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American Journal of Hematology 03/2012; 87(6):646. · 4.67 Impact Factor
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ABSTRACT: The overall impact of hydroxyurea (HU) or pipobroman treatments on the long-term outcome of patients with polycythemia vera (PV) has not been assessed in randomized studies. We report final analyses from the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients younger than age 65 years.
The full methodology has been described previously. FPSG results were updated with a median follow-up of 16.3 years. Statistical analysis was performed by using competing risks on the intention-to-treat population and according to main treatment received.
Median survival was 17 years for the whole cohort, 20.3 years for the HU arm, and 15.4 years for the pipobroman arm (P = .008) and differed significantly from that in the general population. At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02).
Data from this unique randomized trial comparing HU with another cytoreductive drug in PV showed that (1) survival of patients with PV treated with conventional agents differed from survival in the general population, (2) evolution to AML/MDS is the first cause of death, (3) pipobroman is leukemogenic and is unsuitable for first-line therapy, and (4) incidence of evolution to AML/MDS with HU is higher than previously reported, although consideration should be given to the natural evolution of PV.
Journal of Clinical Oncology 09/2011; 29(29):3907-13. · 18.37 Impact Factor
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Blood 05/2011; 117(21):5777-8. · 9.90 Impact Factor
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ABSTRACT: Expression of the urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) has recently been shown to be directly regulated by the Wnt/β-catenin signaling pathway in colon cancer cells, through β-catenin binding to T-cell factor binding element motifs present in their gene promoters. In our study, we present evidence that inhibition of β-catenin causes upregulation of uPA/uPAR gene expression enhancing invasive potential. Using MCF-7, MDA-MB-231 (breast cancer cells) and SW480 (colon cancer cells), we found that siRNA-mediated silencing of β-catenin increased uPA, uPAR and plasminogen activator inhibitor-1 (PAI-1) expression at the mRNA and protein levels. This increase was responsible for the observed enhanced invasive capacity of MDA-MB-231 and SW480 cancer cells. In addition, β-catenin stabilization and accumulation by lithium chloride treatment, a well-known inhibitor of glycogen synthase kinase-3β (GSK-3β), or by β-catenin/T-cell factor-4 expression vectors transfection led to a decrease in uPA, uPAR and PAI-1 mRNA expression in the studied cancer models. Treatment of β-catenin siRNA-transfected cells with a specific inhibitor of nuclear factor-kappaB (NF-κB), SN50, significantly reduced enhancement of uPA, uPAR and PAI-1 expression and cancer cell invasion, observed in β-catenin siRNA-transfected cells. Furthermore, β-catenin siRNA-treated cells exhibited NF-κB nuclear accumulation. These data suggest that β-catenin regulates the uPA/uPAR system in cooperation with NF-κB transcription factor, which constitutes a novel mechanism of regulation.
International Journal of Cancer 03/2011; 128(6):1280-92. · 5.44 Impact Factor
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ABSTRACT: Adult stem cells are critical for maintaining cellular homeostasis throughout life, yet the effects of age on their regenerative capacity are poorly understood. All lymphoid and myeloid blood cell lineages are continuously generated from hematopoietic stem cells present in human bone marrow. With age, significant changes in the function and composition of mature blood cells are observed. In this study, we report that age-related changes also occur in the human hematopoietic stem cell compartment. We find that the proportion of multipotent CD34(+) CD38(-) cells increases in the bone marrow of elderly (>70 years) individuals. CD34(+) CD38(+) CD90(-) CD45RA(+/-) CD10(-) and CD34(+) CD33(+) myeloid progenitors persist at the same level in the bone marrow, while the frequency of early CD34(+) CD38(+) CD90(-) CD45RA(+) CD10(+) and committed CD34(+) CD19(+) B-lymphoid progenitors decreases with age. In contrast to mice models of aging, transplantation experiments with immunodeficient NOD/SCID/IL-2Rγ null (NSG) mice showed that the frequency of NSG repopulating cells does not change significantly with age, and there is a decrease in myeloid lineage reconstitution. An age-related decrease in the capacity of CD34(+) cells to generate myeloid cells was also seen in colony-forming assays in vitro. Thus, with increasing age, human hematopoietic stem/progenitor cells undergo quantitative changes as well as functional modifications.
Aging cell 01/2011; 10(3):542-6. · 7.55 Impact Factor
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ABSTRACT: Aging is accompanied by a reduction in the generation of B lymphocytes leading to impaired immune responses. In this study, we have investigated whether the decline in B lymphopoiesis is due to age-related defects in the hematopoietic stem cell compartment. The ability of hematopoietic stem cells from old mice to generate B cells, as measured in vitro, is decreased 2-5-fold, while myeloid potential remains unchanged. This age-related decrease in B-cell potential is more marked in common lymphoid progenitors (CLP) and was associated with reduced expression of the B-lineage specifying factors, EBF and Pax5. Notably, retrovirus-mediated expression of EBF complemented the age-related loss of B-cell potential in CLP isolated from old mice. Furthermore, transduction of CLP from old mice with a constitutively active form of STAT5 restored both EBF and Pax5 expression and increased B-cell potential. These results are consistent with a mechanism, whereby reduced expression of EBF with age decreases the frequency with which multipotent hematopoietic progenitors commit to a B-cell fate, without altering their potential to generate myeloid cells.
Aging cell 03/2010; 9(3):410-9. · 7.55 Impact Factor
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Valerie Ugo,
Sylvie Tondeur,
Marie-Laurence Menot,
Nadine Bonnin,
Gerald Le Gac,
Carole Tonetti,
Veronique Mansat-De Mas,
Lydie Lecucq,
Jean-Jacques Kiladjian,
Christine Chomienne, Christine Dosquet,
Nathalie Parquet,
Luc Darnige,
Marc Porneuf,
Martine Escoffre-Barbe,
Stephane Giraudier,
Eric Delabesse,
Bruno Cassinat
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ABSTRACT: Myeloproliferative disorders are characterized by clonal expansion of normal mature blood cells. Acquired mutations giving rise to constitutive activation of the JAK2 tyrosine kinase has been shown to be present in the majority of patients. Since the demonstration that the V617F mutation in the exon 14 of the JAK2 gene is present in about 90% of patients with Polycythemia Vera (PV), the detection of this mutation has become a key tool for the diagnosis of these patients. More recently, additional mutations in the exon 12 of the JAK2 gene have been described in 5 to 10% of the patients with erythrocytosis. According to the updated WHO criteria the presence of these mutations should be looked for in PV patients with no JAK2 V617F mutation. Reliable and accurate methods dedicated to the detection of these highly variable mutations are therefore necessary.
For these reasons we have defined the conditions of a High Resolution DNA Melting curve analysis (HRM) method able to detect JAK2 exon 12 mutations. After having validated that the method was able to detect mutated patients, we have verified that it gave reproducible results in repeated experiments, on DNA extracted from either total blood or purified granulocytes. This HRM assay was further validated using 8 samples bearing different mutant sequences in 4 different laboratories, on 3 different instruments.
The assay we have developed is thus a valid method, adapted to routine detection of JAK2 exon 12 mutations with highly reproducible results.
PLoS ONE 01/2010; 5(1):e8893. · 4.09 Impact Factor
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Faten Bougatef,
Cathy Quemener,
Sabrina Kellouche,
Benyoussef Naïmi,
Marie-Pierre Podgorniak,
Guy Millot,
Eric E Gabison,
Fabien Calvo, Christine Dosquet,
Céleste Lebbé,
Suzanne Menashi,
Samia Mourah
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ABSTRACT: Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) is thought to promote tumor angiogenesis mostly through its protease-inducing function and more recently by its ability to increase tumor cell expression of vascular endothelial growth factor (VEGF). In this study, we present evidence that EMMPRIN can promote angiogenesis by a direct effect on endothelial cells through a paracrine regulation of the VEGF/VEGF-receptor (VEGFR) system. Using human microvascular endothelial cell line-1 endothelial cells, we show that EMMPRIN selectively increased the soluble VEGF isoforms (121 and 165), but not the matrix-bound VEGF 189 form. In addition, EMMPRIN up-regulated the expression of VEGFR-2 without an effect on VEGFR-1. This increase in VEGFR-2 was responsible for the observed EMMPRIN stimulation of the migratory and tube formation capacity of endothelial cells. EMMPRIN's effects, which were matrix metalloproteinase and urokinase-type plasminogen activator independent, were mediated primarily through hypoxia-inducible factor-2alpha expression, also up-regulated by EMMPRIN. VEGFR-2 increase was also observed in vivo in a mouse model of xenograph tumors overexpressing EMMPRIN. These results suggest that in addition to increasing protease production, EMMPRIN may contribute to the formation of a reactive stroma also through the up-regulation of hypoxia-inducible factor-2alpha, VEGFR-2, and the soluble forms of VEGF in endothelial cells, thus directly regulating the angiogenic process.
Blood 10/2009; 114(27):5547-56. · 9.90 Impact Factor
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Eirini Kouroupi,
Katerina Zoi,
Nathalie Parquet,
Christine Zoi,
Jean-Jacques Kiladjian,
Vassiliki Grigoraki,
William Vainchenker,
Franck Lellouche,
Christophe Marzac,
Marie-Hélène Schlageter, Christine Dosquet,
Linda M Scott,
Pierre Fenaux,
Dimitris Loukopoulos,
Christine Chomienne,
Bruno Cassinat
British Journal of Haematology 06/2008; 142(4):676-9. · 4.94 Impact Factor
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ABSTRACT: Tumor angiogenesis is a dynamic process that plays a major role in cancer progression. Vascular endothelial growth factor (VEGF) and its receptors play a pivotal role in angiogenesis. The expression of VEGF and its receptors VEGFR-1 and VEGFR-2 in renal cell carcinoma (RCC) was investigated in the perspective of anti-VEGF treatments.
Total VEGF protein levels were quantified by enzyme-linked immunosorbent assay (ELISA) in tumor tissue samples from surgical specimens of 65 patients with clear cell RCC. At the cellular level the VEGF isoforms VEGFR-1 and VEGFR-2 mRNA were quantified by real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in laser-microdissected tumoral epithelial as stromal cells and in corresponding normal tissue compartments. Colocalization of VEGF and VEGFR-1 proteins was studied by triple immunofluorescent labeling.
Protein VEGF in cytosolic extracts was significantly higher in tumoral than in nontumoral tissue (P< .0001). Event-free survival was significantly longer for patients with cytosolic VEGF lower than the cutoff (75th percentile of VEGF protein levels, P= .02). In laser-microdissected epithelial cells, VEGF(121) and VEGFR-1 mRNA expressions were higher in RCC than in corresponding nontumoral kidney (P= .007 and P= .002, respectively); they were also higher in stromal cells of RCC compared with nontumoral kidney (P= .02 and P= .003, respectively). There was no differential VEGFR-2 expression in epithelial or in stromal cells of tumoral or nontumoral kidney. By immunofluorescent labeling VEGF and VEGFR-1 colocalized on RCC tumor epithelial and stromal cells.
Combined laser microdissection and quantitative RT-PCR, as triple immunofluorescent labeling, underlined the preferential expression of the most soluble VEGF isoform, VEGF(121), and its receptor VEGFR-1, but not VEGFR-2, in epithelial and stromal cells of RCC.
Cancer 01/2008; 112(2):433-42. · 4.77 Impact Factor
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ABSTRACT: Our aim was to obtain a viable and easily available dermal substitute (DS) for the definitive coverage of full-thickness burns. A DS composed of a collagen-glycosaminoglycan-chitosan dermal matrix (DM) colonized with foreskin fibroblasts (FF) is described. FF-colonized DS were compared to the DM seeded with adult dermal fibroblasts (DF). FF-colonized DS expressed more fibrillin and tropoelastin than that with DF. Reconstructed skin obtained with both FF- and DF-colonized DS similarly expressed laminin-5 and collagen VII at the dermal-epidermal junction. Both FF- and DF-colonized DS produced cutaneous wound healing mediators in a dose-dependent manner in the presence of platelet lysate. After freeze-thawing, the FF-colonized DS were recovered in culture and retained their ability to produce vascular endothelial growth factor. Grafting of DS into nude rats achieved a complete healing of a dermal-epidermal lesion with a good epidermalization.
Biochemical and Biophysical Research Communications 12/2007; 363(3):472-8. · 2.48 Impact Factor
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ABSTRACT: During cutaneous wound repair, platelets, dermal fibroblasts (DF) and endothelial cells all cooperate. We have presently investigated the regulation of endothelial cell tubulogenesis by human platelet thrombospondin-1 (TSP-1), in comparison to transforming growth factor-beta1 (TGF-beta1) and total platelet lysates (PL), in a fibrin matrix cell culture system incorporating DF. TSP-1, TGF-beta1 and PL all stimulated VEGF expression in DF dose dependently at mRNA and protein level. TSP-1- and PL-treated DF supernatants significantly stimulated capillary-like structure formation (tubulogenesis) by dermal microvascular endothelial cells (HMEC-1 and HDMEC), in part via VEGF, as confirmed with neutralizing anti-VEGF antibodies. In contrast, TGF-beta1-treated DF supernatants did not induce tubulogenesis. This apparent discrepancy could be explained by the differential expression regulation in HMEC-1 of fibrinolysis and metalloproteinase mediators by TSP-1 and TGF-beta1. TSP-1 potently reduced the expression of plasminogen activator inhibitor-1 (PAI-1) (mRNA and protein), whereas TGF-beta1 enhanced it. The crucial role of PAI-1 in tubulogenesis was confirmed via the addition of active recombinant PAI-1, which abrogated tubulogenesis. In contrast, neutralizing PAI-1 antibodies enhanced tubulogenesis. Our results suggest that platelet TSP-1 released in a wound stimulates endothelial cell tubulogenesis through an upregulation of DF VEGF expression and a downregulation of endothelial cell PAI-1 expression.
Experimental Cell Research 03/2007; 313(3):486-99. · 3.58 Impact Factor
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ABSTRACT: Relations of mediators of inflammation and hemostasis with preclinical atherosclerosis have been poorly analyzed. The aim of this study was to test potential associations of these blood markers with indicators of cardiovascular risk and atherosclerotic burden in asymptomatic, nonsmoking, hypercholesterolemic men.
A total of 87 men underwent cardiovascular risk assessment by means of 10-year Framingham risk calculation (median 9%) and atherosclerotic burden evaluation by means of ultrasonographic measurement of common carotid intima-media thickness and assessment of atherosclerotic plaques at three arterial sites (three-site plaques).
Of the markers C-reactive protein, tumor necrosis factor-alpha, interleukin-10, factor VIIc, fibrinogen, plasminogen activator inhibitor-activator, soluble intercellular adhesion molecule-1, soluble P-selectin (sP-selectin), and von Willebrand factor, only sP-selectin was positively and independently associated with high Framingham risk score (>9%) (71.7 +/- 3.6 ng/mL, n = 33 v 59.6 +/- 2.8, n = 54; mean +/- SEM; P < .05) and with three-site plaques (75.4 +/- 5.7 ng/mL, n = 14 v 62.0 +/- 2.5, n = 73; P < .05). After adjustment for all of the above markers and for cardiovascular risk factors, odd ratios of having high Framingham risk and three-site plaques were 3.38 (1.43 to 10.21) and 5.23 (1.74 to 23.52) respectively, per 1-standard deviation increase in sP-selectin.
These results confirm that among several hemostasis and inflammation mediators, only sP-selectin blood level was associated with preclinical atherosclerosis. It might confer to sP-selectin measurement a clinical usefulness for detecting and managing high cardiovascular risk in primary prevention.
American Journal of Hypertension 10/2006; 19(10):1025-31. · 3.18 Impact Factor
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Claire Pellet,
Delphine Kerob,
Alain Dupuy,
Mary V Carmagnat,
Samia Mourah,
Marie-Pierre Podgorniak,
Cecile Toledano,
Patrice Morel,
Olivier Vérola, Christine Dosquet,
Yamina Hamel,
Fabien Calvo,
Claire Rabian,
Céleste Lebbé
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ABSTRACT: In order to gain further insight on the role of Kaposi's sarcoma-associated herpesvirus (KSHV) in classic and endemic Kaposi's sarcoma (KS) pathogenesis, we aimed to determine (i) whether KSHV is detectable in peripheral blood mononuclear cells (PBMCs), (ii) which PBMCs subpopulation harbor the virus, (iii) which clinical, histologic, and immunologic parameters are associated with KSHV viremia in a population of classic and endemic KS. KSHV viremia and various immunologic parameters were screened on 81 patients. KSHV viremia was positive in 58% of the patients. KSHV was detected in B cells, T cells, and monocytes. CD34+ cells depleted in circulating endothelial cells (CECs) were never infected and 50% of the patients tested had CECs infected by KSHV. We observed a significant increase of IL-2 and IFN-gamma production by CD4 T cells and an increase of IFN-gamma production by CD8 T cells compared to control patients. KS progression (P = 0.001) and KS staging (P = 0.03) were significantly and independently associated with positive KSHV viremia. Our results show that there is no specific immunosuppression in classic or endemic KS. We showed that KSHV can be detected within CECs and that KSHV viremia could be an indicator of circulating mature or precursor spindle cells.
Journal of Investigative Dermatology 04/2006; 126(3):621-7. · 6.31 Impact Factor
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Jerome Larghero,
Delphine Rea,
Helene Esperou,
Nicole Biscay,
Marie-Noelle Maurer,
Marie-Noelle Lacassagne,
Brigitte Ternaux,
Richard Traineau,
Karima Yakouben, Christine Dosquet,
Gerard Socié,
Eliane Gluckman,
Marc Benbunan,
Jean-Pierre Marolleau
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ABSTRACT: Red cell (RBC) depletion is needed to bypass ABO mismatch in allogeneic bone marrow transplantation (BMT). Technical and clinical data obtained after bone marrow (BM) processing with a continuous-flow cell separator (Cobe Spectra, Gambro BCT) are reported.
RBC depletion and recovery of nucleated cells, CD3+ cells, CD34+ cells, and colony-forming unit-granulocyte-macrophage were calculated. Bacteriologic contaminations, side effects of graft infusion, and hematopoietic recovery were analyzed.
A total of 114 BM samples were processed. The mean volume collected was 1099 mL (range, 390-2450 mL). Initial and residual mean RBCs volumes were 309.9 and 4.0 mL corresponding to a depletion of 98.6 +/- 0.78 percent. Before processing, the mean numbers of nucleated cells, granulocytes, CD3+ cells, CD34+ cells, and CFU-GM were 20.28 x 10(9), 12.79 x 10(9), 1.96 x 10(9), 356.7 x 10(6), and 195.6 x 10(5), respectively. The mean corresponding recoveries after processing were 33.66, 48.98, 82.02, 82.2, and 93.9 percent. Limited side effects were observed in 14 patients without correlation with residual RBCs volume. All but two patients engrafted.
BM processing with the Cobe Spectra cell separator provides high rates of RBC depletion without significant side effects after BMT.
Transfusion 04/2006; 46(3):398-402. · 3.22 Impact Factor
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ABSTRACT: Pharmacological concentrations of arsenic trioxide (ATO) and organic arsenic melarsoprol induce apoptosis in malignant plasma cells. In an attempt to further document the interest of the arsenic in vivo, we treated severe combined immunodeficient (SCID) mice transplanted with human myeloma cells by ATO or melarsoprol.
Fifty-two SCID mice were irradiated before intraperitoneal (i.p.) injection of plasma cells from five myeloma patients. Engraftment was assessed by serial measurement of the human monoclonal immunoglobulin G (HuMIgG) concentration in mouse serum. Treatment with ATO (10 microg/g i.p. 5 d a week), melarsoprol (30 microg/g i.p. 5 d a week) or phosphate buffer saline was started when a sustained growth of the tumor cells was demonstrated.
Seventeen mice developed the human tumor. A significant decrease in HuMIgG amounts was observed in three of five mice of the ATO group, including two that achieved an apparent complete remission persisting up to 5 months after ATO discontinuation. In these mice, no human plasma cells were detected in tissue samples collected postmortem. Soluble human interleukin-6 receptor amount, measured in mice sera as a surrogate marker of the plasma cell proliferation, varied in parallel with HuMIgG concentration. A significant difference in survival was observed between control and ATO treated mice (113 and 158 d, respectively; P = 0.01) whereas no difference could be evidenced in control and melarsoprol groups.
Present study confirms in vivo the in vitro effects of ATO on myeloma cells. Delayed relapses were observed suggesting that prolonged or maintenance therapy has to be considered in future clinical trials. Whether or not this will translate into clinically relevant effect of the drug in myeloma patients deserves further consideration.
European Journal Of Haematology 04/2004; 72(3):166-71. · 2.61 Impact Factor
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ABSTRACT: Platelet products have been proposed as adjuvant therapy for wound healing. We undertook this study to determine the healing effect of topically applied frozen autologous platelets (FAP) on chronic venous ulcers, compared with effect of placebo, and whether use of topical FAP modifies local expression of vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), interleukin 8 (IL-8), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in wound fluid.
This randomized, placebo-controlled, double-blind trial was carried out in institutional practice, with ambulatory patients with proved chronic venous leg ulcers. In all patients, whole venous blood was drawn for preparation of FAP. FAP or normal saline solution was applied three times per week for up to 12 weeks, together with hydrocolloids and standardized compression bandages. Leg ulcer surface was assessed with numerical pictures. IL-8, VEGF, KGF, and TIMP-1 levels were determined (enzyme-linked immunosorbent assay) in wound fluid after each 4 weeks of treatment.
Fifteen patients were randomized into two groups with comparable leg ulcer characteristics. Mean percent reduction in ulcer area was 26.2% in the FAP group versus 15.2% in the placebo group (P =.94). One ulcer in each group was completely healed at study end. Levels of TIMP-1 increased significantly during FAP treatment. IL-8 concentration was significantly lower in wound fluid of healing ulcers than in the fluid of nonhealing ulcers, in both FAP and placebo groups. Growth factor levels were not modified with FAP treatment.
Topical autologous platelets have no significant adjuvant effect on healing of chronic venous leg ulcers and increased wound fluid TIMP-1 concentration. Ulcer healing is associated with a decrease in wound fluid IL-8.
Journal of Vascular Surgery 01/2004; 38(6):1342-8. · 3.21 Impact Factor
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ABSTRACT: BACKGROUND: The mechanism of HPC mobilization in humans is unclear. In this study, the relationship between PBPC mobilization and blood levels of G-CSF, endogenous cytokines (IL-8, SCF, thrombopoietin [TPO]), and the vascular cell adhesion molecule-1 (VCAM-1) was analyzed in patients with malignancy who were undergoing a PBPC mobilization regimen.STUDY DESIGN AND METHODS: Fifty-four patients with multiple myeloma (MM) and 29 with breast cancer (BC) underwent a mobilization regimen combining conventional chemotherapy and G-CSF up to the last day of PBPC collection. The CD34+ cell count was determined on each day when leukapheresis was scheduled. Venous blood samples (n = 117) were drawn before apheresis for CD34+ cell count (flow cytometry) and cytokine (G-CSF, IL-8, SCF, TPO) and VCAM-1 measurements (ELISA).RESULTS: In multiple regression analysis, SCF was a significant determinant of CD34+ cell levels in BC patients (R = 0.50, p = 0.03) and of VCAM-1 levels in MM patients (R = 0.32, p = 0.02). SCF was negatively correlated with CD34+ cell count in patients with BC. SCF and VCAM-1 blood levels were correlated in MM and BC patients.CONCLUSION: SCF and VCAM-1 could play a role in PBPC mobilization in patients and could be useful measures by which to study patients undergoing a mobilization regimen.
Transfusion 04/2002; 41(2):206 - 212. · 3.22 Impact Factor
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ABSTRACT: Cell and tissue therapy applications in humans are being used increasingly, particularly for tissue repair. Several reconstructed skin models have been proposed. Wound healing involves overlapping steps of inflammation, cell migration and proliferation, neovascularisation, extracellular matrix production and remodelling. This is regulated by numerous cytokines and other soluble mediators. We have prepared dermal substitutes (DS) consisting of a collagen-GAG, three-dimensional matrix colonized by human dermal fibroblasts (HDF), isolated by skin explant or enzymatic digestion of the skin for potential therapeutic use in humans. To test the functionality of these DS, we measured (ELISA) the stimulatory effect on HDF in the matrix, of serial dilutions of human serum (HS) on the production of wound healing mediators: interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1). We observed: 1). a stimulatory effect of HS on HDF production of the different mediators tested, with a dose-dependent effect in the case of IL-8 and VEGF. 2). A matrix-potentiating effect on the production of the different mediators by HDF. 3). A decrease in the production of IL-8 and VEGF when HDF isolated by enzymatic digestion was used to colonize the matrix as compared with HDF isolated by skin explant. We conclude: 1). that the production by HDF, in a collagen-GAG matrix, of mediators involved in cutaneous wound healing is decreased when HDF are isolated by enzymatic skin digestion rather than by skin explant. 2). That measurement of the production of cytokines or other mediators could be a useful quality control to test the functionality of tissue-engineered DS for tissue repair therapy in humans and more generally of cells prepared for cell therapy.
European cytokine network 14(1):60-4. · 1.73 Impact Factor
