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Objective@#To investigate the safety and efficacy of haploidentical hematopoietic stem cell transplantation with different intensity conditioning regimen in the treatment of childhood aplastic anemia (AA) .@*Methods@#Thirty-seven AA patients who underwent haploidentical transplantation in BaYi Children's Hospital Affiliated to PLA Army General Hospital from January 2013 to January 2017 were enrolled. According to the dosage of conditioning regimen, 34 patients excluding 3 other conditioning regimens were divided into high-dosage group (regimen 2, 22 cases) and low-dosage group (regimen 3, 12 cases). The data of Engraftment, graft-vs-host disease (GVHD), hematopoietic reconstitution, relapse, infection, overall survival (OS) were analyzed. The comparison between the two groups was tested by χ2 test.@*Results@#A total of 35 of 37 patients achieved primary engraftment; 2 cases died of regimen-related toxicity and severe infection before the infusing of the grafts. The activation rate of CMV and EBV was 60% (21/35) . Post-transplant lymphocyte disease (PTLD) of lung occurred in one case. The cumulative incidences of acute GVHD grade Ⅰ-Ⅳ and chronic GVHD were 29% (10/35) and 34% (12/35) respectively and the incidence of extensive chronic GVHD was 6% (2/35) . The median follow-up time was 18.8 (2.9-44.1) months, the OS was 92% (34/37) .All survived patients were no longer dependent on blood transfusion and none of them had recurrence. Comparing the rates of overall survival(86%(19/22) vs.100%(12/12)) and rates of chronic GVHD(40%(8/20) vs. 17%(2/12)) in regimen 2 and regimen 3 group, there were no significant difference (χ2=1.742, 1.841, all P>0.05) . Significant difference was found at the incidence of Ⅰ-Ⅳ acute GVHD (10% (2/20) vs. 50% (6/12) ,χ2=6.200, P=0.013).@*Conclusions@#Haploidentical hematopoietic stem cell transplantation is effective and safe. It is suitable for patients who are not eligible for matched donor transplantation. Application of reduced dose preconditioning in haploid transplantation is worth exploring.
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BACKGROUND:CTLA-4Ig as a tolerance-induction agent is a potential strategy in graft-versus-host disease prevention. OBJECTIVE:To investigate the efficacy of CTLA4Ig-gene-modified bone marrow stromal cels mediated by adenovirus to induce T-cel tolerance of haploidentical donors. METHODS: The bone marrow stromal cels isolated culture from the bone marrow of HLA haploidentical donors were transfected by recombinant adenovirus encoding CTLA4IgcDNA (AdCTLA4Ig) at a multiplicity of infection=50 for 72 hours. The expression rate and the location of CTLA4Ig in the transfected cels were detected by fluorescence microscope after immunofluorescence staining. CTLA4Ig-modified bone marrow stromal cels (2×104, 4×104and 8×104) were respectively co-cultured with 105 T cels from the peripheral blood of HLA haploidentical donors and 105 peripheral blood mononuclear cels from recipients. The proliferative inhibition rate was determined by MTT assay, and the level of interleukin-2 in the supernatant was detected by ELISA. The bone marrow mononuclear cels (1×105/wel) were co-cultured with CTLA4Ig-modified bone marrow stromal cel layers constructed in 6-wel plates. The number of bone marrow mononuclear cels and colony-forming unit-granulocyte macrophages were calculated after 5-day culture. RESULTS AND CONCLUSION: The expression rate of CTLA4Ig at the multiplicity of infection=50 was as high as 85%, and the immunofluorescence signals of CTLA4Ig were distributed unevenly in the cytoplasm. The inhibition rates of 2×104, 4×104, and 8×104 CTLA4Ig-modified bone marrow stromal cels on proliferation of T cels were higher than that of untransfected cels. The levels of interluekin-2 in the corresponding cel groups were significantly lower than that in the untransfected cels (P 0.05). These findings indicate that CTLA4Ig-modified bone marrow stromal cels mediated by adenovirus can induce immune tolerance of T-lymphocyte from HLA haploidentical donors in vitro.
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Objective To investigate the relationship between single nucleotide polymorphisms (SNPs),serum CD31 and HCC.Methods We analyzed three single nucleotide polymorphisms of CD31 gene Leu125Val,Asn563Ser and Gly670Arg in 190 HCC patients and 210 age and sex matched controls in a Chinese population,using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy,and the serum level of CD31 was determined by enzyme-linked immunosorbent assay (ELISA).Results The distributions of CD31 gene Asn563Ser and Gly670Arg polymorphisms were not significantly different between HCC and control group (x2 =0.491,P ＞ 0.05),but the CD31 gene Leu125Val polymorphism was significantly different (x2 =10.988,P ＜ 0.05).The relative risk suffering from HCC of Val allele was 1.583 times of the Leu allele carriers(OR =1.583,95％ CI,1.197-2.093,P =0.001) ; Serum level of CD31 Val allele carriers was significantly higher than that of no carriers(x2 =10.408,P ＜ 0.05).Consistent with the results of the genotyping analyses,CD31 gene Leu125Val,Asn563Ser and Gly670Arg polymorphisms showed strong linkage disequilibrium,the Val-Ser-Arg haplotype was associated with a significantly increased risk of HCC as compared with the controls (OR =1.496,95％CI:1.095-2.046,P =0.011).Conclusions CD31 gene Leu125Val polymorphism and its Val-Ser-Arg haplotype were associated with HCC,Val allele is an important genetic susceptibility gene for HCC.CD31 Val allele carriers may subject to higher risk of HCC with enhanced CD31 expression.
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Objective To explore the effect and feasibility of haplotype allogeneic hematopoietic stem cell transplantation (allo-HSCT) used in the childhood patients with refractory and relapsed leukemia.Methods Thirty children with refractory and relapsed leukemia received haplotype allo-HSCT from June 2007 to June 2011 in Beijing Military General Hospital,including 14 cases of acute myeloid leukemia (AML) and 16 cases of acute lymphoblastic leukemia (ALL).Of the 30 cases,there were 11 cases of initial recurrence,16 cases of second or more relapse,and 3 cases of primary refractory leukemia.The bone marrow and peripheral blood of donors were used for transplantation.All children were subjected to pretreatment consisting of cytarabine,busulfan,fludarabine and total body irradiation (TBI),etc.Graft-versus-host disease (GVHD) was prevented by combining variety of immunosuppressants including Cyclosporin A (CsA),Methotrexate (MTX),Mycophenolate mofetil (MMF) and anti-thymocyte immunoglobulin (ATG),etc.The regimen-associated side effect incidence of GVHD and disease-free survival probabilities were observed after HSCT.Results The results showed that all of the 30 children acquired hematopoietic reconstitution,and the median time of granulocytes exceeding 0.5 × 109/L and platelets exceeding 20 × 109/L which were transplanted 100％ by donors was 18.5 days and 24.2 days respectively.The mean follow-up period was 22.5 months (3 ～48 months).Twelve children had experience of acute GVHD,and 6 children had experience of chronic GVHD.Four children died of GVHD,3 died of infection and 6 died of relapse,and the rest children were alive in free situation.The 2-year disease-free survival rate was 55％.Conclusion Haplotype allo-HSCT was an safe and feasible therapy for the childhood patients with refractory and relapsed leukemia.
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ObjectiveTo investigate the relationship between tumor necrosis factor (TNF) α308,TNF-β252 genotypes and serum TNF-α and TNF-β levels in patients with gastric cancer (GC).MethodsA total of 57 pathological diagnosed GC patients were collected,of which 49 cases were from Zhongnan Hospital of Wuhan University and 8 cases were from Tumor Hospital of Hubei Province.Another 18 age and sex matched healthy controls were enrolled at the same time.The TNF-α308 and TNF -β252 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The serum TNF-α and TNF-β levels of 57 GC patients and 18 healthy controls were measured by ELISA.The difference of TNF serum level in different TNF genotypes of GC and the difference between GC patients and the healthy controls was analyzed.Its relationship with clinical pathological characters was also analyzed.Results With TNF-α308 genotype,GA were 6 cases and GG were 51 cases.With TNF-β252 genotype,GG were 17 cases,GA and AA each were 20 cases.The serum TNF-α level of GC patients was significant higher than that of healthy controls (median 445 × 10-3 μg/L vs 5 × 10-3 μg/L,P＜0.05),and the serum level of each TNF-α308 andTNF-β 252 genotypes was significant higher than that of healthy controls (P＜0.05).However there was no statistical significance in TNF -β level compared with healthy controls (P＞0.05).In addition,the serum TNF-α levels of the TNF-α308G/TNF-β252G and TNF-α308G/TNF β252A haplotypes in GC patients were significant higher than those of the healthy controls (P＜0.05),and the increase like serum TNF-α level was associated with the patients'age and lymph node metastasis (P＜0.05).The TNF-β level in patients with TNF-α308A and TNF-β252G high-risk haplotypes showed a significant relation with smoking history (P＜ 0.05). Conclusions Serum TNF-α level of GC patients was significantly higher,however there was no significant association between the increase and TNF-α308 and TNF-β252 genotypes.The serum TNF-α levels of TNF-α308G/TNF-β252G and TNF-α308G/TNF-β252A haplotypes in GC patients were significant higher,and associated with the patients'age and lympb node metastasis.It was indicated that TNF haplotypes may have certain impact on the TNF expression and clinical subtypes in GC.
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Objective The present report describes the clinical effects of parental haploidentical hematopoietic stem cell transplantation (hi-allo-HSCT) in the treatment of hematologic diseases. Methods A total of 45 patients received parental hiallo- HSCT from July 2007 to January 2011. The therapeutic effects and complications were observed. Results Engraftment was successful in a total of 43 patients. Implantation failed in 2 patients. The incidence of the graft versus host disease (GVHD) was 62.2%. The incidence of acute GVHD was 40.0%, and chronic GVHD occurred in 22.2% of the patients. The incidence of GVHD was lower when the father was the donor compared with the mother was the donor. The incidence of GVHD was related to the age of the donor and the number of HLA matching sites. In addition, infections observed in the present study were mainly blood-borne with cytomegalovirus as the invader and lung infections. During the follow-up period of 6 months to 4 years, six patients died in the 43 patients with successful implantation. The major cause of death was infection and a relapse of their original disease. The disease free survival (DFS) rate was 86.7%. Seven patients additionally received umbilical cord blood, their efficacy in the transplantation seemed better than those who received parental stem cells only, as hematopoietic reconstruction was faster and the incidence of GVHD accounted for only 7.14% of the total incidence rate. Conclusions Parental hi-allo-HSCT is an effective treatment for hematologic diseases. A young male donor with more HLA matching sites is recommended to prevent GVHD and infection. The combination of parental hi-allo-HSCT and umbilical cord blood transplantation could result in positive effects with faster hematopoietic reconstruction and a lower incidence of GVHD.
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Objective To explore the association between genetic polymorphisms and haplotypes of tumor necrosis factor-related apoptosis inducing ligand (Trail) and ulcerative colitis (UC).Methods A total of 331 patients with UC and 832 age and sex-matched healthy controls were collected.After Trail gene was amplified by PCR,the genetic polymorphisms of three single nucleotides (G1525A/G1588A/C1595T) in 3' non coding regions of Trail gene were examined by direct sequencing.The relation between Trail haplotype and UC was analyzed.Results Compared with control group,the frequencies of variant allele A and genotype GA+ AA in Trail G1525A were significantly lower in UC group (both P＜0.01).The frequencies of variant allele A and T in Trail G1588A and C1595T were also significantly lower in UC group than that of control group,and the difference was statistically significant (both P ＜ 0.01 ).In mild and moderate UC patients,the frequencies of variant allele T and CT+TT in Trail C1595T were 49.15％ and 64.51％,in severe UC patients were 72.37％ and 84.21％,and the differences were significant between the two groups (OR=2.710 and 2.935,95％CI:1.598～4.596 and 1.188～7.249,all P ＜0.05).In severe UC patients,the frequency of variant allele A in Trail G1525A was 48.69％,which was higher than that of mild and moderate patients (35.16％,OR=1.750,95％CI:1.082～2.830,P=0.021).In UC group,the frequency of AAT haplotype was significantly lower than that of controls (43.09％ vs 58.41％,P＜0.01).The frequency of GAT haplotype was significantly higher in UC group (10.15％vs 0.18％,95％ CI:0.005 ～ 0.051,P＜ 0.01).Conclusion The genetic polymorphisms and haplotypes of Trail (G1525A/G1588A/C1595T) gene may be closely correlated with the susceptibility to UC.
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Objective To investigate the relationship between the single nucleotide polymorphisms (SNPs) of TLR9 gene and the occurrence of condyloma acuminatum (CA). Methods Peripheral venous blood was obtained from 63 patients with CA and 23 normal human controls with informed consent. DNA was extracted from the blood samples and subjected to the amplification of TLR9 gene by PCR followed by sequence analysis. Results There were 4 SNPs, i.e., SNP1, SNP2, SNP3 and SNP4 at positions 1174, 1635, 1269 and 1724 of the TLR9 gene, respectively. Of these SNPs, SNP1 was located in intron 1, SNP2, SNP3 and SNP4 in exon 2. The registration number is rs352139 for SNP1, rs352140 for SNP2 in NCBI database. SNP3 and SNP4 were newly discovered positions. The frequency at SNP1 position was 0.690 and 0.609 for allele A in the patients and controls, respectively, 0.309 and 0.391 for allele G, respectively (both P > 0.05). No significant difference was observed between the patients and controls in the frequency of allele A or allele G at position SNP2 (0.302 vs. 0.698, 0.369 vs. 0.630, both P > 0.05). There were 4 haplotypes at the SNP1 and SNP2 positions, including AA, AG, GA and GG, with no significant difference in the frequency between the patients and controls (all P> 0.05). Conclusions There are 4 SNPs including SNP1, SNP2, SNP3 and SNP4 in the TLR9 gene in Guangdong Han population. SNP1 and SNP2 appear unrelated to the liability to CA.
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Objective To explore the incidence ,clinical and neuroimaging features, possible risk factors and outcome of central nervous system (CNS) complications one year after hapilo-matched non-ablative hematopoietic stem cells transplantation. Methods The medical records of 36 consecutive patients who underwent hapilo-matched non-ablative hematopoietic stem cells transplantation for malignant and nonmalignant hematologic diseases between February 2004 and May 2009 were reviewed. Results CNS complications occurred in six (16.7 %) patients. Four of the six patients (66.7 %) died. Cerebral infarction occurred in three (8.3 %) patients. Cerebral softenness occurred in two (5.6 %) patients. Cerebral hemarrage occurred in 1 (2.8 %) patient. Epilepsy occurred in 1 (2.8 %) patient. The CNS complications occurred between 12 days and 286 days after stem cells transplantation. The age illness status and death rate were statistically different compared to patients without CNS complications (P ＜0.05). Conclusion The incidence and mortality of CNS complications are higher in those who underwent hapilo-matched non-ablative hematopoietic stem cells transplantation,which will make impacts on the patients' life quality and outcome.The illness status and eldly are probably the risk factors.
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Objective To investigate the association between a few single nucleotide polymorphisms (SNPs)in Fc receptor like 3(FcRL3)and rheumatoid arthritis(RA)in Han nationality of Anhui patients.Methods One hundred and forty RA patients along with one hundred and eighty-seven healthy controls were included in the study.SNPs of FcRL3-1(rs0158440),FcRL3-2(rs2225828),FcRL3-3(rs7528684).FcRL34(rs11284799),FcRL3-5(rs945635),FcRL3-6(rs3761959),FcRL3-7(rs2210913),FcRL3-8(rs2282284)and FcRL3-9(rs2282283)in the FcRL3 gene were genotyped by MALDI-TOF technology.Haplotypes were estimated using PHASE v 2.1 software.Results The frequency of FcRL3-3-1 69C alleles in RA patients was significantly increased compared with healthy controls(X~2=7.348,P=0.007,OR=1.558,CI:1.130～2.150).The decreased compared with healthy controls.ConclusionFcRL3 may be associated with RA susceptibility in Anhui Han population.
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Objective To investigate the correlation between gene polymorphism within human β defensin 1 (DEFB1) and fungal susceptibility to severe sepsis through case-control association study.Methods A total of211 patients with severe sepsis in ICU were enrolled in the present case control study. Sepsis in this study was diagnosed according to the definition of American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference in 1992 and 2002. Based on the development of fungal infection during ICU stay, all 211 patients were divided into fungal infection group (Group Ⅰ) and control group (Group C). Alleles and genotypes of-1816A/G, -390A/T, -52A/G, -44C/G and-20A/G within DEFB1 gene were assayed in all 211 patients by means of DNA direct sequencing, Allele-specific PCR amplifications or high-throughput site-specific TaqMan assay. Genetic analysis was employed to calculate the distribution frequency of haplotypes. The correlation between the genomic variations (allele,genotype and haplotype) and fungal infection was analyzed by Chi-square test or Fisher's exact test.Odds ratio (OR) was employed to reflect the correlation degree of genetic factor with fungal susceptibility to severe sepsis. Results Group Ⅰ enrolled 80 patients, of whom 43 pstients were male, at age of (60.81 ± 18.30) years. Group C enrolled 131 patients, of whom 80 patients were male, at mean age of (60.42 ± 17.03) years. No significant difference was found between two groups in aspect of gender and age (P＞0.05). The genetic locus of -1816A/G, -390A/T, -52A/G, -44C/G and -20A/G of both groups were in agreement with Hardy Weinberg equilibrium. No significant difference was found between two groups in the distribution of allelic frequencies and genotype frequencies (P ＞0.05). No significant difference was found in the distribution frequency of four common haplotypes of the above five genetic locus such as AAACG, ATGCA, GTGGG and ATACG (all P ＞ 0.05). Conclusions Genetic locus of -1816A/G, -390A/T, -52A/G, -44C/G and-20A/G within DEFB1 gene have no correction with fungal infections in severe sepsis, suggesting that DEFB1 gene polymorphism may not serve as a key genetic marker for the predisposition to fungal infection in severe sepsis.
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Objective To evaluate the effect of haploidentical lymphocyte infusion on refractory and relapse acute leukemia. Methods The haploidentical donor lymphocyte infusion was used to treat for relapse acute myeloid leukemia 3 patients (M2 2 eases, M4 lcase), one relapse acute lymphocyte leukemia from April 2006 to October 2007. Four cases who had accepted secondly regimens were ineffective,after relapse. Collecting donor lymphocytes, parents children as donor supply in 3 cases, mother as donor supply one case. Before donor lymphocyte infusion patients received chemotherapy of different regimens. Donor haploidentical iymphocytes irradiated by 6-8 Gy radial were infused when patients white cell count was at the lowest after the chemotherapy. The average of infusion cells was 2.3 (1.4-3.1)×108/kg. Results One patient acquired complete remission and two patients were effective in three relapse acute myeloid leukemia. It was ineffective in relapse acute lymphocyte leukemia. No transfusion related graft versus host disease was observed. One patient has had herpes zoster virus infection. Conclusion Haploidentical donor lymphocyte infusion with chemotherapy are effective for refractory and relapse in acute myeloid leukemia, but the infused cell quantity and irradiated dosage must be further discussed.
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Objective To compare the clinical effect, hematopoietic reconstitution, and adverse effects of compatriots HLA in the same period with haploidentical allogeneic hematopoietic stem cell transplantation among relatives for treatment of haematological malignancies. Methods 9 patients of compatriots HLA and 9 patients of haptoidentical allogeneic were recruited. The clinical effect, hematopoietic reconstitution, and transplant-related adverse effects of the observation groups were retrospectively analyzed. Results There was no statistical difference between the clinical effect in two groups, hematopoietic reconstitution, pretreatment-related toxicity and acute and chronic GVHD. The infusion volume of blood products, CMV infection and fungal infection in haploidentical transplant group was higher than that in compatriots HLA group. Conclusion HLA haploidentical family donor transplantation is a good way to increase the source of donor for the treatment of haematological malignancies.
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Objective:To evaluate the efficacy and safety of haploidentical(from family member donors) hematopoietic stem cell transplantation(HSCT) for children with hematologic malignancies.Methods: Fifty-eight children under fourteen years with hematological malignancies underwent haploidentical HSCT.All patients had poor-risk clinical or cytogenetic features and reclassified into high-risk and standard-risk groups.Transplantation outcomes were analyzed.Results: Of fifty-eight patient/donor pairs,seven(12.1%) were mismatched in two HLA loci,twenty(34.5%) in three loci,and thirty-one(53.4%) in four loci.Follow-ups were performed for a median of 1 663(752-2 664) days after transplantation.All patients achieved stable engraftments.The cumulative incidence of acute graft-versus-host disease(GVHD) of grades 2-4 was(54.8?7.6)%,and that of grades 3-4 was(11.4?4.8)%.The cumulative incidence of chronic GVHD was(45.6?7.8)% for the total and(19.6?6.5)% for the extensive.Thirty-eight patients survived with a 2-year actual overall rate of survival 59.0% and 78.9% in the high-risk and standard-risk group,respectively.The 3-year probability of LFS was(58.6?8.0)% and(68.4?10.7)%,respectively.Conclusion: The results encourage extending haploidentical HSCT without T-cell depletion treatments to children with an indication for transplantation.
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Objective To investigate whether the killer cell immunoglobulin like receptor (KIR) gene polymorphisms are associated with seronegative spondylarthropathies.Methods All 197 HLA B27 positive patients with seronegative spondyloarthro pathies (SpA) and 83 randomly ethnically matched healthy controls were enrolled to detect the KIR genotype using PCR SSP in Shanghai area.Results The KIR3DL1 gene frequency was significantly lower in the patient group (0 763) than in the control group (1 00) (RR=0 76, P =0 003).Meanwhile,the gene frequencies of two pseudogenes (KIR2DP1,KIR3DP1) were significantly higher in SpA group than in healthy control group (RR=1 1, P =0 004).Conclusion There may be a negative association between pathogenesis of SpA and KIR3DL1 gene.The function of KIR3DL1 molecule should be investigated deeply.