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Gesundheit B.,International Center for Cell Therapy and Cancer Immunotherapy | Parkin P.,Hospital for Sick Children | Senger C.,Hospital for Sick Children | Smith C.,Hospital for Sick Children | Klement G.L.,Tufts Medical Center
Journal of Pediatric Hematology/Oncology

PURPOSE: The role of angiogenesis in the transformation of peripheral neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) remains elusive and forms the objective of this study. EXPERIMENTAL DESIGN: Archival tissue from 5 children with NF1 and PNF, who developed MPNST between the ages of 8 and 15 years were analyzed for differences in microvasculature. The role of proangiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF), and its receptors Flk-1 and Flt-1, and vessel maturity, defined as von Willebrand factor (vWf), α-smooth muscle actin (SMA), were evaluated by immuno-histochemistry. RESULTS: A qualitative evaluation of the vasculature showed predominantly α-SMA+/vWf+ more stable vessels in PNF, and an irregular meshwork of α-SMA-/vWf+ endothelial cells structures in MPNST. In NF and PNF tumor cells were VEGF, in contrast to VEGF tumor cells in MPNST. If present, the VEGF stain was confined mainly to the perivascular spaces in PNF, unlike the mainly stromal VEGF stain in MPNST. VEGF receptors also manifested a tumor stage-specific pattern. Flk-1 and Flt-1 were restricted to the mature, well-formed vasculature in PNF, but exhibited a diffuse pattern in MPNST. CONCLUSION: Our study provides a rare opportunity to document consistent and histologically detectable differences in the vascular organization of PNF and MPNST. It permits a pair-wise evaluation of the malignant conversion of benign PNF into its malignant counterpart, in the same patients. The phenotypic variations and characteristics of the vessels in these tumors are consistent with the idea that a strong proangiogenic drive contributes to the progressive growth in MPNST. Copyright © 2010 by Lippincott Williams & Wilkins. Source

Morecki S.,Hadassah University Hospital | Gelfand Y.,Hadassah University Hospital | Yacovlev E.,Hadassah University Hospital | Eizik O.,Hadassah University Hospital | And 4 more authors.
Bone Marrow Transplantation

Selective elimination of alloreactive cells was carried out in the set-up of T-cell-mediated immunotherapy in an effort to gain the benefits of hematopoietic allogeneic transplantation while reducing the risk of GVHD. Low MW chemical compounds were screened for their effect on T-cell-mediated immune responses of murine- and human-derived lymphocytes. Selected compounds were further tested in secondary MLR assays in which sensitization to alloantigens was carried out in vitro, in the presence or absence of a given compound, followed by exposure to related and unrelated alloantigens or T-cell mitogenic stimulation. At a low concentration of <1 μM, a quinazoline derivative named AO#349 2-(3,4,5-trimethoxyphenyl)-N-p-tolylquinazolin-4-amine, was able to induce 78-90% inhibition of a selective allogeneic response while retaining >92% immune reactivity to unrelated alloantigens and mitogenic stimuli in vitro. Following allogeneic sensitization in the presence of AO#349, elimination of alloreactivity to the priming alloantigens was also proved in a murine model of GVHD: 10 out of 15 sub-lethally irradiated mice inoculated with these sensitized cells were GVHD-free for >200 days. AO#349 was efficient in induction of a selective elimination of alloreactivity and should be considered for clinical application in allogeneic cell-mediated immunotherapy. © 2012 Macmillan Publishers Limited All rights reserved. Source

Yarkoni S.,GASR Biotechnology | Prigozhina T.B.,Hadassah University Hospital | Slavin S.,International Center for Cell Therapy and Cancer Immunotherapy
Biology of Blood and Marrow Transplantation

T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2-cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical transplants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3+; 50%) and CD25+FoxP3+ T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro apoptosis in both CD4+CD25- and CD4+CD25+ subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2-cas-pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of CD25highFoxP3+ T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2-targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploidentical GVHD. The mechanism of protection includes direct killing of GVHD effectors, prevention of transition to effector/memory T cells, and induction of regulatory T cell proliferation, which becomes the dominant subset under conditions of homeostatic expansion. © 2012 American Society for Blood and Marrow Transplantation. Source

Bacher U.,University of Hamburg | Bacher U.,MLL Munich Leukemia Laboratory | Klyuchnikov E.,University of Hamburg | Le-Rademacher J.,Medical College of Wisconsin | And 21 more authors.

The best conditioning regimen before allogeneic transplantation for high-risk diffuse large B-cell lymphoma (DLBCL) remains to be clarified. We analyzed data from 396 recipients of allotransplants for DLBCL receiving myeloablative (MAC; n = 165), reduced intensity (RIC; n = 143), or nonmyeloablative conditioning (NMAC; n = 88) regimens. Acute and chronic GVHD rates were similar across the groups. Five-year nonrelapse mortality (NRM) was higher in MAC than RIC and NMAC (56% vs 47% vs 36%; P = .007). Five-year relapse/progression was lower in MAC than in RIC/NMAC (26% vs 38% vs 40%; P = .031). Five-year progression-free survival (15%-25%) and overall survival (18%-26%) did not differ significantly between the cohorts. In multivariate analysis, NMAC and more recent transplant year were associated with lower NRM, whereas a lower Karnofsky performance score (< 90), prior relapse resistant to therapy, and use of unrelated donors were associated with higher NRM. NMAC transplants, no prior use of rituximab, and prior relapse resistant to therapy were associated with a greater risk of relapse/progression. In conclusion, allotransplantation with RIC or NMAC induces long-term progressionfree survival in selected DLBCL patients with a lower risk of NRM but with higher risk of lymphoma progression or relapse. Source

Qin J.D.,Hebrew University of Jerusalem | Qin J.D.,University of Chicago | Weiss L.,Hadassah University Hospital | Slavin S.,Hadassah University Hospital | And 4 more authors.
Cancer Investigation

The anticancer effects of synthetic, non-natural analogs of ceramide were tested using human TSU-Pr1 prostate cancer cells in-vitro as well as in-vivo, following their effects on tumors development in mice. When incubated with the cultured cancer cells, the analogs elevated cellular ceramide and induced a cytotoxicity and death by apoptosis. When a ceramide analog was injected intradermally or intraperitoneally into BALB/c-Nude or NOD-SCID mice bearing a human prostate tumor, a considerable regression of the tumor was observed. The synthetic ceramide analogs should thus be further investigated as potential anticancer drugs. Copyright © 2010 Informa Healthcare USA, Inc. Source

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