bluuebunny/crossref_metadata_2025 huggingface dataset:
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: April 2023

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 Effect of Suppressive Oligodeoxynucleotides on the Development of Inflammation-Induced Papillomas
Authors: Ikeuchi Hidekazu , Kinjo Takeshi , Klinman Dennis M.
Published: April 2023

Abstract
Inflammation contributes to the development of papillomas and squamous cell carcinomas in the well-established 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) model of skin carcinogenesis. Synthetic oligonucleotides (ODN) containing repetitive TTAGGG motifs have been shown to block deleterious inflammatory reactions in murine models of autoimmunity, pneumonitis, and shock. This article examines whether treatment with suppressive (Sup) ODN can interfere with DMBA/TPA-induced inflammation, thereby reducing papilloma formation. Results indicate that Sup ODN block TPA-dependent skin hyperplasia, edema, and leukocytic infiltration. Sup ODN also inhibit the upregulation of genes encoding pro-oncogenic chemokines and other markers of inflammation including CXCL2, CCL2, COX-2, and ODC (ornithine decarboxylase). Of greatest import, Sup ODN reduce papilloma formation in a dose- and sequence-dependent manner. These findings suggest that Sup ODN may provide a novel means of preventing inflammation and associated oncogenesis. Cancer Prev Res; 4(5); 752–7. ©2011 AACR.
Data from Paired Box 5 Methylation Detection by Droplet Digital PCR for Ultra-Sensitive Deep Surgical Margins Analysis of Head and Neck Squamous Cell Carcinoma
Authors: Hayashi Masamichi , Guerrero-Preston Rafael , Sidransky David , Koch Wayne M.
Published: April 2023

Abstract
Molecular deep surgical margin analysis has been shown to predict locoregional recurrences of head and neck squamous cell carcinoma (HNSCC). To improve the accuracy and versatility of the analysis, we used a highly tumor-specific methylation marker and highly sensitive detection technology to test DNA from surgical margins. Histologically cancer-negative deep surgical margin samples were prospectively collected from 82 eligible HNSCC surgeries by an imprinting procedure (n = 75) and primary tissue collection (n = 70). Bisulfite-treated DNA from each sample was analyzed by both conventional quantitative methylation-specific PCR (QMSP) and QMSP by droplet digital PCR (ddQMSP) targeting Paired box 5 (PAX5) gene promoter methylation. The association between the presence of PAX5 methylation and locoregional recurrence-free survival (LRFS) was evaluated. PAX5 methylation was found in 68.0% (51 of 75) of tumors in the imprint samples and 71.4% (50 of 70) in the primary tissue samples. Among cases that did not have postoperative radiation (n = 31 in imprint samples, n = 29 in tissue samples), both conventional QMSP and ddQMSP revealed that PAX5 methylation–positive margins was significantly associated with poor LRFS by univariate analysis. In particular, ddQMSP increased detection of the PAX5 marker from 29% to 71% in the nonradiated imprint cases. Also, PAX5 methylated imprint margins were an excellent predictor of poor LRFS [HR, 3.89; 95% confidence interval (CI), 1.19–17.52; P = 0.023] by multivariate analysis. PAX5 methylation appears to be an excellent tumor-specific marker for molecular deep surgical margin analysis of HNSCC. Moreover, the ddQMSP assay displays increased sensitivity for methylation marker detection. Cancer Prev Res; 8(11); 1017–26. ©2015 AACR.
Data from Hops (Humulus lupulus) Inhibits Oxidative Estrogen Metabolism and Estrogen-Induced Malignant Transformation in Human Mammary Epithelial cells (MCF-10A)
Authors: Hemachandra L.P. , Madhubhani P. , Chandrasena R. , Esala P. , Chen Shao-Nong , Main Matthew , Lankin David C. , Scism Robert A. , Dietz Birgit M. , Pauli Guido F. , Thatcher Gregory R.J. , Bolton Judy L.
Published: April 2023

Abstract
Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor–mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN. Cancer Prev Res; 5(1); 73–81. ©2011 AACR.
Data from The Acetylenic Tricyclic Bis(cyano enone), TBE-31 Inhibits Non–Small Cell Lung Cancer Cell Migration through Direct Binding with Actin
Authors: Chan Eddie , Saito Akira , Honda Tadashi , Di Guglielmo Gianni M.
Published: April 2023

Abstract
The migratory and invasive potential of the epithelial-derived tumor cells depends on epithelial-to-mesenchymal transition (EMT) as well as the reorganization of the cell cytoskeleton. Here, we show that the tricyclic compound acetylenic tricyclic bis(cyano enone), TBE-31, directly binds to actin and inhibits linear and branched actin polymerization in vitro. Furthermore, we observed that TBE-31 inhibits stress fiber formation in fibroblasts as well as in non–small cell lung cancer cells during TGFβ-dependent EMT. Interestingly, TBE-31 does not interfere with TGFβ-dependent signaling or changes in E-cadherin and N-cadherin protein levels during EMT. Finally, we observed that TBE-31 inhibits fibroblast and non–small cell lung tumor cell migration with an IC50 of 1.0 and 2.5 μmol/L, respectively. Taken together, our results suggest that TBE-31 targets linear actin polymerization to alter cell morphology and inhibit cell migration. Cancer Prev Res; 7(7); 727–37. ©2014 AACR.
Data from Biomarkers in Exploring the Frontiers of Diagnosis, Prognosis, and Therapy of Barrett's Esophagus
Authors: Yachimski Patrick , Peek Richard M.
Published: April 2023

Abstract
Barrett's esophagus (BE) is the principal risk factor for esophageal adenocarcinoma. BE patients currently undergo periodic endoscopic surveillance with tissue sampling and histopathologic assessment for dysplasia. They frequently are prescribed proton pump inhibitors to pharmacologically suppress gastric acid that is the cause of BE. These standard endoscopic and pharmacologic approaches for managing BE are crude at best. Identification of novel tissue biomarkers within BE may allow for more accurate endoscopic risk stratification and provide potential targets for chemoprevention. Cancer Prev Res; 4(6); 783–6. ©2011 AACR.
Data from Combined Use of Vitamin D3 and Metformin Exhibits Synergistic Chemopreventive Effects on Colorectal Neoplasia in Rats and Mice
Authors: Li Wan , Wang Qi-Long , Liu Xia , Dong Shu-Hong , Li Hong-Xia , Li Chun-Yang , Guo Li-Shu , Gao Jing-Miao , Berger Nathan A. , Li Li , Ma Lan , Wu Yong-Jie
Published: April 2023

Abstract
Vitamin D3 and metformin are widely used in humans for regulating mineral metabolism and as an antidiabetic drug, respectively; and both of them have been shown to have chemopreventive effects against various tumors. This study was designed to investigate the potential synergistic chemopreventive effects of vitamin D3 and metformin against the development of early colon neoplasia in two models. The first model was a 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon cancer rat model and the second, a DMH-dextran sodium sulfate (DSS)-induced colitis-associated colon neoplasia mouse model. Compared with either vitamin D3 or metformin alone, combined use of vitamin D3 and metformin showed more pronounced effect in reducing the numbers of aberrant crypt foci (ACF) and tumor in the colon. The most prominent inhibitory effects were observed in the vitamin D3 medium dose (100 IU/kg/d) and metformin medium dose (120 mg/kg/d) combination group. Furthermore, our results showed that enhancement of metformin's chemopreventive effects by vitamin D3 was associated with downregulation of S6P expression, via the AMPK (IGFI)/mTOR pathway. In addition, enhancement of vitamin D3′s chemopreventive effects by metformin was associated with inhibition of the protein expressions of c-Myc and Cyclin D1, via the vitamin D receptor/β-catenin pathway. These findings show that the combined use of vitamin D3 and metformin exhibits synergistic effects against the development of early colon neoplasia. They suggest that the combined use of vitamin D3 and metformin may represent a novel strategy for chemoprevention of colorectal cancer. Cancer Prev Res; 8(2); 139–48. ©2014 AACR.
Data from MUC1 Vaccine for Individuals with Advanced Adenoma of the Colon: A Cancer Immunoprevention Feasibility Study
Authors: Kimura Takashi , McKolanis John R. , Dzubinski Lynda A. , Islam Kazi , Potter Douglas M. , Salazar Andres M. , Schoen Robert E. , Finn Olivera J.
Published: April 2023

Abstract
Cancer vaccines based on human tumor-associated antigens (TAA) have been tested in patients with advanced or recurrent cancer, in combination with or following standard therapy. Their immunogenicity and therapeutic efficacy has been difficult to properly evaluate in that setting characterized by multiple highly suppressive effects of the tumor and the standard therapy on the patient's immune system. In animal models of human cancer, vaccines administered in the prophylactic setting are most immunogenic and effectively prevent cancer development and progression. We report results of a clinical study that show that in patients without cancer but with a history of premalignant lesions (advanced colonic adenomas, precursors to colon cancer), a vaccine based on the TAA MUC1 was highly immunogenic in 17 of 39 (43.6%) of vaccinated individuals, eliciting high levels of anti-MUC1 immunoglobulin G (IgG) and long-lasting immune memory. Lack of response in 22 of 39 individuals was correlated with high levels of circulating myeloid-derived suppressor cells (MDSC) prevaccination. Vaccine-elicited MUC1-specific immune response and immune memory were not associated with significant toxicity. Our study shows that vaccines based on human TAAs are immunogenic and safe and capable of eliciting long-term memory that is important for cancer prevention. We also show that in the premalignant setting, immunosuppressive environment (e.g., high levels of MDSC) might already exist in some individuals, suggesting an even earlier premalignant stage or preselection of nonimmunosuppressed patients for prophylactic vaccination. Cancer Prev Res; 6(1); 18–26. ©2012 AACR.
Data from A Pilot Study of Low-Cost, High-Resolution Microendoscopy as a Tool for Identifying Women with Cervical Precancer
Authors: Pierce Mark C. , Guan YaoYao , Quinn Mary Kate , Zhang Xun , Zhang Wen-Hua , Qiao You-Lin , Castle Philip , Richards-Kortum Rebecca
Published: April 2023

Abstract
Cervical cancer remains one of the leading causes of death among women in developing countries. Without resources to support Pap smear cytology and colposcopy, cost-effective approaches which enable single-visit “see-and-treat” protocols offer the potential to reduce morbidity and mortality due to this preventable disease. We carried out a pilot clinical study in Shanxi province, China, to evaluate a low-cost, high-resolution microendoscope (HRME) imaging system which enables evaluation of epithelial cell morphology in vivo. HRME images were obtained at discrete sites on the cervix in 174 women, in addition to visual inspection with acetic acid (VIA) and colposcopic examination. Of 69 sites appearing abnormal on colposcopy, only 12 showed high-grade disease (CIN2+) on pathology. Quantification of the nuclear-to-cytoplasm ratio by HRME enabled an ad hoc threshold to be defined, which correctly classified all 12 sites as abnormal, whilst classifying 38 of the remaining 57 pathology normal sites as normal. All patients with biopsy confirmed high-grade disease also tested positive for high-risk human papilloma virus (HPV) DNA and were classified as abnormal by HRME. Among the remaining patients who tested positive for HPV but were either normal by colposcopy or showed

Visual examination techniques for cervical cancer screening may overestimate the prevalence of precancerous lesions, leading to unnecessary treatment, expense, and patient stress. The results of this study suggest that evaluation of suspicious lesions by HRME may assist in ruling out immediate cryotherapy, thus increasing the efficiency of current see-and-treat programs. Cancer Prev Res; 5(11); 1273–9. ©2012 AACR.
Data from An Evaluation of Novel, Lower-Cost Molecular Screening Tests for Human Papillomavirus in Rural China
Authors: Zhao Fang-Hui , Jeronimo Jose , Qiao You-Lin , Schweizer Johannes , Chen Wen , Valdez Melissa , Lu Peter , Zhang Xun , Kang Le-Ni , Bansil Pooja , Paul Proma , Mahoney Charles , Berard-Bergery Marthe , Bai Ping , Peck Roger , Li Jing , Chen Feng , Stoler Mark H. , Castle Philip E.
Published: April 2023

Abstract
New, lower-cost tests that target high-risk human papillomavirus (HR-HPV) have been developed for cervical cancer screening in lower-resource settings but large, population-based screening studies are lacking. Women ages 25 to 65 years and living in rural China (n = 7,543) self-collected a cervicovaginal specimen, had 2 cervical specimens collected by a clinician, and underwent visual inspection after acetic acid (VIA). The self- and one clinician-collected specimens underwent HR-HPV DNA testing by careHPV (QIAGEN) and Hybrid Capture 2 (HC2; QIAGEN) and the other clinician-collected specimen was tested for HPV16, 18, and 45 E6 using OncoE6 (Arbor Vita Corporation). Women who screened positive for any test and a random sample of those negative on all tests underwent colposcopic evaluation. The percent test positive was 1.8% for HPV E6 oncoprotein, between 14% and 18% for HR-HPV DNA testing, and 7.3% for VIA. The sensitivity for cervical intraepithelial neoplasia grade 3 or more severe (CIN3+; n = 99) was 53.5% for OncoE6, 97.0% for both careHPV and HC2 testing of the clinician-collected specimen, 83.8% for careHPV testing and 90.9% for HC2 testing of the self-collected specimen, and 50.5% for VIA. OncoE6 had the greatest positive predictive value (PPV), at 40.8% for CIN3+, compared with the other tests, which had a PPV of less than 10%. OncoE6 tested 70.3% positive for HPV16, 18, or 45-positive CIN3+ and tested negative for all HPV16-, 18-, or 45-negative CIN3+ (P < 0.0001). HPV E6 oncoprotein detection is useful for identifying women who have cervical precancer and cancer. Cancer Prev Res; 6(9); 938–48. ©2013 AACR.
Data from Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens
Authors: Cramer Daniel W. , Bast Robert C. , Berg Christine D. , Diamandis Eleftherios P. , Godwin Andrew K. , Hartge Patricia , Lokshin Anna E. , Lu Karen H. , McIntosh Martin W. , Mor Gil , Patriotis Christos , Pinsky Paul F. , Thornquist Mark D. , Scholler Nathalie , Skates Steven J. , Sluss Patrick M. , Srivastava Sudhir , Ward David C. , Zhang Zhen , Zhu Claire S. , Urban Nicole
Published: April 2023

Abstract
Establishing a cancer screening biomarker's intended performance requires “phase III” specimens obtained in asymptomatic individuals before clinical diagnosis rather than “phase II” specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network or Ovarian Cancer Specialized Program of Research Excellence sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within 6 months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study. Cancer Prev Res; 4(3); 365–74. ©2011 AACR.
Data from miR-194 as a Predictor for Adenoma Recurrence in Patients with Advanced Colorectal Adenoma after Polypectomy
Authors: Wang Zhen-Hua , Ren Lin-Lin , Zheng Ping , Zheng Hai-Ming , Yu Ya-Nan , Wang Ji-Lin , Lin Yan-Wei , Chen Ying-Xuan , Ge Zhi-Zheng , Chen Xiao-Yu , Hong Jie , Fang Jing-Yuan
Published: April 2023

Abstract
microRNAs (miRNA) are promising predictors in colorectal cancer (CRC). We investigated whether miRNAs could predict adenoma recurrence in patients with advanced colorectal adenoma (ACRA) after polypectomy. miRNA expression profiling was performed by miRNA microarray to identify recurrence-related miRNAs. Candidate miRNAs extracted from formalin-fixed paraffin-embedded blocks of patients with ACRA were measured using real-time PCR. Logistic regression analysis was conducted to investigate whether validated miRNA expression profiles were independent from other known adenoma recurrence risk factors. The prognostic values of six miRNAs and three independent risk factors were assessed by the area under the receiver operating characteristic (ROC) curve analysis. The expressions of six candidate miRNAs were significantly decreased from levels in normal colorectal tissue compared with ARCA with adenoma recurrence (RACRA) in this retrospective cohort. However, only miRNA (miR)-194 emerged as a practical predictor. The sensitivity and specificity of miR-194 as a predictor were 71.0% and 78.0%, respectively, at a cutoff value of 0.1311 in the retrospective cohort. Sensitivity and specificity were 76.1% and 77.2%, respectively, in the prospective cohort using the same cutoff value. Low expression levels of miR-194, adenoma size ≥2 cm, and ≥3 adenomas were independent risk factors for adenoma recurrence. Moreover, low expression of miR-194 was a better predictor of adenoma recurrence than the adenoma size and numbers according to ROC curve analysis. miR-194 may be an independent predictor for adenoma recurrence in patients with ACRA after polypectomy. Cancer Prev Res; 7(6); 607–16. ©2014 AACR.
Data from Chemopreventive Effects of Korean Angelica versus Its Major Pyranocoumarins on Two Lineages of Transgenic Adenocarcinoma of Mouse Prostate Carcinogenesis
Authors: Tang Su-Ni , Zhang Jinhui , Wu Wei , Jiang Peixin , Puppala Manohar , Zhang Yong , Xing Chengguo , Kim Sung-Hoon , Jiang Cheng , Lü Junxuan
Published: April 2023

Abstract
We showed previously that daily gavage of Angelica gigas Nakai (AGN) root ethanolic extract starting 8 weeks of age inhibited growth of prostate epithelium and neuroendocrine carcinomas (NE-Ca) in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Because decursin (D) and its isomer decursinol angelate (DA) are major pyranocoumarins in AGN extract, we tested the hypothesis that D/DA represented active/prodrug compounds against TRAMP carcinogenesis. Three groups of male C57BL/6 TRAMP mice were gavage treated daily with excipient vehicle, AGN (5 mg per mouse), or equimolar D/DA (3 mg per mouse) from 8 weeks to 16 or 28 weeks of age. Measurement of plasma and NE-Ca D, DA, and their common metabolite decursinol indicated similar retention from AGN versus D/DA dosing. The growth of TRAMP dorsolateral prostate (DLP) in AGN- and D/DA-treated mice was inhibited by 66% and 61% at 16 weeks and by 67% and 72% at 28 weeks, respectively. Survival of mice bearing NE-Ca to 28 weeks was improved by AGN, but not by D/DA. Nevertheless, AGN- and D/DA-treated mice had lower NE-Ca burden. Immunohistochemical and mRNA analyses of DLP showed that AGN and D/DA exerted similar inhibition of TRAMP epithelial lesion progression and key cell-cycle genes. Profiling of NE-Ca mRNA showed a greater scope of modulating angiogenesis, epithelial–mesenchymal transition, invasion–metastasis, and inflammation genes by AGN than D/DA. The data therefore support D/DA as probable active/prodrug compounds against TRAMP epithelial lesions, and they cooperate with non-pyranocoumarin compounds to fully express AGN efficacy against NE-Ca. Cancer Prev Res; 8(9); 835–44. ©2015 AACR.
Data from Dietary Vitamin D and Vitamin D Receptor Level Modulate Epithelial Cell Proliferation and Apoptosis in the Prostate
Authors: Kovalenko Pavlo L. , Zhang Zhentao , Yu Jun-Ge , Li Yan , Clinton Steven K. , Fleet James C.
Published: April 2023

Abstract
Low vitamin D (VD) status may increase prostate cancer risk but experimental evidence for this relationship is modest. We tested whether low VD status or VD receptor (VDR) deletion influences prostate epithelial cell (PEC) biology using intact mice, castrated mice, or castrated mice treated with testosterone propionate (TP, 2.5 mg/kg BW). PEC proliferation (Ki-67 staining) and apoptosis (TUNEL method) were determined in the anterior prostate (AP). In study 1, wild-type (WT) and TgAPT121 mice (a model of prostate intraepithelial neoplasia) were fed diets with 25, 200 (reference diet), or 10,000 IU VD/kg diet (as vitamin D3) prior to castration/repletion. Serum 25 hydroxyvitamin D levels were 26, 78, and 237 nmol/L in the three diet groups, respectively. Castration reduced proliferation and increased apoptosis in the AP while TP reversed these effects. Low VD diet increased proliferation in WT (+82%) and TgAPT121 (+24%) mice while it suppressed apoptosis in WT (−29%) and TgAPT121 (−37%) mice. This diet also increased the severity of prostate intraepithelial neoplastic lesions in the AP of intact TgAPT121 mice. In study 2, mice with PEC-specific VDR deletion (PEC VDR KO) were examined after castration/repletion. TUNEL staining was 60% lower in castrated PEC VDR KO mice compared with castrated WT mice. In castrated mice given TP, Ki-67 staining was 2-fold higher in PEC VDR KO compared with WT mice. Our data show that low diet VDR or VDR deletion provide a prostate environment that is permissive to early procarcinogenic events that enhance prostate cancer risk. Cancer Prev Res; 4(10); 1617–25. ©2011 AACR.
Data from Notch1 Mutations Are Drivers of Oral Tumorigenesis
Authors: Izumchenko Evgeny , Sun Kai , Jones Sian , Brait Mariana , Agrawal Nishant , Koch Wayne , McCord Christine L. , Riley David R. , Angiuoli Samuel V. , Velculescu Victor E. , Jiang Wei-Wen , Sidransky David
Published: April 2023

Abstract
Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput PCR-based enrichment technology and next-generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty-nine samples were normal oral mucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies, and 50 were chemoradiation-naïve OSCC samples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of premalignant lesions. Importantly, almost 60% of patients with leukoplakia with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese patients with OSCC with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that premalignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCC progression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations. Cancer Prev Res; 8(4); 277–86. ©2014 AACR.

See related perspectives, p. 259 and p. 262
Data from Plasma Growth Factor Gene Expression and Mammographic Breast Density in Postmenopausal Women
Authors: Akinjiyan Favour A. , Adams Andrea , Xu Shuai , Wang Mei , Toriola Adetunji T.
Published: April 2023

Abstract
Mammographic breast density (MBD) is a risk factor for breast cancer, but its molecular basis is poorly understood. Growth factors stimulate cellular and epithelial proliferation and could influence MBD via these mechanisms. Studies investigating the associations of circulating growth factors with MBD have, however, yielded conflicting results especially in postmenopausal women. We, therefore, investigated the associations of plasma growth factor gene expression [insulin-like growth factor (IGF)-1, IGF-binding protein 3, FGF-1, FGF-12, TGFβ1 and bone morphogenetic protein (BMP)-2] with MBD in postmenopausal women. We used NanoString nCounter platform to quantify plasma growth factor gene expression and Volpara to evaluate volumetric MBD measures. We investigated the associations of growth factor gene expression with MBD using both multiple linear regression (fold change) and multinomial logistic regression models, adjusted for potential confounders. The mean age of the 368 women enrolled was 58 years (range, 50–64). In analyses using linear regression models, one unit increase in IGF-1 gene expression was associated with a 35% higher volumetric percent density (VPD, 1.35; 95% confidence interval (CI), 1.13–1.60; P = 0.001). There were suggestions that TGFβ1 gene expression was positively associated with VPD while BMP-2 gene expression was inversely associated with VPD, but these were not statistically significant. In analyses using multinomial logistic regression, TGFβ1 gene expression was 33% higher (OR = 1.33; 95% CI, 1.13–1.56; P = 0.0008) in women with extremely dense breasts than those with almost entirely fatty breasts. There were no associations between growth factor gene expression and dense volume or nondense volume. Our study provides insights into the associations of growth factors with MBD in postmenopausal women and requires confirmation in other study populations.
Prevention Relevance:
Mammographic breast density is a strong risk factor for breast cancer. Understanding its underlying biological mechanisms could have utility in breast cancer prevention.
Data from Community-Based Pilot Study of a Screening Program for Gastric Cancer in a Chinese Population
Authors: Ji Lin , Liu Zengchao , Zhou Bin , Cai Ying , An Fangmei , Wang Lei , Lv Zhifa , Xia Min , Yang Jianbo , Yuan Jianfen , Wang Hui , Zhou Zhiyi , Yang Shudong , Hu Lei , Zhan Qiang
Published: April 2023

Abstract
A majority of gastric cancer cases in China are diagnosed at advanced stages, chiefly due to lack of an established routine nationwide screening program. This study evaluated the effectiveness of a novel screening program for gastric cancer. Seven geographic communities were randomly selected, and residents ages 40–69 years were screened. Serologic tests of Helicobacter pylori antibodies and pepsinogens, and positive family history of gastric cancer in first-degree relatives (FDR), were used to differentiate individuals for further gastroscopic examination and gastric mucosal biopsies. Among 7,773 individuals who underwent examination of serum markers, gastric cancer was detected in 14 (1.8%; 10 men). The rate in terms of gastric cancer cases per 100 gastroendoscopies was 1.6% (14/872), which was greater than 0.87% previously reported. Eleven of 14 patients with gastric cancer (78.6%) were FDRs of patients with gastric cancer. Two-thirds of the subjects with cardia gastric cancer were FDRs of individuals with gastric cancer rather than cardia gastric cancer. Comparative analysis indicated that the gastric cancer subjects were significantly more likely to be FDRs of patients with gastric cancer, in contrast to those without gastric cancer. All the individuals with gastric cancer were aged ≥50 years. After conducting a reverse analysis, we propose a novel screening program for gastric cancer. In conclusions, the populations most vulnerable to gastric cancer are those with positive family history of gastric cancer in FDRs, male gender, and aged 50 years or older. This screening program using fewer serum markers combined individual risk factors, mainly FDRs, is novel for identification of high-risk individuals for further gastroscopy in detecting early gastric cancer.
Data from Multiparametric Detection of Antibodies against Different EBV Antigens to Predict Risk for Nasopharyngeal Carcinoma in a High-Risk Population of China
Authors: Chen Hao , Chen Shulin , Lu Jie , Wang Xueping , Li Jianpei , Li Linfang , Fu Jihuan , Scheper Thomas , Meyer Wolfgang , Peng Yu-Hui , Liu Wanli
Published: April 2023

Abstract
In this study, we aimed to use the combined detection of multiple antibodies against Epstein–Barr virus (EBV) antigens to develop a model for screening and diagnosis of nasopharyngeal carcinoma (NPC). Samples of 300 nasopharyngeal carcinoma patients and 494 controls, including 294 healthy subjects (HC), 99 non-nasopharyngeal carcinoma cancer patients (NNPC), and 101 patients with benign nasopharyngeal lesions (BNL), were incubated with the EUROLINE Anti-EBV Profile 2, and band intensities were used to establish a risk prediction model. The nasopharyngeal carcinoma risk probability analysis based on the panel of VCAgp125 IgA, EBNA-1 IgA, EA-D IgA, EBNA-1 IgG, EAD IgG, and VCAp19 IgG displayed the best performance. When using 26.1% as the cutoff point in ROC analysis, the AUC value and sensitivity/specificity were 0.951 and 90.7%/86.2%, respectively, in nasopharyngeal carcinoma and all controls. In nasopharyngeal carcinoma and controls without the non-nasopharyngeal carcinoma and BNL groups, the AUC value and sensitivity/specificity were 0.957 and 90.7%/88.1%, respectively. The diagnostic specificity and sensitivity of the EUROLINE Anti-EBV Profile 2 assay for both nasopharyngeal carcinoma and early-stage nasopharyngeal carcinoma were higher than that of mono-antibody detection by immune-enzymatic assay and real-time PCR (EBV DNA). In the VCA-IgA–negative group, 82.6% of nasopharyngeal carcinoma patients showed high probability for nasopharyngeal carcinoma, and the negative predictive value was 97.1%. In the VCA-IgA–positive group, 73.3% of healthy subjects showed low probability. The positive predictive value reached 98.2% in this group. The nasopharyngeal carcinoma risk probability value determined by the EUROLINE Anti-EBV Profile 2 might be a suitable tool for nasopharyngeal carcinoma screening. Cancer Prev Res; 10(9); 542–50. ©2017 AACR.
Data from Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study
Authors: Furniss C. Sloane , Yurgelun Matthew B. , Ukaegbu Chinedu , Constantinou Pamela E. , Lafferty Catherine C. , Talcove-Berko Eliana R. , Schwartz Alison N. , Stopfer Jill E. , Underhill-Blazey Meghan , Kenner Barbara , Nelson Scott H. , Okumura Sydney , Law Sherman , Zhou Alicia Y. , Coffin Tara B. , Rodriguez Nicolette J. , Uno Hajime , Ocean Allyson J. , McAllister Florencia , Lowy Andrew M. , Lippman Scott M. , Klein Alison P. , Madlensky Lisa , Petersen Gloria M. , Garber Judy E. , Goggins Michael G. , Maitra Anirban , Syngal Sapna
Published: April 2023

Abstract
Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches.
Prevention Relevance:
Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.
Data from Proteomic Analysis of Plasma Reveals Fat Mass Influences Cancer-Related Pathways in Healthy Humans Fed Controlled Diets Differing in Glycemic Load
Authors: Garrison Carly B. , Zhang Yuzheng , Navarro Sandi L. , Randolph Timothy W. , Hullar Meredith A.J. , Kratz Mario , Neuhouser Marian L. , Raftery Daniel , Lampe Paul D. , Lampe Johanna W.
Published: April 2023

Abstract
Increased adiposity and diets high in glycemic load (GL) are associated with increased risk of many chronic diseases including cancer. Using plasma from 80 healthy individuals [40 men/40 women, 29 with DXA-derived low fat mass (FM) and 51 with high FM] in a randomized cross-over–controlled feeding trial and arrays populated with 3,504 antibodies, we measured plasma proteins collected at baseline and end of each of two 28-day controlled diets: a low GL diet high in whole grains, legumes, fruits, and vegetables (WG) and a high GL diet high in refined grains and added sugars (RG). Following univariate testing for proteins differing by diet, we evaluated pathway-level involvement. Among all 80 participants, 172 proteins were identified as differing between diets. Stratifying participants by high and low FM identified 221 and 266 proteins, respectively, as differing between diets (unadjusted P < 0.05). These candidate proteins were tested for overrepresentation in Reactome pathways, corresponding to 142 (of 291) pathways in the high-FM group and 72 (of 274) pathways in the low-FM group. We observed that the cancer-related pathways, DNA Repair, DNA Replication, and Cell Cycle, were overrepresented in the high-FM participants while pathways involved in post-translational protein modification were overrepresented in participants with either FM. Although high-GL diets are associated with increased risk of some cancers, our study further suggests that biology associated with consumption of GL diets is variable depending on an individual's adiposity and dietary recommendations related to cancer prevention be made with the additional consideration of an individual's FM.
Data from Analgesic Use and Circulating Estrogens, Androgens, and Their Metabolites in the Women's Health Initiative Observational Study
Authors: Hurwitz Lauren M. , Shadyab Aladdin H. , Tabung Fred K. , Anderson Garnet L. , Saquib Nazmus , Wallace Robert B. , Wild Robert A. , Pfeiffer Ruth M. , Xu Xia , Trabert Britton
Published: April 2023

Abstract
Though studies have observed inverse associations between use of analgesics (aspirin, NSAIDs, and acetaminophen) and the risk of several cancers, the potential biological mechanisms underlying these associations are unclear. We investigated the relationship between analgesic use and serum concentrations of estrogens, androgens, and their metabolites among postmenopausal women to provide insights on whether analgesic use might influence endogenous hormone levels, which could in turn influence hormone-related cancer risk. The study included 1,860 postmenopausal women from two case–control studies nested within the Women's Health Initiative Observational Study. Analgesic use was reported at study baseline. Fifteen estrogens and estrogen metabolites and 12 androgens and androgen metabolites were quantified in baseline serum by LC/MS-MS. Linear regression with inverse probability weighting, stratified by menopausal hormone therapy (MHT) use, was used to estimate adjusted geometric mean concentrations of each hormone by analgesic use. Among women not currently using MHT (n = 951), low-dose aspirin (<100 mg) use was associated with a higher serum concentration of estrone, estradiol, and 2, 4, and 16 hydroxylated metabolites. Use of regular-dose aspirin (≥100 mg), non-aspirin NSAIDs, and acetaminophen was not associated with serum concentrations of estrogens, androgens, or their metabolites. This study highlights the importance of examining aspirin use by dose and suggests that low-dose aspirin may influence endogenous estrogen concentrations.
Prevention relevance:
This study explores a potential pathway by which analgesic medications such as aspirin may prevent hormone-related cancers. The findings support a positive association between low-dose aspirin use and endogenous estrogens, indicating that further elucidation of the interplay between low-dose aspirin, estrogen concentrations, and cancer risk is needed.
Data from Adiposity, Adulthood Weight Change, and Risk of Incident Hepatocellular Carcinoma
Authors: Simon Tracey G. , Kim Mi Na , Luo Xiao , Liu Xing , Yang Wanshui , Ma Yanan , Chong Dawn Q. , Fuchs Charles S. , Stampfer Meir , Giovannucci Edward L. , Chan Andrew T. , Zhang Xuehong
Published: April 2023

Abstract
Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980–2012) and 48,026 men (1986–2012), who recalled young-adult weight [age 18 years (women); 21 years (men)], and provided biennially updated information regarding weight, body mass index (BMI), and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable adjusted HRs (aHR) and 95% confidence intervals (CI). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood [continuous aHRs per each 1 unit = 1.05; 95% CI = 1.02–1.09 (Ptrend = 0.019), and 1.08; 95% CI = 1.06–1.10 (Ptrend = 0.004), respectively]. Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase = 1.03; 95% CI = 1.01–1.08; Ptrend = 0.010), including after further adjusting for young-adult BMI (Ptrend = 0.010) and later-adult BMI (Ptrend = 0.008). Compared with adults with stable weight (±5 kg), the multivariable-aHRs with weight gain of 5–<10 kg, 10–<20 kg, and ≥20 kg were, 1.40 (95% CI = 0.67–2.16), 2.09 (95% CI = 1.11–3.95), and 2.61 (95% CI = 1.42–5.22), respectively. In two prospective, nationwide cohorts, adulthood weight gain was significantly associated with increased HCC risk.
Prevention Relevance:
Our data suggest that maintaining a stable weight during adulthood, specifically by preventing weight gain, could represent an important public health strategy for the prevention of hepatocellular carcinoma.
Data from Lipidomic Profiles of Plasma Exosomes Identify Candidate Biomarkers for Early Detection of Hepatocellular Carcinoma in Patients with Cirrhosis
Authors: Sanchez Jessica I. , Jiao Jingjing , Kwan Suet-Ying , Veillon Lucas , Warmoes Marc O. , Tan Lin , Odewole Mobolaji , Rich Nicole E. , Wei Peng , Lorenzi Philip L. , Singal Amit G. , Beretta Laura
Published: April 2023

Abstract
Novel biomarkers for HCC surveillance in cirrhotic patients are urgently needed. Exosomes and their lipid content in particular represent potentially valuable noninvasive diagnostic biomarkers. We isolated exosomes from plasma of 72 cirrhotic patients, including 31 with HCC. Exosomes and unfractionated plasma were processed for untargeted lipidomics using ultra–high-resolution mass spectrometry. A total of 2,864 lipid species, belonging to 52 classes, were identified. Both exosome fractionation and HCC diagnosis had significant impact on the lipid profiles. Ten lipid classes were enriched in HCC exosomes compared with non-HCC exosomes. Dilysocardiolipins were detected in 35% of the HCC exosomes but in none of the non-HCC exosomes (P < 0.001). Cardiolipins and sphingosines had the highest differential effects (fold change of 133.08, q = 0.001 and 38.57, q < 0.001, respectively). In logistic regression analysis, high abundances of exosomal sphingosines, dilysocardiolipins, lysophosphatidylserines, and (O-acyl)-1-hydroxy fatty acids were strongly associated with HCC [OR (95% confidence interval (CI)), 271.1 (14.0–5,251.9), P < 0.001; 46.5 (2.3–939.9), P = 0.012; 14.9 (4.3–51.2), P < 0.001; 10.3 (3.2–33.1), P < 0.001]. Four lipid classes were depleted in HCC exosomes compared with non-HCC exosomes. In logistic regression analysis, lack of detection of sulfatides and acylGlcSitosterol esters was strongly associated with HCC [OR (95% CI): 215.5 (11.5–4,035.9), P < 0.001; 26.7 (1.4–528.4), P = 0.031]. These HCC-associated changes in lipid composition of exosomes reflected alterations in glycerophospholipid metabolism, retrograde endocannabinoid signaling, and ferroptosis. In conclusion, this study identified candidate biomarkers for early detection of HCC as well as altered pathways in exosomes that may contribute to tumor development and progression.
Prevention Relevance:
This study identifies lipids in circulating exosomes, that could serve as biomarkers for the early detection of hepatocellular carcinoma as well as altered pathways in exosomes that may contribute to tumor development and progression.
Data from Sulforaphane Suppresses the Growth of Triple-negative Breast Cancer Stem-like Cells In vitro and In vivo
Authors: Castro Nadia P. , Rangel Maria C. , Merchant Anand S. , MacKinnon Gabriel , Cuttitta Frank , Salomon David S. , Kim Young S.
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) represents the poorest prognosis among all of breast cancer subtypes with no currently available effective therapy. In this study, we hypothesized that sulforaphane, a dietary component abundant in broccoli and its sprouts, can inhibit malignant cell proliferation and tumor sphere formation of cancer stem-like cells (CSC) in TNBC. CSC population was isolated using FACS analysis with the combined stem cell surface markers, CD44+/CD24−/CD49f+. The effect of sulforaphane on a stem-related embryonic oncogene CRIPTO-1/TDGF1 (CR1) was evaluated via ELISA. In vivo, BalbC/nude mice were supplemented with sulforaphane before and after TNBC cell inoculation (daily intraperitoneal injection of 50 mg sulforaphane/kg for 5 and 3 weeks, respectively), and the effects of sulforaphane during mammary tumor initiation and growth were accessed with NanoString gene analysis. We found that sulforaphane can inhibit cell proliferation and mammosphere formation of CSCs in TNBC. Further analysis of gene expression in these TNBC tumor cells revealed that sulforaphane significantly decreases the expression of cancer-specific CR1, CRIPTO-3/TDGF1P3 (CR3, a homologue of CR1), and various stem cell markers including Nanog, aldehyde dehydrogenase 1A1 (ALDH1A1), Wnt3, and Notch4. Our results suggest that sulforaphane may control the malignant proliferation of CSCs in TNBC via Cripto-mediated pathway by either suppressing its expression and/or by inhibiting Cripto/Alk4 protein complex formation. Thus, the use of sulforaphane for chemoprevention of TNBC is plausible and warrants further clinical evaluation.