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Tadmor T.,Haematology Unit | Zhang Y.,University of Miami | Cho H.-M.,University of Miami | Podack E.R.,University of Miami | Rosenblatt J.D.,University of Miami
Cancer Immunology, Immunotherapy | Year: 2011

Increasing evidence suggests that B lymphocytes play a central role in inhibiting the immune response against certain tumors, but the underlying mechanisms by which B cells facilitate tumor growth are still poorly understood. In this study, we investigated how the presence or absence of B cells affects expansion and function of T-regulatory cells ('T-regs') in a murine breast tumor model (EMT-6). We compared tumor growth, and the number and function of T-reg cells in wild-type immune-competent mice (ICM) and B-cell-deficient mice (BCDM). Mice were either tumor-naive or implanted with EMT-6 mammary adenocarcinoma cells. Tumor growth was markedly inhibited in BCDM, compared to wild-type mice (ICM). Increased T-reg expansion as defined by CD4+/CD25+/FOXP3+ cells was evident following EMT-6 inoculation in ICM in comparison with non-tumor-bearing mice or compared to BCDM in which tumor had been implanted. The percentage and absolute number of T-regs in the spleen, tumor draining lymph nodes, and tumor bed were significantly reduced in BCDM compared to ICM. T-reg function, measured by suppression and proliferation assays, was also reduced in tumor inoculated BCDM compared to ICM. Our studies indicate that absence of B cells may play a role in augmenting the T-cell anti-tumor response, in part due to effects on T-regulatory cell expansion and function. © 2011 Springer-Verlag.

Ostergaard P.,St Georges, University of London | Simpson M.A.,Kings College London | Connell F.C.,Guys and St. Thomas National Health Service NHS | Steward C.G.,Bone Marrow Transplant Unit | And 16 more authors.
Nature Genetics | Year: 2011

We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome. © 2011 Nature America, Inc. All rights reserved.

Petrarca A.,University of Florence | Rigacci L.,Haematology Unit | Caini P.,University of Florence | Colagrande S.,University of Florence | And 9 more authors.
Blood | Year: 2010

The effectiveness of rituximab in hepatitis C virus (HCV)-related mixed cryoglobulinemia (MC) has been shown. However, the risk of an increase in viral replication limits its use in cirrhosis, a condition frequently observed in patients with MC. In this prospective study, 19 HCV-positive patients with MC and advanced liver disease, who were excluded from antiviral therapy, were treated with rituximab and followed for 6 months. MC symptoms included purpura, arthralgias, weakness, sensory-motor polyneuropathy, nephropathy, and leg ulcers. Liver cirrhosis was observed in 15 of 19 patients, with ascitic decompensation in 6 cases. A consistent improvement in MC syndrome was evident at the end-of-treatment (EOT) and end-of-follow-up (EOF-U). Variable modifications in both mean viral titers and alanine aminotransferase values were observed at admission, EOT, third month of follow-up, and EOF-U (2.62 × 106, 4.28 × 106, 4.82 × 106, and 2.02 × 106 IU/mL and 63.6, 49.1, 56.6, and 51.4 IU/L, respectively). Improvement in liver protidosynthetic activity and ascites degree was observed at EOT and EOF-U, especially in more advanced cases. This study shows the effectiveness and safety of rituximab in MC syndrome with advanced liver disease. Moreover, the depletion of CD20+ B cells was also followed by cirrhosis syndrome improvement despite the possibility of transient increases of viremia titers. © 2010 by The American Society of Hematology.

Zhang Y.,University of Miami | Eliav Y.,University of Miami | Shin S.-U.,University of Miami | Schreiber T.H.,University of Miami | And 3 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

The mechanisms by which B lymphocytes inhibit anti-tumor immunity remain poorly understood. Murine EMT-6 mammary tumors grow readily in immune competent mice (BALB/c), but poorly in B-cell-deficient μ-/- BALB/c mice (BCDM). T regulatory cell (Treg) expansion and function were impaired in BCDM compared with BALB/c. In this study, we compared tumor growth, Treg cell proliferation, tumor lymphocyte infiltration and cytolytic T cell activity in BALB/c, BCDM and BCDM partially reconstituted with B cells by adoptive transfer (BCDM+B). Partial reconstitution of BCDM with adoptively transferred B cells restored EMT-6 tumor growth, which was independent of IL-10 secretion by B cells. Instead, high frequencies of intratumoral B cells were associated with increased recruitment and proliferation of Treg cells within the tumor microenvironment. The B-cell-dependent accumulation of Treg within the tumor microenvironment was associated with reduced tumor infiltration by CD49+ NK and CD8+ T cells and reduced cytotoxic T cell activity against EMT-6 targets. Our studies indicate that tumor-dependent immunosuppression of T-cell-mediated anti-tumor immunity is coordinated within the tumor microenvironment by B-cell-dependent cross talk with Treg cells, which does not require production of IL-10 by B cells. © 2012 Springer-Verlag.

Raju N.C.,Haematology Unit | Eikelboom J.W.,Thrombosis Unit | Eikelboom J.W.,McMaster University
Current Opinion in Cardiology | Year: 2012

PURPOSE OF REVIEW: Apparently conflicting meta-analysis results have led to renewed debate about the role of aspirin for the primary prevention of cardiovascular disease. We review the results of meta-analyses comparing aspirin with placebo or no aspirin for the primary prevention of cardiovascular disease and critically evaluate whether aspirin provides a net benefit. RECENT FINDINGS: The results of four independently conducted meta-analyses between 2009 and 2012 involving between 95 000 and 102 621 individuals at low risk of cardiovascular disease are consistent with the results of the 2002 Antithrombotic Trialists' Collaboration meta-analysis, which found that aspirin reduces cardiovascular events primarily by reducing nonfatal myocardial infarction (MI). There is no convincing evidence that aspirin reduces cardiovascular mortality, but estimates from all of the meta-analyses suggest a modest reduction in all-cause mortality. Aspirin reduces ischaemic stroke but increases haemorrhagic stroke and major bleeding. SUMMARY: The meta-analysis results consistently indicate that, in individuals at low risk for cardiovascular disease, aspirin reduces the risk of MI at the cost of an increase in major bleeding and produces a modest nominally significant reduction in total mortality. These results suggest that recommendations for primary prevention with aspirin should be individualized, taking into account the balance between benefits and risks and individual values and preferences. © 2012 Wolters Kluwer Health.

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