bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractChromosomal 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

AbstractDiets 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

Abstract
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

AbstractPurpose: 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

Abstract
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 &gt;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 &lt; 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 &lt; 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

AbstractPurpose: 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

AbstractPurpose: 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

Abstract
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

Abstract
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

AbstractPurpose: 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

Abstract
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 &lt; 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.