Survivin DNA vaccine generated specific antitumor effects in pancreatic carcinoma and lymphoma mouse models.

We investigated the antitumor effect of survivin DNA vaccine in murine pancreatic and lymphoma models, and if xenogenic survivin can generate stronger immune response. We found that mice vaccinated with either human or mouse survivin DNA have significantly slower tumor growth and longer survival than those vaccinated with vector DNA. There was no significant difference between groups that received human and mouse survivin DNA.

Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome. Although front therapy induces a high rate of complete remission (CR), relapse is inevitable and new regimens are much needed for relapsed MCL. The proteasome inhibitor bortezomib (BTZ) induces apoptosis and sensitizes MCL cells to chemotherapy in relapsed MCL, but CR rates are low, with a short duration of response and severe toxicity.

Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis.

Elevated levels of C-reactive protein (CRP) are present in many disease situations including malignancies and may contribute to the pathogenesis of cardiovascular disorders. This study was undertaken in a myeloma setting to determine whether CRP affects tumor cell growth and survival. We show that CRP enhanced myeloma cell proliferation under stressed conditions and protected myeloma cells from chemotherapy drug-induced apoptosis in vitro and in vivo.

Immunotherapy in mantle cell lymphoma: anti-CD20-based therapy and beyond.

Mantle cell lymphoma (MCL), an aggressive non-Hodgkin's lymphoma characterized by t(11; 14)(q13; q32) chromosomal translocation and overexpression of cyclin D1, has the worst prognosis among all lymphomas. Recent advances in biology, genetics, and immunology have supported the development of immunotherapy in MCL. Rituximab monotherapy in MCL has limited activity.

Anti beta2-microglobulin monoclonal antibodies induce apoptosis in myeloma cells by recruiting MHC class I to and excluding growth and survival cytokine receptors from lipid rafts.

We recently showed that monoclonal antibodies (mAbs) against beta2-microglobulin (beta2M) have a remarkably strong apoptotic effect on myeloma cells. The mAbs induced apoptosis by recruiting major histocompatibility complex (MHC) class I to lipid rafts, activated c-Jun N-terminal kinase (JNK), and inhibited phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways. Growth and survival cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-I), which could protect myeloma cells from dexamethasone-induced apoptosis, did not affect mAb-mediated cell death.

A poster-based intervention to promote stair use in blue- and white-collar worksites.

Objective: Previous studies have generally shown the effectiveness of prompts to promote stair use in worksites that mainly consist of white-collar workers. The present study tested whether an intervention using prompts is effective in stimulating stair use in two types of worksites: one consisting mainly of white-collar workers and one mainly of blue-collar workers.

Method: In 2005, elevator and stair use (stair climbing and descent) was monitored in two types of worksites in the Netherlands, namely one office building (n=150 white-collar workers) and one paper factory (n=800 blue-collar workers).

An NKT-mediated autologous vaccine generates CD4 T-cell dependent potent antilymphoma immunity.

Relapses occurring in most patients with lymphoma after antibody or chemotherapy highlight a need for effective vaccination approaches. Autologous tumors are ideal sources of patient-specific tumor antigens for vaccines; however, their poor immunogenicity has been a major obstacle in practice. Natural killer T (NKT) cells have recently emerged as crucial regulators of autoimmunity and tumor immunosurveillance.

The NHF-NRG In Balance-project: the application of Intervention Mapping in the development, implementation and evaluation of weight gain prevention at the worksite.

Very few examples of theory-driven and systematically developed weight gain prevention interventions for adults have been described in the literature. The present paper systematically describes the development, implementation and evaluation framework of a weight gain prevention programme directed at young adults at the worksite, namely the NHF-NRG In Balance-project. It not only can be used as a guide to systematically develop weight gain prevention interventions, but also gives an overview of the current theoretical and empirical knowledge-base in the field of obesity prevention.

Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma.

The identification of novel tumor-associated antigens, especially those shared among patients, is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we examined whether Dickkopf-1 (DKK1), a protein that is not expressed in most normal tissues but is expressed by tumor cells from almost all patients with myeloma, could be a good candidate. We identified and synthesized DKK1 peptides for human leukocyte antigen (HLA)-A*0201 and confirmed their immunogenicity by in vivo immunization in HLA-A*0201 transgenic mice.

Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma.

Background: The objective was to determine the prognostic value of functional imaging (FI) in predicting outcome of patients with recurrent/refractory Hodgkin lymphoma (HL) before undergoing high-dose chemotherapy with autologous stem cell transplantation (ASCT).

Methods: Clinical and imaging data were retrospectively reviewed in 211 consecutive patients treated with ASCT from February 1993 to May 2004. The FI results were correlated with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier survival analysis.

A novel proteoliposomal vaccine elicits potent antitumor immunity in mice.

Therapeutic vaccination against idiotype is a promising strategy for immunotherapy of B-cell malignancies. Its feasibility, however, is limited by the requirement for a patient-specific product. Here we describe a novel vaccine formulation prepared by simply extracting cell-membrane proteins from lymphoma cells and incorporating them together with IL-2 into proteoliposomes.

A novel proteoliposomal vaccine induces antitumor immunity against follicular lymphoma.

Clinical studies suggest that treatment with vaccines comprised of idiotype protein may be associated with improved clinical outcome in follicular lymphoma patients. The time-consuming process required to generate patient-specific vaccines is a major limitation, however. Here we report results of a pilot clinical trial with a novel autologous, tumor-derived proteoliposome vaccine formulation that could be rapidly produced within a single day.

Therapeutic vaccine for lymphoma.

The unique antigenic determinants (Idiotype [Id]) of the immunoglobulin expressed on a given B-cell malignancy can serve as a tumor-specific antigen for active immunotherapy. Therapeutic vaccines targeting the tumor-specific idiotype have demonstrated promising results against lymphomas in phase I/II studies and are currently being evaluated in phase III randomized trials. Additional vaccine therapies being developed include those based on DNA, dendritic cells, gene-modified tumor cells.

Prognostic significance of serum B-lymphocyte stimulator in Hodgkin's lymphoma.

B-lymphocyte stimulator (BLyS) plays a critical role in the survival of B-lymphocytes. In 50 patients with Hodgkin's lymphoma BLyS levels were higher in newly diagnosed patients (median 2.0 ng/mL, range <0.

Study protocol of a cluster randomised controlled trial investigating the effectiveness of a tailored energy balance programme for recent retirees.

Background: People in transitional life stages, such as occupational retirement, are likely to gain weight and accumulate abdominal fat mass caused by changes in physical activity and diet. Hence, retirees are an important target group for weight gain prevention programmes, as described in the present paper.

Methods/design: A systematic and stepwise approach (Intervention Mapping) is used to develop a low-intensity energy balance intervention programme for recent retirees.

Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma.

Background: The objective of this phase II trial was to investigate the safety and efficacy of autologous heat shock protein-peptide complex 96 (HSPPC-96) vaccines prepared from tumor specimens of patients with newly diagnosed or previously treated indolent non-Hodgkin lymphoma (NHL).

Methods: The study was for patients with indolent B-cell NHL with measurable lesions. HSPPC-96 vaccines were prepared from patients' resected tumor specimens and administered as a 25-microg intradermal injection in the absence of disease progression every week for 4 weeks and then every 2 weeks until the vaccine supply was exhausted.

Dose-related safety and immunogenicity of baculovirus-expressed trivalent influenza vaccine: a double-blind, controlled trial in adult patients with non-Hodgkin B cell lymphoma.

In 27 patients randomized to receive commercial trivalent influenza vaccine (TIV) containing 15 microg of the hemagglutinin (HA) of influenza A (H3N2 and H1N1) and B virus or a recombinant vaccine (rHAO) containing 15, 45, or 135 microg of each HA, reactogenicity was minor. Among patients with similar prevaccination titers, 40% given 45 microg and 60% given 135 microg of rHAO developed an increase in influenza A/H3 neutralizing antibody levels; there were no increases in 4 given TIV. For each vaccine, the highest frequencies of increases in neutralizing antibody levels and the highest mean titers occurred in those given the 135- microg vaccine.

Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies.

We discovered that monoclonal antibodies (mAbs) specific to human beta(2)-microglobulin (beta(2)M) induce apoptosis in vitro and were therapeutic in mouse models of myeloma and other hematological tumor cells. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms. The mAbs induced cell death via recruiting MHC class I molecules to lipid rafts and activating Lyn and PLCgamma2, leading to activated JNK and inhibited PI3K/Akt and ERK, compromised mitochondrial integrity, and caspase-9-dependent cascade activation.

Molecular analysis of light-chain switch and acute lymphoblastic leukemia transformation in two follicular lymphomas: implications for lymphomagenesis.

We observed novel transformations of follicular lymphoma (FL), first, a switch in immunoglobulin (Ig) light chain, and second, transformation of FL to acute lymphoblastic leukemia (ALL). Each set of tumors shared a common clonal origin, as demonstrated by expression of identical, unique CDR IIIH sequences, shared somatic mutations in JH, and identical bcl-2 translocation breakpoints of microdissected ALL cells. Molecular analysis of lambda V-gene expression demonstrated lambda-bearing cells in the original kappa tumor, while expansion of the lambda subclone at relapse occurred after active immunotherapy targeting the Ig receptor.

Optimizing immunotherapy in multiple myeloma: Restoring the function of patients' monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells.

Previous studies demonstrated that circulating dendritic cells (DCs) in myeloma patients were functionally abnormal. However, the phenotype and function of patients' monocyte-derived DCs (MoDCs), which are commonly used for immunotherapy, were poorly defined. This study was undertaken to examine the quality of MoDCs from myeloma patients compared with cells from healthy donors.

Therapeutic lymphoma vaccines: importance of T-cell immunity.

The unique antigenic determinants, termed idiotype, of the immunoglobulin expressed on a given B-cell malignancy can serve as a tumor-specific antigen for active immunotherapy. Administration of autologous tumor-derived idiotype protein conjugated to a carrier protein, keyhole limpet hemocyanin, together with granulocyte-macrophage colony-stimulating factor to follicular lymphoma patients in complete clinical remission was associated with induction of tumor-specific cellular and humoral immunity, molecular remissions, and prolonged disease-free survival. Idiotype vaccination in patients with mantle cell lymphoma following rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells, suggesting that vaccines may be used in combination with rituximab.

Prophylactic anti-tumor effects in a B cell lymphoma model with DNA vaccines delivered on polyethylenimine (PEI) functionalized PLGA microparticles.

Idiotypic sequences, specific to the hypervariable regions of immunoglobulins expressed by malignant B cells offer a therapeutic target in B cell lymphoma. Efficient approaches have been described to clone a single chain fragment of the tumor immunoglobulin (Ig) comprising of heavy and light Ig chains (sFv) fused with proinflammatory chemokines. Tumor associated, poorly immunogenic self antigens encoded by plasmid DNA (pDNA) have been rendered immunogenic by chemokine fusion, thereby targeting to antigen presenting cells (APCs) which differentially express chemokine receptors.

Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells.

The aberrant fusion protein NPM-ALK plays an important pathogenetic role in ALK+ anaplastic large-cell lymphoma (ALCL). We previously demonstrated that Jak3 potentiates the activity of NPM-ALK. Jak3 activation is restricted to interleukins that recruit the common gamma chain (gammac) receptor, including IL-9.