Rapid full engraftment and successful immune reconstitution after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in Omenn syndrome.

OS is a variant of SCID characterized by generalized erythroderma, alopecia, eosinophilia, and elevated IgE levels. It is fatal unless treated with allogeneic HSCT, which is the only curative approach. However, treatment related complications and graft rejection are major obstacles to the success of treatment. In this report, we describe a patient with OS, complicated by prolonged cytomegalovirus infection, successfully treated by reduced intensity conditioning allogeneic HSCT from sibling donor.

The biological role of HGF-MET axis in tumor growth and development of metastasis.

Hepatocyte growth factor (HGF) and its receptor MET play an important role in cancer growth and metastasis. Activation of MET elicit multiple cellular responses regulating cell survival, morphogenesis, adhesion, migration, breakdown of extracellular matrix (ECM) and angiogenesis. Numerous disorders related to deregulation of HGF-MET axis have been reported. Thus, new therapeutic agents targeting HGF-MET signaling have been sought. Here, we will present data describing the role of HGF-MET axis in growth and metastasis of tumor cells together with the recent approaches to block this axis.

HSP90 antagonist, geldanamycin, inhibits proliferation, induces apoptosis and blocks migration of rhabdomyosarcoma cells in vitro and seeding into bone marrow in vivo.

In this study, geldanamycin (GA) was found to have an antiproliferative effect on both embryonal and alveolar rhabdomyosarcoma (RMS) cell lines. The maximum level of inhibition reached 80% for both embryonal and alveolar RMS. After GA treatment, cells also became apoptotic as judged by Annexin V-positive staining, activation of caspase-3 pathway and poly(ADP ribose) polymerase cleavage. GA was responsible for the arrest of RMS cells in both G1 and G2/M phases of the cell cycle. G1 blockade, however, was transient and was seen only in the first 24 h of GA treatment. RMS often gives distant metastases to various organs including bone marrow. RMS cells express high levels of MET receptor and respond to hepatocyte growth factor with increased motility. In our study, we found that GA decreased the level of MET expression and inhibited the chemotaxis of RMS cells toward the hepatocyte growth factor gradient. GA also blocked the homing of RMS cells into bone marrow of severe combined immune deficient mice. In all our experiments embryonal RMS cell lines were significantly more sensitive, and lower concentrations of GA were sufficient to block embryonal RMS cell proliferation, induce apoptosis and inhibit motility. Our data show that the HSP90 inhibitor GA has the potential to become a new drug in RMS treatment. It blocks RMS proliferation, decreases cell survival and inhibits motility of RMS cells.

Evidence that platelet-derived microvesicles may transfer platelet-specific immunoreactive antigens to the surface of endothelial cells and CD34+ hematopoietic stem/ progenitor cells--implication for the pathogenesis of immune thrombocytopenias.

The pathogenesis and tissue damage that accompanies destruction of platelets in immune thrombocytopenias (IT) is still not understood very well and in addition to platelets, other cells (e.g. endothelial cells, CD34+ hematopoietic stem/progenitors) may also become affected. Based on our previous work that platelet antigens (e.g., CD41) may be transferred by platelet-derived microvesicles (PMV) to the surface of other cells, we asked if platelet derived-antigens, especially those that are involved in the formation of anti-platelet antibodies in IT (e.g., against antigen HPA 1 a) could be also transferred by similar mechanism. To address this issue normal human CD34+ cells, human umbilical vein-endothelial cells (HUVEC) and monocytic cell line THP-1 were incubated with PMV derived from HPA1a+ donors. We noticed that the HPA1a antigen is highly expressed on PMV-derived from the HPAla positive platelets and is transferred in PMV-dependent manner to the surface of CD34+ cells, HUVEC and monocytic THP-1 cells. These cells covered with HPA1a positive PMV but not by PMV derived from HPAla negative platelets reacted with anti-HPA1a antibodies derived from the alloimmunized pregnant women. More importantly, human hematopoietic cells that were preincubated with HPA1a+ PMV and subsequently exposed to anti-HPA 1 a serum and human NK cells, become subject to elimination by antibody dependent cell cytotoxicity ADCC. Thus, we postulate that PMV-dependent transfer of antigens may playing an important role in "expanding" the population of target cells that may be affected by anti-platelet antibodies and explain several pathologies that accompany IT (e.g. damage of endothelium, cytopenias).

SDF-1 alone and in co-operation with HGF regulates biology of human cervical carcinoma cells.

Stromal Derived Factor-1 (SDF-1)-CXCR4 axis plays a pivotal role in biology and metastasis of several tumors. The aim of this study was to see if SDF-1 alone or in combination with Hepatocyte Growth Factor (HGF) affects biology of human cervical carcinoma (HCC) cells. We found that HCC cell lines investigated in our study highly express CXCR4 on their surface. CXCR4 was also expressed on tumor cells in tissue sections derived from cervical cancer patients. At the same time normal cervical epithelium was negative for CXCR4 expression what suggests a strong correlation between CXCR4 and malignant cell phenotype. Subsequently, we studied a potential role of the SDF-1-CXCR4 axis in HCC and noticed that SDF-1 (i) chemoattracted HCC cells, (ii) enhanced their scattering, (iii) stimulated nuclear localization of beta-catenins and upregulated their target gene cyclin D1 and (iv) at the molecular level induced calcium flux and activated RAS-MAPK, PI3-AKT and JAK-STAT pathways. SDF-1-mediated functions were additionally enhanced in the presence of HGF. Thus, our data show that the SDF-1-CXCR4 axis affects biology of HCC cells. Furthermore, we postulate that this axis might become a potential target to prevent progression of cervical cancer.