bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stress-Activated Mitogen-Activated Protein Kinases c-Jun NH2-Terminal Kinase and p38 Target Cdc25B for Degradation
Authors: Uchida Sanae , Yoshioka Katsuji , Kizu Ryoichi , Nakagama Hitoshi , Matsunaga Tsukasa , Ishizaka Yukihito , Poon Randy Y.C. , Yamashita Katsumi 
Published: August 2009

Abstract
Cdc25 dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Of the three mammalian Cdc25 isoforms, Cdc25A is phosphorylated by genotoxic stress–activated Chk1 or Chk2, which triggers its SCFβ-TrCP–mediated degradation. However, the roles of Cdc25B and Cdc25C in cell stress checkpoints remain inconclusive. We herein report that c-Jun NH2-terminal kinase (JNK) induces the degradation of Cdc25B. Nongenotoxic stress induced by anisomycin caused rapid degradation of Cdc25B as well as Cdc25A. Cdc25B degradation was dependent mainly on JNK and partially on p38 mitogen-activated protein kinase (p38). Accordingly, cotransfection with JNK1, JNK2, or p38 destabilized Cdc25B. In vitro kinase assays and site-directed mutagenesis experiments revealed that the critical JNK and p38 phosphorylation site in Cdc25B was Ser101. Cdc25B with Ser101 mutated to alanine was refractory to anisomycin-induced degradation, and cells expressing such mutant Cdc25B proteins were able to override the anisomycin-induced G2 arrest. These results highlight the importance of a novel JNK/p38-Cdc25B axis for a nongenotoxic stress–induced cell cycle checkpoint. [Cancer Res 2009;69(16):6438–44]
Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells
Authors: Masamha Chioniso Patience , Benbrook Doris Mangiaracina 
Published: August 2009

Abstract
D- and E-type cyclins mediate G1-S phase cell cycle progression through activation of specific cyclin-dependent kinases (cdk) that phosphorylate the retinoblastoma protein (pRb), thereby alleviating repression of E2F-DP transactivation of S-phase genes. Cyclin D1 is often overexpressed in a variety of cancers and is associated with tumorigenesis and metastasis. Loss of cyclin D can cause G1 arrest in some cells, but in other cellular contexts, the downstream cyclin E protein can substitute for cyclin D and facilitate G1-S progression. The objective of this study was to determine if a flexible heteroarotinoid anticancer compound, SHetA2, regulates cell cycle proteins and cell cycle progression in ovarian cancer cells. SHetA2 induced cyclin D1 phosphorylation, ubiquitination, and proteasomal degradation, causing G1 arrest in ovarian cancer cells despite continued cyclin E2 expression and independently of p53 and glycogen synthase kinase-3β. Cyclin D1 loss inhibited pRb S780 phosphorylation by cyclin D1-cdk4/6 and released p21 from cyclin D1-cdk4/6-p21 protein complexes to form cyclin E2-cdk2-p21 complexes, which repressed phosphorylation of pRb S612 by cyclin E2-cdk2 and ultimately E2F-DP transcriptional activity. G1 arrest was prevented by overexpression or preventing degradation of cyclin D1 but not by restoration of pRb S612 phosphorylation through p21 knockdown. In conclusion, we show that loss of cyclin D1 in ovarian cancer cells treated with SHetA2 is sufficient to induce G1 cell cycle arrest and this strategy is not impeded by the presence of cyclin E2. Therefore, cyclin D1 is a sufficient therapeutic target in ovarian cancer cells. [Cancer Res 2009;69(16):6565–72]
Sorafenib Inhibits Non–Small Cell Lung Cancer Cell Growth by Targeting B-RAF in KRAS Wild-Type Cells and C-RAF in KRAS Mutant Cells
Authors: Takezawa Ken , Okamoto Isamu , Yonesaka Kimio , Hatashita Erina , Yamada Yuki , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: August 2009

Abstract
Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non–small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G1 arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G1 arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G1 arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G1 arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant KRAS, respectively. The G1 arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. [Cancer Res 2009;69(16):6515–21]
Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease–Associated Colorectal Cancer
Authors: Edwards Robert A. , Witherspoon Mavee , Wang Kehui , Afrasiabi Kambiz , Pham Trang , Birnbaumer Lutz , Lipkin Steven M. 
Published: August 2009

Abstract
Sporadic human mismatch repair (MMR)–deficient colorectal cancers account for ∼12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein α subunit Giα2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Giα2−/− colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Giα2−/− cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Giα2−/− colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Giα2−/− crypts. Treating Giα2−/− mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase–dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer. [Cancer Res 2009;69(16):6423–9]
A Prospective Study of Dietary Polyunsaturated Fatty Acids and Colorectal Cancer Risk in Chinese Women
Authors: Murff Harvey J. , Shu Xiao-Ou , Li Honglan , Dai Qi , Kallianpur Asha , Yang Gong , Cai Hui , Wen Wanqing , Gao Yu-Tang , Zheng Wei 
Published: August 2009

Abstract
In animal models of colon cancer, n-3 polyunsaturated fatty acids (PUFA) have antineoplastic properties, whereas n-6 PUFAs may promote carcinogenesis. Prior epidemiologic studies have been inconsistent regarding the association of PUFAs and colorectal cancer. We prospectively evaluated the association between PUFA intake and colorectal cancer in a cohort of 73,242 Chinese women who were interviewed in person at the baseline survey for the Shanghai Women's Health Study. Dietary fatty acid consumption was derived using data collected from two food frequency questionnaires administered at baseline and 2 to 3 years later. The dietary total n-6 to n-3 PUFA ratio was strongly associated with colorectal cancer risk. Compared with women in the lowest quintile group, elevated relative risks (RR) were observed for the second [RR, 1.52; 95% confidence intervals (CI), 1.00-2.32], third (RR, 2.20; 95% CI, 1.41-3.45), fourth (RR, 1.65; 95% CI, 0.99-2.75), and fifth (RR, 1.95; 95% CI, 1.07-3.54) quintile groups. Arachidonic acid was associated with colorectal cancer risk with elevated RRs of 1.20Q2-Q1 (95% CI, 0.87-1.64), 1.44Q3-Q1 (95% CI, 1.05-1.98), 1.61Q4-Q1 (95% CI, 1.17-2.23), and 1.39Q5-Q1 (95% CI, 0.97-1.99; Ptrend = 0.03) with increasing dietary quintile. In a subset of 150 cancer cases and 150 controls, we found a statistically significant trend between an increasing n-6 to n-3 PUFA ratio and increasing production of prostaglandin E2 (PGE2) as measured by urinary PGE2 metabolites (P = 0.03). These results suggest that dietary PUFA and the ratio of n-6 to n-3 PUFA intake may be positively associated with colorectal cancer risk, and this association may be mediated in part through PGE2 production. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2283–91)
Socioeconomic and Racial Patterns of Colorectal Cancer Screening among Medicare Enrollees in 2000 to 2005
Authors: Doubeni Chyke A. , Laiyemo Adeyinka O. , Reed George , Field Terry S. , Fletcher Robert H. 
Published: August 2009

Abstract
Background: Lower rates of screening among minorities and low-income populations contribute to colorectal cancer health disparities. Therefore, we examined patterns of colorectal cancer screening and associations with race-ethnicity, education, and income over time.
Methods: Repeated cross-sectional data from the Medicare Current Beneficiary Survey of noninstitutionalized colorectal cancer–free Medicare enrollees ages 65 to 80 years interviewed in 2000 (n = 8,355), 2003 (n = 7,922), and 2005 (n = 7,646). We examined rates of colonoscopy/sigmoidoscopy use within 5 years (recent endoscopy), colonoscopy/sigmoidoscopy use &gt;5 years previously, or fecal occult blood test (FOBT) within 2 years.
Results: Among those included in the analyses, there was a steady increase in recent endoscopy rates and decrease in FOBT use over the 6-year period among all racial, educational, and income groups. During each of the survey years, those less educated or in lower-income groups were less likely to undergo colorectal cancer screening in a dose-response fashion. In multinomial regression analyses that adjusted for factors including health insurance, there were no significant differences in recent endoscopy or FOBT rates between Blacks or Hispanics and Whites, but differences by education and income remained. Compared with those in higher-income group, lower-income enrollees had lower rates of screening, and differences by income were larger for enrollees residing in metropolitan areas.
Conclusion: Among Medicare beneficiaries, there are persistent colorectal cancer screening disparities due to a complex combination of socioeconomic disadvantages from lower education and income, place of residence, and inadequate insurance. However, insurance alone does not eliminate socioeconomic differences in colorectal cancer screening. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2170–5)
Uptake of Risk-Reducing Surgery in Unaffected Women at High Risk of Breast and Ovarian Cancer Is Risk, Age, and Time Dependent
Authors: Evans D. Gareth R. , Lalloo Fiona , Ashcroft Linda , Shenton Andrew , Clancy Tara , Baildam Andrew D. , Brain Anne , Hopwood Penelope , Howell Anthony 
Published: August 2009

Abstract
Purpose: The uptake of risk-reducing surgery in women at increased risk of breast and ovarian cancer is highly variable between countries and centers within countries. We have investigated the rate, timing, and age of uptake of surgery in the northwest of England to report the results after up to 7 years in a Regional Genetics center.
Methods: Uptake was documented in 211 known unaffected BRCA1/2 mutation carriers from 509 families and in 3,515 women at &gt;25% lifetime risk of breast cancer without known mutations.
Results: Of the 211 mutation carriers, 40% opted for bilateral risk-reducing mastectomy (BRRM) and 45% underwent bilateral risk-reducing salpingo-oophorectomy (BRRSPO). Uptake of BRRM was significantly related to lifetime risk and age but continued over several years. In women not known to carry a BRCA mutation, 6.4% of women at 40% to 45% lifetime risk, 2.5% of women at 33% to 39% lifetime risk, and 1.8% of women at 25% to 32% lifetime risk underwent BRRM (P &lt; 0.005). BRRSPO uptake was greater in BRCA1 (52%) than BRCA2 (28%) carriers but in both groups tended to occur within the first 2 years after gene test (except in the youngest age group) and in women between the ages of 35 and 45.
Conclusion: To truly assess the uptake of risk-reducing surgery, longer-term follow-up is necessary particularly in younger women who are likely to delay BRRSPO. Careful risk counseling does seem to influence women's decisions for surgery, although the effect is not immediate. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2318–24)
Genetic Variation in Immune Regulation and DNA Repair Pathways and Stomach Cancer in China
Authors: Hussain Shehnaz K. , Mu Li-Na , Cai Lin , Chang Shen-Chih , Park Sungshim Lani , Oh Sam S. , Wang Yiren , Goldstein Binh Y. , Ding Bao-Guo , Jiang Qingwu , Rao Jianyu , You Nai-Chieh Y. , Yu Shun-Zhang , Papp Jeanette C. , Zhao Jin-Kou , Wang Hua , Zhang Zuo-Feng 
Published: August 2009

Abstract
The incidence of stomach cancer is high in certain parts of the world, particularly in China. Chronic Helicobacter pylori infection is the main risk factor, yet the vast majority of infected individuals remain unaffected with cancer, suggesting an important role of other risk factors. We conducted a population-based case-control study including 196 incident stomach cancer cases and 397 matched controls to test the hypothesis that adverse single nucleotide polymorphism (SNP) genotypes and haplotypes within genes of the DNA repair and immune regulatory pathways are associated with increased stomach cancer risk. Genomic DNA isolated from blood samples was used for genotyping, and results were obtained for 57 putatively functional SNPs in 28 genes. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from adjusted logistic regression models. For PTGS2, a gene involved in the inflammatory response, associations with stomach cancer risk were observed for TC genotype carriers of rs5279 (OR, 0.24; 95% CI, 0.08-0.73), CT genotype carriers of the 3′-untranslated region SNP rs689470 (OR, 7.49; 95% CI, 1.21-46.20), and CTTC haplotype carriers of rs5277, rs5278, rs5279, and rs689470 (OR, 0.41; 95% CI, 0.18-0.95). For ERCC5, a gene involved in nucleotide excision repair, TC genotype carriers of rs1047768 (OR, 0.65; 95% CI, 0.41-1.03), GC genotype carriers of the nonsynonymous SNP rs2227869 (OR, 0.30; 95% CI, 0.13-0.67), and CCG haplotype carriers of rs1047768, rs17655, and rs2227869 (OR, 0.45; 95% CI, 0.20-1.04) were associated with reduced stomach cancer risk. In conclusion, PTGS2 and ERCC5 were associated with stomach cancer risk in a Chinese population. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2304–9)
Qualitative Age Interactions between Low-grade and High-grade Serous Ovarian Carcinomas
Authors: Grimley Philip M. , Matsuno Rayna K. , Rosenberg Philip S. , Henson Donald E. , Schwartz Arnold M. , Anderson William F. 
Published: August 2009

Abstract
Purpose: Ovarian epithelial carcinomas, including the predominant serous ovarian carcinoma (SOC) type, are heterogeneous malignancies. Even though invasive SOCs of low and high grade can be distinguished by morphology and molecular or immunohistochemical profiles, age-specific risks relevant to their separate carcinogenic pathways and clinical features have not been fully explored.
Methods: In search of further clues to the etiology/pathogenesis of low-grade and high-grade SOCs, we analyzed incidence rate patterns. Case and age-adjusted population data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for years 1990 through 2005. Descriptive epidemiology for n = 19,899 cases was supplemented with age-period-cohort models fitted by grade.
Results: SOC age-adjusted incidence rate ratios (IRR) of high to low grade (IRRH/L) were &lt;1.0 before age 40, and &gt;1.0 thereafter. Accordingly, SOC age-specific incidence rates were also greater for low grade before age 40 years, and then greater for high grade. The reversals of IRRH/L, with crossings of the age-specific incidence rate near age 40 years occurred irrespective of early or late SOC stage. These results were reproducible and reliable in age-period-cohort models that were adjusted for period and cohort effects (P ≈ 0 for age interactions by grade).
Conclusions: Robust qualitative age interactions between low-grade and high-grade SOC showed that grade is an age-specific effect modifier in these malignancies. With increasing research interest in identifying the genomic determinants of SOC risk, therapeutic response, and outcome, future analytic studies and clinical trials should be powered to account for age-dependent grade interactions. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2256–61)
Uncovering Disparities in Survival after Non–Small–Cell Lung Cancer among Asian/Pacific Islander Ethnic Populations in California
Authors: Chang Ellen T. , Shema Sarah J. , Wakelee Heather A. , Clarke Christina A. , Gomez Scarlett Lin 
Published: August 2009

Abstract
Asians may have better survival after non–small-cell lung cancer (NSCLC) than non-Asians. However, it is unknown whether survival varies among the heterogeneous U.S. Asian/Pacific Islander (API) populations. Therefore, this study aimed to quantify survival differences among APIs with NSCLC. Differences in overall and disease-specific survival were analyzed in the California Cancer Registry among 16,577 API patients diagnosed with incident NSCLC between 1988 and 2007. Adjusted hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression models with separate baseline hazards by disease stage. Despite better overall and disease-specificsurvival among APIs compared with non-HispanicWhites, differences were evident across API populations. Among women, Japanese (overall survival HR, 1.16; 95% CI, 1.06-1.27) and APIs other than those in the six largest ethnic groups (other APIs; HR, 1.19; 95% CI, 1.07-1.33) had significantly poorer overall and disease-specific survival than Chinese. By contrast, South Asian women had significantly better survival than Chinese (HR, 0.79; 95% CI, 0.63-0.97). Among men, Japanese (HR, 1.15; 95% CI, 1.07-1.24), Vietnamese (HR, 1.07; 95% CI, 1.00-1.16), and other APIs (HR, 1.18; 95% CI, 1.08-1.28) had significantly poorer overall and disease-specific survival than Chinese. Other factors independently associated with poorer survival were lower neighborhood socioeconomic status, involvement with a nonuniversity hospital, unmarried status, older age, and earlier year of diagnosis. APIs have significant ethnic differences in NSCLC survival that may be related to disparate lifestyles, biology, and especially health care access or use. To reduce the nationwide burden of lung cancer mortality, it is critical to identify and ameliorate hidden survival disparities such as those among APIs. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2248–55)
Alcohol Consumption not Associated with Lung Cancer Mortality in Lifelong Nonsmokers
Authors: Thun Michael J. , Hannan Lindsay M. , DeLancey John Oliver L. 
Published: August 2009

Abstract
Although alcohol consumption is associated with increased lung cancer risk in some studies, this relationship is difficult to interpret because of potential confounding by smoking. We measured lung cancer death rates in relation to self-reported alcohol consumption among 223,216 adults who reported no history of regular smoking when enrolled in a large prospective mortality study begun by the American Cancer Society in 1982. Participants were at least 30 years of age when enrolled and, consequently, were considered unlikely to initiate smoking during follow-up. During 24 years of follow-up, we identified 1,058 deaths from lung cancer. Cox proportional hazards analyses were conducted, adjusting for age, education, occupation, and race. No association between lung cancer mortality and any level of alcohol consumption was seen in men or women. Even among those who consumed four or more alcoholic drinks per day, the risk did not differ from those who abstained from alcohol [hazard ratios 0.97 (95% confidence interval, 0.76-1.22) and 0.69 (0.41-1.16) for men and women, respectively]. Due to the large population of lifelong nonsmokers in our cohort and the long period of follow-up, these findings provide substantial evidence against the hypothesis that alcohol consumption independently increases lung cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2269–72)
Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Cardiac Arrhythmogenesis in Heart Failure
Authors: Sag Can M. , Wadsack Daniel P. , Khabbazzadeh Sepideh , Abesser Marco , Grefe Clemens , Neumann Kay , Opiela Marie-Kristin , Backs Johannes , Olson Eric N. , Brown Joan Heller , Neef Stefan , Maier Sebastian K.G. , Maier Lars S. 
Published: August 2009

Background—Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)δCmice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo.Methods and Results—Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10−8M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca]irose clearly on ISO in TG but not in wild-type cells (+20�5% versus +3�4% at 10−6M ISO,P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9�0.5 versus 2.0�0.4 sparks per 100 μm−1�s−1,P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIδ-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%,P<0.05) and late (86% versus 43%,P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05).Conclusions—We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIδCmice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.