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1.  Association between Sex Hormones and Colorectal Cancer Risk in Men and Women 
Background & Aims
There is observational and clinical evidence that indicate that sex hormones affect development of colorectal cancer (CRC) in men and women. However, the relationship between endogenous sex hormone levels and CRC is unclear.
Methods
We collected data on lifestyle, medical history, and diet etc. (through 2008), along with blood samples, from the Nurses’ Health Study, the Women’s Health Study, the Health Professional Follow-Up Study, and the Physicians’ Health Study II. We measured plasma levels of estrone, estradiol, testosterone, sex hormone binding globulin (SHBG), and c-peptide among 730 women (293 cases of CRC and 437 healthy individuals, as controls) and 1158 men (439 CRC cases and 719 controls), and used unconditional logistic regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were 2-sided.
Results
Total testosterone, SHBG, and the ratio of estradiol to testosterone were associated with CRC in men after adjustments for matching and risk factors for CRC, including BMI and plasma levels of C-peptide. The RRs in the highest relative to the lowest quartile were 0.62 for testosterone (95% CI, 0.40–0.96), 0.65 for SHBG (95% CI, 0.42−0.99), and 2.63 for the ratio (95% CI, 1.58–4.36) (P-values for trend ≤0.02). However, in women, only the ratio of estradiol to testosterone was (inversely) associated with CRC after adjustments for all factors (RR, 0.43; 95% CI, 0.22−0.84; P-value for trend, .03).
Conclusions
Based on combined data from 4 population studies, there appears to be an association between levels of sex hormones and CRC risk in men. There also appears to be an inverse association between the ratio of estradiol to testosterone and CRC in postmenopausal women.
doi:10.1016/j.cgh.2012.11.012
PMCID: PMC3594467  PMID: 23200979
estrogen; incidence; colorectal cancer; testosterone
2.  Cathelicidins from the Bullfrog Rana catesbeiana Provides Novel Template for Peptide Antibiotic Design 
PLoS ONE  2014;9(3):e93216.
Cathelicidins, a class of gene-encoded effector molecules of vertebrate innate immunity, provide a first line of defense against microbial invasions. Although cathelicidins from mammals, birds, reptiles and fishes have been extensively studied, little is known about cathelicidins from amphibians. Here we report the identification and characterization of two cathelicidins (cathelicidin-RC1 and cathelicidin-RC2) from the bullfrog Rana catesbeiana. The cDNA sequences (677 and 700 bp, respectively) encoding the two peptides were successfully cloned from the constructed lung cDNA library of R. catesbeiana. And the deduced mature peptides are composed of 28 and 33 residues, respectively. Structural analysis indicated that cathelicidin-RC1 mainly assumes an amphipathic alpha-helical conformation, while cathelicidin-RC2 could not form stable amphipathic structure. Antimicrobial and bacterial killing kinetic analysis indicated that the synthetic cathelicidin-RC1 possesses potent, broad-spectrum and rapid antimicrobial potency, while cathelicidin-RC2 exhibited very weak antimicrobial activity. Besides, the antimicrobial activity of cathelicidin-RC1 is salt-independent and highly stable. Scanning electron microscopy (SEM) analysis indicated that cathelicidin-RC1 kills microorganisms through the disruption of microbial membrane. Moreover, cathelicidin-RC1 exhibited low cytotoxic activity against mammalian normal or tumor cell lines, and low hemolytic activity against human erythrocytes. The potent, broad-spectrum and rapid antimicrobial activity combined with the salt-independence, high stability, low cytotoxic and hemolytic activities make cathelicidin-RC1 an ideal template for the development of novel peptide antibiotics.
doi:10.1371/journal.pone.0093216
PMCID: PMC3968123  PMID: 24675879
3.  Fruit and Vegetable Intake and Risk of Breast Cancer by Hormone Receptor Status 
Background
Estrogen receptor–negative (ER−) breast cancer has few known or modifiable risk factors. Because ER− tumors account for only 15% to 20% of breast cancers, large pooled analyses are necessary to evaluate precisely the suspected inverse association between fruit and vegetable intake and risk of ER− breast cancer.
Methods
Among 993 466 women followed for 11 to 20 years in 20 cohort studies, we documented 19 869 estrogen receptor positive (ER+) and 4821 ER− breast cancers. We calculated study-specific multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression analyses and then combined them using a random-effects model. All statistical tests were two-sided.
Results
Total fruit and vegetable intake was statistically significantly inversely associated with risk of ER− breast cancer but not with risk of breast cancer overall or of ER+ tumors. The inverse association for ER− tumors was observed primarily for vegetable consumption. The pooled relative risks comparing the highest vs lowest quintile of total vegetable consumption were 0.82 (95% CI = 0.74 to 0.90) for ER− breast cancer and 1.04 (95% CI = 0.97 to 1.11) for ER+ breast cancer (P common-effects by ER status < .001). Total fruit consumption was non-statistically significantly associated with risk of ER− breast cancer (pooled multivariable RR comparing the highest vs lowest quintile = 0.94, 95% CI = 0.85 to 1.04).
Conclusions
We observed no association between total fruit and vegetable intake and risk of overall breast cancer. However, vegetable consumption was inversely associated with risk of ER− breast cancer in our large pooled analyses.
doi:10.1093/jnci/djs635
PMCID: PMC3593764  PMID: 23349252
4.  Confocal microscopy study of pertussis toxin and toxoids on CHO-cells 
Pertussis toxin in its detoxified form is a major component of all current acellular pertussis vaccines. Here we report the membrane translocation and internalization activities of pertussis toxin and various pertussis toxoids using Chinese hamster ovary cells and confocal microscopy based on indirect immunofluorescence labeling. Chemically detoxified pertussis toxoids were able to translocate/internalize into cells at the concentration about 1,000 times higher than the native toxin. Pertussis toxoids detoxified with different procedures (glutaraldehyde, glutaraldehyde plus formaldehyde, hydrogen peroxide or genetic mutation) showed differences in fluorescence intensity under the same condition, indicating toxoids from different detoxification methods may have different translocation/internalization activities on cells.
doi:10.4161/hv.22795
PMCID: PMC3859756  PMID: 23291938
CHO cells; confocal microscopy; detoxification; pertussis toxin; toxoid; translocation
5.  Effect of Combined Folic Acid, Vitamin B6, and Vitamin B12 on Colorectal Adenoma 
Background
Folic acid, vitamin B6, and vitamin B12 act in concert in the one-carbon metabolism and may protect against colorectal neoplasia. We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma.
Methods
The Women’s Antioxidant and Folic Acid Cardiovascular Study was a randomized, double-blind, placebo-controlled trial of 5442 female health professionals at high risk for cardiovascular disease from April 1998 through July 2005. Participants were randomly assigned to receive a combination pill of folic acid (2.5mg), vitamin B6 (50mg), and vitamin B12 (1mg) or placebo. This study included 1470 participants who were followed up for as long as 9.2 years and underwent an endoscopy at any point during follow-up. We estimated relative risks using a generalized linear model with a natural logarithm link function and Poisson distributed errors. All statistical tests were two-sided.
Results
The risk of colorectal adenoma was similar among participants receiving treatment (24.3%, 180 of 741 participants) vs placebo (24.0%, 175 of 729 participants) (multivariable adjusted relative risk = 1.00, 95% confidence interval = 0.83 to 1.20). Treatment was not associated with the risk of adenoma when data were analyzed by subsite, size, stage, and the number of adenomas. There was no statistically significant effect modification by alcohol intake, history of cancer or adenoma, or baseline plasma levels or intakes of folate, vitamin B6, or vitamin B12.
Conclusion
Our results indicate no statistically significant effect of combined folic acid, vitamin B6, and vitamin B12 treatment on colorectal adenoma among women at high risk for cardiovascular disease.
doi:10.1093/jnci/djs370
PMCID: PMC3611818  PMID: 23066166
6.  Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status 
Journal of medical genetics  2012;49(9):601-608.
Objective
There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumors with different hormone receptor status.
Material and Methods
Within the Breast and Prostate Cancer Cohort Consortium (BPC3), we analyzed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age- and cohort-adjusted concordance statistic (AUROCa). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement (IDI) was used to measure improvements in risk prediction.
Results
We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROCa going from 2.7 to 4%). Discriminatory ability for all models varied strongly by hormone receptor status
Discussion and Conclusion
Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor positive cases, but the gain in discriminatory quality is not sufficient for clinical application.
doi:10.1136/jmedgenet-2011-100716
PMCID: PMC3793888  PMID: 22972951
breast cancer; risk prediction; genetic factors; hormone receptor status
7.  A rare collision tumor of squamous carcinoma and small cell carcinoma in esophagus involved with separate lymph nodes: a case report 
Journal of Thoracic Disease  2013;5(5):E203-E206.
We report a case of an esophageal collision tumor composed of squamous cell carcinoma and small cell carcinoma (SmCC). A 66-year-old man complained of chest pain after oral intake for nearly one month. The patient received two cycles of neoadjuvant platinum-based combination chemotherapy and enhanced computed tomography showed a partial response of the tumor. He then underwent a thoracolaparoscopic esophagectomy with extensive mediastinal lymphadenectomy. Two cycles of chemotherapy and prophylactic irradiation of the lymphatic drainage region were sequentially achieved after surgery. The patient has survived for more than 18 months with no evidence of recurrent disease since surgical resection.
doi:10.3978/j.issn.2072-1439.2013.09.13
PMCID: PMC3815725  PMID: 24255793
Esophageal cancer; collision tumor; small cell carcinoma; squamous cell carcinoma
8.  Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III 
BMC Medicine  2013;11:187.
Background
Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level.
Methods
We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI).
Results
High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median.
Conclusions
Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are necessary to confirm the findings.
doi:10.1186/1741-7015-11-187
PMCID: PMC3765911  PMID: 23981518
Magnesium intake; Serum 25-hydroxyvitamin D levels; Vitamin D insufficiency; Vitamin D deficiency; Parathyroid hormone; Mortality; Colorectal cancer; Cardiovascular diseases
9.  Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression 
Cancer Research  2012;72(12):3020-3028.
Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell cycle regulators. However, epidemiologic studies evaluating hormone therapy (HT) use and colorectal cancer risk by the status of cell cycle regulators are lacking. In this study, we used data from the prospective Nurses’ Health Study to evaluate whether the association between HT use and colorectal cancer risk differs by the molecular pathological status of microsatellite instability (MSI) and expression of cell cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between HT use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105520 postmenopausal women. We found a difference between HT use and colorectal cancer risk according to CDKN1A expression (p-value for heterogeneity=0.01). Current HT use was associated with a reduced risk for CDKN1A-nonexpressed (multivariate relative risk (RR)=0.61, 95% confidence interval (CI), 0.46–0.82), but not for CDKN1A-expressed (RR=1.32, 95% CI, 0.76–2.31) tumors. The lower risk for CDKN1A-nonexpressed, but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between HT use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular epidemiology findings suggest a preventive effect of HT against colorectal carcinogenesis which depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.
doi:10.1158/0008-5472.CAN-11-2619
PMCID: PMC3377852  PMID: 22511578
10.  Combination of HDAC and topoisomerase inhibitors in small cell lung cancer 
Cancer Biology & Therapy  2012;13(8):614-622.
Histone deacetylase (HDAC) inhibitors, including MGCD0103 and vorinostat, have led to tumor growth inhibition and apoptosis in vivo. However, with limited single-agent activity demonstrated in solid tumor trials, we examined the potential for enhanced effects in combination with topoisomerase I and II inhibitors, a staple for treatment in refractory small cell lung cancer (SCLC). SCLC cell lines were exposed to increasing concentrations of single-agent HDAC inhibitors and topoisomerase inhibitors, in various combinations, to assess for cell viability, additivity or synergy, and apoptosis. We found that MGCD0103 and vorinostat decreased cell viability by at least 60% and 80%, respectively. In the majority of cell lines, the strongest synergism was seen when vorinostat was followed by either etoposide or topotecan; concurrent therapy led to antagonism in most cell lines. Synergistic effects were seen when MGCD0103 was given concurrently or sequentially with both amrubicin and epirubicin. Enhanced additive effects leading to caspase activation were noted for the combination of MGCD0103 or vorinostat with a topoisomerase inhibitor vs. either agent alone. Thus, the combination of HDAC inhibitors and topoisomerase inhibitors showed enhanced cytotoxic effects in SCLC cell lines. Further evaluation in a clinical setting may be warranted.
doi:10.4161/cbt.19848
PMCID: PMC3408970  PMID: 22441819
combination therapy; HDAC; SCLC; survival; topoisomerase inhibitors
11.  The VITamin D and OmegA-3 TriaL (VITAL): Rationale and Design of a Large Randomized Controlled Trial of Vitamin D and Marine Omega-3 Fatty Acid Supplements for the Primary Prevention of Cancer and Cardiovascular Disease 
Contemporary Clinical Trials  2011;33(1):159-171.
Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2×2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (Omacor® fish oil, eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1 g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥50 and women aged ≥55. The mean treatment period will be 5 years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.
doi:10.1016/j.cct.2011.09.009
PMCID: PMC3253961  PMID: 21986389
Cancer; cardiovascular disease; cholecalciferol; primary prevention; omega-3 fatty acids; vitamin D; randomized controlled trial
12.  Sunlight exposure, vitamin D, and risk of non-Hodgkin lymphoma in the Nurses’ Health Study 
Cancer causes & control : CCC  2011;22(12):1731-1741.
Purpose
Case-control studies suggest increased sun exposure reduces non-Hodgkin lymphoma (NHL) risk. Evidence from prospective cohort studies, however, is limited and inconsistent. We evaluated the association between ambient ultraviolet radiation (UV) exposure and NHL in a nationwide cohort of women, the Nurses’ Health Study (NHS).
Methods
Between 1976 and 2006, we identified 1064 incident NHL cases among 115,482 women in the prospective NHS. Exposures assessed included average annual UV-B flux based on residence at various times during life, vitamin D intake, and predicted plasma 25-hydroxyvitamin D levels. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of all NHL and histologic subtypes using Cox proportional hazards models.
Results
NHL risk was increased for women residing in areas of high ambient UV radiation (UV-B flux >113 R-B count × 10−4) compared to those with lower exposure (<113), with positive linear trends at all time points. The multivariable-adjusted RR for high UV area at age 15 was 1.21 (95% CI: 1.00, 1.47; p-trend <0.01). There was no evidence of statistical heterogeneity by subtype, although power was limited for subtype analyses. We observed no association between vitamin D measures and risk of NHL overall or by subtype.
Conclusions
Our findings do not support the hypothesis of a protective effect of UV radiation exposure on NHL risk. We found no association between vitamin D and NHL risk.
doi:10.1007/s10552-011-9849-x
PMCID: PMC3240999  PMID: 21987081
non-Hodgkin lymphoma; sunlight; ultraviolet radiation; vitamin D; epidemiology
13.  N-Acetyltransferase 2 Polymorphisms, Tobacco Smoking, and Breast Cancer Risk in the Breast and Prostate Cancer Cohort Consortium 
American Journal of Epidemiology  2011;174(11):1316-1322.
Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989–2006) in the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions.
doi:10.1093/aje/kwr257
PMCID: PMC3390163  PMID: 22074863
arylamine N-acetyltransferase; breast neoplasms; NAT2 protein, human; polymorphism, single nucleotide; smoking
14.  Interactions Between Genetic Variants and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium 
Background
Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer.
Methods
To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10−4) was done. Case–case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided.
Results
We confirmed the association of 14 SNPs with breast cancer risk (Ptrend = 2.57 × 10−3 –3.96 × 10−19). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor–positive than estrogen receptor–negative breast cancer (Pheterogeneity = .0016 for FGFR2-rs2981582 and Pheterogeneity = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor–positive than progesterone receptor–negative breast cancer (Pheterogeneity = .0028).
Conclusion
This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.
doi:10.1093/jnci/djr265
PMCID: PMC3156803  PMID: 21791674
15.  The Aromatase Gene (CYP19A1) Variants and Circulating Hepatocyte Growth Factor in Postmenopausal Women 
PLoS ONE  2012;7(7):e42079.
Background
Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations.
Design
We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations.
Results
We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′≥97%, r2≥56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ≤0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ≤0.02).
Conclusion
Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size.
doi:10.1371/journal.pone.0042079
PMCID: PMC3405042  PMID: 22848710
16.  Stable silencing of β-lactoglobulin (BLG) gene by lentivirus-mediated RNAi in goat fetal fibroblasts 
Genetics and Molecular Biology  2012;35(3):680-685.
β-lactoglobulin (BLG), a dominant allergen in goat milk, is difficult to remove by traditional biochemical methods. Its elimination from goat milk by genetic modification therefore poses a major challenge for modern goat breeders. A shRNA targeting BLG mRNA with high interference efficiency was identified, with which lentiviral vectors were used for mediating stable shRNA interference in goat-fetal fibroblast cells. Apart from high efficiency in the knockdown of BLG expression in these cells, lentivector-mediated RNAi manifested stable integration into the goat genome itself. Consequently, an in vitro model for goat BLG-content control was compiled, and a goat-cell line for accompanying transgenetic goat production created.
doi:10.1590/S1415-47572012005000042
PMCID: PMC3459420  PMID: 23055809
RNAi; shRNA; lentivirus; BLG; goat
17.  EPLIN Downregulation Promotes Epithelial-Mesenchymal Transition in Prostate Cancer Cells and Correlates With Clinical Lymph Node Metastasis 
Oncogene  2011;30(50):4941-4952.
Epithelial-mesenchymal transition (EMT) is a crucial mechanism for the acquisition of migratory and invasive capabilities by epithelial cancer cells. By conducting quantitative proteomics in experimental models of human prostate cancer (PCa) metastasis, we observed strikingly decreased expression of EPLIN (epithelial protein lost in neoplasm; or LIM domain and actin binding 1, LIMA-1) upon EMT. Biochemical and functional analyses demonstrated that EPLIN is a negative regulator of EMT and invasiveness in PCa cells. EPLIN depletion resulted in the disassembly of adherens junctions, structurally distinct actin remodeling, and activation of β-catenin signaling. Microarray expression analysis identified a subset of putative EPLIN target genes associated with EMT, invasion and metastasis. By immunohistochemistry EPLIN downregulation was also demonstrated in lymph node metastases of human solid tumors including PCa, breast cancer, colorectal cancer and squamous cell carcinoma of the head and neck. This study reveals a novel molecular mechanism for converting cancer cells into a highly invasive and malignant form, and has important implications in prognosing and treating metastasis at early stages.
doi:10.1038/onc.2011.199
PMCID: PMC3165108  PMID: 21625216
EPLIN; epithelial-mesenchymal transition; prostate cancer; lymph node metastasis; cytoskeleton
18.  Prediction and Identification of Potential Immunodominant Epitopes in Glycoproteins B, C, E, G, and I of Herpes Simplex Virus Type 2 
Twenty B candidate epitopes of glycoproteins B (gB2), C (gC2), E (gE2), G (gG2), and I (gI2) of herpes simplex virus type 2 (HSV-2) were predicted using DNAstar, Biosun, and Antheprot methods combined with the polynomial method. Subsequently, the biological functions of the peptides were tested via experiments in vitro. Among the 20 epitope peptides, 17 could react with the antisera to the corresponding parent proteins in the EIA tests. In particular, five peptides, namely, gB2466–473 (EQDRKPRN), gC2216–223 (GRTDRPSA), gE2483–491 (DPPERPDSP), gG2572–579 (EPPDDDDS), and gI2286-295 (CRRRYRRPRG) had strong reaction with the antisera. All conjugates of the five peptides with the carrier protein BSA could stimulate mice into producing antibodies. The antisera to these peptides reacted strongly with the corresponding parent glycoproteins during the Western Blot tests, and the peptides reacted strongly with the antibodies against the parent glycoproteins during the EIA tests. The antisera against the five peptides could neutralize HSV-2 infection in vitro, which has not been reported until now. These results suggest that the immunodominant epitopes screened using software algorithms may be used for virus diagnosis and vaccine design against HSV-2.
doi:10.1155/2012/205313
PMCID: PMC3357521  PMID: 22649465
19.  A Phase I Clinical-Pharmacodynamic Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with the Proteasome Inhibitor Bortezomib in Advanced Acute Leukemias 
Purpose
To determine the safety, target inhibition, and signals of clinical activity of tipifarnib in combination with bortezomib in patients with advanced acute leukemias.
Experimental Design
In a 3+3 design, patients received escalating doses of tipifarnib (days 1–14) and bortezomib (days 1, 4, 8, 11) every 3 weeks until maximum tolerated dose was reached. Peripheral blood mononuclear cells (PBMCs) were collected at days 1, 8, and 22 for measurement of chymotrypsin-like and farnesyltransferase activity. Purified bone marrow leukemic blasts were collected at baseline and at day 8 for measurement of NF-kB activity.
Results
The combination was well-tolerated, and maximum tolerated dose was not reached. Dose-limiting toxicities included diarrhea, fatigue, and sensorimotor neuropathy. Chymotrypsin-like and farnesyltransferase activity within PBMCs were decreased in a majority of patients at day 8. NF-kB activity within leukemic blasts was decreased in a majority of patients at day 8. Complete response with incomplete count recovery was observed in 2 patients, and an additional 5 patients had stable disease.
Conclusions
Tipifarnib and bortezomib combination in patients with advanced leukemias was well-tolerated, demonstrated relevant target inhibition, and was associated with signals of clinical activity in patients with advanced and refractory acute leukemias. Future studies of this combination may be warranted in more selected groups of patients in whom these molecular targets are of particular importance.
doi:10.1158/1078-0432.CCR-10-1878
PMCID: PMC3049960  PMID: 21233404
acute leukemia; NF-kappa B; farnesyltransferase inhibitor; proteasome inhibitor; phase 1
20.  Complete Genome Sequence of Bordetella pertussis CS, a Chinese Pertussis Vaccine Strain ▿  
Journal of Bacteriology  2011;193(15):4017-4018.
Bordetella pertussis is the causative agent of pertussis. Here, we report the genome sequence of Bordetella pertussis strain CS, isolated from an infant patient in Beijing and widely used as a vaccine strain for production of an acellular pertussis vaccine in China.
doi:10.1128/JB.05184-11
PMCID: PMC3147532  PMID: 21622744
21.  PDGF Upregulates Mcl-1 Through Activation of β-Catenin and HIF-1α-Dependent Signaling in Human Prostate Cancer Cells 
PLoS ONE  2012;7(1):e30764.
Background
Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized.
Methodology/Principal Findings
Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells.
Conclusions/Significance
Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis.
doi:10.1371/journal.pone.0030764
PMCID: PMC3262835  PMID: 22276222
22.  Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a pooled analysis of prospective cohort studies 
Cancer causes & control : CCC  2010;21(11):1745-1757.
Objective
To evaluate the associations between intakes of vitamins A, C, and E and risk of colon cancer.
Methods
Using the primary data from 13 cohort studies, we estimated study- and sex-specific relative risks (RR) with Cox proportional hazards models and subsequently pooled RRs using a random effects model.
Results
Among 676,141 men and women, 5,454 colon cancer cases were identified (7–20 years of follow-up across studies). Vitamin A, C, and E intakes from food only were not associated with colon cancer risk. For intakes from food and supplements (total), the pooled multivariate RRs (95% CI) were 0.88 (0.76–1.02, >4,000 vs. ≤1,000 μg/day) for vitamin A, 0.81 (0.71–0.92, >600 vs. ≤100 mg/day) for vitamin C, and 0.78 (0.66–0.92, >200 vs. ≤6 mg/day) for vitamin E. Adjustment for total folate intake attenuated these associations, but the inverse associations with vitamins C and E remained significant. Multivitamin use was significantly inversely associated with colon cancer risk (RR = 0.88, 95% CI: 0.81–0.96).
Conclusions
Modest inverse associations with vitamin C and E intakes may be due to high correlations with folate intake, which had a similar inverse association with colon cancer. An inverse association with multivitamin use, a major source of folate and other vitamins, deserves further study.
doi:10.1007/s10552-010-9549-y
PMCID: PMC3091388  PMID: 20820901
Vitamin A; Vitamin C; Vitamin E; Multivitamin; Colon cancer; Cohort study; Pooled analysis
23.  Risk of Colon Cancer and Coffee, Tea, and Sugar-Sweetened Soft Drink Intake: Pooled Analysis of Prospective Cohort Studies 
Background
The relationships between coffee, tea, and sugar-sweetened carbonated soft drink consumption and colon cancer risk remain unresolved.
Methods
We investigated prospectively the association between coffee, tea, and sugar-sweetened carbonated soft drink consumption and colon cancer risk in a pooled analysis of primary data from 13 cohort studies. Among 731 441 participants followed for up to 6–20 years, 5604 incident colon cancer case patients were identified. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random-effects model. All statistical tests were two-sided.
Results
Compared with nonconsumers, the pooled multivariable relative risks were 1.07 (95% CI = 0.89 to 1.30, Ptrend = .68) for coffee consumption greater than 1400 g/d (about six 8-oz cups) and 1.28 (95% CI = 1.02 to 1.61, Ptrend = .01) for tea consumption greater than 900 g/d (about four 8-oz cups). For sugar-sweetened carbonated soft drink consumption, the pooled multivariable relative risk comparing consumption greater than 550 g/d (about 18 oz) to nonconsumers was 0.94 (95% CI = 0.66 to 1.32, Ptrend = .91). No statistically significant between-studies heterogeneity was observed for the highest category of each beverage consumed (P > .20). The observed associations did not differ by sex, smoking status, alcohol consumption, body mass index, physical activity, or tumor site (P > .05).
Conclusions
Drinking coffee or sugar-sweetened carbonated soft drinks was not associated with colon cancer risk. However, a modest positive association with higher tea consumption is possible and requires further study.
doi:10.1093/jnci/djq107
PMCID: PMC2879415  PMID: 20453203
24.  Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women 
Cancer causes & control : CCC  2010;21(6):897-908.
Objectives
Several lines of evidence have suggested that female hormones may lower risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1) and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2).
Methods
We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women's Health Study aged 45 years or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs).
Results
There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correction ≥0.25). There was also no association with any of the haplotypes examined (p ≥0.15) and no evidence of joint effects of variants in the 5 genes (p ≥0.51).
Conclusion
Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and risk for developing colorectal cancer.
doi:10.1007/s10552-010-9518-5
PMCID: PMC2873149  PMID: 20148360
25.  Estrogen and progesterone-related gene variants and colorectal cancer risk in women 
BMC Medical Genetics  2011;12:78.
Background
Observational studies and randomized trials have suggested that estrogens and/or progesterone may lower the risk for colorectal cancer. Inherited variation in the sex-hormone genes may be one mechanism by which sex hormones affect colorectal cancer, although data are limited.
Method
We conducted a comprehensive evaluation of single nucleotide polymorphisms (SNPs) in genes encoding 3 hormone receptors (ESR1, ESR2, PGR) and 5 hormone synthesizers (CYP19A1 and CYP17A1, HSD17B1, HSD17B2, HSD17B4) among 427 women with incident colorectal cancer and 871 matched controls who were Caucasians of European ancestry from 93676 postmenopausal women enrolled in the Women's Health Initiative Observational cohort. A total of 242 haplotype-tagging and functional SNPs in the 8 genes were included for analysis. Unconditional logistic regression with adjustment for age and hysterectomy status was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
Results
We observed a weak association between the CYP17A1 rs17724534 SNP and colorectal cancer risk (OR per risk allele (A) = 1.39, 95% CI = 1.09-1.78, corrected p-value = 0.07). In addition, a suggestive interaction between rs17724534 and rs10883782 in 2 discrete LD blocks of CYP17A1 was observed in relation to colorectal cancer (empirical p value = 0.04). Moreover, one haplotype block of CYP19A1 was associated with colorectal cancer (corrected global p value = 0.02), which likely reflected the association with the tagging SNP, rs1902584, in the block.
Conclusion
Our findings offer some support for a suggestive association of CYP17A1 and CYP19A1 variants with colorectal cancer risk.
doi:10.1186/1471-2350-12-78
PMCID: PMC3125237  PMID: 21627810

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