bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gemcitabine and Cytosine Arabinoside Cytotoxicity: Association with Lymphoblastoid Cell Expression
Authors: Li Liang , Fridley Brooke , Kalari Krishna , Jenkins Gregory , Batzler Anthony , Safgren Stephanie , Hildebrandt Michelle , Ames Matthew , Schaid Daniel , Wang Liewei 
Published: August 2008

AbstractTwo cytidine analogues, gemcitabine (dFdC) and 1-β-d-arabinofuranosylcytosine (AraC), show significant therapeutic effect in a variety of cancers. However, response to these drugs varies widely. Evidence from tumor biopsy samples shows that expression levels for genes involved in the cytidine transport, metabolism, and bioactivation pathway contribute to this variation in response. In the present study, we set out to test the hypothesis that variation in gene expression both within and outside of this “pathway” might influence sensitivity to gemcitabine and AraC. Specifically, Affymetrix U133 Plus 2.0 GeneChip and cytotoxicity assays were performed to obtain basal mRNA expression and IC50 values for both drugs in 197 ethnically defined Human Variation Panel lymphoblastoid cell lines. Genes with a high degree of association with IC50 values were involved mainly in cell death, cancer, cell cycle, and nucleic acid metabolism pathways. We validated selected significant genes by performing real-time quantitative reverse transcription-PCR and selected two representative candidates, NT5C3 (within the pathway) and FKBP5 (outside of the pathway), for functional validation. Those studies showed that down-regulation of NT5C3 and FKBP5 altered tumor cell sensitivity to both drugs. Our results suggest that cell-based model system studies, when combined with complementary functional characterization, may help to identify biomarkers for response to chemotherapy with these cytidine analogues. [Cancer Res 2008;68(17):7050–8]
EBV Is Necessary for Proliferation of Dually Infected Primary Effusion Lymphoma Cells
Authors: Mack Amanda A. , Sugden Bill 
Published: August 2008

Abstract
Epstein Barr virus (EBV) and Kaposi's sarcoma–associated herpesvirus (KSHV) are found together in ∼80% of primary effusion lymphomas (PEL), but their contribution to these cancers is unclear. We found that dominant-negative derivatives of EBNA1 inhibited EBV-positive PEL cells from forming colonies. Those rare PEL cells that proliferated after expression of the dominant-negative derivatives usually expressed these derivatives at low or undetectable levels and continued to maintain their EBV genomes. Those proliferating cells expressing higher levels of the derivatives expressed mutant derivatives that could not bind DNA. These findings indicate that EBV is required to sustain proliferation, as measured by colony formation of dually infected PEL cells. The dominant-negative derivatives of EBNA1 had no effect on the colony-forming ability of five EBV-negative, KSHV-negative hematopoietic cell lines. Surprisingly, they did inhibit the colony-forming ability of EBV-negative, KSHV-positive PEL cells. The small fraction of cells that continued to proliferate expressed only mutants of the EBNA1 derivatives that could no longer bind DNA. These findings indicate that the site-specific DNA-binding activity of EBNA1 or its derivatives when expressed efficiently in EBV-negative, KSHV-positive PEL cells inhibits their colony formation possibly through their binding to the KSHV genome. [Cancer Res 2008;68(17):6963–8]
Inhibition of Activated Fibroblast Growth Factor Receptor 2 in Endometrial Cancer Cells Induces Cell Death Despite PTEN Abrogation
Authors: Byron Sara A. , Gartside Michael G. , Wellens Candice L. , Mallon Mary A. , Keenan Jack B. , Powell Matthew A. , Goodfellow Paul J. , Pollock Pamela M. 
Published: August 2008

Abstract
KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type. [Cancer Res 2008;68(17):6902–7]
HEXIM1 Regulates 17β-Estradiol/Estrogen Receptor-α–Mediated Expression of Cyclin D1 in Mammary Cells via Modulation of P-TEFb
Authors: Ogba Ndiya , Chaplin Laura J. , Doughman Yong Qiu , Fujinaga Koh , Montano Monica M. 
Published: August 2008

Abstract
Estrogen receptor α (ERα) plays a key role in mammary gland development and is implicated in breast cancer through the transcriptional regulation of genes linked to proliferation and apoptosis. We previously reported that hexamethylene bisacetamide inducible protein 1 (HEXIM1) inhibits the activity of ligand-bound ERα and bridges a functional interaction between ERα and positive transcription elongation factor b (P-TEFb). To examine the consequences of a functional HEXIM1-ERα-P-TEFb interaction in vivo, we generated MMTV/HEXIM1 mice that exhibit mammary epithelial-specific and doxycycline-inducible expression of HEXIM1. Increased HEXIM1 expression in the mammary gland decreased estrogen-driven ductal morphogenesis and inhibited the expression of cyclin D1 and serine 2 phosphorylated RNA polymerase II (S2P RNAP II). In addition, increased HEXIM1 expression in MCF-7 cells led to a decrease in estrogen-induced cyclin D1 expression, whereas down-regulation of HEXIM1 expression led to an enhancement of estrogen-induced cyclin D1 expression. Studies on the mechanism of HEXIM1 regulation on estrogen action indicated a decrease in estrogen-stimulated recruitment of ERα, P-TEFb, and S2P RNAP II to promoter and coding regions of ERα-responsive genes pS2 and CCND1 with increased HEXIM1 expression in MCF-7 cells. Notably, increased HEXIM1 expression decreased only estrogen-induced P-TEFb activity. Whereas there have been previous reports on HEXIM1 inhibition of P-TEFb activity, our studies add a new dimension by showing that E2/ER is an important regulator of the HEXIM1/P-TEFb functional unit in breast cells. Together, these studies provide novel insight into the role of HEXIM1 and ERα in mammary epithelial cell function. [Cancer Res 2008;68(17):7015–24]
Chemoprevention and Treatment of Experimental Cowden's Disease by mTOR Inhibition with Rapamycin
Authors: Squarize Cristiane H. , Castilho Rogerio M. , Gutkind J. Silvio 
Published: August 2008

Abstract
Cowden's disease is an autosomal dominant disorder characterized by the development of multiple mucocutaneous lesions and benign tumors, and enhanced cancer predisposition. Most Cowden's disease patients harbor inactivating mutations in the PTEN tumor suppressor gene which encodes a lipid phosphatase, PTEN, which restrains the phosphatidylinositol 3-kinase–Akt signaling pathway. We observed that the epithelial-specific deletion of Pten in mice causes multiple hyperproliferative and tumor lesions that strikingly resemble Cowden's disease. This animal model system provided an opportunity to explore novel therapeutic approaches in Cowden's disease. Indeed, we show here that rapamycin administration, which inhibits a key downstream target of Akt, mammalian target of rapamycin (mTOR), promotes the rapid regression of advanced mucocutaneous lesions. Furthermore, when administered before disease manifestation, rapamycin can halt the development of Cowden's disease–like lesions, thereby prolonging animal survival. These findings suggest that mTOR inhibition with rapamycin may represent a suitable therapeutic option for the chemoprevention and treatment of Cowden disease patients and others tumor syndromes that involve defective PTEN function. [Cancer Res 2008;68(17):7066–72]
CREB3L2-PPARγ Fusion Mutation Identifies a Thyroid Signaling Pathway Regulated by Intramembrane Proteolysis
Authors: Lui Weng-Onn , Zeng Lingchun , Rehrmann Victoria , Deshpande Seema , Tretiakova Maria , Kaplan Edwin L. , Leibiger Ingo , Leibiger Barbara , Enberg Ulla , Höög Anders , Larsson Catharina , Kroll Todd G. 
Published: August 2008

Abstract
The discovery of gene fusion mutations, particularly in leukemia, has consistently identified new cancer pathways and led to molecular diagnostic assays and molecular-targeted chemotherapies for cancer patients. Here, we report our discovery of a novel CREB3L2-PPARγ fusion mutation in thyroid carcinoma with t(3;7)(p25;q34), showing that a family of somatic PPARγ fusion mutations exist in thyroid cancer. The CREB3L2-PPARγ fusion encodes a CREB3L2-PPARγ fusion protein that is composed of the transactivation domain of CREB3L2 and all functional domains of PPARγ1. CREB3L2-PPARγ was detected in &lt;3% of thyroid follicular carcinomas. Engineered overexpression of CREB3L2-PPARγ induced proliferation by 40% to 45% in primary human thyroid cells, consistent with a dominant oncogenic mechanism. Wild-type CREB3L2 was expressed in the thyroid as a bZIP transcription factor with a transmembrane domain that has flanking S1P and S2P proteolytic cleavage sites. Native CREB3L2 was cleaved to nuclear CREB3L2 by regulated intramembrane proteolysis in normal thyroid cells that expressed the S1P and S2P proteases. Nuclear CREB3L2 stimulated transcription 8-fold from the EVX1 cyclic AMP (cAMP) response element in the absence of cAMP, whereas CREB3L2-PPARγ inhibited transcription 6-fold from EVX1 in the same experiments. CREB3L2-PPARγ also inhibited 4-fold the expression of thyroglobulin, a native cAMP-responsive gene, in primary thyroid cells treated with thyroid-stimulating hormone. Our findings identify a novel CREB3L2-PPARγ gene fusion mutation in thyroid carcinoma and reveal a thyroid signaling pathway that is regulated by intramembrane proteolysis and disrupted in cancer. [Cancer Res 2008;68(17):7156–64]
BCR/ABL and Other Kinases from Chronic Myeloproliferative Disorders Stimulate Single-Strand Annealing, an Unfaithful DNA Double-Strand Break Repair
Authors: Cramer Kimberly , Nieborowska-Skorska Margaret , Koptyra Mateusz , Slupianek Artur , Penserga Emir Tyrone P. , Eaves Connie J. , Aulitzky Walter , Skorski Tomasz 
Published: August 2008

Abstract
Myeloproliferative disorders (MPD) are stem cell–derived clonal diseases arising as a consequence of acquired aberrations in c-ABL, Janus-activated kinase 2 (JAK2), and platelet-derived growth factor receptor (PDGFR) that generate oncogenic fusion tyrosine kinases (FTK), including BCR/ABL, TEL/ABL, TEL/JAK2, and TEL/PDGFβR. Here, we show that FTKs stimulate the formation of reactive oxygen species and DNA double-strand breaks (DSB) both in hematopoietic cell lines and in CD34+ leukemic stem/progenitor cells from patients with chronic myelogenous leukemia (CML). Single-strand annealing (SSA) represents a relatively rare but very unfaithful DSB repair mechanism causing chromosomal aberrations. Using a specific reporter cassette integrated into genomic DNA, we found that BCR/ABL and other FTKs stimulated SSA activity. Imatinib-mediated inhibition of BCR/ABL abrogated this effect, implicating a kinase-dependent mechanism. Y253F, E255K, T315I, and H396P mutants of BCR/ABL that confer imatinib resistance also stimulated SSA. Increased expression of either nonmutated or mutated BCR/ABL kinase, as is typical of blast phase cells and very primitive chronic phase CML cells, was associated with higher SSA activity. BCR/ABL-mediated stimulation of SSA was accompanied by enhanced nuclear colocalization of RAD52 and ERCC1, which play a key role in the repair. Taken together, these findings suggest a role of FTKs in causing disease progression in MPDs by inducing chromosomal instability through the production of DSBs and stimulation of SSA repair. [Cancer Res 2008;68(17):6884–8]
Illegitimate WNT Pathway Activation by β-Catenin Mutation or Autocrine Stimulation in T-Cell Malignancies
Authors: Groen Richard W.J. , Oud Monique E.C.M. , Schilder-Tol Esther J.M. , Overdijk Marije B. , ten Berge Derk , Nusse Roel , Spaargaren Marcel , Pals Steven T. 
Published: August 2008

AbstractRecent studies in mice have shown a role for the canonical WNT pathway in lymphocyte development. Because cancers often arise as a result of aberrant activation of signaling cascades that normally promote the self-renewal and expansion of their progenitor cells, we hypothesized that activation of the WNT pathway might contribute to the pathogenesis of lymphoproliferative disease. Therefore, we screened a large panel (n = 162) of non–Hodgkin lymphomas (NHL), including all major WHO categories, for nuclear expression of β-catenin, a hallmark of “active” WNT signaling. In 16 lymphomas, mostly of T-lineage origin, nuclear localization of β-catenin was detected. Interestingly, some of these tumors contained established gain-of-function mutations in the gene encoding β-catenin (CTNNB1); however, in the majority, mutations in either CTNNB1 or APC were not detected. Functional analysis of WNT signaling in precursor T-lymphoblastic lymphomas/leukemias, the NHL subset in which β-catenin accumulation was most prevalent (33% positive), revealed a constitutively activated, but still responsive, WNT pathway, which controlled T-cell factor–mediated gene transcription and cell growth. Our data indicate that activation of the WNT pathway, either by CTNNB1 mutation or autocrine stimulation, plays a role in the pathogenesis of a subset of NHLs, in particular, those of T-cell origin. [Cancer Res 2008;68(17):6969–77]
Complex Sequelae of Psychological Trauma Among Kosovar Civilian War Victims
Authors: Morina Nexhmedin , Ford Julian D. 
Published: August 2008

Aims: The impact of war trauma on civilians may include, but also extend beyond, post-traumatic stress disorder (PTSD) to include complex sequelae such as those described by the syndrome of Disorders of Extreme Stress Not Otherwise Specified (DESNOS). Methods: In the present study, 102 civilian war victims were interviewed in Kosovo, assessing traumatic life events, PTSD, DESNOS, and depression. Results: Full DESNOS rarely occurred (2% prevalence), however, clinically significant DESNOS symptoms of somatization, altered relationships, and altered systems of meaning were reported by between 24—42% of respondents. Although DESNOS symptoms were correlated with PTSD symptoms, DESNOS symptoms were associated with poorer overall psychological functioning, self-evaluations, satisfaction with life, and social support independent of the effects of PTSD. Conclusion: The findings suggest that DESNOS warrants attention in addition to PTSD in the assessment and treatment of civilians who have been exposed to war and genocide.
The Influence of Socio-Economic Conditions On the Prevalence of Depressive Symptoms and Its Covariates in an Elderly Population With Slight Income Differences: the Bambuí Health and Aging Study (Bhas)
Authors: Carvalhais S.M.M. , Lima-Costa M.F. , Peixoto S.V. , Firmo J.O.A. , Castro-Costa E. , Uchoa E. 
Published: August 2008

Background: The influence of socio-economic conditions on covariates of depression has received little attention. Aims: Examine whether prevalence and covariates of depressive symptoms are affected by socio-economic circumstances. Methods: Participants were 1,499 (86%) residents in Bambuí city, Brazil, aged ->- 60 years. Depressive symptoms were assessed by the GHQ-12 questionnaire and exploratory variables included demographic characteristics, life events, social support, health conditions and health service use. The analysis was stratified by family income (< US$240.00 [lowest tertile] vs. ->- US$240.00). Results: The prevalence of depressive symptoms was higher in those with lower income (43.9%) in comparison with the better off (27.7%). Dissatisfaction with relationships, worse self-rated health and insomnia were independently associated with depressive symptoms in both income groups (OR from 2.00 to 4.74; p < 0.05). Depressive symptoms were associated with number of chronic diseases, functional disability and hospitalizations among the poorer (OR from 1.73 to 2.37; p < 0.05), while old age (OR 2.08) and female gender (OR 2.03) were associated with depressive symptoms among the better off. Conclusion: This study provides evidence that the prevalence of depressive symptoms and their covariates are influenced by socio-economic conditions in a population with slight income differences.
General Mental Health, Quality of Life and Suicide-Related Attitudes Among Kurdish People in Iran
Authors: Mofidi N. , Ghazinour M. , Araste M. , Jacobsson L. , Richter J. 
Published: August 2008

Aim: To investigate (1) general mental health, (2) quality of life and (3) suicide-related attitudes in Kurds living in Iranian Kurdistan. Methods: Cross-sectional investigation; cluster random sampling procedure; 1,000 Kurds were randomly selected from 1,000 of 68,000 households in Sannandaj City, Iran; General Health Questionnaire (GHQ-12); Questionnaire on Attitudes Towards Suicide (ATTS). Results: About 27% of the subjects had to be regarded as probably suffering from a psychological disturbance. There was no gender difference regarding the number of `cases'. These possible `cases' were younger than `non-cases'. The most `cases' occurred among the unemployed. An increasing number of experiences related to suicide and the increasing emotional closeness of those experiences was found to be related to an increased probability that the individual would be classified as a `case' according to the GHQ-12 total score. Unmarried individuals more often evaluated their overall quality of life as `moderate' or `bad' compared to married individuals. Unemployed people, self-employed people and housewives formed the groups who most often reported a `very bad' or `bad' quality of life. Conclusions: Kurdish people in Iran are in need of facilities and interventional programmes aiming to improve general mental health.
Norhealth: Norwegian Health Information System
Authors: Trewin Cassie , Strand Bjørn Heine , Grøholt Else-Karin 
Published: August 2008

Norhealth (www.norgeshelsa.no) is a web-based health information system that monitors health and health related conditions, including risk- and protective factors, over time. Norhealth was developed to create a knowledge base for health promotion and prevention strategies in Norway and is targeted at politicians, decision makers, media, students and health professionals. Norhealth has a Norwegian and English version. Users of Norhealth can create their own tables, graphs, time series, maps and radar diagrams. Most Norhealth elements can be exported to PDF and tables can also be exported to Excel. Norhealth elements can also be pasted into Word or PowerPoint. Norhealth has 40 health indicators, but aims to reach 70. The indicator list corresponds roughly to the European Community Health Indicators (ECHI) short list. Data is presented at the national and regional level and by age group and gender. Around 50 fact sheets are written in Norwegian. Future developments include linking fact sheets to figures in Norhealth, writing annual health reports, translating fact sheets to English, improving user friendliness, adding more health indicators and monitoring social inequalities in health. Conclusions: Norhealth is an interactive web-based health information system that was developed to create a knowledge base for health promotion and prevention strategies in Norway.
Activating mutations in human acute megakaryoblastic leukemia
Authors: Malinge Sébastien , Ragu Christine , Della-Valle Veronique , Pisani Didier , Constantinescu Stefan N. , Perez Christelle , Villeval Jean-Luc , Reinhardt Dirk , Landman-Parker Judith , Michaux Lucienne , Dastugue Nicole , Baruchel André , Vainchenker William , Bourquin Jean-Pierre , Penard-Lacronique Virginie , Bernard Olivier A. 
Published: August 2008

Abstract
Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non–Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using BaF3 cells, showing that JAK3 mutations were activating mutations. Finally, we report a novel constitutively active MPL mutant, MPLT487A, observed in a non–Down syndrome childhood AMKL that induces a myeloproliferative disease in mouse bone marrow transplantation assay.
The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene
Authors: Wang Pin-Yi , Young Fay , Chen Chun-Yu , Stevens Brett M. , Neering Sarah J. , Rossi Randall M. , Bushnell Timothy , Kuzin Igor , Heinrich David , Bottaro Andrea , Jordan Craig T. 
Published: August 2008

Abstract
Recent reports have shown that upon expression of appropriate oncogenes, both stem cells and more differentiated progenitor populations can serve as leukemia-initiating cells. These studies suggest that oncogenic mutations subvert normal development and induce reacquisition of stem-like features. However, no study has described how specific mutations influence the ability of differentiating cell subsets to serve as leukemia-initiating cells and if varying such cellular origins confers a functional difference. We have examined the role of the tumor suppressor gene p19ARF in a murine model of acute lymphoblastic leukemia and found that loss of p19ARF changes the spectrum of cells capable of tumor initiation. With intact p19ARF, only hematopoietic stem cells (HSCs) can be directly transformed by BCR/ABL expression. In a p19ARF-null genetic background expression of the BCR/ABL fusion protein renders functionally defined HSCs, common lymphoid progenitors (CLP), and precursor B-lymphocytes competent to generate leukemia stem cells. Furthermore, we show that leukemias arising from p19ARF-null HSC versus pro-B cells differ biologically, including relative response to drug insult. Our observations elucidate a unique mechanism by which heterogeneity arises in tumor populations harboring identical genetic lesions and show that activity of p19ARF profoundly influences the nature of tumor-initiating cells during BCR/ABL-mediated leukemogenesis.