bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I Biological Study of MG98, an Oligodeoxynucleotide Antisense to DNA Methyltransferase 1, in Patients with High-Risk Myelodysplasia and Acute Myeloid Leukemia
Authors: Klisovic Rebecca B. , Stock Wendy , Cataland Spero , Klisovic Marko I. , Liu Shujun , Blum William , Green Margaret , Odenike Olatoyosi , Godley Lucy , Burgt Jennifer Vanden , Van Laar Emily , Cullen Michael , Macleod A. Robert , Besterman Jeffrey M. , Reid Gregory K. , Byrd John C. , Marcucci Guido
Published: April 2008

Purpose: Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML.

Experimental Design: Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which ≥50% of patients experienced >50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days).

Results: DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients.

Conclusions: No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.
The Use of Magnetic Resonance Imaging to Noninvasively Detect Genetic Signatures in Oligodendroglioma
Authors: Brown Robert , Zlatescu Magdalena , Sijben Angelique , Roldan Gloria , Easaw Jay , Forsyth Peter , Parney Ian , Sevick Robert , Yan Elizabeth , Demetrick Douglas , Schiff David , Cairncross Gregory , Mitchell Ross
Published: April 2008

Background: Some patients with low-grade glioma have extraordinarily long survival times; current, early treatment does not prolong their lives. For this reason, therapies that sometimes have neurologic side effects are often deferred intentionally.

Methods: In a study of oligodendrogliomas, we used a quantitative method of MR analysis based on the S-transform to investigate whether codeletion of chromosomes 1p and 19q, a marker of good prognosis, could be predicted accurately by measuring image texture.

Results: Differences in texture were seen between tumors with codeletion of chromosomes 1p and 19q and those with intact 1p and 19q alleles on contrast-enhanced T1-weighted and T2-weighted MR images. Quantitative MR texture on T2 images predicted codeletion of chromosomes 1p and 19q with high sensitivity and specificity.

Conclusions: This new method of MR image interpretation may have the potential to augment the diagnostic assessment of patients with suspected low-grade glioma.
Randomized, Double-Blinded Phase II Evaluation of Docetaxel with or without Doxercalciferol in Patients with Metastatic, Androgen-Independent Prostate Cancer
Authors: Attia Steven , Eickhoff Jens , Wilding George , McNeel Douglas , Blank Jules , Ahuja Harish , Jumonville Alcee , Eastman Michael , Shevrin Daniel , Glode Michael , Alberti Dona , Staab Mary Jane , Horvath Dottie , Straus Jane , Marnocha Rebecca , Liu Glenn
Published: April 2008

Purpose: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1α-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC.

Experimental Design: Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m2 i.v., days 1, 8, and 15) with or without doxercalciferol (10 μg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat.

Results: Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade ≥3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785).

Conclusions: Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.
EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation
Authors: Trowe Torsten , Boukouvala Sotiria , Calkins Keith , Cutler Richard E. , Fong Ryan , Funke Roel , Gendreau Steven B. , Kim Yong D. , Miller Nicole , Woolfrey John R. , Vysotskaia Valentina , Yang Jing Ping , Gerritsen Mary E. , Matthews David J. , Lamb Peter , Heuer Timothy S.
Published: April 2008

Purpose: Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib.

Experimental Design: We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were dependent on ErbB2 activity for survival and growth.

Results: Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues, with 12 mutated amino acids mapping to the kinase domain. Mutations conferring the greatest lapatinib resistance cluster in the NH2-terminal kinase lobe and hinge region. Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms; including direct steric interference and restriction of conformational flexibility (the inactive state required for lapatinib binding is energetically unfavorable). ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance. ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S and T733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers. The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations. Furthermore, no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity.

Conclusions: Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects.
A Genotype-Phenotype Examination of Cyclin D1 on Risk and Outcome of Squamous Cell Carcinoma of the Head and Neck
Authors: Marsit Carmen J. , Black Candice C. , Posner Marshall R. , Kelsey Karl T.
Published: April 2008

Purpose: The variant allele of CCND1 G870A encodes a splice variant of the cyclin D1 protein, which possesses an increased half-life. To confirm the phenotypic effect of the variant allele, we examined the immunohistochemical staining pattern of the protein in tumors from a case population of head and neck squamous cell carcinoma (HNSCC) and compared it with the genotype of these individuals. We also examined how this genotype was associated with the risk of HNSCC and if this genotype-phenotype association was related to patient outcome.

Experimental Design: In a population-based case-control study of 698 cases and 777 controls, we both genotyped all participants for the CCND1 gene and did immunohistochemical staining of the cyclin D1 protein in the HNSCC tumors.

Results: The variant AA genotype was significantly associated with positive immunohistochemical staining (P < 0.02), and this variant genotype was associated with a significantly elevated odds ratio of 1.5 (95% confidence interval, 1.1-2.0) for HNSCC overall, with risk greatest in oral and laryngeal sites. Positive immunohistochemical staining was inversely related to human papillomavirus 16 DNA present in the tumor (P < 0.03). The AA genotype and superpositive immunohistochemical staining for cyclin D1 also had independent and significant effects on patient survival.

Conclusions: These results strongly suggest that this splice variant, when present in two copies, is a significant predictor of both the occurrence of HNSCC as well as patient survival after treatment. These data further indicate that this variant protein is an important determinant of individual response to therapy for this disease.
Amphiregulin Is a Promising Prognostic Marker for Liver Metastases of Colorectal Cancer
Authors: Yamada Michiyo , Ichikawa Yasushi , Yamagishi Shigeru , Momiyama Nobuyoshi , Ota Mitsuyoshi , Fujii Syoichi , Tanaka Kuniya , Togo Shinji , Ohki Shigeo , Shimada Hiroshi
Published: April 2008

Purpose: Aberrant activation of epidermal growth factor receptors (EGFR/HER1) by ligand stimulation or heterodimerization with human epidermal growth factor 2 (HER2) is considered to play an important role in the development of colorectal carcinoma. Amphiregulin (AR) is a ligand of EGFR that might be related to the development and progression of gastrointestinal tumors. The aim of this study was to determine the AR, EGFR, and HER2 protein expression levels and to evaluate their prognostic relevance to the clinical course of colorectal cancer.

Experimental Design: The AR, EGFR, and HER2 protein levels in primary tumors of colorectal cancer (n = 106) were examined using immunohistochemistry. Metastatic sites in liver specimens (n = 16) were also analyzed in the same manner.

Results: Thirteen (81.6%) metastatic lesions of the liver stained positive for AR. Among the primary lesions of colorectal cancer, 58 (54.7%) stained positive for AR, 13 (12.3%) stained positive for EGFR, and 5 (4.7%) stained positive for HER2. When the relationships between each protein expression level and the clinicopathologic factors were examined, only the AR expression level was significantly related to liver metastasis (P = 0.0296). A multivariate analysis of liver metastasis proved that AR expression was an independent prognostic factor of liver metastasis from colorectal cancer (P = 0.0217).

Conclusions: AR expression in primary lesions of colorectal cancer is an important predictive marker of liver metastasis.
Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma
Authors: Chen Jack S. , Zhou Linda J. , Entin-Meer Michal , Yang Xiaodong , Donker Mila , Knight Zachary A. , Weiss William , Shokat Kevan M. , Haas-Kogan Daphne , Stokoe David
Published: April 2008

The phosphoinositide 3′-kinase (PI3K)–mediated signaling pathway plays a key role in fundamental cellular functions important in normal cellular homeostasis and malignant transformation. Deregulated signaling through this pathway contributes to development of gliomas and their resistance to radiation and chemotherapy. Targeting the PI3K signaling pathway has thus emerged as a promising approach to successful treatment of gliomas. We assessed the radiosensitizing potential of four small-molecule inhibitors that differ in their activities against specific isoforms of the PI3K 110-kDa catalytic subunit (p110). p110α inhibitors blocked phosphorylation of both protein kinase B/Akt and S6 in all cell lines examined, effectively decreased cellular proliferation, and produced additive cytotoxic effects in combination with radiation therapy. The p110β inhibitor exhibited limited biochemical effects and failed to decrease cellular proliferation or viability as either a single agent or in combination with radiation or rapamycin. In vivo studies examining the effects of the p110α inhibitor in combination with radiation indicated a significant reduction in tumor growth rate induced by the combined treatment compared with each treatment modality alone. This translated into a trend toward prolonged time-to-failure for mice in the combination treatment group. In conclusion, PI3K inhibitors are promising agents in the treatment of glioblastomas, especially when used in combination with ionizing radiation. [Mol Cancer Ther 2008;7(4):841–50]
Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models
Authors: Sasaki Yasushi , Negishi Hideaki , Idogawa Masashi , Suzuki Hiromu , Mita Hiroaki , Toyota Minoru , Shinomura Yasuhisa , Imai Kohzoh , Tokino Takashi
Published: April 2008

Therapeutic replacement of the wild-type p53 gene has been pursued as a potential gene therapy strategy in a variety of cancer types; however, some cancer models are resistant to p53 in vivo and in vitro. Therefore, to improve p53 gene therapy, it is important to overcome the resistance to p53-mediated apoptosis. Histone deacetylase inhibitors are a novel class of chemotherapeutic agents that are able to reverse the malignant phenotype of transformed cells. A natural histone deacetylase inhibitor, FK228, is reported to enhance adenovirus infection due in part to the up-regulation of coxsackievirus adenovirus receptor expression. In this study, preclinical experiments were done to establish a mechanistic rationale for the combination of adenovirus-mediated p53 family gene transfer and FK228 pretreatment in future clinical trials. Pretreatment with FK228 enhanced apoptosis in human cancer cells through enhanced transduction of Ad-p53. FK228 also induced hyperacetylation of the p53 protein and specifically enhanced p53-mediated Noxa expression. Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria. The double knockdown of Bax and Noxa expression by small interfering RNA antagonized the synergistic effect of Ad-p53 and FK228 on apoptosis induction. In human cancer xenograft models, FK228 significantly increased the therapeutic effectiveness of p53 as well as p63 gene therapy. These results provide a strong rationale for combining p53 gene therapy and FK228 pretreatment in cancer therapy. [Mol Cancer Ther 2008;7(4):779–87]
Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy
Authors: Zhang Cathy , Lundgren Karen , Yan Zhengming , Arango Maria E. , Price Sharon , Huber Andrea , Higgins Joseph , Troche Gabriel , Skaptason Judith , Koudriakova Tatiana , Nonomiya Jim , Yang Michelle , O'Connor Patrick , Bender Steve , Los Gerrit , Lewis Cristina , Jessen Bart
Published: April 2008

AG-012986 is a multitargeted cyclin-dependent kinase (CDK) inhibitor active against CDK1, CDK2, CDK4/6, CDK5, and CDK9, with selectivity over a diverse panel of non-CDK kinases. Here, we report the potent antitumor efficacies of AG-012986 against multiple tumor lines in vitro and in vivo. AG-012986 showed antiproliferative activities in vitro with IC50s of <100 nmol/L in 14 of 18 tumor cell lines. In vivo, significant antitumor efficacy induced by AG-012986 was seen (tumor growth inhibition, >83.1%) in 10 of 11 human xenograft tumor models when administered at or near the maximum tolerated dose for 8 or 12 days. AG-012986 caused dose-dependent hypophosphorylation at Ser795 of the retinoblastoma protein, cell cycle arrest, and apoptosis in vitro. Colony-forming assays indicated that the potency of AG-012986 substantially decreased with treatment time of <24 h. In vivo, AG-012986 also showed dose-dependent retinoblastoma Ser795 hypophosphorylation, cell cycle arrest, decreased Ki-67 tumor staining, and apoptosis in conjunction with antitumor activity. Studies comparing i.p. bolus with s.c. implanted minipump dosing regimens revealed that in vivo efficacy correlated with the duration of minimally effective plasma levels rather than maximal drug plasma levels. Dosing optimization of AG-012986 provided guidance for selecting a treatment schedule to achieve the best antitumor efficacy while minimizing the risk of adverse side effects. [Mol Cancer Ther 2008;7(4):818–28]
Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells
Authors: Ambrosini Grazia , Cheema Haider S. , Seelman Sharon , Teed Allison , Sambol Elliot B. , Singer Samuel , Schwartz Gary K.
Published: April 2008

Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a very poor prognosis and largely resistant to chemotherapy. MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1. In view of this, MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen-activated protein kinase pathway by the B-Raf inhibitor sorafenib. MPNST (MPNST and ST8814) and dedifferentiated liposarcoma (LS141 and DDLS) human tumor cell lines were characterized for Ras activation and B-Raf expression. Tumor cells were treated with sorafenib and examined for growth inhibition, inhibition of phospho-MEK, phospho-ERK, cell cycle arrest, and changes in cyclin D1 and pRb expression. MPNSTs were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G1 cell cycle arrest. These effects were not seen in the liposarcoma cells, which either did not express B-Raf or showed decreased Ras activation. Small interfering RNA–mediated depletion of B-Raf in MPNSTs also induced a G1 cell cycle arrest in these cells, with a marked inhibition of cyclin D1 expression and Rb phosphorylation, whereas depletion of C-Raf did not affect either. With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST. [Mol Cancer Ther 2008;7(4):890–6]
MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo
Authors: Fournel Marielle , Bonfils Claire , Hou Yu , Yan Pu Theresa , Trachy-Bourget Marie-Claude , Kalita Ann , Liu Jianhong , Lu Ai-Hua , Zhou Nancy Z. , Robert Marie-France , Gillespie Jeffrey , Wang James J. , Ste-Croix Hélène , Rahil Jubrail , Lefebvre Sylvain , Moradei Oscar , Delorme Daniel , MacLeod A. Robert , Besterman Jeffrey M. , Li Zuomei
Published: April 2008

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759–68]
Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia
Authors: Chou C. James , Farkas Michelle E. , Tsai Sherry M. , Alvarez David , Dervan Peter B. , Gottesfeld Joel M.
Published: April 2008

We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(4):769–78]
Impact of Economic, Regulatory, and Patent Policies on Innovation in Cancer Chemoprevention
Authors: Grabowski Henry G. , Moe Jeffrey L.
Published: April 2008

Chemoprevention agents are an emerging new scientific area that holds out the promise of delaying or avoiding a number of common cancers. These new agents face significant scientific, regulatory, and economic barriers, however, which have limited investment in their research and development (R&D). These barriers include above-average clinical trial scales, lengthy time frames between discovery and Food and Drug Administration approval, liability risks (because they are given to healthy individuals), and a growing funding gap for early-stage candidates. The longer time frames and risks associated with chemoprevention also cause exclusivity time on core patents to be limited or subject to significant uncertainties. We conclude that chemoprevention uniquely challenges the structure of incentives embodied in the economic, regulatory, and patent policies for the biopharmaceutical industry. Many of these policy issues are illustrated by the recently Food and Drug Administration–approved preventive agents Gardasil® and raloxifene. Our recommendations to increase R&D investment in chemoprevention agents include (a) increased data exclusivity times on new biological and chemical drugs to compensate for longer gestation periods and increasing R&D costs; chemoprevention is at the far end of the distribution in this regard; (b) policies such as early-stage research grants and clinical development tax credits targeted specifically to chemoprevention agents (these are policies that have been very successful in increasing R&D investment for orphan drugs); and (c) a no-fault liability insurance program like that currently in place for children's vaccines.
Angiotensin II in the Elderly
Authors: Wray D. Walter , Nishiyama Steven K. , Harris Ryan A. , Richardson Russell S.
Published: April 2008

Exercise hyperemia is attenuated in the elderly, which may be attributed to local vasoregulatory pathways within the skeletal muscle vasculature. Therefore, we sought to determine whether healthy aging is associated with changes in angiotensin II (Ang II) receptor sensitivity through measurements of leg blood flow in resting and exercising skeletal muscle. In 12 (n=6 young, 24±1 years; n=6 older, 68±3 years) healthy volunteers, we determined changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of Ang II (0.8 ng/mL of leg blood flow per minute). Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20% and 40% of the maximal work rate (WR
max
). At rest, Ang II infusion decreased leg blood flow to a greater extent in older (−61±8%) subjects compared with younger subjects (−31±5%). Compared with rest, Ang II–mediated vasoconstriction (leg blood flow) during exercise was diminished in both older and younger subjects at 20% (older: −7±5%; younger: −21±2%) and 40% WR
max
(older: −5±4%; younger: −9±3%). These data identify a clear age-related hypersensitivity to Ang II in the resting leg, which may contribute to the recognized decrement in leg blood flow in this cohort. However, the diminished vasoconstriction to Ang II during exercise suggests that the elevation in Ang II type 1 receptor sensitivity documented at rest does not contribute significantly to the blunted exercise hyperemia experienced with advancing age.
Recent Changes in Downward Longwave Radiation at King Sejong Station, Antarctica
Authors: Cho Hi Ku , Kim Jhoon , Jung Yeonjin , Lee Yun Gon , Lee Bang Yong
Published: April 2008

Effects of cloud, air temperature, and specific humidity on downward longwave irradiance and their long-term variabilities are examined by analyzing the measurements made at the King Sejong Station in the Antarctic Peninsula during the period of 1996–2006.

It has been shown that the downward longwave irradiance (DLR) is significantly correlated with three variables: air temperature, specific humidity, and cloudiness. Based on the relationship of the three variables with DLR, a multiple linear regression model has been developed in order to evaluate the relative contribution of each of the variables to the variation of DLR. The three variables together explained 75% of all the variance in daily mean DLR. The respective contribution from specific humidity and cloudiness to the variation of DLR was 46% and 23%; thus most of the DLR variability can be explained by the variations in the two variables. The annual mean of longwave cloud forcing shows 52 W m−2 with no remarkable seasonal cycle. It is also noted that the overcast cloud effect gives an increase by 65 W m−2 with respect to clear-sky flux throughout the year. It is suggested that the multiple regression model can be used to estimate the radiative forcings of variables influencing the DLR variability.

A highly significant decrease in DLR with an average of −1.52 W m−2 yr−1 (−0.54% yr−1) is found in an analysis from the time series of the deseasonalized monthly mean values. Accordingly, the atmospheric flux emissivity, air temperature, and specific humidity have also decreased in their time series, while the cloudiness has increased insignificantly. Consequently, it may be concluded that the recent decrease in DLR is mainly attributed to the net cooling effect due to the decrease in air temperature and specific humidity, which overwhelm the slight warming effect in cloudiness. Analysis of mean monthly trends for individual months shows that, as for the annual data, the variations in DLR are mostly associated with those of air temperature, specific humidity, and cloudiness.
Independent Estimations of the Asymptotic Variability in an Ensemble Forecast System
Authors: Bengtsson Lisa K. , Magnusson Linus , Källén Erland
Published: April 2008

One desirable property within an ensemble forecast system is to have a one-to-one ratio between the root-mean-square error (rmse) of the ensemble mean and the standard deviation of the ensemble (spread). The ensemble spread and forecast error within the ECMWF ensemble prediction system has been extrapolated beyond 10 forecast days using a simple model for error growth. The behavior of the ensemble spread and the rmse at the time of the deterministic predictability are compared with derived relations of rmse at the infinite forecast length and the characteristic variability of the atmosphere in the limit of deterministic predictability. Utilizing this methodology suggests that the forecast model and the atmosphere do not have the same variability, which raises the question of how to obtain a perfect ensemble.
The Challenge and Response to Global Tourism in the Post-modern Era: The Commodification, Reconfiguration and Mutual Transformation of Habana Vieja, Cuba
Authors: Bailey Nick
Published: April 2008

There is a growing literature on the symbolic and cultural meanings of tourism and the ways in which cities are increasingly competing for tourists through the promotion of cultural assets and different forms of spectacle in the `tourist bubble'. To date, research on the role and impact of tourism in cities has largely been confined to those in Western, post-industrial economies. This paper examines the growth of cultural tourism in the central area of Havana, Cuba, and explores the range of unique, devolved, state-owned enterprises that are attempting to use tourism as a funding mechanism to achieve improvements in the social and cultural fabric of the city for the benefit of residents. The paper concludes with an assessment of the implications of this example for our understanding of how the pressures for restructuring and commodification can be moderated at the city level.
The Relationship between Transit Ridership and Urban Decentralisation: Insights from Atlanta
Authors: Brown Jeffrey R. , Thompson Gregory L.
Published: April 2008

Conventional wisdom suggests that the increasing decentralisation of population and employment in US metropolitan areas is to blame for declining public transit mode shares and deteriorating system productivity. Proponents of this view assert that transit performs best when it connects suburbs to central business districts in more centralised urban environments. Our time-series analysis of transit patronage in Atlanta suggests that the previously reported secular decline in transit patronage is attributable to employment decentralisation outside the MARTA service area but that this can be reduced if the transit system makes decentralising employment reachable.
Explaining Effects of Sensationalism on Liking of Television News Stories
Authors: Vettehen Paul Hendriks , Nuijten Koos , Peeters Allerd
Published: April 2008

This study investigates the appeal of sensationalist television news. News stories were content analyzed to measure the presence of sensationalist features. In addition, the stories were watched and evaluated by participants to measure the degree to which the items elicited emotional arousal and the degree to which the items were liked. As predicted, the findings showed that emotional arousal mediates effects of sensationalist features on liking and that the relationship between emotional arousal and liking takes the shape of an inverted U.
Issues in Recruitment, Retention, and Data Collection in a Longitudinal Nutrition Study of Community-Dwelling Older Adults With Early-Stage Alzheimer's Dementia
Authors: Shatenstein Bryna , Kergoat Marie-Jeanne , Reid Isabelle
Published: April 2008

The Nutrition-Memory Study (NMS) followed evolution of nutrition status among elderly community-dwelling individuals with Alzheimer's disease (AD). Participants, age-matched to cognitively intact controls, were recruited from three university hospital memory clinics. Incentives encouraged retention; flexible procedures and caregiver collaboration permitted collection of nutrition information from AD patients. Of 71 patients referred by the clinics, 55 (77.5%) were eligible, 42 (76.4% of eligible) were recruited with their caregivers, and 40 (72.7%) completed the baseline. Thirty-two patient—caregiver dyads completed the first three interviews (58.1% of eligible; 80% of recruited); 26 of the 32 dyads (81.3% of recruited) completed four of the five interviews, and 14 (43.8% of recruited) were seen at all five study visits. Ensuring successful recruitment and retention in this clientele requires strong links between the research team and target community, ensuring relevance of the study to participants, and being mindful of the burden levied on patient—caregiver dyads.
Taking Child Abuse and Mothering Into Account
Authors: Damant Dominique , Lapierre Simon , Kouraga Anne , Fortin Andrée , Hamelin-Brabant Louise , Lavergne Chantal , Lessard Geneviève
Published: April 2008

Feminist scholars have been engaged in an ongoing debate to determine which theoretical perspective offers the best framework for understanding domestic violence, and this debate has been crystallized around two pole positions: radical and postmodern feminism. This article presents a journey throughout the development of a theoretical perspective for the study of domestic violence, child abuse, and mothering. It argues that the intersectional feminist perspective has much to offer these debates and that it constitutes a promising theoretical framework for understanding domestic violence that takes into account issues of child abuse and mothering.
Depression in African American Women
Authors: Jones Lani V. , Ford Briggett
Published: April 2008

Social work interventions that emphasize culturally relevant services from a strengths-based perspective may be more appropriate than traditional mental health services for African American women who suffer from depression. An examination of the literature on epidemiology, etiology, and use of services for this population highlights the paucity of empirical studies, and an exploration of the treatment literature reveals insufficient application of culturally relevant approaches to African American women. Psychosocial competence, a strengths-based approach, and the Black feminist perspective offer the opportunity to gain a clearer understanding of the intersection and influence of oppression among depressed African American women and provide a useful framework for mental health practice with this population. A case vignette is provided, and future directions for research, practice, and policy are discussed.
A Black Woman's Journey Into a Predominately White Academic World
Authors: Carter-Black Jan
Published: April 2008

The paucity of Black women at predominately White institutions of higher education is well recognized. Like me, some Black women survived the gauntlet of coursework, qualifying examinations, and dissertation research and writing in pursuit of doctoral degrees, followed by the whirlwind campus visits that are integral to the faculty recruitment process. Upon our arrival, we were confronted by the challenges of being African American and female in a majority White university community. This article is a personal journey that spans 40 years of my life—from an 18-year-old freshman to a tenure-track assistant professor—at the same university.
Alice Paul
Authors: Hawranick Sylvia , Doris Joan M. , Daugherty Robert
Published: April 2008

Alice Paul was one of the foremost advocates for woman at the end of the Progressive Era, working successfully for passage of the 19th Amendment. In her work for suffrage, she pioneered methods and techniques that were to become standard tools for later successful social movements. She was one of the first graduates of the New York School of Applied Philanthropy and spent her early career working in both settlement houses and Charity Organization Societies; however, Paul has been conspicuously absent from the social work literature.
Factors associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico
Authors: Negrón AM , Molina MJ , Mayor AM , Rodríguez VE , Vilá LM
Published: April 2008

The aim of this study was to determine the factors associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico. A total of 204 patients with systemic lupus erythematosus (per the American College of Rheumatology classification criteria) were evaluated. Metabolic syndrome was assessed using the American Heart Association and the National Heart, Lung, and Blood Institute classification. Socioeconomic–demographic parameters, health-related behaviours, clinical manifestations, autoantibodies, pharmacological treatments, disease activity (per the Systemic Lupus Activity Measure—Revised), and damage accrual (per the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were determined at study visit. Factors associated with metabolic syndrome were examined by univariable analyses and multivariable logistic regression models. A total of 196 (96.2%) were women. The mean age at study visit was 43.6 ± 13.0 years, and the mean disease duration was 8.7 ± 7.7 years. Seventy-eight patients (38.2%) had metabolic syndrome. In the multivariable analysis, age (odds ratio [OR] = 1.05; 95% confidence interval [CI] 1.02–1.09), government health insurance (OR = 2.06; 95% CI 1.07–4.22), exercise (OR = 0.33; 95% CI 0.14–0.92), thrombocytopenia (OR = 4.19; 95% CI 1.54–11.37), erythrocyte sedimentation rate (OR = 1.64; 95% CI 1.03–2.63), disease activity (OR = 1.14; 95% CI 1.00–1.30), and prednisone >10 mg/day (OR = 3.69; 95% CI 1.22–11.11) were associated with metabolic syndrome. In conclusion, older age, low socioeconomic status, lack of exercise, thrombocytopenia, increased erythrocyte sedimentation rate , higher disease activity, and prednisone >10 mg/day were independently associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico.
Clinical and laboratory characteristics of Finnish lupus erythematosus patients with cutaneous manifestations
Authors: Koskenmies S , Järvinen TM , Onkamo P , Panelius J , Tuovinen U , Hasan T , Ranki A , Saarialho-Kere U
Published: April 2008

Our objective was to characterize clinical features, laboratory findings, concomitant autoimmune diseases, and smoking habits of lupus erythematosus subgroups in genetically homogeneous patients from two Dermatology Departments of Finnish University hospitals. One hundred and seventy eight discoid lupus erythematosus, 55 subacute cutaneous lupus erythematosus, and 77 systemic lupus erythematosus patients were enrolled using patients’ charts from institutional database (1995–2006) and during routine control visits. Clustering analysis was performed to reveal natural groupings. Smoking at the onset of disease was significantly more common in all subgroups (57% for discoid lupus erythematosus, 35% for subacute cutaneous lupus erythematosus, and 34% for systemic lupus erythematosus) compared with the age/gender-matched prevalence in the Finnish population, suggesting smoking to be a trigger factor for cutaneous lupus. Leukopenia (38%) and lymphopenia (52%) were observed more often in patients with systemic lupus erythematosus than reported previously. Photosensitivity characterized all groups, especially patients with subacute cutaneous lupus erythematosus (87%). Of the autoimmune diseases, Sjögren’s syndrome was the most common (22% of patients with systemic lupus erythematosus), followed by autoimmune thyroid disease (13% of patients with subacute cutaneous lupus erythematosus). The clustering analysis showed environmental factors (smoking) to be more involved in disease development in discoid lupus erythematosus, whereas immunological factors were more significant in initiating systemic lupus erythematosus. The high prevalence of autoimmune thyroid disease, together with photosensitivity, and the clustering profiles suggest that lupus erythematosus subtypes, especially discoid lupus erythematosus, are heterogeneic in their pathomechanisms.
Prognostic factors of lupus myelopathy
Authors: Lu X , Gu Y , Wang Y , Chen S , Ye S
Published: April 2008

Myelopathy is a rare but severe neurological manifestation of systemic lupus erythematosus (SLE) with a high morbidity. The factors that contribute to prognosis are unknown. In this study, 14 patients with lupus myelopathy (LM) from our centre were retrospectively studied. Another 23 patients with other neuropsychiatric SLE (NPSLE) features were enrolled as a comparison group. The morbidity of LM was evaluated by the ASIA Impairment Scale. The clinical and serological characteristics and prognostic factors for LM were investigated. The age, gender, duration of SLE, non-CNS disease activity and autoantibody profile in patients with LM was not different in the NPSLE cohort. A relatively low prevalence of anti–phospholipid antibodies (aPL) in LM sera compared to NPSLE (28.6% vs 52.2%, P = 0.19) was observed. Longitudinal lesion detected by magnetic resonance imaging (MRI) was identified in 33.3% of patients with LM, whereas 50% showed focal speckle-like lesions. The morbidity of LM is 50%. Muscle strength of grade 3 or higher on admission was a strong indicator for a better prognosis ( P = 0.006), whereas other parameters including longitudinal lesion, sensory deficit level, disease activity and aPL did not discriminate good from poor outcome in LM. Early aggressive immunosuppressive therapy (within 2 weeks of onset of myelopathy) tend to associate with a favourable outcome ( P = 0.07).
Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance
Authors: Vargas-Rojas MI , Crispín JC , Richaud-Patin Y , Alcocer-Varela J
Published: April 2008

Previous reports have suggested that regulatory T cells (Treg) are abnormal in patients with systemic lupus erythematosus (SLE). In the present work, we quantified CD4+FOXP3+ Treg cells in patients with SLE and found no quantitative alterations. However, we found a clear defect in suppression assays. Surprisingly, SLE-derived Treg cells exhibited a normal phenotype and functional capacity. Conversely, SLE-derived CD4+CD25− effector T cells resisted suppression by autologous and allogeneic regulatory cells. Our findings strongly suggest that the defect in T-cell suppression observed in SLE is because of effector cell resistance and not because of an abnormal regulatory function.
Cellular Automata for Distributed Sensor Networks
Authors: Allegretti Dylan G. , Kenyon Garrett T. , Priedhorsky William C.
Published: April 2008

Distributed Sensor Networks (DSNs) may be useful for detecting and tracking moving objects. Although such systems have important surveillance and homeland security applications, several technical problems exist. The cheap, low-powered sensors necessary for deployment over large areas may function poorly in low signal-to-noise environments. Although combining information from multiple sensors improves detection capabilities, long-range communication with a central computer may exhaust local power resources. We consider cellular automata rules that address these problems. By communicating locally, sensors can accurately track a moving object in a noisy environment. By communicating anonymously, they can use low-powered radio transmitters and receivers and avoid complex digital communication protocols. Our computer simulations show that DSNs can use cellular automata to greatly enhance the detection capabilities of individual sensors and reduce the amount of long-range communication by an order of magnitude.
`Without Affection or Enthusiasm' Problems of Involvement and Attachment in `Responsive' Public Management
Authors: Paul Du Gay
Published: April 2008

The paper focuses on the changing ethical template that programmes of `responsive' or `entrepreneurial' managerial reform require of civil servants. Contemporary demands for responsive public management contain two emotional injunctions to public bureaucrats. The first, derived from populist doctrines of political right, requires bureaucrats to be responsive to the needs of their `clients'. In the name of `recognition' and the `politics of care', for example, it is thought vital to inculcate in bureaucratic conduct a sense of `compassion' or close identification with others' feelings. Secondly, in the name of responsiveness to political superiors and the delivery of their policy objectives, bureaucrats are expected to exhibit `ownership' of and identification with particular policies. They are required to be committed champions for and enthusiastic advocates of those policies. Both of these injunctions are deemed to be more in tune with democratic principles and the currents of contemporary ethical culture (`diversity' or `human rights', for example) than what is represented as the unlamented Weberian world of rule-bound hierarchy. The paper seeks to question this assessment.
The Enterprising Self: An Unsuitable Job for an Older Worker
Authors: Ainsworth Susan , Hardy Cynthia
Published: April 2008

The discourse of enterprise has permeated contemporary society with significant implications for government, organizations and individuals alike. In particular, enterprise prescribes an ideal identity, that of the `enterprising self'. This study examines the ability of the older worker to become part of this enterprise culture through the analysis of an Australian government inquiry. Our findings show that certain categories of identity—such as older workers—are unable to don the mantle of enterprise, although they are nonetheless subjected to it, helping to explain why the discourse of enterprise is so persistent and durable.
Intra-Preneurship and Enrolment: Building Networks of Ideas
Authors: Whittle Andrea , Mueller Frank
Published: April 2008

In this paper we draw on and develop an actor-network perspective on organizational entrepreneurship—the study of enterprising behaviour within the firm. Based on the findings of an in-depth study of management consultants in a UK telecommunications firm, we argue that ideas do not flourish because they are inherently more `enterprising' or `innovative' than others, but rather because of the success (or otherwise) of the process of `enrolment'. Our study shows that the consultants were not `intermediaries without discretion', tasked with the diffusion of an already-established template. Rather, they acted as mediators by actively seeking to construct and maintain a network around their idea. By revealing the political tactics and power plays involved in this enrolment process, our study contributes to the actor-network literature by highlighting the link to organizational power and politics. The study also contributes by drawing attention to the subjectivity of network-builders—an issue often left under-explored in actor-network studies. We illuminate the identity processes involved in organizational entrepreneurship, including the link to systems of organizational control. This was fuelled by a mixture of anxiety, insecurity and the desire to be recognized as an `intra-preneur'.