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This study proposes a sequential Monte Carlo (SMC) implementation to the Mahler's group probability hypothesis density filter (PHDF) for partly unresolvable group targets tracking problem. Therefore, the authors have to jointly extract the group number and states from the proposed group SMC-PHDF at each time step. The authors propose to fit the resampled particles of the group SMC-PHDF by application of Gaussian mixture models with unknown component number. The Markov chain Monte Carlo (MCMC) algorithm is proposed to estimate the component parameters of the mixture. The estimate of component number of the mixture can be derived by a component management strategy. In simulation, the proposed group SMC-PHDF with the expectation maximum (EM) and MCMC extractions are, respectively, used to detect and track the groups. Hundreds of Monte Carlo simulation results show that the latter outperforms the former a lot in estimating the group number and states, although the computational requirement of the MCMC extraction is more expensive than the EM extraction.

Cultured human umbilical cord mesenchymal stem cells (hUC-MSCs) are being tested in several clinical trials and encouraging outcomes have been observed. To determine whether in vitro expansion influences the genomic stability of hUC-MSCs, we maintained nine hUC-MSC clones in long-term culture and comparatively analyzed them at early and late passages. All of the clones senesced in culture, exhibiting decreased telomerase activity and shortened telomeres. Two clones showed no DNA copy number variations (CNVs) at passage 30 (P30). Seven clones had ≥1 CNVs at P30 compared with P3, and one of these clones appeared trisomic chromosome 10 at the late passage. No tumor developed in immunodeficient mice injected with hUC-MSCs, regardless of whether the cells had CNVs at the late passage. mRNA-Seq analysis indicated that pathways of cell cycle control and DNA damage response were downregulated during in vitro culture in hUC-MSC clones that showed genomic instability, but the same pathways were upregulated in the clones with good genomic stability. These results demonstrated that hUC-MSCs can be cultured for many passages and attain a large number of cells, but most of the cultured hUC-MSCs develop genomic alterations. Although hUC-MSCs with genomic alterations do not undergo malignant transformation, periodic genomic monitoring and donor management focusing on genomic stability are recommended before these cells are used for clinical applications.

Poor in vivo homing capacity of hematopoietic stem/progenitor cells (HS/PCs) from umbilical cord blood (UCB) can be reversed by short-term ex vivo manipulation with recombinant human stem cell factor (rHuSCF). This study was designed to evaluate the effect of ex vivo manipulation of UCB-derived HS/PCs with rHuSCF on human cell engraftment rates in xenotransplanted NOD/SCID mouse model. The human cell engraftment rates in xenotransplanted primary and secondary NOD/SCID mice were characterized using four-color flow cytometric analysis and progenitor assay. Grafts of rHuSCF-treated UCB CD34(+) cells resulted in significantly higher levels of human cell engraftment than that of nontreated ones in both xenotransplanted primary and secondary NOD/SCID recipients. Fresh UCB CD34(+) cells did not express either of the matrix metalloproteinase (MMP) family members MMP-2 or MMP-9. rHuSCF-treated UCB CD34(+) cells expressed significant levels of MMP-2 and MMP-9. Pretreatment of UCB CD34(+) cells with the specific MMP inhibitor completely blocked human cell engraftment in xenotransplanted NOD/SCID recipients. Our results indicate that ex vivo manipulation of human HS/PCs with rHuSCF might provide an optimal approach to develop more effective stem cell-based therapies in situations where engraftment is delayed due to limiting HS/PCs number, for example, UCB transplantation.

Considerable studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in leukemia dissemination and extramedullary infiltration. Tissue inhibitors of matrix metalloproteinases (TIMPs) are multifunctional proteins with MMPs inhibitory effects. However, little is known about the application of TIMPs in the treatment of leukemia. Here, we investigated the effects of TIMP-3 overexpression via adenoviral gene delivery on the in vitro growth and invasiveness of leukemic cells and the in vivo progress of K562-derived xenografts in nude mice. The in vitro invasiveness of K562 cells was markedly impaired by AdTIMP-3 infection. Moreover, TIMP-3 significantly inhibited K562-derived angiogenic factors-induced proliferation, migration and bFGF-induced tube formation of endothelial cells (ECs) in vitro , and reduced VEGF-induced gelatinases expression and activation in ECs. Although TIMP-3 overexpression had no direct effect on the growth of K562 cells in vitro , repeated intratumoral injection of AdTIMP-3 significantly inhibited the growth of K562 xenografts in nude mice. Furthermore, lower microvessel density, less vessel maturity and increased apoptosis were observed in AdTIMP-3-treated K562 xenografts, suggesting the importance of antiangiogenic action of TIMP-3. These data demonstrated the potential of applying AdTIMP-3 as an effective antiangiogenic adjuvant in the treatment of leukemia progression.

Autologous Transplantation of Granulocyte Colony–Stimulating Factor–Mobilized Peripheral Blood Mononuclear Cells Improves Critical Limb Ischemia in Diabetes Pingping Huang , MD 1 2 , Shangzhu Li , MSPH 1 , Mingzhe Han , PHD 1 , Zhijian Xiao , MD 1 , Renchi Yang , MD 1 and Zhong Chao Han , PHD, MD 1 2 1 National Research Center for Stem Cell Engineering and Technology, State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union of Medical College, Tianjin, China 2 TEDA Center of Life Science & Technology, Tianjin, China Address correspondence and reprint requests to Dr. Zhong Chao Han, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union of Medical College, 288 Nanjing Rd., Tianjin, 300020, China. E-mail: tihzchan{at}public.tpt.tj.cn Abstract OBJECTIVE — To assess the application of autologous transplantation of granulocyte colony–stimulating factor (G-CSF)–mobilized peripheral blood mononuclear cells (PBMNCs) in the treatment of critical limb ischemia (CLI) of diabetic patients and to evaluate the safety, efficacy, and feasibility of this novel therapeutic approach. RESEARCH DESIGN AND METHODS —Twenty-eight diabetic patients with CLI were enrolled and randomized to either the transplant group or the control group. In the transplant group, the patients received subcutaneous injections of recombinant human G-CSF (600 μg/day) for 5 days to mobilize stem/progenitor cells, and their PBMNCs were collected and transplanted by multiple intramuscular injections into ischemic limbs. All of the patients were followed up after at least 3 months. RESULTS —At the end of the 3-month follow-up, the main manifestations, including lower limb pain and ulcers, were significantly improved in the patients of the transplant group. Their laser Doppler blood perfusion of lower limbs increased from 0.44 ± 0.11 to 0.57 ± 0.14 perfusion units ( P < 0.001). Mean ankle-brachial pressure index increased from 0.50 ± 0.21 to 0.63 ± 0.25 ( P < 0.001). A total of 14 of 18 limb ulcers (77.8%) of transplanted patients were completely healed after cell transplantation, whereas only 38.9% of limb ulcers (7 of 18) were healed in the control patients ( P = 0.016 vs. the transplant group). No adverse effects specifically due to cell transplantation were observed, and no lower limb amputation occurred in the transplanted patients. In contrast, five control patients had to receive a lower limb amputation ( P = 0.007, transplant vs. control group). Angiographic scores were significantly improved in the transplant group when compared with the control group ( P = 0.003). CONCLUSIONS —These results provide pilot evidence indicating that the autologous transplantation of G-CSF–mobilized PBMNCs represents a simple, safe, effective, and novel therapeutic approach for diabetic CLI. ABI, ankle-brachial pressure index CLI, critical limb ischemia EPC, endothelial progenitor cell G-CSF, granulocyte colony–stimulating factor PAD, peripheral arterial disease PBMNC, peripheral blood mononuclear cell Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted June 13, 2005. Received February 3, 2005. DIABETES CARE

An antisense strategy by targeting both bcr3/abl2 and VEGF was designed to suppress the growth of Philadephia 1 leukemia cells in vitro and in vivo in mice. In vitro , although bcr3/abl2 or VEGF antisense oligodeoxyribonucleotides (AS-ODNs) alone was able to inhibit the proliferation of K562 cells, the combination of bcr3/abl2 and VEGF AS-ODNs produced an additive inhibitory effect on the growth of K562 cells and significantly enhanced the sensibility of K562 cells to apoptosis-inducing stimuli including STI571. In vivo , the nude mice xenografted with K562 cells received intratumoral injections of bcr3/abl2 and VEGF AS-ODNs showed a significant reduction in leukemia tumor size and microvessel density and an increase of apoptosis in the tumors when compared to the mice that received an individual agent. These results demonstrate that targeting both bcr3/abl2 and VEGF can result in an additive tumor-suppressive action and may represent an excellent strategy to augment the efficacy of chemotherapy in CML.

[...]WCE was performed to learn more about the small bowel mucosa in CCS. A barium enema and small bowel series were performed to look for cancerous changes and to evaluate risk, although this was based on only anecdotal evidence (4th ICCE 2005).

Our previous in-vitro and in-vivo studies showed that heparin enhanced murine and human megakaryocytopoiesis. 20 patients with chronic immune thrombocytopenic purpura were randomly divided into two groups and given 10 mg per day of prednisone for 30 days, for haemostatic purposes. One group received in addition heparin (1250 IU twice a day subcutaneously for 30 days). From day 10, a significant increase in platelet count was observed in eight of the ten patients treated with heparin (p<0·05), with return to the initial value after heparin cessation in six of the responders. These data demonstrate the effectiveness of heparin and suggest its use or that of other related compounds for therapy of chronic immune thrombocytopenic purpura.

The multidrug resistance (MDR) mediated by P-glycoprotein (P-gp), the MDR1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a MDR1-targeted small interfering RNA (si-MDR1) approach for reversal of P-gp-mediated MDR in the MDR human leukemia cell line k562/A02. It was found that si-MDR1 significantly inhibited MDR1 expression at both mRNA and protein levels. Depletion of MDR1 by si-MDR1 correlated with the increased sensitivity of the cells to cytotoxic agents and with the enhanced intracellular retention of daunorubicin (DNR). One base-pair mutated control (si-MDR1-Mut) lost the effect of si-MDR1 on both the degradation of mdr1 mRNA and the reduction of P-gp expression. These findings indicate that siRNA specifically and efficiently interferes with the expression of mdr1 and could be used as a molecularly defined therapeutic approach for MDR in the treatment of leukemia.