bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Urinary Metabolites of Prostanoids and Risk of Recurrent Colorectal Adenomas in the Aspirin/Folate Polyp Prevention Study (AFPPS)
Authors: Fedirko Veronika , Bradshaw Patrick T. , Figueiredo Jane C. , Sandler Robert S. , Barry Elizabeth L. , Ahnen Dennis J. , Milne Ginger L. , Bresalier Robert S. , Baron John A.
Published: April 2023

Abstract
Aspirin has been shown to protect against colorectal neoplasms; however, the optimal chemopreventive dose and underlying mechanisms are unclear. We aimed to study the relationship between prostanoid metabolites and aspirin's effect on adenoma occurrence. We used data from the Aspirin/Folate Polyp Prevention Study, in which 1,121 participants with a recent adenoma were randomized to placebo or two doses of aspirin (81 or 325 mg/d) to be taken until the next surveillance colonoscopy, anticipated about 3 years later. Urinary metabolites of prostanoids (PGE-M, PGI-M, and dTxB2) were measured using liquid chromatography/mass spectrometry or GC/NICI-MS in 876 participants near the end of treatment follow-up. Poisson regression with a robust error variance was used to calculate relative risks and 95% confidence intervals. PGE-M, PGI-M, and dTxB2 levels were 28%, 37%, and 60% proportionately lower, respectively, in individuals who took 325 mg of aspirin compared with individuals who took placebo (all P < 0.001). Similarly, among individuals who took 81 mg of aspirin, PGE-M, PGI-M, and dTxB2 were, respectively, 18%, 30%, and 57% proportionally lower compared with placebo (all P < 0.005). None of the metabolites or their ratios were statistically significantly associated with the risk of adenoma occurrence. The effect of aspirin in reducing adenoma risk was independent of prostanoid levels. Aspirin use is associated with lower levels of urinary prostanoid metabolites. However, our findings do not support the hypothesis that these metabolites are associated with adenoma occurrence, suggesting that COX-dependent mechanisms may not completely explain the chemopreventive effect of aspirin on colorectal neoplasms. Cancer Prev Res; 8(11); 1061–8. ©2015 AACR.
Data from HIST1H2BB and MAGI2 Methylation and Somatic Mutations as Precision Medicine Biomarkers for Diagnosis and Prognosis of High-grade Serous Ovarian Cancer
Authors: Valle Blanca L. , Rodriguez-Torres Sebastian , Kuhn Elisabetta , Díaz-Montes Teresa , Parrilla-Castellar Edgardo , Lawson Fahcina P. , Folawiyo Oluwasina , Ili-Gangas Carmen , Brebi-Mieville Priscilla , Eshleman James R. , Herman James , Shih Ie-Ming , Sidransky David , Guerrero-Preston Rafael
Published: April 2023

Abstract
Molecular alterations that contribute to long-term (LT) and short-term (ST) survival in ovarian high-grade serous carcinoma (HGSC) may be used as precision medicine biomarkers. DNA promoter methylation is an early event in tumorigenesis, which can be detected in blood and urine, making it a feasible companion biomarker to somatic mutations for early detection and targeted treatment workflows. We compared the methylation profile in 12 HGSC tissue samples to 30 fallopian tube epithelium samples, using the Infinium Human Methylation 450K Array. We also used 450K methylation arrays to compare methylation among HGSCs long-term survivors (more than 5 years) and short-term survivors (less than 3 years). We verified the array results using bisulfite sequencing and methylation-specific PCR (qMSP). in another cohort of HGSC patient samples (n = 35). Immunoblot and clonogenic assays after pharmacologic unmasking show that HIST1H2BB and MAGI2 promoter methylation downregulates mRNA expression levels in ovarian cancer cells. We then used qMSP in paired tissue, ascites, plasma/serum, vaginal swabs, and urine from a third cohort of patients with HGSC cancer (n = 85) to test the clinical potential of HIST1H2BB and MAGI2 in precision medicine workflows. We also performed next-generation exome sequencing of 50 frequently mutated in human cancer genes, using the Ion AmpliSeqCancer Hotspot Panel, to show that the somatic mutation profile found in tissue and plasma can be quantified in paired urine samples from patients with HGSC. Our results suggest that HIST1H2BB and MAGI2 have growth-suppressing roles and can be used as HGSC precision medicine biomarkers.
Data from Urgent Need for Novel Investigations of Treatments to Quit E-cigarettes: Findings from a Systematic Review
Authors: Palmer Amanda M. , Price Sarah N. , Foster Madeline G. , Sanford Brandon T. , Fucito Lisa M. , Toll Benjamin A.
Published: April 2023

Abstract
E-cigarette use has been increasing globally over the past decade. Many use e-cigarettes as an alternative or method to quit cigarette smoking, whereas others use these products recreationally. As technology has advanced, many individuals have reported symptoms of dependence on these products and continue to use them beyond achieving abstinence from smoking. Despite individuals reporting interest in quitting, little is known about e-cigarette cessation. This systematic review sought to identify and evaluate all human subjects literature published on the outcome of e-cigarette cessation through September 2021. Of the 79 articles identified, 56 were cross-sectional, 6 were qualitative, 5 were cohort studies, 3 were experimental, 2 were mixed methods, and 7 reported intervention or case studies of e-cigarette cessation. Results showed youth generally had high intent to quit e-cigarettes, whereas results were mixed with adult samples. Youth were motivated to quit e-cigarettes by health concerns, whereas adults were motivated to quit e-cigarettes by cost, lack of satisfaction, and psychologic factors. Adults were more likely to report past e-cigarette quit attempts, most commonly “cold turkey.” Few interventions tested strategies for e-cigarette cessation, with a majority targeted for youth. Given the lack of information on e-cigarette cessation, recommendations for future studies are outlined.
Data from Estimating the Breast Cancer Burden in Germany and Implications for Risk-based Screening
Authors: Quante Anne S. , Hüsing Anika , Chang-Claude Jenny , Kiechle Marion , Kaaks Rudolf , Pfeiffer Ruth M.
Published: April 2023

Abstract
In Germany, it is currently recommended that women start mammographic breast cancer screening at age 50. However, recently updated guidelines state that for women younger than 50 and older than 70 years of age, screening decisions should be based on individual risk. International clinical guidelines recommend starting screening when a woman's 5-year risk of breast cancer exceeds 1.7%. We thus compared the performance of the current age-based screening practice with an alternative risk-adapted approach using data from a German population representative survey. We found that 10,498,000 German women ages 50–69 years are eligible for mammographic screening based on age alone. Applying the 5-year risk threshold of 1.7% to individual breast cancer risk estimated from a model that considers a woman's reproductive and personal characteristics, 39,000 German women ages 40–49 years would additionally be eligible. Among those women, the number needed to screen to detect one breast cancer case, NNS, was 282, which was close to the NNS = 292 among all 50- to 69-year-old women. In contrast, NNS = 703 for the 113,000 German women ages 50–69 years old with 5-year breast cancer risk <0.8%, the median 5-year breast cancer risk for German women ages 45–49 years, which we used as a low-risk threshold. For these low-risk women, longer screening intervals might be considered to avoid unnecessary diagnostic procedures. In conclusion, we show that risk-adapted mammographic screening could benefit German women ages 40–49 years who are at elevated breast cancer risk and reduce cost and burden among low-risk women ages 50–69 years.
Prevention Relevance:
We show that a risk-based approach to mammography screening for German women can help detect breast cancer in women ages 40–49 years with increased risk and reduce screening costs and burdens for low-risk women ages 50–69 years. However, before recommending a particular implementation of a risk-based mammographic screening approach, further investigations of models and thresholds used are needed.
Data from Celecoxib Colorectal Bioavailability and Chemopreventive Response in Patients with Familial Adenomatous Polyposis
Authors: Yang Peiying , Zuo Xiangsheng , Advani Shailesh , Wei Bo , Malek Jessica , Day Rena Sue , Shureiqi Imad
Published: April 2023

Abstract
Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven patients with FAP completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-S-hydroxyoctadecadienoic acid (13-HODE), 15-HETE, 12-HETE, and LTB4 levels by LC/MS-MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in patients with FAP.
Prevention Relevance:
This study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in patients with FAP. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in patients with FAP.

See related Spotlight, p. 205
Data from “Rescue” of Nonparticipants in Colorectal Cancer Screening: A Randomized Controlled Trial of Three Noninvasive Test Options
Authors: Young Graeme Paul , Chen Gang , Wilson Carlene J. , McGrane Ellen , Hughes-Barton Donna Lee-Ann , Flight Ingrid Helen K. , Symonds Erin Leigh
Published: April 2023

Abstract
Few studies have directly targeted nonparticipants in colorectal cancer screening to identify effective engagement strategies. We undertook a randomized controlled trial that targeted nonparticipants in a previous trial of average-risk subjects which compared participation rates for mailed invitations offering a fecal test, a blood test or a choice of either. Nonparticipants (n = 899) were randomized to be offered a kit containing a fecal immunochemical test (FIT), directions on how to arrange a blood DNA test, or the option of doing either. Screening participation was assessed 12 weeks after the offer. To assess the cognitive and attitudinal variables related to participation and invitee choice, invitees were surveyed after 12 weeks, and associations were investigated using multinomial logistic regression. Participation rates were similar between groups (P = 0.88): 12.0% for FIT (35/292), 13.3% for the blood test (39/293), and 13.4% for choice (39/290). Within the choice group, participation was significantly higher with FIT (9.7%, 28/290) compared with the blood test (3.8%, 11/290, P = 0.005). The only variable significantly associated with participation was socioeconomic status when offered FIT, and age when offered choice but there was none when offered the blood test. Survey respondents indicated that convenience, time-saving, comfort, and familiarity were major influences on participation. There was no clear advantage between a fecal test, blood test, or choice of test although, when given a choice, the fecal test was preferred. Differences in variables associated with participation according to invitation strategy warrant consideration when deciding upon an invitation strategy for screening nonparticipants.
Prevention Relevance:
This trial of screening for those at average risk for colorectal cancer targeted past fecal-test nonparticipants and compared participation rates for mailed invitations offering a fecal test, blood test, or choice of either. Although there was no clear advantage between strategies, factors associated with participation differed between each strategy.
Data from Endoscopic History and Provider Characteristics Influence Gastric Cancer Survival in Asian Americans
Authors: Jeon Christie Y. , Lin Yu-Chen , Klempner Samuel J. , Wu Bechien U. , Kim Sungjin , Waters Kevin M. , Haile Robert W.
Published: April 2023

Abstract
Gastric carcinoma (GC) disproportionately affects Asian Americans. We examined whether history of upper gastrointestinal (GI) endoscopy was associated with lower stage at GC diagnosis among Asian Americans and whether origin of providers influenced referral for endoscopy. We employed Surveillance Epidemiology and End Results–Medicare data on Asian Americans diagnosed with GC in 2004–2013 (n = 1,554). Stage distribution, GI conditions at diagnosis, and history of endoscopy were compared between Asian ethnic groups. Multivariate logistic regression adjusting for age, sex, poverty level, tumor location, and histology was used to examine the association of ethnicity and endoscopic history with stage I disease at diagnosis of GC. Koreans were more likely to be diagnosed with stage I, T1a GC and have prior history of endoscopy, compared with other Asian ethnicities (24% vs. 8% for stage I, T1a; 40% vs. 15% for endoscopy). Patients with primary care providers of concordant ethnic origin were more likely to have history of endoscopy. Asian American patients with GC with history of endoscopy were more likely to be diagnosed with GC at stage I disease (adjusted OR, 3.07; 95% confidence interval, 2.34–4.02). Compared with other Asian Americans, Koreans were diagnosed with GC at earlier stages owing to common history of endoscopy, which was more often undergone by patients with primary care providers of concordant ethnic origin. Overall, upper GI endoscopy was associated with early detection of GC in Asian Americans. Novelty and Impact. It is well-established that Asian Americans in the United States are disproportionately affected by gastric cancer. In our study we found that Asian American patients treated by physicians of similar ethnic background are more likely to undergo upper GI endoscopy in the United States, leading to early detection of gastric cancer and longer survival. Given this, targeted endoscopic screening in Asian Americans should be considered for early detection of GC.
Data from Reversing the Genomic, Epigenetic, and Triple-Negative Breast Cancer–Enhancing Effects of Obesity
Authors: Bowers Laura W. , Doerstling Steven S. , Shamsunder Meghana G. , Lineberger Claire G. , Rossi Emily L. , Montgomery Stephanie A. , Coleman Michael F. , Gong Weida , Parker Joel S. , Howell Anthony , Harvie Michelle , Hursting Stephen D.
Published: April 2023

Abstract
The reversibility of the procancer effects of obesity was interrogated in formerly obese C57BL/6 mice that lost weight via a nonrestricted low-fat diet (LFD) or 3 distinct calorie-restricted (CR) regimens (low-fat CR, Mediterranean-style CR, or intermittent CR). These mice, along with continuously obese mice and lean control mice, were orthotopically injected with E0771 cells, a mouse model of triple-negative breast cancer. Tumor weight, systemic cytokines, and incidence of lung metastases were elevated in the continuously obese and nonrestricted LFD mice relative to the 3 CR groups. Gene expression differed between the obese and all CR groups, but not the nonrestricted LFD group, for numerous tumoral genes associated with epithelial-to-mesenchymal transition as well as several genes in the normal mammary tissue associated with hypoxia, reactive oxygen species production, and p53 signaling. A high degree of concordance existed between differentially expressed mammary tissue genes from obese versus all CR mice and a microarray dataset from overweight/obese women randomized to either no intervention or a CR diet. Assessment of differentially methylated regions in mouse mammary tissues revealed that obesity, relative to the 4 weight loss groups, was associated with significant DNA hypermethylation. However, the anticancer effects of the CR interventions were independent of their ability to reverse obesity-associated mammary epigenetic reprogramming. Taken together, these preclinical data showing that the procancer effects of obesity are reversible by various forms of CR diets strongly support translational exploration of restricted dietary patterns for reducing the burden of obesity-associated cancers.
Prevention Relevance:
Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC). Given rising global rates of obesity and TNBC, strategies to reduce the burden of obesity-driven TNBC are urgently needed. We report the genomic, epigenetic, and procancer effects of obesity are reversible by various calorie restriction regimens.
Data from Prevention of Skin Carcinogenesis by the Non-β-blocking R-carvedilol Enantiomer
Authors: Liang Sherry , Shamim Md Abdullah , Shahid Ayaz , Chen Mengbing , Cleveland Kristan H. , Parsa Cyrus , Orlando Robert , Andresen Bradley T. , Huang Ying
Published: April 2023

Abstract
Skin cancer is the most common malignancy worldwide and is rapidly rising in incidence, representing a significant public health challenge. The β-blocker, carvedilol, has shown promising effects in preventing skin cancer. However, as a potent β-blocker, repurposing carvedilol to an anticancer agent is limited by cardiovascular effects. Carvedilol is a racemic mixture consisting of equimolar S- and R-carvedilol, whereas the R-carvedilol enantiomer does not possess β-blocking activity. Because previous studies suggest that carvedilol's cancer preventive activity is independent of β-blockade, we examined the skin cancer preventive activity of R-carvedilol compared with S-carvedilol and the racemic carvedilol. R- and S-carvedilol were equally effective in preventing EGF-induced neoplastic transformation of the mouse epidermal JB6 Cl 41-5a (JB6 P+) cells and displayed similar attenuation of EGF-induced ELK-1 activity. R-carvedilol appeared slightly better than S-carvedilol against UV-induced intracellular oxidative stress and release of prostaglandin E2 from the JB6 P+ cells. In an acute UV-induced skin damage and inflammation mouse model using a single irradiation of 300 mJ/cm2 UV, topical treatment with R-carvedilol dose dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, and IL6 and IL1β mRNA levels similar to carvedilol. In a chronic UV (50–150 mJ/cm2) induced skin carcinogenesis model in mice with pretreatment of test agents, topical treatment with R-carvedilol, but not racemic carvedilol, significantly delayed and reduced skin squamous cell carcinoma development. Therefore, as an enantiomer present in an FDA-approved agent, R-carvedilol may be a better option for developing a safer and more effective preventive agent for skin carcinogenesis.
Prevention Relevance:
In this study, we demonstrated the skin cancer preventive activity of R-carvedilol, the non-β-blocking enantiomer present in the racemic β-blocker, carvedilol. As R-carvedilol does not have β-blocking activity, such a preventive treatment would not lead to common cardiovascular side effects of β-blockers.
Data from Dietary Intake of Branched-Chain Amino Acids and Risk of Colorectal Cancer
Authors: Katagiri Ryoko , Song Mingyang , Zhang Xuehong , Lee Dong Hoon , Tabung Fred K. , Fuchs Charles S. , Meyerhardt Jeffrey A. , Nishihara Reiko , Chan Andrew T. , Joshi Amit D. , Iwasaki Motoki , Ogino Shuji , Willett Walter C. , Giovannucci Edward , Wu Kana
Published: April 2023

Abstract
Branched-chain amino acids (BCAA) are essential amino acids, and emerging evidence suggests that BCAAs may mediate pathways related to cancer progression, possibly due to their involvement in insulin metabolism. We investigated the association between dietary intake of BCAAs with colorectal cancer risk in three prospective cohorts: the Nurses' Health Study I [(NHS), number of participants (n) at baseline = 77,017], NHS II (n = 92,984), and the Health Professionals Follow-up Study [(HPFS) n = 47,255]. Validated food frequency questionnaires were administered every 4 years and follow-up questionnaires on lifestyle biennially. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression models. Pooled HRs were obtained using random effect models. After up to 28 years of follow-up, 1,660 cases were observed in NHS, 306 in NHS II, and 1,343 in HPFS. In multivariable adjusted models, we observed a weak inverse association between BCAA intake and colorectal cancer [highest vs. lowest quintile, pooled HR including all three cohorts (95% CI): 0.89 (0.80–1.00), Ptrend = 0.06, HR per standard deviation (SD) increment 0.95 (0.92–0.99)]. However, after including dairy calcium to the models, BCAA intake was no longer associated with risk of colorectal cancer [HR 0.96 (0.85–1.08), Ptrend = 0.50, HR per SD increment 0.97 (0.93–1.01)]. We did not find evidence that higher dietary BCAA intake is associated with higher risk of colorectal cancer. As this is the first prospective study to examine the association between BCAA intake and colorectal cancer, our findings warrant investigation in other cohorts.
Data from Dietary Advanced Glycation End-products (AGE) and Risk of Breast Cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)
Authors: Omofuma Omonefe O. , Turner David P. , Peterson Lindsay L. , Merchant Anwar T. , Zhang Jiajia , Steck Susan E.
Published: April 2023

Abstract
Advanced glycation end-products (AGEs) are implicated in the pathogenesis of several chronic diseases including cancer. AGEs are produced endogenously but can also be consumed from foods. AGE formation in food is accelerated during cooking at high temperatures. Certain high fat or highly processed foods have high AGE values. The objective of the study was to assign and quantify Nε-carboxymethyl-lysine (CML)-AGE content in food and investigate the association between dietary AGE intake and breast cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The study included women enrolled in the intervention arm who were cancer-free at baseline and completed a baseline questionnaire and food frequency questionnaire (DQX). CML-AGE values were assigned and quantified to foods in the DQX using a published AGE database. Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer among all women, and stratified by race/ethnicity, invasiveness of disease, and hormone receptor status. After a median 11.5 years of follow-up, 1,592 women were diagnosed with breast cancer. Higher CML-AGE intake was associated with increased risk of breast cancer among all women (HRQ5VSQ1, 1.30; 95% CI, 1.04–1.62; Ptrend = 0.04) and in non-Hispanic white women (HRT3VST1, 1.21; 95% CI, 1.02–1.44). Increased CML-AGE intake was associated with increased risk of in situ (HRT3VST1, 1.49; 95% CI, 1.11–2.01) and hormone receptor–positive (HRT3VST1, 1.24; 95% CI, 1.01–1.53) breast cancers. In conclusion, high intake of dietary AGE may contribute to increased breast cancer.
Data from Targeting of CD40 and PD-L1 Pathways Inhibits Progression of Oral Premalignant Lesions in a Carcinogen-induced Model of Oral Squamous Cell Carcinoma
Authors: Monteiro de Oliveira Novaes Jose A. , Hirz Taghreed , Guijarro Irene , Nilsson Monique , Pisegna Marlese A. , Poteete Alissa , Barsoumian Hampartsoum B. , Fradette Jared J. , Chen Limo N. , Gibbons Don L. , Tian Xiangjun , Wang Jing , Myers Jeffrey N. , McArthur Mark J. , Bell Diana , William William N. , Heymach John V.
Published: April 2023

Abstract
We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (OSCC). It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed this study to further characterize the immune landscape of oral premalignant lesions (OPL) and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1–knockout (PD-L1ko) mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist mAb was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1ko, also reduced progression of OPLs to OSCC, albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as potential immunoprevention agents in this setting.
Prevention Relevance:
PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted.
Data from Serum Levels of Androgens, Estrogens, and Sex Hormone Binding Globulin and Risk of Primary Gastric Cancer in Chinese Men: A Nested Case–Control Study
Authors: Zhu Zhikai , Chen Yingxi , Ren Jiansong , Dawsey Sanford M. , Yin Jian , Freedman Neal D. , Fan Jin-Hu , Taylor Philip R. , Liu Yuanli , Qiao You-Lin , Abnet Christian C.
Published: April 2023

Abstract
Gastric cancer shows a strong male predominance, and sex steroid hormones have been hypothesized to explain this sex disparity. Previous studies examining the associations between sex hormones and sex hormone binding globulin (SHBG) and risk of gastric cancer come primarily from western populations and additional studies in diverse populations will help us better understand the association. We performed a nested case–control study in Linxian Nutrition Intervention Trials cohorts to evaluate the associations among Chinese men, where we had sufficient cases to perform a well-powered study. Using radioimmunoassays and immunoassays, we quantitated androgens, estrogens, and SHBG in baseline serum from 328 men that developed noncardia gastric cancer and matched controls. We used multivariable unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) and explored interactions with body mass index (BMI), age, alcohol drinking, smoking, and follow-up time. Subjects with SHBG in the highest quartile, as compared with those in the lowest quartile, had a significantly increased risk of gastric cancer (OR = 1.87; 95% CI, 1.01–3.44). We found some evidence for associations of sex steroid hormones in men with lower BMI. Our study found a novel association suggesting that higher serum concentrations of SHBG may be associated with risk of gastric cancer in men. We found no overall associations with sex hormones themselves, but future studies should expand the scope of these studies to include women and further explore whether BMI modifies a potential association.
Prevention Relevance:
It was the first study to investigate the association of gastric cancer with prediagnostic sex steroid hormones and SHBG in an Asian male population. Although there were no overall associations for sex steroid hormone concentrations, higher concentrations of SHBG was associated with increased risk of noncardia gastric cancer.
Data from Addressing Disparities in Cancer Screening among U.S. Immigrants: Progress and Opportunities
Authors: Fang Carolyn Y. , Ragin Camille C.
Published: April 2023

Abstract
The United States is home to 47 million foreign-born individuals, which currently represents over 14% of the U.S. population. With greater length of U.S. residence, immigrants experience increased risk for chronic disease including selected cancers; yet, they are less likely to access preventive health care services and undergo cancer screening. As a result, there have been concerted efforts to address disparities in cancer screening in immigrant populations. This minireview describes current progress in promoting participation in cancer screening among U.S. immigrants and explores potential opportunities for improving impact. Of the 42 studies included in the review, the majority targeted Asian and Latino immigrant populations and included some form of culturally specific educational programming, often delivered in-person by community health workers and/or using a multimedia format. Twenty-eight of the 42 studies also offered navigation assistance to help overcome logistical and access barriers to care, and these studies yielded somewhat greater increases in screening. Yet, despite considerable effort over the past 20+ years, screening rates remain well below national goals. Opportunities to harness digital health tools to increase awareness and engagement, evaluating nonclinic-based screening paradigms to promote greater participation, and increasing efforts to address the needs of other immigrant subgroups are likely to have beneficial outcomes. Together, these strategies may help reduce inequities in access and uptake of cancer screening in U.S. immigrant populations.

See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention
Data from Scutellarin Suppresses Patient-Derived Xenograft Tumor Growth by Directly Targeting AKT in Esophageal Squamous Cell Carcinoma
Authors: Liu Feifei , Zu Xueyin , Xie Xiaomeng , Zhang Yuanyuan , Liu Kangdong , Chen Hanyong , Wang Ting , Bode Ann M. , Dong Zigang , Kim Dong Joon
Published: April 2023

Abstract
Scutellarin is a flavonoid compound that is found in Scutellaria barbata. It has been reported to exhibit anticancer and anti-inflammation activities. However, the anticancer properties of scutellarin and its molecular targets have not been investigated in esophageal squamous cell carcinoma (ESCC). In the current study, we report that scutellarin is a potential AKT inhibitor that suppresses patient-derived xenograft ESCC tumor growth. To identify possible molecular targets of scutellarin, potential candidate proteins were screened by an in vitro kinase assay and Western blotting. We found that scutellarin directly binds to the AKT1/2 proteins and inhibits activities of AKT1/2 in vitro. The AKT protein is activated in ESCC tissues and knockdown of AKT significantly suppresses growth of ESCC cells. Scutellarin significantly inhibits anchorage-dependent and independent cell growth and induces G2 phase cell-cycle arrest in ESCC cells. The inhibition of cell growth by scutellarin is dependent on the expression of the AKT protein. Notably, scutellarin strongly suppresses patient-derived xenograft ESCC tumor growth in an in vivo mouse model. Taken together, our data suggest that scutellarin is a novel AKT inhibitor that may prevent progression of ESCC.
Data from Interventions to Reduce Future Cancer Incidence from Diesel Engine Exhaust: What Might Work?
Authors: Carey Renee N. , Fritschi Lin , Driscoll Timothy R. , Peters Susan , Glass Deborah C. , Benke Geza , Reid Alison
Published: April 2023

Abstract
Exposure to diesel engine exhaust (DEE) contributes appreciably to the burden of occupational cancer. This study aims to estimate the potential impact of a range of interventions on the future burden of cancer from occupational exposure to DEE in Australia. The future excess fraction method, a novel method based on the lifetime risk approach, was used to model changes in the future burden of cancer among the Australian working age population exposed to DEE at work in 2012 under various intervention strategies. The interventions modeled were based on the widely accepted hierarchy of control model. At baseline, 600 (0.4%) future bladder and 4,450 (0.6%) future lung cancer cases over the lifetime of the cohort were estimated to be attributable to occupational exposure to DEE in those exposed in 2012. Up to 2,000 of these cases were estimated to be avoidable through the use of various interventions. Exhaust hoses (engineering controls) were estimated to be particularly effective. This study provides an indication of which intervention strategies may be most useful in reducing the future burden of cancer associated with occupational DEE exposure. These results show the potential effect of changing current exposure, rather than focusing on past exposures, and thus provide relevant information for policy planning.
Data from Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts
Authors: Zhou Cindy Ke , Daugherty Sarah E. , Liao Linda M. , Freedman Neal D. , Abnet Christian C. , Pfeiffer Ruth , Cook Michael B.
Published: April 2023

Abstract
Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer–specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75–0.90) and 15% (HR = 0.85; 95% CI = 0.77–0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72–0.95) and 25% (HR = 0.75; 95% CI = 0.66–0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410–20. ©2017 AACR.
Data from Expression of miR-18a and miR-210 in Normal Breast Tissue as Candidate Biomarkers of Breast Cancer Risk
Authors: Shidfar Ali , Costa Fabricio F. , Scholtens Denise , Bischof Jared M. , Sullivan Megan E. , Ivancic David Z. , Vanin Elio F. , Soares Marcelo B. , Wang Jun , Khan Seema A.
Published: April 2023

Abstract
miRNAs are noncoding RNAs with abnormal expression in breast cancer; their expression in high-risk benign breast tissue may relate to breast cancer risk. We examined miRNA profiles in contralateral unaffected breasts (CUB) of patients with breast cancer and validated resulting candidates in two additional sample sets. Expression profiles of 754 mature miRNAs were examined using TaqMan Low Density Arrays in 30 breast cancer samples [15 estrogen receptor (ER)-positive and 15 ER-negative] and paired CUBs and 15 reduction mammoplasty controls. Pairwise comparisons identified miRNAs with significantly differential expression. Seven candidate miRNAs were examined using qRT-PCR in a second CUB sample set (40 cases, 20 ER+, 20 ER−) and 20 reduction mammoplasty controls. Further validation was performed in 80 benign breast biopsy (BBB) samples; 40 from cases who subsequently developed breast cancer and 40 from controls who did not. Logistic regression, using tertiles of miRNA expression, was used to discriminate cases from controls. Seven miRNAs were differentially expressed in tumors and CUBs versus reduction mammoplasty samples. Among them, miR-18a and miR-210 were validated in the second CUB set, showing significantly higher expression in tumor and CUBs than in reduction mammoplasty controls. The expression of miR-18a and miR-210 was also significantly higher in BBB cases than in BBB controls. When both miR-18a and miR-210 were expressed in the upper tertiles in BBB, OR for subsequent cancer was 3.20, P = 0.023. miR-18a and miR-210 are expressed at higher levels in CUBs of patients with breast cancer, and in BBB prior to cancer development, and are therefore candidate breast cancer risk biomarkers. Cancer Prev Res; 10(1); 89–97. ©2016 AACR.
Data from Smoking, Helicobacter Pylori Serology, and Gastric Cancer Risk in Prospective Studies from China, Japan, and Korea
Authors: Butt Julia , Varga Matthew G. , Wang Tianyi , Tsugane Shoichiro , Shimazu Taichi , Zheng Wei , Abnet Christian C. , Yoo Keun-Young , Park Sue K. , Kim Jeongseon , Jee Sun Ha , Qiao You-lin , Shu Xiao-Ou , Waterboer Tim , Pawlita Michael , Epplein Meira
Published: April 2023

Abstract
Smoking is an established risk factor for gastric cancer development. In this study, we aimed to assess prospectively the association of smoking with gastric cancer risk in 1,446 non-cardia gastric cancer cases and 1,796 controls from China, Japan, and Korea with consideration of Helicobacter pylori infection as a potential effect modifier. Applying logistic regression models stratified by study and adjusted for age and sex we found that current, but not former, smoking was significantly associated with gastric cancer risk [OR = 1.33; 95% confidence interval (CI), 1.07–1.65]. However, the association was significant only in H. pylori sero-positive individuals determined by 3 different sero-markers: overall sero-positivity, sero-positivity to the onco-protein CagA, and sero-positivity to the gastric cancer associated sero-marker HP0305 and HP1564. Specifically, a significant interaction was found when stratifying by HP0305/HP1564 (Pinteraction = 0.01) with a 46% increased risk of gastric cancer among HP0305/HP1564 sero-positive current smokers (95% CI, 1.10–1.93) as opposed to no increased gastric cancer risk among HP0305/HP1564 sero-negative current smokers (OR = 0.93; 95% CI, 0.65–1.33). We confirmed that current smoking is associated with an increased gastric cancer risk, however, only among individuals that are simultaneously sero-positive for the leading causal factor for gastric cancer, H. pylori.
Data from Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model
Authors: Qin Xian-Yang , Tatsukawa Hideki , Hitomi Kiyotaka , Shirakami Yohei , Ishibashi Naoto , Shimizu Masahito , Moriwaki Hisataka , Kojima Soichi
Published: April 2023

Abstract
Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma. The objective of this study was to gain insights into molecular basis of the antitumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. ACR significantly counteracted against acceleration of lipogenesis but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a proinflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammation–mediated tumorigenesis of the liver. As a molecular mechanism of the ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP transcription factor 2, also known as NR2F2, was associated with the metabolic effect of ACR in human hepatocellular carcinoma cells. Our study provided potential therapeutic targets for the chemoprevention of hepatocellular carcinoma as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis. Cancer Prev Res; 9(3); 205–14. ©2016 AACR.
Data from Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse
Authors: Wang Lei , Guo Xiaolan , Wang Ji , Jiang Cheng , Bosland Maarten C. , Lü Junxuan , Deng Yibin
Published: April 2023

Abstract
Monomethylated selenium (MM-Se) forms that are precursors of methylselenol, such as methylseleninic acid (MSeA), differ in metabolism and anticancer activities in preclinical cell and animal models from seleno-methionine that had failed to exert preventive efficacy against prostate cancer in North American men. Given that human prostate cancer arises from precancerous lesions such as high-grade prostatic intraepithelial neoplasia (HG-PIN), which frequently have lost phosphatase and tensin homolog (PTEN) tumor suppressor permitting phosphatidylinositol-3-OH kinase (PI3K)–protein kinase B (AKT) oncogenic signaling, we tested the efficacy of MSeA to inhibit HG-PIN progression in Pten prostate-specific knockout (KO) mice and assessed the mechanistic involvement of p53-mediated cellular senescence and of the androgen receptor (AR). We observed that short-term (4 weeks) oral MSeA treatment significantly increased expression of P53 and P21Cip1 proteins and senescence-associated-β-galactosidase staining, and reduced Ki67 cell proliferation index in Pten KO prostate epithelium. Long-term (25 weeks) MSeA administration significantly suppressed HG-PIN phenotype, tumor weight, and prevented emergence of invasive carcinoma in Pten KO mice. Mechanistically, the long-term MSeA treatment not only sustained P53-mediated senescence, but also markedly reduced AKT phosphorylation and AR abundance in the Pten KO prostate. Importantly, these cellular and molecular changes were not observed in the prostate of wild-type littermates which were similarly treated with MSeA. Because p53 signaling is likely to be intact in HG-PIN compared with advanced prostate cancer, the selective superactivation of p53-mediated senescence by MSeA suggests a new paradigm of cancer chemoprevention by strengthening a cancer progression barrier through induction of irreversible senescence with additional suppression of AR and AKT oncogenic signaling. Cancer Prev Res; 9(1); 35–42. ©2015 AACR.
Data from Caloric Restriction Prevents Carcinogen-Initiated Liver Tumorigenesis in Mice
Authors: Ploeger Jonathan M. , Manivel Juan C. , Boatner Lauren N. , Mashek Douglas G.
Published: April 2023

Abstract
Caloric restriction (CR) and endurance exercise elicit wide-ranging health benefits including reduced risk of select cancers. In addition, diet composition influences oncogenesis, although its interactions with exercise and CR are not well understood. Therefore, to investigate the potential interactions between diet and lifestyle interventions on liver tumorigenesis, the carcinogen diethylnitrosamine was administered to 72 male C57Bl/6 mice that were subsequently fed diets enriched with lard (CTL) or olive oil and were further stratified to voluntary wheel running (Ex) or 30% CR for 49 weeks. Although Ex and diet composition did not influence liver oncogenesis, CR prevented hepatic tumor formation. In addition, CR reduced steatosis, hepatocyte ballooning, inflammation, and immune cell infiltration, all of which are hallmarks in the progression of nonalcoholic fatty liver disease to liver tumorigenesis. RNA sequencing of nontransformed liver tissues from CR mice revealed changes in metabolic pathways and reduced inflammation, cytokine production, stellate cell activation and migration, and genes associated with liver injury and oncogenesis. These data demonstrate that CR protects against steatosis, liver inflammation, and liver injury and is a robust deterrent of carcinogen-induced hepatic oncogenesis. Cancer Prev Res; 10(11); 660–70. ©2017 AACR.
Data from DNA Methylation in Peripheral Blood and Risk of Gastric Cancer: A Prospective Nested Case–control Study
Authors: Chamberlain James A , Dugué Pierre-Antoine , Bassett Julie K. , Milne Roger L. , Joo Jihoon E. , Wong Ee Ming , Brinkman Maree T. , Stuart Geoffrey W. , Boussioutas Alex , Southey Melissa C. , Giles Graham G. , Mitchell Hazel , English Dallas R. , Hodge Allison M.
Published: April 2023

Abstract
DNA methylation in peripheral blood is a potential biomarker of gastric cancer risk which could be used for early detection. We conducted a prospective case–control study nested within the Melbourne Collaborative Cohort Study. Genomic DNA was prepared from blood samples collected a median of 12 years before diagnosis for cases (N = 168). Controls (N = 163) were matched to cases on sex, year of birth, country of birth, and blood sample type using incidence density sampling. Genome-wide DNA methylation was measured using the Infinium HumanMethylation450K Beadchip. Global measures of DNA methylation were defined as the median methylation M value, calculated for each of 13 CpG subsets representing genomic function, mean methylation and location, and reliability of measurement. Conditional logistic regression was conducted to assess associations between these global measures of methylation and gastric cancer risk, adjusting for Helicobacter pylori and other potential confounders. We tested nonlinear associations using quintiles of the global measure distribution. A genome-wide association study of DNA methylation and gastric cancer risk was also conducted (N = 484,989 CpGs) using conditional logistic regression, adjusting for potential confounders. Differentially methylated regions (DMR) were investigated using the R package DMRcate. We found no evidence of associations with gastric cancer risk for individual CpGs or DMRs (P > 7.6 × 10−6). No evidence of association was observed with global measures of methylation (OR 1.07 per SD of overall median methylation; 95% confidence interval, 0.80–1.44; P = 0.65). We found no evidence that blood DNA methylation is prospectively associated with gastric cancer risk.

Prevention Relevance: We studied DNA methylation in blood to try and predict who was at risk of gastric cancer before symptoms developed, by which stage survival is poor. We did not find any such markers, but the importance of early diagnosis in gastric cancer remains, and the search for markers continues.