plants and plays an important role in many biological processes. Relying on the unique feature of methylation-dependent digestion, the family of methylation-requiring restriction-like endonuclease, such as MspJI and its homologs, was suggested for a potential usage in methylation detection.
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CXCR4 is a good survival prognostic indicator in multiple myeloma patients.
Leuk. Res.
PUBLISHED: 05-29-2013
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SDF-1? and its receptor CXCR4 are involved in multiple myeloma (MM) by attracting and activating plasma cells in the bone marrow. CXCR4 expression in MM cells is inversely correlated with disease activity. The aim of this study was to evaluate CXCR4 as a prognostic tool in MM, as well as other markers of disease, such as chromosomal aberrancies. Purpose was to investigate the expression levels of SDF-1? before and after bortezomib and thalidomide treatment. From February 2006 to April 2012, CXCR4 expression was prospectively assessed in bone marrow samples from a large population of patients (n=227) using flow cytometry. Clinical characteristics were collected and chromosomal aberrancies were assessed in 144 patients. SDF-1? levels were determined using ELISA in peripheral blood samples from 40 patients before and after chemotherapy. Our results show that CXCR4 was present in 43.2% (98/227) of newly diagnosed MM patients and that CXCR4 expression was significantly correlated with CD117 (P<0.05). CXCR4-positive MM patients had a significantly longer estimated survival time than CXCR4-negative patients (median of 48 vs. 42 months, P<0.05). Multivariate survival analyses identified that the +1q21/CXCR4- phenotype is an independent survival predictor, along with the International Staging System (ISS) stage. No significant difference was observed in expression levels of SDF-1? before and after bortezomib/thalidomide treatment. In conclusion, +1q21/CXCR4- could be an independent survival prognosis predictor in MM patients. Expression levels of SDF-1? before and after bortezomib/thalidomide treatment are not different, although they are higher than in controls.
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Advancement of human leukocyte antigen-partially matched related hematopoietic stem cell transplantation.
Front Med
PUBLISHED: 05-24-2013
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Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective options for hematological malignancies, and human leukocyte antigen-partially matched related donors (PMRDs) are a valuable option for HSCT. Several protocols (with or without ex vivo T-cell depletion (TCD)) have been established worldwide. TCD including CD34(+) positive selection and CD3/CD19 depletion has successfully overcome the human leukocyte antigen disparity. However, TCD is associated with prolonged immune deficiencies, increased risks of infectious complications, and high transplantation-related mortality. PMRD HSCTwithout ex vivo TCD is well developed, and numerous patients have benefitted from it. Here, we review the literature on PMRD HSCT.
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Comparable outcomes of partially matched related and matched related allogeneic hematopoietic cell transplantation following reduced-intensity conditioning in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia.
Int. J. Hematol.
PUBLISHED: 05-16-2013
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Reports from multiple centers have shown that reduced-intensity allogeneic hematopoietic cell transplantation (RIC-HCT) is able to benefit some adult patients suffering from Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL). However, the relationship between donor cell source and outcome of RIC-HCT in (Ph-)ALL patients has not been elucidated. In this study, we present the outcome of 57 (Ph-)ALL patients treated with reduced-intensity conditioning (RIC) followed by HCT from HLA-matched related (MRD, n = 34) or HLA partially matched related (PMRD, n = 23) donors from a multicenter cohort. Neutrophil recovery at day 100 occurred in 91.3 % of the PMRD group and 97.1 % of the MRD group (P = 0.84). One hundred days after treatment, the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 30.4 % (95 % confidence interval [CI], 13.0-53.0 %) in patients who received PMRD grafts, and 27.3 % (95 % CI, 15.0-48.0 %) for those who received MRD grafts (P = 0.76). The cumulative risk of developing chronic GVHD was 59.4 % (95 % CI, 31.0-72.0 %) in the MRD group and 23.4 % (95 % CI, 4.0-43.0 %) in the PMRD group (P = 0.03). The cumulative incidence of relapse in patients who received PMRD grafts was 18.8 % (95 % CI, 3.0-34.0 %), while for those who received MRD grafts it was 37.2 % (95 % CI, 15.0-48.0 %) (P = 0.32). Overall treatment-related mortality was 41.6 % (95 % CI, 20.0-62.0 %) in the PMRD group and 19.9 % (95 % CI, 7.0-35.0 %) in the MRD group (P = 0.08). Relapse was the most common cause of mortality in the MRD group, while infection contributed to the majority of deaths in the PMRD group. The 3-year probability of disease-free survival did not differ significantly between the two groups (55.5 % for the PMRD group vs. 48.4 % for the MRD group; P = 0.81). These data strongly suggest that RIC-HCT performed with PMRD may represent an alternative treatment option for adult patients with (Ph-)ALL.
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Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies.
Oncol Lett
PUBLISHED: 04-26-2013
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Contemporary combined therapies that include the use of all-trans retinoic acid (ATRA) and arsenic compounds have reduced relapse rates from ~50 to <10% in acute promyelocytic leukemia (APL) patients, however relapse treatment remains controversial. Treatment outcomes in relapsed patients with APL previously treated with combined ATRA + arsenic compound therapy were investigated. A retrospective, observational study was conducted of 25 patients with APL (male to female ratio, 17:8; mean age, 36.4±10.3 years) exhibiting first-time relapse following combined ATRA + arsenic compound therapy. These patients were subsequently treated with secondary ATRA + arsenic compound therapy, salvage chemotherapy, monoclonal antibody therapy or intrathecal chemotherapy, between January 1994 and December 2010. The overall remission rate, duration of remission and toxic effects were assessed. Patient outcomes included mortality during secondary induction therapy (6/25, 24.0%); complete recovery from central nervous system (CNS) relapse following intrathecal chemotherapy (1/25, 4.0%); complete remission following ATRA + arsenic compound therapy (10/25, 40.0%), chemotherapy (3/25, 12.0%) and targeted therapy (1/25, 4.0%); and non-remission (NR) following ATRA + arsenic compound therapy (4/25, 16%). Four (16.0%) patients were subsequently treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), two of which remained disease-free at the end of the study period and two of which succumbed to the disease. Secondary bone marrow and CNS relapse occurred in 14 (56.0%) patients and one (4.0%) patient, respectively. ATRA + arsenic compound-based combination therapy was effective in re-inducing morphological remission in relapsed patients with APL with previous exposure to ATRA + arsenic compounds, producing low molecular remission rates and high risk of secondary relapse. Furthermore, investigation of early allo-HSCT is required to determine its potential as a therapeutic option for re-inducing morphological remission in relapsed patients with APL with previous exposure to ATRA + arsenic compounds.
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Integrated detection of both 5-mC and 5-hmC by high-throughput tag sequencing technology highlights methylation reprogramming of bivalent genes during cellular differentiation.
Epigenetics
PUBLISHED: 03-15-2013
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5-methylcytosine (5-mC) can be oxidized to 5-hydroxymethylcytosine (5-hmC). Genome-wide profiling of 5-hmC thus far indicates 5-hmC may not only be an intermediate form of DNA demethylation but could also constitute an epigenetic mark per se. Here we describe a cost-effective and selective method to detect both the hydroxymethylation and methylation status of cytosines in a subset of cytosines in the human genome. This method involves the selective glucosylation of 5-hmC residues, short-sequence tag generation and high-throughput sequencing. We tested this method by screening H9 human embryonic stem cells and their differentiated embroid body cells, and found that differential hydroxymethylation preferentially occurs in bivalent genes during cellular differentiation. Especially, our results support hydroxymethylation can regulate key transcription regulators with bivalent marks through demethylation and affect cellular decision on choosing active or inactive state of these genes upon cellular differentiation. Future application of this technology would enable us to uncover the status of methylation and hydroxymethylation in dynamic biological processes and disease development in multiple biological samples.
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CD34 expression on bone marrow blasts is a novel predictor of poor prognosis independent of FlT3-ITD in acute myeloid leukemia with the NPM1-mutation.
Leuk. Res.
PUBLISHED: 02-11-2013
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To explore the prognostic value of CD34 expression in NPM1-mutated acute myeloid leukemia (NPM1m+AML), seventy-one NPM1m+AML patients were retrospectively analyzed. The patients with >7% CD34 expression (according to the ROC analysis) had a lower complete remission (CR) rate after 1 course of induction, disease-free survival (DFS), and overall survival (OS) compared to those with ?7% CD34 expression (p=0.0038; p=0.001; p<0.0001). A multivariate analysis revealed that CD34 expression is a prognostic factor that is independent of FlT3-ITD for relapse, DFS and OS. We established a novel prognostic model based on the CD34 and FLT3 status at diagnosis, which could facilitate the segregation of patients into three prognostically different subgroups. We demonstrate that CD34 expression on blasts is a novel, poor predictor independent of FlT3-ITD in NPM1-mutated patients and established a new prognostic model based on the CD34 and FLT3 status at diagnosis, which may facilitate immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices.
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Infusion of megakaryocytic progenitor products generated from cord blood hematopoietic stem/progenitor cells: results of the phase 1 study.
PLoS ONE
PUBLISHED: 02-04-2013
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Currently, a constant shortage in the supply of platelets has become an important medical and society challenge, especially in developing country, and the in vitro production of megakaryocytic progenitor cells (MPs) from cord blood could represent an effective platelet substitute. In the present study, our objective was to determine the safety and feasibility of ex vivo generated MPs in patients.
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Late-onset hemorrhagic cystitis after haploidentical hematopoietic stem cell transplantation in patients with advanced leukemia: differences in ATG dosage are key.
Int. J. Hematol.
PUBLISHED: 02-02-2013
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Late-onset hemorrhagic cystitis (LOHC) is a common complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its cause remains obscure. More attention to risk factors for LOHC is needed. We retrospectively analyzed patients with advanced leukemia who had been treated with ATG-containing conditioning regimens to evaluate the influence of different doses of ATG on LOHC after haploidentical HSCT. Seventy-five patients undergoing haploidentical HSCT from January 2003 to February 2011 were evaluated. A total of 39 patients receiving transplantation before June 2008 were treated with high-dose ATG (10 mg/kg), whereas 36 patients received low-dose ATG (6 mg/kg) thereafter. LOHC occurred in 16.7% of the patients with low-dose ATG, and in 38.5% of the patients with high-dose ATG (P = 0.027). Univariate analysis showed high-dose ATG, male gender and cytomegalovirus reactivation to be significant risk factors for LOHC. However, only high-dose ATG (HR 2.96, 95% CI 1.143-7.663, P = 0.025) and male gender (HR 4.033, 95% CI 1.355-12.008, P = 0.012) were independent risk factors, as shown by multivariate analysis. In the setting of haploidentical HSCT, we concluded that LOHC is more prevalent in recipients of high-dose ATG and male patients. Future studies should focus on immune reconstitution and virus infection after haploidentical HSCT with 6 mg/kg or 10 mg/kg ATG.
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Molecular monitoring and stepwise preemptive therapy for Epstein-Barr virus viremia after allogeneic stem cell transplantation.
Am. J. Hematol.
PUBLISHED: 01-19-2013
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The optimal preemptive therapy for Epstein-Barr virus (EBV)-associated diseases remains under discussion. We developed a stepwise preemptive therapy (antiviral agents and reduction of immunosuppressants [RI] followed by rituximab) for EBV viremia, based on duration of EBV viremia and changes of viral loads. The blood EBV-DNA loads were regularly monitored by quantitative real-time polymerase chain reaction in 251 recipients undergoing allogeneic stem cell transplantation. The 3-year cumulative incidence of EBV viremia and EBV-associated diseases were 31.1%?±?3.1% and 15.6%?±?2.5%, which rose steeply with greater numbers of major risk factors. Of the 64 patients undergoing first-step preemption, 24 achieved complete response (CR) and 40 showed no response, including 25 progressing to EBV-associated diseases. The effective rates of antiviral agents and RI plus antiviral agents were 2/16 and 22/48 (P?=?0.017). Fourteen achieved CR and one progressed to lymphoproliferative disease in the 15 patients undergoing rituximab preemption. Of the 26 patients progressing to EBV-associated diseases during preemptive therapy, 20 obtained CR in the 23 cases with rituximab-based treatments. The preemptive efficacy of RI plus antiviral agents was correlated with the numbers of major risk factors (rs ?=?-0.298; P?=?0.04). B-cell reconstitution was significantly delayed for at least 6 months in patients with rituximab preemption. The risk of herpesvirus infection was similar in patients who showed effective progress to first-step and rituximab preemption (P?=?0.094). RI plus antiviral agents could be given priority to low-risk patients, whereas more frequent monitoring of blood EBV-DNA and earlier preemptive rituximab should be advocated in high-risk patients. Am. J. Hematol. 00:000-000, 2013. © 2013 Wiley Periodicals, Inc.
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[Simultaneous determination of 15 anti-obesity drugs in blood by high performance liquid chromatography-tandem mass spectrometry].
Se Pu
PUBLISHED: 12-02-2011
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An analytical method for the simultaneous determination of 15 anti-obesity drugs (caffeine, sibutramine, phenformin, etc.) in blood sample was developed using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). After a simple protein precipitation step, the HPLC separation was performed on an UltimateXB-C18 column with methanol and 20 mmol/L ammonium acetate (containing 0.1% (v/v) of glacial acetic acid) as the mobile phases in a gradient elution mode. The MS/MS detection was achieved by electrospray ionization in both positive and negative modes by rapid switching with selective reaction monitoring (SRM). The results showed that the limits of quantification of all anti-obesity drugs were in the range of 0.001 -0.05 mg/L. The calibration curves of all anti-obesity drugs showed good linearity and the correlation coefficients were more than 0.99. The recoveries of all antiobesity drugs at 3 spiked levels were in the range of 77.3% - 110.8% with the intra-day and inter-day precisions less than 12.3%. The mass spectrum characterizations of 15 anti-obesity drugs were studied. The method is sensitive and reproducible for the detection of the 15 anti-obesity drugs in blood, and can also be applied to the determination of the anti-obesity drugs in pharmaceuticals or foods.
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Characterization of CD3+CD4-CD8- (double negative) T cells reconstitution in patients following hematopoietic stem-cell transplantation.
Transpl. Immunol.
PUBLISHED: 06-12-2011
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CD3+CD4-CD8-double negative (DN) T cells, as a distinct subset of regulatory T cells (Tregs), played a pivotal role in patients following hematopoietic stem-cell transplantation.
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Coinfusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation: a randomized, controlled clinical study.
Stem Cells Dev.
PUBLISHED: 02-05-2011
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Previous studies have suggested that mesenchymal stromal cells (MSCs) enhance the engraftment of hematopoietic stem cells and modulate the hosts immune response. However, there are no randomized studies to confirm these results. Moreover, there are some concerns about the risk of tumor recurrence because of the immunosuppressive property of MSCs. We conducted an open-label, randomized phase II clinical study to assess the outcome of MSC coinfusion (3-5 × 10(5) cells/kg) during haploidentical hematopoietic stem cell transplantation. From June 2007 to June 2008, a total of 55 patients who were diagnosed with leukemia in complete remission entered the study (27 in the treatment group and 28 in the control group). No immediate or long-term toxic side effects related to MSC infusion were noted, and the median times of white blood cell and platelet engraftment were comparable between the 2 groups. However, within 100 days, the time to a platelet concentration of >50 × 10(9) cells/L was markedly faster in the treatment group compared with the control group (22 days vs. 28 days; P = 0.036). Stromal-derived factor-1? (SDF-1?) reached a peak concentration more rapidly in the treatment group compared with the control group (8th vs. 16th day). The concentrations of SDF-1?, thrombopoietin (TPO), and interleukin-11 were also elevated in the MSC-treated group compared with the control group. The accumulative occurrence rate of acute graft-versus-host disease greater than grade 2 was 51.8% and 38.9% in the treatment and control groups (P = 0.422), respectively, whereas the occurrence rate of chronic graft-versus-host disease was 51.4% and 74.1% (P = 0.261), respectively. Through March 2010, which marked 2 years, the overall survival rate was 69.7% for the MSC-treated group and 64.3% for the control group (P = 0.737). Three patients in the treatment group and 2 patients in the control group experienced a hematological relapse and died of leukemia.
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Effect of Feining on bleomycin-induced pulmonary injuries in rats.
J Ethnopharmacol
PUBLISHED: 01-29-2011
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The flowers of Gentiana veitchiorum has been widely used in decoction form in the traditional medicine of Tibet against tussis, tracheitis, angina for their anti-inflammatory, antimicrobial and alexipharmic properties.
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Related HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion: observations of a single Chinese center.
Clin Transpl
PUBLISHED: 01-01-2011
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The Institute of Hematology, Peking University, is the largest hematopoietic stem cell transplantation (HSCT) center in China. A total of 400 HSCTs performed in 2010 accounted for a quarter of all allogeneic HSCTs performed in China. The GIAC protocol, which uses HLA-mismatched/haploidentical blood or bone marrow transplantation without in vitro T-cell depletion, entails administration of granulocyte-colony stimulating factor (G-CSF) to all donors, intensified immunological suppression, and treatment with anti-human thymocyte immunoglobulin. The stem cell grafts are a combination of G-CSF-primed bone marrow cells and G-CSF-mobilized peripheral blood stem cells, which may be critical to the success of this protocol through the immune modulation of G-CSF. Using this protocol, more than 99% engraftment and complete donor chimerism were achieved in pediatric and adult patients with hematological malignancies. The incidence of graft-versus-host disease (GVHD) grades 3 and 4 was 13.4% and that of extensive chronic GVHD 22.6%. Comparable relapse rates were observed between patients who received unmanipulated haploidentical transplantation, and those who received HLA-identical or unrelated HSCT. Patients with confirmed minimal residual disease, (expression levels of Wilms tumor suppressor gene 1 and flow cytometry) after HSCT received pre-emptive modified donor lymphocyte infusion to prevent relapse. Infection was the main cause of non-relapse death. Prospective studies are ongoing to investigate the mechanisms of immune reconstitution in order to refine the protocol. In 1964, a patient with severe aplastic anemia received a bone marrow infusion from her syngeneic, pregnant sister, and remained disease-free over a 40-year follow-up period. Following this success, there was a 20-year interruption in the transplantation program at our center. The hiatus ended in 1981 with the first allogeneic HSCT, which was used to treat a girl with acute lymphoblastic leukemia (ALL). In the mid-1990s, the facility performed allo-HSCTs from unrelated donors (URD) and umbilical cord blood (UCB). Then, in 2000, a patient with refractory acute leukemia received related haploidentical HSCT and achieved long-term survival without relapse over an 11-year followup period. Coincident with the rapid economic development experienced in China since 2000, the transplantation program at our Institute has been expanded to include broadened indications, multiple sources of stem cells and improved outcomes. The Institute is the largest HSCT center in China, now with 130 beds in four wards, 33 of which are laminar-flow rooms. Between 2007 and 2009, over 350 HSCTs were performed per year, rising to a total of 400 in 2010. Further, in 2010, 94% of these HSCTs were allogeneic transplants, accounting for a quarter of all allo-HSCTs performed in China. Of these, transplants from URD accounted for 6%-7%, those using UCB for less than 5%, those from identical siblings for 25%-30%, and those from the related haploidentical for 55%-65%. The most common indications for treatment with allo-HSCT are intermediate-to-high risk of acute leukemia or myelodysplastic syndrome, advanced chronic myeloid leukemia (CML), refractory lymphoma, or severe aplastic anemia.
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[Chemical constituents from root barks of Morus atropurpurea].
Zhongguo Zhong Yao Za Zhi
PUBLISHED: 10-12-2010
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To study the chemical constituents from the root barks of Morus atropurpurea.
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Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 09-22-2010
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Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3K? enzyme. In addition, a novel synthetic route was developed for these analogs.
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Aberrant expression of CKLF-like MARVEL transmembrane member 5 (CMTM5) by promoter methylation in myeloid leukemia.
Leuk. Res.
PUBLISHED: 08-10-2010
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CMTM5 has been shown to exhibit tumor suppressor activities, however, its role in leukemia is unclear. Herein we firstly reported the expression and function of CMTM5 in myeloid leukemia. CMTM5 was down-regulated, or undetectable, in leukemia cell lines and bone marrow cells from leukemia patients with promoter methylation. Ectopic expression of CMTM5-v1 strongly inhibited the proliferation of K562 and MEG-01 cells. In addition, significant negative correlations were observed between CMTM5 and three leukemia-specific fusion genes (AML1-ETO, PML-RAR? and BCR/ABL1). CMTM5 expression was up-regulated in patients who had undergone treatment. Therefore, CMTM5 may be involved in the pathomechanism of myeloid leukemias.
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Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-07-2010
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Prolonged thrombocytopenia is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, its pathogenesis has remained obscure. In the present study, we used flow cytometry to determine the frequency of bone marrow megakaryocytes (MKs) and MK ploidy distributions in allo-HSCT recipients with or without prolonged thrombocytopenia (n = 32 and 27, respectively) and healthy volunteers (n = 13). In addition, the expression of c-Mpl in MKs was measured. The results indicate that the proportions of MKs in marrow mononuclear cells or the percentages of CD110(+) MKs in total MKs did not significantly differ between the 3 groups; however, in a comparison of nonthrombocytopenic allo-HSCT recipients to healthy volunteers, the allo-HSCT patients who had prolonged thrombocytopenia exhibited significant shifts toward low ploidy cells (left shift), which were accompanied by a marked increase in ? 8N cells (P = .036 and P < .001, respectively) and significant decreases in 16N cells (P < .001 and P < .001, respectively) and ? 32N cells (P = .01 and P <.001, respectively). These results indicate that there were more immature MKs in allo-HSCT recipients who had prolonged thrombocytopenia, in comparison to nonthrombocytopenic allo-HSCT recipients and healthy volunteers. We conclude that prolonged thrombocytopenia and slow platelet engraftment after allo-HSCT may be related to a reduction in ploidy and an immaturation of MKs.
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[Chemical constituents from fruits of Ligustrum lucidum].
Zhongguo Zhong Yao Za Zhi
PUBLISHED: 06-26-2010
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To study the chemical constituents from the fruits of Ligustrum lucidum.
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A proteomic approach for plasma biomarker discovery with 8-plex iTRAQ labeling and SCX-LC-MS/MS.
Mol. Cell. Biochem.
PUBLISHED: 03-26-2010
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Plasma is recognized as a promising source of disease-related biomarkers, and proteomic approaches for identifying novel plasma biomarkers are in great demand. However, the complexity and dynamic protein concentration range of plasma remain the main obstacles for current research in this field. In this study, plasma proteins were prefractioned by immunodepletion and Protein Equalizer Technology to remove high abundant proteins, then labeled with an 8-plex isobaric tags for relative and absolute quantitation (iTRAQ) to improve the peptide ionization, and analyzed by strong-cation-exchange(SCX) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our results showed that both prefraction methods were complementary, with regard to the number of identified proteins. Good chromatographic technique is important to further fractionate the iTRAQ labeling peptides, which allowed 320 and 248 different proteins to be characterized from two prefraction methods, respectively, encompassing a wide array of biological functions and a broad dynamic range of 10(7). Furthermore, the accuracy of iTRAQ relative quantitation for differentially expressed proteins is associated with the number of peptides hits per protein.
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Examination of copy number variations of CHST9 in multiple types of hematologic malignancies.
Cancer Genet. Cytogenet.
PUBLISHED: 03-16-2010
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Carbohydrate N-acetylgalactosamine 4-0 sulfotransferase 9 (CHST9) belongs to the N-acetylgalactosamine 4-sulfotransferase (GalNAc4ST) family. A recent array-based study implicated the presence of copy-number variations (CNV) of the region encompassing CHST9 in the genomes of acute myelogenous leukemia. Most of the current studies, however, focused on the genome-wide screening of CNV, and the functional impact of such regions needs to be extensively investigated in large amounts of clinical samples. In our study, we collected 617 bone marrow samples from multi-types of hematologic malignancies, as well as healthy controls, and detected the CNV of CHST9 by real-time polymerase chain reaction (PCR). We found significant association between the CNV of CHST9 and these hematologic malignancies including acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, and myelodysplastic syndrome. We also examined CHST9 mRNA expression in the samples with one or two copies of DNA, and observed a weak yet positive correlation between the relative expression level and gene dosage. In general, the CNV of CHST9 have been shown to associate with hematologic malignancies. The functional consequences of CNV, however, need to be investigated extensively in the future.
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Characteristics of BCR-ABL kinase domain point mutations in Chinese imatinib-resistant chronic myeloid leukemia patients.
Ann. Hematol.
PUBLISHED: 03-07-2010
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To explore the characteristics of BCR-ABL kinase domain point mutations in Chinese chronic myeloid leukemia (CML) patients, a cohort of 127 patients with hematologic or cytogenetic resistance to imatinib are screened by direct sequencing. Mutations are found in 74 patients (58%). More patients with hematologic resistance show mutations compared to patients with cytogenetic resistance (70% vs 44%, p = 0.002), and more patients with acquired resistance present mutations compared to patients with primary resistance (68% vs 48%, p = 0.031). Frequencies of mutations were similar in early chronic phase (ECP), late chronic phase (LCP), accelerated phase, and blast phase (BP) patients (56%, 58%, 50%, and 69%, respectively; p > 0.05). Overall, 25 mutants are found in 21 amino acid sites, and four of them (I418V, E450A, E453L, and E455K) are first reported here. All patients with these four mutants either progress to or reenter the BP. The most frequent mutant is M244V, followed by Y253H, F359C/V/I, G250E, E255K, and T315I. Only seven patients (9%) have T315I mutants, and all showed hematologic resistance. Three of them were in the ECP and three in the LCP. Look-back studies show that mutants were detected 0-20 (median 7) months ahead of the appearance of clinical resistance in 15 tested patients with acquired resistance. ABL mutations are common in Chinese imatinib-resistant CML patients and are associated with clinical resistance. Chinese patients also seem to have unique profiles in the types and frequencies of some mutants, the disease phases of patients with T315I mutation, and the frequency of mutations in CP patients.
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Diarrhea during the conditioning regimen is correlated with the occurrence of severe acute graft-versus-host disease through systemic release of inflammatory cytokines.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-04-2010
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Graft-versus-host disease (GVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although many indicators have been used to predict GVHD, the prediction of GVHD remains very difficult. Determining how to predict the occurrence of acute GVHD (aGVHD) as exactly as possible has been a huge challenge so far. Systemic release of inflammatory cytokines during the conditioning regimen and early-phase post-HSCT plays a crucial role in the generation of aGVHD; additionally, the conditioning regimen causes the damage to the intestinal tract. Diarrhea is a common symptom of intestinal tract damage during the conditioning regimen. We therefore performed a prospective study to investigate the relationship between diarrhea related to the conditioning regimen, systemic release of inflammatory cytokines during the conditioning regimen and the early-phase post-HSCT, and the development of aGVHD. This study demonstrated that duration of diarrhea was >5.5 days, with a maximal volume >8.72 mL/kg and a mean volume of diarrhea for days -3 to 0 >7.94 mL/kg were risk factors of grade II to IV aGVHD. Diarrhea with any 1 risk factor was defined as severe diarrhea. Furthermore, this study first confirmed that the correlation between diarrhea and aGVHD was related to the serum levels of tumor necrosis factor (TNF)-? and interleukin (IL)-6 during the conditioning regimen and during the early phase after transplantation. Our study demonstrated that diarrhea related to the conditioning regimen could be used as a marker for the prediction of aGVHD and further explain the possible mechanism underlying the linkage described here. Therefore, for the patients with severe diarrhea related to the conditioning regimen, low-dose glucocorticoid may be used to reduce the levels of inflammatory cytokine release by a damaged intestinal tract, and possibly further reduce the occurrence of aGVHD. For these patients, prophylaxis of aGVHD may be need to be adjusted individually.
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Analysis of copy number variations of BS69 in multiple types of hematological malignancies.
Ann. Hematol.
PUBLISHED: 02-19-2010
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BS69 was originally identified as an adenovirus E1A-binding protein and was found to be involved in multiple cellular events. A recent array-based study implicated the presence of copy number variations (CNVs) of BS69 in the genomes of acute myelogenous leukemia. CNVs are present in the general population at varying degrees and have been found to associate with various types of diseases including hematological malignancies. However, most of the current studies focused on the genome-wide screening of CNVs, and the functional impact of such regions needs to be extensively investigated in large amount of clinical samples. Thus, in our study, we collected 617 bone marrow samples from multi-types of hematological malignancies as well as healthy controls. We found significant association between the CNVs of BS69 and these hematological malignancies including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), and myelodysplastic syndrome (MDS). We also examined the expression of BS69 mRNA in the samples with one or two copies of DNA, and observed a weak yet positive correlation between the relative expression level and gene dosage. In general, the CNVs of BS69 have the potential to serve as a diagnostic indicator, alone or in combination with other markers, for hematological malignancies.
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[Studies on chemical constituents from stems of Cudrania tricuspidata].
Zhongguo Zhong Yao Za Zhi
PUBLISHED: 08-19-2009
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To study the chemical constituents from the stems of Cudrania tricuspidata.
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Molecular responses of late chronic phase chronic myeloid leukemia patients after achieving complete cytogenetic responses with imatinib treatment: a 6-year follow-up.
Ann. Hematol.
PUBLISHED: 04-02-2009
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To explore the long-term efficacy of imatinib to chronic myeloid leukemia, a total of 46 late chronic phase (CP) patients were assessed after achieving complete cytogenetic response (CCyR). The median duration of imatinib treatment was 68 (61-74) months. Two hundred fifty-three bone marrow samples were detected BCR-ABL messenger RNA (mRNA) levels by TaqMan-based real-time quantitative reverse transcription-polymerase chain reaction. The median time when CCyR was first achieved was eight (3-72) months. Thirty-four patients achieved major molecular response (MMoR), and their median time when MMoR was first achieved was 35 (3-65) months. More patients achieving CCyR within 18 months obtained MMoR than those after 18 months (85% vs 42%, p = 0.006). One patient progressed into blastic crisis, and four patients suffered cytogenetic relapse later. The estimated 6-year event-free survival (EFS) rate of all patients was 81%. The BCR-ABL mRNA levels at the time of first CCyR of relapsed patients were significantly higher than those in continuous CCyR (p = 0.011). The 6-year estimated EFS rate of MMoR patients was significantly higher than that of non-MMoR patients (100% vs 44%, p = 0.0001). Achieving CCyR within 18 months had a higher probability of achieving MMoR within 6 years. The 6-year estimated EFS rate was significantly higher for patients achieving CCyR within 12 months than those after 12 months (97% vs 55%, p = 0.05). The time when MMoR was first achieved did not affect 6-year estimated EFS. Therefore, imatinib could induce most late CP patients to achieve long-term durable responses after achieving CCyR. Both the time when CCyR was first achieved and the depth of BCR-ABL reduction after CCyR are relevant to long-term EFS.
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Expression patterns of WT1 and PRAME in acute myeloid leukemia patients and their usefulness for monitoring minimal residual disease.
Leuk. Res.
PUBLISHED: 02-28-2009
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Both WT1 and PRAME are highly expressed in acute myeloid leukemia (AML) patients. To assess the efficacy of their simultaneous detection for the purpose of monitoring minimal residual disease (MRD), we used real-time quantitative RT-PCR to quantify both WT1 and PRAME transcript levels in the bone marrow of 204 newly diagnosed AML patients, and 21 patients were serially monitored for a median of 11 months. The 22 normal bone marrow samples which served as controls collectively expressed low levels of WT1 and PRAME. An increase of >1-log over the upper limit of normal bone marrow was defined as positive. The positive rates of WT1 and PRAME for all patients were 79.2% and 55.4%, respectively. For the 108 patients lacking a specific fusion gene, the positive rate of WT1 was significantly higher than that of PRAME (76.9% vs. 35.2%, P<0.001). PRAME was positive in 9/25 WT1 (-) patients and the log increase of PRAME was higher than that of WT1 in 12/83 WT1 (+) patients. Dynamic patterns of WT1 and PRAME during follow-up showed that a consistent elevation or a rise over time to exceed the normal range predicted clinical relapse. The exception was that one patients WT1 significantly decreased at relapse compared to diagnosis. Therefore, a simultaneous detection of WT1 and PRAME might not only provide AML patients with either a positive or a more sensitive molecular marker for MRD monitoring. Moreover, it might also avoid false negativity in the case of expression alteration.
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The preparation of LiCoO2 nanoplates via a hydrothermal process and the investigation of their electrochemical behavior at high rates.
Nanotechnology
PUBLISHED: 02-25-2009
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We report an alternative hydrothermal process for the preparation of pure phase LiCoO(2) cathode material for potential application under high rates. By adjusting the hydrothermal conditions, nanoplate-like LiCoO(2) crystals were obtained, with grain size about 200 nm. It was found in the experiment that the H(2)O(2) concentration and hydrothermal temperature were the two key factors that influence the phase purity and crystal shape, while LiOH concentration has only a slight effect on the crystal size of the product. The electrochemical test revealed a good rate behavior of the synthesized pure phase LiCoO(2) nanoplates, demonstrating a potential of the hydrothermal process for mass production.
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Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematologic malignancies in children.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-17-2009
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To evaluate the efficacy and safety of haploidentical (from family member donors) hematopoietic stem cell transplantation (HSCT) for children.
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Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1.
Arterioscler. Thromb. Vasc. Biol.
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Although the matricellular protein thrombospondin-1 (TSP1) is highly expressed in the vessel wall in response to injury, its pathophysiological role in the development of vascular disease is poorly understood. This study was designed to test the hypothesis that TSP1 stimulates reactive oxygen species production in vascular smooth muscle cells and induces vascular dysfunction by promoting oxidative stress.
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Calmodulin-binding locations on the skeletal and cardiac ryanodine receptors.
J. Biol. Chem.
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Ryanodine receptor types 1 (RyR1) and 2 (RyR2) are calcium release channels that are highly enriched in skeletal and cardiac muscle, respectively, where they play an essential role in excitation-contraction coupling. Apocalmodulin (apo-CaM) weakly activates RyR1 but inhibits RyR2, whereas Ca(2+)-calmodulin inhibits both isoforms. Previous cryo-EM studies showed distinctly different binding locations on RyR1 for the two states of CaM. However, recent studies employing FRET appear to challenge these findings. Here, using cryo-EM, we have determined that a CaM mutant that is incapable of binding calcium binds to RyR1 at the apo site, regardless of the calcium concentration. We have also re-determined the location of RyR1-bound Ca(2+)-CaM using uniform experimental conditions. Our results show the existence of the two overlapping but distinct binding sites for CaM in RyR1 and imply that the binding location switch is due to Ca(2+) binding to CaM, as opposed to direct effects of Ca(2+) on RyR1. We also discuss explanations that could resolve the apparent conflict between the cryo-EM and FRET results. Interestingly, apo-CaM binds to RyR2 at a similar binding location to that of Ca(2+)-CaM on RyR1, in seeming agreement with the inhibitory effects of these two forms of CaM on their respective receptors.
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Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3K? and mTOR.
Bioorg. Med. Chem. Lett.
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Lead optimization efforts that employed structure base drug design and physicochemical property based optimization leading to the discovery of a novel series of 4-methylpyrido pyrimidinone (MPP) are discussed. Synthesis and profile of 1, a PI3K?/mTOR dual inhibitor, is highlighted.
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DNA methylation of microRNA genes in multiple myeloma.
Carcinogenesis
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DNA methylation is one of the heritable epigenetic modifications, leading to repressed gene expressions and consequent phenotypic alterations without changing the DNA sequence. MicroRNA (miRNA) is a novel class of short non-coding RNA molecules regulating a wide range of cellular functions through translational repression of their target genes. Recently, epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM). This article presents a brief overview of the pathogenesis of MM, the role of DNA methylation in cancer biology, methods of DNA methylation analysis, miRNA biology and dysregulation of miRNAs in MM and summaries the current data on the role of DNA methylation of tumor-suppressive miRNAs in MM.
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Comparative analysis of the variable 3 UTR and gene expression of the KIN and KIN-homologous LEA genes in Capsella bursa-pastoris.
Plant Cell Rep.
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As the crucial members of the cold-regulated (COR) gene family, KIN genes are involved in diverse abiotic stress responses in plants. In the present study, KIN genes from the widespread plant Capsella bursa-pastoris were identified and analyzed to better understand the powerful adaptation of this species. Two KIN genes were cloned and sequenced by 3 RACE. As some COR genes are homologous to LEA genes, three KIN-homologous LEA genes were also identified. We deduced the amino acid sequences of the five proteins to estimate their phylogenetic relationships, and grouped them into three subfamilies (CI, CII, and CIII). Variable 3 UTRs were found in CI, CII, and CIII genes. Using qPCR, we evaluated the transcriptional levels of the five genes in different organs and embryonic stages. Two CI genes were exclusively expressed in early embryos and flowers. The CII and CIII genes showed obvious up-regulation in young leaves after heat stress, cold stress, and ABA treatment. Two of the CI genes, however, rarely responded to those stresses in young leaves. In contrast, all five genes showed differential responses in flowers when C. bursa-pastoris plants were sprayed with ABA. Furthermore, the expression of these genes in C. bursa-pastoris was compared to that of the corresponding Arabidopsis genes, and similar gene expression profiles were found in both species. Our findings suggest that these five genes play different roles in development and the responses to abiotic stresses in C. bursa-pastoris. Key message We characterized two KIN and three KIN-homologous LEA genes, and analyzed their variable 3UTR and organ-specific, embryo-developmental, stress-induced gene expression in Capsella bursa-pastoris.
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Plasma level of lipopolysaccharide-binding protein is indicative of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.
Int. J. Hematol.
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Acute graft-versus-host disease (aGVHD) is the major cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation. To date, there are no consensus specific plasma biomarkers for aGVHD. We recently identified several candidates differentially expressed in aGVHD patients. Here, we have validated one such candidate: lipopolysaccharide-binding protein (LBP). We detected plasma LBP level by ELISA in 73 patients and performed correlation analysis with the progression and severity of aGVHD. We found that plasma LBP level increased during the period of aGVHD and decreased markedly as aGVHD was resolved. LBP level in patients with moderate aGVHD (25-50 % skin rash area of grade 1 and grade 2) was higher than in patients with no, little (skin rash area <25 % of grade 1), or severe aGVHD (grade 3-4). Higher LBP level indicated higher probability of aGVHD. Multivariate analysis showed that LBP level above 15000 ng/ml was significantly associated with an increased risk of aGVHD (HR 2.43; 95 % CI 1.29-4.58; P = 0.006). If LBP level exceeded 15000 ng/ml at d7 and d14 after HSCT, the subsequent probability of aGVHD increased markedly, especially at the time point of d14. There was no correlation between LBP level and the site of aGVHD. In conclusion, our study demonstrated that an elevated LBP level of >15000 ng/ml may serve as a biomarker for the prediction and monitoring of aGVHD.
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Multicenter, randomized, open-label study comparing the efficacy and safety of micafungin versus itraconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplant.
Biol. Blood Marrow Transplant.
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This multicenter, randomized, open-label phase III study compared the efficacy and safety of micafungin and itraconazole in prophylaxis of invasive fungal infections in neutropenic patients undergoing hematopoietic stem cell transplants in China. Micafungin (50 mg/day i.v.) or itraconazole (5 mg/kg/day p.o.) was administered for ?42 days. The primary endpoint, treatment success, was defined as no proven, probable, or suspected invasive fungal infection through therapy and the absence of proven or probable invasive fungal infection through the end of 4 weeks after therapy. Noninferiority of micafungin against itraconazole was established if the lower boundary of the 95% confidence interval (CI) was >10%. Of 287 patients, 283 were evaluable for efficacy (136 for micafungin, 147 for itraconazole, intent-to-treat population). Treatment success was documented in 92.6% (126 of 136) of micafungin-treated patients and 94.6% (139 of 147) of itraconazole-treated patients (95% CI, -7.562% to 3.482%; P = .48), indicating noninferiority of micafungin against itraconazole. Results were similar for patients treated per protocol. Whereas the rates of proven or probable invasive fungal infection were numerically higher with micafungin than itraconazole at 4.4% (6 of 136) and 1.4% (2 of 147), rates of suspected invasive fungal infection were similar at 5.9% (8 of 136) and 7.5% (11 of 147), respectively. More patients treated with micafungin than itraconazole completed the study (82.9% versus 67.3%, respectively). Significant differences in incidence of withdrawal due to an adverse event (4.4% versus 21.1%) and drug-related adverse events (8% versus 26.5%) were shown between micafungin and itraconazole (P = .00, chi-square test). Micafungin was as effective as itraconazole in preventing invasive fungal infections in patients with neutropenia. In comparison to itraconazole, treatment tolerance was much better with micafungin.
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A multicenter, open-label study of posaconazole oral suspension in the treatment of invasive fungal infections in patients refractory to or intolerant of first-line therapy.
Future Microbiol
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Invasive fungal infections pose a severe health threat to patients. Despite recent advances in drug development, treatment of recurrent fungal infections remains difficult. Posaconazole is a broad-spectrum triazole antifungal drug available for oral administration. Although initial studies have described its use in treating various fungal infections, its efficacy and safety in patients with invasive fungal infections remains to be further confirmed.
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