A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms.

Despite considerable advances in our understanding of the pathophysiology of graft-versus-host disease (GVHD), its prediction remains unresolved and depends mainly on clinical data. The aim of this study is to build a predictive model based on clinical variables and cytokine gene polymorphism for predicting acute GVHD (aGVHD) and chronic GVHD (cGVHD) from the analysis of a large cohort of HLA-identical sibling donor allogeneic stem cell transplant (allo-SCT) patients. A total of 25 SNPs in 12 cytokine genes were evaluated in 509 patients.

Bone marrow VEGFC expression is associated with multilineage dysplasia and several prognostic markers in adult acute myeloid leukemia, but not with survival.

Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients.

Association of RBP4 genetic variants with childhood obesity and cardiovascular risk factors.

Background: Recent data suggest that retinol-binding protein 4 (RBP4) gene variants could be associated with a risk of obesity and its co-morbidities, such as metabolic syndrome, which increases the risk of developing type 2 diabetes mellitus and cardiovascular disease.

Objectives: The present study examined the potential association of RBP4 single nucleotide polymorphisms (SNPs) with childhood obesity and its metabolic complications.

Methods: Four RBP4 SNPs, rs3758538 (3944A>C), rs3758539 (4406G>A), rs12265684 (12177G>C) and rs34571439 (14684T>G), were genotyped in a population of 180 Spanish Caucasian children (97 obese and 83 normal-weight children).

The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity.

BCL2 gene polymorphisms and splicing variants in chronic myeloid leukemia.

Recent data suggest that constitutional genetic variation in the antiapoptotic BCL2 gene could be associated with the susceptibility to develop chronic myeloid leukemia (CML) and the clinical outcome in several hematological malignancies. The present study examines whether BCL2 single nucleotide polymorphisms (SNPs) predispose to CML or may potentially influence the disease characteristics at diagnosis. Notably, no association was observed between the four candidate BCL2 SNPs and the risk of developing CML.

Risk factors for non-melanoma skin cancer in patients with essential thrombocythemia and polycythemia vera.

Objectives: Population-based studies have reported an increased incidence of skin cancer in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We have examined the risk factors for non-melanoma skin cancer (NMSC) in patients diagnosed with ET or PV during 1973-2012.

Methods: A case-control study was performed to compare the clinical and treatment-related data of 51 ET/PV patients who had NMSC with that of 401 patients who did not.

A polymorphism in the TYMP gene is associated with the outcome of HLA-identical sibling allogeneic stem cell transplantation.

Thymidine phosphorylase (TYMP), an enzyme involved in nucleotide synthesis, has been implicated in critical biological processes such as DNA replication, protection against mutations, and tissue repair. In this work, we retrospectively evaluated the influence of a polymorphism in the TYMP gene (rs112723255; G/A) upon the outcome of 448 patients subjected to allogeneic stem cell transplantation (allo-SCT) from an human leukocyte antigen (HLA)-identical sibling donor. The TYMP genotype of patients correlated with overall survival-carriers of the minor allele (A) being at an increased risk of dying after transplantation (hazard ratio, HR = 1.

A polymorphism in the XPD gene predisposes to leukemic transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera.

Patients with essential thrombocythemia (ET) and polycythemia vera (PV) have an increased incidence of acute myeloid leukemia and new nonhematologic malignancies compared with the general population. However, information on the factors determining the risk for such complications is limited. In the present study, we investigated whether constitutional genetic variations in DNA repair predispose to leukemic transformation and new nonmyeloid neoplasias in patients with ET and PV.

Functional polymorphisms in SOCS1 and PTPN22 genes correlate with the response to imatinib treatment in newly diagnosed chronic-phase chronic myeloid leukemia.

The function of the natural modulators of BCR-ABL-induced signaling pathways could influence the results to imatinib treatment. We assessed the association between single nucleotide polymorphisms (SNPs) on genes of the phosphatase family and the suppressors of cytokine signaling and the response to imatinib in 105 patients newly diagnosed with chronic-phase CML. SNPs in SOCS1 (rs243327) and PTPN22 (rs2476601) genes correlated with the risk of primary resistance to imatinib.

Donor CTLA-4 genotype influences clinical outcome after T cell-depleted allogeneic hematopoietic stem cell transplantation from HLA-identical sibling donors.

CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection.

An XRCC1 polymorphism is associated with the outcome of patients with lymphoma undergoing autologous stem cell transplant.

High-dose chemotherapy supported by autologous stem cell transplant (ASCT) remains the treatment of choice for patients with lymphoma failing first-line chemotherapy. Recent evidence suggests a relationship between the genetic variations in genes involved in DNA repair and the outcome of patients with a number of malignancies. In this work, we retrospectively evaluated the influence of an XRCC1 polymorphism (rs25487) on the treatment results in a series of 73 patients with lymphoma subjected to ASCT.

Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia.

The association between seven polymorphisms in the genes hOCT1 and MDR1, encoding for imatinib transporter proteins, and the response to imatinib 400mg/daily was investigated in 65 patients newly diagnosed with chronic-phase chronic myeloid leukemia. The AA genotype at the rs6935207 hOCT1 polymorphic locus was not detected in patients with inadequate response to imatinib. The CC genotype at the rs1045642 (C3435T) MDR1 locus was associated with primary failure, whereas a T allele at the rs2032582 (G2677T/A) MDR1 locus seemed to protect from primary failure.

XPC genetic polymorphisms correlate with the response to imatinib treatment in patients with chronic phase chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is driven by the BCR-ABL protein, which promotes the proliferation and viability of the leukemic cells. Moreover, BCR-ABL induces genomic instability that can contribute to the emergence of resistant clones to the ABL kinase inhibitors. It is currently unknown whether the inherited individual capability to repair DNA damage could affect the treatment results.

Influence of DNA damage and repair upon the risk of treatment related leukemia.

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) are malignancies occurring after exposure to chemotherapy and/or radiotherapy. Several studies have addressed cumulative dose, dose intensity and exposure to specific agents of preceding cytotoxic therapy in relation to the risk of developing such leukemia. Since only a small percentage of patients exposed to cytotoxic therapy develop t-MDS/AML, it has been suggested that some genetic predisposition may be involved, specifically associated to polymorphisms in certain genes involved in chemotherapy/radiotherapy response - fundamentally genes intervening in drug detoxification and DNA synthesis and repair.

Targeted oligonucleotide delivery in human lymphoma cell lines using a polyethyleneimine based immunopolyplex.

The efficacy of antisense gene therapy depends on efficient delivery of oligonucleotides into targeted cells. Although polyethyleneimine based polyplexes have been reported as good transfection reagents, they are inefficient in lymphoid cell transfection. We report the construction of an immunopolyplex, a targeted nonviral vector based on a polyplex backbone and its application for oligonucleotide transfer on human lymphoma cell lines.

Polyethyleneimine-based immunopolyplex for targeted gene transfer in human lymphoma cell lines.

Background: Specific and efficient delivery of genes into targeted cells is a priority objective in non-viral gene therapy. Polyethyleneimine-based polyplexes have been reported to be good non-viral transfection reagents. However, polyplex-mediated DNA delivery occurs through a non-specific mechanism.