bluuebunny/crossref_metadata_2025 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

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

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

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 < 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

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

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

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 < 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

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

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

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 < 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

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

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 < 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 (<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

In 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.
Circulating Methylated-DCR2Gene in Serum as an Indicator of Prognosis and Therapeutic Efficacy in Patients withMYCNNonamplified Neuroblastoma
Authors: Yagyu Shigeki , Gotoh Takahiro , Iehara Tomoko , Miyachi Mitsuru , Katsumi Yoshiki , Tsubai-Shimizu Satoko , Kikuchi Ken , Tamura Shinichi , Tsuchiya Kunihiko , Imamura Toshihiko , Misawa-Furihata Akiko , Sugimoto Tohru , Sawada Tadashi , Hosoi Hajime
Published: November 2008

Background: MYCN amplification (MNA) in neuroblastoma is a strong indicator of poor prognosis. However, some MYCN nonamplified (non-MNA) cases show poor outcomes, and examining the status of the gene requires an operation, which may have surgical complications. Therefore, a new marker is needed to identify cases of non-MNA neuroblastomas with poor prognoses using less risky procedures. Aberrant hypermethylation of the DCR2 promoter has recently been associated with rapidly progressing neuroblastoma. We aimed to develop a noninvasive DCR2 methylation assay for patients with neuroblastoma using serum DNA, which predominantly originates from tumor-released DNA.

Methods: Using DNA-based real-time PCR, we simultaneously quantified a methylated-DCR2 specific sequence (M) and a reference sequence (R) located in the promoter region in serum DNA, and evaluated DCR2 methylation status as M/R ratios in 86 patients with neuroblastoma.

Results: Serum DCR2 M/R ratios were strongly correlated with those in the tumor (r = 0.67; P = 0.002). DCR2 methylation was associated with stage both in the whole neuroblastoma group and in the non-MNA group (P < 0.001), and DCR2-methylated patients showed significantly poorer 5-year event-free survival in the whole neuroblastoma group (43% versus 84%; P < 0.001), especially in the non-MNA group (12% versus 96%;P < 0.001). Among five DCR2-methylated patients whose clinical courses were followed, serum M/R ratios were close to 0 in the patients in remission, whereas the ratios increased in patients who relapsed.

Conclusions: Detection of methylated-DCR2 in serum DNA has promise as a noninvasive assay for predicting prognosis and therapeutic efficacy in neuroblastoma, especially in non-MNA cases. Furthermore, it might be a sensitive marker of tumor recurrence in DCR2-methylated cases.
DNA Vaccines Targeting Tumor Antigens to B7 Molecules on Antigen-Presenting Cells Induce Protective Antitumor Immunity and Delay Onset of HER-2/Neu-Driven Mammary Carcinoma
Authors: Sloots Arjen , Mastini Cristina , Rohrbach Florian , Weth Robert , Curcio Claudia , Burkhardt Ute , Jäger Elke , Forni Guido , Cavallo Federica , Wels Winfried S.
Published: November 2008

Purpose: Presentation of tumor antigens by professional antigen-presenting cells (APC) is critical for the induction of tumor-specific T-cell responses. To facilitate targeted delivery of tumor antigens to APC, we generated DNA vaccines that encode secreted fusion proteins consisting of the extracellular domain of CTLA-4 for binding to costimulatory B7 molecules on APC, fused to residues 1 to 222 of human ErbB2 (HER-2) or a corresponding 224 residues fragment of its rat homologue Neu.

Experimental Design: Induction of humoral and cellular immune responses and antitumoral activity of the DNA vaccines were tested in murine tumor models with transfected renal carcinoma cells expressing the respective antigens and in transgenic BALB-neuT mice developing spontaneous Neu-driven mammary carcinomas.

Results: Vaccination of BALB/c mice with CTLA-4-ErbB2222 plasmid DNA markedly improved tumor-free survival on challenge with ErbB2-expressing Renca cells in comparison with untargeted ErbB2222, accompanied by induction of stronger ErbB2-specific antibody and CTL responses. Likewise, a CTLA-4 vaccine carrying the unrelated NY-ESO-1 cancer-germline antigen was more effective than untargeted NY-ESO-1 in the protection of mice from challenge with NY-ESO-1-expressing tumor cells. Importantly, antitumoral activity of such a CTLA-4 fusion vaccine could be reproduced in immunotolerant BALB-neuT mice, where a corresponding CTLA-4-Neu224 DNA vaccine markedly delayed the onset of spontaneous Neu-driven mammary carcinomas.

Conclusions: Our results show that plasmid DNA vaccines for in vivo expression of tumor antigens targeted to APC induce potent immune responses and antitumoral activities, providing a rationale for further development of this approach for specific cancer immunotherapy.
Genetic Screening for Oral Human Papillomavirus Infections and Cancers of the Head and Neck
Authors: Sok John C. , Grandis Jennifer R.
Published: November 2008

Detection and type-specific identification of human papillomavirus infection obtained from oral rinse sampling may have future clinical utility for identifying individuals at higher risk for a subset of oropharyngeal cancers.
Friend Me if You Facebook: Generation Y and Performative Surveillance
Authors: Westlake E.J.
Published: November 2008

Facebook was founded as a way to enhance face-to-face contact on university campuses, and so its virtual and physical life are unique on the internet. The performance of self online versus the performance of self “on ground” constitutes a particular dynamic. Members of the Facebook community use it to build and enhance their “real” relationships through their unique performances of online self, and these fluid performances, which may look like exhibitionism, are energetic engagements with the panoptic gaze: as people offer themselves up for surveillance, they also resist being fixed as rigid, unchanging subjects.
Gossip, Ghosts, and Memory: Mother Courage and the Forging of the Berliner Ensemble
Authors: Honegger Gitta
Published: November 2008

Any actor taking on the role of Mother Courage takes on not only the ghost of Helene Weigel, whose performance of the role made theatre history, but also the notable past of the Berliner Ensemble, which began with the casting for the 1949 Berlin production under Soviet patronage and amidst the devastation of World War II and the Holocaust. The model ensemble was forged from a ragtag assembly of survivors whose individual and collective histories—professional and political—are deeply embedded in the play. In these times of endangered privacy and civil liberties, the genealogy of this historic ensemble serves again as a challenging model to examine the role of the theatre in society.
Average Predictability Time. Part II: Seamless Diagnoses of Predictability on Multiple Time Scales
Authors: DelSole Timothy , Tippett Michael K.
Published: November 2008

This paper proposes a new method for diagnosing predictability on multiple time scales without time averaging. The method finds components that maximize the average predictability time (APT) of a system, where APT is defined as the integral of the average predictability over all lead times. Basing the predictability measure on the Mahalanobis metric leads to a complete, uncorrelated set of components that can be ordered by their contribution to APT, analogous to the way principal components decompose variance. The components and associated APTs are invariant to nonsingular linear transformations, allowing variables with different units and natural variability to be considered in a single state vector without normalization. For prediction models derived from linear regression, maximizing APT is equivalent to maximizing the sum of squared multiple correlations between the component and the time-lagged state vector. The new method is used to diagnose predictability of 1000-hPa zonal velocity on time scales from 6 h to decades. The leading predictable component is dominated by a linear trend and presumably identifies a climate change signal. The next component is strongly correlated with ENSO indices and hence is identified with seasonal-to-interannual predictability. The third component is related to annular modes and presents decadal variability as well as a trend. The next few components have APTs exceeding 10 days. A reconstruction of the tropical zonal wind field based on the leading seven components reveals eastward propagation of anomalies with time scales consistent with the Madden–Julian oscillation. The remaining components have time scales less than a week and hence are identified with weather predictability. The detection of predictability on these time scales without time averaging is possible by virtue of the fact that predictability on different time scales is characterized by different spatial structures, which can be optimally extracted by suitable projections.
A Climatology of the Gravest Waves in the Equatorial Lower and Middle Stratosphere: Method and Results for the ERA-40 Re-Analysis and the LMDz GCM
Authors: Lott François , Kuttippurath Jayanarayanan , Vial François
Published: November 2008

A climatology of the three-dimensional life cycle of the gravest waves in the tropical lower and middle stratosphere is presented. It shows that at periods around 10 days the gravest waves correspond to Kelvin and Rossby–gravity wave packets that substantially affect specific regions in the lower stratosphere. It also shows that the planetary-scale Kelvin waves with zonal wavenumber s = 1 and periods between 10 and 20 days produce a substantial signal. Still at the planetary scales, the climatology also shows that the global planetary Rossby waves with s = 1 and periods around 5 and 16 days have a substantial equatorial signature. This climatology is for all the dynamical fields (horizontal wind, temperature, and geopotential height) and relates the equatorial waves to the equatorial zonal mean flow evolution associated with the quasi-biennial oscillation.

The method used to extract the climatology is a composite analysis of the dynamical fields keyed on simple indexes measuring when the waves enter in the stratosphere. For the Kelvin waves, the Rossby–gravity waves, and the 5- and 16-day Rossby planetary waves, these indexes are related to the latitudinal means over the equatorial band of the temperature, the meridional wind, the geopotential height, and the zonal wind respectively. The method is applied first to ERA-40 and then to a simulation done with the LMDz GCM. When compared to the results from ERA-40, this reveals that the LMDz GCM underestimates the Rossby–gravity wave packets and a fraction of the Kelvin wave packets. This deficit is attributed to the fact that the model has a too coarse vertical resolution and an insufficient tropospheric forcing for the horizontal wavenumbers s > 3.
Decadal Climatic Variability, Trends, and Future Scenarios for the North China Plain
Authors: Fu Guobin , Charles Stephen P. , Yu Jingjie , Liu Changming
Published: November 2008

Observed decadal climatic variability and trends for the north China plain (NCP) are assessed for significance with Kendall’s test and discussed in light of future climate scenarios from multi-GCM outputs from the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4). The results indicate that the NCP has become warmer and drier over the last four decades. The annual precipitation has declined by about 43.9 mm (6.7%, although not statistically significant), and the annual means of daily mean, maximum, and minimum temperatures have increased by 0.83°, 0.18°, and 1.46°C, respectively, during the past 40 yr. Both trends for annual means of daily mean and minimum temperatures are statistically significant. The future climate of the NCP is projected to be warmer and, with less confidence, wetter. However, streamflow could decline under these projections, based on the results of the two-parameter climate elasticity of streamflow index. This will produce serious challenges for water resources management and likely lead to exacerbated problems for agriculture, industry, urban communities, and the environment.
Alongshelf Variability of Inner-Shelf Circulation along the Central Oregon Coast during Summer
Authors: Kirincich Anthony R. , Barth John A.
Published: November 2008

The spatial and temporal variability of inner-shelf circulation along the central Oregon coast during the 2004 upwelling season is described using a 70-km-long array of moorings along the 15-m isobath. Circulation at three stations located onshore of a submarine bank differed from that of a station north of the bank, despite the relatively uniform wind forcing and inner-shelf bathymetry present. During upwelling-favorable winds, strong southward alongshelf flow occurred north of the bank, no alongshelf flow occurred onshore of the northern part of the bank, and increasing southward flow occurred onshore of the southern part of the bank. During downwelling-favorable winds, strong northward flow occurred in the inner shelf onshore of the bank while weak flow occurred north of the bank. These alongshelf differences in inner-shelf circulation were due to the effects of the bank, which isolated the inner shelf onshore of the bank from the regional upwelling circulation that was evident at the northernmost station. As a result, circulation onshore of the bank was driven primarily by local wind forcing, while flow north of the bank was only partially driven by local winds. A secondary mode of variability, attributed to the movement of the regional upwelling jet due to remote forcings, contributed the bulk of the variability observed north of the bank. With the time-dependent wind forcing present, acceleration was an important term in the depth-averaged alongshelf momentum equation at all stations. During upwelling, bottom stress and acceleration opposed the wind stress north of the bank, while bottom stress was weaker onshore of the bank where the across-shelf momentum flux and the alongshelf pressure gradient balanced the residual of the acceleration and stresses. During downwelling, waters onshore of the bank surged northward at magnitudes much larger than that found north of the bank. These spatial variations developed as the season progressed and the regional upwelling circulation intensified, explaining known variations in growth and recruitment of nearshore invertebrate species.
A New Scheme for Improving the Seasonal Prediction of Summer Precipitation Anomalies
Authors: Wang Huijun , Fan Ke
Published: November 2008

A new scheme is developed to improve the seasonal prediction of summer precipitation in the East Asian and western Pacific region. The scheme is applied to the Development of a European Multimodel Ensemble System for Seasonal to Interannual Prediction (DEMETER) results. The new scheme is designed to consider both model predictions and observed spatial patterns of historical “analog years.” In this paper, the anomaly pattern correlation coefficient (ACC) between the prediction and the observation, as well as the root-mean-square error, is used to measure the prediction skill. For the prediction of summer precipitation in East Asia and the western Pacific (0°–40°N, 80°–130°E), the prediction skill for the six model ensemble hindcasts for the years of 1979–2001 was increased to 0.22 by using the new scheme from 0.12 for the original scheme. All models were initiated in May and were composed of nine member predictions, and all showed improvement when applying the new scheme. The skill levels of the predictions for the six models increased from 0.08, 0.08, 0.01, 0.14, −0.07, and 0.07 for the original scheme to 0.11, 0.14, 0.10, 0.22, 0.04, and 0.13, respectively, for the new scheme.
Feminist Relational Advocacy
Authors: Goodman Lisa A. , Glenn Catherine , Bohlig Amanda , Banyard Victoria , Borges Angela
Published: November 2008

This article describes a qualitative study of how low-income women who are struggling with symptoms of depression experience feminist relational advocacy, a new model that is informed by feminist, multicultural, and community psychology theories. Using qualitative content analysis of participant interviews, the authors describe the processes and outcomes of feminist relational advocacy from participants' perspectives; they also consider how emergent themes fit with principles of the model, including the importance of women's narratives, the inseparability of emotional and practical support, the centrality of the advocacy relationship, and oppression as a source of emotional distress. The article concludes with a discussion of the practice and research implications of the study, highlighting the possibilities of feminist relational advocacy as a new tool for counseling psychologists and the lessons for advocacy models in general.
Is Access Sufficient? An Examination of the Effects of the MedShare Program to Expand Access to Prescription Drugs for Indigent Populations
Authors: Shaw Thomas , Carrozza Mark
Published: November 2008

We conduct an evaluation of MedShare, a program designed to enhance access to prescription drugs for indigent patients in the Greater Cincinnati area. The program expands access to drugs by providing subsidies to reduce the costs paid by patients for their prescriptions. The assumption is that by expanding access to prescription drugs, participant health outcomes as measured by quality of life improve. Although the program appears outwardly successful, we found little difference between program participants and comparison groups. We feel that these findings point to a major flaw with existing health policy: access alone is not sufficient to improve health outcomes. Too often programs are created and, provided they show outwards signs of success (e.g., enrollment and utilization), are assumed to be improving the health of the community. Our findings indicate that one must look beyond just expanding access to ensure that programs are indeed achieving their overall objectives.
Assessing School Effectiveness
Authors: Klein Stephen , Freedman David , Shavelson Richard , Bolus Roger
Published: November 2008

The Collegiate Learning Assessment (CLA) program measures value added in colleges and universities, by testing the ability of freshmen and seniors to think logically and write clearly. The program is popular enough that it has attracted critics. In this paper, we outline the methods used by the CLA to determine value added. We summarize the criticisms, which revolve around the question of which students take the CLA tests. Typically, samples are not random, so that selection bias is a concern, as is confounding. We respond by showing that criticisms of CLA procedures are not supported by the data.
Now It's Personal
Authors: Granitz Neil A. , Koernig Stephen K. , Harich Katrin R.
Published: November 2008

Rapport refers to when two people “click.” Although business education researchers have begun to study rapport, past research has principally focused on students' perceptions of rapport, whereas faculty's perceptions of rapport have never been studied or contrasted with those of students. Understanding this is critical as rapport between faculty and students can improve learning and bestow other positive student and faculty benefits. Employing qualitative research, this study uncovers faculty's views of the antecedents and outcomes of rapport between faculty and students. Based on the results of this study, a faculty-student model of rapport is developed. This model shows that approach, personality, and homophily factors serve as antecedents to such rapport. Student benefits such as enhanced learning, greater involvement, and greater customization are important outcomes of rapport. Other outcomes include faculty benefits, outside-of-the-classroom benefits, as well as benefits for both faculty—students. Contrasts to past research and recommendations for faculty to build rapport are presented.
A Test of the Political Control of Bureaucracies Under Asymmetric Information
Authors: Whitford Andrew B.
Published: November 2008

How does the informational role of interest groups interact with institutions when politicians seek to control the bureaucracy? In 1992, Banks and Weingast argued that bureaucrats hold an informational advantage vis-à-vis political principals concerning policy-relevant variables, and that when it is prohibitively costly to audit, the agency may over- or understate the extent of a public problem. This is less likely to happen if there is a low-cost monitoring technology and if interest groups can monitor the agency's choices. I test this hypothesis using data on bureaucratic statements that estimate the importance of a number of hazardous waste problems from a group of state-level environmental agencies. The results provide evidence for the Banks—Weingast hypothesis.
Interpersonal Discussion Following Citizen Engagement About Nanotechnology
Authors: Besley John C. , Kramer Victoria L. , Qingjiang Yao  , Toumey Chris
Published: November 2008

The current study explores interpersonal discussion following participation in a novel program of citizen engagement about nanotechnology. Participants answered closed- and open-ended questions about their discursive behavior in a postengagement survey. The study seeks to address whether organizers of citizen engagement can expect participants to extend the impacts of engagement beyond direct participants through interpersonal discussion. Respondents reported moderate levels of postengagement discussion and appeared to say positive things about both nanotechnology and the experts who contributed to the engagement program. Respondents also reported primarily talking about nanotechnology in terms of scientific progress while using a range of fairness and competence frames to discuss experts and the program.
The Influence of Disfigurement on Conversational Recall
Authors: Stevenage Sarah V. , Furness Catherine
Published: November 2008

Two experiments are reported which examine the degree to which conversational recall is affected by facial disfigurement. In Experiment 1, participants viewed a video interview and then immediately recalled the information given by the speaker. Recall fell from 68 per cent to 52 per cent when a fake disfigurement was visible on the speaker's face. In Experiment 2, these results were replicated in a more realistic simulated webcam interaction. Again, immediate conversational recall fell substantially from 85 per cent to 51 per cent when the speaker had a fake disfigurement. In both experiments, however, overt reactions through personality ratings were unaffected by appearance. Reasons for such reactions are discussed, together with the value to the individual in knowing and expecting such reactions.
Access to Social Support in Life and in the Laboratory
Authors: O'Donovan Aoife , Hughes Brian M.
Published: November 2008

Social support is associated with lower cardiovascular disease risk. We examined the effects of perceived network support and availability of functional support in the laboratory on blood pressure and heart rate (HR) reactivity to acute stress. When functional support was available, participants with low perceived network support had significantly lower HR reactivity than participants with high perceived network support ( p = .04). Conversely, when functional support was not available, participants with low perceived network support had significantly higher HR reactivity ( p = .05). Self-reported anxiety post-stressor was significantly higher when functional support was not mentioned ( p = .03).
Does Depression Cause Obesity?
Authors: Blaine Bruce
Published: November 2008

To evaluate the causal effects of depression on obesity, longitudinal tests of the effect of depression on follow-up obesity status were meta-analyzed. Combining data from 16 studies the results confirmed that, after controlling for potential confounding variables, depressed compared to nondepressed people were at significantly higher risk for developing obesity. The risk among depressed people for later obesity was particularly high for adolescent females (odds ratio: 2.57, 95% CI: 2.27, 2.91). These findings highlight the importance of depression screening and treatment programs, especially among adolescents, to assist in the prevention of adult obesity.
Predictors of Quality of Life in Hospitalized Cardiac Patients
Authors: Bruscia Kenneth , Shultis Carol , Dennery Karen , Dileo Cheryl
Published: November 2008

This cross-sectional investigation examined relationships between Sense of Coherence (SOC), age, gender, race, education, length of illness, and Quality of Life (QOLS) in 121 hospitalized cardiac patients (mean age 61.7 years), varying in condition and treatment regimen. QOLS scores were relatively good; SOC scores were slightly lower than other groups. SOC predicted QOLS alone, and in conjunction with age, gender, race, length of illness, and education, which did not predict QOLS separately. Thus, an important interdisciplinary goal is to help cardiac patients perceive life as comprehensible, manageable, and meaningful (as measured by SOC), as this greatly influences Quality of Life.