bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing the Antitumor Activity of Adriamycin and Ionizing Radiation
Authors: Sun Wenqing , Kalen Amanda L. , Smith Brian J. , Cullen Joseph J. , Oberley Larry W. 
Published: April 2009

Abstract
Overexpression of manganese superoxide dismutase (MnSOD), when combined with certain chemicals that inhibit peroxide removal, increases cancer cell cytotoxicity. Elevating MnSOD levels in cells enhances the conversion of superoxide (O2•−) to hydrogen peroxide (H2O2), combined with inhibiting the removal of H2O2, further increases H2O2 levels, leading to increased cytotoxicity. We hypothesized that increasing endogenous O2•− production in cells that were pretreated with adenoviral MnSOD (AdMnSOD) plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) would lead to an increased level of intracellular H2O2 accumulation and increased cell killing. The cytotoxic effects of Adriamycin or radiation, agents known to produce O2•−, were determined in MDA-MB-231 breast cancer cells pretreated with AdMnSOD plus BCNU both in vitro and in vivo. In vitro, AdMnSOD plus BCNU sensitized cells to the cytotoxicity of Adriamycin or radiation. In vivo, AdMnSOD, BCNU, and Adriamycin or ionizing radiation inhibited tumor growth and prolonged survival. The results suggest that agents that produce O2•− in combination with AdMnSOD plus BCNU may represent a powerful new antitumor regimen against breast cancer. [Cancer Res 2009;69(10):4294–300]
Loss of VHL and Hypoxia Provokes PAX2 Up-Regulation in Clear Cell Renal Cell Carcinoma
Authors: Luu Van-Duc , Boysen Gunther , Struckmann Kirsten , Casagrande Silvia , von Teichman Adriana , Wild Peter J. , Sulser Tullio , Schraml Peter , Moch Holger 
Published: April 2009

Abstract
Purpose: The paired box gene 2, PAX2, encodes for a transcription factor that is up-regulated during nephrogenesis and becomes silenced in mature epithelium of the glomeruli, the proximal, and distal tubules. Reactivation of PAX2 has been frequently observed in clear cell renal cell carcinoma (ccRCC), a tumor type characterized by loss of von Hippel-Lindau (VHL) tumor suppressor function. The regulation of PAX2 expression in ccRCC is unknown.
Experimental Design: We applied reporter gene assays to investigate PAX2 promoter regulation. Furthermore, PAX2 expression was determined in ccRCC cell lines under normoxic and hypoxic condition in a VHL wild-type and mutated background. PAX2 expression was also assessed in 831 human ccRCC and correlated with hypoxia-inducible factor α (HIFα) and clinical parameters.
Results: Here, we show that both loss of VHL protein (pVHL) function and hypoxia leads to strong PAX2 reexpression. Using luciferase reporter gene assays, no induction was obtained in spite of six hypoxia response element motifs identified in the promoter of PAX2. Comprehensive immunohistochemical analyses showed significant correlations between PAX2, HIF1α, and HIF2α—target CCND1 expression patterns in ccRCC patients. Notably, PAX2 expression was highly associated with early-stage, well-differentiated ccRCC and, consequently, better clinical outcome (P &lt; 0.0001 each). Additional analyses indicated that PAX2 repressor WT1 and cancer-linked hypomethylation are not important for transcriptional regulation of PAX2 in ccRCC.
Conclusion: We conclude that in ccRCC, PAX2 reactivation is driven by HIF-dependent mechanisms following pVHL loss.
In vitroandIn vivoCharacterization of MDX-1401 for Therapy of Malignant Lymphoma
Authors: Cardarelli Pina M. , Moldovan-Loomis Maria-Cristina , Preston Ben , Black Amelia , Passmore David , Chen Tseng-Hui , Chen Sharline , Liu Jie , Kuhne Michelle R. , Srinivasan Mohan , Assad Albert , Witte Alison , Graziano Robert F. , King David J. 
Published: April 2009

AbstractPurpose: This study was undertaken to evaluate the effects of MDX-1401, a nonfucosylated fully human monoclonal antibody that binds to human CD30, and to determine whether it exhibits greater in vitro and in vivo activity than its parental antibody.Experimental Design: Assays measuring antibody binding to CD30-expressing cells and FcγRIIIa (CD16) transfectants as well as antibody-dependent cellular cytotoxicity (ADCC) were conducted. Antitumor activity was determined using a Karpas-299 systemic model.Results: The binding of MDX-1401 to CD30 antigen was identical to fucose-containing parental anti-CD30 antibody (MDX-060). In contrast, MDX-1401 showed increased binding affinity to FcγRIIIa-transfected cells resulting in increased effector function. MDX-1401 greatly improved ADCC activity as evidenced by a decrease in half-maximal effective concentration (EC50) and an increase in maximum cell lysis when compared with MDX-060. Increased ADCC activity was observed among a panel of cell lines, including one with very low CD30 antigen expression in which parental antibody failed to induce any detectable ADCC. MDX-1401 activity with all FcγRIIIa polymorphic variants, including less active Phe/Phe158 and Phe/Val158 effector cells, was shown. Furthermore, MDX-1401 was efficacious in inhibiting tumor growth in CD30+ lymphoma xenografts.Conclusions: The low doses of antibody required for ADCC activity irrespective of donor genotype, the ability to mediate ADCC in target cells expressing low levels of CD30, and increased in vivo efficacy support the development of MDX-1401 for treatment of malignant lymphoma.
Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Human BCR-ABL–Positive Cells
Authors: Kominsky Douglas J. , Klawitter Jelena , Brown Jaimi L. , Boros Laszlo G. , Melo Junia V. , Eckhardt S. Gail , Serkova Natalie J. 
Published: April 2009

Abstract
The development of imatinib resistance has become a significant therapeutic problem in which the etiology seems to be multifactorial and poorly understood. As of today, clinical criteria to predict the development of imatinib resistance in chronic myelogenous leukemia (CML), other than rebound of the myeloproliferation, are under development. However, there is evidence that the control of glucose-substrate flux is an important mechanism of the antiproliferative action of imatinib because imatinib-resistant gastrointestinal stromal KIT-positive tumors reveal highly elevated glucose uptake in radiologic images. We used nuclear magnetic resonance spectroscopy and gas chromatography mass spectrometry to assess 13C glucose uptake and metabolism (glycolysis, TCA cycle, and nucleic acid ribose synthesis) during imatinib treatment in CML cell lines with different sensitivities to imatinib. Our results show that sensitive K562-s and LAMA84-s BCR-ABL–positive cells have decreased glucose uptake, decreased lactate production, and an improved oxidative TCA cycle following imatinib treatment. The resistant K562-r and LAMA84-r cells maintained a highly glycolytic metabolic phenotype with elevated glucose uptake and lactate production. In addition, oxidative synthesis of RNA ribose from 13C-glucose via glucose-6-phosphate dehydrogenase was decreased, and RNA synthesis via the nonoxidative transketolase pathway was increased in imatinib-resistant cells. CML cells which exhibited a (oxidative/nonoxidative) flux ratio for nucleic acid ribose synthesis of &gt;1 were sensitive to imatinib. The resistant K562-r and LAMA84-r exhibited a (oxidative/nonoxidative) flux ratio of &lt;0.7. The changes in glucose uptake and metabolism were accompanied by intracellular translocation of GLUT-1 from the plasma membrane into the intracellular fraction in sensitive cells treated with imatinib, whereas GLUT-1 remained located at the plasma membrane in LAMA84-r and K562-r cells. The total protein load of GLUT-1 was unchanged among treated sensitive and resistant cell lines. In summary, elevated glucose uptake and nonoxidative glycolytic metabolic phenotype can be used as sensitive markers for early detection of imatinib resistance in BCR-ABL–positive cells.
Cancer Prevention and Treatment with Resveratrol: From Rodent Studies to Clinical Trials
Authors: Bishayee Anupam 
Published: April 2009

Abstract
Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a dietary polyphenol derived from grapes, berries, peanuts, and other plant sources. During the last decade, resveratrol has been shown to possess a fascinating spectrum of pharmacologic properties. Multiple biochemical and molecular actions seem to contribute to resveratrol effects against precancerous or cancer cells. Resveratrol affects all three discrete stages of carcinogenesis (initiation, promotion, and progression) by modulating signal transduction pathways that control cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis. The anticancer property of resveratrol has been supported by its ability to inhibit proliferation of a wide variety of human tumor cells in vitro. These in vitro data have led to numerous preclinical animal studies to evaluate the potential of this drug for cancer chemoprevention and chemotherapy. This review provides concise, comprehensive data from preclinical in vivo studies in various rodent models of human cancers, highlighting the related mechanisms of action. Bioavailability, pharmacokinetic, and potential toxicity studies of resveratrol in humans and ongoing interventional clinical trials are also presented. The conclusion describes directions for future resveratrol research to establish its activity and utility as a human cancer preventive and therapeutic drug.
Methyl-Selenium Compounds Inhibit Prostate Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate Model with Survival Benefit
Authors: Wang Lei , Bonorden Melissa J.L. , Li Guang-xun , Lee Hyo-Jeong , Hu Hongbo , Zhang Yong , Liao Joshua D. , Cleary Margot P. , Lü Junxuan 
Published: April 2009

Abstract
Chemoprevention of prostate cancer by second-generation selenium compounds in reference to selenomethionine holds strong promise to deal with the disease at the root. Here we used the transgenic adenocarcinoma mouse prostate (TRAMP) model to establish the efficacy of methylseleninic acid (MSeA) and methylselenocysteine (MSeC) against prostate carcinogenesis and to characterize potential mechanisms. Eight-week-old male TRAMP mice (C57B/6 background) were given a daily oral dose of water, MSeA, or MSeC at 3 mg Se/kg body weight and were euthanized at either 18 or 26 weeks of age. By 18 weeks of age, the genitourinary tract and dorsolateral prostate weights for the MSeA- and MSeC-treated groups were lower than for the control (P &lt; 0.01). At 26 weeks, 4 of 10 control mice had genitourinary weight &gt;2 g, and only 1 of 10 in each of the Se groups did. The efficacy was accompanied by delayed lesion progression, increased apoptosis, and decreased proliferation without appreciable changes of T-antigen expression in the dorsolateral prostate of Se-treated mice and decreased serum insulin-like growth factor I when compared with control mice. In another experiment, giving MSeA to TRAMP mice from 10 or 16 weeks of age increased their survival to 50 weeks of age, and delayed the death due to synaptophysin-positive neuroendocrine carcinomas and synaptophysin-negative prostate lesions and seminal vesicle hypertrophy. Wild-type mice receiving MSeA from 10 weeks did not exhibit decreased body weight or genitourinary weight or increased serum alanine aminotransferase compared with the control mice. Therefore, these selenium compounds may effectively inhibit this model of prostate cancer carcinogenesis.
Glutathione S-Transferase Polymorphisms and Risk of Second Primary Malignancy after Index Squamous Cell Carcinoma of the Head and Neck
Authors: Zafereo Mark E. , Sturgis Erich M. , Aleem Sal , Chaung Katrina , Wei Qingyi , Li Guojun 
Published: April 2009

Abstract
Glutathione S-transferases (GST) detoxify carcinogens in tobacco smoke, which plays a major role in development of not only squamous cell carcinoma of the head and neck (SCCHN) but also second primary malignancy (SPM) after index SCCHN.
We hypothesized that GSTM1 null, GSTT1 null, GSTP1 Ile105Val, and GSTP1 Ala114Val polymorphisms would individually and, more likely, collectively show an association with risk of SPM after index SCCHN. One thousand three hundred seventy-six incident SCCHN patients were prospectively recruited between May 1996 and December 2006, genotyped, and followed for SPM development.
One hundred ten patients (8%) developed SPM: 43 (39%) second SCCHN, 38 (35%) other tobacco-associated sites, and 29 (26%) other non–tobacco-associated sites. Patients with GSTP1 Ile105Val polymorphism had a statistically significant association with risk of SPM development (adjusted hazard ratio, 1.7; 95% confidence interval, 1.1-2.5). However, no statistically significant associations were observed with GSTM1, GSTT1, or GSTP1 Ala114Val polymorphisms. After combining risk genotypes for all four polymorphisms, rates of SPM development with 0 to 1, 2, 3, and 4 risk genotypes were 6.4%, 8.4%, 10.9%, and 15.1%, respectively, and a stepwise increase in SPM risk was observed with increasing number of risk genotypes (P = 0.004 for trend). Patients with 3 to 4 risk genotypes had a 1.7-fold increased risk for SPM compared with patients with 0 to 2 risk genotypes (hazard ratio, 1.70; 95% confidence interval, 1.2-2.5).
This large prospective cohort study supports a modestly increased risk of SPM after index SCCHN with GSTP1 Ile105Val polymorphism and an even greater risk of SPM with multiple combined GST risk genotypes.
Constitutive Short Telomere Length of Chromosome 17p and 12q but not 11q and 2p Is Associated with an Increased Risk for Esophageal Cancer
Authors: Xing Jinliang , Ajani Jaffer A. , Chen Meng , Izzo Julie , Lin Jie , Chen Zhinan , Gu Jian , Wu Xifeng 
Published: April 2009

Abstract
Shortened telomere length may cause chromosomal instability in Barrett's esophagus and thus promote tumorigenesis. However, whether short telomere length in all chromosomes or just some of them is associated with increased esophageal cancer (EC) risk is largely unknown. To address this question, we examined the overall and chromosome-specific telomere lengths of 17p, 12q, 2p, and 11q and assessed their associations with EC risk. In a case-control study with 94 EC cases and 94 matched controls, the overall telomere length and the chromosome-specific telomere lengths of 17p, 12q, 2p, and 11q in peripheral blood lymphocytes were determined by a real-time PCR and a modified single telomere length analysis assay, respectively. Multivariate logistic regression analysis was used to assess the association between telomere length and EC risk. Compared with controls, EC patients had significantly shorter overall telomere lengths (P = 0.004) and chromosome-specific telomere lengths of 17p (P = 0.003) and 12q (P = 0.006) but not of 11q (P = 0.632) and 2p (P = 0.972). Furthermore, the multivariate logistic regression analysis showed that the short overall telomere length and chromosome-specific telomere lengths of 17p and 12q were associated with a dose-dependent increase in EC risk. Our study provides the first epidemiologic evidence that short telomere length of 17p and 12q plays an important role in esophageal carcinogenesis, suggesting that short telomere length of specific chromosomes is associated with the etiology of different cancer types.
Objective Detection and Delineation of Oral Neoplasia Using Autofluorescence Imaging
Authors: Roblyer Darren , Kurachi Cristina , Stepanek Vanda , Williams Michelle D. , El-Naggar Adel K. , Lee J. Jack , Gillenwater Ann M. , Richards-Kortum Rebecca 
Published: April 2009

Abstract
Although the oral cavity is easily accessible to inspection, patients with oral cancer most often present at a late stage, leading to high morbidity and mortality. Autofluorescence imaging has emerged as a promising technology to aid clinicians in screening for oral neoplasia and as an aid to resection, but current approaches rely on subjective interpretation. We present a new method to objectively delineate neoplastic oral mucosa using autofluorescence imaging.
Autofluorescence images were obtained from 56 patients with oral lesions and 11 normal volunteers. From these images, 276 measurements from 159 unique regions of interest (ROI) sites corresponding to normal and confirmed neoplastic areas were identified. Data from ROIs in the first 46 subjects were used to develop a simple classification algorithm based on the ratio of red-to-green fluorescence; performance of this algorithm was then validated using data from the ROIs in the last 21 subjects. This algorithm was applied to patient images to create visual disease probability maps across the field of view. Histologic sections of resected tissue were used to validate the disease probability maps.
The best discrimination between neoplastic and nonneoplastic areas was obtained at 405 nm excitation; normal tissue could be discriminated from dysplasia and invasive cancer with a 95.9% sensitivity and 96.2% specificity in the training set, and with a 100% sensitivity and 91.4% specificity in the validation set. Disease probability maps qualitatively agreed with both clinical impression and histology. Autofluorescence imaging coupled with objective image analysis provided a sensitive and noninvasive tool for the detection of oral neoplasia.
Short-term Prophylactic Tamoxifen Reduces the Incidence of Antiestrogen-Resistant/Estrogen Receptor–Positive/Progesterone Receptor–Negative Mammary Tumors
Authors: Rose-Hellekant Teresa A. , Skildum Andrew J. , Zhdankin Olga , Greene Amy L. , Regal Ronald R. , Kundel Katherine D. , Kundel Donald W. 
Published: April 2009

Abstract
Although many estrogen receptor–positive (ER+) breast cancers are effectively treated with selective estrogen receptor modulators and down-regulators (SERM/SERD), some are highly resistant. Resistance is more likely if primary cancers are devoid of progesterone receptors (PR−) or have high levels of growth factor activity. In this study, a transgenic mouse line that expresses transforming growth factor-α (NRL-TGFα mice) and that develops ER+/PR− mammary tumors was used to assess the possible effects of (a) therapeutic delivery of the SERM, tamoxifen, or SERD, ICI I82,780 (ICI), on the growth of established tumors and (b) short-term prophylactic tamoxifen administration on the initial development of new mammary tumors. To determine the therapeutic effects of tamoxifen and ICI on the growth of established tumors, mice were exposed to 3 weeks of drug treatment. Neither drug influenced tumor growth or glandular pathology. To determine if early prophylactic tamoxifen could alter tumorigenesis, a 60-day tamoxifen treatment was initiated in 8-week-old mice. Compared with placebo-treated mice, tamoxifen reduced tumor incidence by 50% and significantly decreased the degree of mammary hyperplasia. Prophylactic tamoxifen also significantly extended the life span of tumor-free mice. These data show that in this mouse model, established ER+/PR− mammary tumors are resistant to SERM/SERD treatment but the development of new mammary tumors can be prevented by an early course of tamoxifen. This study validates the utility of NRL-TGFα mice for (a) identifying candidate biomarkers of efficacious tamoxifen chemoprevention and (b) modeling the evolution of tamoxifen resistance.
Nonsteroidal Anti-inflammatory Drug-Activated Gene-1 Expression Inhibits Urethane-Induced Pulmonary Tumorigenesis in Transgenic Mice
Authors: Cekanova Maria , Lee Seong-Ho , Donnell Robert L. , Sukhthankar Mugdha , Eling Thomas E. , Fischer Susan M. , Baek Seung Joon 
Published: April 2009

Abstract
The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) inhibits gastrointestinal tumorigenesis in NAG-1 transgenic mice (C57/BL6 background). In the present study, we investigated whether the NAG-1 protein would alter urethane-induced pulmonary lesions in NAG-1 transgenic mice on an FVB background (NAG-1Tg+/FVB). NAG-1Tg+/FVB mice had both decreased number and size of urethane-induced tumors, compared with control littermates (NAG-1Tg+/FVB = 16 ± 4 per mouse versus control = 20 ± 7 per mouse, P &lt; 0.05). Urethane-induced pulmonary adenomas and adenocarcinomas were observed in control mice; however, only pulmonary adenomas were observed in NAG-1Tg+/FVB mice. Urethane-induced tumors from control littermates and NAG-1Tg+/FVB mice highly expressed proteins in the arachidonic acid pathway (cyclooxygenases 1/2, prostaglandin E synthase, and prostaglandin E2 receptor) and highly activated several kinases (phospho-Raf-1 and phosphorylated extracellular signal-regulated kinase 1/2). However, only urethane-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation was decreased in NAG-1Tg+/FVB mice. Furthermore, significantly increased apoptosis in tumors of NAG-1Tg+/FVB mice compared with control mice was observed as assessed by caspase-3/7 activity. In addition, fewer inflammatory cells were observed in the lung tissue isolated from urethane-treated NAG-1Tg+/FVB mice compared with control mice. These results paralleled in vitro assays using human A549 pulmonary carcinoma cells. Less phosphorylated p38 MAPK was observed in cells overexpressing NAG-1 compared with control cells. Overall, our study revealed for the first time that the NAG-1 protein inhibits urethane-induced tumor formation, probably mediated by the p38 MAPK pathway, and is a possible new target for lung cancer chemoprevention.
Arctic Mixed-Phase Stratiform Cloud Properties from Multiple Years of Surface-Based Measurements at Two High-Latitude Locations
Authors: de Boer Gijs , Eloranta Edwin W. , Shupe Matthew D. 
Published: April 2009

Abstract
Macro- and microphysical properties of single-layer stratiform mixed-phase clouds are derived from multiple years of lidar, radar, and radiosonde observations. Measurements were made as part of the Mixed-Phase Arctic Clouds Experiment (MPACE) and the Study of Environmental Arctic Change (SEARCH) in Barrow, Alaska, and Eureka, Nunavut, Canada, respectively. Single-layer mixed-phase clouds occurred between 4% and 26% of the total time observed, varying with season and location. They had mean cloud-base heights between ∼700 and 2100 m and thicknesses between ∼200 and 700 m. Seasonal mean cloud optical depths ranged from 2.2 up. The clouds existed at temperatures of ∼242–271 K and occurred under different wind conditions, depending on season. Utilizing retrievals from a combination of lidar, radar, and microwave radiometer, mean cloud microphysical properties were derived, with mean liquid effective diameters estimated from 16 to 49 μm, mean liquid number densities on the order of 104–105 L−1, and mean water contents estimated between 0.07 and 0.28 g m−3. Ice precipitation was shown to have mean ice effective diameters of 50–125 μm, mean ice number densities on the order of 10 L−1, and mean water contents estimated between 0.012 and 0.031 g m−3. Mean cloud liquid water paths ranged from 25 to 100 g m−2. All results are compared to previous studies, and potential retrieval errors are discussed. Additionally, seasonal variation in macro- and microphysical properties was highlighted. Finally, fraction of liquid water to ice mass was shown to decrease with decreasing temperature.