bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Tumor-specific CD4+ T Lymphocytes by Major Histocompatibility Complex Class II Tumor Cell Vaccines
Authors: Dissanayake Samudra K. , Thompson James A. , Bosch Jacobus J. , Clements Virginia K. , Chen Peter W. , Ksander Bruce R. , Ostrand-Rosenberg Suzanne 
Published: September 2005

AbstractMouse tumor cells transfected with syngeneic MHC class II and costimulatory molecule genes are therapeutic vaccines in mice, provided they do not coexpress the class II-associated invariant chain (Ii). We demonstrated previously that the vaccine cells present tumor peptides via the endogenous antigen presentation pathway to activate CD4+ and CD8+ T cells. Because of their efficacy in mice, we are translating this vaccine strategy for clinical use. To obtain MHC class II+CD80+Ii− human tumor cells, we developed retroviruses encoding HLA-DR and CD80. The HLA-DR virus encodes the DRα and DRβ0101 chains using an internal ribosomal entry site to coordinate expression. SUM159PT mammary carcinoma and Mel 202 ocular melanoma cells transduced with the retroviruses DRB1/CD80 express high levels of DRB0101 and CD80 on the cell surface in the absence of Ii. Irradiated SUM159PT/DR1/CD80 vaccines stimulate proliferation of non-HLA-DRB0101 peripheral blood mononuclear cells and present an exogenous DR1-restricted tetanus toxoid (TT) peptide, indicating that the transduced DRB0101 is functional. SUM159PT/DR1/CD80 vaccines were further transduced with a retrovirus encoding the TT fragment C gene, as a model tumor antigen. These cells stimulate IFN-γ release from TT-primed human DRB0101 peripheral blood mononuclear cells, demonstrating their ability to present “endogenous” tumor antigen. Depletion and antibody blocking experiments confirm that MHC class II-restricted, endogenously synthesized epitopes are presented to CD4+ T cells. Therefore, the MHC class II vaccines are efficient antigen-presenting cells that activate tumor-specific MHC class II-restricted, CD4+ T lymphocytes, and they are a novel and potential immunotherapeutic for metastatic cancers.
Inhibition of
MUC4
Expression Suppresses Pancreatic Tumor Cell Growth and Metastasis
Authors: Singh Ajay P. , Moniaux Nicolas , Chauhan Subhash C. , Meza Jane L. , Batra Surinder K. 
Published: September 2005

Abstract
The MUC4 mucin is a high molecular weight membrane-bound glycoprotein. It is aberrantly expressed in pancreatic tumors and tumor cell lines with no detectable expression in the normal pancreas. A progressive increase of MUC4 expression has also been observed in pancreatic intraepithelial neoplasia, suggesting its association with disease development. Here, we investigated the consequences of silencing MUC4 expression in an aggressive and highly metastatic pancreatic tumor cell line CD18/HPAF that expresses high levels of MUC4. The expression of MUC4 was down-regulated by the stable integration of a plasmid-construct expressing antisense-MUC4 RNA. A decrease in MUC4 expression, confirmed by Western blot and immunofluorescence analyses, resulted in diminished growth and clonogenic ability of antisense-MUC4-transfected (EIAS19) cells compared with parental, empty vector (ZEO) and sense transfected (ES6) control cells. In addition, EIAS19 cells displayed a significant decrease in tumor growth and metastatic properties when transplanted orthotopically into the immunodeficient mice. In vitro biological assays for motility, adhesion, and aggregation demonstrated a 3-fold decrease in motility of EIAS19 cells compared with control cells, whereas these cells adhered more and showed an increase in cellular aggregation. Interestingly, MUC4 down-regulation also correlated with the reduced expression of its putative interacting partner, HER2/neu, in antisense-MUC4-transfected cells. In conclusion, the present work demonstrates, for the first time, a direct association of the MUC4 mucin with the metastatic pancreatic cancer phenotype and provides experimental evidence for a functional role of MUC4 in altered growth and behavioral properties of the tumor cell.
Surgical Removal of Primary Tumor Reverses Tumor-Induced Immunosuppression Despite the Presence of Metastatic Disease
Authors: Danna Erika A. , Sinha Pratima , Gilbert Mileka , Clements Virginia K. , Pulaski Beth A. , Ostrand-Rosenberg Suzanne 
Published: September 2005

AbstractImmunotherapy is a promising approach for the management of malignancies. It may be particularly useful for tumors that do not respond to conventional therapies, such as many metastatic cancers. The efficacy of immunotherapy will depend on many factors, one of which is the immunocompetence of the host. Patients with large primary tumors frequently are immunosuppressed, making them poor candidates for immunotherapy. Although a few studies have reported that surgical removal of primary tumor reverses immunosuppression, it is not known whether metastatic disease in postsurgery patients inhibits this recovery. To determine the role of metastatic disease, we examined tumor-free mice versus mice with primary tumor and metastatic disease versus mice whose primary tumors were removed surgically but who had metastatic disease. We have used the mouse 4T1 mammary carcinoma, a BALB/c-derived transplantable tumor that shares many characteristics with human breast cancer and is an established model for spontaneous, metastatic cancer. Cell-mediated and humoral adaptive immunity, as measured by rejection of allogeneic tumor, antigen-specific T-cell proliferation, and antigen-specific antibody responses, was suppressed in 4T1-bearing nonsurgery mice relative to tumor-free mice. Surgical removal of primary tumor resulted in rebounding of antibody and cell-mediated responses, even in mice with metastatic disease. Macrophage activity, as measured by lipopolysaccharide responsiveness, and dendritic cell function, as measured by nominal and alloantigen presentation, were not suppressed in tumor-bearing mice. Therefore, the presence of primary tumor suppresses T-cell and antibody responses; however, surgical removal of primary tumor restores immunocompetence even when disseminated metastatic disease is present.
Endogenous Control of Cell Cycle Progression by Autocrine Transforming Growth Factor β in Breast Cancer Cells
Authors: Ammanamanchi Sudhakar , Tillekeratne Manoranjani P. M. , Ko Tien C. , Brattain Michael G. 
Published: September 2005

Abstract
Tumor progression due to loss of autocrine negative transforming growth factor-β (TGF-β) activity was reported in various cancers of epithelial origin. Estrogen receptor expressing (ER+) breast cancer cells are refractory to TGF-β effects and exhibit malignant behavior due to loss or inadequate expression of TGF-β receptor type II (RII). The exogenous TGF-β effects on the modulation of cell cycle machinery were analyzed previously. However, very little is known regarding the endogenous control of cell cycle progression by autocrine TGF-β. In this study, we have used a tetracycline regulatable RII cDNA expression vector to demonstrate that RII replacement reconstitutes autocrine negative TGF-β activity in ER+ breast cancer cells as evidenced by the delayed entry into S phase by the RII transfectants. Reversal of the delayed entry into S phase by the RII transfectants in the presence of tetracycline in addition to the decreased steady state transcription from a promoter containing the TGF-β responsive element (p3TP-Lux) by TGF-β neutralizing antibody treatment of the RII transfected cells confirmed that autocrine-negative TGF-β activity was induced in the transfectants. Histone H1 kinase assays indicated that the delayed entry of RII transfectants into phase was associated with markedly reduced cyclin-dependent kinase (CDK)2 kinase activity. This reduction in kinase activity was due to the induction of CDK inhibitors p21/waf1/cip1 and p27/kip, and their association with CDK2. Tetracycline treatment of RII transfectants led to the suppression of p21/waf1/cip1and p27/kip expression, thus, directly demonstrating induction of CDK inhibitors by autocrine TGF-β leading to growth control of ER+ breast cancer cells.
Increased Metastatic Dissemination in Human Melanoma Xenografts after Subcurative Radiation Treatment
Authors: Rofstad Einar K. , Mathiesen Berit , Galappathi Kanthi 
Published: September 2005

Abstract
Cancer patients showing local failure after radiation treatment have increased probability for developing metastatic disease. The mechanisms behind this observation have not been identified. In the present work, metastatic spread after inadequate radiation therapy was studied by using R-18 human melanoma xenografts as models of cancer in humans. Pimonidazole was used as a hypoxia marker, and hypoxia and urokinase-type plasminogen activator receptor (uPAR) expression were detected by immunohistochemistry. R-18 tumors regrowing after subcurative irradiation showed a higher frequency of lymph node metastasis than unirradiated tumors. The expression of uPAR was up-regulated in hypoxic tumor regions, and the fractions of hypoxic and uPAR-positive cells were ∼2-fold higher in regrowing irradiated tumors than in untreated tumors. Treatment with anti-uPAR antibody blocked metastasis almost completely in irradiated as well as unirradiated tumors. The metastatic frequency was higher in tumors regrowing after irradiation than in unirradiated tumors because the irradiation induced tumor hypoxia, and tumor hypoxia induced up-regulation of uPAR.
High-Resolution Magnetic Resonance Imaging of Disparities in the Transcapillary Transfer Rates in Orthotopically Inoculated Invasive Breast Tumors
Authors: Dadiani Maya , Margalit Raanan , Sela Noa , Degani Hadassa 
Published: September 2005

Abstract
In vivo mapping of the transcapillary fluxes in tumors can help predict the efficacy of delivery of blood-borne anticancer drugs. These fluxes are primarily affected by the vascular permeability and the pressure gradients across the blood vessels’ walls. We describe herein high-resolution dynamic contrast-enhanced magnetic resonance imaging of the influx and outflux transcapillary transfer rates in vivo in invasive MDA-MB-231 tumors orthotopically inoculated in severe combined immunodeficient mice. The tumors were noted for rapid growth, impaired drainage of fluid, and subsequent formation of cysts. Consequently, the time evolution of the contrast enhancement, induced by i.v. injection of Gadolinium diethylene-triamine-penta-acetate, exhibited two distinct patterns: transcapillary transfer in the cellular regions and simple diffusion in the cyst fluid. Both processes were analyzed at pixel resolution applying to each a physiological model and a corresponding algorithm. In the cellular region, the influx and outflux transcapillary transfer rates decreased during tumor growth; however, an increased disparity between the transfer constants was observed, with the outflux rate exceeding the influx rate. This quantitative spatial and temporal mapping of this disparity can provide a means to assess the physiological barriers to tracer delivery. It is hypothesized that both the increased disparity in transcapillary transfer rates and impaired fluid drainage in these tumors could arise from the development of interstitial hypertension.
Deficient Nucleotide Excision Repair Capacity Enhances Human Prostate Cancer Risk
Authors: Hu Jennifer J. , Hall M. Craig , Grossman Lawrence , Hedayati Mohammad , McCullough David L. , Lohman Kurt , Case L. Douglas 
Published: September 2005

Abstract
Prostate cancer (CaP) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death in American men. The etiology of CaP is not fully understood. Because most of the DNA adducts generated by some CaP-related carcinogens, including polycyclic aromatic hydrocarbons, heterocyclic amines, and pesticides, are removed by the nucleotide excision repair (NER) pathway, we pilot tested the hypothesis that CaP is associated with deficient NER capacity (NERC), measured by a plasmid-based host reactivation assay. Using cryopreserved lymphocytes collected in an ongoing, clinic-based case-control study, our results showed that the mean NERC was significantly lower (P = 0.03) in 140 cases (mean ± SD, 8.06 ± 5.17) than in 96 controls (9.64 ± 5.49). There was a significant association between below-median NERC and CaP risk: odds ratio (OR), 2.14; 95% confidence interval (CI), 1.19–3.86, after adjustment for age, race/ethnicity, smoking history, benign prostatic hyperplasia, and family history. This association was stronger in younger (&lt;60 years of age) subjects (OR, 3.98; 95% CI, 1.13–14.02) compared with older (≥60) subjects (OR, 1.74; 95% CI, 0.90–3.37). When we stratified NERC values by quartiles of controls, there was a significant dose-dependent association between lower NERC and elevated CaP risk (p test for linear trend, 0.01). Compared with the highest quartile of NERC as the referent group, the adjusted ORs for the 75th, 50th, and 25th quartiles were: 1.09 (95% CI, 0.46–2.59); 1.81 (95% CI, 0.77–4.27); and 2.63 (95% CI, 1.17–5.95), respectively. This pilot study is the first direct evidence associating deficient NERC with human CaP risk.
Selenium Deficiency Abrogates Inflammation-Dependent Plasma Cell Tumors in Mice
Authors: Felix Klaus , Gerstmeier Simone , Kyriakopoulos Antonios , Howard O. M. Zack , Dong Hui-Fang , Eckhaus Michael , Behne Dietrich , Bornkamm Georg W. , Janz Siegfried 
Published: September 2005

AbstractThe role of the micronutrient, selenium, in human cancers associated with chronic inflammations and persistent infections is poorly understood. Peritoneal plasmacytomas (PCTs) in strain BALB/c (C), the premier experimental model of inflammation-dependent plasma cell transformation in mice, may afford an opportunity to gain additional insights into the significance of selenium in neoplastic development. Here, we report that selenium-depleted C mice (n = 32) maintained on a torula-based low-selenium diet (5–8 μg of selenium/kg) were totally refractory to pristane induction of PCT. In contrast, 11 of 26 (42.3%) control mice maintained on a selenium adequate torula diet (300 μg of selenium/kg) and 15 of 40 (37.5%) control mice fed standard Purina chow (440 μg of selenium/kg) developed PCT by 275 days postpristane. Abrogation of PCT was caused in part by the striking inhibition of the formation of the inflammatory tissue in which PCT develop (pristane granuloma). This was associated with the reduced responsiveness of selenium-deficient inflammatory cells (monocytes and neutrophils) to chemoattractants, such as thioredoxin and chemokines. Selenium-deficient C mice exhibited little evidence of disturbed redox homeostasis and increased mutant frequency of a transgenic lacZ reporter gene in vivo. These findings implicate selenium, via the selenoproteins, in the promotion of inflammation-induced PCT and suggest that small drug inhibitors of selenoproteins might be useful for preventing human cancers linked with chronic inflammations and persistent infections.
HIV-1 Protease Inhibitor, Ritonavir
Authors: Ikezoe Takayuki , Hisatake Yasuko , Takeuchi Tamotsu , Ohtsuki Yuji , Yang Yang , Said Jonathan W. , Taguchi Hirokuni , Koeffler H. Phillip 
Published: September 2005

Abstract
We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all–trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10−5 mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor κB (NFκB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFκB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.
A Small Interfering RNA Targeting Vascular Endothelial Growth Factor as Cancer Therapeutics
Authors: Takei Yoshifumi , Kadomatsu Kenji , Yuzawa Yukio , Matsuo Seiichi , Muramatsu Takashi 
Published: September 2005

Abstract
Vascular endothelial growth factor (VEGF) plays a critical role during normal embryonic angiogenesis and also in the pathological angiogenesis that occurs in a number of diseases, including cancer. We developed a novel VEGF blockade system using RNA interference. The small interfering RNA (siRNA) targeting human VEGF almost completely inhibited the secretion of VEGF in a human prostate cancer cell line, PC-3, whereas the control scramble siRNA showed no effects. The VEGF siRNA with atelocollagen dramatically suppressed tumor angiogenesis and tumor growth in a PC-3 s.c. xenograft model. Atelocollagen provided a beneficial delivering means by which stabilization and efficient transfection of the siRNA injected into the tumors were achieved.
Polyclonal Development of Mouse Mammary Preneoplastic Nodules
Authors: Kisseberth William C. , Sandgren Eric P. 
Published: September 2005

Abstract
Studies of cellular interactions are critical to the understanding of tumorigenesis. Although many studies have demonstrated a monoclonal composition of advanced neoplasms in humans and mice, the clonal composition of smaller, antecedent lesions has been studied less thoroughly. To examine the clonal development of breast cancer, we generated chimeric mammary glands using mouse mammary epithelium with an inherited predisposition for neoplasia. Analysis of whey acidic protein-transforming growth factor-α transgenic mouse mammary glands, chimeric for two different cell lineage markers, revealed that mammary ducts and alveoli are polyclonal, and putative early preneoplastic lesions, hyperplastic alveolar nodules (HANs), frequently are polyclonal. Furthermore, the chimeric patch patterns in individual HANs were similar to the patterns observed in pregnant chimeric mammary glands. Thus, polyclonality in HANs appears to reflect persistence of the polyclonal architecture of ducts and/or alveoli, suggesting that hyperplasia formation can be the result of non-cell autonomous local tissue microenvironmental influences on groups of cells, rather than clonal progression of a single initiated cell.
A Genome-Wide Screen in
Saccharomyces cerevisiae
Reveals Altered Transport As a Mechanism of Resistance to the Anticancer Drug Bleomycin
Authors: Aouida Mustapha , Pagé Nicolas , Leduc Anick , Peter Matthias , Ramotar Dindial 
Published: September 2005

Abstract
The potent DNA damaging agent bleomycin (BLM) is highly effective for treating various cancers, although, in certain individuals, the development of cellular resistance to the drug can severely diminish its antineoplastic properties. We performed two independent genome-wide screens using a Saccharomyces cerevisiae mutant collection to isolate variants exhibiting either sensitivity or resistance to BLM. This procedure reproducibly identified a relatively large collection of 231 BLM-hypersensitive mutants, representing genes belonging to diverse functional groups. In contrast, only five BLM-resistant mutants could be recovered by our screens. Among these latter mutants, three were deleted for genes involved in plasma membrane transport, including the l-carnitine transporter Agp2, as well as the kinases Ptk2 and Sky1, which are involved in regulating polyamine transport. We further showed that Agp2 acts as a transporter of BLM and that overexpression of this transporter significantly enhances BLM-induced cell killing. Our data strongly implicate membrane transport as a key determinant in BLM resistance in yeast. This finding is critical, given that very little is known about BLM transport in human cells. Indeed, characterization of analogous mechanisms in humans may ultimately lead to enhancement of the antitumor properties of BLM.
Mapping Tumor Epitope Space by Direct Selection of Single-Chain Fv Antibody Libraries on Prostate Cancer Cells
Authors: Liu Bin , Conrad Fraser , Cooperberg Matthew R. , Kirpotin Dmitri B. , Marks James D. 
Published: September 2005

Abstract
The identification of tumor-specific cell surface antigens is a critical step toward the development of targeted therapeutics for cancer. The epitope space at the tumor cell surface is highly complex, composed of proteins, carbohydrates, and other membrane-associated determinants including post-translational modification products, which are difficult to probe by approaches based on gene expression. This epitope space can be efficiently mapped by complementary monoclonal antibodies. By selecting human antibody gene diversity libraries directly on the surface of prostate cancer cells, we have taken a functional approach to identifying fully human, tumor-specific monoclonal antibodies without prior knowledge of their target antigens. Selection conditions have been optimized to favor tumor-specific antibody binding and internalization. To date, we have discovered &gt;90 monoclonal antibodies that specifically bind and enter prostate cancer cells, with little or no binding to control cells. These antibodies are able to efficiently deliver intracellular payloads when attached to nanoparticles such as liposomes. In addition, a subset of the antibodies displayed intrinsic antiproliferative activity. These tumor-specific internalizing antibodies are likely to be useful for targeted therapeutics either alone or in combination with effector molecules. The antigens they bind constitute a tumor-specific internalizing epitope space that is likely to play a significant role in cancer cell homeostasis. Targeting components of this epitope space may facilitate development of immunotherapeutic and small molecule-based strategies as well as the use of other therapeutic agents that rely upon delivery to the interior of the tumor cell.