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Li H.,Chinese Institute of Basic Medical Sciences | Jiang Y.,Second Artillery General Hospital | Jiang X.,Chinese Institute of Basic Medical Sciences | Guo X.,Chinese Institute of Basic Medical Sciences | And 9 more authors.
Stem Cells | Year: 2014

Inefficient homing of systemically infused mesenchymal stem cells (MSCs) limits the efficacy of existing MSC-based clinical graft-versus-host disease (GvHD) therapies. Secondary lymphoid organs (SLOs) are the major niches for generating immune responses or tolerance. MSCs home to a wide range of organs, but rarely to SLOs after intravenous infusion. Thus, we hypothesized that targeted migration of MSCs into SLOs may significantly improve their immunomodulatory effect. Here, chemokine receptor 7 (CCR7) gene, encoding a receptor that specifically guides migration of immune cells into SLOs, was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (MSCs/CCR7). We found that infusion of MSCs/CCR7 potently prolonged the survival of GvHD mouse model. The infused MSCs/CCR7 migrate to SLOs, relocate in proximity with T lymphocytes, therefore, potently inhibited their proliferation, activation, and cytotoxicity. Natural killer (NK) cells contribute to the early control of leukemia relapse. Although MSCs/CCR7 inhibited NK cell activity in vitro coculture, they did not impact on the proportion and cytotoxic capacities of NK cells in the peripheral blood of GvHD mice. In an EL4 leukemia cell loaded GvHD model, MSCs/CCR7 infusion preserved the graft-versus-leukemia (GvL) effect. In conclusion, this study demonstrates that CCR7 guides migration of MSCs to SLOs and thus highly intensify their in vivo immunomodulatory effect while preserving the GvL activity. This exciting therapeutic strategy may improve the clinical efficacy of MSC based therapy for immune diseases. Stem Cells 2014;32:1890-1903 © 2014 AlphaMed Press.


Lv W.,Second Artillery General Hospital | Chen L.,Chinese PLA General Hospital | Zhou D.-H.,Second Artillery General Hospital | Wei B.,Chinese PLA General Hospital
Cancer Biotherapy and Radiopharmaceuticals | Year: 2010

The influence of specific blocking of the Delta-like ligand 4 (DLL4)/Notch signal transduction pathway on the biological behavior of human umbilical vein endothelial cells (HUVECs) has been studied. Recombinant adeno-associated virus (rAAV) vectors expressing an active small interfering RNA (siRNA) (vector 6) targeting the DLL4 (rAAV-DLL4-short hairpin RNA [shRNA]) was used to infect HUVECs. The same cell line infected with empty plasmid (rAAV-EGFP) was used as a control. Stable transfection and expression of DLL4-mRNA in HUVECs were determined by semiquantitative RT-polymerase chain reaction (PCR). Protein expression of DLL4 was examined by western blotting. The distribution of cells in cell cycle was assessed by flow cytometry and cell growth was analyzed by MTT assay. HUVECs were seeded on type I collagen and cultured in a three-dimensional culture system to allow for tubule-like structure (TLS) formation. Compared with negative controls, semiquantitative RT-PCR and western blot analysis showed that the expression of DLL4 mRNA and protein was downregulated in stably transfected cells (p = 0.024, p = 0.033). HUVEC growth and proliferation were stimulated following infection with rAAV vectors containing active siRNA against DLL4, whereas infection with empty plasmid had no specific effect. The proliferation index of rAAV-DLL4-shRNA-infected HUVECs was 39.90% ± 2.19% compared with 25.63% ± 4.54% (p = 0.036) for control-treated cells. TLS formation was significantly induced in cells expressing the rAAV vector; the average length of TLS was greater than the control group (p = 0.028). Altogether, the data suggest that inhibiting the DLL4/Notch signal transduction pathway stimulated proliferation of HUVECs, thereby facilitating angiogenesis. © 2010, Mary Ann Liebert, Inc.


Yang B.,Chinese PLA General Hospital | Lu X.-C.,Chinese PLA General Hospital | Yu R.-L.,Chinese PLA General Hospital | Chi X.-H.,Second Artillery General Hospital | And 6 more authors.
Hematological Oncology | Year: 2012

The elderly population is susceptible to haematological malignancies, and these elderly patients are intolerant to cytotoxic drugs. Therefore, the exploration of a safe and reliable strategy exclusive of chemotherapy is critical in improving the prognosis of elderly patients with haematological malignancies. We evaluated the safety and the efficacy of autologous cytokine-induced killer (CIK) cells combined with recombinant human interleukin 2 (rhIL-2) in the treatment of haematological malignancies in elderly patients. Peripheral blood mononuclear cells were isolated from 20 elderly patients with haematological malignancies, then augmented by priming with interferon gamma, rhIL-2 and CD3 monoclonal antibody. The autologous CIK cells (2-3×109) were transfused back to patients, followed by a subcutaneous injection of IL-2 (1mU/day) for 10 consecutive days. The regimen was repeated every 4weeks. The host cellular immune function, tumour-related biological parameters, imaging characteristics, disease condition, quality of life and survival time were assessed. Fourteen patients received 8 cycles of transfusion and 6 received 4 cycles. No adverse effects were observed. The percentages of CD3+, CD3+CD8+ and CD3+CD56+ cells were significantly increased (p<0.05), and the levels of serum β2 microglobulin and lactate dehydrogenase (LDH) were markedly decreased (p<0.05) after autologous CIK cell transfusion. Cancer-related symptoms were profoundly alleviated, as demonstrated by the improved quality of life (p<0.01). Complete remission was observed in 11 patients, persistent partial remission in 7 patients and stable disease in 2 patients. At the end of follow-up, the mean survival time was 20months. Transfusion with autologous CIK cells plus rhIL-2 treatment is safe and effective for treating haematological malignancies in elderly patients. © 2011 John Wiley & Sons, Ltd.


Ding J.-H.,Cleveland Clinic | Ding J.-H.,Second Artillery General Hospital | Canedo J.,Cleveland Clinic | Lee S.-H.,Cleveland Clinic | And 3 more authors.
Diseases of the Colon and Rectum | Year: 2012

BACKGROUND: The surgical approach to recurrent full-thickness rectal prolapse after perineal rectosigmoidectomy is complicated by recurrent prolapse. The majority of patients who undergo perineal rectosigmoidectomy are elderly with comorbidities. Therefore, redo perineal rectosigmoidectomy is usually selected to avoid postoperative complications. OBJECTIVE: This study aimed to evaluate the safety and efficacy of redo perineal rectosigmoidectomy for recurrent full-thickness rectal prolapse. DESIGN: This is a retrospective cohort study. SETTING: This study was conducted at Cleveland Clinic Florida, from January 2000 to March 2009. PATIENTS: One hundred thirty-six patients (129 women), mean age 78 (range, 31-98) years, were included in the study; 113 patients with full-thickness rectal prolapse underwent primary perineal rectosigmoidectomy, and 23 patients with recurrent full-thickness rectal prolapse underwent redo perineal rectosigmoidectomy. INTERVENTIONS: All patients underwent perineal rectosigmoidectomy. MAIN OUTCOME MEASURES: Perioperative outcomes, recurrence curves, and risk of recurrence were compared between the 2 groups. Age, anterior compartment prolapse, concurrent levatorplasty, and length of bowel resection were analyzed to identify factors potentially influencing recurrence. RESULTS: Both groups had comparable demographics, BMI, and ASA scores. Operative time, blood loss, length of bowel resection, hospital stay, and follow-up (mean, 42.5 months) were similar in both groups. There was no significant difference in overall complication rates (redo perineal rectosigmoidectomy 17.4% vs primary perineal rectosigmoidectomy 16.8%; p = 1.00). The recurrence rate for full-thickness rectal prolapse was significantly higher for redo perineal rectosigmoidectomy than primary perineal rectosigmoidectomy (39% vs 18%; p = 0.007). None of the factors analyzed was associated with recurrence in either group. LIMITATIONS: This study was limited by its retrospective methodology. In addition, functional outcomes were not evaluated, because many of the patients died during the follow-up period or were unavailable because of advanced age. CONCLUSIONS: Redo perineal rectosigmoidectomy is as safe and feasible as primary perineal rectosigmoidectomy in elderly and fragile patients with recurrent full-thickness rectal prolapse. However, the re-recurrence rate for full-thickness rectal prolapse is substantially higher for redo perineal rectosigmoidectomy than primary perineal rectosigmoidectomy. © The ASCRS 2012.


Wang L.,Second Artillery General Hospital | Li Y.,Cleveland Clinic
Journal of the Neurological Sciences | Year: 2015

Objective To analyze the clinical characteristics and outcome of patients with neurosarcoidosis manifesting as longitudinal transverse myelitis spanning 6 or more spinal segments. Method Retrospective analysis of 7 cases from a single institution. Results Four males and 5 African-American were included. The mean onset age for neurological symptoms was 49.1 years old. Only 1 patient had a prior diagnosis of sarcoidosis. In all patients, spinal MRI showed contiguous cervical and/or thoracic cord lesions predominantly in a central or centrodorsal location, associated with parenchymal or leptomeningeal gadolinium enhancement. Cerebral spinal fluid (CSF) pleocytosis was present in all and hypoglycorrhachia in 3 patients. Angiotensin-converting enzyme (ACE) level was elevated in the serum of 1 patient while being normal in the CSF of all 4 cases tested. Chest imaging facilitated the diagnosis of sarcoidosis in all cases. The use of corticosteroid and immunosuppressive agents including infliximab and methotrexate led to improved outcome. Conclusions Neurosarcoidosis should be considered in the differential diagnosis of longitudinal ultra-extensive myelitis, even in the absence of previously diagnosed sarcoidosis. Timely usage of corticosteroid and immunosuppressive agents improves the clinical outcome of patients with ultra-extensive spinal cord sarcoidosis. © 2015 Elsevier B.V. All rights reserved.


Li X.,Capital Medical University | Sun W.-J.,Second Artillery General Hospital
OncoTargets and Therapy | Year: 2015

This study aimed to investigate the activity of arsenic trioxide (As2O3) combined with ascorbic acid, ifosfamide, and prednisone chemotherapy in patients with repeatedly relapsed and refractory multiple myeloma (MM). Here, we retrospectively analyzed medical data of 30 MM patients showing progressive disease after receiving at least two previous lines of treatment including an immunomodulatory agent (thalidomide or lenalidomide) and a proteasome inhibitor. There were 19 men and eleven women, aged 54–73 (median 65) years, in this study. The distribution of different isotypes included immunoglobulin G(IgG) (12 patients), IgA (six patients), IgD (three), and light chain (nine patients). All the patients were Durie–Salmon stage III and had relapsed at least three times; the median cycles of prior therapies was 15 (range 10–18). The patients were treated with As2O3, ascorbic acid, and CP (ifosfamide 1 g on day 1, day 3, day 5, and day 7; prednisone 30 mg taken orally for 2 weeks). As2O3 was administered as an intravenous infusion at a dose of 10 mg/d and ascorbic acid at a dose of 2 g/d for 14 days of each 4-week cycle. The results showed that after 2 cycles of therapy, there were five patients that attained partial response, 15 had minimal response, five had no change, and five had progressive disease. The overall response rate was 66.7% (20/30 cases), 50% (10/20 cases), and 40% (2/5 cases), respectively, after 2, 4, and 6 cycles of the therapy. But there were no patients that attained complete remission. The median time of overall survival and progression-free survival were 48 (29–120) and 6 (2–8) months, respectively. The most common treatment-related adverse events included neutropenia, fatigue, anemia, thrombocytopenia, and infection that could be tolerated. The results showed that As2O3 combined with ascorbic acid, ifosfamide, and prednisone chemotherapy may be a choice treatment for repeatedly relapsed and refractory MM patients. © 2015 Li and Sun.


Zhang J.,Capital Medical University | Zhang X.,Capital Medical University | Liu L.,Second Artillery General Hospital | Tong W.,Second Artillery General Hospital
Transplantation Proceedings | Year: 2010

Optimal blood levels of tacrolimus in transplant recipients are critically important to preserve the allograft. Suboptimal doses of the immunosuppressant can result in allograft toxicity or rejection. In the present study, we determined CYP3A5 genotypes of patients and analyzed their medical documents in 2 successive periods. In the first period, a fixed initial dosage of 0.1 mg/kg was prescribed daily for 28 patients regardless of their CYP3A5 genotype. In the second period, CYP3A5 genotyping was performed with polymerase chain reactionrestriction fragment length polymorphism and DNA sequencing. The frequency distribution of CYP3A5 genotypes was 47.4% (38/78) for (*)1/ (*)3, 2.6% (2/78) for (*)1/ (*)1, and 50% (39/78) for (*)3/ (*)3. The patients with (*)1/ (*)3 had shown significantly lower tacrolimus blood levels than those with the (*)3/ (*)3 when the initial dose of 0.10 mg/kg was given for 2 weeks postoperatively. In the second period, initial dosages were selected according to individuals' CYP3A5 genotypes, 0.08 mg/kg/d for recipients with CYP3A5 (*)3/ (*)3 and 0.15 mg/kg/d for recipients with (*)1/ (*)3. Adjustment of the initial dosage of tacrolimus was documented to improve the proportion of patients achieving target drug blood levels in the early postoperative stage: from 46.7% to 81.8% of the (*)1/ (*)3 group and from 46.2% to 73.1% of the (*)3/ (*)3 group on the third day. In conclusion, CYP3A5 polymorphism plays an important role in influencing tacrolimus blood levels. Initial tacrolimus dosage selection based on CYP3A5 genotyping can improve drug blood levels in the early stage following renal transplantation. © 2010 by Elsevier Inc. All rights reserved.


Guo M.,Academy of Military Medical science | Hu K.-X.,Academy of Military Medical science | Yu C.-L.,Academy of Military Medical science | Sun Q.-Y.,Academy of Military Medical science | And 10 more authors.
Blood | Year: 2011

Treatment outcome of acute myeloid leukemia (AML) in elderly patients remains unsatisfactory. It has been shown that the infusion of granulocyte colony-stimulating factor-mobilized donor peripheral blood stem cells (G-PBSCs) can enhance graft-versus-leukemia effects and speed hematopoietic recovery. Fifty-eight AML patients aged 60-88 years were randomly assigned to receive induction chemotherapy with cytarabine and mitoxantrone (control group; n = 28) or it plus human leukocyte antigen-mismatched G-PBSCs (G-PBSC group; n = 30). Patients who achieved complete remission received another 2 cycles of postremission therapy with intermediate-dose cytarabine or it plus G-PBSCs. The complete remission rate was significantly higher in the G-PBSC group than in the control group (80.0% vs 42.8%; P = .006). The median recovery times of neutrophils and platelets were 11 days and 14.5 days, respectively, in the G-PBSC group and 16 days and 20 days, respectively, in the control group after chemotherapy. The 2-year probability of disease-free survival was significantly higher in the G-PBSC group than in the control group (38.9% vs 10.0%; P = .01). No graft-versus-host disease was observed in any patient. Persistent donor microchimerism was successfully detected in all of the 4 female patients. These results indicate that G-PBSCs in combination with conventional chemotherapy may provide a promising treatment method for AML in elderly patients. © 2011 by The American Society of Hematology.


Zhao Y.,Second Artillery General Hospital | Ding J.-H.,Second Artillery General Hospital | Yin S.-H.,Second Artillery General Hospital | Hou X.-L.,PLA General Hospital | Zhao K.,Second Artillery General Hospital
Colorectal Disease | Year: 2014

Aim: Moderate to severe pain after stapled haemorrhoidopexy (SH) is not uncommon. This study was designed to identify the predictors of postoperative pain after SH in a single centre. Method: Seventy-six patients with Grade II to IV haemorrhoids who underwent SH were selected from a prospectively compiled database. Preoperative data, including patient characteristics, manometry results and surgical data, were documented. Pain was evaluated during the first 24 h after the operation. Its intensity was classified into three grades according to the visual analogue scale (VAS) score: mild (VAS ≤ 3), moderate (VAS >3 to <5) and severe (VAS ≥ 5). Analgesics were not routinely given but were administered if the patient had moderate or severe pain. Both univariate and multivariate analyses were used to determine the predictors of postoperative pain. Results: Moderate and severe pain was noted in 43 (58.9%) patients. No patient was readmitted due to persistent anal pain during the month following discharge. Postoperative pain was significantly associated with gender (P = 0.017), age (P = 0.014), first initial sensory volume (P = 0.023) and constipation (P = 0.005) in univariate analysis. Multivariate analysis identified male gender as an independent predictor of postoperative moderate to severe pain (P = 0.037, OR = 3.1, 95% CI 1.07-9.09). The initial sensory volume and preoperative coexisting constipation were negative predictors of postoperative moderate to severe pain after SH (P = 0.037, OR = 0.320, 95% CI 0.110-0.934, and P = 0.036, OR = 0.255, 95% CI 0.071-0.913, respectively). Conclusion: Male gender and the initial sensory volume are predictors of postoperative pain after SH. Anal manometry is recommended before the SH procedure. An active analgesia protocol should be considered for male patients with a low initial sensory volume after SH. © 2013 The Association of Coloproctology of Great Britain and Ireland.


Ding X.-P.,Second Artillery General Hospital | Feng L.,Second Artillery General Hospital | Ma L.,Second Artillery General Hospital
Asian Pacific Journal of Cancer Prevention | Year: 2012

Background: Many studies have investigated possible association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and ovarian cancer risk, but the impact is still unclear owing to the obvious inconsistencies. This study was performed to quantify the strength of the association with a metaanalysis. Methods: We searched the PubMed, Embase, and CNKI databases for studies relating the association between MTHFR C677T polymorphism and ovarian cancer risk and estimated summary odds ratios (ORs) with confidence intervals (CIs) for assessment. Results: Finally, eight studies with a total of 3,379 ovarian cancer cases and 4,078 controls were included into this meta-analysis. Overall the showed that MTHFR C677T polymorphism was not associated with ovarian cancer risk under all genetic models (ORT versus C = 1.03, 95%CI 0.90-1.18; ORTT versus CC = 1.08, 95%CI 0.79-1.47; ORTT versus TC+CC = 1.05, 95%CI 0.80-1.37; ORTT + TC versus CC = 1.05, 95%CI 0.86-1.21). Meta-analyses of studies with confirmation of HWE also showed no significant association. Subgroup analyses by ethnicity showed there was no significant association in the Caucasians but MTHFR C677T polymorphic variant T contributed to increased risk of ovarian cancer in East Asians. No evidence of publication bias was observed. Conclusion: Meta-analyses of available data show that MTHFR C677T polymorphism is not associated with ovarian cancer risk in Caucasians, but the MTHFR polymorphic variant T may contribute to increased risk in East Asians.

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