bluuebunny/crossref_metadata_2025 huggingface dataset:
Critical Role and Regulation of Transcription Factor FoxM1 in Human Gastric Cancer Angiogenesis and Progression
Authors: Li Qiang , Zhang Nu , Jia Zhiliang , Le Xiangdong , Dai Bingbing , Wei Daoyan , Huang Suyun , Tan Dongfeng , Xie Keping
Published: April 2009

The mammalian forkhead box (Fox) transcription factor FoxM1b is implicated in tumorigenesis. However, the presence of expression and role of FoxM1b in gastric cancer remain unknown. Therefore, we investigated FoxM1b expression in 86 cases of primary gastric cancer and 57 normal gastric tissue specimens. We further investigated the underlying mechanisms of altered FoxM1b expression in and the effect of this altered expression on gastric cancer growth and metastasis using in vitro and animal models of gastric cancer. We found weak expression of FoxM1b protein in the mucous neck region of gastric mucosa, whereas we observed strong staining for FoxM1b in tumor cell nuclei in various gastric tumors and lymph node metastases. A Cox proportional hazards model revealed that FoxM1b expression was an independent prognostic factor in multivariate analysis (P < 0.001). Experimentally, overexpression of FoxM1b by gene transfer significantly promoted the growth and metastasis of gastric cancer cells in orthotopic mouse models, whereas knockdown of FoxM1b expression by small interfering RNA did the opposite. Promotion of gastric tumorigenesis by FoxM1b directly and significantly correlated with transactivation of vascular endothelial growth factor expression and elevation of angiogenesis. Given the importance of FoxM1b to regulation of the expression of genes key to cancer biology overall, dysregulated expression and activation of FoxM1b may play important roles in gastric cancer development and progression. [Cancer Res 2009;69(8):3501–9]
LEF1 in Androgen-Independent Prostate Cancer: Regulation of Androgen Receptor Expression, Prostate Cancer Growth, and Invasion
Authors: Li Yirong , Wang Longgui , Zhang Miao , Melamed Jonathan , Liu Xiaomei , Reiter Robert , Wei Jianjun , Peng Yi , Zou Xuanyi , Pellicer Angel , Garabedian Michael J. , Ferrari Anna , Lee Peng
Published: April 2009

A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth, and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LEF1 overexpression in LNCaP cells resulted in increased AR expression and consequently enhanced growth and invasion ability, whereas LEF1 knockdown in LNCaP-AI cells decreased AR expression and, subsequently, growth and invasion capacity. Chromatin immunoprecipitation, gel shift, and luciferase assays confirmed LEF1 occupancy and regulation of the AR promoter. Thus, we identified LEF1 as a potential marker for androgen-independent disease and as a key regulator of AR expression and prostate cancer growth and invasion. LEF1 is highly expressed in androgen-independent prostate cancer, potentially serving as a marker for androgen-independent disease. [Cancer Res 2009;69(8):3332–8]
A CreER-Based Random Induction Strategy for Modeling Translocation-Associated Sarcomas in Mice
Authors: Haldar Malay , Hedberg Matthew L. , Hockin Matthew F. , Capecchi Mario R.
Published: April 2009

Previously, we reported modeling synovial sarcomas in mice by conditionally expressing the human t(X;18) translocation–derived SYT-SSX2 fusion protein in Myf5-expressing myoblasts. Using a tamoxifen-inducible CreER system in mice, we show here that sporadic expression of SYT-SSX2 across multiple tissue types leads to exclusive formation of synovial sarcoma–like tumors, whereas its widespread expression is lethal. Certain clinical and histologic features of tumors in this new model suggest additional nonmyoblast origin for synovial sarcoma. CreER-based sporadic expression both avoids the severe early developmental phenotypes associated with widespread SYT-SSX2 expression and better models natural pathogenesis of cancers in which transformed cells usually arise within an environment of largely normal cells. Furthermore, this strategy may recapitulate multiple potential cellular origins within a single model system. [Cancer Res 2009;69(8):3657–64]
Genetic Subgrouping of Melanoma Reveals New Opportunities for Targeted Therapy
Authors: Smalley Keiran S.M. , Nathanson Katherine L. , Flaherty Keith T.
Published: April 2009

The discovery of activating oncogenic BRAF V600E mutations in the majority of melanomas has not yet been translated into more effective therapy. The failure of agents may be due to lack of sufficiently targeted therapeutics, but is more likely based on the activation of multiple oncogenic pathways in melanomas in addition to the mitogen-activated protein kinase signaling pathway. In contrast, there are groups of melanomas that instead rely on either c-KIT or CRAF signaling that may be amenable to single-agent targeted therapy. In the current review, we discuss how knowledge about these new melanoma subgroups may lead to improved strategies for treating melanomas harboring BRAF V600E mutations. [Cancer Res 2009;69(8):3241–4]
The Role of the Mouse Y Chromosome on Susceptibility to Testicular Germ Cell Tumors
Authors: Anderson Philip D. , Lam Man-Yee , Poirier Christophe , Bishop Colin E. , Nadeau Joseph H.
Published: April 2009

Testicular germ cell tumors (TGCT) are sex limited, occurring only in males with a Y chromosome. Recently, the gr/gr deletion on the human Y chromosome was associated with increased risk of TGCTs. In addition, the presence of Y chromosome sequences is associated with TGCTs in cases of gonadal dysgenesis. TGCTs in strain 129 males recapitulate many aspects of testicular cancer in human infants and can be used to evaluate the role of the Y chromosome in TGCT risk. We used chromosome substitution strains and a sex-reversing mutant to test the role of the Y chromosome on TGCT susceptibility. Our results show that a Y-linked gene that does not differ among the tested strains is essential for tumorigenesis. [Cancer Res 2009;69(8):3614–8]
Risk Information Exposure and Direct-to-Consumer Genetic Testing for BRCA Mutations among Women with a Personal or Family History of Breast or Ovarian Cancer
Authors: Gray Stacy W. , O'Grady Cristin , Karp Lauren , Smith Daniel , Schwartz J. Sanford , Hornik Robert C. , Armstrong Katrina
Published: April 2009

Background: Direct-to-consumer (DTC) BRCA testing may expand access to genetic testing and enhance cancer prevention efforts. It is not known, however, if current DTC websites provide adequate risk information for informed medical decision making.

Methods: A total of 284 women with a personal or family history of breast/ovarian cancer were randomly assigned to view a “mock” DTC commercial website [control condition (CC); n = 93] or the same “mock” website that included information on the potential risks of obtaining genetic testing online. Risk information was framed two ways: risk information attributed to expert sources (ES; n = 98) and unattributed risk information (URI; n = 93). Participants completed an online survey. End points were intentions to get BRCA testing, testing site preference, and beliefs about DTC BRCA testing.

Results: The sample was 82% white, had a mean age of 39 years (range, 18-70 years) and had a mean education of 3 years of college. Women exposed to risk information had lower intentions to get BRCA testing than women in the CC [adjusted odds ratio (OR), 0.48; 95% confidence interval (95% CI) 0.26-0.87; P = 0.016], and less positive beliefs about online BRCA testing (adjusted OR, 0.48; 95% CI, 0.27-0.86; P = 0.014). Women in the ES condition were more likely to prefer clinic-based testing than were women in the CC (adjusted OR, 2.05; 95% CI, 1.07-3.90; P = 0.030).

Conclusion: Exposing women to information on the potential risks of online BRCA testing altered their intentions, beliefs, and preferences for BRCA testing. Policy makers may want to consider the content and framing of risk information on DTC websites as they formulate regulation for this rapidly growing industry. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1303–11)
Long-Term Survivors of Childhood Cancers in the United States
Authors: Mariotto Angela B. , Rowland Julia H. , Yabroff K. Robin , Scoppa Steve , Hachey Mark , Ries Lynn , Feuer Eric J.
Published: April 2009

Purpose: To estimate the number of individuals in the United States diagnosed with cancer as children (ages 0-19 years) as of 2005, with a focus on those surviving for >30 years.

Methods: To estimate the national prevalence of survivors of childhood cancers, we used data from the Surveillance Epidemiology and End Results program from 1975 to 2004. Long-term childhood cancer survivors, diagnosed before 1975, were estimated using incidence and survival models extrapolated into years before 1975.

Results: We estimated that there are a total of 328,652 survivors of childhood cancer in the United States as of January 1, 2005, of these, 24% have survived >30 years since diagnosis. The cancer sites with the largest number of survivors are brain (51,650), acute lymphoblastic leukemia (49,271), germ cell tumors (34,169), and Hodgkin lymphoma (31,598). Sites with higher proportions of survivors diagnosed >30 years ago are germ cell (43%), soft tissue (38%), renal (34%), and bone (26%). Historical trends from Connecticut data show major improvements in survival for all of the childhood cancer sites.

Conclusion: The number of survivors of childhood cancers is expected to increase in the future consequent to the lifesaving advances in treatment introduced after 1970, especially for acute lymphoblastic leukemia. Because this population is at increased risk for illness-related morbidity and mortality, appreciating the number of survivors who were treated as children is important both to determining the national cancer burden and planning for the future health care needs of these individuals. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1033–40)
Association between Glioma and History of Allergies, Asthma, and Eczema: A Case-Control Study with Three Groups of Controls
Authors: Il'yasova Dora , McCarthy Bridget , Marcello Jennifer , Schildkraut Joellen M. , Moorman Patricia G. , Krishnamachari Bhuma , Ali-Osman Francis , Bigner Darell D. , Davis Faith
Published: April 2009

Because glioma etiology is largely unknown, the inverse association of glioma risk with atopic conditions is promising and deserves close scrutiny. We examined the association between a history of allergies, asthma, and eczema, and glioma risk using sibling, friend, and clinic-based controls. This analysis included 388 incident glioma cases and 80 sibling, 191 friend, and 177 clinic-based controls. Each subject's medical history was assessed via a Web-based or telephone survey. Odds ratios (OR) and their 95% confidence intervals (CI) for the associations with allergies, asthma, eczema, and the overall number of these conditions were calculated from conditional (for sibling and friend controls) and unconditional (for clinic-based controls) logistic models. Allergies were consistently inversely associated with the glioma: ORs were 0.53 (95% CI, 0.15-1.84), 0.54 (95% CI, 0.28-1.07), and 0.34 (95% CI, 0.23-0.50) with sibling, friend, and clinic-based controls, respectively. Asthma showed an inverse association only in the comparison with sibling controls (OR, 0.43; 95% CI, 0.19-1.00). Eczema showed an inverse association only in the comparison with friend controls (OR, 0.42; 95% CI, 0.15-1.18). The overall number of these conditions (ordinal score 0, 1, 2, 3) was inversely associated with glioma: The risk decreased 31% to 45% with each addition of an atopic condition. These estimates were the most stable when different control groups were considered. Comparing the prevalence of these conditions in the three control groups with published data, we note that clinic-based controls generally better approximate the prevalence data for population-based groups. These controls seem to present a reasonable choice for clinic-centered case-control studies. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1232–8)
Risk of Non–Hodgkin Lymphoma Associated with Germline Variation in Genes that Regulate the Cell Cycle, Apoptosis, and Lymphocyte Development
Authors: Morton Lindsay M. , Purdue Mark P. , Zheng Tongzhang , Wang Sophia S. , Armstrong Bruce , Zhang Yawei , Menashe Idan , Chatterjee Nilanjan , Davis Scott , Lan Qing , Vajdic Claire M. , Severson Richard K. , Holford Theodore R. , Kricker Anne , Cerhan James R. , Leaderer Brian , Grulich Andrew , Yeager Meredith , Cozen Wendy , Hoar Zahm Shelia , Chanock Stephen J. , Rothman Nathaniel , Hartge Patricia
Published: April 2009

Chromosomal translocations are the hallmark genetic aberration in non–Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNP) was conducted in 1,946 NHL cases and 1,808 controls pooled from 3 independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the proapoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (ORAG, 1.41; 95% CI, 1.10-1.81; ORGG, 1.65; 95% CI, 1.25-2.19; Ptrend = 0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (ORAG, 1.34; 95% CI, 1.08-1.68; ORAA, 1.60; 95% CI, 1.22-2.08; Ptrend = 0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1259–70)
Glycemic Index, Carbohydrates, Glycemic Load, and the Risk of Pancreatic Cancer in a Prospective Cohort Study
Authors: Jiao Li , Flood Andrew , Subar Amy F. , Hollenbeck Albert R. , Schatzkin Arthur , Stolzenberg-Solomon Rachael
Published: April 2009

Diets with high glycemic index and glycemic load have been associated with insulin resistance. Insulin resistance has been implicated in the etiology of pancreatic cancer. We prospectively investigated the associations between glycemic index, carbohydrates, glycemic load, and available carbohydrates dietary constituents (starch and simple sugar) intake and the risk of pancreatic cancer. We followed the participants in the NIH-AARP Diet and Health Study from 1995/1996 through December 2003. A baseline self-administered food frequency questionnaire was used to assess the dietary intake and exposure information. A total of 1,151 exocrine pancreatic cancer cases were identified from 482,362 participants after excluding first-year of follow-up. We used multivariate Cox proportional hazards regression models to calculate relative risks (RR) and 95% confidence intervals (95% CI) for pancreatic cancer. There were no associations between glycemic index, total or available carbohydrates, gycemic load, and pancreatic cancer risk. Participants with high free fructose and glucose intake were at a greater risk of developing pancreatic cancer (highest compared with lowest quintile, RR, 1.29; 95% CI, 1.04-1.59; P trend = 0.004 and RR, 1.35; 95% CI, 1.10-1.67; P trend = 0.005, respectively). There were no statistically significant interactions by body mass index, physical activity, or smoking status. Our results do not support an association between glycemic index, total or available carbohydrate intake, and glycemic load and pancreatic cancer risk. The higher risk associated with high free fructose intake needs further confirmation and elucidation. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1144–51)
Interdisciplinary, Translational, and Community-Based Participatory Research: Finding a Common Language to Improve Cancer Research
Authors: Hebert James R. , Brandt Heather M. , Armstead Cheryl A. , Adams Swann A. , Steck Susan E.
Published: April 2009

Preventing cancer, downstaging disease at diagnosis, and reducing mortality require that relevant research findings be translated across scientific disciplines and into clinical and public health practice. Interdisciplinary research focuses on using the languages of different scientific disciplines to share techniques and philosophical perspectives to enhance discovery and development of innovations; (i.e., from the “left end” of the research continuum). Community-based participatory research (CBPR), whose relevance often is relegated to the “right end” (i.e., delivery and dissemination) of the research continuum, represents an important means for understanding how many cancers are caused as well as for ensuring that basic science research findings affect cancer outcomes in materially important ways. Effective interdisciplinary research and CBPR both require an ability to communicate effectively across groups that often start out neither understanding each other's worldviews nor even speaking the same language. Both demand an ability and willingness to treat individuals from other communities with respect and understanding. We describe the similarities between CBPR and both translational and interdisciplinary research, and then illustrate our points using squamous cell carcinoma of the esophagus as an example of how to deepen understanding and increase relevance by applying techniques of CBPR and interdisciplinary engagement. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1213–7)
CD20-Directed Small Modular Immunopharmaceutical, TRU-015, Depletes Normal and Malignant B Cells
Authors: Hayden-Ledbetter Martha S. , Cerveny Chuck G. , Espling Erik , Brady William A. , Grosmaire Laura S. , Tan Philip , Bader Robert , Slater Sonya , Nilsson Christy A. , Barone Dauphine S. , Simon Alexander , Bradley Cheryl , Thompson Peter A. , Wahl Alan F. , Ledbetter Jeffrey A.
Published: April 2009

Purpose: CD20-directed therapy with rituximab is effective in many patients with malignant lymphoma or follicular lymphoma. However, relapse frequently occurs within 1 year, and patients become increasingly refractory to retreatment. Our purpose was to produce a compact, single-chain CD20-targeting immunotherapeutic that could offer therapeutic advantages in the treatment of B-cell lymphoma.

Experimental Design: Rituximab is a chimeric antibody containing two heavy chains and two light chains. Here, we describe the properties of TRU-015, a small modular immunopharmaceutical specific for CD20, encoded by a single-chain construct containing a single-chain Fv specific for CD20 linked to human IgG1 hinge, CH2, and CH3 domains but devoid of CH1 and CL domains.

Results: TRU-015 mediates potent direct signaling and antibody-dependent cellular cytotoxicity but has reduced size and complement-mediated cytotoxicity activity compared with rituximab. TRU-015 is a compact dimer of 104 kDa that comigrates with albumin in size exclusion chromatography and retains a long half-life in vivo. TRU-015 induced growth arrest in multiple B lymphoma cell lines in vitro and showed effective antitumor activity against large, established subcutaneous Ramos or Daudi xenograft tumors in nude mice. TRU-015 also showed rapid, dose-dependent, and durable depletion of peripheral blood B cells following single-dose administration to nonhuman primates.

Conclusion: These results indicate that TRU-015 may improve CD20-directed therapy by effectively depleting embedded malignant B cells and nonmalignant pathogenic B cells and do so with reduced complement activation.
Nucleophosmin as a Candidate Prognostic Biomarker of Ewing's Sarcoma Revealed by Proteomics
Authors: Kikuta Kazutaka , Tochigi Naobumi , Shimoda Tadakazu , Yabe Hiroki , Morioka Hideo , Toyama Yoshiaki , Hosono Ako , Beppu Yasuo , Kawai Akira , Hirohashi Setsuo , Kondo Tadashi
Published: April 2009

Purpose: We aimed to identify novel prognostic biomarkers for Ewing's sarcoma by investigating the global protein expression profile of Ewing's sarcoma patients.

Experimental Design: We examined the proteomic profile of eight biopsy samples from Ewing's sarcoma patients using two-dimensional difference gel electrophoresis. Three patients were alive and continuously disease-free over 3 years after the initial diagnosis (good prognosis group) and five had died of the disease within 2 years of the initial diagnosis (poor prognosis group).

Results: The protein expression profiles produced using two-dimensional difference gel electrophoresis consisted of 2,364 protein spots, among which we identified 66 protein spots whose intensity showed >2-fold difference between the two patient groups. Mass spectrometric protein identification showed that the 66 spots corresponded to 53 distinct gene products. Pathway analysis revealed that 31 of 53 proteins, including nucleophosmin, were significantly related to bone tissue neoplasms (P < 0.000001). The prognostic performance of nucleophosmin was evaluated immunohistochemically on an additional 34 Ewing's sarcoma cases. Univariate and multivariate analyses revealed that nucleophosmin expression significantly correlated with overall survival (P < 0.01).

Conclusions: These results establish nucleophosmin as a candidate of independent prognostic marker for Ewing's sarcoma patients. Measuring nucleophosmin in biopsy samples before treatment may contribute to the effective management of Ewing's sarcoma.
Efficacy of Systemically Administered Oncolytic Vaccinia Virotherapy for Malignant Gliomas Is Enhanced by Combination Therapy with Rapamycin or Cyclophosphamide
Authors: Lun Xue Qing , Jang Ji-Hyun , Tang Nan , Deng Helen , Head Renee , Bell John C. , Stojdl David F. , Nutt Catherine L. , Senger Donna L. , Forsyth Peter A. , McCart J. Andrea
Published: April 2009

Purpose: The oncolytic effects of a systemically delivered, replicating, double-deleted vaccinia virus has been previously shown for the treatment of many cancers, including colon, ovarian, and others. The purpose of this study was to investigate the oncolytic potential of double-deleted vaccinia virus alone or in combination with rapamycin or cyclophosphamide to treat malignant gliomas in vitro and in vivo.

Experimental Design: Rat (RG2, F98, C6) and human (A172, U87MG, U118) glioma cell lines were cultured in vitro and treated with live or UV-inactivated vaccinia virus. Viral gene [enhanced green fluorescent protein (EGFP)] expression by fluorescence-activated cell sorting, relative cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and assays for cytopathic effects were examined. S.c. murine tumor xenografts (U87MG, U118, C6) and i.c. (RG2, F98) tumor models in immunocompetent rats were treated with systemic administration of EGFP-expressing vaccinia virus (vvDD-EGFP), alone or in combination with rapamycin or cyclophosphamide, or controls. Tumor size, viral biodistribution, and animal survival were assessed. Lastly, the oncolytic effects of vvDD-EGFP on human malignant glioma explants were evaluated.

Results: vvDD-EGFP was able to infect and kill glioma cells in vitro. A single systemic dose of vvDD-EGFP significantly inhibited the growth of xenografts in athymic mice. Systemic delivery of vvDD-EGFP alone was able to target solitary and multifocal i.c. tumors and prolong survival of immunocompetent rats, whereas combination therapy with rapamycin or cyclophosphamide enhanced viral replication and further prolonged survival. Finally, vvDD-EGFP was able to infect and kill ex vivo primary human malignant gliomas.

Conclusions: These results suggest that vvDD-EGFP is a promising novel agent for human malignant glioma therapy, and in combination with immunosuppressive agents, may lead to prolonged survival from this disease.
Gene Expression Patterns in Mismatch Repair-Deficient Colorectal Cancers Highlight the Potential Therapeutic Role of Inhibitors of the Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway
Authors: Vilar Eduardo , Mukherjee Bhramar , Kuick Rork , Raskin Leon , Misek David E. , Taylor Jeremy M.G. , Giordano Thomas J. , Hanash Samir M. , Fearon Eric R. , Rennert Gad , Gruber Stephen B.
Published: April 2009

Purpose: High-frequency microsatellite-instable (MSI-H) tumors account for ∼15% of colorectal cancers. Therapeutic decisions for colorectal cancer are empirically based and currently do not emphasize molecular subclassification despite an increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI colorectal cancers using combined gene expression data sets.

Experimental Design: Three expression/query signatures (discovery data set) characterizing MSI-H colorectal cancer were matched with information derived from changes induced in cell lines by 164 compounds using the systems biology tool “Connectivity Map.” A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle, and apoptosis effects of validated compounds were evaluated in a panel of cell lines.

Results: Fourteen of the 164 compounds were validated as targeting MSI-H cell lines using the bioinformatics approach; rapamycin, LY-294002, 17-(allylamino)-17-demethoxygeldanamycin, and trichostatin A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by rapamycin (18.3 versus 4.4 μmol/L; P = 0.0824) and LY-294002 (15.02 versus 10.37 μmol/L; P = 0.0385) when compared with microsatellite-stable cells. Preferential activity was also observed in MSH2 and MSH6 mutant cells.

Conclusion: Our study shows that the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is of special relevance in mismatch repair-deficient colorectal cancer. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.
FDG-PET/CT Imaging Predicts Histopathologic Treatment Responses after the Initial Cycle of Neoadjuvant Chemotherapy in High-Grade Soft-Tissue Sarcomas
Authors: Benz Matthias R. , Czernin Johannes , Allen-Auerbach Martin S. , Tap William D. , Dry Sarah M. , Elashoff David , Chow Kira , Evilevitch Vladimir , Eckardt Jeff J. , Phelps Michael E. , Weber Wolfgang A. , Eilber Fritz C.
Published: April 2009

Purpose: In patients with soft-tissue sarcoma (STS), the early assessment of treatment responses is important. Using positron emission tomography/computed tomography (PET/CT) with [18F]fluorodeoxyglucose (FDG), we determined whether changes in tumor FDG uptake predict histopathologic treatment responses in high-grade STS after the initial cycle of neoadjuvant chemotherapy.

Experimental Design: From February 2006 to March 2008, 50 patients with resectable high-grade STS scheduled for neoadjuvant therapy and subsequent tumor resection were enrolled prospectively. FDG-PET/CT before (baseline), after the first cycle (early follow-up), and after completion of neoadjuvant therapy (late follow-up) was done. Tumor FDG uptake and changes were measured by standardized uptake values. Histopathologic examination of the resected specimen provided an assessment of treatment response. Patients with ≥95% pathologic necrosis were classified as treatment responders. FDG-PET/CT results were compared with histopathologic findings.

Results: At early follow-up, FDG uptake decreased significantly more in 8 (16%) responders than in the 42 (84%) nonresponders (−55% versus −23%; P = 0.002). All responders and 14 of 42 nonresponders had a ≥35% reduction in standardized uptake value between baseline and early follow-up. Using a ≥35% reduction in FDG uptake as early metabolic response threshold resulted in a sensitivity and specificity of FDG-PET for histopathologic response of 100% and 67%, respectively. Applying a higher threshold at late follow-up improved specificity but not sensitivity. CT had no value at response prediction.

Conclusion: A 35% reduction in tumor FDG uptake at early follow-up is a sensitive predictor of histopathologic tumor response. Early treatment decisions such as discontinuation of chemotherapy in nonresponding patients could be based on FDG-PET criteria.
Noninvasive Detection of EGFR T790M in Gefitinib or Erlotinib Resistant Non–Small Cell Lung Cancer
Authors: Kuang Yanan , Rogers Andrew , Yeap Beow Y. , Wang Lilin , Makrigiorgos Mike , Vetrand Kristi , Thiede Sara , Distel Robert J. , Jänne Pasi A.
Published: April 2009

Purpose: Tumors from 50% of epidermal growth factor receptor (EGFR) mutant non–small cell lung cancer patients that develop resistance to gefitinib or erlotinib will contain a secondary EGFR T790M mutation. As most patients do not undergo repeated tumor biopsies we evaluated whether EGFR T790M could be detected using plasma DNA.

Experimental Design: DNA from plasma of 54 patients with known clinical response to gefitinib or erlotinib was extracted and used to detect both EGFR-activating and EGFR T790M mutations. Forty-three (80%) of patients had tumor EGFR sequencing (EGFR mutant/wild type: 30/13) and seven patients also had EGFR T790M gefitinib/erlotinib-resistant tumors. EGFR mutations were detected using two methods, the Scorpion Amplification Refractory Mutation System and the WAVE/Surveyor, combined with whole genome amplification.

Results: Both EGFR-activating and EGFR T790M were identified in 70% of patients with known tumor EGFR-activating (21 of 30) or T790M (5 of 7) mutations. EGFR T790M was identified from plasma DNA in 54% (15 of 28) of patients with prior clinical response to gefitinib/erlotinib, 29% (4 of 14) with prior stable disease, and in 0% (0 of 12) that had primary progressive disease or were untreated with gefitinib/erlotinib.

Conclusions: EGFR T790M can be detected using plasma DNA from gefitinib- or erlotinib-resistant patients. This noninvasive method may aid in monitoring drug resistance and in directing the course of subsequent therapy.
G3139, an Anti-Bcl-2 Antisense Oligomer That Binds Heparin-Binding Growth Factors and Collagen I, AltersIn vitroEndothelial Cell Growth and Tubular Morphogenesis
Authors: Stein C.A. , Wu SiJian , Voskresenskiy Anatoliy M. , Zhou Jin-Feng , Shin Joongho , Miller Paul , Souleimanian Naira , Benimetskaya Luba
Published: April 2009

Purpose: We examined the effects of G3139 on the interaction of heparin-binding proteins [e.g., fibroblast growth factor 2 (FGF2) and collagen I] with endothelial cells. G3139 is an 18-mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA. A randomized, prospective global phase III trial in advanced melanoma (GM301) has evaluated G3139 in combination with dacarbazine. However, the mechanism of action of G3139 is incompletely understood because it is unlikely that Bcl-2 silencing is the sole mechanism for chemosensitization in melanoma cells.

Experimental Design: The ability of G3139 to interact with and protect heparin-binding proteins was quantitated. The effects of G3139 on the binding of FGF2 to high-affinity cell surface receptors and the induction of cellular mitogenesis and tubular morphogenesis in HMEC-1 and human umbilical vascular endothelial cells were determined.

Results: G3139 binds with picomolar affinity to collagen I. By replacing heparin, the drug can potentiate the binding of FGF2 to FGFR1 IIIc, and it protects FGF from oxidation and proteolysis. G3139 can increase endothelial cell mitogenesis and tubular morphogenesis of HMEC-1 cells in three-dimensional collagen gels, increases the mitogenesis of human umbilical vascular endothelial cells similarly, and induces vessel sprouts in the rat aortic ring model.

Conclusions: G3139 dramatically affects the behavior of endothelial cells. There may be a correlation between this observation and the treatment interaction with lactate dehydrogenase observed clinically.
Synuclein-γ Is Closely Involved in Perineural Invasion and Distant Metastasis in Mouse Models and Is a Novel Prognostic Factor in Pancreatic Cancer
Authors: Hibi Taizo , Mori Taisuke , Fukuma Mariko , Yamazaki Ken , Hashiguchi Akinori , Yamada Taketo , Tanabe Minoru , Aiura Koichi , Kawakami Takao , Ogiwara Atsushi , Kosuge Tomoo , Kitajima Masaki , Kitagawa Yuko , Sakamoto Michiie
Published: April 2009

Purpose: Perineural invasion is associated with the high incidence of local recurrence and a dismal prognosis in pancreatic cancer. We previously reported a novel perineural invasion model and distinguished high– and low–perineural invasion groups in pancreatic cancer cell lines. This study aimed to elucidate the molecular mechanism of perineural invasion.

Experimental Design: To identify key biological markers involved in perineural invasion, differentially expressed molecules were investigated by proteomics and transcriptomics. Synuclein-γ emerged as the only up-regulated molecule in high–perineural invasion group by both analyses. The clinical significance and the biological property of synuclein-γ were examined in 62 resected cases of pancreatic cancer and mouse models.

Results: Synuclein-γ overexpression was observed in 38 (61%) cases and correlated with major invasive parameters, including perineural invasion and lymph node metastasis (P < 0.05). Multivariate analyses revealed synuclein-γ overexpression as the only independent predictor of diminished overall survival [hazard ratio, 3.4 (95% confidence interval, 1.51-7.51)] and the strongest negative indicator of disease-free survival [2.8 (1.26-6.02)]. In mouse perineural invasion and orthotopic transplantation models, stable synuclein-γ suppression by short hairpin RNA significantly reduced the incidence of perineural invasion (P = 0.009) and liver/lymph node metastasis (P = 0.019 and P = 0.020, respectively) compared with the control.

Conclusions: This is the first study to provide in vivo evidence that synuclein-γ is closely involved in perineural invasion/distant metastasis and is a significant prognostic factor in pancreatic cancer. Synuclein-γ may serve as a promising molecular target of early diagnosis and anticancer therapy.
Mesenchymal Hamartoma of the Liver: A Benign Tumor with Deceptive Prognosis in the Perinatal Period
Authors: Cornette J. , Festen S. , van den Hoonaard T.L. , Steegers E.A.P.
Published: April 2009

This article reports a case of perinatal mesenchymal hepatic hamartoma and reviews the literature on the subject. A fetus presented with polyhydramnios and a large multiloculated cystic abdominal mass at 33 weeks of gestation. The ultrasound appearance was most consistent with a mesenteric cyst. Prenatal drainage was considered, due to the size of the lesion. However, a conservative management was opted for. A female infant was born at 35 weeks by classical cesarean section. The immediate postnatal period was characterized by hemodynamic instability. Laparotomy revealed a pedunculated mesenchymal hamartoma of the liver, which could not completely be resected. The infant had an uneventful postoperative recovery and is doing well at 6 months of age. Hepatic mesenchymal hamartoma are rare benign tumors. Most cases are detected in early childhood. They usually present as a cystic rapidly growing abdominal mass. Prenatal diagnosis remains challenging. In children diagnosed in the perinatal period, the outcome seems worse and determined by the compressive effect of the mass.
Obesity, Inflammation, and Insulin Resistance – A Mini-Review
Authors: Zeyda Maximilian , Stulnig Thomas M.
Published: April 2009

The association of obesity, insulin resistance, and chronic low-grade inflammation has been evident for several years by now. Since obesity, insulin resistance, and inflammation all are related to aging as well, the mechanisms underlying this association are of critical importance for gerontology. Although several molecular and cellular mechanisms by which inflammatory events decrease the sensitivity to insulin in obese patients have recently been elucidated, the pathogenesis of obesity-induced insulin resistance is still obscure in many aspects. This review aims at giving a general view on the known mechanisms and summarizing the recent progress. Research currently focuses on adipose tissue inflammation as predominantly driven by adipose tissue macrophages, but also related alterations in other organs (liver, muscle, pancreas) have to be considered. Moreover, novel approaches for treatment and prevention of insulin resistance and type 2 diabetes by targeting obesity-induced inflammatory processes are discussed here.
Palliative day care – a study of well-being and health-related quality of life
Authors: Andersson Svidén G , Fürst CJ , von Koch L , Borell L
Published: April 2009

Aim

The aim of the study was to study the outcomes of palliative day care, in terms of health-related quality of life and the emotional well-being of cancer patients participating in a palliative day care programme for a period of five weeks, compared with a group of palliative cancer patients not participating in day-care.

Methods

The day care sample comprised of patients in a palliative day care programme delivered in two different day care facilities. Participants in the comparison group were recruited from a palliative home care service facility. All patients had a cancer diagnosis. The participants were invited to respond to two questionnaires once a week for a period of five weeks; the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) and the Mood Adjective List (MACL).

Results

The participants in the day care group and the comparison group reported similar levels of perceived functioning and symptoms, as measured by the EORTC QLQ-30, with no significant differences between the groups. However, the day care group reported higher levels of emotional well-being as measured by the MACL than the comparison group reported, although these differences were not statistically significant.
An investigation of the subacute effects of ecstasy on neuropsychological performance, sleep and mood in regular ecstasy users
Authors: Pirona A. , Morgan MJ
Published: April 2009

The aim of this study was to differentiate the subacute from the chronic effects of ecstasy. Regular ecstasy users who subsequently chose to take ecstasy (experimental group: E, N = 16) were compared with regular ecstasy users who opted not to (control group: C, N = 16). Groups were assessed with neuropsychological and psychometric measures at drug-free baseline before ecstasy use and 1 and 4 days after use. Ecstasy users who consumed ecstasy (E) did not differ from those who did not (C) in relation to age, estimated IQ, personality or past substance use, including ecstasy. At baseline, E reported being more energetic, lively and cheerful whereas the day after ecstasy use they reported being more muddled, afraid, sad and dejected than C. However, this was not significant after controlling for sleep deprivation. Mood returned to baseline within 3 days and there were no group differences in Beck depression inventory scores at any of the three testing sessions. There were no subacute effects of ecstasy on working memory, story recall, impulsivity, or decision-making. However, at baseline and the day after use ecstasy users made poorer decisions, and were less sensitive to punishment, in the Somatic marker sensitivity test. These findings suggest that previous reports of marked subacute effects of ecstasy use may have been confounded by chronic polydrug use before use, co-substance use and sleep disturbances after use.
Recording of clinical information in a Scotland-wide drug deaths study
Authors: Baldacchino A. , Crome IB , Zador D. , McGarrol S. , Taylor A. , Hutchison S. , Fahey T. , Hickman M. , Kidd B.
Published: April 2009

The aim of this study was to analyse the nature and extent of data extracted from case files of deceased individuals in contact with services 6 months prior to drug deaths in Scotland during 2003. A cross-sectional descriptive analysis of 317 case notes of 237 individuals who had drug-related deaths was undertaken, using a data linkage process. All contacts made with services in the 6 months prior to death were identified. Information on clinical and social circumstances obtained from social care, specialist drug treatment, mental health, non-statutory services, the Scottish Prison Service and Criminal Records Office was collated. More than 70% (n = 237) were seen 6 months prior to their drug death. Sociodemographic details were reported much more frequently than medical problems, for example, ethnicity (49%), living accommodation (66%), education and income (52%) and dependent children (73%). Medical and psychiatric history was recorded in only 12%, blood-borne viral status in 17% and life events in 26%. This paucity of information was a feature of treatment plans and progress recorded. The 237 drug deaths were not a population unknown to services. Highly relevant data were missing. Improved training to promote in-depth recording and effective monitoring may result in better understanding and reduction of drug deaths.
An Exploratory Investigation of the Factor Structure of the Reynolds Intellectual Assessment Scales (RIAS)
Authors: Dombrowski Stefan C. , Watkins Marley W. , Brogan Michael J.
Published: April 2009

This study investigated the factor structure of the Reynolds Intellectual Assessment Scales (RIAS) using rigorous exploratory factor analytic and factor extraction procedures. The results of this study indicate that the RIAS is a single factor test. Despite these results, higher order factor analysis using the Schmid—Leiman procedure indicates that all subtests are aligned with their theoretically consistent factors. All analyses in this study, including the minimum average partial test, parallel analysis, the Schmid—Leiman procedure, as well as principal factors with orthogonal and oblique rotation, support interpretation at the composite intelligence index level and suggest caution when moving to interpretation at the verbal and nonverbal index levels. The memory subtests should continue to be separated from the main IQ battery because of poor g-loadings and contribution to cross loadings of the intelligence subtests. Interpretation at the subtest level should be eschewed.
A Study of Novice Special Educators' Views of Evidence-Based Practices
Authors: Jones Melissa L.
Published: April 2009

With the implementation of the No Child Left Behind Act (2001), the Council for Exceptional Children's Content Standards for Beginning Special Education Teachers (2002), and the reauthorization of the Individuals with Disabilities Education Improvement Act (2004), the research to practice gap in special education has garnered increased attention. The author utilizes collective case studies to explore this phenomenon through the eyes of 10 novice special educators. Specifically, the author seeks to determine the teachers' perceptions of research in general as well as their use of six broad practices that are supported by research for students with high-incidence disabilities. The use of interviews, observations, and self-report measures resulted in findings that indicate low rates of implementation and a lack of alignment between the beginning teachers' words and actions. The author identifies barriers and facilitating factors, discusses implications for preservice preparation, and presents recommendations for further research.
Mental Health and Special Education Services at School Entry for Children Who Were Involved With the Child Welfare System as Infants
Authors: Ringeisen Heather , Casanueva Cecilia , Cross Theodore P. , Urato Matthew
Published: April 2009

This study examines mental health and special education needs and service use at school entry among children involved in maltreatment investigations as infants. Data are from the National Survey of Child and Adolescent Well-Being, a national probability study of 5,501 children investigated for maltreatment. The study sample comprised 959 children who were infants at baseline and 5 to 6 years old at the last follow-up. Half had behavioral or cognitive needs at entry to school. About a quarter received outpatient mental health or special education services. Logistic regression showed that compared to children residing with biological parents, adopted and foster children were more likely to receive mental health services, and children adopted or in kinship care were more likely to receive educational services. Increased monitoring of behavioral and cognitive needs of infants reported for maltreatment may facilitate their access to services and ease the transition to school.
The Teaching-Family Model
Authors: De Wein Matthieu , Miller L. Keith
Published: April 2009

This article is a description of a program that may be effective for reducing the aggressive behaviors of adults with intellectual disabilities. Data are presented in the form of a naturally occurring multiple baseline across two participants. Results suggest that an intervention anchored in teaching-family model (TFM) procedures was effective to reduce the mean value of (a) physical aggression toward people or property and (b) verbal aggression. Quality-of-life data taken before and after participation in TFM indicated that quality of life improved for both participants. Social validity data indicated that parents, teachers, and employers were all highly satisfied with the program procedures and outcomes.
Coding Issues in Modality Analysis
Authors: Popping Roel , Roberts Carl W.
Published: April 2009

Ambiguous phrases are the bane of researchers' attempts to ensure acceptably high interrater agreement in the encoding of texts. When modal usages and their associated rationales are encoded as part of a text analysis, ambiguities arise in characteristic (and thus identifiable) ways. This article illustrates the typical sources of disagreement among coders involved in encoding data during a modality analysis and provides concrete strategies for improving interrater agreement.
IUHPE and social determinants of health: setting an action agenda
Authors: De Castro Freire Sara Bensaude , Manoncourt Erma , Mukhopadhyay Alok
Published: April 2009

This commentary introduces the recently created IUHPE Global Working Group (GWG) on Social Determinants of Health, which provides a unique opportunity to bring a global health promotion response to the social inequalities that result from the unequal distribution of the social determinants of health.

The two launch meetings of the GWG, which were held in the context of the conference `Closing the gap in a generation', enabled direct discussion and reaction with respect to the implementation of the WHO Commission on Social Determinants of Health's (CSDH) recommendations. Over the course of these meetings the group identified five main areas of work to specifically focus on over the next 18 months, leading to the 20th IUHPE World Conference on `Health, equity and sustainable development'. The discussions also facilitated the revision of the GWG's terms of reference, as presented in this commentary (Global Health Promotion, 2009; Supp (1): pp. 89—92)