bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibuprofen does not affect serum electrolyte concentrations after an ultradistance run
Authors: Dumke Charles L , Nieman David C , Oley Kevin , Lind Robert H 
Published: March 2007

Objective:To determine the effects of ibuprofen on serum electrolyte concentrations after a 160 km running race.Methods:Twenty nine subjects (mean (SD) age 47.9 (7.4) years) ingested 600 mg ibuprofen the day before, and 1200 mg ibuprofen during, a 160 km competitive trail running race (approximately every 4 h in 200 mg doses). Twenty five control subjects (mean (SD) age 46.8 (10.3) years) avoided ingestion of ibuprofen before or during the race. Blood was drawn on the day before the race and immediately after the race. Serum biochemical profiles were analysed by a clinical laboratory. Significant effects of treatment and time were determined with a general linear model with repeated measures.Results:Subjects in the two groups did not differ by age, training volume, race experience, body mass index, body fat, or finishing time (25.8 (3.3) vs 25.6 (3.9) h). Body weight did not change significantly over the race (measured before, mid-race (90 km), and after). Ibuprofen ingestion did not significantly affect any of the serum markers including creatine kinase (p = 0.16). A significant decrease in serum sodium (p = 0.006), potassium (p = 0.001), chloride (p<0.001), calcium (p<0.001), albumin (p<0.001) and globulin (p<0.001) was observed after the race. Increases were seen in creatine kinase (p<0.001), creatinine (p<0.001), blood urea nitrogen (p<0.001), uric acid (p<0.001) and glucose (p<0.001) as the result of the race.Conclusions:These data suggest that the non-specific cyclo-oxygenase inhibitor, ibuprofen, does not alter serum electrolyte concentrations during ultradistance running. However, the stress of ultradistance running appears to be related to significant changes in certain serum markers.
Bladder cancer incidence and exposure to polycyclic aromatic hydrocarbons among asphalt pavers
Authors: Burstyn Igor , Kromhout Hans , Johansen Christoffer , Langard Sverre , Kauppinen Timo , Shaham Judith , Ferro Gilles , Boffetta Paolo 
Published: March 2007

Objectives:To investigate the association between exposures to polycyclic aromatic hydrocarbons (PAH) that arises during asphalt paving, and risk of bladder cancer.Methods:7298 men included in the historical cohort were first employed between 1913 and 1999 in companies applying asphalt in Denmark, Norway, Finland and Israel. The minimal duration of employment for inclusion in the cohort was two seasons of work. Occupational histories were extracted from personnel files. A follow-up for cancer incidence was conducted through national cancer registries. The authors estimated exposures to benzo(a)pyrene as a marker for 4–6 ring PAH. Exposures were reconstructed by using information about changes in asphalt paving technology in each company over time, the modelled relation between production characteristics and exposure levels, and job histories. Relative risks and associated 95% confidence intervals were estimated using Poisson regression.Results:48 bladder cancers among asphalt paving workers were detected; of these, 39 cases were exposed at least 15 years before the diagnosis. Cumulative exposure to PAH was not associated with the incidence of bladder cancer. The association with average exposure became stronger when 15-year lag was considered, revealing a twofold increase in relative bladder cancer risk in the two higher exposure categories. There was an indication of exposure-response association with lagged averaged exposure. Risk estimates were adjusted for age, country, duration of employment and calendar period, did not show heterogeneity among countries and did not materially change when re-estimated after excluding non-primary cancers from follow-up. Previously conducted sensitivity analysis indicates that confounding by cigarette smoking is an unlikely explanation for the observed exposure-response trends.Conclusions:The authors were unable to control for all possible sources of confounding and bias. The results do not allow conclusion on the presence or absence of a causal link between exposures to PAH and risk of bladder cancer among asphalt workers.
Down-regulation of Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 Expression by Soy Isoflavones Enhances Prostate Cancer Radiotherapy In vitro and In vivo
Authors: Raffoul Julian J. , Banerjee Sanjeev , Singh-Gupta Vinita , Knoll Zvi E. , Fite Alemu , Zhang Hao , Abrams Judith , Sarkar Fazlul H. , Hillman Gilda G. 
Published: March 2007

Abstract
We previously showed that genistein, the major bioactive component of soy isoflavones, acts as a radiosensitizer and potentiates prostate tumor cell killing by radiation in vitro and in animal tumor models in vivo. However, when given alone in vivo, pure genistein promoted increased lymph node metastasis, which was not observed with a soy isoflavone mixture consisting of genistein, daidzein, and glycitein. In this study, we show that soy inhibit tumor cell growth and potentiates radiation-induced cell killing in vitro like pure genistein. In an orthotopic model, combining soy isoflavones with tumor irradiation inhibited prostate tumor growth. To determine the molecular mechanisms by which soy isoflavones potentiate radiotherapy, we investigated apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) and nuclear factor κB (NF-κB), two signaling molecules involved in survival pathways. Soy isoflavones decreased APE1/Ref-1 expression in vitro, whereas radiation up-regulated it. Pretreatment with soy isoflavones followed by radiation inhibited APE1/Ref-1 expression. APE1/Ref-1 decrease correlated with decreased DNA-binding activity of NF-κB mediated by soy isoflavones and radiation, thus promoting cell killing. In vivo treatment of prostate tumors with soy isoflavones and radiation down-regulated APE1/Ref-1 protein expression and NF-κB activity, confirming the molecular alterations observed in vitro. The down-regulation of APE1/Ref-1 and NF-κB by isoflavones, in vitro and in vivo, supports our hypothesis that these markers represent biological targets of isoflavones. Indeed, a 2-fold increase in APE1/Ref-1 expression, obtained by cDNA transfection, resulted in a 2-fold increase in NF-κB DNA-binding activity, and both of which were down-regulated by soy isoflavones, confirming the cross-talk between these molecules and, in turn, causing radiosensitization. [Cancer Res 2007;67(5):2141–9]
A Novel Small-Molecule Inhibitor of Transforming Growth Factor β Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection
Authors: Suzuki Eiji , Kim Samuel , Cheung H.-Kam , Corbley Michael J. , Zhang Xiamei , Sun Lihong , Shan Feng , Singh Juswinder , Lee Wen-Cherng , Albelda Steven M. , Ling Leona E. 
Published: March 2007

Abstract
Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor β (TGFβ). We investigated the efficacy of a novel small-molecule TGFβ type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGFβ signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC50, ∼200 nmol/L). SM16 penetrated tumor cells in vivo, suppressing tumor phosphorylated Smad2/3 levels for at least 3 h following treatment of tumor-bearing mice with a single i.p. bolus of 20 mg/kg SM16. The growth of established AB12 tumors was significantly inhibited by 5 mg/kg/d SM16 (P &lt; 0.001) delivered via s.c. miniosmotic pumps over 28 days. The efficacy of SM16 was a result of a CD8+ antitumor response because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice and (b) CD8+ T cells isolated from spleens of mice treated with SM16 showed strong antitumor cytolytic effects whereas CD8+ T cells isolated from spleens of tumor-bearing mice treated with control vehicle showed minimal activity. Treatment of mice bearing large tumors with 5 mg/kg/d SM16 after debulking surgery reduced the extent of tumor recurrence from 80% to &lt;20% (P &lt; 0.05). SM16 was also highly effective in blocking and regressing tumors when given p.o. at doses of 0.45 or 0.65 g/kg in mouse chow. Thus, SM16 shows potent activity against established AB12 malignant mesothelioma tumors using an immune-mediated mechanism and can significantly prevent tumor recurrence after resection of bulky AB12 malignant mesothelioma tumors. These data suggest that ALK5 inhibitors, such as SM16, offer significant potential for the treatment of malignant mesothelioma and possibly other cancers. [Cancer Res 2007;67(5):2351–9]
The Asn418-Linked N-Glycan of ErbB3 Plays a Crucial Role in Preventing Spontaneous Heterodimerization and Tumor Promotion
Authors: Yokoe Shunichi , Takahashi Motoko , Asahi Michio , Lee Seung Ho , Li Wei , Osumi Daisuke , Miyoshi Eiji , Taniguchi Naoyuki 
Published: March 2007

Abstract
ErbB2 and ErbB3, two members of the ErbB family, form a high-affinity heregulin coreceptor that elicits potent mitogenic and transforming signals, and clinical studies indicate that these receptors play an important role in tumor incidence and progression. To determine whether N-glycosylation is involved in the function of ErbB3, a series of human ErbB3 molecules devoid of N-glycans were prepared and transfected to Flp-In-CHO cells for stable expression. A cross-linking study showed that the Asn418 to Gln mutant (N418Q) of ErbB3 underwent autodimerization without its ligand, heregulin. The wild-type or N418Q mutant of ErbB3 was next coexpressed with ErbB2 in Flp-In-CHO cells, and the effect of N-glycan on heterodimerization was examined. The N418Q mutant of ErbB3 was autodimerized with ErbB2 without ligand stimulation, and receptor tyrosine phosphorylation and subsequent extracellular signal-regulated kinase (ERK) and Akt phosphorylation were promoted in the absence of heregulin. A cell proliferation assay and a soft agar colony formation assay showed that the N418Q mutant of ErbB3 coexpressed with ErbB2 promoted cell proliferation and colony formation in soft agar in an ERK- and Akt-dependent manner. The mutation also promoted the growth of tumors in athymic mice when injected s.c. These findings suggest that the Asn418-linked N-glycan in ErbB3 plays an essential role in regulating receptor heterodimerization with ErbB2 and might have an effect on transforming activity. [Cancer Res 2007;67(5):1935–42]
Estrogen Receptors α and β Are Inhibitory Modifiers of Apc-Dependent Tumorigenesis in the Proximal Colon of Min/+ Mice
Authors: Cho Nancy L. , Javid Sara H. , Carothers Adelaide M. , Redston Mark , Bertagnolli Monica M. 
Published: March 2007

Abstract
Estrogen replacement therapy in postmenopausal women is associated with a reduction in colorectal cancer risk, potentially via interactions between 17β-estradiol (E2) and the estrogen receptors (ER) α and β. To study the role of E2 in intestinal tumor inhibition, we separately crossed C57BL/6J-Min/+ (Min/+) mice with Erα+/− and Erβ+/− mice to generate ER-deficient Min/+ progeny. We found an increased incidence of visible colon tumors and dysplastic microadenomas in ER-deficient Min/+ relative to Er+/+Min/+ controls. Small intestinal tumor numbers were unaffected. Invasive carcinomas were found only in Erα+/−Min/+ mice, suggesting that ERα plays additional non–cell autonomous roles that limit tumor progression. Histologic analyses of ER-deficient Min/+ colons, as well as colons from ovariectomized Min/+ mice (OvxMin/+) and E2-treated OvxMin/+ mice (OvxMin/+ +E2), revealed significant differences in crypt architecture, enterocyte proliferation, and goblet cell differentiation relative to Min/+ and Er+/+Apc+/+ (wild-type) controls. The expression of ERα and ERβ was regionally compartmentalized along the colonic crypt axis, suggesting functional antagonism. Our results indicate that ERα and ERβ are inhibitory modifiers of Apc-dependent colon tumorigenesis. As a result, loss of E2 and ER signaling in postmenopausal women may contribute to colorectal cancer development. [Cancer Res 2007;67(5):2366–72]
Curcumin, a Dietary Component, Has Anticancer, Chemosensitization, and Radiosensitization Effects by Down-regulating the MDM2 Oncogene through the PI3K/mTOR/ETS2 Pathway
Authors: Li Mao , Zhang Zhuo , Hill Donald L. , Wang Hui , Zhang Ruiwen 
Published: March 2007

Abstract
The oncoprotein MDM2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and p53-independent activities. We have identified curcumin, which has previously been shown to have anticancer activity, as an inhibitor of MDM2 expression. Curcumin down-regulates MDM2, independent of p53. In a human prostate cancer cell lines PC3 (p53null), curcumin reduced MDM2 protein and mRNA in a dose- and time-dependent manner, and enhanced the expression of the tumor suppressor p21Waf1/CIP1. The inhibitory effects occur at the transcriptional level and seem to involve the phosphatidylinositol 3-kinase/mammalian target of rapamycin/erythroblastosis virus transcription factor 2 pathway. Curcumin induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM2 overexpression and knockdown reduced these effects. Curcumin also inhibited the growth of these cells and enhanced the cytotoxic effects of gemcitabine. When it was administered to tumor-bearing nude mice, curcumin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of MDM2. Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of action that may be essential for its chemopreventive and chemotherapeutic effects. Our observations help to elucidate the process by which mitogens up-regulate MDM2, independent of p53, and identify a mechanism by which curcumin functions as an anticancer agent. [Cancer Res 2007;67(5):1988–96]
PARC and CUL7 Form Atypical Cullin RING Ligase Complexes
Authors: Skaar Jeffrey R. , Florens Laurence , Tsutsumi Takeya , Arai Takehiro , Tron Adriana , Swanson Selene K. , Washburn Michael P. , DeCaprio James A. 
Published: March 2007

Abstract
CUL7 and the p53-associated, PARkin-like cytoplasmic protein (PARC) were previously reported to form homodimers and heterodimers, the first demonstration of cullin dimerization. Although a CUL7-based SKP1/CUL1/F-box (SCF)–like complex has been observed, little is known about the existence of a PARC-based SCF-like complex and how PARC interacts with CUL7-based complexes. To further characterize PARC-containing complexes, we examined the ability of PARC to form an SCF-like complex. PARC binds RBX1 and is covalently modified by NEDD8, defining PARC as a true cullin. However, PARC fails to bind SKP1 or F-box proteins, including the CUL7-associated FBXW8. To examine the assembly of PARC- and CUL7-containing complexes, tandem affinity purification followed by multidimensional protein identification technology were used. Multidimensional protein identification technology analysis revealed that the CUL7 interaction with FBXW8 was mutually exclusive of CUL7 binding to PARC or p53. Notably, although heterodimers of CUL7 and PARC bind p53, p53 is not required for the dimerization of CUL7 and PARC. The observed physical separation of FBXW8 and PARC is supported functionally by the generation of Parc−/−, Fbxw8−/− mice, which do not show exacerbation of the Fbxw8−/− phenotype. Finally, all of the PARC and CUL7 subcomplexes examined exhibit E3 ubiquitin ligase activity in vitro. Together, these findings indicate that the intricate assembly of PARC- and CUL7-containing complexes is highly regulated, and multiple subcomplexes may exhibit ubiquitin ligase activity. [Cancer Res 2007;67(5):2006–14]
Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers
Authors: Feldmann Georg , Dhara Surajit , Fendrich Volker , Bedja Djahida , Beaty Robert , Mullendore Michael , Karikari Collins , Alvarez Hector , Iacobuzio-Donahue Christine , Jimeno Antonio , Gabrielson Kathleen L. , Matsui William , Maitra Anirban 
Published: March 2007

Abstract
In the context of pancreatic cancer, metastasis remains the most critical determinant of resectability, and hence survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in pancreatic cancer invasion and metastasis because this is likely to have profound clinical implications. In pancreatic cancer cell lines, Hh inhibition with cyclopamine resulted in down-regulation of snail and up-regulation of E-cadherin, consistent with inhibition of epithelial-to-mesenchymal transition, and was mirrored by a striking reduction of in vitro invasive capacity (P &lt; 0.0001). Conversely, Gli1 overexpression in immortalized human pancreatic ductal epithelial cells led to a markedly invasive phenotype (P &lt; 0.0001) and near total down-regulation of E-cadherin. In an orthotopic xenograft model, cyclopamine profoundly inhibited metastatic spread; only one of seven cyclopamine-treated mice developed pulmonary micrometastases versus seven of seven mice with multiple macrometastases in control animals. Combination of gemcitabine and cyclopamine completely abrogated metastases while also significantly reducing the size of “primary” tumors. Gli1 levels were up-regulated in tissue samples of metastatic human pancreatic cancer samples compared with matched primary tumors. Aldehyde dehydrogenase (ALDH) overexpression is characteristic for both hematopoietic progenitors and leukemic stem cells; cyclopamine preferentially reduced “ALDH-high” cells by ∼3-fold (P = 0.048). We confirm pharmacologic Hh pathway inhibition as a valid therapeutic strategy for pancreatic cancer and show for the first time its particular efficacy against metastatic spread. By targeting specific cellular subpopulations likely involved in tumor initiation at metastatic sites, Hh inhibitors may provide a new paradigm for therapy of disseminated malignancies, particularly when used in combination with conventional antimetabolites that reduce “bulk” tumor size. [Cancer Res 2007;67(5):2187–96]
Tumor Cells Expressing Anti-CD137 scFv Induce a Tumor-Destructive Environment
Authors: Yang Yi , Yang Shilin , Ye Zhengmao , Jaffar Jade , Zhou Yifeng , Cutter Erin , Lieber Andre , Hellström Ingegerd , Hellström Karl Erik 
Published: March 2007

AbstractFor immunotherapy to become more effective, there is a need to maximize the antitumor response at the tumor site as well as to eliminate tumor cell variants that lack a given tumor antigen or the ability to present it. We have previously shown that wild-type (WT) cells from the K1735 melanoma (K1735-WT) are rejected following vaccination with cells (K1735-1D8) transfected to express scFv from the anti-CD137 monoclonal antibody 1D8, and that CD4+ T cells and natural killer (NK) cells are needed for this rejection. We now show that tumors harvested 4 to 10 days after mice had been transplanted with K1735-1D8 cells or a mixture of K1735-1D8 and K1735-WT cells contained more NK cells and that they had an increased percentage of CD4+ T lymphocytes producing IFNγ or tumor necrosis factor-α. We further show that the percentage of NK cells was higher in B16-1D8 melanomas expressing anti-CD137 scFv than in the WT tumors and that the percentage of FoxP3+ cells was lower. Admixture of 10% K1735-1D8 cells prevented the progressive growth of transplanted K1735-WT cells in syngeneic mice and also of cells from the antigenically different sarcoma Ag104. Inhibition of WT tumor cells by tumor cells transfected to express anti-CD137 scFv was shown also with the TC1 carcinoma and B16 melanoma. Furthermore, injection of an adenovirus vector, Ad-1D8, which encodes anti-CD137 scFv into established B16 melanomas, significantly prolonged the survival of tumor-bearing mice and could induce regression. Our data suggest that targeting of anti-CD137 scFv to tumors should be explored for therapy for some human cancers. [Cancer Res 2007;67(5):2339–44]
Cyclooxygenase-2 Inhibits UVB-Induced Apoptosis in Mouse Skin by Activating the Prostaglandin E2 Receptors, EP2 and EP4
Authors: Chun Kyung-Soo , Akunda Jacqueline K. , Langenbach Robert 
Published: March 2007

Abstract
Cyclooxygenase-2 (COX-2) is induced by UVB light and reduces UVB-induced epidermal apoptosis; however, the mechanism is unclear. Therefore, wild-type (WT) and COX-2−/− mice were acutely treated with UVB (5 kJ/m2), and apoptotic signaling pathways were compared. Following exposure, apoptosis was 2.5-fold higher in COX-2−/− compared with WT mice. Because prostaglandin E2 (PGE2) is the major UV-induced prostaglandin and manifests its activity via four receptors, EP1 to EP4, possible differences in EP signaling were investigated in WT and COX-2−/− mice. Following UVB exposure, protein levels of EP1, EP2, and EP4 were elevated in WT mice, but EP2 and EP4 levels were 50% lower in COX-2−/− mice. Activated cyclic AMP-dependent protein kinase (PKA) and Akt are downstream in EP2 and EP4 signaling, and their levels were reduced in UVB-exposed COX-2−/− mice. Furthermore, p-Bad (Ser136 and Ser155), antiapoptotic products of activated Akt and PKA, respectively, were significantly reduced in UVB-exposed COX-2−/− mice. To further study the roles of EP2 and EP4, UVB-exposed CD-1 mice were topically treated with indomethacin to block endogenous PGE2 production, and PGE2, the EP2 agonist (butaprost) or EP4 agonist (PGE1 alcohol), was applied. Indomethacin reduced PKA and Akt activation by ∼60%, but PGE2 and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2−/− mice by 50%. The data suggest that COX-2–generated PGE2 has antiapoptotic roles in UVB-exposed mouse skin that involves EP2- and EP4-mediated signaling. [Cancer Res 2007;67(5):2015–21]
Phenethyl Isothiocyanate Inhibits Angiogenesis In vitro and Ex vivo
Authors: Xiao Dong , Singh Shivendra V. 
Published: March 2007

Abstract
Previous studies, including those from our laboratory, have revealed that phenethyl isothiocyanate (PEITC), a constituent of many edible cruciferous vegetables, not only affords significant protection against chemically induced cancer in animal models but also inhibits growth of cancer cells in culture and in vivo by causing cell cycle arrest and apoptosis induction. We now report a novel response to PEITC involving inhibition of angiogenesis in vitro and ex vivo at pharmacologically achievable concentrations. The PEITC treatment caused a decrease in survival of human umbilical vein endothelial cells (HUVEC) in a concentration- and time-dependent manner. The capillary-like tube structure formation (in vitro neovascularization) and migration (invasion potential) by HUVEC was also inhibited significantly in the presence of PEITC at pharmacologically relevant concentrations (&lt;1 μmol/L). The PEITC-mediated inhibition of angiogenic features of HUVEC in vitro was associated with suppression of vascular endothelial growth factor (VEGF) secretion, down-regulation of VEGF receptor 2 protein levels, and inactivation of prosurvival serine-threonine kinase Akt. The PEITC treatment reduced migration by PC-3 human prostate cancer cells, which correlated with inactivation of Akt and suppression of VEGF, epidermal growth factor (EGF), and granulocyte colony-stimulating factor (G-CSF) secretion. The PEITC-mediated inhibition of PC-3 cell migration was statistically significantly attenuated by ectopic expression of constitutively active Akt. Most importantly, PEITC treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay. In conclusion, the present study suggests that inhibition of angiogenesis may be an important mechanism in cancer chemoprevention by PEITC. [Cancer Res 2007;67(5):2239–46]