bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-phase screening procedure for simulation experiments
Authors: Sanchez Susan M. , Wan Hong , Lucas Thomas W.
Published: April 2009

Analysts examining complex simulation models often conduct screening experiments to identify important factors. The controlled sequential bifurcation screening procedures CSB and CSB-X use a sequence of tests to classify factors as important or unimportant, while controlling Type I error and power. These procedures require analysts to identify the directions of the effects prior to experimentation, which can be problematic. We propose hybrid two-phase approaches, FFCSB and FFCSBX, as alternatives. Phase 1 uses an efficient fractional factorial to estimate factor effect directions; phase 2 uses CSB or CSB-X. Empirical investigations show these outperform CSB(X) in efficiency and effectiveness for many situations of practical interest.
A framework for software safety in safety-critical systems
Authors: Medikonda Ben Swarup , Panchumarthy Seetha Ramaiah
Published: April 2009

Software for safety-critical systems must deal with the hazards identified by safety analysis in order to make the system safe, risk-free, and fail-safe. Because human lives may be lost and tremendous economic costs may result if the software fails, the development of high-integrity software adopts practices that impose greater rigor on the software development processes. Software safety is a composite of many factors. Existing software quality models like McCall's and Boehm's and ISO 9126 are inadequate in addressing the software safety issues of real time safety-critical embedded systems. At present there does not exist any standard framework that comprehensively addresses the factors, criteria and metrics (FCM) approach of the quality models in respect of software safety. The safety of a software component must be considered within the context of both the overall system of which it is a component and the environment in which this system operates. It is not useful to investigate the safety of a software component in isolation. This paper proposes a new framework for software safety based on the McCall's software quality model that specifically identifies the criteria corresponding to software safety in safety critical applications. The criteria in the proposed software safety framework pertains to system hazard analysis, completeness of requirements, identification of software-related safety-critical requirements, safety-constraints based design, run-time issues management, and software safety-critical testing. This framework is then applied to a prototype safety-critical system viz. a software--based Railroad Crossing Control System (RCCS) to validate its utility.
Categorizing web queries
Authors: Nelson Stephen , Bayrak Coşkun
Published: April 2009

Over the past ten years, the user base for the World Wide Web (WWW) has grown over 400% [1]. This increased user base has naturally led to an enormous amount of data available for users to search. Corporations, such as Google, often store user search records and there are many concerns, as well as positive aspects, for how search records may be used. One aspect in particular, categorizing web queries, presents several challenges. This paper will discuss the challenging aspects of categorizing web queries, review previous categorical research, and conclude with a method for tackling one of the challenging aspects.
Initial observations on economics, pricing, and penetration of the internet of things market
Authors: Bohli Jens-Matthias , Sorge Christoph , Westhoff Dirk
Published: April 2009

One expectation about the future Internet is the participation of billions of sensor nodes, integrating the physical with the digital world. This Internet of Things can offer new and enhanced services and applications based on knowledge about the environment and the entities within. Millions of micro-providers could come into existence, forming a highly fragmented market place with new business opportunities to offer commercial services. In the related field of Internet and Telecommunication services, the design of markets and pricing schemes has been a vital research area in itself. We discuss how these findings can be transferred to the Internet of Things. Both the appropriate market structure and corresponding pricing schemes need to be well understood to enable a commercial success of sensor-based services. We show some steps that an evolutionary establishment of this market might have to take.
Double-blind reviewing
Authors: Schulzrinne Henning
Published: April 2009

In double-blind reviewing (DBR), both reviewers and authors are unaware of each others' identities and affiliations. DBR is said to increase review fairness. However, DBR may only be marginally effective in combating the randomness of the typical conference review process for highly-selective conferences. DBR may also make it more difficult to adequately review conference submissions that build on earlier work of the authors and have been partially published in workshops. I believe that DBR mainly increases the perceived fairness of the reviewing process, but that may be an important benefit. Rather than waiting until the final stages, the reviewing process needs to explicitly address the issue of workshop publications early on.
NF-κB regulates thrombin-induced ICAM-1 gene expression in cooperation with NFAT by binding to the intronic NF-κB site in the ICAM-1 gene
Authors: Xue Jiaping , Thippegowda Prabhakar B. , Hu Guochang , Bachmaier Kurt , Christman John W. , Malik Asrar B. , Tiruppathi Chinnaswamy
Published: April 2009

Activation of NF-κB is essential for protease-activated receptor-1 (PAR-1)-mediated ICAM-1 expression in endothelial cells. Here we show that PAR-1 activation induces binding of both p65/RelA and NFATc1 to the NF-κB binding site localized in intron-1 of the ICAM-1 gene to initiate transcription in endothelial cells. We discovered the presence of two NF-κB binding sites in intron-1 (+70, NF-κB site 1; +611, NF-κB site 2) of the human ICAM-1 gene. Chromatin immunoprecipitation results showed that thrombin induced binding of p65/RelA and of NFATc1 specifically to intronic NF-κB site 1 of the ICAM-1 gene. Electrophoretic mobility shift and supershift assays confirmed the binding of p65/RelA and NFATc1 to the intronic NF-κB site 1 in thrombin-stimulated cells. Thrombin increased the expression of ICAM-1-promoter-intron 1-reporter (−1,385 to +234) construct ∼25-fold and mutation of intronic NF-κB site 1 markedly reduced thrombin-induced reporter expression. Moreover, inhibition of calcineurin, knockdown of either NFATc1 or p65/RelA with siRNA significantly reduced thrombin-induced ICAM-1 expression and polymorphonuclear leukocyte adhesion to endothelial cells. In contrast, NFATc1 knockdown had no effect on TNF-α-induced ICAM-1 expression. Thus these results suggest that p65/RelA and NFATc1 bind to the intronic NF-κB site 1 sequence to induce optimal transcription of the ICAM-1 gene in response to thrombin in endothelial cells.
Adhesion of Respiratory‐Infection‐Associated Microorganisms on Degradable Thermoplastic Composites
Authors: Tirri Teemu , Söderling Eva , Malin Minna , Peltola Matti , Seppälä Jukka V. , Närhi Timo O.
Published: April 2009

The purpose of this study was to evaluate bacterial adhesion and early colonization on a composite consisting of bioactive glass (BAG) particles and copolymer of ε‐caprolactone/D,L‐lactide. Materials were incubated with suspensions of both type strains and clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa for 30 minutes (adhesion) and 4 hours (colonization). Clear differences exist in the microorganisms′ ability to adhere on the experimental materials. However, the presence of BAG particles does not inhibit bacterial adhesion, but early colonization of the materials with P. aeruginosa was inhibited by the addition of 90–315 μm BAG particles.
Defective Repair of Oxidative DNA Damage in Triple-Negative Breast Cancer Confers Sensitivity to Inhibition of Poly(ADP-Ribose) Polymerase
Authors: Alli Elizabeth , Sharma Vandana B. , Sunderesakumar Preethi , Ford James M.
Published: April 2009

Subtypes of breast cancer that represent the two major types of epithelial cells in the breast (luminal and basal) carry distinct histopathologic profiles. Breast cancers of the basal-like subtype, which include the majority of hereditary breast cancers due to mutations in the breast cancer susceptibility gene 1 (BRCA1), frequently assume triple-negative status, i.e., they lack expression of estrogen receptor-α and progesterone receptor, and lack overexpression or amplification of the HER2/NEU oncogene. Defects in DNA damage response pathways result in genome instability and lead to carcinogenesis, but may also be exploited for therapeutic purposes. We analyzed repair of oxidative DNA damage by the base-excision repair (BER) pathway, which when aberrant leads to genomic instability and breast carcinogenesis, in cell lines that represent the different subtypes of breast cancer and in the presence of BRCA1 deficiency. We found that basal-like and BRCA1-mutated breast cancer cells were defective in BER of oxidative DNA damage, and that this defect conferred sensitivity to inhibition of poly(ADP-ribose) polymerase, a DNA repair enzyme. The defect may be attributed, at least in part, to a novel role for BRCA1 in the BER pathway. Overall, these data offer preventive, prognostic, and therapeutic usefulness. [Cancer Res 2009;69(8):3589–96]
Detection of Precancerous Cervical Lesions Is Differential by Human Papillomavirus Type
Authors: Safaeian Mahboobeh , Schiffman Mark , Gage Julia , Solomon Diane , Wheeler Cosette M. , Castle Philip E.
Published: April 2009

Epidemiologic studies have reported the underrepresentation of cervical precancerous lesions caused by human papillomavirus (HPV) types 18 and 45 (HPV18/45) compared with the proportion of cervical cancers attributed to these HPV types. We investigated the timing of diagnosis of histologic cervical intraepithelial neoplasia grade 3 or worse (CIN3+) using data from the atypical squamous cells of undetermined significance–low-grade squamous intraepithelial lesion triage study (ALTS). Of the 2,725 women who underwent enrollment colposcopy, 412 of 472 (87.3%) diagnosed with histologic CIN3+ over the 2-year duration of ALTS could be assigned to a HPV type or group of types and were included in this analysis. Eighty-four percent of HPV16-positive CIN3+ were diagnosed at enrollment, compared with 57% of HPV18/45-positive CIN3+, and 58% of CIN3 positive for other carcinogenic HPV types at enrollment. In contrast, only 8% of HPV16-positive CIN3+ were diagnosed at exit, whereas 31% were HPV18/45 positive and 22% were positive for other carcinogenic types at study exit (P < 0.001). These results indicate the underrepresentation of HPV18/45 in precancers, whereas HPV16-associated CIN3+ is diagnosed much earlier. Whether the underrepresentation of 18/45 may be due to occult pathology needs further investigation. [Cancer Res 2009;69(8):3262–6]
Thrombin Induces Tumor Cell Cycle Activation and Spontaneous Growth by Down-regulation of p27Kip1, in Association with the Up-regulation of Skp2 and MiR-222
Authors: Hu Liang , Ibrahim Sherif , Liu Cynthia , Skaar Jeffrey , Pagano Michele , Karpatkin Simon
Published: April 2009

The effect of thrombin on tumor cell cycle activation and spontaneous growth was examined in synchronized serum-starved tumor cell lines and a model of spontaneous prostate cancer development in TRAMP mice. BrdUrd incorporation and propidium iodide staining of prostate LNCaP cells arrested in G0 and treated with thrombin or serum revealed a 48- and 29-fold increase in S phase cells, respectively, at 8 hours. Similar results were obtained with TRAMP cells and a glioblastoma cell line, T98G. Cell cycle kinases and inhibitors in synchronized tumor cells revealed high levels of p27Kip1 and low levels of Skp2 and cyclins D1 and A. Addition of thrombin, TFLLRN, or serum down-regulated p27Kip1 with concomitant induction of Skp2, Cyclin D1, and Cyclin A with similar kinetics. LNCaP p27Kip1-transfected cells or Skp2 knockdown cells were refractory to thrombin-induced cell cycle activation. MicroRNA 222, an inhibitor of p27Kip1, was robustly up-regulated by thrombin. The in vitro observations were tested in vivo with transgenic TRAMP mice. Repetitive thrombin injection enhanced prostate tumor volume 6- to 8-fold (P < 0.04). Repetitive hirudin, a specific potent antithrombin, decreased tumor volume 13- to 24-fold (P < 0.04). Thus, thrombin stimulates tumor cell growth in vivo by down-regulation of p27Kip1. [Cancer Res 2009;69(8):3374–81]
New Tricks for Animal MicroRNAs: Targeting of Amino Acid Coding Regions at Conserved and Nonconserved Sites
Authors: Rigoutsos Isidore
Published: April 2009

MicroRNAs (miRNA) are short RNAs that affect the expression of a protein-coding gene either by directing the degradation of its “target” mRNA or by disrupting its translation into amino acids. Target selection depends on the underlying sequence as well as other, currently not understood, factors. In plants, miRNAs typically interact with the amino acid coding region of the target mRNA. However, in animals, research has been nearly exclusively confined to studying miRNA interactions with the 3′ untranslated region of their mRNA targets. This region-limited view of animal miRNA activity, together with the assumption that bona fide animal miRNA targets ought to be conserved across organisms, have been in effect for many years. Recent work has shown that miRNAs can target extensively the amino acid coding region of animal mRNAs and can do so at locations that are not necessarily conserved across organisms. [Cancer Res 2009;69(8):3245–8]
Childhood Soy Intake and Breast Cancer Risk in Asian American Women
Authors: Korde Larissa A. , Wu Anna H. , Fears Thomas , Nomura Abraham M.Y. , West Dee W. , Kolonel Laurence N. , Pike Malcolm C. , Hoover Robert N. , Ziegler Regina G.
Published: April 2009

Introduction: Historically, breast cancer incidence has been substantially higher in the United States than in Asia. When Asian women migrate to the United States, their breast cancer risk increases over several generations and approaches that for U.S. Whites. Thus, modifiable factors, such as diet, may be responsible.

Methods: In this population-based case-control study of breast cancer among women of Chinese, Japanese, and Filipino descent, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California) and Oahu (Hawaii), we interviewed 597 cases (70% of those eligible) and 966 controls (75%) about adolescent and adult diet and cultural practices. For subjects with mothers living in the United States (39% of participants), we interviewed mothers of 99 cases (43% of eligible) and 156 controls (40%) about the daughter's childhood exposures. Seventy-three percent of study participants were premenopausal at diagnosis.

Results: Comparing highest with lowest tertiles, the multivariate relative risks (95% confidence interval) for childhood, adolescent, and adult soy intake were 0.40 (0.18-0.83; Ptrend = 0.03), 0.80 (0.59-1.08; Ptrend = 0.12), and 0.76 (0.56-1.02; Ptrend = 0.04), respectively. Inverse associations with childhood intake were noted in all three races, all three study sites, and women born in Asia and the United States. Adjustment for measures of westernization attenuated the associations with adolescent and adult soy intake but did not affect the inverse relationship with childhood soy intake.

Discussion: Soy intake during childhood, adolescence, and adult life was associated with decreased breast cancer risk, with the strongest, most consistent effect for childhood intake. Soy may be a hormonally related, early-life exposure that influences breast cancer incidence. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1050–9)
Age of Diagnosis of Squamous Cell Cervical Carcinoma and Early Sexual Experience
Authors: Edelstein Zoe R. , Madeleine Margaret M. , Hughes James P. , Johnson Lisa G. , Schwartz Stephen M. , Galloway Denise A. , Carter Joseph J. , Koutsky Laura A.
Published: April 2009

Background: Given the established links among young age at first intercourse (AFI), number of sex partners, high-risk human papillomavirus infection, and squamous cell cervical cancer (SCC), we hypothesized that women diagnosed with SCC at younger ages would be more likely to report young AFI than women diagnosed later in life.

Methods: We performed a population-based investigation among invasive SCC cases who were diagnosed between 1986 and 2004, were ages 22 to 53 years, and lived in the metropolitan Seattle-Puget Sound region (n = 333). Using multivariate linear regression, we estimated coefficients and 95% confidence intervals (95% CI) to assess the association between age at SCC diagnosis and AFI (<15, 15-18, ≥19 years) and number of sex partners at age <20 years (0, 1, 2-4, 5-14, ≥15), accounting for birth year and other factors. Interactions were assessed using the likelihood ratio test.

Results: The interval between AFI and SCC diagnosis ranged from 4 to 35 years. In a multivariate model, compared with SCC cases reporting AFI ≥19, the mean age of diagnosis was 3.1 years younger for SCC cases reporting AFI <15 (95% CI, -5.8 to -0.5) and 2.6 years younger for SCC cases reporting AFI 15 to 18 (95% CI, -4.6 to -0.6). Although number of sex partners at age <20 years was associated with age at SCC diagnosis in a crude analysis, the association was not independent of AFI. However, in the AFI ≥19 and <15 groups, differences in effect were seen by number of sex partners at age <20 years (Pinteraction = 0.08), with the association remaining strong and significant only in the AFI <15 group that had ≥2 partners at age <20 years (coefficient, -4.2; 95% CI, -6.3 to -2.1).

Conclusion: Among younger and middle-aged women with SCC, early age of diagnosis was associated with early AFI, although the effect appeared to be modified by number of sex partners at age <20 years. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1070–6)
Gender is an Age-Specific Effect Modifier for Papillary Cancers of the Thyroid Gland
Authors: Kilfoy Briseis A. , Devesa Susan S. , Ward Mary H. , Zhang Yawei , Rosenberg Philip S. , Holford Theodore R. , Anderson William F.
Published: April 2009

Background: Thyroid cancer incidence rates have increased worldwide for decades, although more for papillary carcinomas than other types and more for females than males. There are few known thyroid cancer risk factors except female gender, and the reasons for the increasing incidence and gender differences are unknown.

Methods: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results 9 Registries Database for cases diagnosed during 1976-2005 to develop etiological clues regarding gender-related differences in papillary thyroid cancer incidence. Standard descriptive epidemiology was supplemented with age-period-cohort (APC) models, simultaneously adjusted for age, calendar-period and birth-cohort effects.

Results: The papillary thyroid cancer incidence rate among females was 2.6 times that among males (9.2 versus 3.6 per 100,000 person-years, respectively), with a widening gender gap over time. Age-specific rates were higher among women than men across all age groups, and the female-to-male rate ratio declined quite consistently from more than five at ages 20-24 to 3.4 at ages 35-44 and approached one at ages 80+. APC models for papillary thyroid cancers confirmed statistically different age-specific effects among women and men (P < 0.001 for the null hypothesis of no difference by gender), adjusted for calendar-period and birth-cohort effects.

Conclusion: Gender was an age-specific effect modifier for papillary thyroid cancer incidence. Future analytic studies attempting to identify the risk factors responsible for rising papillary thyroid cancer incidence should be designed with adequate power to assess this age-specific interaction among females and males. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1092–100)
Components of Metabolic Syndrome and Metachronous Colorectal Neoplasia
Authors: Ashbeck Erin L. , Jacobs Elizabeth T. , Martínez María Elena , Gerner Eugene W. , Lance Peter , Thompson Patricia A.
Published: April 2009

Background: The consistent association between obesity and colorectal cancer is thought to be explained by metabolic disturbances common, but not exclusive, to the obese.

Methods: We assessed the relation between metachronous neoplasia and the components of metabolic syndrome (MetS) as defined by the National Cholesterol Education Program's Adult Treatment Panel III in 2,392 participants of two previously conducted chemoprevention trials. Waist circumference, fasting plasma glucose, trigylcerides, high-density lipoprotein, and systolic and diastolic blood pressure were measured at baseline.

Results: MetS classification was associated with increased odds of metachronous neoplasia among women [odds ratio (OR), 1.37; 95% confidence interval (95% CI), 1.01-1.85] but not among men (OR, 0.99; 95% CI, 0.81-1.21). High waist circumference in men (OR, 1.41; 95% CI, 1.15-1.72) and women (OR, 1.41; 95% CI, 1.05-1.90) and elevated fasting glucose in women (OR, 1.46; 95% CI, 1.09-1.96), as defined by Adult Treatment Panel III cutpoints, were associated with increased odds, whereas none of the other criteria were independently associated with metachronous neoplasia. When each trait was evaluated using quartiles, elevated glucose among women and large waist circumference among men were significantly associated with metachronous lesions. Exploratory analysis of waist circumference and fasting glucose suggested an interaction, where only the combination of large waist circumference and elevated glucose conferred significant increased odds of metachronous neoplasia among both men (OR, 1.36; 95% CI, 1.04-1.78; Pinteraction = 0.08) and women (OR, 1.83; 95% CI, 1.26-2.67; Pinteraction = 0.12).

Conclusions: These results suggest that, of the specific components of MetS, those that capture impaired glucose uptake increased the odds of metachronous neoplasia. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1134–43)
Associations between Polymorphisms in DNA Repair Genes and Glioblastoma
Authors: McKean-Cowdin Roberta , Barnholtz-Sloan Jill , Inskip Peter D. , Ruder Avima M. , Butler MaryAnn , Rajaraman Preetha , Razavi Pedram , Patoka Joe , Wiencke John K. , Bondy Melissa L. , Wrensch Margaret
Published: April 2009

A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme, the most common and deadliest form of adult brain tumors. Genetic data for ∼1,000 glioblastoma multiforme cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies on adult glioblastoma multiforme, including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M. D. Anderson Cancer Center, and the University of California at San Francisco. Twelve DNA repair single-nucleotide polymorphisms were selected for investigation in the pilot collaborative project. The C allele of the PARP1 rs1136410 variant was associated with a 20% reduction in risk for glioblastoma multiforme (odds ratioCT or CC, 0.80; 95% confidence interval, 0.67-0.95). A 44% increase in risk for glioblastoma multiforme was found for individuals homozygous for the G allele of the PRKDC rs7003908 variant (odds ratioGG, 1.44; 95% confidence interval, 1.13-1.84); there was a statistically significant trend (P = 0.009) with increasing number of G alleles. A significant, protective effect was found when three single-nucleotide polymorphisms (ERCC2 rs13181, ERCC1 rs3212986, and GLTSCR1 rs1035938) located near each other on chromosome 19 were modeled as a haplotype. The most common haplotype (AGC) was associated with a 23% reduction in risk (P = 0.03) compared with all other haplotypes combined. Few studies have reported on the associations between variants in DNA repair genes and brain tumors, and few specifically have examined their impact on glioblastoma multiforme. Our results suggest that common variation in DNA repair genes may be associated with risk for glioblastoma multiforme. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1118–26)
Association of Nonsteroidal Anti-Inflammatory Drugs with Lung Cancer: Results from a Large Cohort Study
Authors: Slatore Christopher G. , Au David H. , Littman Alyson J. , Satia Jessie A. , White Emily
Published: April 2009

Background: Lung cancer is the most common cause of cancer-related mortality. Smoking cessation is crucial to decrease risk, but additional prevention modalities are needed. The use of nonsteroidal anti-inflammatory drugs (NSAID) may be promising.

Methods: The study was a prospective cohort of 77,125 men and women, ages 50 to 76 years, from Washington state recruited in 2000 to 2002 (the VITamin And Lifestyle study). Lung cancer cases were identified through the Seattle-Puget Sound Surveillance, Epidemiology and End Results cancer registry during 5 years of follow-up. Hazard ratios (HR) associated with 10-year average use of total NSAIDs (excluding low-dose aspirin) and specific categories of NSAIDs were calculated for total incident lung cancer and specific morphologies.

Results: A total of 665 lung cancer cases were identified. After adjusting for smoking, age, gender, and acetaminophen use, there was a borderline-significant inverse trend with total NSAID use [>4.2 d/wk for >10 years versus none: HR, 0.82; 95% confidence interval (95% CI), 0.64-1.04; P for trend = 0.05]. The association was strongest for adenocarcinoma (HR, 0.59; 95% CI, 0.37-0.94; P for trend = 0.01) and seemed to be limited to men (HR, 0.66; 95% CI, 0.47-0.92; P for trend = 0.01) and to long-term (≥10 years) former smokers (HR, 0.65; 95% CI, 0.44-0.96; P for trend = 0.04). There were no appreciable differences by NSAID type.

Conclusions: Total NSAID use was associated with a small reduced risk of lung cancer, which was strongest for adenocarcinoma, men, and long-term former smokers. These findings are supported by known lung carcinogenesis mechanisms and suggest that NSAIDS may be useful for chemoprevention. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1203–7)
Role of Eotaxin-1 Signaling in Ovarian Cancer
Authors: Levina Vera , Nolen Brian M. , Marrangoni Adele M. , Cheng Peng , Marks Jeffrey R. , Szczepanski Miroslaw J. , Szajnik Marta E. , Gorelik Elieser , Lokshin Anna E.
Published: April 2009

Purpose: Tumor cell growth and migration can be directly regulated by chemokines. In the present study, the association of CCL11 with ovarian cancer has been investigated.

Experimental Design and Results: Circulating levels of CCL11 in sera of patients with ovarian cancer were significantly lower than those in healthy women or women with breast, lung, liver, pancreatic, or colon cancer. Cultured ovarian carcinoma cells absorbed soluble CCL11, indicating that absorption by tumor cells could be responsible for the observed reduction of serum level of CCL11 in ovarian cancer. Postoperative CCL11 levels in women with ovarian cancer negatively correlated with relapse-free survival. Ovarian tumors overexpressed three known cognate receptors of CCL11, CC chemokine receptors (CCR) 2, 3, and 5. Strong positive correlation was observed between expression of individual receptors and tumor grade. CCL11 potently stimulated proliferation and migration/invasion of ovarian carcinoma cell lines, and these effects were inhibited by neutralizing antibodies against CCR2, CCR3, and CCR5. The growth-stimulatory effects of CCL11 were likely associated with activation of extracellular signal-regulated kinase 1/2, MEK1, and STAT3 phosphoproteins and with increased production of multiple cytokines, growth factors, and angiogenic factors. Inhibition of CCL11 signaling by the combination of neutralizing antibodies against the ligand and its receptors significantly increased sensitivity to cisplatin in ovarian carcinoma cells.

Conclusion: We conclude that CCL11 signaling plays an important role in proliferation and invasion of ovarian carcinoma cells and CCL11 pathway could be targeted for therapy in ovarian cancer. Furthermore, CCL11 could be used as a biomarker and a prognostic factor of relapse-free survival in ovarian cancer.
RhoGDI2 Expression Is Associated with Tumor Growth and Malignant Progression of Gastric Cancer
Authors: Cho Hee Jun , Baek Kyoung Eun , Park Sun-Mi , Kim In-Kyu , Choi Yeong-Lim , Cho Hye-Jung , Nam In-Koo , Hwang Eun Mi , Park Jae-Yong , Han Jae Yoon , Kang Sang Soo , Kim Dong Chul , Lee Won Sup , Lee Mi-Ni , Oh Goo Taeg , Kim Jae Won , Lee Chang Won , Yoo Jiyun
Published: April 2009

Purpose: Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of Rho family GTPase. However, there is currently no direct evidence suggesting whether RhoGDI2 activates or inhibits Rho family GTPase in vivo (and which type), and the role of RhoGDI2 in tumor remains controversial. Here, we assessed the effects of RhoGDI2 expression on gastric tumor growth and metastasis progression.

Experimental Design: Proteomic analysis was done to investigate the tumor-specific protein expression in gastric cancer and RhoGDI2 was selected for further study. Immunohistochemistry was used to detect RhoGDI2 expression in clinical samples of primary gastric tumor tissues which have different pathologic stages. Gain-of-function and loss-of-function approaches were done to examine the malignant phenotypes of the RhoGDI2-expressing or RhoGDI2-depleting cells.

Results: RhoGDI2 expression was correlated positively with tumor progression and metastasis potential in human gastric tumor tissues, as well as cell lines. The forced expression of RhoGDI2 caused a significant increase in gastric cancer cell invasion in vitro, and tumor growth, angiogenesis, and metastasis in vivo, whereas RhoGDI2 depletion evidenced opposite effects.

Conclusion: Our findings indicate that RhoGDI2 is involved in gastric tumor growth and metastasis, and that RhoGDI2 may be a useful marker for tumor progression of human gastric cancer.
Fine Mapping of Chromosome 6q23-25 Region in Familial Lung Cancer Families Reveals RGS17 as a Likely Candidate Gene
Authors: You Ming , Wang Daolong , Liu Pengyuan , Vikis Haris , James Michael , Lu Yan , Wang Yian , Wang Min , Chen Qiong , Jia Dongmei , Liu Yan , Wen Weidong , Yang Ping , Sun Zhifu , Pinney Susan M. , Zheng Wei , Shu Xiao-Ou , Long Jirong , Gao Yu-Tang , Xiang Yong-Bing , Chow Wong-Ho , Rothman Nat , Petersen Gloria M. , de Andrade Mariza , Wu Yanhong , Cunningham Julie M. , Wiest Jonathan S. , Fain Pamela R. , Schwartz Ann G. , Girard Luc , Gazdar Adi , Gaba Colette , Rothschild Henry , Mandal Diptasri , Coons Teresa , Lee Juwon , Kupert Elena , Seminara Daniela , Minna John , Bailey-Wilson Joan E. , Amos Christopher I. , Anderson Marshall W.
Published: April 2009

Purpose: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP).

Experimental Design: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members.

Results: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels.

Conclusion: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.
Increased Vascular Endothelial Growth Factor-C Expression Is Insufficient to Induce Lymphatic Metastasis in Human Soft-Tissue Sarcomas
Authors: Lahat Guy , Lazar Alexander , Wang Xuemei , Wang Wei-Lien , Zhu Quan-Sheng , Hunt Kelly K. , Pollock Raphael E. , Lev Dina
Published: April 2009

Purpose: Unlike carcinomas, soft-tissue sarcoma (STS) rarely exhibit lymphatic spread. Consequently, we examined expression and function of vascular endothelial growth factor (VEGF)-C and STS-associated lymphatic vessel density (LVD) components of this process.

Experimental Design: VEGF-C and VEGF-A mRNA and VEGF-C protein expression were evaluated in STS, STS cell lines, and breast cancers (reverse transcription-PCR, quantitative reverse transcription-PCR, and ELISA). STS cell conditioned medium after VEGF-C knockdown was examined for endothelial cell proliferation and migration effects (MTS and migration assays). Paraffin-embedded human lymph node-negative and lymph node-positive STS and lymph node-negative and lymph node-positive breast cancers were examined for VEGF-C, D2-40, and CD31 expression (immunohistochemistry). LVD differences were analyzed by Wilcoxon rank-sum tests.

Results: STS and breast cancer VEGF-C expression was comparable and higher than normal tissue levels. STS cells secreted functional VEGF-C: STS conditioned medium induced lymphatic endothelial cell proliferation and migration, which was abrogated by STS cell VEGF-C knockdown. STS and breast cancer intratumoral LVD was similar. STS peritumoral LVD (PT-LVD) was reduced versus breast cancer PT-LVD (P < 0.001). Significantly higher PT-LVD was observed in lymph node-positive versus lymph node-negative STS; lymphatic spreading STS subtypes also had higher LVD. STS VEGF-C expression and PT-LVD lacked correlation, and many lymph node-negative STS had high PT-LVD, suggesting complexity in this metastatic process.

Conclusions: Compared with breast cancers, STS exhibited lower PT-LVD independent of VEGF-C expression, which may underlie STS lymph node metastasis rarity. Moreover, lymphatic vessels appear necessary but not sufficient to sustain STS lymphatic spread. Examining STS “nonlymphatic” dissemination may help elucidate mechanisms of lymphatic spread, insights critically important to cancer metastasis control.
Surgical Stress Promotes Tumor Growth in Ovarian Carcinoma
Authors: Lee Jeong-Won , Shahzad Mian M.K. , Lin Yvonne G. , Armaiz-Pena Guillermo , Mangala Lingegowda S. , Han Hee-Dong , Kim Hye-Sun , Nam Eun Ji , Jennings Nicholas B. , Halder Jyotsnabaran , Nick Alpa M. , Stone Rebecca L. , Lu Chunhua , Lutgendorf Susan K. , Cole Steve W. , Lokshin Anna E. , Sood Anil K.
Published: April 2009

Purpose: Surgical stress has been suggested to facilitate the growth of preexisting micrometastases as well as small residual tumor postoperatively. The purpose of this study was to examine the effects of surgical stress on ovarian cancer growth and to determine underlying mechanisms responsible for increased growth.

Experimental Design: To mimic the effects of surgery, we did a laparotomy or mastectomy under isoflurane inhalation on athymic nude mice 4 days after i.p. tumor cell injection. Propranolol infusion via Alzet pumps was used to block the influence of sympathetic nervous system activation by surgical stress.

Results: In both HeyA8 and SKOV3ip1 models, the mice in the laparotomy and mastectomy groups had significantly greater tumor weight (P < 0.05) and nodules (P < 0.05) compared with anesthesia only controls. There was no increase in tumor weight following surgery in the β-adrenergic receptor–negative RMG-II model. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for β-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment.

Conclusion: These results indicate that surgical stress could enhance tumor growth and angiogenesis, and β-blockade might be effective in preventing such effects.
Skin Occlusion: Treatment or Drug-Like Device?
Authors: Berardesca E. , Maibach H.I.
Published: April 2009

The effects of occlusion on skin function are described and reviewed. Occlusion seems to be not only a device applied on the skin surface, but, under certain conditions, a powerful treatment capable of inducing several changes on epidermal metabolism, skin flora, sweat glands and epidermal morphology.
Immunohistochemical Screening for Neurochemical Markers in Uremic Patients on Maintenance Hemodialysis
Authors: Johansson O. , Hilliges M. , Han S.-W. , Ståhle-Bäckdahl M. , Hägermark Ö.
Published: April 2009

The epidermis and dermis of 12 uremic patients on maintenance hemodialysis were investigated utilizing the indirect immunofluorescence technique as a tool to study the distribution of neurochemical markers, such as neuropeptides. No differences between controls and the patients were revealed.
Influence of the Size of the Area of Treatment on Percutaneous Absorption of Estradiol in the Rat
Authors: Chanez J.F. , de Lignières B. , Marty J.P. , Wepierre J.
Published: April 2009

The influence of the dose, as well as the application area of topically applied 3H-estradiol in a volatile solution on its systemic bioavailability was investigated in hairless rats in vivo. The bioavailability was determined by comparing the urinary and fecal excretion of radioactivity after intravenous injection and after topical application. Whatever the size of the surface of application (1, 4 or 16 cm2), the bioavailability was similar (47–65%) 4 days after the application of a single low dose (50 nmol). When the surface of application was washed 24 h after dosing, the absorption was the same for the areas of 3 and 9 cm2. In all cases average fluxes on the first day were higher for the larger area. When applied doses were increased (1,000 and 10,000 nmol), the percentage of percutaneous absorption decreased with the reduction in the areas of application. Thus, with a dose of 1,000 nmol applied on a surface of 1, 4 and 16 cm2, absorption was equal to 18.7, 21 and 37%, respectively, of the dose. There was a linear relationship between the log of the dose applied per unit of skin area and the percentage of absorption after 4 days (r = 0.99 with washing; r = 0.98 without washing). For a determined dose of estradiol (D) it is thus possible to predict the total quantity (Q) which will be absorbed depending on the application area (A) according to the relationship: Q=(-alogD/A + b)/100 ×D, where a and b are equal to 18.7 and 73.8, respectively, for an application without washing and 20.4 and 68.8 with washing. From these results it appears that when estradiol is applied in a volatile solvent at low concentration the horny layer acts as a reservoir. After evaporation of the vehicle and for a single dose the bioavailability is equivalent for a large range of application areas. Thus, with a volatile solvent it would not appear necessary to control both the dose and the surface of application in order to obtain controlled dosage for systemic effects.
Migration of Polymorphonuclear Leukocytes in Psoriasis
Authors: van de Kerkhof P.C.M. , Chang A.
Published: April 2009

A characteristic feature of the early and active psoriatic lesion is the intraepidermal penetration of polymorphonuclear leukocytes (PMN) with the formation of intraepidermal micropustules of Kogoj and microabscesses of Munro, localized in the stratum corneum. In pustular psoriasis the accumulation of PMN dominates the clinical picture. During the last decade our insight into the regulation of the migration of PMN has increased. The properties of the circulating blood PMN and the biochemical nature and biological effects of mediators of inflammation have been studied in detail. Several groups have demonstrated that the transdermal and epidermal migration of PMN following challenge with a chemoattractant is slightly diminished in the clinically uninvolved skin and profoundly decreased in the lesional skin of psoriatics, compared to the responsiveness in normal controls. The molecular nature of this process of tachyphylaxis has not yet been established. However, it has been hypothesised that some mediators of inflammation, cytochrome P-450, endothelial cell function, and protease inhibitors might be of relevance in this respect. This report is a review of the literature on transdermal and epidermal migration of PMN in normal and psoriatic skin. The aim of this review is to clarify further the position of the PMN in the pathogenesis of psoriasis and its role as a target for antipsoriatic treatments.
Topical Corticosteroids Delay the Proliferative Response to Sellotape Stripping
Authors: Bauer F.W. , Boezeman J.B.M. , Rijzewijk J.J. , de Grood R.M.
Published: April 2009

Tape stripping of normal human skin results in a hyperproliferative response brought about by a recruitment of resting (G₀) cells. The effect of diprosone and hydrocortisone on this response was studied by flow cytometric techniques. Both corticosteroids were found to delay the appearance of the cohort of recruited cells in the S-phase, the more potent antipsoriatic (diprosone) giving the greatest delay. These data indicate that corticosteroids cause a temporary block in late G1 or an inhibition of the recruitment process itself. The model may serve for the evaluation of (future) antipsoriatic drugs.
Effect of Antihistamines on Argon Laser-Induced Cutaneous Sensory and Pain Thresholds and on Histamine-Induced Wheal and Flare
Authors: Bjerring Peter
Published: April 2009

A double-blind, randomized, placebo-controlled comparison of the analgesic and antihistaminic effects of four commonly used antihistamines (terfenadine, antazoline, diphenhydramine and cimetidine) was performed. Wheal and flare areas after histamine skin prick and sensory and pain thresholds induced by cutaneous argon laser irradiation were determined. Terfenadine, antazoline and diphenhydramine significantly reduced wheal and flare after histamine skin pricks. Only diphenhydramine increased the pain threshold to noxious cutaneous laser stimulations (22%) with a concomitant reduction of histamine wheal (61.5%) and flare (52.8%). The sensory threshold was not affected significantly. The antihistaminic and analgesic effects were not related.
Experimental Evidence for Amide Hydrolysis of Indomethacin in Rabbit Skin
Authors: Behrendt Hans , Korting Hans C.
Published: April 2009

Amide hydrolysis of indomethacin was investigated in rabbit skin using the isolated perfused rabbit ear model. Indomethacin was applied topically on the surface area of 4 rabbit ears using a 1 % alcoholic solution (Elmetacin®). Indomethacin and its hydrolytic product N-deschloro-benzoyl-indomethacin (DBI) were determined in the venous efflux. The concentrations of indomethacin and DBI increased during the first 160 min and remained constant thereafter, the concentrations amounting from 0.041 ± 0.001 to 0.497 ± 0.018 nmol/min/cm2 (indomethacin) and from 0.84 ± 0.03 to 3.24 ± 0.31 pmol/min/cm2 (DBI). Thus steady state was reached with both substances, indicating a formation of DBI in the range of 0.65–2.01 %. Considering the low hydrolytic turnover rate, the limited efficacy of topically applied indomethacin in the treatment of skin diseases does not seem to be due to extensive metabolic inactivation via amide hydrolysis in this target organ.
Studies on the Pharmacokinetics and Metabolism of Prednicarbate after Cutaneous and Oral Administration
Authors: Barth J. , Lehr K.H. , Derendorf H. , Möllmann H.W. , Höhler T. , Hochhaus G.
Published: April 2009

Prednicarbate (PC) is a nonhalogenated derivative of prednisolone which is used for the local treatment of corticoid-sensitive skin diseases. In this study, the pharmacokinetics and the metabolism of PC in humans are investigated after cutaneous ointment application (75 mg PC) and after systemic oral administration (40 mg PC) in 8 healthy volunteers. In addition, the possible suppression of endogenous cortisol secretion by both application forms was monitored. After oral administration no intact PC, but significant levels of the first metabolite prednisolone-17-ethylcarbon-ate (PRED-17-EC) were determined. PRED-17-EC was further metabolized with a half life of 1.6 h to prednisolone. After percutaneous administration neither PC nor other known metabolites could be detected system-ically. The low systemic bioavailability after dermal application was also reflected in an unchanged cortisol secretion pattern. According to animal studies our metabolic studies in humans suggest that the prednisolone-17-ester PRED-17-EC, which has a receptor binding affinity comparable to that of dexamethasone is the pharmacologically active compound. As PRED-17-EC subsequently undergoes an inactivation step to the low active prednisolone this may be the reason for the dissociation of good local efficacy and low systemic side effects.
Effect of Inducers on the Activity of Glutathione S-Transferase and Other Enzymes of the Glutathione Pathway in Cultured Human Keratinocytes
Authors: Vessey Donald A. , Lee Kyung-Hee , Blacker Kerry L. , Boyer Thomas D.
Published: April 2009

Known inducers of the hepatic glutathione (GSH) S-transferases were tested at the limits of their solubility as inducers of the enzyme in cultured human keratinocytes. Neither phenobarbital, trans-stilbene oxide, propylthiouracil, nor butylated hydroxyanisole increased GSH S-transferase activity or led to the appearance of α- or μ-forms of the enzyme, as judged by Western blotting. Only the π-form of the enzyme was found before and after all treatments. Thus, the enzyme is not indu-cible in keratinocytes. However, 4 mM propylthiouracil did lead to a 50% increase in GSH reductase activity, and phenobarbital at 4 mM completely abolished GSH peroxidase and GSH reductase activity and led to a significant loss of viability.
Increased Superoxide Anion Production in Dermal Fibroblasts of Psoriatic Patients
Authors: Er-raki A. , Charveron M. , Bonafé J.L.
Published: April 2009

We studied the superoxide anion activity of psoriatic and normal dermal fibroblasts in culture. Superoxide anion production was measured by the technique of Pick and Mizel in fibroblasts cultured from biopsies of involved and uninvolved skin of patients with psoriasis and from skin biopsies of normal controls. Our results show that the liberation of superoxide anion was sig nificantly increased (p < 0.001) in fibroblasts obtained from involved areas of skin (5.58 nmol O2-/106cells/50 min) and also from uninvolved skin (p < 0.01) (4.60 nmol O2-/106 cells/50 min) of psoriatic patients, compared to controls (2.25 nmol O2-/106 cells/50 min). The increase in superoxide anion liberation was 100 and 150% in uninvolved and involved psoriatic fibroblasts, respectively. This suggests an important role for dermal fibroblasts in the inflammatory mechanism of psoriasis.