Ghulam J Mufti

..As the functional mechanisms behind these chromosomal changes are being revealed, new therapies based on these mechanisms are currently being made and tested...

..We have identified a number of CT antigens with expression in presentation AML samples but not normal donor samples, which may provide effective targets for future immunotherapy treatments early in disease...

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..Timing of available therapies, including stem cell transplantation, should be incorporated into the new treatment paradigm, with end goals of prolonging survival and optimizing patient outcomes...

..Recommendations should be applied in the context of the WHO classification...

..The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q- and CK with -5/5q-, possibly implies two different mechanistic roles for TP53 protein...

..On multivariate analysis, age (> 50 years) was associated with a higher incidence of TET2 mutation (P = .02)...

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..Identification of MAFB and five additional targets and their subsequent confirmation as mir-130a targets by western blot analysis and knockdown experiments validates this strategy for the functional identification of miRNA targets...

..001) and age (92% for age < 50 years vs 71% ≥ 50 years, P < .001). Our data suggest that the use of an alemtuzumab-based HSCT regimen for SAA results in durable engraftment with a low incidence of chronic GVHD...

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..4% to 22.5%). These studies demonstrated that vaccination of patients with CD80/IL2-transduced AML cells could provide a powerful strategy for T/NK cell-mediated stimulation of anti-leukaemic immunological responses...

..In conclusion CHOP-Z is safe and in those who achieve a complete response it was associated with prolonged overall survival...

..The clonally restricted expansion of Th1 cells is most likely to be antigen-driven, and induces an inflammatory environment, that exacerbate the functional impairment of Tregs, which are reduced in number...

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..This type of interaction in the peripheral vasculature may explain the constitutive NF-κB activation and the overexpression of Bcl-2 family proteins commonly seen in this disease...

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..Antigen presentation assays using monocyte-derived dendritic cells (mo-DCs) showed that PASD1 could stimulate autologous T-cell responses, suggesting that PASD1 could be a promising target for future immunotherapy clinical trials...

..Using the methodology described, we have shown SEREX to be effective for the isolation of leukaemia-associated antigens, which may act as targets for immunotherapy...

..These data suggest that the generation of increased constitutive DNA damage may be a common pathway for the creation of NHEJ-dependent genomic instability...

..This method will allow us to study of the effects of a variety of gene products in cell types that were previously resistant to gene transfection studies...

..Reversal of these immunosuppressive effects and restoration of normal immune responses in patients with AML would improve the success of immunotherapy protocols...

..We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling...

..Thus, our data indicate that constitutive DNA damage is coupled to delayed DNA replication in BS cells...

..We demonstrate that pDLI safely promotes durable remission after TCD RIC HSCT for AML or MDS, and that tDLI salvages patients after late relapse with greater efficacy...

..005). In conclusion, the presence of JAK2V617F predicts hepatic and extrahepatic thrombotic complications after LT. Testing for TET2 mutations can identify another 7% of idiopathic BCS patients with molecular MPDs...

..9, P = .003) and age more than 37 years (hazard ratio = 4.7, P = .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848...

..This new experimental platform provides a more precise screening of new therapeutics for improved efficacy of tumour cell killing within the bone marrow microenvironment...

..Vaccination with LV-CD80/IL2 therefore provides a potential strategy to enhance anti-leukaemia immune responses without a concomitant stimulation of Treg-mediated inhibition of cytotoxic immunological responses...

..Future studies need to be directed towards establishing the underlying factors that dictate T-cell engraftment, expansion and homing post-transplantation...

..Our findings suggest that an overactive NHEJ system and, specifically, aberrant Ku70/86 activity is a candidate mechanism for chromosomal instability in myeloid leukemias...

..RIC allogeneic HSCT using this protocol appears to be safe and permits durable donor engraftment. Longer follow-up is required to confirm any potential survival advantage...

..The 'unfavourable' Th17:Tregs ratio in low risk MDS may explain the higher risk of autoimmunity and the improved response to immune suppression in patients with low risk MDS compared to those with high risk disease...

..This review examines the potential role of several genes, including RPS14, in the pathogenesis of the 5q- syndrome and recent advances in clinical management, with particular emphasis on the role and mechanism of action of lenalidomide...

..Furthermore, a drop in meC also marks 3' transcription termination, and a peak of meC occurs at stop codons. This mimics the 3' nucleosomal distribution in yeast, which we show does not occur in human T cells...

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..Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT...

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..This aberrant repair is dependent upon the presence of the Ku70/86 heterodimer, a key component in the NHEJ pathway. We propose that aberrant NHEJ is a candidate mechanism for the generation of chromosomal instability in BS...

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..RIC regimens using VUD was associated with durable long-term survival even in older patients with MDS, and the use of a pre-transplant comorbidity index may help to improve patient selection for transplantation...

..Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of apoptosis...

..032). Our data suggest that CD4+ Treg expansion is a feature of high-risk MDS and progression to aggressive subtypes of the disease...

..A clonal mutation in JAK2 tyrosine kinase (JAK2V617F) occurs in a high proportion of patients with MPD and is of use in the characterization of latent MPD in BCS...

..9% and 3.0% respectively. Despite in vivo T-cell depletion with alemtuzumab, the incidence of toxoplasma disease in our cohort was comparable with previously reported T-cell replete HSCT studies...

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..We investigated the sequence integrity of 4q24 candidate tumor suppressor gene TET2 in MDS patients with UPD on chromosome 4...

..In human allogeneic mixed lymphocyte reactions (MLRs), we found no single costimulatory molecule was more effective, suggesting that the induction of a universal anti-tumor response will require a combination of costimulatory molecules...

..However, transfusion requirements were significantly higher in the SCo group, due at least partly to earlier onset of bone marrow hypoplasia...

..5 year DFS to those receiving conventional regimens...

..10%, P = 0.19). None of the nine myeloablative HSCT recipients survived (median survival: 9 d). Six of the 15 reduced-intensity conditioned HSCT recipients survived beyond 1 year (median survival: 1050 d, range: 438-1437)...

..001). We show, for the first time, that SNP microarray analysis in low-risk MDS patients reveals hitherto unrecognized UPD and CN changes that may allow stratification of these patients for early therapeutic interventions...

..The graft versus dysplasia effect resulting from allogeneic HSCT and the infusion of donor leukocytes has led to a greater understanding of the immunological mechanisms that govern outcome following transplantation in MDS...

..Expression profiling and proteomic technologies may offer the best means to unravel this process...

..We will aim to provide a brief overview of the latest data from our group and considerations for the use of this treatment modality in clinical trials for AML...

..In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer...

..Rituximab may be useful in preventing progression of NHL until surgical extirpation is possible...

..This mutation was un-detectable in pancreatic cancer tissue samples (n=65) and pancreatic cell line (n=10) DNA suggesting that pancreatic cancer progression is mainly dependent on the K-Ras mutation...

..This paper outlines the apoptotic process in normal hematopoietic cells and summarizes current data regarding the role, potential causes and clinical implications of altered apoptosis in MDS...

..Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed...

..We conclude that alterations of CHK2 and possible involvement in the pathogenesis of MDS may be a rare event...

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..Thus, STI571 induces an accumulation of FoxO3a activity which in turn binds directly to an FHRE in the promoter to activate Bim expression and apoptosis...

..The colocalization of BCL-2 and RAS in the bone marrow of MDS/AML patients offers targeting either oncogene as a therapeutic strategy...

..These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML...

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..001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT...

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..In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS...

..g. according to age, risk, classification, and cytogenetic profile), and the combination strategies, particularly with histone deacetylase inhibitors, in the management of MDS...

..Only three out of 15 patients had adequate progenitor cell collections for potential use in autologous transplantation...