bluuebunny/crossref_metadata_2025 huggingface dataset:
Regionalizing global trade patterns, 1981–2001: application of a new method
Authors: ANDRESEN MARTIN A.
Published: February 2009

This paper investigates the establishment of trading regions in the global economy at the national level using a measure of trade intensity and a regional assignment algorithm that generates economically meaningful trading regions. Although there is definite regionalization in the global economy with regard to international trade, there is no evidence of an increase in the concentration of that regionalization over time. The geography of international trade is incredibly dynamic, with change related to political, historical and economic forces. Overall, trading regions have relatively few members and are increasingly a set of geographically close countries.
Rural children's perceptions of life on the land in Southwestern Ontario
Authors: CUMMINS HELENE
Published: February 2009

What are the life experiences of farm children in rural southwestern Ontario? Within the rural sociological literature, little research has been undertaken on the geographies of Canadian children in rural settings. Play, leisure, work and future aspirations are important to their lives. However, little is known about these issues and children's use of space and place on the farm. This study focuses on these issues from the point of view of the child and examines how gender, age and socialization processes work together with agrarianism to frame the lifeworlds of these children. In general, these children do not aspire to farm in the future, but are interested in future residence in the country. They value the way of life to be found in farming but some experience loneliness on the farm. For farm children, space and farm animals act as comfort in their lives and make for unique experiences.
Political geography and geopolitics
Authors: KUUS MERJE
Published: February 2009

This essay discusses the key contributions of Canadian political geographers to the remarkable growth of the subfield in the past two decades. I focus on two burgeoning strands of work: first, the transformation of state power, and second, the current phase of war, militarization and surveillance globally. My goal is not to review the field of political geography. Rather, I use the two themes to foreground prominent strands of recent work and delineate some lines of inquiry that require more attention and are likely to grow in importance. In particular, I underscore the need for closer attention to human agency—that is, capacity to act—in political geography and geopolitics.
Gendered Power in Cultural Contexts: Part II. Middle Class African American Heterosexual Couples with Young Children
Authors: COWDERY RANDI S. , SCARBOROUGH NORMA , KNUDSON‐MARTIN CARMEN , SESHADRI GITA , LEWIS MONIQUE E. , MAHONEY ANNE RANKIN
Published: February 2009

When race and gender intersect, understanding gendered power may be complicated. The authors first describe the historical context that serves as important background for understanding gender and power in heterosexual African American relationships. Then they show how family solidarity in the face of social injustices often overrides gender equality as a goal for middle class African American couples with young children. The findings illustrate pragmatic equality within couple relationships and the willful suspension of gender roles for the well‐being of the family as a whole. However, gendered power impacts couples in a variety of ways. Sometimes a woman's fear that the man might leave, for example, diminished her power in the relationship. Often a woman accommodated a man's greater power in the family because of her perception that he was often denied power in the larger society. Societal discrimination of women was less visible to couples. Implications for practice are provided.
Multidimensional Family Therapy HIV/STD Risk‐Reduction Intervention: An Integrative Family‐Based Model for Drug‐Involved Juvenile Offenders
Authors: MARVEL FRANCOISE , ROWE CYNTHIA L. , COLON‐PEREZ LISSETTE , DICLEMENTE RALPH J. , LIDDLE HOWARD A.
Published: February 2009

Drug and juvenile justice involved youths show remarkably high rates of human immunodeficiency virus (HIV)/sexually transmitted disease (STD) risk behaviors. However, existing interventions aimed at reducing adolescent HIV risk behavior have rarely targeted these vulnerable young adolescents, and many approaches focus on individual‐level change without attention to family or contextual influences. We describe a new, family‐based HIV/STD prevention model that embeds HIV/STD focused multifamily groups within an adolescent drug abuse and delinquency evidence‐based treatment, Multidimensional Family Therapy (MDFT). The approach has been evaluated in a multisite randomized clinical trial with juvenile justice involved youths in the National Institute on Drug Abuse Criminal Justice Drug Abuse Treatment Studies (http://www.cjdats.org). Preliminary baseline to 6‐month outcomes are promising. We describe research on family risk and protective factors for adolescent problem behaviors, and offer a rationale for family‐based approaches to reduce HIV/STD risk in this population. We describe the development and implementation of the Multidimensional Family Therapy HIV/STD risk‐reduction intervention (MDFT‐HIV/STD) in terms of using multifamily groups and their integration in standard MDFT and also offers a clinical vignette. The potential significance of this empirically based intervention development work is high; MDFT‐HIV/STD is the first model to address largely unmet HIV/STD prevention and sexual health needs of substance abusing juvenile offenders within the context of a family‐oriented evidence‐based intervention.
Cultural, Gender, and Socioeconomic Contexts in Therapeutic and Social Policy Work
Authors: WALDEGRAVE CHARLES
Published: February 2009

The contention of this paper is that the context of social and therapeutic problems is critical to their resolution, and that many of them stem from historical and structural injustice. It focuses on the contextual issues of cultural, gender, and socioeconomic equity as providing important insights into authentic notions of social inclusion and well‐being, and encourages therapists, service providers, researchers, and policy makers to take responsibility to ensure that these injustices are addressed, and become part of the public discourse about the sources and solutions of endemic social problems. Critique and deconstruction of institutional power in our public, private, and voluntary services is encouraged in a manner that honors diversity and enables sensitive therapy, other forms of service delivery and policy making that genuinely reflect the range of cultural, gender, and socioeconomic experiences of citizens.
Collaborative Helping: A Practice Framework for Family‐Centered Services
Authors: MADSEN WILLIAM C.
Published: February 2009

This article offers a framework for collaborative family‐centered practice that can reinvigorate our work with families who have not responded to more traditional approaches. Collaborative Helping is grounded in family‐centered principles that include: striving for cultural curiosity, believing in resourcefulness, working in partnership, and making our work more accountable to the clients we serve. The article introduces collaborative inquiry as an organizing metaphor for clinical practice and offers a five‐step practice framework with clinical illustrations and sample questions. The framework draws from appreciative inquiry, motivational interviewing, the signs of safety approach to child protection work, and solution‐focused and narrative therapies.
Forensic Characteristics of Suicide by Electrocution in Bulgaria
Authors: Dokov William
Published: February 2009

Abstract:  Suicides by electrocution (SE) are relatively rare and insufficiently studied. The purpose of this study is to present a more detailed picture of SE in Bulgaria. Forensic medical files of 59 SE cases were examined. spss 11.0 software was applied to produce the descriptive statistical analyses. Values of p < 0.05 were assumed to be statistically significant. We studied 59 SE cases, which account for 6.24% of all deaths by electrocution and 0.09% of all forensic autopsies. The average age of victims was 45.19 years old. Males prevailed: 91.53%. Children below 18 years old accounted for 3.39%. 42.37% of the victims applied low voltage (<220 V), and 33.99% applied high voltage (>220 V). The preferred method of SE was by direct contact victim/electrical cable: 47.45%. The summer months June through September account for 49.15% of all cases.
Fatal Venous Air Embolism Following Intravenous Infusion*
Authors: Agarwal Swapnil Sudhirkumar , Kumar Lavlesh , Chavali Krishnadutt Harishankar , Mestri Shashidhar Chennamallapa
Published: February 2009

Abstract:  Venous air embolism has been reported as a complication of invasive diagnostic and therapeutic procedures or accidental trauma. Little is known about the incidence of air embolism after minimal intravenous manipulations such as the insertion of a peripheral intravenous cannula. Only when large amounts of air sufficient enough to block the cardiovascular system enter, the patient develops symptoms and signs of severe neurological injury, cardiovascular collapse, or death. The dead body of a 14‐year‐old boy was brought for postmortem examination with allegations of death from negligence during treatment. He was treated for pain in the abdomen in a hospital by attendants in telephonic consultation with a medical practitioner. Following intravenous infusions, the boy died suddenly in respiratory distress. Gross findings indicated the death to be from venous air embolism. Chemical analysis, histopathology, and microbiology ruled out other causes of death. Dilemmas of the case with difficulties in diagnosis are being presented herewith.
Mechanisms underlying fibronectin‐induced up‐regulation of P2X4R expression in microglia: distinct roles of PI3K–Akt and MEK–ERK signalling pathways
Authors: Tsuda Makoto , Toyomitsu Emika , Kometani Miho , Tozaki‐Saitoh Hidetoshi , Inoue Kazuhide
Published: February 2009

Microglia are resident immune cells in the central nervous system that become activated and produce pro‐inflammatory and neurotrophic factors upon activation of various cell‐surface receptors. The P2X4 receptor (P2X4R) is a sub‐type of the purinergic ion‐channel receptors expressed in microglia. P2X4R expression is up‐regulated under inflammatory or neurodegenerative conditions, and this up‐regulation is implicated in disease pathology. However, the molecular mechanism underlying up‐regulation of P2X4R in microglia remains unknown. In the present study, we investigated the intracellular signal transduction pathway that promotes P2X4R expression in microglia in response to fibronectin, an extracellular matrix protein that has previously been shown to stimulate P2X4R expression. We found that in fibronectin‐stimulated microglia, activation of phosphatidylinositol 3‐kinase (PI3K)–Akt and mitogen‐activated protein kinase kinase (MAPK kinase, MEK)–extracellular signal‐regulated kinase (ERK) signalling cascades occurred divergently downstream of Src‐family kinases (SFKs). Pharmacological interference of PI3K–Akt signalling inhibited fibronectin‐induced P2X4R gene expression. Activation of PI3K–Akt signalling resulted in a decrease in the protein level of the transcription factor p53 via mouse double minute 2 (MDM2), an effect that was prevented by MG‐132, an inhibitor of the proteasome. In microglia pre‐treated with MG‐132, fibronectin failed to up‐regulate P2X4R expression. Conversely, an inhibitor of p53 caused increased expression of P2X4R, implying a negative regulatory role of p53. On the other hand, inhibiting MEK–ERK signalling activated by fibronectin suppressed an increase in P2X4R protein but interestingly did not affect the level of P2X4R mRNA. We also found that fibronectin stimulation resulted in the activation of the translational factor eIF4E via MAPK‐interacting protein kinase‐1 (MNK1) in an MEK–ERK signalling‐dependent manner, and an MNK1 inhibitor attenuated the increase in P2X4R protein. Together, these results suggest that the PI3K–Akt and MEK–ERK signalling cascades have distinct roles in the up‐regulation of P2X4R expression in microglia at transcriptional and post‐transcriptional levels, respectively.
Functional characterization and pharmacological rescue of melanocortin‐4 receptor mutations identified from obese patients
Authors: Fan Zhen‐Chuan , Tao Ya‐Xiong
Published: February 2009

As the most common monogenic form of human obesity, about 130 naturally occurring melanocortin‐4 receptor (MC4R) gene mutations have been identified. In this study, we reported detailed functional characterization of 10 novel human MC4R (hMC4R) mutants including R7C, C84R, S127L, S136F, W174C, A219V, P230L, F261S, I317V and L325F. Flow cytometry experiments showed that six mutants, including R7C, C84R, S127L, W174C, P230L and F261S, have decreased cell surface expression. The other four mutants are expressed at similar levels as the wild‐type hMC4R. Binding assays showed that the mutants have similar binding affinities for the agonist and endogenous antagonist agouti‐related protein. Signalling assays showed that S136F is defective in signalling. Multiple mutagenesis showed that S136 of hMC4R is required for the normal function of the receptor. To identify potential therapeutic approaches for patients with intracellularly retained MC4R mutants, we tested the effect of an MC4R inverse agonist, ML00253764, on C84R and W174C. We showed that ML00253764 could function as a pharmacological chaperone rescuing the mutant MC4Rs to the cell surface. The rescued mutants are functional with increased cAMP production in response to agonist stimulation. In conclusion, of 10 mutants we studied, 6 had decreased cell surface expression. Pharmacological chaperone is a potential approach for treating obesity caused by MC4R mutations that result in intracellular retention.
p27Kip1 as a prognostic factor in breast cancer: a systematic review and meta‐analysis
Authors: Guan Xiaoxiang , Wang Yucai , Xie Ruilian , Chen Longbang , Bai Jianling , Lu Jia , Kuo Macus Tien
Published: February 2009

The aim of this study was to comprehensively evaluate via a meta‐analysis the association between p27 expression and clinical outcome in breast cancer patients. We conducted a meta‐analysis of 20 studies (n= 6463 patients) that evaluated the correlation between p27 expression and indicators of breast cancer clinical outcome, including overall survival (OS), disease‐free survival (DFS) and relapse‐free survival (RFS). Data pooling was performed by RevMan 4.2. A total of 60% (9 of 15) of the studies showed a significant association between p27 high expression and OS, whereas 25% (2 of 8) and 60% (3 of 5) studies demonstrated a correlation between p27 high expression and DFS and RFS, respectively. The relative risks (RRs) were 1.34 (1.26–1.42) for OS (P < 0.00001), 1.27 (1.10–1.47) for DFS (P= 0.001) and 1.49 (0.92–2.42) for RFS (P= 0.10). In lymph node‐negative breast cancer patients, the RRs for OS and RFS were 1.84 (1.30–2.59; P= 0.0005) and 1.30 (0.20–8.50; P= 0.78), respectively. In lymph node‐positive breast cancer patients, the RRs for OS and RFS were 2.99 (1.77–5.07; P < 0.0001) and 1.49 (0.80–2.77; P= 0.21), respectively. This meta‐analysis indicates that reduced p27 is an independent prognostic factor for poor overall and disease‐free cancer survival.
Habitat selection by an Alpine ungulate: the significance of forage characteristics varies with scale and season
Authors: Zweifel‐Schielly Barbara , Kreuzer Michael , Ewald Klaus C. , Suter Werner
Published: February 2009

Habitat selection in ungulates should ensure access to abundant forage of sufficiently high quality. Species living in rugged mountain areas have to face nutritional bottlenecks regularly and should show particularly sophisticated habitat selection behaviour. However, patterns and mechanisms of such adaptations remain little studied. We analysed habitat selection and its seasonal variability of 10 GPS‐collared red deerCervus elaphusliving in a topographically challenging landscape of the Swiss Alps. We hypothesised that resource selection by red deer was scale‐dependent and predicted that scale‐dependence would vary among seasons in relation to seasonal changes of available forage biomass and quality, which we sampled across the entire study area of 250 km2. The studied population of Alpine red deer undertook altitudinal migrations and showed scale‐dependent habitat selection that was strongest in winter and declined through spring and summer. Selection occurred mostly at the larger (landscape/home‐range location) scale and less so at the smaller (within home‐range) scale. Topographic parameters were selected mainly at the landscape scale and mostly in winter. About 70% of all instances of preference for habitat parameters were associated with above‐average forage characteristics, represented mostly by higher crude protein content, in a few cases also by higher biomass or both. The overall pattern of space use by red deer characterised by migration and seasonal habitat selection was therefore closely linked to the quality of food resources, although some trade‐offs with avoiding human disturbance may also have been involved.
Assessing the dominance of Phleum pratense cv. climax, a species commonly used for ski trail restoration
Authors: Isselin‐Nondedeu Francis , Bédécarrats Alain
Published: February 2009

Questions: (1) Are some species used for ski trail restoration too dominant to allow native species to re‐establish? (2) What plant traits can be used to predict which species are good competitors? We tested the hypothesis that limited native species establishment on ski trails is caused by (1) the dominance of Phleum pratense cv. climax (PPC) and (2) the asymmetry of competitive interactions.

Location: Sub‐alpine area in the northern French Alps.

Methods: PPC was cultivated outdoors over 2 years with 15 alpine species in a systematic design with high‐ and low‐nutrient soil conditions. For each species relative survival, competitive performance and relationships with plant traits were measured.

Results: PPC exerted strong dominance on most of its neighbouring species. Survival performance of Anthyllis vulneraria, Luzula sudetica and Lotus alpinus were dramatically reduced. Results of above‐ground competition showed that species were trapped in asymmetric competition. Festuca rubra, Trifolium repens, Alchemilla xanthochlora, Trifolium pratense and Plantago alpina best counteracted PPC. Below‐ground competition was more symmetric, particularly at the high nutrient level. Plant traits such as biomass, canopy size and specific leaf area were positively correlated with competitive performance of the species.

Conclusion: The study has implications for the management of restored ski trails since PPC may hinder the establishment of native sub‐alpine species. Consequently, recommendations should focus on (1) maintaining a low proportion or decreasing the proportion of PPC seeds in the revegetation mix and (2) reducing soil fertilization. Plant traits and competition experiments can help to predict changes in restored grasslands.
Estrogen Hydroxylation—The Good and the Bad
Authors: Sepkovic Daniel W. , Bradlow H. Leon
Published: February 2009

Although estradiol itself is primarily responsible for female development, the metabolites are responsible for many of the other positive and negative properties of estrogens. Phase I metabolism of estradiol is exclusively oxidative unlike the other steroid hormones and involves a series of hydroxylations. The specific hydroxylations can be induced or suppressed by endogenous or exogenous compounds that influence the cytochrome enzymes that act on specific sites on the molecule. Modulation of estrogen hydroxylation is essential since some of the other metabolites increase the risk of breast and other hormone‐related cancers. The various hydroxylation pathways are discussed as well as the effects of the products of estrogen hydroxylation. The interaction between the human papilloma virus (HPV) and 16α‐hydroxyestrone is discussed with reference to recurrent respiratory papillomatosis, cervical dysplasia, and cervical cancer. The role of estrogen metabolites in predicting the relative risk for breast cancer is evaluated using prospective and case‐control studies. In one pilot study a factor that is a component of body fat is identified to be an inhibitor of estrogen C‐2 hydroxylation. The role of environmental toxins like the phthalate esters and how these compounds increase risk for hormonal cancers is examined in a second pilot study.
The Development of Steroid Sulfatase Inhibitors for Hormone‐Dependent Cancer Therapy
Authors: Day Joanna M. , Purohit Atul , Tutill Helena J. , Foster Paul A. , Woo L. W. Lawrence , Potter Barry V. L. , Reed Michael J.
Published: February 2009

Steroid sulfatase (STS) regulates the hydrolysis of steroid sulfates to their unconjugated forms. Estrone sulfate and dehydroepiandrosterone sulfate can be hydrolyzed by STS to estrone and dehydroepiandrosterone, respectively, with these steroids being the precursors for the synthesis of more biologically active estrogens or androgens. A number of potent STS inhibitors have now been developed including STX64, which entered a phase I trial for the treatment of postmenopausal women with advanced metastatic hormone‐dependent breast cancer. The results from this phase I trial were encouraging, suggesting that STS inhibitors may also have a role in the treatment of other hormone‐dependent cancers including those of the endometrium, ovary, and prostate. In this paper the potential use of STS inhibitors to treat these hormone‐dependent cancers is reviewed. In addition, results from in vitro studies show that Ishikawa endometrial cancer cells, OVCAR‐3 ovarian cancer cells, and LNCaP prostate cancer cells all possess significant STS activity. Furthermore, STS activity in these cells can be almost completely inhibited by STX64 or the second‐generation STS inhibitor, STX213. Results from these investigations therefore suggest that STS inhibitors could have therapeutic potential for the treatment of a range of hormone‐dependent cancers.
The Unilateral Nigral Lesion Induces Dramatic Bilateral Modification on Rat Brain Monoamine Neurochemistry
Authors: Pierucci Massimo , Di Matteo Vincenzo , Benigno Arcangelo , Crescimanno Giuseppe , Esposito Ennio , Di Giovanni Giuseppe
Published: February 2009

6‐Hydroxydopamine (6‐OHDA) is a neurotoxic compound commonly used to induce dopamine (DA) depletion in the nigrostriatal system, mimicking Parkinson's disease (PD) in animals. The aim of the present study was to evaluate the 7‐day effect of unilateral nigral lesion on rat brain monoamine neurochemistry. Five brain regions were examined: the brain stem, cerebellum, hippocampus, striatum, and cortex. 6‐OHDA‐unilateral lesion dramatically modified DA, serotonin (5‐HT) and their metabolites contents in both sides of the different brain nuclei. Furthermore, unilateral 6‐OHDA lesion reduced DA and 5‐HT contents and produced a robust inversion of their turnover in the nonlesioned side compared to sham‐operated rats. These data suggest that 6‐OHDA unilateral nigral lesion produces bilateral monoamine level modifications, and this piece of evidence should be taken into account when one interprets data from animal models of unilateral PD.
Translational Research in Hormone‐Related Cancer
Authors: Massimo Luisa M. , Tonini Gian Paolo
Published: February 2009

Hormones are implicated in various types of cancer, however, several aspects of steroid activity on carcinogenesis remain elusive. Recent progress has made it possible for us to directly study the biological mechanisms of disease development, including hormone−cancer relationships, from numerous viewpoints, from numerous viewpoints, including genome abnormalities. One tool is comparative genomic hybridization array (aCGH). Furthermore, it is possible to identify the so‐called “cancer signature” by gene expression profiling, which provides new information about the role of steroids on carcinogenesis. DNA mutations and gene expression abnormalities may be associated with hormone‐related cancer. The recent discovery of microRNA provides new opportunities for understanding the fine regulation of gene expression in cancer cells, and the role of microRNA in the relationship between hormones and cancer. From these experimental models we should be able to rapidly develop translation‐to‐treatment protocols. The final goal should be to design specific labs on a microchip for prognosis and therapy of individual patients. While in clinical research there is renewed attention to stratification of patients, especially those at high risk.
Parkinson's Disease and Cancer
Authors: D'Amelio Marco , Ragonese Paolo , Sconzo Gabriella , Aridon Paolo , Savettieri Giovanni
Published: February 2009

Epidemiological evidence suggests a reduced incidence of many common types of cancers in individuals with Parkinson's disease (PD). Parkinson's disease and cancer are two diseases that result from an excessive signaling by one of two forces driving cells to opposite directions. PD results from the excessive death of dopaminergic neurons in the substantia nigra pars compacta (SNc) in the brain, while uncontrolled growth is the key property of cancer. Parkinson's disease is a complex disorder, probably due in most of the cases to the interaction of environment and genes. Many genes responsible for familial forms of PD are supposed to have a supportive role in regulating or maintaining the cell cycle, a fact that allows us to assume their interaction in tumorigenesis. Understanding the nature of these processes may help researchers find new and more efficacious therapeutic approaches for both diseases.
Low Levels of Both Xanthine Dehydrogenase and Cellular Retinol Binding Protein Are Responsible for Retinoic Acid Deficiency in Malignant Human Mammary Epithelial Cells
Authors: Taibi Gennaro , Carruba Giuseppe , Cocciadiferro Letizia , Granata Orazia M. , Nicotra Concetta M.A.
Published: February 2009

The seeming impairment of retinoid metabolism in human breast tumor cells has been attributed to the lower expression of cellular retinol binding proteins (CRBPs), of alcohol/retinol dehydrogenases, or aldehyde/retinaldehyde dehydrogenases. In a previous study we indicated that xanthine dehydrogenase (XDH) is able to oxidize actively both all‐trans‐retinol (t‐ROL) bound to the CRBP (holo‐CRBP) and all‐trans‐retinaldehyde (t‐RAL) to all‐trans‐retinoic acid (t‐RA) in human mammary epithelial cells (HMEC). Since both XDH and CRBP are required for the biosynthesis of t‐RA, we have inspected their bioavailability in both estrogen‐responsive and nonresponsive human mammary epithelial cancer cells. The XDH activity, as assessed in the crude and purified extracts of both MCF7 and MDA‐MB 231 cells by measuring the substrate t‐RAL (that unlike t‐ROL does not need CRBP), was 6 to 10 times lower than that previously encountered in normal HMEC. In addition, CRBP expression was absent in either cell line. Based on this preliminary evidence, we propose here that the low levels of XDH activity and the associated absence of CRBP in both MCF7 and MDA‐MB 231 human breast cancer cells might be responsible for the retinoic acid deficiency observed in these cell model systems. This defect may be the crux of the impairment to stem cell differentiation and, hence, may be primarily implicated in human mammary carcinogenesis.
Dietary Enterolactone Affects Androgen and Estrogen Levels in Healthy Postmenopausal Women
Authors: Granata Orazia M. , Traina Adele , Ramirez Stefania , Campisi Ildegarda , Zarcone Maurizio , Amodio Rosalba , Polito Lucia M. , Carruba Giuseppe
Published: February 2009

In this randomized dietary intervention study (DI) we analyzed levels of androgens, phytoestrogens, and estrogens in 12‐h urine samples of 69 healthy postmenopausal women, 37 of whom followed a traditional Mediterranean diet for 6 months (intervention group) as compared to 32 women who followed their regular diet (control group). Circulating levels of both insulin and testosterone (T) were also assayed. Overall, enterolactone (ENL) was the most prominent phytoestrogen in urines of both control and intervention women, and its levels increased by a 20% after DI. At the baseline the ENL levels were seen to be significantly associated with both the total androgens (TOT‐A) (r= 0.371, P= 0.002) and the TOT‐A/total estrogen (TOT‐E) ratio (r= 0.351, P= 0.005) in all 69 postmenopausal women. Furthermore, the DI resulted in a more pronounced negative association of both ENL with insulin (r=−0.321, P= 0.05) and insulin with TOT‐A (r=−0.421, P= 0.01). Regarding urinary androgens, ENL associated with both 3α‐androsterone (5α‐androgen, r= 0.363, P= 0.002) and 3α‐etiocolanolone (5β‐androgen, r= 0.295, P= 0.01) at baseline, while after DI, circulating insulin and T exhibited a significant negative association with the 5β‐androgen metabolite etiocolanolone (r=−0.487, P= 0.002; and r=−0.336, P= 0.042, respectively). We conclude that lignan components of the Mediterranean diet, notably ENL, are associated with urinary levels of products of androgen metabolism, including both 5α‐ and 5β‐reductase enzymes, in healthy postmenopausal women. Further studies are necessary to better understand the interplay of sex hormones with dietary phytoestrogens.
Endocrine Therapy in Metastatic Breast Cancer
Authors: Amodio Rosalba , Zarcone Maurizio , Agostara Biagio , Staiti Rosalba , Granata Orazia Maria , Carruba Giuseppe , Traina Adele
Published: February 2009

This study compares the survival of breast cancer patients who are metastatic at diagnosis (DMBC) and of recurrent metastatic breast cancer (RMBC) patients. We analyzed retrospectively the population‐based data of Breast Cancer Registry of Palermo and collected a total of 4459 breast cancer cases in the years 1999–2005. Survival analysis did not show statistically significant differences between DMBC and RMBC patients (P= 0.882). Endocrine manipulation is the treatment of choice in the case of hormone receptor‐positive breast tumors. In 91 receptor‐positive DMBC patients the endocrine treatment was associated with a prolonged overall survival (OS) (median survival 33.5 months compared to 29 months for receptor‐positive patients who did not receive hormone treatment). Receptor‐negative patients who underwent endocrine therapy (76% of cases) survived longer than receptor‐negative patients who did not receive hormone treatment (median survival 28.5 months vs. 15 months, respectively). This evidence supports the concept that endocrine therapies impinging upon molecular targets other than hormone receptors may increase survival rates of breast cancer patients.
Phase 3 Trials of Aromatase Inhibitors for Breast Cancer Prevention
Authors: Dunn Barbara K. , Ryan Anne
Published: February 2009

The third‐generation aromatase inhibitors (AIs), anastrozole, exemestane, and letrozole are potential agents for preventing estrogen receptor (ER)‐positive breast cancer (BC) in high‐risk postmenopausal women. No AI has yet been fully evaluated for prevention. Each AI is incorporated into the design of a phase 3 randomized BC prevention trial based on hypothesis‐generating contralateral breast cancer (CLBC) data from a corresponding adjuvant trial. Arimidex, tamoxifen alone or in combination (ATAC) pitted anastrozole against tamoxifen for 5 years as “initial adjuvant” therapy, showing at 33.3 months fewer CLBCs with anastrozole versus tamoxifen (odds ratio [OR] 0.42 overall; OR 0.29 ER‐positive BCs), offering the hypothesis on which IBIS‐II (International Breast Cancer Intervention Study) is based. “High‐risk” IBIS‐II compares anastrozole to placebo for the primary prevention of BC in 6000 postmenopausal women. IES (Intergroup Exemestane Study) compared exemestane to tamoxifen following 2–3 years of adjuvant tamoxifen in 4742 postmenopausal women with ER‐positive BCs. The benefit from “switching” to exemestane in reducing CLBCs (HR 0.44 at 30.6 months) underlies MAP.3 (Mammary Prevention 3), which compares exemestane to placebo for primary BC risk reduction in 4560 postmenopausal women. MA.17 showed reduced CLBC incidence (HR 0.57) at 2.4 years in postmenopausal women with receptor‐positive tumors receiving “extended adjuvant” letrozole compared to placebo following 5 years of tamoxifen. The Study of Letrozole and Raloxifene (STELLAR), using as the control raloxifene, the new U.S. standard drug for BC prevention, would complete the trio of AI prevention trials, but STELLAR is currently on hold.
Aromatase and Amphiregulin Are Correspondingly Expressed in Human Liver Cancer Cells
Authors: Miceli Vitale , Cervello Melchiorre , Azzolina Antonina , Montalto Giuseppe , Calabrò Maurizio , Carruba Giuseppe
Published: February 2009

Human hepatocellular carcinoma (HCC) is associated with high mortality rates, being the third most common cause of cancer death worldwide. Although estrogens have been implicated in HCC, their potential role in development and/or progression of this malignancy remains unclear. In this study we investigated mRNA and protein expression of aromatase (Aro) and amphiregulin (AREG) in relation to estrogen receptors (ERs), in HepG2, Huh7, and HA22T human malignant liver cell lines, using RT‐PCR and Western blot analyses. Aro expression was significantly higher (∼13‐fold, P= 0.003) in HepG2 cells than in Huh7 cells, while no Aro expression could be detected in HA22T cells. Interestingly, the patterns of AREG expression were consistently associated with those of Aro, with ∼3‐fold and ∼8‐fold higher levels being seen in HepG2 cells than in Huh7 cells (P= 0.002) and HA22T cells (P= 0.0014), respectively. Using a specific set of primers, ERα46 is the only ER variant expressed in all cell lines, while the wild‐type ERα66 could not be detected. Western blot analysis revealed a corresponding figure. This evidence suggests that AREG expression may be upregulated by estrogens in human HCC and that locally elevated aromatase activity also may increase malignant cell proliferation through AREG signaling.
Organization, Integration, and Assembly of Genetic and Epigenetic Regulatory Machinery in Nuclear Microenvironments
Authors: Stein Gary S. , Zaidi Sayyed K. , Stein Janet L. , Lian Jane B. , Van Wijnen Andre J. , Montecino Martin , Young Daniel W. , Javed Amjad , Pratap Jitesh , Choi Je‐Yong , Ali Syed A. , Pande Sandhya , Hassan Mohammad Q.
Published: February 2009

There is growing awareness that the fidelity of gene expression necessitates coordination of transcription factor metabolism and organization of genes and regulatory proteins within the three‐dimensional context of nuclear architecture. The regulatory machinery that governs genetic and epigenetic control of gene expression is compartmentalized in nuclear microenvironments. Temporal and spatial parameters of regulatory complex organization and assembly are functionally linked to biological control and are compromised with the onset and progression of tumorigenesis. High throughput imaging of cells, tissues, and tumors, including live cell analysis, is expanding research's capabilities toward translating components of nuclear organization into novel strategies for cancer diagnosis and therapy.
Cyclooxygenase‐2 Expression in Chronic Liver Diseases and Hepatocellular Carcinoma
Authors: Giannitrapani Lydia , Ingrao Sabrina , Soresi Maurizio , Florena Ada Maria , Spada Emanuele La , Sandonato Luigi , D'Alessandro Natale , Cervello Melchiorre , Montalto Giuseppe
Published: February 2009

Hepatocarcinogenesis is a multistep process characterized by hepatocyte inflammation, regeneration, and proliferation. These changes are believed to depend on the aberrant expression of various tumor suppressor genes, oncogenes and growth factors. Several studies have shown the involvement of cyclooxygenase‐2 (COX‐2), the inducible isoform of the enzymes that catalyze prostaglandin synthesis in various aspects of carcinogenesis. COX‐2 has been described as being overexpressed in hepatocellular carcinoma (HCC) patients. Using immunohistochemistry, we studied COX‐2 expression in different chronic liver diseases (CLD) including nonalcoholic steatohepatitis (NASH), chronic hepatitis (CH), liver cirrhosis (LC), and HCC in a population referred to a tertiary center in western Sicily, an area moderately endemic for CLD. Sixteen NASH, 35 CH, 15 LC, and 21 HCC samples were analyzed. Positive signs of COX‐2 were observed in the cytoplasm of hepatocytes and median values were 6 (3–9) for NASH, 7 (3–9) for CH, 6 (4–9) for LC, and 4 (0–7) for HCC. COX‐2 expression was significantly lower in HCC than in NASH (P < 0.001), CH (P < 0.0001), and LC (P < 0.0001). In HCC we found a wide range of COX‐2 expression: from no expression in poorly differentiated areas to a high expression in well‐differentiated ones, with an inverse correlation between COX‐2 and tumor grading, according to Edmonson (ρ=−0.67, P < 0.0001). In conclusion: (a) COX‐2 expression was significantly lower in HCC than in the other CLD; (b) COX‐2 expression inversely correlated with tumor differentiation status. These results suggest that COX‐2 expression could be related to the inflammatory phenomena present in the early phases of CLD and eventually to the induction of hepatocarcinogenesis.
Steroid Hormone Transforming Aldo‐Keto Reductases and Cancer
Authors: Penning Trevor M. , Byrns Michael C.
Published: February 2009

Prostate and breast cancer are hormone‐dependent malignancies of the aging male and female and require the local production of androgens and estrogens to stimulate cell proliferation. Aldo‐keto reductases (AKR) play key roles in this process. In the prostate, AKR1C3 (type 5 17β‐HSD) reduces Δ4‐androstene‐3,17‐dione to yield testosterone while AKR1C2 (type 3 3α‐HSD) eliminates 5α‐dihydrotestosterone (5α‐DHT), and AKR1C1 forms 3β‐androstanediol (a ligand for ERβ). In the breast, AKR1C3 forms testosterone, which is converted to 17β‐estradiol by aromatase or reduces estrone to 17β‐estradiol directly. AKR1C3 also acts as a prostaglandin (PG) F synthase and forms PGF2α and 11β‐PGF2α, which stimulate the FP receptor and prevent the activation of PPARγ by PGJ2 ligands. This proproliferative signaling may stimulate the growth of hormone‐dependent and ‐independent prostate and breast cancer.
Prostaglandin E2 Receptors and COX Enzymes in Human Hepatocellular Carcinoma
Authors: Cusimano Antonella , Foderà Daniela , Lampiasi Nadia , Azzolina Antonina , Notarbartolo Monica , Giannitrapani Lydia , D'Alessandro Natale , Montalto Giuseppe , Cervello Melchiorre
Published: February 2009

The aim of this study was to investigate the expression of prostaglandin E2 receptors (EP1–4), cyclooxygenase‐1 (COX‐1), and COX‐2 in nontumor and tumor human liver tissues, and also to evaluate the antitumor activity of selective EP1 receptor antagonist used alone or in combination with COX‐1 and COX‐2 selective inhibitors. Semiquantitative PCR analyses revealed that EP1–4, COX‐1, and COX‐2 mRNA expression was detected in nearly all the tissue samples assayed, although with a high variability between nontumor and tumor tissues. In vitro EP1 receptor antagonist inhibited anchorage‐independent cell growth and reduced the viability of hepatocellular carcinoma (HCC) cells in a dose‐dependent manner. Moreover, treatment with the combination of EP1 receptor antagonist and COX inhibitors produced a significantly greater cell growth inhibition than the single agent alone. These findings suggest that the EP1 receptor may represent an important target for HCC treatment, and in addition they could provide preclinical support for a combined chemotherapeutic approach with EP1 antagonists and COX inhibitors in the treatment of liver cancer.
Inflammation and Liver Cancer
Authors: Berasain C. , Castillo J. , Perugorria M.J. , Latasa M.U. , Prieto J. , Avila M.A.
Published: February 2009

A connection between inflammation and cancer has been long suspected. Epidemiological studies have established that many tumors occur in association with chronic infectious diseases, and it is also known that persistent inflammation in the absence of infections increases the risk and accelerates the development of cancer. One clear example of inflammation‐related cancer is hepatocellular carcinoma (HCC). HCC is a type tumor that slowly unfolds on a background of chronic inflammation mainly triggered by exposure to infectious agents (hepatotropic viruses) or to toxic compounds (ethanol). The molecular links that connect inflammation and cancer are not completely known, but evidences gathered over the past few years are beginning to define the precise mechanisms. In this article we review the most compelling evidences on the role of transcription factors such as NF‐κB and STAT3, cytokines like IL‐6 and IL‐1α, ligands of the EGF receptor and other inflammatory mediators in cancer development, with special emphasis in HCC. The molecular dissection of the pathways connecting the inflammatory reaction and neoplasia will pave the way for better therapies to treat cancers.
Regulation of Aromatase Expression in Breast Cancer Tissue
Authors: Bulun S.E. , Lin Z. , Zhao H. , Lu M. , Amin S. , Reierstad S. , Chen D.
Published: February 2009

Epithelial−stromal interactions play key roles for aromatase expression and estrogen production in breast cancer tissue. Upregulated aromatase expression in breast fibroblasts increases the tissue concentration of estradiol (E2), which then activates a large number of carcinogenic genes via estrogen receptor‐α (ERα) in malignant epithelial cells. This clinically pertains, since aromatase inhibitors (AIs) are the most effective hormonal treatment of ERα‐positive breast tumors. A single gene encodes aromatase, the key enzyme in estrogen biosynthesis, the inhibition of which by an AI effectively eliminates E2 production. Since alternative promoters regulated by distinct signaling pathways control aromatase expression, it is possible to target these pathways and inhibit estrogen production in a tissue‐selective fashion. We and others previously found that the majority of estrogen production in breast cancer tissue was accounted for by the aberrant activation of the proximal promoter I.3/II region. PGE2 that is secreted in large amounts by malignant breast epithelial cells is the most potent known natural inducer of this promoter region in breast adipose fibroblasts. Signaling effectors/transcriptional regulators that mediate PGE2 action include the activator pathways p38/CREB‐ATF and JNK/jun and the inhibitory factor BRCA1 in breast adipose fibroblasts. Selective inhibition of this promoter region may treat breast cancer while permitting aromatase expression via alternative promoters in the brain and bone and thus obviate the key side effects of the current AIs. The signaling pathways that mediate the regulation of the promoter I.3/II region in undifferentiated fibroblasts in malignant breast tumors are reviewed.
Potential Role of UGT Pharmacogenetics in Cancer Treatment and Prevention
Authors: Lazarus Philip , Blevins‐Primeau Andrea S. , Zheng Yan , Sun Dongxiao
Published: February 2009

Tamoxifen (TAM) is a selective estrogen receptor modulator that is widely used in the prevention and treatment of estrogen receptor‐positive (ER+) breast cancer. Its use has significantly contributed to a decline in breast cancer mortality, since breast cancer patients treated with TAM for 5 years exhibit a 30–50% reduction in both the rate of disease recurrence after 10 years of patient follow‐up and occurrence of contralateral breast cancer. However, in patients treated with TAM there is substantial interindividual variability in the development of resistance to TAM therapy, and in the incidence of TAM‐induced adverse events, including deep vein thrombosis, hot flashes, and the development of endometrial cancer. This article will focus on the UDP glucuronosyltransferases, a family of metabolizing enzymes that are responsible for the deactivation and clearance of TAM and TAM metabolites, and how interindividual differences in these enzymes may play a role in patient response to TAM.
Sex Steroids Upregulate the IGF‐1R in Prostate Cancer Cells through a Nongenotropic Pathway
Authors: Pandini Giuseppe , Genua Marco , Frasca Francesco , Vigneri Riccardo , Belfiore Antonino
Published: February 2009

Most types of prostate cancer (PCa) are usually initially responsive to androgenic regulation and, therefore, to androgen ablation therapy. However, in several patients tumors may progress to androgen resistance and be poorly responsive to any therapy. Many factors may account for this progression to androgen independence, including increased responsiveness to estrogens and peptide growth factors. The role of estrogens in androgen independence has been suggested by the observation that both primary and metastatic PCa express the estrogen receptor (ER‐β), a recently discovered ER subtype. On the other hand, peptide growth factors, like IGF‐1, IGF‐2, and the insulin‐like growth factor receptor (IGF‐1R), may play a role in regulating growth, survival, and invasion of PCa cells. Here, we show that both androgens and estrogens markedly upregulate the IGF‐1R expression in PCa cells by activating a nongenotropic pathway and sensitizing cells to the biological effects of IGF‐1. This effect is specific for IGF‐1R because it does not involve the highly homologous insulin receptor. IGF‐1R upregulation is caused by increased mRNA transcription. However, it does not require steroid receptor binding to DNA, but involves AR and ER binding to c‐Src and subsequent activation of ERK1/2 and other cytoplasmatic kinases, which eventually stimulate IGF‐1R promoter activity. In conclusion, our data indicate that both androgens and estrogens contribute to IGF system deregulation in PCa and may play a role in tumor progression to androgen independence. Inhibition of the IGF‐1R or the Src–ERK pathway should be considered, therefore, as an adjuvant therapy in PCa.
Automobility and the Geographies of the Car
Authors: Merriman Peter
Published: February 2009

The motor car or automobile has had a profound impact on global mobility, settlement patterns, the global economy, and the environment. Transport policy‐makers and environmentalists highlight the unsustainable nature of contemporary petrol‐car usage, yet despite widespread calls to rethink contemporary automobility and move towards more sustainable forms of public and private travel, it is only in recent years that social scientists have started to examine the social and cultural geography of the motor car, driving and the spaces of the street, road and motorway in any depth. In this article, I outline some of the research which has been undertaken on the geographies and sociologies of the spaces and practices of driving, focusing in particular on the UK. First, the article outlines the major impact the motor car has had on the geographies of road space. It examines how motor roads have shaped our experience of space and place, and outlines studies of their design, inhabitation, and regulation. Second, this article discusses embodied inhabitations of the spaces of the car: how motor cars have been consumed; how they have shaped our embodied apprehensions of our surroundings; and how they facilitate social and cultural relations. Finally, this article concludes by examining the innovative methods which are increasingly being utilised and developed by social scientists to explore the socialities of automotive spaces.