bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study
Authors: Dick F D , De Palma G , Ahmadi A , Scott N W , Prescott G J , Bennett J , Semple S , Dick S , Counsell C , Mozzoni P , Haites N , Wettinger S Bezzina , Mutti A , Otelea M , Seaton A , Söderkvist P , Felice A 
Published: March 2007

Objective:To investigate the associations between Parkinson’s disease and other degenerative parkinsonian syndromes and environmental factors in five European countries.Methods:A case–control study of 959 prevalent cases of parkinsonism (767 with Parkinson’s disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson’s Disease Society Brain Bank criteria, and those with drug-induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer-administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job-exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson’s disease.Results:Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson’s disease/parkinsonism with an exposure–response relationship for pesticides (low vs no exposure, odds ratio (OR) = 1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR = 1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR = 1.35, 95% CI 1.09 to 1.68, more than once vs never, OR = 2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson’s disease showed significantly increased odds ratios. Tobacco use was protective (OR = 0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson’s disease gave similar results.Conclusions:The association of pesticide exposure with Parkinson’s disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.
Decline in lung function and mortality: implications for medical monitoring
Authors: Sircar Kanta , Hnizdo Eva , Petsonk Edward , Attfield Michael 
Published: March 2007

Aim:To investigate the risk of death associated with selected cut-off points for rate of decline of forced expiratory volume in one second (FEV1).Methods:Mortality rates of a cohort of 1730 coal miners who had performed two pulmonary function tests 12.8 years apart were followed up for an additional 12 years. Based on previous studies, cut-off points for FEV1rate of decline (ml/year) were selected as 30, 60 and 90 ml/year. Cox proportional hazard regression was used to estimate multivariate risk ratio of death in each category.Results:The risk ratios (compared to “below 30 ml/year”) were 1.39 (95% CI 0.99 to 1.97) in the “60 to less than 90 ml/year” category and 1.90 (95% CI 1.32 to 2.76) in the “90 ml/year and above” category. Rates of decline above 90 ml/year were consistently related to excess mortality. In non-smokers and those with neither restrictive nor obstructive patterns at the first survey, rates of decline above 60 ml/year were significantly associated with increased mortality.Conclusions:Risk of death increases in individuals with rates of decline above about 60 ml/year and is statistically significant with declines of 90 ml/year or more. These results should be useful to healthcare providers in assessing lung function declines observed in individuals.
Characteristics of metabolically obese normal-weight (MONW) subjects
Authors: Conus Florence , Rabasa-Lhoret Rémi , Péronnet François 
Published: March 2007

The existence of a subgroup of normal-weight individuals displaying obesity-related phenotypic characteristics was first proposed in 1981. These individuals were identified as metabolically obese but normal weight (MONW). It was hypothesized that these individuals might be characterized by hyperinsulinemia and (or) insulin resistance, as well as by hypertriglyceridemia and high blood pressure despite having a body mass index (BMI) < 25 kg/m2. Such characteristics could confer upon MONW subjects a higher cardiovascular risk; however, scientific data on MONW subjects are scarce since only 9 publications are directly related to this topic. Despite differences in the criteria for identifying MONW subjects and the small number of subjects involved in most of these studies, their consistent results indicate that: (i) the prevalence of the MONW syndrome ranges between 5% and 45%, depending on the criteria used, age, BMI, and ethnicity; (ii) when compared with control subjects, MONW subjects display an altered insulin sensitivity, a higher abdominal and visceral adiposity, a more atherogenic lipid profile, a higher blood pressure, and a lower physical activity energy expenditure; and (iii) MONW subjects are at higher risks for type 2 diabetes and cardiovascular diseases.
RIL, a LIM Gene on 5q31, Is Silenced by Methylation in Cancer and Sensitizes Cancer Cells to Apoptosis
Authors: Boumber Yanis A. , Kondo Yutaka , Chen Xuqi , Shen Lanlan , Gharibyan Vazganush , Konishi Kazuo , Estey Elihu , Kantarjian Hagop , Garcia-Manero Guillermo , Issa Jean-Pierre J. 
Published: March 2007

Abstract
Gene silencing associated with promoter methylation can inactivate tumor suppressor genes (TSG) in cancer. We identified RIL, a LIM domain gene mapping to 5q31, a region frequently deleted in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), as methylated in 55 of 79 (70%) of cancer cell lines tested. In a variety of primary tumors, we found RIL methylation in 55 of 92 (60%) cases, with highest methylation in AML and colon cancer, and in 30 of 83 (36%) MDS samples, whereas normal tissues showed either absence or substantially lower levels of methylation, which correlates with age. RIL is ubiquitously expressed but silenced in methylated cancers and could be reactivated by the hypomethylating agent 5-aza-2′-deoxycytidine. Restoring RIL expression in colon cancer cells by stable transfection resulted in reduced cell growth and clonogenicity and an ∼2.0-fold increase in apoptosis following UV exposure. In MDS, RIL methylation is a marker of adverse prognosis independent of chromosome 5 and 7 deletions. Our data suggest that RIL is a good candidate TSG silenced by hypermethylation in cancer. [Cancer Res 2007;67(5):1997–2005]
Attenuation of the Glucocorticoid Response during Ad5IL-12 Adenovirus Vector Treatment Enhances Natural Killer Cell–Mediated Killing of MHC Class I–Negative LNCaP Prostate Tumors
Authors: Raja Gabaglia Claudia , Diaz de Durana Yaiza , Graham Frank L. , Gauldie Jack , Sercarz Eli E. , Braciak Todd A. 
Published: March 2007

AbstractTumor cells can evolve to evade immune responses by down-modulating surface MHC class I expression and become refractory to T cell–directed immunotherapy. We employed a strategy to bypass this escape mechanism using a recombinant adenovirus vector expressing interleukin-12 (Ad5IL-12) to target natural killer (NK) cell–mediated killing of human prostate tumors in NOD.scid mice. Fluorescence-activated cell sorting analysis revealed that LNCaP tumor cells bear negligible levels of MHC class I molecules; yet, they express MICA/B molecules, ligands for the NKG2D receptors found on NK cells. Transduction of LNCaP cells with the Ad5IL-12 vector prevented tumor formation in NOD.scid mice, indicating that NK cells alone can conduct tumor immunosurveillance and mediate protection. Intratumor injection of the Ad5IL-12 vector to established LNCaP tumors in NOD.scid mice resulted in a significant delay of tumor growth mediated by NK cell killing activity. The dependency of NK cells in this protective response was shown by the complete loss of Ad5IL-12 therapeutic efficacy on LNCaP tumors established in NOD.Cg-Rag1tm1MomPrf1tm1Sdz congenic mice, which are devoid of NK cell activity. More pronounced attenuation of tumor growth and enhanced NK killing activity was observed when pharmacologic adrenalectomy with mitotane was done in combination with Ad5IL-12 vector treatment. The Ad5IL-12 vector treatment also induced killing of MICA/B-negative MHC class I–positive PC3 tumors formed in NOD.scid mice. Together, these results indicate that a targeted NK cell response could provide a generic approach for cancer immunotherapy, and that enhancing the NK cell response via control of cortisol levels may provide an additional therapeutic avenue in cancer. [Cancer Res 2007;67(5):2290–7]
In vitro Biological Characterization of a Novel, Synthetic Diaryl Pyrazole Resorcinol Class of Heat Shock Protein 90 Inhibitors
Authors: Sharp Swee Y. , Boxall Kathy , Rowlands Martin , Prodromou Chrisostomos , Roe S. Mark , Maloney Alison , Powers Marissa , Clarke Paul A. , Box Gary , Sanderson Sharon , Patterson Lisa , Matthews Thomas P. , Cheung Kwai-Ming J. , Ball Karen , Hayes Angela , Raynaud Florence , Marais Richard , Pearl Laurence , Eccles Sue , Aherne Wynne , McDonald Edward , Workman Paul 
Published: March 2007

Abstract
The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting molecular target. Derivatives of the natural product geldanamycin, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), were the first HSP90 ATPase inhibitors to enter clinical trial. Synthetic small-molecule HSP90 inhibitors have potential advantages. Here, we describe the biological properties of the lead compound of a new class of 3,4-diaryl pyrazole resorcinol HSP90 inhibitor (CCT018159), which we identified by high-throughput screening. CCT018159 inhibited human HSP90β with comparable potency to 17-AAG and with similar ATP-competitive kinetics. X-ray crystallographic structures of the NH2-terminal domain of yeast Hsp90 complexed with CCT018159 or its analogues showed binding properties similar to radicicol. The mean cellular GI50 value of CCT018159 across a panel of human cancer cell lines, including melanoma, was 5.3 μmol/L. Unlike 17-AAG, the in vitro antitumor activity of the pyrazole resorcinol analogues is independent of NQO1/DT-diaphorase and P-glycoprotein expression. The molecular signature of HSP90 inhibition, comprising increased expression of HSP72 protein and depletion of ERBB2, CDK4, C-RAF, and mutant B-RAF, was shown by Western blotting and quantified by time-resolved fluorescent-Cellisa in human cancer cell lines treated with CCT018159. CCT018159 caused cell cytostasis associated with a G1 arrest and induced apoptosis. CCT018159 also inhibited key endothelial and tumor cell functions implicated in invasion and angiogenesis. Overall, we have shown that diaryl pyrazole resorcinols exhibited similar cellular properties to 17-AAG with potential advantages (e.g., aqueous solubility, independence from NQO1 and P-glycoprotein). These compounds form the basis for further structure-based optimization to identify more potent inhibitors suitable for clinical development. [Cancer Res 2007;67(5):2206–16]
Systemic Stromal Effects of Estrogen Promote the Growth of Estrogen Receptor–Negative Cancers
Authors: Gupta Piyush B. , Proia David , Cingoz Oya , Weremowicz Janusz , Naber Stephen P. , Weinberg Robert A. , Kuperwasser Charlotte 
Published: March 2007

Abstract
Numerous hormonal factors contribute to the lifetime risk of breast cancer development. These include inherited genetic mutations, age of menarche, age of menopause, and parity. Inexplicably, there is evidence indicating that ovariectomy prevents the formation of both estrogen receptor (ER)–positive and ER-negative breast cancers, suggesting that ER-negative breast cancers are dependent on ovarian hormones for their formation. To examine the mechanism(s) by which this may be occurring, we investigated the hypothesis that steroid hormones promote the outgrowth of ER-negative cancers by influencing host cell types distinct from the mammary epithelial cells. We used a novel xenograft mouse model of parturition-induced breast carcinoma formation, in which the tumors that arise following pregnancy lack the expression of nuclear hormone receptors, thereby recapitulating many clinical cases of this disease. Despite lacking ER expression, the tumors arising following pregnancy in this model require circulating estrogens for their formation. Moreover, increasing the levels of circulating estrogens sufficed to promote the formation and progression of ER-negative cancers, which was accompanied by a systemic increase in host angiogenesis and was attendant with the recruitment of bone marrow–derived stromal cells. Furthermore, bone marrow cells from estrogen-treated mice were sufficient to promote tumor growth. These results reveal a novel mechanism by which estrogens promote the growth of ER-negative cancers. [Cancer Res 2007;67(5):2062–71]
Inhibition of CXCR4-Mediated Breast Cancer Metastasis: A Potential Role for Heparinoids?
Authors: Harvey James R. , Mellor Paul , Eldaly Hesham , Lennard Thomas W.J. , Kirby John A. , Ali Simi 
Published: March 2007

AbstractPurpose: The pattern of breast cancer metastasis may be determined by interactions between CXCR4 on breast cancer cells and CXCL12 within normal tissues. Glycosaminoglycans bind chemokines for presentation to responsive cells. This study was designed to test the hypothesis that soluble heparinoid glycosaminoglycan molecules can disrupt the normal response to CXCL12, thereby reducing the metastasis of CXCR4-expressing cancer cells.Experimental Design: Inhibition of the response of CXCR4-expressing Chinese hamster ovary cells to CXCL12 was assessed by measurement of calcium flux and chemotaxis. Radioligand binding was also assessed to quantify the potential of soluble heparinoids to prevent specific receptor ligation. The human breast cancer cell line MDA-MB-231 and a range of sublines were assessed for their sensitivity to heparinoid-mediated inhibition of chemotaxis. A model of hematogenous breast cancer metastasis was established, and the potential of clinically relevant doses of heparinoids to inhibit CXCL12 presentation and metastatic disease was assessed.Results: Unfractionated heparin and the low-molecular-weight heparin tinzaparin inhibited receptor ligation and the response of CXCR4-expressing Chinese hamster ovary cells and human breast cancer cell lines to CXCL12. Heparin also removed CXCL12 from its normal site of expression on the surface of parenchymal cells in the murine lung. Both heparin and two clinically relevant dose regimens of tinzaparin reduced hematogenous metastatic spread of human breast cancer cells to the lung in a murine model.Conclusions: Clinically relevant concentrations of tinzaparin inhibit the interaction between CXCL12 and CXCR4 and may be useful to prevent chemokine-driven breast cancer metastasis.
Translating Expression Profiling into a Clinically Feasible Test to Predict Neuroblastoma Outcome
Authors: Schramm Alexander , Vandesompele Jo , Schulte Johannes H. , Dreesmann Sabine , Kaderali Lars , Brors Benedikt , Eils Roland , Speleman Frank , Eggert Angelika 
Published: March 2007

Abstract
Purpose: To assess the feasibility of predicting neuroblastoma outcome using highly parallel quantitative real-time PCR data.
Experimental Design: We generated expression profiles of 63 neuroblastoma patients, 47 of which were analyzed by both Affymetrix U95A microarrays and highly parallel real-time PCR on microfluidic cards (MFC; Applied Biosystems). Top-ranked genes discriminating patients with event-free survival or relapse according to high-level analysis of Affymetrix chip data, as well as known neuroblastoma marker genes (MYCN and NTRK1/TrkA), were quantified simultaneously by real-time PCR. Analysis of PCR data was accomplished using high-level bioinformatics methods including prediction analysis of microarray, significance analysis of microarray, and Computerized Affected Sibling Pair Analyzer and Reporter.
Results: Internal validation of the MFC method proved it highly reproducible. Correlation of MFC and chip expression data varied markedly for some genes. Outcome prediction using prediction analysis of microarray on real-time PCR data resulted in 80% accuracy, which is comparable to results obtained using the Affymetrix platform. Real-time PCR data were useful for risk assessment of relapsing neuroblastoma (P = 0.0006, log-rank test) when Computerized Affected Sibling Pair Analyzer and Reporter analysis was applied.
Conclusions: These data suggest that multiplex real-time PCR might be a promising approach to reduce the complexity of information obtained from whole-genome array experiments. It could provide a more convenient and less expensive tool for routine application in a clinical setting.
Virus-Associated Tumor Imaging by Induction of Viral Gene Expression
Authors: Fu De-Xue , Tanhehco Yvette C. , Chen Jianmeng , Foss Catherine A. , Fox James J. , Lemas Victor , Chong Ja-Mun , Ambinder Richard F. , Pomper Martin G. 
Published: March 2007

Abstract
Purpose: EBV and other herpesviruses are associated with a variety of malignancies. The EBV thymidine kinase (TK) is either not expressed or is expressed at very low levels in EBV-associated tumors. However, EBV-TK expression can be induced in vitro with several chemotherapeutic agents that promote viral lytic induction. The goal of this study is to image EBV-associated tumors by induction of viral TK expression with radiolabeled 2′-fluoro-2′-deoxy-β-d-5-iodouracil-arabinofuranoside (FIAU).
Experimental Design: Immunoblot, luciferase reporter assay, and in vitro assay with [14C]FIAU were used to show the effects of bortezomib on the induction of lytic gene expression of EBV-associated tumor cells. In vivo imaging and ex vivo biodistribution studies with [125I]FIAU on EBV-associated tumors were done to visualize and confirm, respectively, the EBV(+) tumor–specific effects of bortezomib.
Results: In vitro assays with [14C]FIAU and ex vivo biodistribution studies with [125I]FIAU showed that uptake and retention of radiolabeled FIAU was specific for cells that express EBV-TK. Planar gamma imaging of EBV(+) Burkitt's lymphoma xenografts in severe combined immunodeficient mice showed [125I]FIAU localization within tumors following treatment with bortezomib.
Conclusions: These results indicate the feasibility of imaging chemotherapy-mediated viral lytic induction by radiopharmaceutical-based techniques such as single photon emission computed tomography and positron emission tomography.
Brain Activation for Lexical Decision and Reading Aloud: Two Sides of the Same Coin?
Authors: Carreiras Manuel , Mechelli Andrea , Estévez Adelina , Price Cathy J. 
Published: March 2007

Abstract
This functional magnetic resonance imaging study compared the neuronal implementation of word and pseudoword processing during two commonly used word recognition tasks: lexical decision and reading aloud. In the lexical decision task, participants made a finger-press response to indicate whether a visually presented letter string is a word or a pseudoword (e.g., “paple”). In the reading-aloud task, participants read aloud visually presented words and pseudowords. The same sets of words and pseudowords were used for both tasks. This enabled us to look for the effects of task (lexical decision vs. reading aloud), lexicality (words vs. nonwords), and the interaction of lexicality with task. We found very similar patterns of activation for lexical decision and reading aloud in areas associated with word recognition and lexical retrieval (e.g., left fusiform gyrus, posterior temporal cortex, pars opercularis, and bilateral insulae), but task differences were observed bilaterally in sensorimotor areas. Lexical decision increased activation in areas associated with decision making and finger tapping (bilateral postcentral gyri, supplementary motor area, and right cerebellum), whereas reading aloud increased activation in areas associated with articulation and hearing the sound of the spoken response (bilateral precentral gyri, superior temporal gyri, and posterior cerebellum). The effect of lexicality (pseudoword vs. words) was also remarkably consistent across tasks. Nevertheless, increased activation for pseudowords relative to words was greater in the left precentral cortex for reading than lexical decision, and greater in the right inferior frontal cortex for lexical decision than reading. We attribute these effects to differences in the demands on speech production and decision-making processes, respectively.
An Event-related fMRI Study of Exogenous Facilitation and Inhibition of Return in the Auditory Modality
Authors: Mayer Andrew R. , Harrington Deborah L. , Stephen Julia , Adair John C. , Lee Roland R. 
Published: March 2007

Abstract
The orienting of attention to different locations in space is fundamental to most organisms and occurs in all sensory modalities. Orienting has been extensively studied in vision, but to date, few studies have investigated neuronal networks underlying automatic orienting of attention and inhibition of return to auditory signals. In the current experiment, functional magnetic resonance imaging and behavioral data were collected while healthy volunteers performed an auditory orienting task in which a monaurally presented tone pip (cue) correctly or incorrectly cued the location of a target tone pip. The stimulus onset asynchrony (SOA) between the cue and target was 100 or 800 msec. Behavioral results were consistent with previous studies showing that valid auditory cues produced facilitation at the short SOA and inhibition of return at the long SOA. Functional results indicated that the reorienting of attention (100 msec SOA) and inhibition of return (800 msec SOA) were mediated by both common and distinct neuronal structures. Both attention mechanisms commonly activated a network consisting of fronto-oculomotor areas, the left postcentral gyrus, right premotor area, and bilateral tonsil of the cerebellum. Several distinct areas of frontal and parietal activation were identified for the reorienting condition, whereas the right inferior parietal lobule was the only structure uniquely associated with inhibition of return.