bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of Antitumor Invariant Natural Killer T Cell Lines in Multiple Myeloma and Promotion of Their Functions via Lenalidomide: A Strategy for Immunotherapy
Authors: Song Weihua , van der Vliet Hans J.J. , Tai Yu-Tzu , Prabhala Rao , Wang Ruojie , Podar Klaus , Catley Laurence , Shammas Masood A. , Anderson Kenneth C. , Balk Steven P. , Exley Mark A. , Munshi Nikhil C. 
Published: November 2008

Abstract
Purpose: CD1d-restricted invariant natural killer T (iNKT) cells are important immunoregulatory cells in antitumor immune responses. However, the quantitative and qualitative defects of iNKT cells in advanced multiple myeloma hamper their antitumor effects. Therefore, the development of functional iNKT cells may provide a novel strategy for the immunotherapy in multiple myeloma.
Experimental Design: We activated and expanded iNKT cells from multiple myeloma patients with α-galactosylceramide (α-GalCer)-pulsed dendritic cells, characterized their antitumor effects by the cytokine production profile and cytotoxicity against multiple myeloma cells, and explored the effects of immunomodulatory drug lenalidomide on these iNKT cells. We also investigated the expression of CD1d by primary multiple myeloma cells and its function to activate iNKT cells.
Results: We established highly purified functional iNKT cell lines from newly diagnosed and advanced multiple myeloma patients. These CD1d-restricted iNKT cell lines produced high level of antitumor Th1 cytokine in response to α-GalCer-pulsed primary multiple myeloma cells, CD1d-transfected MM1S cell line, and dendritic cells. Moreover, iNKT cell lines displayed strong cytotoxicity against α-GalCer-pulsed primary multiple myeloma cells. Importantly, lenalidomide further augmented the Th1 polarization by iNKT cell lines via increased Th1 cytokine production and reduced Th2 cytokine production. We also showed that CD1d was expressed in primary multiple myeloma cells at mRNA and protein levels from the majority of multiple myeloma patients, but not in normal plasma cells and multiple myeloma cell lines, and CD1d+ primary multiple myeloma cells presented antigens to activate iNKT cell lines.
Conclusions: Taken together, our results provide the preclinical evidence for the iNKT cell-mediated immunotherapy and a rationale for their use in combination with lenalidomide in multiple myeloma treatment.
Reduced Erlotinib Sensitivity of Epidermal Growth Factor Receptor-Mutant Non–Small Cell Lung Cancer following Cisplatin Exposure: A Cell Culture Model of Second-line Erlotinib Treatment
Authors: Chin Tan Min , Quinlan Margaret P. , Singh Anurag , Sequist Lecia V. , Lynch Thomas J. , Haber Daniel A. , Sharma Sreenath V. , Settleman Jeffrey 
Published: November 2008

Abstract
Purpose: Epidermal growth factor receptor (EGFR) kinase inhibitors induce dramatic clinical responses in a subset of non-small cell lung cancer (NSCLC) patients with advanced disease, and such responses are correlated with the presence of somatic activating mutations within the EGFR kinase domain. Consequently, one of these inhibitors, erlotinib, has been Food and Drug Administration-approved as a second- or third-line treatment for chemotherapy-refractory advanced NSCLC. However, responses are typically relatively short-lived due to acquired drug resistance, prompting studies to determine whether first-line treatment with EGFR inhibitors could provide greater clinical benefit. NSCLC-derived cell lines have provided a powerful system for modeling EGFR mutation-correlated sensitivity to EGFR inhibitors and for modeling mechanisms of acquired drug resistance that are observed clinically.
Experimental Design: In a cell culture model of an erlotinib-sensitive EGFR-mutant NSCLC cell line, we tested the hypothesis that prior exposure to platinum agents, a standard component of NSCLC chemotherapy treatment, affects the subsequent response to erlotinib.
Results: Indeed, NSCLC cells initially selected for growth in cisplatin exhibit 5-fold reduced sensitivity to erlotinib, even after propagating the cisplatin-treated cells in the absence of cisplatin for several months. This lingering effect of cisplatin exposure appears to reflect changes in PTEN tumor suppressor activity and persistent EGFR-independent signaling through the phosphatidylinositol 3-kinase/AKT survival pathway.
Conclusions: These preclinical findings suggest that first-line chemotherapy treatment of EGFR-mutant NSCLCs may reduce the benefit of subsequent treatment with EGFR kinase inhibitors and should prompt further clinical investigation of these inhibitors as a first-line therapy in NSCLC.
Expression of MAP4K4 Is Associated with Worse Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma
Authors: Liang John J. , Wang Hua , Rashid Asif , Tan Tse-Hua , Hwang Rosa F. , Hamilton Stanley R. , Abbruzzese James L. , Evans Douglas B. , Wang Huamin 
Published: November 2008

Abstract
Purpose: Mitogen-activated protein 4 kinase 4 (MAP4K4) is a serine/threonine kinase and belongs to the mammalian STE20/MAP4K family. Recent studies have shown that MAP4K4 is overexpressed in many types of human cancer and cancer cell lines. MAP4K4 plays an important role in transformation, invasiveness, adhesion, and cell migration. However, the expression of MAP4K4 and its significance in pancreatic ductal adenocarcinoma (PDA) has not been studied.
Experimental Design: We examined the expression of MAP4K4 by immunohistochemistry using tissue microarrays consisting of 66 stage II PDA and their paired benign pancreatic tissue. The staining results were categorized as MAP4K4-H or MAP4K4-L. The results were correlated with clinicopathologic features and patient survival.
Results: MAP4K4 was overexpressed (MAP4K4-H) in 30 of 66 (46%) PDAs and was higher than the paired benign pancreatic tissue samples (19%; P = 0.002). The median overall and recurrence-free survival for patients with MAP4K4-H PDAs were 19.5 and 9.3 months, respectively, compared with 65.2 and 28.8 months for patients with MAP4K4-L tumor (P = 0.02 and 0.0005, log-rank test). MAP4K4 expression was associated with poor overall and recurrence-free survival in univariate analysis (P = 0.02 and 0.001). In multivariate analysis, MAP4K4 expression significantly correlated with overall and recurrence-free survival (P = 0.025 and 0.004) independent of age, tumor size, differentiation, and stage. MAP4K4 expression was also associated with higher frequency of recurrence/metastasis, larger tumor size, and increased number of positive lymph nodes (P &lt; 0.05).
Conclusion: MAP4K4 was overexpressed in about half of PDAs. Overexpression of MAP4K4 was associated with worse prognosis and is a prognostic marker for stage II PDAs.
Identification of Metastasis-Related Proteins and Their Clinical Relevance to Triple-Negative Human Breast Cancer
Authors: Sun Baocun , Zhang Shiwu , Zhang Danfang , Li Yan , Zhao Xiulan , Luo Ye , Guo Yuhong 
Published: November 2008

Abstract
Purpose: Currently, there are no definite biomarkers of triple-negative breast cancer. The study aims to identify the metastasis-associated proteins of triple-negative breast tumors.
Experimental Design: A murine metastatic breast cancer model has been established by using TA2 mice. Parallel proteomic analyses were done on a murine metastatic breast cancer model and its primary breast cancer using two-dimensional gel electrophoresis. The differentially expressed proteins were detected in TA2 mice developing spontaneous breast cancer and lung metastasis. Furthermore, their expression were detected in human breast cancer with or without metastasis, and their prediction values were assessed in a second set of samples.
Results: Nineteen of 36 differentially expressed proteins were identified by peptide mass fingerprinting using matrix-assisted laser-desorption ionization-time of flight-mass spectrometry. These proteins were also validated in mouse tumor tissues by immunohistochemical staining. Actin, 14-3-3, vimentin, HSP70, CK18, and moesin were up-regulated in the metastatic tumors, whereas HSP90 and tubulin were absent or down-regulated. Furthermore, 61 patients with triple-negative breast cancer and 39 patients with estrogen receptor-positive/progesterone receptor-positive breast cancer were selected for exploring the clinical relevance of these identified proteins to human breast cancer metastasis. Expression of 14-3-3 and HSP70 was significantly correlated with metastasis of human triple-negative breast cancer. Moreover, the validation study in the second set confirmed that 14-3-3, HSP70, and their combination had high sensitivities and specificities in predicting metastatic potential of triple-negative breast cancer.
Conclusions: These tumor metastasis-associated proteins validated may be useful as biomarkers and targets for diagnosis and treatment of human triple-negative breast cancer.
A Phase I Study of Intravenous Oncolytic Reovirus Type 3 Dearing in Patients with Advanced Cancer
Authors: Vidal Laura , Pandha Hardev S. , Yap Timothy A. , White Christine L. , Twigger Katie , Vile Richard G. , Melcher Alan , Coffey Matt , Harrington Kevin J. , DeBono Johann S. 
Published: November 2008

Abstract
Purpose: To determine the safety and feasibility of daily i.v. administration of wild-type oncolytic reovirus (type 3 Dearing) to patients with advanced cancer, assess viral excretion kinetics and antiviral immune responses, identify tumor localization and replication, and describe antitumor activity.
Experimental Design: Patients received escalating doses of reovirus up to 3 × 1010 TCID50 for 5 consecutive days every 4 weeks. Viral excretion was assessed by reverse transcription-PCR and antibody response by cytotoxicity neutralization assay. Pretreatment and post-treatment tumor biopsies were obtained to measure viral uptake and replication.
Results: Thirty-three patients received 76 courses of reovirus from 1 × 108 for 1 day up to 3 × 1010 TCID50 for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade 1 to 2 toxicities included fever, fatigue, and headache, which were dose and cycle independent. Viral excretion at day 15 was not detected by reverse transcription-PCR at 25 cycles and only in 5 patients at 35 cycles. Neutralizing antibodies were detected in all patients and peaked at 4 weeks. Viral localization and replication in tumor biopsies were confirmed in 3 patients. Antitumor activity was seen by radiologic and tumor marker (carcinoembryonic antigen, CA19.9, and prostate-specific antigen) evaluation.
Conclusions: Oncolytic reovirus can be safely and repeatedly administered by i.v. injection at doses up to 3 × 1010 TCID50 for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infection of metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies.
Exploiting Gene Expression Profiling to Identify Novel Minimal Residual Disease Markers of Neuroblastoma
Authors: Cheung Irene Y. , Feng Yi , Gerald William , Cheung Nai-Kong V. 
Published: November 2008

Abstract
Purpose: Minimal residual disease (MRD) presents a significant hurdle to curing metastatic neuroblastoma. Biological therapies directed against MRD can improve outcome. Evaluating treatment efficacy requires MRD measurement, which serves as surrogate endpoint. Because of tumor heterogeneity, no single marker will likely be adequate. Genome-wide expression profiling can uncover potential MRD markers differentially expressed in tumors over normal marrow/blood.
Experimental Design: Gene expression array was carried out on 48 stage 4 tumors and 9 remission marrows using the Affymetrix U95 gene chip. Thirty-four genes with a tumor-to-marrow expression ratio higher than tyrosine hydroxylase were identified. Quantitative reverse transcription-PCR was done on all 34 genes to study the dynamic range of tumor cell detection and the expression of these genes in normal marrow/blood samples and in stage 4 neuroblastoma tumors. Top ranking markers were then tested for prognostic significance in the marrows of stage 4 patients collected from the same treatment protocol after two cycles of immunotherapy.
Results: Based on sensitivity assays, 8 top-ranking markers were identified: CCND1, CRMP1, DDC, GABRB3, ISL1, KIF1A, PHOX2B, and TACC2. They were abundantly expressed in stage IV neuroblastoma tumors (n = 20) and had low to no detection in normal marrow/blood samples (n = 20). Moreover, expression of CCND1, DDC, GABRB3, ISL1, KIF1A, and PHOX2B in 116 marrows sampled after two treatment cycles was highly prognostic of progression-free and overall survival (P &lt; 0.001).
Conclusions: Marker discovery based on differential gene expression profiling, stringent sensitivity and specificity assays, and well-annotated patient samples can rapidly prioritize and identify potential MRD markers of neuroblastoma.
KIT Gene Mutations and Copy Number in Melanoma Subtypes
Authors: Beadling Carol , Jacobson-Dunlop Erick , Hodi F. Stephen , Le Claudia , Warrick Andrea , Patterson Janice , Town Ajia , Harlow Amy , Cruz Frank , Azar Sharl , Rubin Brian P. , Muller Susan , West Rob , Heinrich Michael C. , Corless Christopher L. 
Published: November 2008

Abstract
Purpose: We recently identified a KIT exon 11 mutation in an anorectal melanoma of a patient who had an excellent response to treatment with imatinib. To determine the frequency of KIT mutations across melanoma subtypes, we surveyed a large series of tumors.
Experimental Design: One hundred eighty-nine melanomas were screened for mutations in KIT exons 11, 13, and 17. KIT copy number was assessed by quantitative PCR. A subset of cases was evaluated for BRAF and NRAS mutations. Immunohistochemistry was done to assess KIT (CD117) expression.
Results: KIT mutations were detected in 23% (3 of 13) of acral melanomas, 15.6% (7 of 45) of mucosal melanomas, 7.7% (1 of 13) of conjunctival melanomas, 1.7% (1 of 58) of cutaneous melanomas, and 0% (0 of 60) of choroidal melanomas. Almost all the KIT mutations were of the type predicted to be imatinib sensitive. There was no overlap with NRAS mutations (11.1% of acral and 24.3% of mucosal tumors) or with BRAF mutations (absent in mucosal tumors). Increased KIT copy number was detected in 27.3% (3 of 11) of acral and 26.3% (10 of 38) of mucosal melanomas, but was less common among cutaneous (6.7%; 3 of 45), conjunctival (7.1%; 1 of 14), and choroidal melanomas (0 of 28). CD117 expression, present in 39% of 105 tumors representing all melanoma types, did not correlate with either KIT mutation status or KIT copy number.
Conclusions: Our findings confirm that KIT mutations are most common in acral and mucosal melanomas but do not necessarily correlate with KIT copy number or CD117 expression. Screening for KIT mutations may open up new treatment options for melanoma patients.
Acquired Resistance to Small Molecule ErbB2 Tyrosine Kinase Inhibitors
Authors: Chen Franklin L. , Xia Wenle , Spector Neil L. 
Published: November 2008

Abstract
Breast cancers overexpressing the ErbB2 (HER2) receptor tyrosine kinase oncogene are treated with targeted therapies such as trastuzumab (Herceptin), an anti-ErbB2 antibody, and lapatinib (GW572016/Tykerb), a selective small molecule inhibitor of ErbB2 and epidermal growth factor receptor tyrosine kinases that was recently approved for ErbB2+ breast cancers that progressed on trastuzumab-based therapy. The efficacy of lapatinib as a monotherapy or in combination with chemotherapy, however, is limited by the development of therapeutic resistance that typically occurs within 12 months of starting therapy. In contrast to small molecule inhibitors targeting other receptor tyrosine kinases where resistance has been attributed to mutations within the targeted receptor, ErbB2 mutations have not been commonly found in breast tumors. Instead, acquired resistance to lapatinib seems to be mediated by redundant survival pathways that are activated as a consequence of marked inhibition of ErbB2 kinase activity. For example, inhibition of phosphatidylinositol3 kinase-Akt in lapatinib-treated cells leads to derepression of FOXO3A, a transcription factor that up-regulates estrogen receptor (ER) signaling, resulting in a switch in the regulation of survival factors (e.g., survivin) and cell survival from ErbB2 alone to ER and ErbB2 in resistant cells. In this review, we discuss the effects of lapatinib on signaling networks in ErbB2+ breast cancer cells to elucidate potential mechanisms of therapeutic resistance and strategies to overcome or prevent its development.
SCCRO (DCUN1D1) Induces Extracellular Matrix Invasion by Activating Matrix Metalloproteinase 2
Authors: O-charoenrat Pornchai , Sarkaria Inderpal , Talbot Simon G. , Reddy Pabbathi , Dao Su , Ngai Ivan , Shaha Ashok , Kraus Dennis , Shah Jatin , Rusch Valerie , Ramanathan Y. , Singh Bhuvanesh 
Published: November 2008

Abstract
Purpose: Ectopic expression of squamous cell carcinoma–related oncogene (SCCRO or DCUN1D1) in NIH-3T3 cells induces invasion in vitro and produces highly invasive xenografts in nude mice with a propensity for regional lymphatical metastasis. The aim of this study was to identify the molecular mechanism underlying SCCRO-induced invasion and metastasis.
Experimental Design: The molecular mechanism of SCCRO-mediated effects on matrix metalloproteinase-2 (MMP2) levels and activity were assessed using a combination of cell biological and molecular methods, including real-time PCR, reporter assay, RNA interference, and chromatin immunoprecipitation assay. Tumor specimens from primary upper aerodigestive tract carcinomas (n = 89) were examined for levels of SCCRO, MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA by real-time PCR.
Results: Overexpression of SCCRO increases MMP2 levels and activity, which is required for SCCRO-induced invasion. Modified McKay assays reveal that SCCRO does not bind to the MMP2 promoter, suggesting that its transcriptional effects are indirect. Deletion or mutation of the activator protein-2 (AP2) and p53 binding element within the MMP2 promoter abrogates SCCRO-driven activation. Ectopic expression of SCCRO increases AP2 levels and promotes the binding of p53 to the MMP2 promoter. Consistent with these findings, SCCRO and MMP2 are coexpressed (P &lt; 0.0001; r2 = 0.58; 95% confidence interval, 0.46-0.69) in primary (upper aerodigestive tract) carcinomas (n = 89), and this coexpression is associated with an increased prevalence of regional nodal metastasis (P = 0.04; relative risk, 1.53).
Conclusions: SCCRO-induced invasion involves activation of MMP2 transcription in an AP2- and p53-dependent manner. SCCRO is a potential marker for metastatic progression in affected cancers.
Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers
Authors: Yonesaka Kimio , Zejnullahu Kreshnik , Lindeman Neal , Homes Alison J. , Jackman David M. , Zhao Feng , Rogers Andrew M. , Johnson Bruce E. , Jänne Pasi A. 
Published: November 2008

Abstract
Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, lead to significant tumor regressions in 10% to 15% of non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, 30% to 40% of NSCLC patients, majority of whom are EGFR wild-type, develop stable disease following EGFR tyrosine kinase inhibitor therapy. EGFR-directed antibodies (cetuximab) are effective treatments for head and neck squamous cell carcinomas, which seldom contain EGFR mutations. The determinant(s) of efficacy of EGFR-targeted therapies in EGFR wild-type cancers is not well defined.
Experimental Design: We examined the relationship of EGFR ligands, EGF, transforming growth factor-α,and amphiregulin and the efficacy of gefitinib and cetuximab in EGFR wild-type NSCLC (n = 10) and head and neck squamous cell carcinoma (n = 4) cell lines. We compared amphiregulin expression using immunohistochemistry in EGFR wild-type NSCLC patients (n = 24) that developed either stable or progressive disease following erlotinib or gefitinib treatment.
Results: Cell lines which produced ≥20 pmol/L amphiregulin, as detected by an ELISA, were significantly more likely to be growth inhibited by both gefitinib and cetuximab than those that produced minimal or no amphiregulin. In these cell lines, both cetuximab and gefitinib led to cell cycle arrest at the G1-S boundary and was associated with preferential inhibition of extracellular signal-regulated kinase 1/2 but not Akt signaling. Amphiregulin expression was significantly higher in NSCLC patients that developed stable disease compared with those that developed disease progression following gefitinib or erlotinib treatment.
Conclusions: Amphiregulin expression may help select EGFR wild-type patients who are likely to develop stable disease from EGFR-targeted therapies.
Serum YKL-40 and Interleukin 6 Levels in Hodgkin Lymphoma
Authors: Biggar Robert J. , Johansen Julia S. , Smedby Karin Ekström , Rostgaard Klaus , Chang Ellen T. , Adami Hans-Olov , Glimelius Bengt , Molin Daniel , Hamilton-Dutoit Stephen , Melbye Mads , Hjalgrim Henrik 
Published: November 2008

Abstract
Purpose: Serum levels of the inflammatory markers YKL-40 and interleukin 6 (IL-6) are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma, a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis Hodgkin lymphoma.
Experimental Design: We analyzed Danish and Swedish patients with incident Hodgkin lymphoma (N = 470) and population controls from Denmark (n = 245 for YKL-40; n = 348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analyzed by linear regression, adjusting for age and sex.
Results: Serum levels of YKL-40 and IL-6 increased in Hodgkin lymphoma patients compared with controls (YKL-40, 3.6-fold; IL-6, 8.3-fold; both, P &lt; 0.0001). In pretreatment samples from pretreatment Hodgkin lymphoma patients (n = 176), levels were correlated with more advanced stages (Ptrend, 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms; however, levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (&lt;45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pretreatment patients; however, even ≥6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased compared with controls. In patients who died (n = 12), pretreatment levels for YKL-40 and IL-6 were higher than in survivors, although not statistically significantly.
Conclusions: Serum YKL-40 and IL-6 levels were increased in untreated Hodgkin lymphoma patients and those with more advanced stages but did not differ significantly by Hodgkin lymphoma histology. Following treatment, serum levels were significantly lower.
Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review
Authors: Morgan Meredith A. , Parsels Leslie A. , Maybaum Jonathan , Lawrence Theodore S. 
Published: November 2008

AbstractIn the last three decades, gemcitabine has progressed from the status of a laboratory cytotoxic drug to a standard clinical chemotherapeutic agent and a potent radiation sensitizer. In an effort to improve the efficacy of gemcitabine, additional chemotherapeutic agents have been combined with gemcitabine (both with and without radiation) but with toxicity proving to be a major limitation. Therefore, the integration of molecularly targeted agents, which potentially produce less toxicity than standard chemotherapy, with gemcitabine radiation is a promising strategy for improving chemoradiation. Two of the most promising targets, described in this review, for improving the efficacy of gemcitabine radiation are epidermal growth factor receptor and checkpoint kinase 1.