Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BACKGROUND: Modulation of the immune system by genetically modified lymphoma cell vaccines is of potential therapeutic value in the treatment of B cell lymphoma. However, the anti-tumor effect of any single immunogene transfer has so far been limited. Combination treatment of recombinant IL-2 and IL-12 has been reported to be synergistic for inducing anti-tumor responses in solid tumors but the potential of IL-2/IL-12 gene modified B cell lymphoma cells has not been explored yet. METHODS: Using three different human B cell lymphoma cell lines and primary samples from patients with B cell neoplasms, expression levels of the coxsackie B-adenovirus receptor (CAR) and alpha (v) integrins were analyzed by fluorescence-activated cell sorter (FACS). Adenoviral transduction efficiencies were determined by GFP expression analysis and IL-2 and IL-12 cytokine production was quantified by enzyme-linked immunosorbent (ELISA) assays. Proliferative activities of peripheral blood mononuclear cells (PBMC) stimulated with either cytokine derived from supernatants of transduced lymphoma cells were measured by cell proliferation (MTT) assays. An EuTDA cytotoxicity assay was used to compare cytotoxic activities of IL-2 and/or IL-12 stimulated PBMC against unmodified lymphoma cells. RESULTS: We found that B cell lymphoma cell lines could be transduced with much higher efficiency than primary tumor samples, which appeared to correlate with the expression of CAR. Adenoviral-expressed IL-2 and IL-12 similarly led to dose-dependent increases in proliferation rates of PBMC obtained from healthy donors. IL-2 and/or IL-12 transduced lymphoma cells were co-cultured with PBMC, which were assayed for their cytolytic activity against unmodified lymphoma cells. We found that IL-2 stimulated PBMC elicited a significant anti-tumor effect but not the combined effect of IL-2/IL-12 or IL-12 alone. CONCLUSION: This study demonstrates that the generation of recombinant adenovirus modified lymphoma cell vaccines based on lymphoma cell lines expressing IL-2 and IL-12 cytokine genes is technically feasible, induces increases in proliferation rates and cytotoxic activity of co-cultured PBMC, and warrants further development for the treatment of lymphoma patients in the future.
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PMID:Effects of recombinant adenovirus-mediated expression of IL-2 and IL-12 in human B lymphoma cells on co-cultured PBMC. 1548 77

Interleukin 10 (IL-10) is a Th2 anti-inflammatory cytokine that participates in the regulation of the immune response at several levels. Its production has been implicated in the immunosuppression frequently observed in tumor bearing hosts. The broad spectrum of IL-10 biologic activities is mediated by its binding to its cognate receptor (IL-10R). We have already demonstrated the overproduction of IL-10 by B-cell lymphoma tumor bearing rats and, also, that IL-10 could act as a growth factor for metastatic cells. Considering the importance to unravel each feature of the complex biology of metastasis, the goal of the present study was to investigate the expression of IL-10 receptor (IL-10R), at mRNA and protein level, in primary tumor and metastatic cells from a rat B-cell lymphoma, along with the production of IL-10 by both tumor cell types. Our results indicate that IL-10, besides its immunoregulatory effect, would act as an autocrine growth factor for cells with metastatic phenotype. Also, the up-regulation of IL-10 and IL-10R expression would be part of the transition from primary tumor to the metastatic phenotype.
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PMID:The transition to the metastatic phenotype of rat lymphoma cells involves up-regulation of IL-10 receptor expression and IL-10 secretion. 1608 33

Mantle-cell lymphoma (MCL) is a mature B-cell lymphoma with an aggressive course and generally poor prognosis. Conventional chemotherapy has little efficacy. Bortezomib is a novel, reversible, and highly specific proteasome inhibitor that appears as a new hope for MCL treatment. We have analyzed the in vitro sensitivity to bortezomib in 4 MCL cell lines and in primary tumor cells from 10 MCL patients. Bortezomib induced phosphatidylserine exposure, mitochondrial depolarization, ROS generation, Bax and Bak conformational changes, and caspase activation. In addition, ROS scavengers, but not pancaspase inhibitors, blocked all apoptosis hallmarks. Protein and mRNA-expression analysis, revealed marked up-regulation of the BH3-only protein Noxa, between 4 to 6 hours after bortezomib addition, independent of p53 status. However, this up-regulation was faster and higher in cells with functional p53. Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing to this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells. Noxa interacts with the antiapoptotic protein Mcl-1 and promotes Bak release from Mcl-1, suggesting that up-regulation of Noxa might counteract Mcl-1 accumulation after bortezomib treatment. These findings should be useful to extend the therapeutic strategies in MCL patients and to improve their prognosis.
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PMID:The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. 1616 92

G protein-coupled receptors (GPCRs) play important roles in a variety of biological and pathological processes. They are considered among the most desirable targets for drug development. Recent studies have demonstrated that many GPCRs, such as endothelin receptors, chemokine receptors and lysophosphatidic acid receptors have been implicated in the tumorigenesis and metastasis of multiple human cancers. In this study, we conducted an in silico analysis of GPCR gene expression in primary human tumors by analyzing some publicly available gene expression profiling data. Statistical analysis was performed on eight microarray data sets of non-small cell lung cancer, breast cancer, prostate cancer, melanoma, gastric cancer and diffused large B cell lymphoma to identify GPCRs that are up-regulated in primary or metastatic cancer cells. Our analysis has demonstrated overexpression of several GPCRs in primary tumor cells, including chemokine receptors and protease-activated receptors that were shown to be important for tumorigenesis by previous studies. In addition, we have uncovered several GPCRs, such as neuropeptide receptors, adenosine A2B receptor, P2Y purinoceptor, calcium-sensing receptor and metabotropic glutamate receptors, that are expressed at a significantly higher level in some cancer tissue and may play a role in cancer progression. Analysis of cancer samples in different disease stages also suggests that some GPCRs, such as endothelin receptor A, may be involved in early tumor progression and others, such as CXCR4, may play a critical role in tumor invasion and metastasis. The present study demonstrates the value of publicly available microarray data as a resource to gain more understanding of cancer biology, to validate previous findings from in vitro experiments, and to identify potential novel anticancer targets and biomarkers.
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PMID:Overexpression of G protein-coupled receptors in cancer cells: involvement in tumor progression. 1621 Dec 29

Infiltration by dendritic cells (DCs) is a common feature of most human tumors. Prior studies evaluating the interaction of DCs with tumors have focused largely on their immunologic properties (for review see Banchereau, J., and R.M. Steinman. 1998. Nature. 392:245-252). In this study, we show that the clonogenicity of several human tumor cell lines and primary tumor cells from myeloma patients is enhanced by their interactions with DCs. Myeloma cells cultured in the presence of DCs have an altered phenotype with an increased proportion of cells lacking terminal plasma cell differentiation marker CD138. DC-tumor interaction also leads to the up-regulation of B cell lymphoma 6 expression in myeloma cells. Effects of DCs on myeloma cells are inhibited by blockade of the receptor activator of NF-kB (RANK)-RANK ligand and B cell-activating factor-APRIL (a proliferation-inducing ligand)-mediated interactions. Together, these data suggest that tumor-DC interactions may directly impact the biology of human tumors, particularly multiple myeloma, and may be a target for therapeutic intervention.
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PMID:Enhancement of clonogenicity of human multiple myeloma by dendritic cells. 1688 Feb 56

Primary pancreatic lymphoma is rare, comprising 0.2-4.9% of all pancreatic malignancies and less than 1% of cases of non-Hodgkin's lymphoma. Many patients are diagnosed with lymphoma after radical resection. We report a rare presentation of diffuse large B cell lymphoma, appearing as a primary tumor of the pancreas. A 61-year old female was admitted to the hospital with the complaint of right upper abdominal pain. Computed tomography of the abdomen showed a well defined mass located at the head of the pancreas. A frozen section of pancreas, during laparotomy, revealed lymphoma. The patient received 6 cycles of chemotherapy and is currently in complete remission. This case underscores the importance of differentiating primary lymphoma from the more common adenocarcinoma of the pancreas as treatment and prognosis differ significantly. Primary pancreatic lymphoma should be considered in the differential diagnosis of pancreatic tumors and an attempt to obtain a tissue diagnosis is always necessary before proceeding to radical surgery, especially on young patients.
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PMID:A case of primary pancreatic non-Hodgkin's lymphoma. 1691 43

Along with a brief review of the literature, we report the clinicopathologic features of 12 cases of extramammary malignancies metastatic to the breast. Histological diagnoses of the primary tumor were as follows: non-Hodgkin diffuse large B-cell lymphoma (3 patients), acute mycloid leukemia (3 patients), serous papillary adenocarcinoma, well-differentiated adenocarcinoma, squamous cell carcinoma, undifferentiated neoplasm, mesothelioma, and melanoma. The most common mammographic finding was a well-circumscribed mass with increased density but without speculation, calcifications or other signs that characterize the majority of primary carcinomas. Ultrasound revealed well-circumscribed masses without retrotumor acoustic shadowing. The interval between diagnosis of primary cancer and the appearance of breast metastasis ranged from 0 to 108 months (mean: 17, median: 1). Survival after the detection of the breast metastases ranged from 0.2 to 144 months (mean: 23, median: 9.5). In conclusion, metastasis can mimic either benign disease or primary malignancy and is often an unexpected diagnosis in a patient presenting with a breast mass. Thus, an accurate diagnosis is important to avoid unnecessary mutilating surgery. These masses generally indicate disseminated metastatic disease, with a very poor survival rate.
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PMID:Metastases to the breast from extramammary malignancies: a clinicopathologic study of 12 cases. 1721 43

The Mix1 homeobox-like (MIXL1) gene encodes a paired class homeobox transcription factor that is involved in embryogenesis. Previous studies have shown that the MIXL1 gene product is expressed in B- and T-cell progenitors of normal bone marrow and, in some cell lines derived from hematopoietic neoplasms. The status of MIXL1 expression and subcellular localization in human lymphomas is unknown. Using a highly specific antibody, we assessed for MIXL1 expression in lymphoma cell lines of B- and T-cell lineage by reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry. We also assessed for MIXL1 expression using immunohistochemical methods in 193 lymphoid tumors, including 140 B-cell non-Hodgkin lymphomas (NHL), 36 T-cell NHL, and 17 Hodgkin lymphomas (HL). MIXL1 was detected predominantly in the nuclear fraction of all cell lines tested and was predominantly nuclear in primary tumor specimens. Based on the distribution of the staining results (histogram), a 50% cutoff was selected for high versus low MIXL1 expression. High MIXL1 expression was detected more frequently in Burkitt lymphoma and diffuse large B-cell lymphoma compared with other types of B-cell NHL (P < .0001, chi(2) test). Most cases of T-cell NHL and all cases of HL also highly expressed MIXL1. Most plasma cell myelomas were negative for MIXL1, but rare cases had low MIXL1 expression. MIXL1 expression significantly correlated with proliferation index (Ki-67) in B-cell NHL (P < .0001). The frequent and high expression of MIXL1 in aggressive B-cell NHL, T-cell NHL, and HL suggests that MIXL1 may be involved in lymphomagenesis.
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PMID:Differential expression of the human MIXL1 gene product in non-Hodgkin and Hodgkin lymphomas. 1730

We aimed to estimate the frequency of association between non-Hodgkin lymphoma (NHL) with abdominal, gastric, or intestinal involvement and Helicobacter pylori in childhood. Between February 2003 and June 2006, we evaluated 15 children with newly diagnosed NHL who were diagnosed and treated at the Pediatric Oncology Department of Hacettepe University. Patients who were given chemotherapy previously or who received H. pylori eradication therapy were excluded from the study. Routine procedures were done for staging. Pathologic diagnosis was made by examining the biopsy samples. The presence of H. pylori was confirmed by H. pylori IgG serology with urea breath test (UBT) in cooperated children. Endoscopic examination was also planned for patients with positive test results. Twelve male and 3 female patients, with a median age of 7 (range: 3 to 16), were evaluated. They had extensive abdominal, gastric, and/or intestinal involvement. Six had stage IV characteristics, whereas another 9 patients had stage III disease. Ten had high-grade B-cell lymphoma. Only 3 patients had H. pylori IgG and UBT positivity (20%). First patient had T-cell lymphoma and stage IV disease with involvement in stomach, mediastinum, peripheral lymph nodes, and bone marrow. The second one had anaplastic large cell lymphoma exclusively in abdominal lymph nodes. Last patient had Burkitt lymphoma and stage IV disease, with primary tumor localization in abdominal lymph nodes, liver, and kidneys. The H. pylori IgG and UBT were both positive in 3 patients on admission. We did not find any positive test results in the other 12 patients with intestinal, stomach, or abdominal disease. Preliminary results of our study suggest that H. pylori may not be the responsible agent for NHL involved the abdomen in childhood.
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PMID:Association of Helicobacter pylori and childhood lymphoma. 1748 6

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. Here we evaluated whether BTZ is additive or synergistic with cyclophosphamide (CTX) and rituximab (RTX). Increasing doses of BTZ with a fixed dose of RTX and CTX (BRC regimen) resulted in markedly synergistic growth inhibition of MCL cells. BRC significantly enhanced apoptosis in MCL cell lines and primary tumor cells compared with single-agent treatment. Furthermore, western blotting analysis indicated that BRC induces apoptosis earlier via activation and cleavage of caspases-8, -9 and -3, and poly (ADP-ribose) polymerase, than single-agent treatment. The pan-caspase inhibitor completely blocked apoptosis induced by BRC. In vivo studies showed that BRC eradicated subcutaneous tumors in MCL-bearing SCID mice and significantly prolonged the long-term event-free survival in 70% of the mice. Hence, our study demonstrates that cytoreductive chemotherapy with both BTZ and anti-CD20 antibody may offer a better therapeutic modality for relapsed MCL.
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PMID:Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. 1789 87


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