bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular Signal-Regulated Kinase Positively Regulates the Oncogenic Activity of MCT-1 in Diffuse Large B-Cell Lymphoma
Authors: Dai Bojie , Zhao X. Frank , Hagner Patrick , Shapiro Paul , Mazan-Mamczarz Krystyna , Zhao Shuchun , Natkunam Yasodha , Gartenhaus Ronald B. 
Published: September 2009

Abstract
The MCT-1 oncogene was originally identified from lymphoma cell lines. Herein we establish that MCT-1 is highly expressed in 85% of human diffuse large B-cell lymphomas (DLBCL) and that knocking down MCT-1 by a specific short hairpin RNA in DLBCL cells induces apoptosis, supporting a critical role for MCT-1 in DLBCL cell survival. However, the mechanism underlying MCT-1 regulation is largely unknown. We find that MCT-1 is phosphorylated and up-regulated by extracellular signal-regulated kinase (ERK). Furthermore, by using a small inhibitory molecule targeting ERK, we interrupted MCT-1 phosphorylation and stability. Significantly, cells with distinct levels of MCT-1 protein displayed differential sensitivity to ERK inhibitor–induced apoptosis. Treatment with the ERK inhibitor showed marked in vivo antitumor activity in a human DLBCL xenograft model. Our findings establish a functional molecular interaction between MCT-1 and the MEK/ERK signaling pathway and suggest that the activation of MCT-1 function by its upstream kinase ERK plays an important role in lymphomagenesis. [Cancer Res 2009;69(19):7835–43]
RAS Mutations Affect Tumor Necrosis Factor–Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits Along with Non-ERK Pathway Effects
Authors: Kreeger Pamela K. , Mandhana Roli , Alford Shannon K. , Haigis Kevin M. , Lauffenburger Douglas A. 
Published: September 2009

Abstract
More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-α (TNFα)–induced apoptosis. When the dynamics of phosphorylated ERK response to TNFα were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-α. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-α autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFα treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence. [Cancer Res 2009;69(20):8191–9]
Proinflammatory Mediators Upregulate Snail in Head and Neck Squamous Cell Carcinoma
Authors: St. John Maie A. , Dohadwala Mariam , Luo Jie , Wang Guanyu , Lee Gina , Shih Hubert , Heinrich Eileen , Krysan Kostantyn , Walser Tonya , Hazra Saswati , Zhu Li , Lai Chi , Abemayor Elliot , Fishbein Michael , Elashoff David A. , Sharma Sherven , Dubinett Steven M. 
Published: September 2009

Abstract
Purpose: Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1β (IL-1β) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC.
Experimental Design: We evaluated the effect of IL-1β on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression.
Results: Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1β caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1β–treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1β exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA–mediated knockdown of Snail interrupted the capacity of IL-1β to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens.
Conclusions: IL-1β modulates Snail and thereby regulates COX-2–dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy. (Clin Cancer Res 2009;15(19):6018–27)
Associations of a Polymorphism in the Ornithine Decarboxylase Gene with Colorectal Cancer Survival
Authors: Zell Jason A. , Ziogas Argyrios , Ignatenko Natalia , Honda Jane , Qu Ning , Bobbs Alexander S. , Neuhausen Susan L. , Gerner Eugene W. , Anton-Culver Hoda 
Published: September 2009

Abstract
Purpose: Activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is required for normal growth and is elevated in many cancers, including colorectal cancer. We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer–specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells.
Experimental Design: The study included 400 incident stage I-III colorectal cancer cases from the population-based University of California Irvine Gene-Environment Study of Familial Colorectal Cancer (diagnosed from 1994 to 1996 with follow-up through March 2008). The primary outcome was colorectal cancer–specific survival dependent on ODC1 (rs2302615) genotype (GG versus GA/AA). In human colon cancer cell lines, ODC1 allele-specific binding of E-box transcription factors was determined via Western blotting and chromatin immunoprecipitation assays. ODC1 allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MAD1.
Results: Genotype-specific survival differences were observed among colorectal cancer cases: compared with cases with the ODC1 GG genotype (hazards ratio, 1; reference) the adjusted colorectal cancer–specific survival hazards ratio was 2.02 (95% confidence interval, 1.17-3.50) for ODC1 GA/AA cases (P = 0.012). In colon cancer cells, the ODC1 SNP, flanked by two E-boxes, predicts ODC1 promoter activity. The E-box activator c-MYC and repressors MAD1 and MAD4 preferentially bind to ODC1 minor A-alleles, compared with major G-alleles, in cultured cells.
Conclusions: These results have implications for conditional regulation of polyamine homeostasis and suggest a model in which the ODC1 SNP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis. (Clin Cancer Res 2009;15(19):6208–16)
Lymph Node–Targeted Immunotherapy Mediates Potent Immunity Resulting in Regression of Isolated or Metastatic Human Papillomavirus–Transformed Tumors
Authors: Smith Kent A. , Meisenburg Brenna L. , Tam Victor L. , Pagarigan Robb R. , Wong Raymond , Joea Diljeet K. , Lantzy Liz , Carrillo Mayra A. , Gross Todd M. , Malyankar Uriel M. , Chiang Chih-Sheng , Da Silva Diane M. , Kündig Thomas M. , Kast W. Martin , Qiu Zhiyong , Bot Adrian 
Published: September 2009

Abstract
Purpose: The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic human papillomavirus 16–transformed murine tumors.
Experimental Design: Animals bearing E7-expressing tumors were coimmunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and antitumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease.
Results: In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen–specific T lymphocytes in the range of 1/10 CD8+ T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with antitumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T-cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization.
Conclusions: This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells. (Clin Cancer Res 2009;15(19):6167–76)
Blockade of MGMT Expression by O6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis
Authors: Konduri Santhi D. , Ticku Jonathan , Bobustuc George C. , Sutphin Robert M. , Colon Jimmie , Isley Beth , Bhakat Kishor K. , Kalkunte Srivenugopal S. , Baker Cheryl H. 
Published: September 2009

Abstract
Purpose: We sought to determine whether administration of a MGMT blocker, O6-benzyl guanine (O6BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth.
Experimental Design: Human pancreatic cancer L3.6pl and PANC1 cells were treated with O6BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated.
Results: O6BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O6BG. In sharp contrast, protein expression and mRNA message of p21cip1 were significantly increased. Interestingly, O6BG increases p53-mediated p21cip1 transcriptional activity and suppresses cyclin B1. In addition, our results indicate that p53 is recruited to p21 promoter. Furthermore, an increase in p21cip1 and a decrease in cyclin transcription are p53 dependent. The volume of pancreatic tumors was reduced by 27% in mice treated with gemcitabine alone, by 47% in those treated with O6BG alone, and by 65% in those mice given combination. Immunohistochemical analysis showed that O6BG inhibited expression of MGMT and cyclins, and increased expression of p21cip1. Furthermore, there was a significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis.
Conclusions: Collectively, our results show that decreased MGMT expression is correlated with p53 activation, and significantly reduced primary pancreatic tumor growth. These findings suggest that O6BG either alone or in combination with gemcitabine may provide a novel and effective approach for the treatment of human pancreatic cancer. (Clin Cancer Res 2009;15(19):6087–95)
Rapid Development of Hypertension by Sorafenib: Toxicity or Target?
Authors: Humphreys Benjamin D. , Atkins Michael B. 
Published: September 2009

Abstract
Blood pressure elevation is likely a pharmacodynamic marker of VEGF signaling pathway (VSP) inhibition and could be useful for optimizing safe and effective VSP inhibitor dosing. Blood pressure rises on the first day of treatment, facilitating design and interpretation of future trials aiming to correlate blood pressure changes with clinical outcomes. (Clin Cancer Res 2009;15(19):5947–9)
Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1α activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect
Authors: Lee Woo Hyung , Kim Young Woo , Choi Jae Hoon , Brooks Samuel Carroll , Lee Mi-Ock , Kim Sang Geon 
Published: September 2009

AbstractHypoxia-inducible factor-1α (HIF-1α) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1α, and the augmented HIF-1α activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1α activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1α expression through an increase in ubiquitination, thereby accelerating HIF-1α degradation and inhibiting HIF-1α–dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1α activity. CA-S6K1 overexpression reversed HIF-1α inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1α was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-α to restore the ability of insulin to increase HIF-1α against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H2O2 production, thereby preventing H2O2-enhanced HIF-1α expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1α activity and HIF-1α–dependent tumor growth, which may result from a decrease in HIF-1α stability through S6K1 inhibition in combination with an H2O2-scavenging effect. [Mol Cancer Ther 2009;8(10):2791–802]
Pharmacokinetics-pharmacodynamics and antitumor activity of mercaptoacetamide-based histone deacetylase inhibitors
Authors: Konsoula Zacharoula , Cao Hong , Velena Alfredo , Jung Mira 
Published: September 2009

Abstract
Structurally diverse histone deacetylase inhibitors (HDACI) have emerged as chemotherapeutic agents. Here, we report the first mercaptoacetamide HDACIs (coded 6MAQH and 5MABMA) for use in treatment against prostate cancer cells in vitro and in vivo and correlate their plasma pharmacokinetics and tissue-pharmacodynamics with tumor sensitivity. HDACIs were assessed for in vitro microsomal stability and growth inhibition against prostate cancer and nonmalignant cells. Antitumor activity was determined following i.p. administration of 6MAQH and 5MABMA (0.5 and 5 mg/Kg) using mice bearing PC3 tumor xenografts (n = 10). The plasma pharmacokinetics of 6MAQH and 5MABMA and their effects on the acetylation of histone H4 in tissues were determined in athymic mice. Both HDACIs significantly inhibited the growth of cancer cells while exerting limited effect on nonmalignant cells. They exhibited stability in human, dog, and rat microsomes [t1/2 (min) = 83, 72, and 66 for 6MAQH and 68, 43, and 70 for 5MABMA, respectively]. Both HDACIs (0.5 mg/Kg) led to tumor regression (P &lt; 0.01), which was sustained for at least 60 days. In vivo data show favorable plasma pharmacokinetics with the area under the curve of 4.97 ± 0.6 μmol/L × h for 6MAQH and 4.23 ± 0.43 μmol/L × h for 5MABMA. The clearance rates for 6MAQH and 5MABMA were 4.05 ± 0.15 and 4.87 ± 0.2 L/h, whereas the half-lives were 2.2 ± 0.33 and 1.98 ± 0.21 h, respectively. Both HDACIs markedly enhanced the acetylation of histone H4 within 30 minutes in tissues, including the brain, liver, and spleen. Taken together, the results provide a rationale for further investigation of these mercaptoacetamide HDACIs as potent anticancer agents. [Mol Cancer Ther 2009;8(10):2844–51]
A Model of Gene-Environment Interaction Reveals Altered Mammary Gland Gene Expression and Increased Tumor Growth following Social Isolation
Authors: Williams J. Bradley , Pang Diana , Delgado Bertha , Kocherginsky Masha , Tretiakova Maria , Krausz Thomas , Pan Deng , He Jane , McClintock Martha K. , Conzen Suzanne D. 
Published: September 2009

Abstract
Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a preclinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the premalignant mammary gland. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic pathway gene expression—both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer.
Genre without a Name: Was There a Hebrew Term for “Apocalypse”?
Authors: Kulik Alexander 
Published: September 2009

AbstractAlthough the term for “apocalypse” is not attested as a title or genre definition in the extant corpus of Hebrew or Jewish Aramaic documents, some early Hebrew, Syriac, and Arabic texts may contain rudimentary evidence in favor of the existence of a Hebrew or Jewish Aramaic equivalent for the term. Moreover, its reconstruction can contribute to better understanding of certain wide spread apocalyptic imagery, which must be closely connected to the semantics of this term.
Partisan Thought
Authors: Toscano Alberto 
Published: September 2009

AbstractWhat is the relationship between materialism and partisanship today? Starting with an outline of the elements of Lenin's understanding of the partisan character of truth, this intervention outlines some of the challenges posed to a Marxist understanding of partisanship by the influential positions of Michel Foucault and Carl Schmitt, as well as by the recent turn to vitalism and complexity in social theory. On the basis of the confrontation between a Leninist conception of materialist partisanship and its contemporary challengers, the article considers Alain Badiou's recent attempt to revive a 'materialist dialectic' in order to think through the present conditions for formulating a partisan and universalist conception of political truth that would not collapse into mere partiality or outright dogmatism.
Why Did Latife Cover Her Hair?
Authors: Bakan Birol 
Published: September 2009

AbstractThis paper uncovers the Orientalist assumptions dominating studies of Ataturk reforms as to women's rights in Turkey and proposes an alternative approach, which drops messianic approach to Ataturk reforms and calls for situating them within a broader historical strategic context. It argues that Ataturk's clique was one of the many contenders competing for political power in post-WWI Turkey. In an effort to pacify and eliminate its opponents, the political regime pursued a policy of corporatist regime construction, by which no autonomous social institution was left alone. Such a reading of early Republican history suggests that granting women certain rights was part of authoritarian regime consolidation. This essay argues the case further; suggesting that being contained within an authoritarian regime caused the nascent feminist movement to lose its potential to reach to broader women groups in Turkey.
Inexpensive Time-Lapse Digital Cameras for Studying Transient Meteorological Phenomena: Dust Devils and Playa Flooding
Authors: Lorenz Ralph D. , Jackson Brian , Barnes Jason W. 
Published: September 2009

Abstract
The authors describe the design and performance of inexpensive and compact time-lapse cameras suitable for field deployment in remote locations for long periods and their application to studying two time-variable meteorological phenomena in arid regions: desert dust devils and transient flooding of playa lakes. The camera units (with a total parts cost of ∼$80) are based around commercial “point and shoot” digital cameras, storing ∼1500 images on a solid-state memory card over a period between an hour to several months powered by alkaline batteries. A microcontroller can trigger image acquisition based on sensor inputs or at regular intervals. Some example results are presented, showing an association of cumulus clouds with thermals from dust devils, a region of dust enhancement around a dust devil, and a dramatic range of conditions at Racetrack Playa in Death Valley National Park. Alternative systems and applications are also discussed.