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1.  Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: A nested case-control study 
HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases) and among 108 matched HIV/KSHV coinfected controls who did not develop KS. Throughout the 6 years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p < 0.0001), and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting.
PMCID: PMC4529666  PMID: 25395177
HIV-associated Kaposi's sarcoma; sub-Saharan Africa; Kaposi's sarcoma associated-herpesvirus; HIV; AIDS
2.  The Influence of Type-Specific Human Papillomavirus Infections on the Detection of Cervical Precancer and Cancer: A Population-based Study of Opportunistic Cervical Screening in the United States 
There are limited data on the prospective risks of detecting cervical precancer and cancer in United States (U.S.) populations specifically where the delivery of opportunistic cervical screening takes place outside managed care and in the absence of organized national programs. Such data will inform the management of women with positive screening results before and after widespread human papillomavirus (HPV) vaccination and establishes a baseline preceding recent changes in U.S. cervical cancer screening guidelines. Using data reported to the statewide passive surveillance systems of the New Mexico HPV Pap Registry, we measured the three-year HPV type-specific cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and grade 3 or more severe (CIN3+) detected during real-world health care delivery across a diversity of organizations, payers, clinical settings, providers and patients.
A stratified sample of 47,541 cervical cytology specimens from a screening population of 379,000 women underwent HPV genotyping. Three-year risks for different combinations of cytologic interpretation and HPV risk group ranged from <1% (for several combinations) to approximately 70% for CIN2+ and 55% for CIN3+ in women with high-grade (HSIL) cytology and HPV16 infection. A substantial proportion of CIN2+ (35.7%) and CIN3+ (30.9%) were diagnosed following negative cytology, of which 62.3% and 78.2%, respectively, were high-risk HPV positive. HPV16 had the greatest three-year risks (10.9% for CIN2+, 8.0% for CIN3+) followed by HPV33, HPV31, and HPV18. Positive results for high-risk HPV, especially HPV16, the severity of cytologic interpretation, and age contribute independently to the risks of CIN2+ and CIN3+.
PMCID: PMC4020996  PMID: 24226935
Cervical intraepithelial neoplasia (CIN); cervical cancer; human papillomavirus (HPV); HPV vaccine effectiveness; cervical screening effectiveness; US opportunistic cervical screening; cytology; Pap test
3.  Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice 
Recent studies suggest health benefits including protection from cancer after eating fermented foods such as probiotic yogurt, though the mechanisms are not well understood. Here we tested mechanistic hypotheses using two different animal models: the first model studied development of mammary cancer when eating a Westernized diet, and the second studied animals with a genetic predilection to breast cancer. For the first model, outbred Swiss mice were fed a Westernized chow putting them at increased risk for development of mammary tumors. In this Westernized diet model, mammary carcinogenesis was inhibited by routine exposure to Lactobacillus reuteri ATCC-PTA-6475 in drinking water. The second model was FVB strain erbB2 (HER2) mutant mice, genetically susceptible to mammary tumors mimicking breast cancers in humans, being fed a regular (non-Westernized) chow diet. We found that oral supplement with these purified lactic acid bacteria alone was sufficient to inhibit features of mammary neoplasia in both models. The protective mechanism was determined to be microbially-triggered CD4+CD25+ lymphocytes. When isolated and transplanted into other subjects, these L. reuteri-stimulated lymphocytes were sufficient to convey transplantable anti-cancer protection in the cell recipient animals. These data demonstrate that host immune responses to environmental microbes significantly impact and inhibit cancer progression in distal tissues such as mammary glands, even in genetically susceptible mice. This leads us to conclude that consuming fermentative microbes such as L. reuteri may offer a tractable public health approach to help counteract the accumulated dietary and genetic carcinogenic events integral in the Westernized diet and lifestyle.
PMCID: PMC4131439  PMID: 24382758
mammary cancer; probiotics; bacteria, inflammation; L. reuteri
4.  Epigenetic determinants of ovarian clear cell carcinoma biology 
Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC, and 4 corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1 binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p<0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process.
PMCID: PMC4522155  PMID: 24382740
ovarian clear cell carcinoma; HNF1; ERalpha; methylation; epigenetic characterization
We explored the potential impact of HPV testing on women’s intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 from an ongoing trial were sent a questionnaire to assess women’s intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioural control and direct and indirect subjective norms. Demographic data and scales that were significantly different (p<0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2016 invitations emailed, 1538 were received, and 981 completed surveys for a response rate of 63% (981/1538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age 25. Predictors of intentions to undergo screening were attitudes (OR 1.22; 95%CI 1.15, 1.30), indirect subjective norms (OR 1.02; 95%CI 1.01, 1.03) and perceived behavioural control (OR 1.16; 95% CI 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates.
PMCID: PMC4515309  PMID: 23754203
HPV; cervical cancer screening; intention; Theory of Planned Behavior
6.  Physical activity and cancer-specific mortality in the NIH-AARP Diet and Health Study cohort 
Higher physical activity levels have been associated with a lower risk of developing various cancers and all-cancer mortality, but the impact of pre-diagnosis physical activity on cancer-specific death has not been fully characterized. In the prospective National Institutes of Health-AARP Diet and Health Study with 293,511 men and women, we studied pre-diagnosis moderate to vigorous intensity leisure time physical activity (MVPA) in the past 10 years and cancer-specific mortality. Over a median 12.1 years we observed 15,001 cancer deaths. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for MVPA with cancer mortality overall and by 20 specific cancer sites, adjusting for relevant risk factors. Compared to participants reporting never/rare MVPA, those reporting >7 hours/week MVPA had a lower risk of total cancer mortality (HR=0.89, 95% CI 0.84–0.94; p-trend<.001). When analyzed by cancer site-specific deaths, comparing those reporting >7 hours/week of MVPA to those reporting never/rare MVPA, we observed a lower risk of death from colon (HR=0.70; 95% CI 0.57–0.85; p-trend<.001), liver (0.71; 0.52–0.98; p-trend=.012) and lung cancer (0.84; 0.77–0.92; p-trend<.001) and a significant p-trend for non-Hodgkins lymphoma (0.80; 0.62–1.04; p-trend=.017). An unexpected increased mortality p-trend with increasing MVPA was observed for death from kidney cancer (1.42; 0.98–2.03; p-trend=.016). Our findings suggest that higher pre-diagnosis leisure time physical activity is associated with lower risk of overall cancer mortality and mortality from multiple cancer sites. Future studies should confirm observed associations and further explore timing of physical activity and underlying biological mechanisms.
PMCID: PMC4016110  PMID: 24311115
physical activity; cancer; mortality
Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damage to urothelial cells. Using data and samples from 988 cases and 1,004 controls enrolled in the Los Angeles County Bladder Cancer Study and the Shanghai Bladder Cancer Study we investigated associations between bladder cancer risk and 632 tagSNPs that comprehensively capture genetic variation in 28 DNA repair genes from four DNA repair pathways: base excision repai, nucleotide excision repair (NER), non-homologous end-joining (NHEJ), and homologous recombination repair (HHR). Odds ratios (ORs) and 95% confidence intervals (CIs) for each tagSNP were corrected for multiple testing for all SNPs within each gene using pACT, and for genes within each pathway and across pathways with Bonferroni. Gene and pathway summary estimates were obtained using ARTP. We observed an association between bladder cancer and POLB rs7832529 (BER) (pACT = 0.003; ppathway = 0.021) among all, and SNPs in XPC (NER) and OGG1 (BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NER p = 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (Smoking status interaction pgene = 0.001, ppathway = 0.008, poverall = 0.034). Our findings support a role in bladder carcinogenesis for regions that map close to or within BER (POLB, OGG1) and NER genes (XPC). A SNP that tags both the XRCC6 and SREBF2 genes strongly modifies the association between bladder cancer risk and smoking.
PMCID: PMC4016180  PMID: 24382701
Bladder cancer; smoking; DNA repair; POLB; XRCC6
8.  Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma 
If diagnosed at early stages, patients with hepatocellular carcinoma (HCC) can receive curative therapies, whereas therapeutic options at later stages are very limited. Here, we addressed the potential of soluble Axl (sAxl) as a biomarker of early HCC by analyzing levels of sAxl in 311 HCC and 237 control serum samples from centers in Europe and China. Serum concentrations of sAxl were significantly increased in HCC (18.575 ng/mL) as compared to healthy (13.388 ng/mL) or cirrhotic (12.169 ng/mL) controls. Receiver operating characteristic curve analysis of sAxl in very early stage HCC patients (BCLC 0) showed an area under the curve (AUC) of 0.848, with a sensitivity of 76.9% and a specificity of 69.2%. α-Fetoprotein (AFP)-negative HCC patients displayed an AUC of 0.803, with sensitivity and specificity of 73% and 70.8%. Combination of sAxl and AFP improved diagnostic accuracy to 0.936 in very early HCC patients and to 0.937 in all HCC. Differential diagnosis of very early HCC versus liver cirrhosis showed a combined performance for sAxl and AFP of 0.901 with a sensitivity of 88.5% and a specificity of 76.7%. Furthermore, sAxl levels failed to be elevated in primary ovarian, colorectal and breast carcinomas as well as in secondary hepatic malignancies derived from colon. In summary, sAxl outperforms AFP in detecting very early HCC as compared to healthy or cirrhotic controls and shows high diagnostic accuracy for AFP-negative patients. sAxl is specific for HCC and suggested as a biomarker for routine clinical use.
PMCID: PMC4450342  PMID: 25529751
soluble Axl; hepatocellular carcinoma; biomarker; α-fetoprotein
9.  Effects of α-Tocopherol and β-Carotene Supplementation on Cancer Incidence and Mortality: 18-Year Post-Intervention Follow-Up of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study 
In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study among 29,133 Finnish male smokers aged 50–69 years, daily α-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the post-intervention effects of α-tocopherol and β-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n=2,881) was 1.04 (95% confidence interval [CI], 0.96–1.11) among β-carotene recipients compared with nonrecipients. For prostate cancer (n=2,321) RR was 0.97 (95% CI, 0.89–1.05) among α-tocopherol recipients compared with nonrecipients with the preventive effect of α-tocopherol continuing approximately 8 years post-intervention. Body mass index significantly modified the effect of α-tocopherol on prostate cancer (P for interaction=0.01): RR 1.00 (95% CI, 0.88–1.14) in normal-weight men, 0.87 (95% CI, 0.77–0.98) in overweight men, and 1.25 (95% CI, 1.01–1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98–1.05) for α-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99–1.05) for β-carotene recipients compared with nonrecipients. α-Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70–0.99), whereas β-carotene increased it (RR, 1.20; 95% CI, 1.01–1.42). In conclusion, supplementation with α-tocopherol and β-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose α-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality.
PMCID: PMC3991754  PMID: 24338499
α-tocopherol; β-carotene; cancer; mortality; post-trial
10.  Filamin A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress cancer cell invasion and metastasis 
Identifying key mediators of cancer invasion and metastasis is crucial to the development of new and more effective therapies. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important inhibitor of cell migration and invasion. FILIP1L expression was inversely correlated with the invasive potential of ovarian tumors. In our present study, we established an orthotopic ovarian cancer model, wherein FILIP1L expression can be regulated in vivo. Using this model, we observed that expression of FILIP1L in ovarian cancer cells inhibited spontaneous lung metastasis. Experimental lung metastases (established via tail vein injection of cancer cells) as well as the extravasation step of metastasis were not inhibited by FILIP1L, suggesting that FILIP1L inhibits the earlier steps of metastasis such as invasion and intravasation. FILIP1L inhibited matrix metalloproteinase (MMP)-dependent invasion in vivo. MMP3, -7 and -9 were transcriptionally down-regulated, and MMP9 protein expression and activity were inhibited in FILIP1L-expressing tumors. Importantly, overexpression of MMP9 compensated for the anti-invasive activity of FILIP1L. Furthermore, our studies suggest that FILIP1L regulates invasion and metastasis by inhibiting components of the WNT signaling pathway. FILIP1L expression reduced the induction of WNT target genes such as MMP3, -7 and -9, and β-catenin-directed transcriptional activity, suggesting inhibition of the canonical WNT pathway. Nuclear β-catenin, an indicator of an active canonical WNT pathway, was reduced in FILIP1L-expressing tumors. Overall, these findings suggest that FILIP1L reduces β-catenin levels, which may lead to the transcriptional down-regulation of WNT target genes such as MMPs, resulting in inhibition of metastasis. Modulation of FILIP1L expression has the potential to be a target for cancer therapy.
PMCID: PMC3991758  PMID: 24327474
Metastasis; Invasion; FILIP1L; MMP; WNT
11.  CXCR2 Inhibition Enhances Sulindac-Mediated Suppression of Colon Cancer Development 
Small chemical compound sulindac has been approved as a preventive approach against colon cancer for its effectiveness in treatment of precancerous adenoma. Due to its severe toxicities in the cardiovascular, gastrointestinal and renal systems, however, a combination of low-dose sulindac with other chemopreventive agents has been sought after as an alternative therapeutic strategy that could increase its effectiveness, while minimizing its adverse effects. In order to identify the promising alternative approach, we investigated the therapeutic potential of targeting the Interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals. We found that deletion of CXCR2 gene and ectopic expression of IL-8 suppresses and enhances, respectively, intestinal tumor development caused by a mutation in the APC gene. Moreover, a single copy deletion of CXCR2 gene resulted in abrogation of COX-2 and Gro-α upregulation in intestinal tumors caused by the APC mutation. Moreover, a single copy (heterozygote) deletion of CXCR2 gene was sufficient to synergize with a low-dose sulindac treatment in suppressing APCmin-induced intestinal polyposis. Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention.
PMCID: PMC4166491  PMID: 24338666
Interleukin-8; CXCR2; adenomatous polyposis coli; colon cancer; sulindac
12.  Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis 
The steady increase in the incidence and mortality of hepatocellular carcinoma (HCC) signifies a crucial need to understand better its pathogenesis to improve clinical management and prevention of the disease. The aim of this study was to investigate molecular mechanisms for the chemopreventive effects of folic acid and tributyrin alone or in combination on rat hepatocarcinogenesis. Male Wistar rats were subjected to a classic “resistant hepatocyte” model of liver carcinogenesis and treated with folic acid and tributyrin alone or in combination for 5 weeks during promotion stage. Treatment with folic acid and tributyrin alone or in combination strongly inhibited the development of glutathione-S-transferase placental form (GSTP)-positive foci. Microarray analysis showed significant changes in gene expression. A total of 501, 655, and 940 of differentially expressed genes, involved in cell cycle, p53-signaling, angiogenesis, and Wnt pathways, was identified in the livers of rats treated with folic acid, tributyrin or folic acid and tributyrin. A detailed analysis of these differentially expressed genes revealed that treatments inhibited angiogenesis in the preneoplastic livers. This was evidenced by the fact that 30 out of 77 differentially expressed genes common to all three treatments are involved in the regulation of the angiogenesis pathway. The inhibition of angiogenesis was confirmed by reduced levels of CD34 protein. In conclusion, the tumor-suppressing activity of folic acid and tributyrin is associated with inhibition of angiogenesis at early stages of rat liver carcinogenesis. Importantly, the combination of folic acid and tributyrin has stronger chemopreventive effect than each of the compounds alone.
PMCID: PMC4229010  PMID: 24302446
Hepatocarcinogenesis; chemoprevention; angiogenesis; folic acid; tributyrin
13.  Circulating concentrations of insulin-like growth factor-I, insulin-like growth factor binding protein-3, genetic polymorphisms and mammographic density in premenopausal Mexican women: results from the ESMaestras cohort 
The insulin-like growth factor (IGF) axis plays an essential role in the development of the mammary gland. High circulating levels of IGF-I and of its major binding protein IGFBP3 have been related with increased mammographic density in Caucasian premenopausal women. Some common single nucleotide polymorphisms (SNPs) in genes of the IGF pathway have also been suggested to play a role in mammographic density. We conducted a cross-sectional study nested within the large Mexican ESMaestras cohort, to investigate the relation between circulating levels of IGF-I, IGFBP-3, the IGF-I/IGFBP-3 ratio, five common SNPs in the IGF-1, IGFBP-3 and IGF-1R genes, and mammographic density in 593 premenopausal Mexican women. Mean age at mammogram was 43.1 (standard deviation–SD=3.7) years, and average body mass index (BMI) at recruitment was 28.5 kg/m2. Mean percent mammographic density was 36.5% (SD: 17.1), with mean dense tissue area of 48.3 (SD: 33.3) cm2. Mean IGF-I and IGFBP-3 concentrations were 15.33 (SD: 5.52) nmol/l and 114.96 (SD: 21.34) nmol/l, respectively. No significant associations were seen between percent density and biomarker concentrations but women with higher IGF-I and IGF-I/IGFBP-3 concentrations had lower absolute dense (ptrend =0.03 and 0.09, respectively) and non-dense tissue areas (ptrend <0.001 for both parameters). However, these associations were null after adjustment by BMI. SNPs in specific genes were associated with circulating levels of growth factors, but not with mammographic density features. These results do not support the hypothesis of a strong association between circulating levels of growth hormones and mammographic density in Mexican premenopausal women.
PMCID: PMC4487637  PMID: 24037648
IGF; mammographic density; genetic polymorphisms; Mexican premenopausal women
14.  Body size and breast cancer risk: the Multiethnic Cohort 
The influence of body size on postmenopausal breast cancer risk was investigated among five racial/ethnic groups in the Multiethnic Cohort. Participants were 45–75 years old at recruitment (1993–1996), living in Hawaii and California. Of the 82,971 White, African American, Native Hawaiian, Japanese and Latina women included in this analysis, 3,030 were diagnosed with invasive breast cancer. Body mass index (BMI), height, weight and adulthood weight gain were associated with a significantly higher risk and, with the exception of height, were found to vary across ethnic groups. Native Hawaiians and Japanese with a BMI ≥30.0 compared to 20.0–24.9 kg/m2 had the highest risk (hazard ratio = 1.82, 95% confidence interval: 1.31, 2.54, p-trend = 0.001, and hazard ratio = 1.59, 95% confidence interval: 1.24, 2.05, p-trend < 0.0001, respectively). Current hormone replacement therapy use modified the impact of a high BMI, as non- and former users had a significantly higher risk compared to current users. BMI also had a more pronounced risk for advanced tumors compared to localized tumors. When both BMI and adult weight gain were analyzed simultaneously, adult weight gain, rather than BMI, was a significant risk factor overall. These findings emphasize the significance of maintaining a healthy weight throughout adulthood for the prevention of postmenopausal breast cancer.
PMCID: PMC4484854  PMID: 22120517
breast cancer; body size; body mass index
15.  Lung cancer risk among bricklayers in a pooled analysis of case–control studies 
Bricklayers may be exposed to several lung carcinogens, including crystalline silica and asbestos. Previous studies that analyzed lung cancer risk among these workers had several study design limitations. We examined lung cancer risk among bricklayers within SYNERGY, a large international pooled analysis of case–control studies on lung cancer and the joint effects of occupational carcinogens. For men ever employed as bricklayers we estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for study center, age, lifetime smoking history and employment in occupations with exposures to known or suspected lung carcinogens. Among 15,608 cases and 18,531 controls, there were 695 cases and 469 controls who had ever worked as bricklayers (OR: 1.47; 95% CI: 1.28–1.68). In studies using population controls the OR was 1.55 (95% CI: 1.32–1.81, 540/349 cases/controls), while it was 1.24 (95% CI: 0.93–1.64, 155/120 cases/controls) in hospital-based studies. There was a clear positive trend with length of employment (p < 0.001). The relative risk was higher for squamous (OR: 1.68, 95% CI: 1.42–1.98, 309 cases) and small cell carcinomas (OR: 1.78, 95% CI: 1.44–2.20, 140 cases), than for adenocarcinoma (OR: 1.17, 95% CI: 0.95–1.43, 150 cases) (p-homogeneity: 0.0007). ORs were still elevated after additional adjustment for education and in analyses using blue collar workers as referents. This study provided robust evidence of increased lung cancer risk in bricklayers. Although non-causal explanations cannot be completely ruled out, the association is plausible in view of the potential for exposure to several carcinogens, notably crystalline silica and to a lesser extent asbestos.
What's new?
In their work, bricklayers can be exposed to various airborne carcinogens, including crystalline silica and asbestos. Previous studies of cancer risk have not accounted for full employment history or smoking status, and failed to establish a firm relationship between bricklaying and lung cancer. In this study, the authors used data from the largest collection of case-control studies on lung cancer with complete occupational and smoking history existing today, the SYNERGY project. They found clear evidence that lung cancer risk increases in proportion to the length of time spent working as a bricklayer, paving the way for better protection and compensation for those in this occupation.
PMCID: PMC4477910  PMID: 24861979
lung neoplasms; case–control studies; bricklayers; occupational health; epidemiology
16.  A three-gene signature and clinical outcome in esophageal squamous cell carcinoma 
It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications. GASC1, member of the histone demethylases affecting heterochromatin formation and transcriptional repression, has been found to be dysregulation in many types of cancers including breast cancer, prostate cancer, metastatic lung sarcomatoid carcinoma, and leukemia. In this study, we examined the expression of GASC1 and certain GASC1-targeted genes (KLF4, MYC, SOX2, PPARG, MDM2, and NANOG) and identified a three-gene prognostic signature (PPARG, MDM2, and NANOG), using risk scores based on immunohistochemical analyses of 149 tumor specimens from patients with esophageal squamous cell carcinoma (ESCC). The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased overall survival (OS) of the patients. We validated the predictive value of the three-gene signature in a second independent cohort of 101 patients with ESCC in order to determine whether it had predictive value. The results were similar to those in 149 patients. According to multivariate Cox proportional hazards analyses, the predictive model of a three-gene signature was an independent predictor for OS (p = 0.005 in cohort 1, p = 0.025 in cohort 2). In addition, ROC analysis indicated that the predictive ability of the three-gene model was more robust than that of a single biomarker. Therefore, our three-gene signature is closely associated with OS among patients with ESCC and may serve as a predictor for the poor prognosis of ESCC patients.
What's new?
Epigenetic alterations that involve modifications to histones are thought to play critical roles in cancer, with effects on processes ranging from tumor development to metastasis. The present investigation focused on the expression of the histone demethylase GASC1 and its gene targets in tumors from patients with esophageal squamous cell carcinoma (ESCC). Using risk scores from immunohistochemical analyses, the authors developed a three-gene prognostic signature involving the genes PPARG, MDM2, and NANOG. The signature was associated with a reduction in overall survival of ESCC patients, suggesting that it is predictive for poor prognosis in ESCC.
PMCID: PMC4477912  PMID: 25220908
esophageal squamous cell carcinoma; histone demethylase; gene prognostic signature; histopathology
17.  Dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women’s Health Study 
Nitrate and nitrite are precursors of endogenously formed N-nitroso compounds (NOC), known animal carcinogens. Nitrosation reactions forming NOCs can be inhibited by vitamin C and other antioxidants. We prospectively investigated the association between dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women’s Health Study, a cohort of 73,118 women ages 40 to 70 residing in Shanghai. We evaluated effect modification by factors that affect endogenous formation of NOCs: vitamin C (at or above/below median) and red meat intake (at or above/below median). Nitrate, nitrite and other dietary intakes were estimated from a 77-item food frequency questionnaire administered at baseline. Over a mean of 11 years of follow-up, we identified 619 colorectal cancer cases (n=383, colon; n=236, rectum). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression. Overall, nitrate intake was not associated with colorectal cancer risk (HR = 1.08; 95% CI: 0.73–1.59). However, among women with vitamin C intake below the median (83.9 mg/day) and hence higher potential exposure to NOCs, risk of colorectal cancer increased with increasing quintiles of nitrate intake (highest vs. lowest quintile HR = 2.45; 95% CI: 1.15–5.18; p-trend = 0.02). There was no association among women with higher vitamin C intake. We found no association between nitrite intake and risk of colorectal cancer overall or by intake level of vitamin C. Our findings suggest that high dietary nitrate intake among subgroups expected to have higher exposure to endogenously-formed NOCs increases risk of colorectal cancer.
PMCID: PMC3980001  PMID: 24242755
18.  Subpopulations of Myeloid-Derived Suppressor Cells (MDSC) impair T cell responses through independent nitric oxide-related pathways 
The accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator for the induction of T cell suppression in cancer. MDSC can be divided phenotypically into granulocytic (G-MDSC) and monocytic (Mo-MDSC) subgroups. Several mechanisms mediate the induction of T cell anergy by MDSC; however, the specific role of these pathways in the inhibitory activity of MDSC subpopulations remains unclear. Therefore, we aimed to determine the effector mechanisms by which subsets of tumor-infiltrating MDSC block T cell function. We found that G-MDSC had a higher ability to impair proliferation and expression of effector molecules in activated T cells, as compared to Mo-MDSC. Interestingly, both MDSC subgroups inhibited T cells through nitric oxide (NO)-related pathways, but expressed different effector inhibitory mechanisms. Specifically, G-MDSC impaired T cells through the production of peroxynitrites (PNT), while Mo-MDSC suppressed by the release of NO. The production of PNT in G-MDSC depended on the expression of gp91phox and endothelial NO synthase (eNOS), while inducible NO synthase (iNOS) mediated the generation of NO in Mo-MDSC. Deletion of eNOS and gp91phox or scavenging of PNT blocked the suppressive function of G-MDSC and induced anti-tumoral effects, without altering Mo-MDSC inhibitory activity. Furthermore, NO-scavenging or iNOS knockdown prevented Mo-MDSC function, but did not affect PNT production or suppression by G-MDSC. These results suggest that MDSC subpopulations utilize independent effector mechanisms to regulate T cell function. Inhibition of these pathways is expected to specifically block MDSC subsets and overcome immune suppression in cancer.
PMCID: PMC3980009  PMID: 24259296
19.  Genetic and epigenetic changes in fibrosis-associated hepatocarcinogenesis in mice 
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis-associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and non-tumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H-ras, Ctnnb1, and Hnf1α genes were not mutated in tumors in mice treated with DEN+CCl4. In contrast, the increased tumor incidence in mice treated with DEN+CCl4 was associated with marked epigenetic changes in liver tumors and non-tumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3), and promoter hypermethylation and functional down-regulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements (LINE) 1 and short interspersed nucleotide elements (SINE) B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer-related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis-associated liver cancer.
PMCID: PMC4209252  PMID: 24242335
20.  Induction of Osteopontin Expression by Nicotine and Cigarette Smoke in the Pancreas and Pancreatic Ductal Adenocarcinoma Cells 
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with etiological association with cigarette smoking. Nicotine, an important component of cigarettes, exists at high concentrations in the bloodstream of smokers. Osteopontin (OPN) is a secreted phosphoprotein that confers on cancer cells a migratory phenotype and activates signaling pathways that induce cell survival, proliferation, invasion, and metastasis. Here, we investigated the potential molecular basis of nicotine’s role in PDA through studying its effect on OPN. Nicotine significantly (p<0.02) increased OPN mRNA and protein secretion in PDA cells through activation of the OPN gene promoter. The OPN mRNA induction was inhibited by the nicotinic acetylcholine receptor antagonist, mechamylamine. Further, the tyrosine kinase inhibitor genistein inhibited the nicotine-mediated induction of OPN, suggesting that mitogen activated protein kinase signaling mechanism is involved.
Nicotine activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the nicotine-induced OPN synthesis. Rats exposed to cigarette smoke showed a dose-dependent increase in pancreatic OPN that paralleled the rise of pancreatic and plasma nicotine levels. Analysis of cancer tissue from invasive PDA patients, the majority of whom were smokers, showed the presence of significant amounts of OPN in the malignant ducts and the surrounding pancreatic acini. Our data suggest that nicotine may contribute to PDA pathogenesis through upregulation of OPN. They provide the first insight into a nicotine-initiated signal transduction pathway that regulates OPN as a possible tumorigenic mechanism in PDA.
PMCID: PMC4465299  PMID: 19358273
pancreatic cancer; nicotine; cigarette smoke; osteopontin
21.  SDF-1α stiffens myeloma bone marrow mesenchymal stromal cells through the activation of RhoA-ROCK-Myosin II 
Multiple myeloma (MM) is a B lymphocyte malignancy that remains incurable despite extensive research efforts. This is due, in part, to frequent disease recurrences associated with the persistence of myeloma cancer stem cells (mCSCs). Bone marrow mesenchymal stromal cells (BMSCs) play critical roles in supporting mCSCs through genetic or biochemical alterations. Previously, we identified mechanical distinctions between BMSCs isolated from MM patients (mBMSCs) and those present in the BM of healthy individuals (nBMSCs). These properties of mBMSC contributed to their ability to preferentially support mCSCs. To further illustrate mechanisms underlying the differences between mBMSCs and nBMSCs, here we report that (i) mBMSCs express an abnormal, constitutively high level of phosphorylated Myosin II, which leads to stiffer membrane mechanics, (ii) mBMSCs are more sensitive to SDF-1α-induced activation of MYL2 through the G(i./o)-PI3K-RhoA-ROCK-Myosin II signaling pathway, affecting Young’s modulus in BMSCs and (iii) activated Myosin II confers increased cell contractile potential, leading to enhanced collagen matrix remodeling and promoting the cell–cell interaction between mCSCs and mBMSCs. Together, our findings suggest that interfering with SDF-1α signaling may serve as a new therapeutic approach for eliminating mCSCs by disrupting their interaction with mBMSCs.
PMCID: PMC4454501  PMID: 25137150
multiple myeloma; SDF-1α; mesenchymal stromal cells; RhoA-ROCK-Myosin II
22.  Intraoperative fluorescence delineation of head and neck cancer with a fluorescent anti-epidermal growth factor receptor nanobody 
Intraoperative near-infrared (NIR) fluorescence imaging is a technology with high potential to provide the surgeon with real-time visualization of tumors during surgery. This study explores the feasibility for clinical translation of an epidermal growth factor receptor (EGFR) targeting nanobody for intraoperative imaging and resection of orthotopic tongue tumors and cervical lymph node metastases. The anti-EGFR nanobody 7D12 and the negative control nanobody R2 were conjugated to the NIR fluorophore IRDye800CW (7D12-800CW and R2-800CW). Orthotopic tongue tumors were induced in nude mice using the OSC-19-luc2-cGFP cell line. Tumor bearing mice were injected with 25µg 7D12-800CW, R2-800CW or 11µg 800CW. Subsequently, other mice were injected with 50 µg or 75 µg of 7D12-800CW. The FLARE imaging system and the IVIS spectrum were used to identify, delineate and resect the primary tumor and cervical lymph node metastases. All tumors could be clearly identified using 7D12-800CW. A significantly higher tumor-to-background ratio (TBR) was observed in mice injected with 7D12-800CW compared to mice injected with R2-800CW and 800CW. The highest average TBR (2.00 ± 0.34 and 2.72 ± 0.17 for FLARE and IVIS spectrum, respectively) was observed 24 hours after administration of the EGFR-specific nanobody. After injection of 75 µg 7D12-800CW cervical lymph node metastases could be clearly detected. Orthotopic tongue tumors and cervical lymph node metastases in a mouse model were clearly identified intraoperatively using a recently developed fluorescent EGFR targeting nanobody. Translation of this approach to the clinic would potentially improve the rate of radical surgical resections.
PMCID: PMC3960332  PMID: 24222574
image-guided surgery; near-infrared fluorescence; oral squamous cell carcinoma; nanobody; Epidermal Growth Factor Receptor
23.  Physical Activity and Risk of Endometrial Adenocarcinoma in the Nurses’ Health Study 
Studies suggest greater physical activity may reduce endometrial cancer risk. However, the role of the timing, duration, and intensity of activity is unclear. We therefore examined recent and past recreational activities in relation to incident endometrial adenocarcinoma, and compared the importance of total and moderate- or vigorous-intensity activities, as well as walking. We analyzed data from 71,570 women in the Nurses’ Health Study, a prospective cohort that assessed activity in 1986, with updates every 2–4 years. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). During follow-up from 1986–2008 (1.2 million person-years), 777 invasive endometrial adenocarcinoma cases were documented. In multivariable models, compared with <3 MET-hrs/wk (<1 hr/wk walking), women engaged in moderate (9–<18 MET-hrs/wk: RR=0.61, 95% CI: 0.48–0.78) or high (≥27 MET-hrs/wk: RR=0.73, 95% CI: 0.58–0.92) amounts of recent total recreational activity were at reduced risk (P-trend=0.001). Past total activity was unassociated with risk. Greater recent moderate- or vigorous-intensity activity was associated with reduced risk (≥4 vs 0 hrs/wk: RR=0.65, 95% CI: 0.47–0.88, P-trend=0.002). Among women who did not perform any vigorous activity, recent walking was associated with reduced risk (≥3 vs <0.5 hrs/wk: RR=0.65, 95% CI: 0.45–0.93, P-trend=0.01), and faster walking pace was independently associated with risk reduction. After additional adjustment for body mass index, all associations were statistically non-significant. Greater recent physical activity may reduce endometrial adenocarcinoma risk, including activity of moderate duration and intensity such as walking. This relation is largely mediated or confounded by body mass index.
PMCID: PMC3960316  PMID: 24213924
physical activity; exercise; endometrial cancer; endometrial adenocarcinoma; prospective study
24.  Occupational sun exposure and risk of melanoma according to anatomical site 
Although sunburn and intermittent sun exposures are associated with increased melanoma risk, most studies have found null or inverse associations between occupational (more continuous pattern) sun exposure and melanoma risk. The association of melanoma with occupational sun exposure may differ according to anatomical site, with some studies finding a positive association with melanoma on the head and neck. We examined the association between occupational sun exposure (self-reported weekday sun exposure) and melanoma risk according to anatomical site, using data from two multi-centre population-based case-control studies: the Australian Melanoma Family Study (588 cases, 472 controls) and the Genes, Environment and Melanoma study (GEM; 1079 cases, 2181 controls). Unconditional logistic regression was used to estimate odds ratios (OR) and their 95% confidence intervals, adjusting for potential confounders. Occupational sun exposure was not positively associated with melanoma risk overall or at different body sites in both studies. The GEM study found inverse associations between occupational sun exposure and melanoma on the head and neck (OR for highest vs. lowest quartile: 0.56, 95% CI 0.36-0.86, Ptrend 0.02), and between the proportion of total sun exposure occurring on weekdays and melanoma on the upper limbs (OR for highest vs. lowest quartile: 0.66, 95% CI 0.42-1.02, Ptrend 0.03). Our results suggest that occupational sun exposure does not increase risk of melanoma, even of melanomas situated on the head and neck. This finding appeared not to be due to negative confounding of occupational sun exposure by weekend sun.
PMCID: PMC3960350  PMID: 24288300
Melanoma; risk factors; sunlight; case-control studies
25.  Vitamin D binding protein, circulating vitamin D, and risk of renal cell carcinoma 
Cell culture experiments suggest that vitamin D may inhibit renal carcinogenesis, but human studies of circulating 25-hydroxyvitamin D (25(OH)D), the accepted measure of vitamin D status, and kidney cancer have been null. Limited research has examined the role of circulating vitamin D binding protein (DBP) in the association between 25(OH)D and disease risk, and it is unclear whether free 25(OH)D in circulation is a better measure of effective exposure, or if DBP may independently impact outcomes. We conducted a nested case-control analysis within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study to examine whether circulating DBP concentration was prospectively associated with risk of renal cell carcinoma, and whether it modified the association with 25(OH)D. Renal cell carcinoma cases (n=262) were matched 1:1 to controls on age (± 1 year) and date of blood collection (± 30 days). We estimated odds ratios and 95% confidence intervals of renal cell carcinoma risk by quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. Men with higher DBP concentrations were at significantly decreased risk of kidney cancer (Q4 vs. Q1: OR=0.17, 95% CI=0.08–0.33; p-trend<0.0001), a finding unchanged by adjustment for 25(OH)D. Although we observed no association with total 25(OH)D, we found slightly increased risk with higher levels of estimated free 25(OH)D (Q4 vs. Q1 of the 25(OH)D:DBP ratio, OR=1.61, 95% CI=0.95–2.73; p-trend=0.09). The strong protective association observed between higher circulating DBP concentration and kidney cancer risk requires replication but suggests a vitamin D-independent influence of DBP.
PMCID: PMC3960365  PMID: 24214881

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