bluuebunny/crossref_metadata_2025_split huggingface dataset:
Met Receptor Contributes to Trastuzumab Resistance of Her2-Overexpressing Breast Cancer Cells
Authors: Shattuck David L. , Miller Jamie K. , Carraway Kermit L. , Sweeney Colleen 
Published: March 2008

Abstract
Her2 is overexpressed in 20% to 30% of breast tumors and correlates with reduced disease-free and overall patient survival. Trastuzumab, a humanized monoclonal antibody directed against Her2, represents the first Her2-targeted therapy, which decreases the risk of relapse and prolongs patient survival. Resistance to trastuzumab, both inherent and treatment-acquired, represents a significant barrier to the effective treatment of Her2 (+) breast cancer. The Met receptor tyrosine kinase is aberrantly expressed in breast cancer and predicts poor patient prognosis. In this study, we find that Met is frequently expressed in Her2-overexpressing breast cancer cells, as well as Her2 (+) breast cancer. Importantly, Met contributes to trastuzumab resistance, as inhibition of Met sensitizes cells to trastuzumab-mediated growth inhibition, whereas Met activation protects cells against trastuzumab by abrogating p27 induction. Remarkably, Her2-overexpressing breast cancer cells rapidly up-regulate Met expression after trastuzumab treatment, promoting their own resistance. Our study suggests that a subset of Her2 (+) patients may benefit from combined inhibition of Her2 and Met. [Cancer Res 2008;68(5):1471–7]
H-2Kb–Restricted CTL Epitopes from Mouse Heparanase Elicit an Antitumor Immune Response In vivo
Authors: Tang Xu-Dong , Wan Yin , Chen Ling , Chen Ting , Yu Song-Tao , Xiong Zhen , Fang Dian-Chun , Liang Guang-Ping , Yang Shi-Ming 
Published: March 2008

Abstract
The identification of CTL epitopes from tumor antigens is very important for the development of peptide-based, cancer-specific immunotherapy. Heparanase is broadly expressed in various advanced tumors and can serve as a universal tumor-associated antigen. Although several epitopes of heparanase antigen are known in humans, the corresponding knowledge in mice is still rather limited. The present study was designed to predict and identify the CTL epitopes in the mouse heparanase protein. For this purpose, H-2Kb–restricted CTL epitopes were identified by using the following four-step procedure: (a) a computer-based epitope prediction from the amino acid sequence of mouse heparanase, (b) a peptide-binding assay to determine the affinity of the predicted epitopes with the H-2Kb molecule, (c) the testing of the induction of CTLs toward various carcinoma cells expressing heparanase antigens and H-2Kb, and (d) the induction of immunoprotection and immunotherapy in vivo. The results showed that, of the tested peptides, effectors induced by peptides of mouse heparanase at residue positions 398 to 405 (LSLLFKKL; mHpa398) and 519 to 526 (FSYGFFVI; mHpa519) lysed three kinds of carcinoma cells expressing both heparanase and H-2Kb (B16 melanoma cells, EL-4 lymphoma cells, and Lewis lung cancer cells). In vivo experiments indicated that mHpa398 and mHpa519 peptides offered the possibility of not only immunizing against tumors but also treating tumor-bearing hosts successfully. Our results suggest that the mHpa398 and mHpa519 peptides are novel H-2Kb–restricted CTL epitopes capable of inducing heparanase-specific CTLs in vitro and in vivo. These epitopes may serve as valuable tools for the preclinical evaluation of vaccination strategies. [Cancer Res 2008;68(5):1529–37]
Use of Preoperative Plasma Endoglin for Prediction of Lymph Node Metastasis in Patients with Clinically Localized Prostate Cancer
Authors: Karam Jose A. , Svatek Robert S. , Karakiewicz Pierre I. , Gallina Andrea , Roehrborn Claus G. , Slawin Kevin M. , Shariat Shahrokh F. 
Published: March 2008

AbstractPurpose: Current predictive tools and imaging modalities are not accurate enough to preoperatively diagnose lymph node metastases in patients with prostate cancer. The aim of the study was to evaluate whether preoperative plasma endoglin improves the prediction of lymph node metastases in patients with clinically localized prostate cancer.Experimental Design: Endoglin levels were measured using a commercially available ELISA assay in banked plasma from 425 patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma at two university hospitals between July 1994 and November 1997. Logistic regression analyses were undertaken to evaluate whether endoglin improves the accuracy of a standard preoperative model for prediction of lymph node metastasis and to build a predictive nomogram.Results: Preoperative plasma endoglin levels were higher in patients with higher preoperative total serum prostate-specific antigen (PSA; Spearman correlation coefficient 0.296, P &lt; 0.001), positive surgical margins (P = 0.03), higher pathologic Gleason sum (P = 0.04), and lymph node metastasis (P &lt; 0.001). In a preoperative multivariable logistic regression analysis that included PSA and clinical stage, only preoperative endoglin (odds ratio, 1.17; 95% confidence interval, 1.09-1.26; P &lt; 0.001) and biopsy Gleason sum (odds ratio, 18.57; 95% confidence interval, 1.08-318.36; P = 0.04) were associated with metastasis to lymph nodes. The addition of endoglin to a standard preoperative model (including PSA, clinical stage, and biopsy Gleason sum) significantly improved its accuracy for prediction of lymph node metastasis from 89.4% to 97.8% (P &lt; 0.001).Conclusions: Preoperative plasma endoglin improves the accuracy for prediction of pelvic lymph node metastasis in patients treated with radical prostatectomy for clinically localized prostate cancer by a statistically and clinically significant margin.
Combining the Antigen Processing Components TAP and Tapasin Elicits Enhanced Tumor-Free Survival
Authors: Lou Yuanmei , Basha Genc , Seipp Robyn P. , Cai Bing , Chen Susan S. , Moise Alexander R. , Jeffries Andrew P. , Gopaul Ray S. , Vitalis Timothy Z. , Jefferies Wilfred A. 
Published: March 2008

AbstractPurpose: Tpn is a member of the MHC class I loading complex and functions to bridge the TAP peptide transporter to MHC class I molecules. Metastatic human carcinomas often express low levels of the antigen-processing components Tapasin and TAP and display few functional surface MHC class I molecules. As a result, carcinomas are unrecognizable by effector CTLs. The aim of this study is to examine if Tapasin (Tpn) plays a critical role in the escape of tumors from immunologic recognition.Experimental Design: To test our hypothesis, a nonreplicating adenovirus vector encoding human Tpn (AdhTpn) was constructed to restore Tpn expression in vitro and in vivo in a murine lung carcinoma cell line (CMT.64) that is characterized by down-regulation of surface MHC class I due to deficiency in antigen-processing components.Results: Ex vivo, Tpn expression increased surface MHC class I and restored susceptibility of tumor cells to antigen-specific CTL killing, and AdhTpn infection of dendritic cells also significantly increased cross-presentation and cross-priming. Furthermore, tumor-bearing animals inoculated with AdhTpn demonstrated a significant increase in CD8+ and CD4+ T cells and CD11c+ dendritic cells infiltrating the tumors. Provocatively, whereas syngeneic mice bearing tumors that were inoculated with AdhTpn a significant reduction in tumor growth and increased survival compared with vector controls, combining AdhTpn inoculation with AdhTAP1 resulted in a significant augmentation of protection from tumor-induced death than either component alone.Conclusions: This is the first demonstration that Tpn alone can enhance survival and immunity against tumors but additionally suggests that Tpn and TAP should be used together as components of immunotherapeutic vaccine protocols to eradicate tumors.
Cell Adhesion Molecules, Vascular Endothelial Growth Factor, and Basic Fibroblast Growth Factor in Patients with Non–Small Cell Lung Cancer Treated with Chemotherapy with or without Bevacizumab—an Eastern Cooperative Oncology Group Study
Authors: Dowlati Afshin , Gray Robert , Sandler Alan B. , Schiller Joan H. , Johnson David H. 
Published: March 2008

AbstractBackground: E4599 was a phase II/phase III trial, in which 878 patients with advanced non–small cell lung cancer were randomized to carboplatin + paclitaxel (PC arm) or PC + bevacizumab (BPC arm). Survival and progression-free survival were superior on the BPC arm. The rationale for markers used in this correlative study was based on elevated vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), soluble intercellular adhesion molecule (ICAM) and E-selectin in a variety of malignances and changes in response to endothelial cell apoptosis.Materials and Methods: Prospective correlates included measurements of pretreatment plasma VEGF, as well as pretreatment and week 7, bFGF, ICAM, and E-selectin. Low and high levels were defined as less than or equal to or more than the median.Results: E-selectin (P &lt; 0.0001) showed a decrease and bFGF showed an increase (P = 0.004) from baseline at week 7, which were similar in both arms. Baseline ICAM showed significant associations with response and survival in both groups. Patients with low baseline ICAM had a higher response rate (32% versus 14%; P = 0.02), better overall survival (P = 0.00005), and better 1-year survival (65% versus 25%) than those with high ICAM, respectively, regardless of treatment arm. Patients with high VEGF levels were more likely to respond to BPC compared with PC, but this was not predictive of survival. The results also suggest a benefit from bevacizumab for patients with low baseline ICAM levels (53% reduction in the progression-free survival hazard rate).Conclusions: In this study, baseline ICAM levels were prognostic for survival and predictive of response to chemotherapy with or without bevacizumab. VEGF levels were predictive of response to bevacizumab but not survival.
Acquirement of Rituximab Resistance in Lymphoma Cell Lines Is Associated with Both GlobalCD20Gene and Protein Down-Regulation Regulated at the Pretranscriptional and Posttranscriptional Levels
Authors: Czuczman Myron S. , Olejniczak Scott , Gowda Aruna , Kotowski Adam , Binder Arvinder , Kaur Harman , Knight Joy , Starostik Petr , Deans Julie , Hernandez-Ilizaliturri Francisco J. 
Published: March 2008

AbstractAcquirement of resistance to rituximab has been observed in lymphoma patients. To define mechanisms associated with rituximab resistance, we developed various rituximab-resistant cell lines (RRCL) and studied changes in CD20 expression/structure, lipid raft domain (LRD) reorganization, calcium mobilization, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity (CMC) between parental and RRCL. Significant changes in surface CD20 antigen expression were shown in RRCL. Decreased calcium mobilization and redistribution of CD20 into LRD were found in RRCL. Western blotting identified a unique 35 kDa protein band in RRCL, which was not seen in parental cells and was secondary to an increase in surface and cytoplasmic expression of IgM light chains. CD20 gene expression was decreased in RRCL. In vitro exposure to PS341 increased CD20 expression in RRCL and minimally improved the sensitivity to rituximab-associated CMC. Our data strongly suggest that the acquisition of rituximab resistance is associated with global gene and protein down-regulation of the CD20 antigen affecting LRD organization and downstream signaling. CD20 expression seems to be regulated at the pretranscriptional and posttranscriptional levels. Proteasome inhibition partially reversed rituximab resistance, suggesting the existence of additional mediators of rituximab resistance. Future research is geared to identify drugs and/or biological agents that are effective against RRCL.
Acquired Resistance to Rituximab Is Associated with Chemotherapy Resistance Resulting from Decreased Bax and Bak Expression
Authors: Olejniczak Scott H. , Hernandez-Ilizaliturri Francisco J. , Clements James L. , Czuczman Myron S. 
Published: March 2008

Abstract
Purpose: Targeting malignant B cells using rituximab (anti-CD20) has improved the efficacy of chemotherapy regimens used to treat patients with non-Hodgkin's lymphoma. Despite the promising clinical results obtained using rituximab, many patients relapse with therapy-resistant disease following rituximab-based treatments. We have created a cell line model of rituximab resistance using three B-cell non-Hodgkin's lymphoma–derived cell lines (Raji, RL, and SUDHL-4). In an attempt to define strategies to overcome rituximab resistance, we sought to determine the chemotherapy sensitivity of our rituximab-resistant cell lines (RRCL).
Experimental Design: Parental, rituximab-sensitive cell lines (RSCL) Raji, RL, and SUDHL-4, along with RRCLs derived from them, were exposed to several chemotherapeutic agents with different mechanisms of action and the ability of these agents to induce apoptotic cell death was measured. Expression of multidomain Bcl-2 family proteins was studied as potential mediators of chemotherapy/rituximab resistance.
Results: We found that RRCLs are resistant to multiple chemotherapeutic agents and have significantly decreased expression of the Bcl-2 family proteins Bax, Bak, and Bcl-2. RRCLs do not undergo rituximab- or chemotherapy-induced apoptosis but die in a caspase-dependent manner when either wild-type Bax or Bak is exogenously expressed. Furthermore, forced expression of Bak sensitized RRCL to chemotherapy-induced apoptosis.
Conclusions: Whereas a single or limited exposure of lymphoma cells to rituximab may lead to a favorable ratio of proapoptotic to antiapoptotic Bcl-2 family proteins, repeated exposure to rituximab is associated with a therapy-resistant phenotype via modulation of Bax and Bak expression.
HMGA1 Is a Molecular Determinant of Chemoresistance to Gemcitabine in Pancreatic Adenocarcinoma
Authors: Liau Siong-Seng , Whang Edward 
Published: March 2008

Abstract
Purpose: HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. We previously have shown that RNA interference targeting the HMGA1 gene may represent a potential chemosensitizing strategy in pancreatic adenocarcinoma cells. In this study, we tested the hypothesis that HMGA1 promotes chemoresistance to gemcitabine in pancreatic cancer cells.
Experimental Design and Results: Stable short hairpin RNA–mediated HMGA1 silencing in BxPC3 and MiaPaCa2 cells promoted chemosensitivity to gemcitabine, with reductions in gemcitabine IC50 and increases in gemcitabine-induced apoptosis and caspase-3 activation. In contrast, forced HMGA1 overexpression in MiaPaCa2 cells promoted chemoresistance to gemcitabine, with increases in gemcitabine IC50 and reductions in gemcitabine-induced apoptosis and caspase-3 activation. Dominant negative Akt abrogated HMGA1 overexpression–induced increases in chemoresistance to gemcitabine. Finally, HMGA1 silencing promoted chemosensitivity to gemcitabine in vivo in a nude mouse xenograft model of pancreatic adenocarcinoma.
Conclusion: Our findings suggest that HMGA1 promotes chemoresistance to gemcitabine through an Akt-dependent mechanism. Targeted therapies directed at HMGA1 represent a potential strategy for ameliorating chemoresistance in pancreatic adenocarcinoma.
Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer
Authors: Chiappori Alberto A. , Haura Eric , Rodriguez Francisco A. , Boulware David , Kapoor Rachna , Neuger Anthony M. , Lush Richard , Padilla Barbara , Burton Michelle , Williams Charles , Simon George , Antonia Scott , Sullivan Daniel M. , Bepler Gerold 
Published: March 2008

Abstract
Purpose: Endothelins and their cell membrane receptors (ETAR and ETBR) are implicated in neoplastic pathogenesis. Atrasentan, a potent, selective ETAR antagonist, has a direct effect on tumor proliferation, apoptosis, and angiogenesis. This study was designed to assess the influence of atrasentan on paclitaxel pharmacokinetics and to determine the safety and efficacy of atrasentan in combination with paclitaxel-carboplatin.
Experimental Design: Chemonaive patients with stage IIIB (malignant pleural effusion) and IV non–small cell lung cancer were enrolled. Toxicity and response were determined using the National Cancer Institute Common Toxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6) administered on day 1 every 3 weeks. A fixed 10 mg daily oral dose of atrasentan was administered continuously, starting on day 4 of cycle 1. Paclitaxel clearance was calculated during the first two cycles (pre- and post-atrasentan) in the first 10 patients.
Results: All 44 patients were evaluable for survival, toxicity, and response. No significant change in mean paclitaxel clearance was detected (mean ± SD, 21.2 ± 4.5 L/h versus 21.3 ± 4.9 L/h) for pre- and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities ≥10% were lymphopenia (22.7%), neutropenia (20.5%), dyspnea (11.4%), and hyperglycemia (11.4%). Response rate was 18.2%, with progression-free survival of 4.2 months, median survival of 10.6 months, and 1-year survival of 43%.
Conclusion: Atrasentan plus paclitaxel-carboplatin was safe and well tolerated, with no apparent paclitaxel-atrasentan pharmacokinetic interaction. Efficacy and survival in advanced non–small cell lung cancer were comparable with studies of chemotherapy alone.
Sensitive and Specific New Enzyme-Linked Immunosorbent Assay for N-ERC/Mesothelin Increases its Potential as a Useful Serum Tumor Marker for Mesothelioma
Authors: Shiomi Kazu , Hagiwara Yoshiaki , Sonoue Kouji , Segawa Tatsuya , Miyashita Kazuya , Maeda Masahiro , Izumi Hiroshi , Masuda Kimihiko , Hirabayashi Masataka , Moroboshi Takao , Yoshiyama Takashi , Ishida Atsuko , Natori Yuji , Inoue Akira , Kobayashi Masashi , Sakao Yukinori , Miyamoto Hideaki , Takahashi Kazuhisa , Hino Okio 
Published: March 2008

Abstract
Background: Because mesothelioma initially progresses on the surface of the pleura and peritoneum without forming masses, it has been difficult to diagnose at an early stage. It would be very useful to identify a tumor marker that could be used for screening to enable more diagnoses to be made at an early, treatable stage.
Materials and Methods: We had previously identified N-ERC/mesothelin as a potential biomarker for mesothelioma. In the current work, we used a newly developed ELISA system to gain data on N-ERC/mesothelin levels in various clinical settings. A total of 102 healthy volunteers were recruited. In addition, 39 patients were diagnosed with mesothelioma, 53 patients were diagnosed with diseases that should be distinguished from mesothelioma, and 201 subjects were diagnosed with asbestos-related nonmalignant diseases (including simple exposure to asbestosis) who were treated at any of the cooperating hospitals were enrolled.
Results: Serum N-ERC/mesothelin levels measured by a new ELISA system showed that the median values from patients with mesothelioma were extremely high compared with levels obtained from other patients. Analysis in terms of histologic type showed that serum levels of N-ERC/mesothelin were elevated in epithelioid type mesothelioma, especially. In four important models of clinical settings, the sensitivity and specificity of N-ERC/mesothelin were about 71% to 90% and 88% to 93%, respectively.
Conclusion: N-ERC/mesothelin is a very promising tumor marker for mesothelioma, especially epithelioid mesothelioma.
Oncolytic Herpes Simplex Virus Type-1 Therapy in a Highly Infiltrative Animal Model of Human Glioblastoma
Authors: Huszthy Peter C. , Goplen Dorota , Thorsen Frits , Immervoll Heike , Wang Jian , Gutermann Anja , Miletic Hrvoje , Bjerkvig Rolf 
Published: March 2008

Abstract
We have examined the spread and antitumor efficacy of an oncolytic herpes simplex virus-1–based vector (G207) in glioblastoma biopsy spheroids in vitro and in vivo after local delivery to corresponding intracranial xenografts. Spheroids from three patients were infected with increasing doses of G207 and transgene expression was quantified. Other infected spheroids were followed for 10 days to assess cytotoxic effects. For the in vivo study, spheroids were grafted intracerebrally into Rowett nude rats. The resulting highly infiltrative xenografts were injected with 3.4 × 106 plaque-forming units (penetration study) or 6.8 × 106 plaque-forming units (therapeutic study) of G207 using microprocessor-controlled stereotaxic delivery. Vector spread was tracked by histochemical staining. In the therapeutic study, tumor volumes were monitored weekly by magnetic resonance imaging, and survival data were collected. In vitro, lacZ expression was seen at the spheroid surfaces 24 h postinfection, whereas the spheroid cores were transgene positive after 96 h. Cytotoxic susceptibility varied between the patients, showing a 36% to 95% lysis 10 days postinfection. Local delivery of G207 into intracranial xenografts resulted in extensive vector spread throughout the lesions. In the therapeutic study, G207 application reduced tumor volumes compared with controls, but did not significantly improve survival of the animals. Histologic analysis revealed infection of host structures such as the ventricular and choroid plexus ependyma. In conclusion, G207 replicates in patient-derived glioblastoma multiforme xenografts and tumor volumes are reduced after intratumoral delivery; however, the survival data suggest that the therapeutic effect could be improved by repeated vector application or through combination with other treatment modalities.
Platinum Resistance: The Role of DNA Repair Pathways
Authors: Martin Lainie P. , Hamilton Thomas C. , Schilder Russell J. 
Published: March 2008

Abstract
Although platinum chemotherapeutic agents such as carboplatin, cisplatin, and oxaliplatin are used to treat a broad range of malignant diseases, their efficacy in most cancers is limited by the development of resistance. There are multiple factors that contribute to platinum resistance but alterations of DNA repair processes have been known for some time to be important in mediating resistance. Recently acquired knowledge has provided insight into the molecular mechanisms of DNA repair pathways and their effect on response to chemotherapy. This review will discuss the most important DNA repair pathways known to be involved in the platinum response, i.e., nucleotide excision repair (NER) and mismatch repair (MMR), and will briefly touch on the role of BRCA in DNA repair. The therapeutic implications of alterations in DNA repair which affect response to platinum in the treatment of patients with malignant disease, such as excision repair cross-complementation group 1 (ERCC1) deficiency and mismatch repair deficiency, will be reviewed.