bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from SERMs Attenuate Estrogen-Induced Malignant Transformation of Human Mammary Epithelial Cells by Upregulating Detoxification of Oxidative Metabolites
Authors: Hemachandra L.P. Madhubhani P. , Patel Hitisha , Chandrasena R. Esala P. , Choi Jaewoo , Piyankarage Sujeewa C. , Wang Shuai , Wang Yijin , Thayer Emily N. , Scism Robert A. , Michalsen Bradley T. , Xiong Rui , Siklos Marton I. , Bolton Judy L. , Thatcher Gregory R.J.
Published: March 2024

Abstract
The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER) and to chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Nontumorigenic MCF-10A human breast epithelial cells are classified as ER− and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERM), in use for breast cancer chemoprevention and for postmenopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular reactive oxygen species (ROS), and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of phase II rather than phase I metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of phase II metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs. Cancer Prev Res; 7(5); 505–15. ©2014 AACR.
Data from Randomized Phase II Trial of Lyophilized Strawberries in Patients with Dysplastic Precancerous Lesions of the Esophagus
Authors: Chen Tong , Yan Fei , Qian Jiaming , Guo Mingzhou , Zhang Hongbing , Tang Xiaofei , Chen Fang , Stoner Gary D. , Wang Xiaomin
Published: March 2024

Abstract
Dysplasia is a histologic precursor of esophageal squamous cell carcinoma (SCC). We previously showed that dietary freeze-dried, or lyophilized, strawberry powder inhibits N-nitrosomethylbenzylamine-induced SCC in the rat esophagus. On the basis of this observation, we conducted a randomized (noncomparative) phase II trial in China to investigate the effects of two doses of freeze-dried strawberries in patients with esophageal dysplastic lesions in a high-risk area for esophageal cancer. We randomly assigned 75 patients identified by endoscopy to have dysplastic esophageal premalignant lesions to receive freeze-dried strawberry powder at either 30 g/d (37 patients) or 60 g/d (38 patients) for six months; the powder was mixed with water and drunk. After six months, we assessed the changes in histologic grade of these lesions (primary endpoint) in a blinded fashion. The dose of 30 g/d, did not significantly affect histology or any other measured parameter. The dose of 60 g/d, however, reduced the histologic grade of dysplastic premalignant lesions in 29 (80.6%) of the 36 patients at this dose who were evaluated for histology (P < 0.0001). The strawberry powder was well tolerated, with no toxic effects or serious adverse events. Strawberries (60 g/d) also reduced protein expression levels of inducible nitric oxide synthase (iNOS) by 79.5% (P < 0.001), cyclooxygenase-2 (COX-2) by 62.9% (P < 0.001), phospho-nuclear factor kappa B (NFκB)-p65 (pNFκB-p65) by 62.6% (P < 0.001), and phospho-S6 (pS6) by 73.2% (P < 0.001). Freeze-dried strawberries (60 g/d) also significantly inhibited the Ki-67 labeling index by 37.9% (P = 0.023). Our present results indicate the potential of freeze-dried strawberry powder for preventing human esophageal cancer, supporting further clinical testing of this natural agent in this setting. Cancer Prev Res; 5(1); 41–50. ©2011 AACR.
Data from Acyl-Coenzyme A–Binding Protein Regulates Beta-Oxidation Required for Growth and Survival of Non–Small Cell Lung Cancer
Authors: Harris Fredrick T. , Rahman S.M. Jamshedur , Hassanein Mohamed , Qian Jun , Hoeksema Megan D. , Chen Heidi , Eisenberg Rosana , Chaurand Pierre , Caprioli Richard M. , Shiota Masakazu , Massion Pierre P.
Published: March 2024

Abstract
We identified acyl-coenzyme A–binding protein (ACBP) as part of a proteomic signature predicting the risk of having lung cancer. Because ACBP is known to regulate β-oxidation, which in turn controls cellular proliferation, we hypothesized that ACBP contributes to regulation of cellular proliferation and survival of non–small cell lung cancer (NSCLC) by modulating β-oxidation. We used matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) and immunohistochemistry (IHC) to confirm the tissue localization of ABCP in pre-invasive and invasive NSCLCs. We correlated ACBP gene expression levels in NSCLCs with clinical outcomes. In loss-of-function studies, we tested the effect of the downregulation of ACBP on cellular proliferation and apoptosis in normal bronchial and NSCLC cell lines. Using tritiated-palmitate (3H-palmitate), we measured β-oxidation levels and tested the effect of etomoxir, a β-oxidation inhibitor, on proliferation and apoptosis. MALDI-IMS and IHC analysis confirmed that ACBP is overexpressed in pre-invasive and invasive lung cancers. High ACBP gene expression levels in NSCLCs correlated with worse survival (HR = 1.73). We observed a 40% decrease in β-oxidation and concordant decreases in proliferation and increases in apoptosis in ACBP-depleted NSCLC cells as compared with bronchial airway epithelial cells. Inhibition of β-oxidation by etomoxir in ACBP-overexpressing cells produced dose-dependent decrease in proliferation and increase in apoptosis (P = 0.01 and P < 0.001, respectively). These data suggest a role for ACBP in controlling lung cancer progression by regulating β-oxidation. Cancer Prev Res; 7(7); 748–57. ©2014 AACR.
Data from Pubertal Bisphenol A Exposure Alters Murine Mammary Stem Cell Function Leading to Early Neoplasia in Regenerated Glands
Authors: Wang Danhan , Gao Hui , Bandyopadhyay Abhik , Wu Anqi , Yeh I-Tien , Chen Yidong , Zou Yi , Huang Changjiang , Walter Christi A. , Dong Qiaoxiang , Sun Lu-Zhe
Published: March 2024

Abstract
Perinatal exposure to bisphenol A (BPA) has been shown to cause aberrant mammary gland morphogenesis and mammary neoplastic transformation. Yet, the underlying mechanism is poorly understood. We tested the hypothesis that mammary glands exposed to BPA during a susceptible window may lead to its susceptibility to tumorigenesis through a stem cell–mediated mechanism. We exposed 21-day-old Balb/c mice to BPA by gavage (25 μg/kg/d) during puberty for 3 weeks, and a subset of animals were further challenged with one oral dose (30 mg/kg) of 7,12-dimethylbenz(a)anthracene (DMBA) at 2 months of age. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age for murine mammary stem cell (MaSC) quantification and function analysis. Pubertal exposure to the low-dose BPA increased lateral branches and hyperplasia in adult mammary glands and caused an acute increase of MaSC in 6-week-old glands and a delayed increase of luminal progenitors in 4-month-old adult gland. Most importantly, pubertal BPA exposure altered the function of MaSC from different age groups, causing early neoplastic lesions in their regenerated glands similar to those induced by DMBA exposure, which indicates that MaSCs are susceptible to BPA-induced transformation. Deep sequencing analysis on MaSC-enriched mammospheres identified a set of aberrantly expressed genes associated with early neoplastic lesions in patients with human breast cancer. Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation. Cancer Prev Res; 7(4); 445–55. ©2014 AACR.
Data from Soy Isoflavone Supplementation for Breast Cancer Risk Reduction: A Randomized Phase II Trial
Authors: Khan Seema A. , Chatterton Robert T. , Michel Nancy , Bryk Michelle , Lee Oukseub , Ivancic David , Heinz Richard , Zalles Carola M. , Helenowski Irene B. , Jovanovic Borko D. , Franke Adrian A. , Bosland Maarten C. , Wang Jun , Hansen Nora M. , Bethke Kevin P. , Dew Alexander , Coomes Margerie , Bergan Raymond C.
Published: March 2024

Abstract
Soy isoflavone consumption may protect against breast cancer development. We conducted a phase IIB trial of soy isoflavone supplementation to examine its effect on breast epithelial proliferation and other biomarkers in the healthy high-risk breast. One hundred and twenty-six consented women underwent a random fine-needle aspiration (rFNA); those with 4,000 or more epithelial cells were randomized to a double-blind 6-month intervention of mixed soy isoflavones (PTIG-2535) or placebo, followed by repeat rFNA. Cells were examined for Ki-67 labeling index and atypia. Expression of 28 genes related to proliferation, apoptosis, and estrogenic effect was measured using quantitative reverse transcriptase PCR. Hormone and protein levels were measured in nipple aspirate fluid (NAF). All statistical tests were two-sided. Ninety-eight women were evaluable for Ki-67 labeling index. In 49 treated women, the median Ki-67 labeling index was 1.18 at entry and 1.12 post intervention, whereas in 49 placebo subjects, it was 0.97 and 0.92 (P for between-group change: 0.32). Menopausal stratification yielded similar results between groups, but within premenopausal soy-treated women, Ki-67 labeling index increased from 1.71 to 2.18 (P = 0.04). We saw no treatment effect on cytologic atypia or NAF parameters. There were significant increases in the expression of 14 of 28 genes within the soy, but not the control group, without significant between-group differences. Plasma genistein values showed excellent compliance. A 6-month intervention of mixed soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, suggesting a lack of efficacy for breast cancer prevention and a possible adverse effect in premenopausal women. Cancer Prev Res; 5(2); 309–19. ©2012 AACR.
Data from Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus
Authors: Li Xiaohong , Paulson Thomas G. , Galipeau Patricia C. , Sanchez Carissa A. , Liu Karen , Kuhner Mary K. , Maley Carlo C. , Self Steven G. , Vaughan Thomas L. , Reid Brian J. , Blount Patricia L.
Published: March 2024

Abstract
Cancers detected at a late stage are often refractory to treatments and ultimately lethal. Early detection can significantly increase survival probability, but attempts to reduce mortality by early detection have frequently increased overdiagnosis of indolent conditions that do not progress over a lifetime. Study designs that incorporate biomarker trajectories in time and space are needed to distinguish patients who progress to an early cancer from those who follow an indolent course. Esophageal adenocarcinoma is characterized by evolution of punctuated and catastrophic somatic chromosomal alterations and high levels of overall mutations but few recurrently mutated genes aside from TP53. Endoscopic surveillance of Barrett's esophagus for early cancer detection provides an opportunity for assessment of alterations for cancer risk in patients who progress to esophageal adenocarcinoma compared with nonprogressors. We investigated 1,272 longitudinally collected esophageal biopsies in a 248 Barrett's patient case–cohort study with 20,425 person-months of follow-up, including 79 who progressed to early-stage esophageal adenocarcinoma. Cancer progression risk was assessed for total chromosomal alterations, diversity, and chromosomal region-specific alterations measured with single-nucleotide polymorphism arrays in biopsies obtained over esophageal space and time. A model using 29 chromosomal features was developed for cancer risk prediction (area under receiver operator curve, 0.94). The model prediction performance was robust in two independent esophageal adenocarcinoma sets and outperformed TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia. This study offers a strategy to reduce overdiagnosis in Barrett's esophagus and improve early detection of esophageal adenocarcinoma and potentially other cancers characterized by punctuated and catastrophic chromosomal evolution. Cancer Prev Res; 8(9); 845–56. ©2015 AACR.
Data from Red Wine Consumption is Inversely Associated with 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine–DNA Adduct Levels in Prostate
Authors: Rybicki Benjamin A. , Neslund-Dudas Christine , Bock Cathryn H. , Nock Nora L. , Rundle Andrew , Jankowski Michelle , Levin Albert M. , Beebe-Dimmer Jennifer , Savera Adnan T. , Takahashi Satoru , Shirai Tomoyuki , Tang Deliang
Published: March 2024

Abstract
In humans, genetic variation and dietary factors may alter the biological effects of exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the major heterocyclic amines generated from cooking meats at high temperatures that has carcinogenic potential through the formation of DNA adducts. Previously, we reported grilled red meat consumption associated with PhIP–DNA adduct levels in human prostate. In this study, we expanded our investigation to estimate the associations between beverage consumption and PhIP–DNA adduct levels in prostate for 391 prostate cancer cases. Of the 15 beverages analyzed, red wine consumption had the strongest association with PhIP–DNA adduct levels showing an inverse correlation in both tumor (P = 0.006) and nontumor (P = 0.002) prostate cells. Red wine consumption was significantly lower in African American compared with white cases, but PhIP–DNA adduct levels in prostate did not vary by race. In African Americans compared with whites, however, associations between red wine consumption and PhIP–DNA adduct levels were not as strong as associations with specific (e.g., SULT1A1 and UGT1A10 genotypes) and nonspecific (e.g., African ancestry) genetic variation. In a multivariable model, the covariate for red wine consumption explained a comparable percentage (13%–16%) of the variation in PhIP–DNA adduct levels in prostate across the two racial groups, but the aforementioned genetic factors explained 33% of the PhIP–DNA adduct variation in African American cases, whereas only 19% of the PhIP–DNA adduct variation in whites. We conclude that red wine consumption may counteract biological effects of PhIP exposure in human prostate, but genetic factors may play an even larger role, particularly in African Americans. Cancer Prev Res; 4(10); 1636–44. ©2011 AACR.
Data from Honokiol Decreases Lung Cancer Metastasis through Inhibition of the STAT3 Signaling Pathway
Authors: Pan Jing , Lee Yongik , Zhang Qi , Xiong Donghai , Wan Tina C. , Wang Yian , You Ming
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer death in the United States. Metastasis to lymph nodes and distal organs, especially brain, leads to severe complications and death. Preventing lung cancer development and metastases is an important strategy to reduce lung cancer mortality. Honokiol (HNK), a natural compound present in the extracts of magnolia bark, has a favorable bioavailability profile and recently has been shown to readily cross the blood–brain barrier. In the current study, we evaluated the antimetastatic effects of HNK in both the lymph node and brain mouse models of lung tumor metastasis. We tested the efficacy of HNK in preventing 18 H2030-BrM3 cell (brain-seeking human lung tumor cells) migration to lymph node or brain. In an orthotopic mouse model, HNK significantly decreased lung tumor growth compared with the vehicle control group. HNK also significantly reduced the incidence of lymph node metastasis and the weight of mediastinal lymph nodes. In a brain metastasis model, HNK inhibits metastasis of lung cancer cells to the brain to approximately one third of that observed in control mice. We analyzed HNK's mechanism of action, which indicated that its effect is mediated primarily by inhibiting the STAT3 pathway. HNK specifically inhibits STAT3 phosphorylation irrespective of the mutation status of EGFR, and knockdown of STAT3 abrogated both the antiproliferative and the antimetastatic effects of HNK. These observations suggest that HNK could provide novel chemopreventive or therapeutic options for preventing both lung tumor progression and lung cancer metastasis. Cancer Prev Res; 10(2); 133–41. ©2016 AACR.
Data from A Prospective Study of Nut Consumption and Risk of Primary Hepatocellular Carcinoma in the U.S. Women and Men
Authors: Sui Jing , Yang Wanshui , Ma Yanan , Li Tricia Y. , Simon Tracey G. , Meyerhardt Jeffrey A. , Liang Geyu , Giovannucci Edward L. , Chan Andrew T. , Zhang Xuehong
Published: March 2024

Abstract
Although increasing evidence suggests a potential beneficial effect of nut consumption on various diseases, no epidemiologic study has yet examined the association between nut consumption and risk of hepatocellular carcinoma (HCC). We prospectively examined this association in 88,783 women from the Nurses’ Health Study and 51,492 men from the Health Professionals Follow-up Study. Nut consumption was assessed every 4 years using validated food frequency questionnaires. Multivariable HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression models after adjusting for HCC risk factors. After an average of 27.9 years of follow-up, we identified a total of 162 incident HCC cases. Higher total nut consumption was not significantly associated with HCC risk (the highest vs. lowest tertile intake, HR, 0.84; 95% CI, 0.56–1.26). For the same comparison, higher tree nut consumption was associated with a lower HCC risk (HR, 0.64; 95% CI, 0.43–0.95). We found nonsignificant inverse associations with consumption of walnuts, peanuts, and peanut butter. Overall, nut consumption was not strongly associated with HCC risk. There was a suggestive inverse association with tree nut consumption. Future studies should carefully consider hepatitis B or C virus infections and examine these associations in other racial/ethnic groups.
Data from A Distinct Epidemiologic Pattern of Precancerous Lesions of Esophageal Squamous Cell Carcinoma in a High-risk Area of Huai'an, Jiangsu Province, China
Authors: Pan Da , Su Ming , Zhang Ting , Miao Caiyun , Fu Lingmeng , Yang Ligang , Song Guang , Raine Philip J. , Wang Shaokang , Sun Guiju
Published: March 2024

Abstract
Better understanding of esophageal precancerous lesions (EPL) can inform prevention strategies for esophageal squamous cell carcinoma (ESCC). Here, a cross-sectional epidemiologic study based on the Early Diagnosis and Early Treatment Project of Esophageal Cancer database from 2011 to 2017 was performed to fully investigate and characterize the epidemiology of EPL in rural Huai'an District. Data of 11,518 participants ages 35–75 years were collected through face-to-face interviews by questionnaire. Participants underwent a routine endoscopy examination, tissues were biopsied, and diagnosed according to the histologic criteria of dysplasia. Unconditional univariate and multivariate logistic regression analyses were performed to obtain crude and adjusted odds ratios and corresponding 95% confidence intervals, respectively. A total of 667 subjects were diagnosed with EPL. Factors associated with an increased risk of EPL included: drinking shallow well water and surface water, irregular diet, excessive smoking, exposure to secondhand smoke, consumption of corn, corn flour, pickled food, fried food, and hot food, and having a history of digestive system diseases. In addition, liquor use, but not other alcohol types, contributed to risk of EPL. Consumption of deep well water and vegetables, fruits, and animal livers were associated with lower EPL risk. This study suggested a completely distinct pattern that alcohol use plays only a minor role in EPL and excessive tobacco use shows a significant association in rural Huai'an District, while eating habits and environmental exposure may be the dominant factors. This work may be promising to provide scientific evidence to support primary prevention of ESCC in this region.
Data from Evaluation of the Associations Between Cervical Microbiota and HPV Infection, Clearance, and Persistence in Cytologically Normal Women
Authors: Ritu Wu , Enqi Wu , Zheng Siriguleng , Wang Jiandong , Ling Yaqin , Wang Yan
Published: March 2024

Abstract
The aim of this study was to investigate the associations between cervical microbiota and different human papillomavirus (HPV) infection statuses in cytologically normal women. The cervical microbiota of HPV-positive or -negative women with a normal cytologic diagnosis was characterized and compared using 16S rDNA-based high-throughput sequencing, and the differences in cervical microbiota associated with new acquisition, persistence, and clearances of HPV genotypes were analyzed via one-year follow-up. The results showed that the cervical microbial richness of HPV-positive women was lower than for HPV-negative women, and the difference was more significant in the postmenopausal group relative to the premenopausal group. Ureaplasma parvum and related taxa were associated with baseline HPV positivity, while Brochothrix, Diplorickettsia, Ezakiella, Faecalibacterium, and Fusobacterium genera and their related taxa and Pseudomonas aeruginosa were associated with baseline HPV negativity. For HPV-positive women, the baseline abundance of Actinomyces was negatively associated with new HPV infection, Alloprevotella tannerae, Prevotella nigrescens, and Prevotella oulorum; and Dialister invisus were positively associated with new HPV-type infection within the year of follow-up. Lactobacillus delbrueckii was found to be negatively associated with persistent HPV infection and 9 taxa belonging to Prevotella, Dialister, and Lachnospiraceae were found to be positively associated with persistence, and/or negatively associated with clearance of HPV types. We also observed 10 novel taxa associated with the clearance/persistence of HPV that had not been reported elsewhere. Those taxa associated with different infection statuses of HPV could be used as a biomarker to help predict the risk of developing persistent HPV infection.
Data from A Novel Biomarker Panel for the Early Detection and Risk Assessment of Hepatocellular Carcinoma in Patients with Cirrhosis
Authors: Khan Ilvira M. , Gjuka Donjeta , Jiao Jingjing , Song Xiaoling , Wang Ying , Wang Jing , Wei Peng , El-Serag Hashem B. , Marrero Jorge A. , Beretta Laura
Published: March 2024

Abstract
Novel biomarkers for hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis are urgently needed. We previously identified osteopontin (OPN) as a promising biomarker for the early detection of HCC. This study is to further validate the performance of OPN and identify fatty acids (FA) that could improve OPN's performance in HCC risk assessment in patients with cirrhosis. To that end, we selected 103 patients with cirrhosis under surveillance. Among them, 40 patients developed HCC during follow-up. We investigated in these 103 patients, the association between HCC incidence and prediagnostic serum levels of AFP, OPN, and 46 FAs. OPN performance was higher than AFP in detecting prediagnosis HCCs and the combination with AFP further improved OPN's performance. For patients with a diagnosis of HCC within 18 months of follow-up (HCC < 18 months), AUC for OPN + AFP was 0.77. Abundance of 11 FAs [four long-chain saturated FAs (SFA), four n-3 poly-unsaturated FAs (PUFA), and three n-6 PUFAs] were statistically different between patients who developed HCC and those who did not. Abundance changes correlated with time to diagnosis for the PUFAs, but not for the SFAs. Adding arachidic acid (20:0) and n-3 docosapentaenoic acid (22:5n3) to OPN and AFP improved the discriminatory performance (AUC = 0.83). AUC for this panel reached 0.87 for HCC < 18 months (82% sensitivity at 81% specificity). In conclusion, we identified a panel of 4 markers with strong performances that could have significant utility in HCC early detection in patients with cirrhosis under surveillance.
Prevention Relevance:
This study identified a panel of 4 biomarkers that identifies with high performance patients with cirrhosis at high risk for HCC. This panel could have utility in HCC early detection in patients with cirrhosis under surveillance.
Data from Simultaneous Measurement of 92 Serum Protein Biomarkers for the Development of a Multiprotein Classifier for Ovarian Cancer Detection
Authors: Skubitz Amy P.N. , Boylan Kristin L.M. , Geschwind Kate , Cao Qing , Starr Timothy K. , Geller Melissa A. , Celestino Joseph , Bast Robert C. , Lu Karen H. , Koopmeiners Joseph S.
Published: March 2024

Abstract
The best known ovarian cancer biomarker, CA125, is neither adequately sensitive nor specific for screening the general population. By using a combination of proteins for screening, it may be possible to increase the sensitivity and specificity over CA125 alone. In this study, we used Proseek Multiplex Oncology II plates to simultaneously measure the expression of 92 cancer-related proteins in serum using proximity extension assays. This technology combines the sensitivity of the PCR with the specificity of antibody-based detection methods, allowing multiplex biomarker detection and high-throughput quantification. We analyzed 1 μL of sera from each of 61 women with ovarian cancer and compared the values obtained with those from 88 age-matched healthy women. Principle component analysis and unsupervised hierarchical clustering separated the ovarian cancer patients from the healthy, with minimal misclassification. Data from the Proseek plates for CA125 levels exhibited a strong correlation with clinical values for CA125. We identified 52 proteins that differed significantly (P < 0.006) between ovarian cancer and healthy samples, several of which are novel serum biomarkers for ovarian cancer. In total, 40 proteins had an estimated area under the ROC curve of 0.70 or greater, suggesting their potential to serve as biomarkers for ovarian cancer. CA125 alone achieved a sensitivity of 93.4% at a specificity of 98%. By adding the Oncology II values for five proteins to CA125 in a multiprotein classifier, we increased the assay sensitivity to 98.4% at a specificity of 98%, thereby improving the sensitivity and specificity of CA125 alone.
Data from Unconjugated Bilirubin Is a Novel Prognostic Biomarker for Nasopharyngeal Carcinoma and Inhibits Its Metastasis via Antioxidation Activity
Authors: Deng Cheng-Cheng , Xu Miao , Li Jing , Luo Xiao-Lin , Zhu Yu-Jia , Jiang Rou , Zhang Meng-Xia , Lei Jin-Ju , Lian Yi-Fan , Zou Xiong , You Rui , Chen Li-Zhen , Feng Qi-Sheng , Bei Jin-Xin , Chen Ming-Yuan , Zeng Yi-Xin
Published: March 2024

Abstract
Distant metastasis is the most common cause of treatment failure and mortality in nasopharyngeal carcinoma (NPC) patients. Thus, it is important to understand the mechanism of NPC metastasis and identify reliable prognostic factors. In this study, we investigated the prognostic value of unconjugated bilirubin (UCB), which was previously considered a byproduct of heme catabolism, in NPC patients and examined the effects of UCB on NPC metastasis. The receiver operating characteristic analysis–generated UCB cutoff point for DMFS was 9.7 μmol/L. We found that higher UCB levels were significantly associated with favorable distant metastasis-free survival (DMFS, 93.3% vs. 84.2%, P < 0.001) in NPC patients and was an independent predictor for DMFS (HR, 0.416; 95% confidence interval, 0.280–0.618; P < 0.001). We next found that UCB treatment impaired the invasion capability of NPC cells and potently inhibited lung metastasis of NPC cells in nude mice. Further investigation showed that UCB inhibited reactive oxygen species production, which is involved in the repression of ERK1/2 activation and matrix metalloproteinase-2 (MMP-2) expression. Moreover, lower levels of ERK1/2 phosphorylation and MMP-2 expression were observed in the NPC lung metastases of nude mice administered UCB. Taken together, our results indicate that UCB is a significantly favorable factor for DMFS in NPC patients and may play an important role in NPC chemoprevention. Cancer Prev Res; 9(2); 180–8. ©2015 AACR.
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: March 2024

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 Temporal Efficacy of a Sulforaphane-Based Broccoli Sprout Diet in Prevention of Breast Cancer through Modulation of Epigenetic Mechanisms
Authors: Li Yuanyuan , Buckhaults Phillip , Li Shizhao , Tollefsbol Trygve
Published: March 2024

Abstract
Breast cancer is the most common cancer and the second leading cause of cancer-related death among women. An important risk factor for breast cancer is individual genetic background, which is initially generated early in human life, for example, during the processes of embryogenesis and fetal development in utero. Bioactive dietary components such as sulforaphane (SFN), an isothiocyanate from cruciferous vegetables including broccoli sprouts (BSp), cabbage, and kale, has been shown to reduce the risk of developing many common cancers through regulation of epigenetic mechanisms. Our study indicates a prenatal/maternal BSp dietary treatment exhibited maximal preventive effects in inhibiting breast cancer development compared with postnatal early-life and adult BSp treatments in two transgenic mouse models that can develop breast cancer. Postnatal early-life BSp treatment starting prior to puberty onset showed protective effects in prevention of breast cancer but was not as effective as the prenatal/maternal BSp treatment. However, adulthood-administered BSp diet did not reduce mammary tumorigenesis. Our results suggest that the prenatal/maternal BSp bioactive natural plant product may impact early embryonic development by regulating global differential gene expression through affecting epigenetic profiles resulting in differential susceptibility to breast cancer later in life. These results suggest that a temporal exposure to epigenetic-modulating dietary components such as cruciferous vegetables could be a key factor for maximizing chemopreventive effects on human breast cancer. This study may lead to translational breast cancer chemopreventive potential by appropriate administration of key dietary components leading to early breast cancer prevention in humans. Cancer Prev Res; 11(8); 451–64. ©2018 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: March 2024

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 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: March 2024

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 Immune Checkpoint Inhibition is Safe and Effective for Liver Cancer Prevention in a Mouse Model of Hepatocellular Carcinoma
Authors: Chung Andrew S. , Mettlen Marcel , Ganguly Debolina , Lu Tianshi , Wang Tao , Brekken Rolf A. , Hsiehchen David , Zhu Hao
Published: March 2024

Abstract
Cirrhosis is a high-risk state for hepatocellular carcinoma (HCC) development and represents an opportunity to prevent cancer. In the precancerous state of cirrhosis, there is an accumulation of neoantigens that may be specifically targetable through immunotherapy. We asked whether immune checkpoint inhibition could prevent tumorigenesis in a mouse model of diethylnitrosamine and carbon tetrachloride–induced HCC. We found that initiation of anti-PD-1 therapy prior to tumorigenesis could prevent up to 46% of liver tumors. This significant reduction in tumor burden was accompanied by infiltration of CD4+ Th cells and CD8+ cytotoxic T cells into the liver parenchyma. Importantly, anti-PD-1 therapy did not exacerbate liver dysfunction or worsen overall health in this liver disease model. Given the safety and preservation of quality of life observed with long-term immunotherapy use, an immunotherapy chemoprevention strategy is likely associated with a low risk-to-benefit ratio and high value care in select patients. These results encourage a prevention trial in cirrhotic patients with the highest risk of developing HCC.

See related Spotlight by Mohammed et al., p. 897
Data from COX-2 Inhibitors Decrease Expression of PD-L1 in Colon Tumors and Increase the Influx of Type I Tumor-infiltrating Lymphocytes
Authors: Cecil Denise L. , Gad Ekram A. , Corulli Lauren R. , Drovetto Nicholas , Lubet Ronald A. , Disis Mary L.
Published: March 2024

Abstract
Colon cancer is initiated under inflammatory conditions associated with upregulation of immune checkpoint proteins. We evaluated immune modulation induced by nonsteroidal anti-inflammatory agents used for colon cancer prevention. Both celecoxib and naproxen inhibited polyp growth in APC Min mice. Treatment of mice with either drug significantly decreased PD-L1 expression on polyps in a dose-dependent manner (P < 0.0001 for both). The decrease in PD-L1 was associated with an influx of CD8+ T cells into polyps (P < 0.0001, celecoxib; P = 0.048, naproxen) compared with lesions from untreated animals and correlated with disease control. Naproxen is a nonselective inhibitor of both COX-1 and COX-2, and we questioned the role of the different cyclooxygenases in PD-L1 regulation. Silencing either COX-2 or COX-1 RNA in the murine colon cancer cell line MC38, reduced PD-L1 expression by 86% in COX-2–silenced cells (P < 0.0001) while there was little effect with COX-1 siRNA compared with control. Naproxen could inhibit the growth of MC38 in vivo. Naproxen-treated mice demonstrated a significant reduction in MC38 growth as compared with control (P < 0001). Both Tbet+ CD4 and CD8 tumor-infiltrating lymphocytes (TIL) were significantly increased (P = 0.04 and P = 0.038, respectively) without a concurrent increase in GATA3+ TIL (P > 0.05). CD8+ TIL highly expressed the activation marker, CD69. Not only was PD-L1 expression decreased on tumors, but LAG3+CD8+ T cells and PD-1 and LAG3 expression on regulatory T cells was also reduced (P = 0.008 and P = 0.002, respectively). These data demonstrate COX-2 inhibitors significantly decrease PD-L1 in colonic lesions and favorably impact the phenotype of tumor-infiltrating lymphocytes to control tumor growth.
Prevention Relevance:
Nonsteroidal anti-inflammatories (NSAID) are an essential component of any combination chemoprevention of colon cancer. We show NSAID treatment reduces PD-L1 expression on intestinal tumor cells. NSAID regulation of PD-L1 is dependent on COX-2 expression. These data underscore an important immunologic mechanism of action for NSAID in colon cancer prevention.

Watch the interview with Denise Cecil, PhD, recipient of the 2024 Cancer Prevention Research Award for Outstanding Journal Article: https://vimeo.com/992981665

See related Spotlight, p. 209
Data from Temporal Dissection of Tumorigenesis in Primary Cancers
Authors: Durinck Steffen , Ho Christine , Wang Nicholas J. , Liao Wilson , Jakkula Lakshmi R. , Collisson Eric A. , Pons Jennifer , Chan Sai-Wing , Lam Ernest T. , Chu Catherine , Park Kyunghee , Hong Sung-woo , Hur Joe S. , Huh Nam , Neuhaus Isaac M. , Yu Siegrid S. , Grekin Roy C. , Mauro Theodora M. , Cleaver James E. , Kwok Pui-Yan , LeBoit Philip E. , Getz Gad , Cibulskis Kristian , Aster Jon C. , Huang Haiyan , Purdom Elizabeth , Li Jian , Bolund Lars , Arron Sarah T. , Gray Joe W. , Spellman Paul T. , Cho Raymond J.
Published: March 2024

Abstract
Timely intervention for cancer requires knowledge of its earliest genetic aberrations. Sequencing of tumors and their metastases reveals numerous abnormalities occurring late in progression. A means to temporally order aberrations in a single cancer, rather than inferring them from serially acquired samples, would define changes preceding even clinically evident disease. We integrate DNA sequence and copy number information to reconstruct the order of abnormalities as individual tumors evolve for 2 separate cancer types. We detect vast, unreported expansion of simple mutations sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCC) and serous ovarian adenocarcinomas, in the former surpassing 50 mutations per megabase. In cSCCs, we also report diverse secondary mutations in known and novel oncogenic pathways, illustrating how such expanded mutagenesis directly promotes malignant progression. These results reframe paradigms in which TP53 mutation is required later, to bypass senescence induced by driver oncogenes.

Significance: Our approach reveals sequential ordering of oncogenic events in individual cancers, based on chromosomal rearrangements. Identifying the earliest abnormalities in cancer represents a critical step in timely diagnosis and deployment of targeted therapeutics. Cancer Discovery; 1(2); 137–43. © 2011 AACR.

This article is highlighted in the In This Issue feature, p. 91
Data from An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide)
Authors: Korpal Manav , Korn Joshua M. , Gao Xueliang , Rakiec Daniel P. , Ruddy David A. , Doshi Shivang , Yuan Jing , Kovats Steve G. , Kim Sunkyu , Cooke Vesselina G. , Monahan John E. , Stegmeier Frank , Roberts Thomas M. , Sellers William R. , Zhou Wenlai , Zhu Ping
Published: March 2024

Abstract
Castration-resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of an F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that ARF876L confers an antagonist-to-agonist switch that drives phenotypic resistance. Finally, treatment with distinct antiandrogens or cyclin-dependent kinase (CDK)4/6 inhibitors effectively antagonized ARF876L function. Together, these findings suggest that emergence of F876L may (i) serve as a novel biomarker for prediction of drug sensitivity, (ii) predict a “withdrawal” response to MDV3100, and (iii) be suitably targeted with other antiandrogens or CDK4/6 inhibitors.

Significance: We uncovered an F876L agonist-switch mutation in AR that confers genetic and phenotypic resistance to the antiandrogen drug MDV3100. On the basis of this finding, we propose new therapeutic strategies to treat patients with prostate cancer presenting with this AR mutation. Cancer Discov; 3(9); 1030–43. ©2013 AACR.

See related commentary by Nelson and Yegnasubramanian, p. 971

This article is highlighted in the In This Issue feature, p. 953
Data from Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non–Small Cell Lung Cancer
Authors: Sang Jim , Acquaviva Jaime , Friedland Julie C. , Smith Donald L. , Sequeira Manuel , Zhang Chaohua , Jiang Qin , Xue Liquan , Lovly Christine M. , Jimenez John-Paul , Shaw Alice T. , Doebele Robert C. , He Suqin , Bates Richard C. , Camidge D. Ross , Morris Stephan W. , El-Hariry Iman , Proia David A.
Published: March 2024

Abstract
EML4–ALK gene rearrangements define a unique subset of patients with non–small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4–ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a patient with crizotinib-resistant NSCLC. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC.

Significance: In addition to direct kinase inhibition, pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK. The bioactivity profile of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC. Cancer Discov; 3(4); 430–43. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 363