bluuebunny/crossref_metadata_2025 huggingface dataset:
Dimensionality Reduction and Channel Selection of Motor Imagery Electroencephalographic Data
Authors: Naeem Muhammad , Brunner Clemens , Pfurtscheller Gert
Published: June 2009

The performance of spatial filters based on independent components analysis (ICA) was evaluated by employing principal component analysis (PCA) preprocessing for dimensional reduction. The PCA preprocessing was not found to be a suitable method that could retain motor imagery information in a smaller set of components. In contrast, 6 ICA components selected on the basis of visual inspection performed comparably (61.9%) to the full range of 22 components (63.9%). An automated selection of ICA components based on a variance criterion was also carried out. Only 8 components chosen this way performed better (63.1%) than visually selected components. A similar analysis on the reduced set of electrodes over mid‐central and centro‐parietal regions of the brain revealed that common spatial patterns (CSPs) and Infomax were able to detect motor imagery activity with a satisfactory accuracy.
Synthesis of Luminescent Ink from Europium-Doped Y2O3 Dispersed in Polyvinyl Alcohol Solution
Authors: Astuti  , Abdullah Mikrajuddin , Khairurrijal
Published: June 2009

Luminescent ink from europium-doped Y2O3 ( Y2O3:Eu) has been synthesized by two steps method: first, synthesis of luminescent powder of Y2O3:Eu by simple heating of metallic nitrates in a polymer solution and second, dispersing the powder in a polyvinyl alcohol (PVA) solution. The stability of the ink (luminescent colloid) was strongly affected by mixing process of the powder and the solution. Mixing process must be performed for a long time (about 8 hours) at above room temperature to product stable colloids. We observed that mixing at 30–40∘C resulted in a stable and highly dispersed colloid. The writing test was performed on a white paper to show the potential use of the colloid for making security codes.
Unique Positive Almost Periodic Solution for Discrete Nonlinear Delay Survival Red Blood Cells Model
Authors: Yang Xitao , Tang Siping
Published: June 2009

We obtain sufficient conditions which guarantee the global attractivity
of solutions for nonlinear delay survival red blood cells model. Then, some criteria are established
for the existence, uniqueness and global attractivity of positive almost periodic solutions of the
almost periodic system.
Human Schwannomas Express Activated Platelet-Derived Growth Factor Receptors and c-kit and Are Growth Inhibited by Gleevec (Imatinib Mesylate)
Authors: Mukherjee Joydeep , Kamnasaran Deepak , Balasubramaniam Anand , Radovanovic Ivan , Zadeh Gelareh , Kiehl Tim-Rasmus , Guha Abhijit
Published: June 2009

Schwannomas, although benign, can be fatal or give rise to significant morbidity due to an unpredictable growth rate. They can reoccur after surgery or radiation, current treatments each with significant inherent risks. These risks are further amplified in neurofibromatosis type 2 (NF2), a germ line predisposition syndrome characterized by multiple schwannomas, underlying the need for biological targeted therapies. Gleevec (STI571, imatinib mesylate), in addition to the bcr-abl oncogene in chronic myelogenous leukemia, inhibits c-kit and platelet-derived growth factor receptor (PDGFR) signaling, thereby expanding its use to several malignant and benign human diseases. In the present study, we show that human sporadic and NF2-associated schwannomas have increased expression along with activation of PDGFR-α, PDGFR-β, and c-kit receptors, compared with normal or traumatic nerve. Using the human NF2-null HEI-193 schwannoma cell line, Gleevec inhibited schwannoma viability, proliferation, and anchorage-independent growth, as well as induced apoptosis in a dose-dependent manner (IC50 5–10 μmol/L). These antitumorigenic effects were correlated to inhibition of PDGFR-α, PDGFR-β, and c-kit activation/phosphorylation and major downstream signaling pathways. Lack of robust xenograft or transgenic models of schwannomas prevents extension of these studies in vivo. However, the established long track record and tolerable toxicity of Gleevec already in clinical use and our preclinical data lead us to propose that Gleevec should be evaluated in human schwannomas with shown progressive growth. [Cancer Res 2009;69(12):5099–107]
Bispecific T-Cell Engaging Antibodies for Cancer Therapy
Authors: Baeuerle Patrick A. , Reinhardt Carsten
Published: June 2009

There is increasing evidence that T cells are able to control tumor growth and survival in cancer patients, both in early and late stages of the disease. However, tumor-specific T-cell responses are difficult to mount and sustain in cancer patients, and are limited by numerous immune escape mechanisms of tumor cells selected during immunoediting. An alternative approach to engage T cells for cancer therapy are antibodies, which are bispecific for a surface target antigen on cancer cells, and for CD3 on T cells. These are capable of connecting any kind of cytotoxic T cell to a cancer cell, independently of T-cell receptor specificity, costimulation, or peptide antigen presentation. Here, we review the principle of a new class of bispecific antibodies called BiTE (for “bispecific T-cell engager”) antibodies. Recent results from clinical studies with a CD19/CD3-bispecific BiTE antibody suggest that this therapeutic paradigm is finally showing promise for treatment of both bulky and minimal residual disease. [Cancer Res 2009;69(12):4941–4]
Fecal Cyclooxygenase 2 Plus Matrix Metalloproteinase 7 mRNA Assays as a Marker for Colorectal Cancer Screening
Authors: Takai Tetsunari , Kanaoka Shigeru , Yoshida Ken-ichi , Hamaya Yasushi , Ikuma Mutsuhiro , Miura Naoyuki , Sugimura Haruhiko , Kajimura Masayoshi , Hishida Akira
Published: June 2009

We previously reported that fecal cyclooxygenase 2 (COX-2) mRNA assay, detecting COX-2 mRNA in feces, is useful for identifying subjects with colorectal cancer (CRC). To further improve the sensitivity, we evaluated the usefulness of the combination of COX-2 mRNA and matrix metalloproteinase 7 (MMP-7) mRNA assays as a marker of CRC. The study cohort included 62 patients with CRC and 29 control patients without colorectal neoplasia. RNA was isolated from routinely collected fecal samples. The expression levels of COX-2 and MMP-7 mRNAs were determined by nested reverse transcription-PCR. PCR conditions were optimized where the specificity of fecal COX-2 and MMP-7 mRNA assay result in 100%. The sensitivity of each fecal assay was 87% [95% confidence interval (95% CI), 76-94%] and 65% (95% CI, 51-76%) for CRC, respectively. The sensitivity of fecal RNA test (either marker being positive) was high for CRC (90%; 95% CI, 80-96%). The sensitivity of the fecal RNA test was also high (93%; 95% CI, 80-98%) in patients with stage I or II who are often cured by surgical resection. The fecal RNA test using COX-2 and MMP-7 mRNAs improved the sensitivity to detect CRC without decreasing the specificity. These results suggest that the fecal RNA test would be a promising approach for CRC screening, although larger clinical investigations are indicated. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1888–93)
Cytokine and Cytokine Receptor Single-Nucleotide Polymorphisms Predict Risk for Non–Small Cell Lung Cancer among Women
Authors: Van Dyke Alison L. , Cote Michele L. , Wenzlaff Angie S. , Chen Wei , Abrams Judith , Land Susan , Giroux Craig N. , Schwartz Ann G.
Published: June 2009

Studies on the relationships between inflammatory pathway genes and lung cancer risk have not included African-Americans and have only included a handful of genes. In a population-based case-control study on 198 African-American and 744 Caucasian women, we examined the association between 70 cytokine and cytokine receptor single-nucleotide polymorphisms (SNPs) and risk of non–small cell lung cancer (NSCLC). Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals in a dominant model adjusting for major risk factors for lung cancer. Separate analyses were conducted by race and by smoking history and history of chronic obstructive pulmonary disease among Caucasians. Random forest analysis was conducted by race. On logistic regression analysis, IL6 (interleukin 6), IL7R, IL15, TNF (tumor necrosis factor), and IL10 SNP were associated with risk of non–small cell lung cancer among African-Americans; IL7R and IL10 SNPs were also associated with risk of lung cancer among Caucasians. Although random forest analysis showed IL7R and IL10 SNPs as being associated with risk for lung cancer among African-Americans, it also identified TNFRSF10A SNP as an important predictor. On random forest analysis, an IL1A SNP was identified as an important predictor of lung cancer among Caucasian women. Inflammatory SNPs differentially predicted risk for NSCLC according to race, as well as based on smoking history and history of chronic obstructive pulmonary disease among Caucasian women. Pathway analysis results are presented. Inflammatory pathway genotypes may serve to define a high risk group; further exploration of these genes in minority populations is warranted. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1829–40)
Novel Fucosylated Biomarkers for the Early Detection of Hepatocellular Carcinoma
Authors: Wang Mengjun , Long Ronald E. , Comunale Mary Ann , Junaidi Omer , Marrero Jorge , Di Bisceglie Adrian M. , Block Timothy M. , Mehta Anand S.
Published: June 2009

Changes in glycosylation, most notably fucosylation, have been associated with the development of hepatocellular carcinoma (HCC). In this report, the levels of fucosylated kininogen (Fc-Kin) and fucosylated α-1-antitrypsin were analyzed individually and in combination with the currently used marker, α-fetoprotein, and a previously identified biomarker, Golgi protein 73 (GP73), for the ability to distinguish between a diagnosis of cirrhosis and HCC. This analysis was done on serum from 113 patients with cirrhosis and 164 serum samples from patients with cirrhosis plus HCC. The levels of Fc-Kin and fucosylated α-1-antitrypsin were significantly higher in patients with HCC compared with those with cirrhosis (P < 0.0001). Greatest performance was achieved through the combination of Fc-Kin, α-fetoprotein, and GP73, giving an optimal sensitivity of 95%, a specificity of 70%, and an area under the receiver operating characteristic of 0.94. In conclusion, the altered glycosylation of serum glycoproteins can act as potential biomarkers of primary HCC when used independently or in combination with other markers of HCC. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1914–21)
Two Independent Prostate Cancer Risk–Associated Loci at 11q13
Authors: Zheng S. Lilly , Stevens Victoria L. , Wiklund Fredrik , Isaacs Sarah D. , Sun Jielin , Smith Shelly , Pruett Kristen , Wiley Kathleen E. , Kim Seong-Tae , Zhu Yi , Zhang Zheng , Hsu Fang-Chi , Turner Aubrey R. , Johansson Jan-Erik , Liu Wennuan , Kim Jin Woo , Chang Bao-Li , Duggan David , Carpten John , Rodriguez Carmen , Isaacs William , Grönberg Henrik , Xu Jianfeng
Published: June 2009

Single nucleotide polymorphisms (SNP) at 11q13 were recently implicated in prostate cancer risk by two genome-wide association studies and were consistently replicated in multiple study populations. To explore prostate cancer association in the regions flanking these SNPs, we genotyped 31 tagging SNPs in a ∼110 kb region at 11q13 in a Swedish case-control study (Cancer of the Prostate in Sweden), including 2,899 cases and 1,722 controls. We found evidence of prostate cancer association for the previously implicated SNPs including rs10896449, which we termed locus 1. In addition, multiple SNPs on the centromeric side of the region, including rs12418451, were also significantly associated with prostate cancer risk (termed locus 2). The two groups of SNPs were separated by a recombination hotspot. We then evaluated these two representative SNPs in an additional ∼4,000 cases and ∼3,000 controls from three study populations and confirmed both loci at 11q13. In the combined allelic test of all four populations, P = 4.0 × 10−11 for rs10896449 at locus 1 and P = 1.2 × 10−6 for rs12418451 at locus 2, and both remained significant after adjusting for the other locus and study population. The prostate cancer association at these two 11q13 loci was unlikely confounded by prostate-specific antigen (PSA) detection bias because neither SNP was associated with PSA levels in controls. Unlike locus 1, in which no known gene is located, several putative mRNAs are in close proximity to locus 2. Additional confirmation studies at locus 2 and functional studies for both loci are needed to advance our knowledge on the etiology of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1815–20)
Intakes of Fruit, Vegetables, and Carotenoids and Renal Cell Cancer Risk: A Pooled Analysis of 13 Prospective Studies
Authors: Lee Jung Eun , Männistö Satu , Spiegelman Donna , Hunter David J. , Bernstein Leslie , van den Brandt Piet A. , Buring Julie E. , Cho Eunyoung , English Dallas R. , Flood Andrew , Freudenheim Jo L. , Giles Graham G. , Giovannucci Edward , Håkansson Niclas , Horn-Ross Pamela L. , Jacobs Eric J. , Leitzmann Michael F. , Marshall James R. , McCullough Marjorie L. , Miller Anthony B. , Rohan Thomas E. , Ross Julie A. , Schatzkin Arthur , Schouten Leo J. , Virtamo Jarmo , Wolk Alicja , Zhang Shumin M. , Smith-Warner Stephanie A.
Published: June 2009

Fruit and vegetable consumption has been hypothesized to reduce the risk of renal cell cancer. We conducted a pooled analysis of 13 prospective studies, including 1,478 incident cases of renal cell cancer (709 women and 769 men) among 530,469 women and 244,483 men followed for up to 7 to 20 years. Participants completed a validated food-frequency questionnaire at baseline. Using the primary data from each study, the study-specific relative risks (RR) were calculated using the Cox proportional hazards model and then pooled using a random effects model. We found that fruit and vegetable consumption was associated with a reduced risk of renal cell cancer. Compared with <200 g/d of fruit and vegetable intake, the pooled multivariate RR for ≥600 g/d was 0.68 [95% confidence interval (95% CI) = 0.54-0.87; P for between-studies heterogeneity = 0.86; P for trend = 0.001]. Compared with <100 g/d, the pooled multivariate RRs (95% CI) for ≥400 g/d were 0.79 (0.63-0.99; P for trend = 0.03) for total fruit and 0.72 (0.48-1.08; P for trend = 0.07) for total vegetables. For specific carotenoids, the pooled multivariate RRs (95% CIs) comparing the highest and lowest quintiles were 0.87 (0.73-1.03) for α-carotene, 0.82 (0.69-0.98) for β-carotene, 0.86 (0.73-1.01) for β-cryptoxanthin, 0.82 (0.64-1.06) for lutein/zeaxanthin, and 1.13 (0.95-1.34) for lycopene. In conclusion, increasing fruit and vegetable consumption is associated with decreasing risk of renal cell cancer; carotenoids present in fruit and vegetables may partly contribute to this protection. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1730–9)
Human Papillomavirus Infections and Vulvar Disease Development
Authors: Garland Suzanne M. , Insinga Ralph P. , Sings Heather L. , Haupt Richard M. , Joura Elmar A.
Published: June 2009

Background: We describe the prevalence of 14 common types [human papillomavirus (HPV)-6/11/16/18/31/33/35/39/45/51/52/56/58/59] in vulvar intraepithelial neoplasia grades 1 to 3 (VIN 1-3) and HPV genotype–specific infection in relation to the development of VIN 1-3.

Methods: Data were analyzed from women enrolled in the placebo arms of three randomized double-blind trials. Anogenital examinations, including collection of labial/vulvar/perineal/perianal swabs, occurred at day 1 and every 6 to 12 months through 48 months. Lesions that were possibly, probably, or definitely HPV related or of unknown etiology were biopsied. Biopsies and swabs were HPV typed. Biopsies were read for endpoint determination (VIN 1-3) by up to four pathologists.

Results: Incident infection with HPV-16 was the most common (6.0/100 person-years). The mean time from incident infection to the development of VIN 1-3 was 18.5 months (95% confidence interval, 13.4-23.6). HPV-6 or -11 was observed in 64.5% of VIN 1 and 29.0% of VIN 2/3, whereas HPV-16 was observed in 6.5% of VIN 1 and 64.5% of VIN 2/3.

Conclusion: A vaccine that includes both low- and high-risk types could prevent more than half of VIN 1-3 lesions, including the precursor lesions to HPV-related vulvar carcinoma. Understanding the incidence and duration of vulvar HPV infection and risk for progression to VIN 1-3 may inform therapeutic decisions for vulvar disease and mathematical models that assess the cost-effectiveness of vaccination. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1777–84)
Mammographic Density and Breast Cancer Risk: Evaluation of a Novel Method of Measuring Breast Tissue Volumes
Authors: Boyd Norman , Martin Lisa , Gunasekara Anoma , Melnichouk Olga , Maudsley Gord , Peressotti Chris , Yaffe Martin , Minkin Salomon
Published: June 2009

Background: Mammographic density has been found to be strongly associated with risk of breast cancer. We have assessed a novel method of assessing breast tissue that is fully automated, does not require an observer, and measures the volume, rather than the projected area, of the relevant tissues in digitized screen-film mammogram.

Methods: Sixteen mammography machines in seven locations in Toronto were calibrated to allow the estimation of the proportion of radiologically dense (stromal and epithelial tissue) and nondense (fatty) tissue represented in each pixel of the mammographic image. This information was combined with a measurement of breast thickness to calculate the volumes of these tissues. Women with newly diagnosed breast cancer (cases) identified on these mammography machines during the years 2000 to 2003 were compared with other women of the same age who did not have breast cancer (controls).

Results: Three hundred sixty-four cases and 656 controls were recruited, epidemiologic data were collected, screen-film mammograms were digitized and measured using both a computer-assisted thresholding method, and the new measure of the volume of density. After adjustment for other risk factors, the odds ratio for those in the 5th quintile compared with the 1st quintile was 1.98 (95% confidence interval, 1.3-3.1) for the volume measure and 1.86 (95% CI, 1.1-3.0) for the area measurement. After inclusion of the volume and area measures in a predictive model, the volume measure lost significance, whereas the area measure remained significant.

Conclusions: Contrary to our expectations, measurement of the volume of breast tissue did not improve prediction of breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1754–62)
No Breast Cancer Association for Transforming Growth Factor-β Pathway Colorectal Cancer Single Nucleotide Polymorphisms
Authors: Gibson Lorna , Johnson Nichola , Fraser Agnes , dos Santos Silva Isabel , Houlston Richard , Peto Julian , Fletcher Olivia
Published: June 2009

SMAD7 and GREM1 are signaling components on the transforming growth factor-β pathway, which regulates normal mammary gland development and has been implicated in breast tumor invasion and metastasis. Three variants within SMAD7 and two variants in CRAC1 (a colorectal cancer–associated region on chromosome 15 in which GREM1 is located) have been associated with colorectal cancer risks [odds ratios (OR), 0.85-1.26; all P < 10−7]. We genotyped these five variants in a series of 1,267 bilateral breast cancer cases and 900 controls to determine whether they are associated with breast as well as colorectal cancer risk. None of these single nucleotide polymorphisms were associated with breast cancer risk in our study and the 95% confidence limits of our data, pooled with data from the Cancer Genetic Markers of Susceptibility study, exclude per allele ORs of <0.94 or >1.08. One or more of these variants may be associated with a very small OR for breast cancer, but our data suggest that the effects of these alleles are cancer site–specific. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1934–6)
IGF2R Missense Single-Nucleotide Polymorphisms and Breast Cancer Risk: The Multiethnic Cohort Study
Authors: Cheng Iona , Stram Daniel O. , Burtt Noël P. , Gianniny Lauren , Garcia Rachel R. , Pooler Loreall , Henderson Brian E. , Le Marchand Loïc , Haiman Christopher A.
Published: June 2009

IGF2R has been proposed to be a tumor suppressor gene given its antagonist role on cellular growth and evidence of loss of heterozygosity in several cancers, including breast cancer. To investigate whether inherited differences in potentially functional IGF2R variants influence the risk of breast cancer, we sequenced 46 exons of IGF2R to identify novel missense single-nucleotide polymorphisms (SNP) and tested 12 missense SNPs for their associations with breast cancer risk among 1,614 breast cancer cases and 1,960 controls from the Multiethnic Cohort. None of these missense SNPs were significantly associated with breast cancer risk. Our findings provide no evidence that missense SNPs in IGF2R influence breast cancer susceptibility.(Cancer Epidemiol Biomarkers Prev 2009;18(6):1922–4)
Dietary Acrylamide Intake and Prostate Cancer Risk in a Prospective Cohort of Swedish Men
Authors: Larsson Susanna C. , Åkesson Agneta , Wolk Alicja
Published: June 2009

Background: Acrylamide is a probable human carcinogen that can be formed in foods prepared at high temperatures. Whereas evidence indicates that acrylamide causes cancer in laboratory animals, epidemiologic data on dietary acrylamide intake in relation to cancer risk are limited and mainly null. We examined the association between dietary acrylamide intake and risk of prostate cancer in a cohort of men.

Methods: The Cohort of Swedish Men is a population-based prospective study of 45,306 men who were cancer-free and completed a food frequency questionnaire at enrollment in 1997. Cox proportional hazards models were used to estimate relative risks adjusted for potential confounders.

Results: During a mean follow-up of 9.1 years, we ascertained 2,696 incident cases of prostate cancer. We observed no association between acrylamide intake and risk of prostate cancer. Compared with the lowest quintile of acrylamide intake (mean, 23.7 μg/d), the multivariable relative risks (95% confidence interval) for the highest quintile (mean, 49.8 μg/d) were 0.88 (0.70-1.09) for total prostate cancer, 1.07 (0.87-1.32) for localized prostate cancer (n = 1,088), and 0.98 (0.78-1.22) for advanced prostate cancer (n = 951).

Conclusions: Results from this prospective study provide no evidence that dietary acrylamide in amounts typically consumed by Swedish men is associated with risk of prostate cancer.(Cancer Epidemiol Biomarkers Prev 2009;18(6):1939–41)
Electrochemical Sensor for Multiplex Biomarkers Detection
Authors: Wei Fang , Patel Prabhudas , Liao Wei , Chaudhry Kishore , Zhang Lei , Arellano-Garcia Martha , Hu Shen , Elashoff David , Zhou Hui , Shukla Shilin , Shah Franky , Ho Chih-Ming , Wong David T.
Published: June 2009

Purpose: Multiplexing assay of biomarkers at the point-of-care is an elusive goal for molecular diagnostics.

Experimental Design: Here, we report an electrochemical (EC) sensor for oral cancer detection based on the simultaneous detection of two salivary biomarkers: interleukin (IL)-8 mRNA and IL-8 protein.

Results: Under the multiplexing mode, the limit of detection of salivary IL-8 mRNA reaches to 3.9 fM and 7.4 pg/mL for IL-8 protein in saliva. Multiplex assay of these 2 biomarkers directly from 28 cancer and 28 matched control saliva samples shows significant difference between the two groups. From the receiver operating characteristic analysis, the EC sensor yields around 90% sensitivity and specificity for both IL-8 mRNA and IL-8 protein, which are very close to the data measured by traditional assays (ELISA and PCR) with the same group of saliva. Combined IL-8 mRNA and protein show better AUC compared with single biomarker.

Conclusions: We show, for the first time, concurrently multiplexing detection of salivary mRNA and protein biomarkers using point-of-care EC sensor.
The Pyk2 FERM domain as a target to inhibit glioma migration
Authors: Loftus Joseph C. , Yang Zhongbo , Tran Nhan L. , Kloss Jean , Viso Carole , Berens Michael E. , Lipinski Christopher A.
Published: June 2009

The invasion of malignant glioma cells into the surrounding normal brain precludes effective clinical treatment. In this report, we investigated the role of the NH2-terminal FERM domain in the regulation of the promigratory function of Pyk2. We report that the substitution of residues that constitute a small cleft on the surface of the F3 module of the FERM domain do not significantly alter Pyk2 expression but result in the loss of Pyk2 phosphorylation. A monoclonal antibody, designated 12A10, specifically targeting the Pyk2 FERM domain was generated and recognizes an epitope located on the β5C-α1C surface of the F3 module of the FERM domain. Amino acid substitutions in the F3 module that resulted in the loss of Pyk2 phosphorylation also inhibited the binding of 12A10, suggesting that the 12A10 epitope overlaps a site that plays a role in Pyk2 activity. Conjugation of 12A10 to a membrane transport peptide led to intracellular accumulation and inhibition of glioma cell migration in a concentration-dependent manner. A single chain Fv fragment of 12A10 was stable when expressed in the intracellular environment, interacted directly with Pyk2, reduced Pyk2 phosphorylation, and inhibited glioma cell migration in vitro. Stable intracellular expression of the 12A10 scFv significantly extended survival in a glioma xenograft model. Together, these data substantiate a central role for the FERM domain in regulation of Pyk2 activity and identify the F3 module as a novel target to inhibit Pyk2 activity and inhibit glioma progression. [Mol Cancer Ther 2009;8(6):1505–14]
Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice
Authors: Li Hui , Wang Dongmei , Zhang Hong , Kirmani Kashif , Zhao Zhenwen , Steinmetz Rosemary , Xu Yan
Published: June 2009

We have already established human xenographic models for the effect of lysophosphatidic acid (LPA) on tumor metastasis in vivo. The purpose of this work is to establish a preclinical LPA effect model in immunocompetent mice. We first characterized the mouse epithelial ovarian cancer (EOC) cell line ID8 for its responsiveness to LPA in cell proliferation, migration, and invasion and compared these properties with those of human EOC. The signaling pathways related to cell migration were further investigated using pharmacologic and genetic approaches. The effects of LPA on the tumorigenesis of ID8 cells and mouse survival were then examined using two different mouse models (i.p. and orthotopic injections). LPA stimulated cell proliferation, migration, and invasion of mouse EOC ID8 cells in a manner closely resembling its activity in human EOC cells. The signaling pathways involved in LPA-induced cell migration in ID8 cells were also similar to those identified in human EOC cells. We have identified cyclooxygenase-1 and 15-lipoxygenase as two new signaling molecules involved in LPA-induced cell migration in both human and mouse EOC cells. In addition, LPA enhanced the tumorigenesis/metastasis of ID8 cell in vivo as assessed by increased tumor size, early onset of ascites formation, and reduced animal survival. We have established the first LPA-EOC preclinical model in immunocompetent mice. Because ID8 cells respond to LPA similar to human EOC cells, this model is very valuable in developing and testing therapeutic reagents targeting LPA in EOC. [Mol Cancer Ther 2009;8(6):1692–701]
Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer
Authors: Dokmanovic Milos , Hirsch Dianne S. , Shen Yi , Wu Wen Jin
Published: June 2009

Although treatment with trastuzumab improves outcomes for women with ErbB2-positive breast cancer, many patients who achieve an initial response to trastuzumab subsequently acquire resistance within 1 year. Rac1, a Ras-like small GTPase, has been implicated in the control of cell growth and morphology and is believed to be associated with breast cancer progression and metastasis. Here, we show that when parental SKBR3 cells become resistant to trastuzumab, Rac1 activity is increased, leading to altered cell morphology, which is accompanied by significant cytoskeleton disorganization. Furthermore, both trastuzumab-mediated down-regulation of ErbB2 and epidermal growth factor–induced down-regulation of epidermal growth factor receptor are impaired in the trastuzumab-resistant SKBR3 cells, indicating that the endocytic down-regulation of ErbB receptors is compromised in the resistant cells. This results in an aberrant accumulation of ErbB2 on the cell surface and enhanced ErbB2 and extracellular signal-regulated kinase activity in trastuzumab-resistant SKBR3 cells. Additionally, overexpression of constitutively active Rac1G12V in parental SKBR3 cells reduces sensitivity to trastuzumab. After reduction of Rac1 activity by NSC23766, a specific Rac1 inhibitor, trastuzumab-resistant SKBR3 cells display a cellular morphology similar to parental SKBR3 cells. Moreover, we show that NSC23766 restores trastuzumab-mediated endocytic down-regulation of ErbB2 and reduces extracellular signal-regulated kinase activity in resistant SKBR3 cells. Our findings highlight an important role for Rac1 in trastuzumab resistance of human breast cancer cells and identify the impaired trastuzumab-mediated endocytic down-regulation of ErbB2 as a novel mechanism of trastuzumab resistance. The significant effects of NSC23766 on trastuzumab-resistant SKBR3 cells warrant further study of NSC23766 as a potential treatment of trastuzumab-resistant breast cancers. [Mol Cancer Ther 2009;8(6):1557–69]
Engineering a leucine zipper-TRAIL homotrimer with improved cytotoxicity in tumor cells
Authors: Rozanov Dmitri V. , Savinov Alexei Y. , Golubkov Vladislav S. , Rozanova Olga L. , Postnova Tatiana I. , Sergienko Eduard A. , Vasile Stefan , Aleshin Alexander E. , Rega Michele F. , Pellecchia Maurizio , Strongin Alex Y.
Published: June 2009

Successful cancer therapies aim to induce selective apoptosis in neoplastic cells. The current suboptimal efficiency and selectivity drugs have therapeutic limitations and induce concomitant side effects. Recently, novel cancer therapies based on the use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have emerged. TRAIL, a key component of the natural antitumor immune response, selectively kills many tumor cell types. Earlier studies with recombinant TRAIL, however, revealed its many shortcomings including a short half-life, off-target toxicity, and existence of TRAIL-resistant tumor cells. We improved the efficacy of recombinant TRAIL by redesigning its structure and the expression and purification procedures. The result is a highly stable leucine zipper (LZ)-TRAIL chimera that is simple to produce and purify. This chimera functions as a trimer in a manner that is similar to natural TRAIL. The formulation of the recombinant LZ-TRAIL we have developed has displayed high specific activity in both cell-based assays in vitro and animal tests in vivo. Our results have shown that the half-life of LZ-TRAIL is improved and now exceeds 1 h in mice compared with a half-life of only minutes reported earlier for recombinant TRAIL. We have concluded that our LZ-TRAIL construct will serve as a foundation for a new generation of fully human LZ-TRAIL proteins suitable for use in preclinical and clinical studies and for effective combination therapies to overcome tumor resistance to TRAIL. [Mol Cancer Ther 2009;8(6):1515–]
Testicular Varicocele: An Overview
Authors: Mohammed Aza , Chinegwundoh Frank
Published: June 2009

Testicular varicocele or varicocele is one of the common causes of scrotal swelling. It is predominantly found in the adolescent and young adult age group and it can adversely affect testicular function in a variety of ways. There is a considerable debate about the effects of varicoceles on future fertility, but the current evidence suggests that varicoceles are found in a higher percentage among males attending the infertility clinics and that treatment of varicoceles is associated with increased spontaneous conception rates among infertile couples. In this article we give an overall view on the aetiology, adverse effects and management of varicoceles.
Expression of DLC-1 in Clear Cell Renal Cell Carcinoma: Prognostic Significance for Progression and Metastasis
Authors: Zhang Tao , Zheng Jingcun , Liu Chunfang , Lu Yuan
Published: June 2009

Introduction: Metastatic renal cell carcinoma (RCC) remains the leading cause of mortality in patients with clear cell RCC. While deleted in liver cancer (DLC-1) is known to be closely associated with tumor growth and metastasis in several kinds of human tumors, the function of DLC-1 in clear cell RCC is unclear. Materials and Methods: We quantified DLC-1 mRNA expression in paired tumor and non-tumor samples from 62 patients in clear cell RCC using a real-time reverse transcription polymerase chain reaction (RT-PCR), and DLC-1 protein using Western blotting and immunohistochemistry. The association between DLC-1 and matrix metalloproteinase-2 were analyzed. Results: A high level of DLC-1 mRNA and protein expression in approximately 90% of normal renal specimens, the expression levels of DLC-1 in the primary tumors with synchronous metastases were lower than in those without metastases (p < 0.01). Furthermore, DLC-1 expression inversely correlated with advanced histological grade and stage (p < 0.05). Moreover, it is likely that down-regulated DLC-1 increases matrix invasion abilities of RCC via enhancing matrix metalloproteinase-2 expression. Conclusion: Together, it seems that reduced DLC-1 is involved in tumor expansion phenomena associated with tumor progression, invasion and distant metastasis of RCC.
Impact of Thymidine Phosphorylase-Expressing Macrophages for Surgical Margin in Partial Nephrectomy
Authors: Liu Hongming , Takayama Tatsuya , Ogawa Hiroshi , Kai Fumitake , Sugiyama Takayuki , Aoki Takahiro , Harada Masaki , Otsuka Atsushi , Furuse Hiroshi , Kurita Yutaka , Mugiya Soichi , Ushiyama Tomomi , Ozono Seiichiro
Published: June 2009

Objectives: We investigated the relationship between the surgical margin in partial nephrectomy (PN) and thymidine phosphorylase (TP)-expressing macrophages in peritumoral tissue of renal cell carcinoma (RCC). Methods: In 46 patients who underwent radical nephrectomy, we measured TP protein levels in tumor tissue, peritumoral tissue and normal tissue, and conducted immunohistochemical staining for TP and macrophages. In addition, we prospectively conducted PN with a 5-mm margin in 11 patients with pT1a RCC. Results: The TP protein level and TP-positive macrophages were correlated with T classification, histological grade, mode of infiltration and venous invasion. However, for pT1 RCC, TP-positive macrophages in pT1a were significantly lower than in pT1b (p = 0.0140), while there was no significant difference in TP protein levels between pT1a and pT1b. No surgical margin was positive in 11 patients who underwent PN with a 5-mm margin, and no patient had local recurrence or distant metastasis during follow-up. Conclusions: The TP protein level and TP-positive macrophages in the peritumor area are thought to be associated with tumor progression in RCC, while a similar relationship was not found in pT1a RCC. These data suggest that a 5-mm margin might be safe to reduce the risk of local recurrence when PN is performed for treatment of solitary pT1a RCC.
Our Experience with Genitourinary Fistulae
Authors: Kumar Abhay , Goyal Neeraj K. , Das Suren K. , Trivedi Sameer , Dwivedi Udai S. , Singh Pratap B.
Published: June 2009

Introduction: Our objective was to analyze the incidence, etiopathology, diagnosis and therapeutic aspects of the genitourinary fistula in an Indian population. Methods: This is a retrospective analysis of the genitourinary fistulae repaired at the Department of Urology, Institute of Medical Sciences, Banaras Hindu University, between January 1990 and December 2006. The surgical approach varied in each patient. Interposition grafts or flaps were used as and when required. The main outcomes analyzed were the incidence, etiology, surgical approaches, accessory procedure required, need for tissue interposition, cure rate per repair and overall success rate. Results: Out of 558 cases, 403 were vesicovaginal, 84 ureterovaginal, 43 urethrovaginal and 28 vesicouterine fistulae. The most common etiology was obstructed labor (72.2%), followed by hysterectomy. The transvaginal route was preferred for repair wherever possible. The transabdominal route was adopted for the repair of supratrigonal vesicovaginal, ureterovaginal and vesicouterine fistulae and if bladder augmentation was required. Conservative management was successful in 1.9% of the vesicovaginal fistulae and in 8 cases of ureterovaginal fistula. The remaining cases were managed surgically with excellent results. Conclusion: Genitourinary fistulae are not life-threatening but are socially debilitating. Surgical repair provides the definitive cure, but expectant treatment can be tried in selective patients.
Bulbocavernosus Muscle Flap for the Repair of Vesicovaginal Fistula
Authors: Fu Qiang , Bian Wei , Lv Jiajv
Published: June 2009

Introduction: Anatomical studies on the bulbocavernosus muscle (BCM) and its supporting blood vessels were performed to explore the clinical roles of BCM flaps in the repair of complicated vesicovaginal fistulas. Methods: BCM and the supporting blood vessels of 15 female adult cadavers were anatomized. Pedicled BCM flaps were transposed to repair complicated vesicovaginal fistulas in 11 patients. Results: The left side of BCMs was 9.1 ± 1.8 cm in length and 1.5 ± 0.2 cm in width, whereas the right side was 9.0 ± 1.9 cm in length and 1.5 ± 0.4 cm in width. No significant difference between the two sides was identified (p > 0.05). The bulbocavernosus (BC) artery forms an angle with the superficial transverse perineal muscle at 64 ± 14° to the left and 68 ± 15° to the right. No significant difference between the two sides was found (p > 0.05). None of the 11 patients reported any postoperative urine leakage in the vagina or urinary incontinence. Follow-ups ranging from 6 months to 10 years found no urinary incontinence or urethral stricture; all patients have normal sexual function. Conclusion: Anatomical studies of BCM and its supporting blood vessels provide useful data for clinical application, especially the reduction of muscle flap death and the increase in the cure rate of complicated vesicovaginal fistulas.
Histomorphological Differences of Spermatic Cords regarding Subinguinal versus Inguinal Levels: A Cadaveric Study
Authors: Tuccar Eray , Yaman Onder , Erdemli Esra , Zeyrek Tugba , Esmer Ali Firat , Kilic Ozcan , Avunduk Mustafa Cihat
Published: June 2009

Aim: Varicocele is a common disorder among male population and is the most common cause of secondary infertility. Microsurgical inguinal or subinguinal operations are the preferred approaches but the two differ in technical difficulty. Therefore, we examined the histomorphological differences of spermatic cords at both subinguinal and inguinal levels in this cadaveric study. Methods: Spermatic cords from 9 adult male cadavers were examined at both the inguinal and subinguinal levels using a light microscope with an image analysis program in the anatomy and histology laboratories of Ankara University Medical School between July 15, 2006 and February 15, 2007. Results: In terms of number and wall thickness, we did not observe any significant histomorphological differences in spermatic cord veins and arteries between the subinguinal and inguinal levels. Conclusion: We conclude that the subinguinal approach is not a harder technique than the inguinal approach concerning vessel dissection, but more studies must be made to compare subinguinal versus inguinal varicocelectomy.
Paratesticular Sarcomas in Brazil
Authors: Korkes Fernando , Castro Marília G. , Romero Frederico R. , Godoy Guilherme , Amary Maria F. , Fernandes Roni C. , Perez Marjo D.
Published: June 2009

Purpose: Paratesticular sarcomas are rare and frequently reported as isolated case reports. Studies evaluating the relative frequency of the paratesticular sarcomas are limited, and to the best of our knowledge, this is the first study of paratesticular sarcomas in the Brazilian population. Patients and Methods: Medical records of all patients undergoing treatment for paratesticular sarcomas between 1993 and 2006 were retrieved from the archives of our institution. Results: Complete data from 12 patients (39 ± 23 years, range 13–78) with paratesticular sarcomas were available, which represented 6.7% of all orchiectomies performed for testicular malignancies in the same period. At the time of diagnosis, 3 patients had retroperitoneal spread of the disease, all of which had elevated serum lactic dehydrogenase levels. The remaining 9 patients had normal serum markers. There were 6 rhabdomyosarcomas, 4 leiomyosarcomas, 1 liposarcoma and 1 undifferentiated sarcoma. Median follow-up was 31.4 months. Primary surgical excision by inguinal approach was performed in all cases (radical orchiectomy in 10 and preservation of the testis in 2). Retroperitoneal lymph node dissection was performed in 3 patients and excision of the hemiscrotum in 1. Eight patients received adjuvant chemotherapy. Mean overall survival time was 27.8 ± 6.2 months after orchiectomy. Conclusion: Patients with paratesticular sarcomas are at high risk of disease progression, and systemic relapse remains a significant problem, determining poor prognosis. The high risk of local recurrence demands long-term follow-up, and intraoperative frozen section analysis might be of benefit. Elevated lactic dehydrogenase might also be a marker of retroperitoneal disease and poor prognosis. Improvement in survival requires effective systemic adjuvant therapy.
Is There Any Additional Benefit of Venous Diameter and Retrograde Flow Volume as Measured by Ultrasonography to the Diagnosis of Suspected Low-Grade Varicoceles?
Authors: Bakirtas Hasan , Cakan Murat , Tuygun Can , Soylu Serra Ozbal , Ersoy Hamit
Published: June 2009

Aims: To investigate the relation between the findings of physical examination and ultrasonography and to evaluate whether venous diameter (VD) and retrograde flow volume (RFV) have any additional benefit to the diagnosis of suspected low-grade varicoceles. Methods: Five hundred and fifty-two patients who applied to our outpatient clinic due to infertility were assessed by physical examination (PE) and B-mode and color Doppler ultrasonography (CDUS). The correlation of VD and RFV with clinical grade and with each other was investigated in cases diagnosed as unilateral left varicocele. Results: Unilateral left varicocele was detected in 184 (33.3%) of 552 patients: mean VD of the subjects was 3.17 ± 1.02 mm and mean RFV in 160 patients with a reflux was 24.01 ± 13.76 ml/min. There was a correlation of clinical grade both with VD and RFV (r = 0.669, p < 0.001 and r = 0.603, p < 0.001, respectively). Considering VD and RFV, there was a significant difference between grade (G)1–G2 and G2–G3 (p < 0.001, p < 0.001, respectively) except between subclinic-G1 varicocele groups (p = 0.626, p = 0.529, respectively). The best cut-off point predicting the palpable varicocele on physical examination was 3.1 mm (sensitivity 58.2%) for VD and 14.5 ml/min (sensitivity 83.8%) for RFV. Conclusions: Measurement of RFV is more sensitive than that of VD in predicting palpable varicocele. However, neither of them seem to have any additional benefit to PE in clarifying the diagnosis of suspected low-grade varicoceles.
Painful Leg: A Very Unusual Presentation of Renal Cell Carcinoma
Authors: Gözen Ali Serdar , Canda Abdullah Erdem , Naser Muhaned , Stock Christian , Rassweiler Jens , Teber Dogu
Published: June 2009

Introduction: An unusual case of isolated synchronous solitary gastrocnemius muscle metastases of renal cell carcinoma (RCC) is reported. A review of the literature with particular emphasis on diagnostic and therapeutic approaches is also included and discussed. Material and Methods: A complete review of the English literature using MEDLINE was performed between 1979 and 2008 on RCC and skeletal muscle metastasis. Results: Overall, 23 cases have been reported to have skeletal muscle metastasis by RCC. We report a 58-year-old male patient who was admitted to the orthopedics clinic with a painful left leg swelling. Physical examination revealed a hard mass on his posterior left leg. Magnetic resonance imaging demonstrated a 2 × 4 cm sized mass. Incisional biopsy revealed surprisingly clear cell RCC metastasis. Abdominal radiologic studies demonstrated a 7 × 7 × 6 cm sized left renal mass. Left radical nephrectomy was performed with additional excision of the metastatic mass with negative surgical margins. External radiotherapy to the left leg and 3 cycles of Hannover immunochemotherapy were administered thereafter. The patient was disease-free at the first year of follow-up. Conclusions: Presentation of RCC as a solitary metastasis in the skeletal muscle is a very unusual and poorly documented site of metastasis which can be treated successfully by excision of the metastasis and renal tumor with additional local radiotherapy and immunochemotherapy.
Sebaceous Carcinoma of the Penis
Authors: Ornellas Antonio Augusto , Frota Rodrigo , Lopes da Silva Luis Felipe , Dauster Breno , Quirino Raul , de Santos Schwindt Aline Barros , Pereira Maria Rita
Published: June 2009

Sebaceous carcinoma is a very aggressive malignant tumor, derived from the adnexal epithelium of sebaceous glands. Extraocular sebaceous carcinoma is a very uncommon neoplasm usually localized on the head and neck. To our knowledge, there are only 2 previously reported cases of sebaceous carcinoma on the penis. We report the clinicopathologic data on 3 additional cases of sebaceous carcinoma arising in the penis. Treatment is debatable in view of the fact that this kind of tumor has a high recurrence rate and early regional lymph node involvement. Considering these facts, we used preoperative lymphoscintigraphy, intraoperative lymph node mapping and sentinel node biopsy before performing a bilateral inguinal lymphadenectomy in 1 of 3 patients treated in our institute.