bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of a participatory ergonomics intervention on psychosocial factors at work in a randomised controlled trial
Authors: Haukka Eija , Pehkonen Irmeli , Leino-Arjas Päivi , Viikari-Juntura Eira , Takala Esa-Pekka , Malmivaara Antti , Hopsu Leila , Mutanen Pertti , Ketola Ritva , Virtanen Tuija , Holtari-Leino Merja , Nykänen Jaana , Stenholm Sari , Ojajärvi Anneli , Riihimäki Hilkka 
Published: September 2009

ObjectivesTo study the effect of a participatory ergonomics intervention on psychosocial factors among kitchen workers.DesignA cluster randomised controlled trial.SettingFour cities in Finland, 2002–2005.Participants504 workers in 119 municipal kitchens.InterventionKitchens were randomised to intervention (n=59) and control (n=60) groups. The intervention lasted 11–14 months and was based on the workers' active participation in work analysis, planning and implementing the ergonomic changes aimed at decreasing the physical and mental workload.Main outcome measuresMental stress, mental strenuousness of work, hurry, job satisfaction, job control, skill discretion, co-worker relationships and supervisor support. Data were collected by questionnaire at baseline, at the end of the intervention, and at a 12-month follow-up (PI12).ResultsAt the end of the intervention, the OR of job dissatisfaction for the intervention group as compared with the control group was 3.0 (95% CI 1.1 to 8.5), of mental stress 2.3 (1.2 to 4.7) and of poor co-worker relationships 2.3 (1.0 to 5.2). At the PI12, the OR of job dissatisfaction was 3.0 (1.2 to 7.8). Analysis of the independent and joint effects of the intervention and unconnected organisational reforms showed that adverse changes were accentuated among those with exposure to both.ConclusionsNo favourable effects on psychosocial factors at work were found. The adverse changes were due to a joint effect of the intervention and the unconnected organisational reforms. The findings do not support the usefulness of this kind of intervention in changing unsatisfactory psychosocial working conditions.
Occupation and renal cell cancer in Central and Eastern Europe
Authors: Heck J E , Charbotel B , Moore L E , Karami S , Zaridze D G , Matveev V , Janout V , Kollárová H , Foretova L , Bencko V , Szeszenia-Dabrowska N , Lissowska J , Mates D , Ferro G , Chow W-H , Rothman N , Stewart P , Brennan P , Boffetta P 
Published: September 2009

Objective:Central and Eastern Europe has among the highest rates of renal cell cancer worldwide. Few studies have been conducted in these areas to investigate the possible role of occupational exposures in renal cell cancer aetiology. The purpose of this study was to examine the association of renal cell cancer with employment in specific occupations and industries.Methods:From 1999 to 2003, we conducted a hospital-based case-control study in seven areas of the Czech Republic, Poland, Romania and Russia. A detailed occupational history was collected from renal cell cancer cases and controls, together with information on potential confounders. Odds ratios (ORs) and 95% CI of cancer risk were calculated for having ever been employed in selected jobs and industries, with follow-up analyses examining duration of employment.Results:A total of 992 histologically confirmed incident renal cell cancer cases and 1459 controls were included in the analysis. An increased risk of renal cell cancer was observed for workers in agricultural labour and animal husbandry (OR 1.43; 95% CI 1.05 to 1.93), particularly among women employed as general farm workers (OR 2.73; 95% CI 1.05 to 7.13). Risk gradients for agricultural work increased with longer employment. An overall increased risk of renal cell cancer was seen among architects and engineers (OR 1.89; 95% CI 1.35 to 2.65), and mechanical engineers (OR 1.71; 95% CI 1.03 to 2.84).Conclusions:Our data suggest an association between renal cell cancer and agricultural work, particularly among female workers.
Tumor Vaccines Expressing Flt3 Ligand Synergize with CTLA-4 Blockade to Reject Preimplanted Tumors
Authors: Curran Michael A. , Allison James P. 
Published: September 2009

AbstractThe transformation of a healthy cell into a malignant neoplasm involves numerous genetic mutations and aberrations in gene expression. As few of these changes are shared between individuals or types of cancer, the best source for eliciting broad-spectrum tumor immunity remains each patient's own tumor. Previously, we have shown that combining blockade of the T-cell–negative costimulatory molecule CTL-associated antigen 4 (CTLA-4) and vaccination with irradiated B16 tumor expressing granulocyte macrophage colony-stimulating factor (GM-CSF; Gvax) promotes rejection of established murine melanomas. Here we show that, like GM-CSF, the cytokine Flt3 ligand (Flt3L) expressed in B16 and coupled with CTLA-4 blockade promotes both prophylactic and therapeutic rejection of B16. When administered at the site of growing tumor, Gvax fails to prevent tumor outgrowth in any mice, whereas the B16-Flt3L vaccine (Fl3vax) induces the rejection of 75% of melanomas implanted 3 days before vaccination. Relative to Gvax, Fl3vax promotes greater infiltration of both the vaccine site and the tumor site by CD8+ T cells and “sentinel” and plasmacytoid dendritic cells. Gvax and Fl3vax did not synergize when used in combination in treating B16 melanoma even in the context of CD25+ regulatory T-cell depletion. Further, we show that a combination of Flt3L expression and CTLA-4 blockade can also promote the rejection of established TRAMP prostate adenocarcinomas, proving that the utility of this treatment extends beyond melanoma. Engineering Flt3L to be constitutively secreted and attaching an IgG2a tail yielded a B16 vaccine that, when combined with CTLA-4 blockade, prevented the outgrowth of significantly more 5-day implanted B16-BL6 tumors than did Gvax. [Cancer Res 2009;69(19):7747–55]
Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development
Authors: Kim Woo-Young , Jin Quanri , Oh Seung-Hyun , Kim Edward S. , Yang Youn Joo , Lee Dong Hoon , Feng Lei , Behrens Carmen , Prudkin Ludmila , Miller York E. , Lee J. Jack , Lippman Scott M. , Hong Waun Ki , Wistuba Ignacio I. , Lee Ho-Young 
Published: September 2009

AbstractInsulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-I and IGF-II levels in bronchial tissue specimens containing high-grade dysplasia were significantly higher than in those containing normal epithelium, hyperplasia, and squamous metaplasia. Derivatives of human bronchial epithelial cell lines with activation mutation in KRAS(V12) or loss of p53 overexpressed IGF-I and IGF-II. The transformed characteristics of these cells were significantly suppressed by inactivation of IGF-IR or inhibition of IGF-I or IGF-II expression but enhanced by overexpression of IGF-IR or exposure to the tobacco carcinogens (TC) 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone and benzo(a)pyrene. We further determined the role of IGF-IR signaling in lung tumorigenesis by determining the antitumor activities of the selective IGF-IR tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine using an in vitro progressive cell system and an in vivo mouse model with a lung-specific IGF-I transgene after exposure to TCs, including 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone plus benzo(a)pyrene. Our results show that airway epithelial cells produce IGFs in an autocrine or paracrine manner, and these IGFs act jointly with TCs to enhance lung carcinogenesis. Furthermore, the use of selective IGF-IR inhibitors may be a rational approach to controlling lung cancer. [Cancer Res 2009;69(18):7439–48]
Advances in Ewing's Sarcoma Research: Where Are We Now and What Lies Ahead?
Authors: Ordóñez José Luis , Osuna Daniel , Herrero David , de Álava Enrique , Madoz-Gúrpide Juan 
Published: September 2009

Abstract
Ewing's sarcoma family tumors (EFT) are characterized by specific chromosomal translocations, which lead to EWS/ETS transcription factors. Elucidation of EWS/ETS target gene networks within the context of other signaling pathways, together with the identification of the initiating cell, and the development of genetically engineered mice will hopefully lead to biology-based therapeutic strategies for these tumors. [Cancer Res 2009;69(18):7140–50]
Insulin Receptor Substrate-1 Suppresses Transforming Growth Factor-β1–Mediated Epithelial-Mesenchymal Transition
Authors: Shi Jian , Wang Dong-Mei , Wang Chun-Mei , Hu Ying , Liu Ai-Hua , Zhang Yong-Lian , Sun Bing , Song Jian-Guo 
Published: September 2009

Abstract
We investigated the regulatory effect of insulin receptor substrate-1 (IRS-1) on transforming growth factor-β1 (TGF-β1)–induced epithelial-mesenchymal transition (EMT). TGF-β1–induced EMT and cell migration in A549 cells are associated with a decrease in IRS-1 tyrosine phosphorylation and protein levels. Tissue microarray analysis of human lung carcinoma shows a correlation between IRS-1 protein levels and E-cadherin protein levels. High IRS-1 levels coexist with high E-cadherin levels, whereas low IRS-1 levels coexist with low E-cadherin levels, implying a possibility that IRS-1 protein levels may be linked with EMT. Surprisingly, overexpression of IRS-1 in A549 cells completely blocked TGF-β1–induced EMT and cell migration, inhibited TGF-β1–mediated expression of snail and slug genes, and abolished TGF-β1–mediated repression of E-cadherin promoter activity. In contrast, IRS-1 knockdown by RNAi increased the expression of snail and slug genes and induced EMT. Inhibition of protein tyrosine phosphatase with sodium vanadate, which greatly increased the levels of tyrosine-phosphorylated IRS-1, suppressed TGF-β1–induced actin remodeling and cell morphologic changes. These results show for the first time that TGF-β1 induces EMT through mechanisms involving the modulation of IRS-1 signaling, and that IRS-1 functions as a critical EMT suppressor that suppresses TGF-β1–induced EMT via inhibition of snail and slug expression. [Cancer Res 2009;69(18):7180–7]
Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents
Authors: Shaked Yuval , Tang Terence , Woloszynek Jill , Daenen Laura G. , Man Shan , Xu Ping , Cai Shi-Rong , Arbeit Jeffrey M. , Voest Emile E. , Chaplin David J. , Smythe Jon , Harris Adrian , Nathan Paul , Judson Ian , Rustin Gordon , Bertolini Francesco , Link Daniel C. , Kerbel Robert S. 
Published: September 2009

Abstract
Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow–derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R−/− mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R−/− mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target. [Cancer Res 2009;69(19):7524–8]
Irradiation Alters Selection for Oncogenic Mutations in Hematopoietic Progenitors
Authors: Marusyk Andriy , Casás-Selves Matias , Henry Curtis J. , Zaberezhnyy Vadym , Klawitter Jelena , Christians Uwe , DeGregori James 
Published: September 2009

AbstractExposure to ionizing radiation and other DNA-damaging carcinogens is strongly associated with induction of malignancies. Prevailing paradigms attribute this association to the induction of oncogenic mutations, as the incidence of oncogenic events is thought to limit initiation and progression of cancers. On the other hand, random mutagenic and genotoxic effects of irradiation are likely to alter progenitor cell populations and the microenvironment, thus altering the selective effects of oncogenic mutations. Using competitive bone marrow transplantation experiments in mice, we show that ionizing irradiation leads to a persistent decline in the numbers and fitness of hematopoietic stem cells, in part resulting from persistent induction of reactive oxygen species. Previous irradiation dramatically alters the selective effects of some oncogenic mutations, substantially inhibiting clonal expansion and leukemogenesis driven by Bcr-Abl or activated N-Ras oncogenes but enhancing the selection for and leukemogenesis driven by the activated Notch1 mutant ICN. Irradiation-dependent selection for ICN expression occurs in a hematopoietic stem cell–enriched pool, which should facilitate the accumulation of additional oncogenic events at a committed T-progenitor stage critical for formation of T-lymphocytic leukemia stem cells. Enhancement of ICN-driven selection and leukemogenesis by previous irradiation is in part non–cell autonomous, as partial restoration of normal hematopoiesis can reverse these effects of irradiation. These studies show that irradiation substantially alters the adaptive landscape in hematopoietic progenitors and suggest that the causal link between irradiation and carcinogenesis might involve increased selection for particular oncogenic mutations. [Cancer Res 2009;69(18):7262–9]
The Receptor Tyrosine Kinase EPHB4 Has Tumor Suppressor Activities in Intestinal Tumorigenesis
Authors: Dopeso Higinio , Mateo-Lozano Silvia , Mazzolini Rocco , Rodrigues Paulo , Lagares-Tena Laura , Ceron Julian , Romero Jordi , Esteves Marielle , Landolfi Stefania , Hernández-Losa Javier , Castaño Julio , Wilson Andrew J. , Ramon y Cajal Santiago , Mariadason John M. , Schwartz Simo , Arango Diego 
Published: September 2009

Abstract
Colorectal cancer is the second cause of cancer-related death in the western world, and although the genetic and molecular mechanisms involved in the initiation and progression of these tumors are among the best characterized, there are significant gaps in our understanding of this disease. The role of EPHB signaling in colorectal cancer has only recently been realized. Here, we use animal models to investigate the role of EphB4 in intestinal tumorigenesis. Modulation of EPHB4 levels in colon cancer cell lines resulted in significant differences in tumor growth in a xenograft model, with low levels of EPHB4 associated with faster growth. In addition, using a genetic model of intestinal tumorigenesis where adenomatous polyposis coli (Apc) mutations lead to initiation of the tumorigenic process (Apcmin mice), we show that inactivation of a single allele of EphB4 results in higher proliferation in both the normal epithelium and intestinal tumors, significantly larger tumors in the small intestine, and a 10-fold increase in the number of tumors in the large intestine. This was associated with a 25% reduction in the lifespan of Apcmin mice (P &lt; 0.0001). Gene expression analysis showed that EphB4 mutations result in a profound transcriptional reprogramming, affecting genes involved in cell proliferation, remodeling of the extracellular matrix, and cell attachment to the basement membrane among other functional groups of genes. Importantly, in agreement with the expression profiling experiments, using an in vitro assay, we show that loss of EPHB4 in colon cancer cells results in a significantly increased potential to invade through a complex extracellular matrix. Collectively, these results indicate that EphB4 has tumor suppressor activities and that regulation of cell proliferation, extracellular matrix remodeling, and invasive potential are important mechanisms of tumor suppression. [Cancer Res 2009;69(18):7430–8]
BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells
Authors: Mani Mala , Carrasco Daniel E. , Zhang Yunyu , Takada Kohichi , Gatt Moshe E. , Dutta-Simmons Jui , Ikeda Hiroshi , Diaz-Griffero Felipe , Pena-Cruz Victor , Bertagnolli Monica , Myeroff Lois L. , Markowitz Sanford D. , Anderson Kenneth C. , Carrasco Daniel R. 
Published: September 2009

AbstractSeveral components of the Wnt signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances β-catenin–mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling. [Cancer Res 2009;69(19):7577–86]
c-Jun Protects Hypoxia-Inducible Factor-1α from Degradation via Its Oxygen-Dependent Degradation Domain in a Nontranscriptional Manner
Authors: Yu Bing , Miao Ze-Hong , Jiang Yi , Li Mei-Hong , Yang Na , Li Ting , Ding Jian 
Published: September 2009

Abstract
Although hypoxia-inducible factor-1α (HIF-1α) has long been intensively investigated as a drug target by interfering with its expression or transcriptional function, the regulatory mechanisms of HIF-1α remain to be further clarified. We report here that c-Jun associates with HIF-1α via its oxygen-dependent degradation domain, masks the sites for ubiquitination, and thus protects HIF-1α from proteasome-executing degradation. All of these together resulted in the stabilization and accumulation of HIF-1α, consequently promoting the transcription of its target gene and driving angiogenesis-related events. The stabilization of HIF-1α was dependent on the domains of c-Jun for DNA binding and heterodimerization but independent of the Ser63/73 phosphorylation that is critical for transcriptional function. These findings highlight a previously unrecognized nontranscriptional function of c-Jun on the one hand and a distinct regulatory mechanism of HIF-1α activity on the other, consequently offering profound mechanistic insights into multiple events simultaneously involving both c-Jun and HIF-1α in tumor progression. [Cancer Res 2009;69(19):7704–12]
A Genetic Variant of Aurora Kinase A Promotes Genomic Instability Leading to Highly Malignant Skin Tumors
Authors: Torchia Enrique C. , Chen Yiyun , Sheng Hong , Katayama Hiroshi , Fitzpatrick James , Brinkley William R. , Caulin Carlos , Sen Subrata , Roop Dennis R. 
Published: September 2009

Abstract
Aurora kinase A (Aurora-A) belongs to a highly conserved family of mitotis-regulating serine/threonine kinases implicated in epithelial cancers. Initially we examined Aurora-A expression levels at different stages of human skin cancer. Nuclear Aurora-A was detected in benign lesions and became more diffused but broadly expressed in well and poorly differentiated squamous cell carcinomas (SCC), indicating that Aurora-A deregulation may contribute to SCC development. To mimic the overexpression of Aurora-A observed in human skin cancers, we established a gene-switch mouse model in which the human variant of Aurora-A (Phe31Ile) was expressed in the epidermis upon topical application of the inducer RU486 (Aurora-AGS). Overexpression of Aurora-A alone or in combination with the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), did not result in SCC formation in Aurora-AGS mice. Moreover, Aurora-A overexpression in naive keratinocytes resulted in spindle defects in vitro and marked cell death in vivo, suggesting that the failure of Aurora-A to initiate tumorigenesis was due to induction of catastrophic cell death. However, Aurora-A overexpression combined with exposure to TPA and the mutagen 7,12-dimethylbenz(a)anthracene accelerated SCC development with greater metastastic activity than control mice, indicating that Aurora-A cannot initiate skin carcinogenesis but rather promotes the malignant conversion of skin papillomas. Further characterization of SCCs revealed centrosome amplification and genomic alterations by array CGH analysis, indicating that Aurora-A overexpression induces a high level of genomic instability that favors the development of aggressive and metastatic tumors. Our findings strongly implicate Aurora-A overexpression in the malignant progression of skin tumors and suggest that Aurora-A may be an important therapeutic target. [Cancer Res 2009;69(18):7207–15]
Epigenetic Loss of Mucosa-Associated Lymphoid Tissue 1 Expression in Patients with Oral Carcinomas
Authors: Chiba Tadashige , Maeda Genta , Kawashiri Shuichi , Kato Koroku , Imai Kazushi 
Published: September 2009

Abstract
Mucosa-associated lymphoid tissue 1 (MALT1), which is located in a genomic region that encodes unknown tumor suppressor gene(s), activates nuclear factor-κB in lymphocyte lineages. However, its expression and role in the pathology of malignant tumors of epithelial origin is not known. In the present study, we examined MALT1 expression and its implications for the pathology of oral carcinomas. Immunostaining localized MALT1 in the nucleus of normal oral epithelial cells, but the expression was absent in 45.0% of carcinomas (49 of 109 cases) especially at the invasive front. The loss of expression was correlated with tumor recurrence (P = 0.007) and poor patient survival (P &lt; 0.001), and it was an independent prognostic determinant (P &lt; 0.001). MALT1-negative carcinomas exhibited microsatellite instability at the MALT1 locus and a specific cytosine methylation positioned at −256 from the gene, and the expression was recovered by demethylation treatment. In contrast to lymphocyte lineages, carcinoma cells showed MALT1 located at the nucleus independent of its domain structures, and its loss of expression induced the epithelial-mesenchymal transition. These results show that MALT1 is expressed in the nucleus of oral epithelial cells and that its expression is epigenetically inactivated during tumor progression, suggesting that the detection of MALT1 expression is a useful predictive and prognostic determinant in the clinical management of oral carcinomas. [Cancer Res 2009;69(18):7216–23]