bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure Legends from HIST1H2BB and MAGI2 Methylation and Somatic Mutations as Precision Medicine Biomarkers for Diagnosis and Prognosis of High-grade Serous Ovarian Cancer
Authors: Valle Blanca L. , Rodriguez-Torres Sebastian , Kuhn Elisabetta , Díaz-Montes Teresa , Parrilla-Castellar Edgardo , Lawson Fahcina P. , Folawiyo Oluwasina , Ili-Gangas Carmen , Brebi-Mieville Priscilla , Eshleman James R. , Herman James , Shih Ie-Ming , Sidransky David , Guerrero-Preston Rafael
Published: April 2023

Legends for Supplementary Figures 1-4
Figure S2 from In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation
Authors: Borras Ester , Chang Kyle , Pande Mala , Cuddy Amanda , Bosch Jennifer L. , Bannon Sarah A. , Mork Maureen E. , Rodriguez-Bigas Miguel A. , Taggart Melissa W. , Lynch Patrick M. , You Y. Nancy , Vilar Eduardo
Published: April 2023

Supplementary Figure S2. A. Proportion of VUS with different pathogenic probabilities estimated from a calibrated algorithm based on customized MAPP and Polyphen2 scores; B. Proportion of VUS per gene with different pathogenic probabilities; C. Distribution of probabilities of pathogenicity for all four MMR genes; D. MLH1; E. MSH2; F. MSH6; G. PMS2 genes.
Supplementary Table S4 from Validation of an Abridged Breast Cancer Risk Prediction Model for the General Population
Authors: Spaeth Erika L. , Dite Gillian S. , Hopper John L. , Allman Richard
Published: April 2023

Supplementary Table S4 shows the expected and observed 5-year risks for each model by decile of risk
Data from Association between Serum Phospholipid Fatty Acids and Intraprostatic Inflammation in the Placebo Arm of the Prostate Cancer Prevention Trial
Authors: Nash Sarah H. , Schenk Jeannette M. , Kristal Alan R. , Goodman Phillis J. , Lucia M. Scott , Parnes Howard L. , Thompson Ian M. , Lippman Scott M. , Song Xiaoling , Gurel Bora , De Marzo Angelo , Platz Elizabeth A.
Published: April 2023

Abstract
Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inflammation; studies have shown that long-chain n-3 polyunsaturated fatty acids are anti-inflammatory, whereas n-6 and trans fatty acids are proinflammatory. We evaluated whether serum phospholipid n-3, n-6, and trans fatty acids were associated with intraprostatic inflammation, separately in 191 prostate cancer cases and 247 controls from the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Men without a prostate cancer diagnosis underwent prostate biopsy at trial end, and benign prostate tissue inflammation was evaluated in approximately three biopsy cores per man; this was expressed as no, some, or all cores with inflammation. In controls, serum eicosapentaenoic acid [OR of all cores with inflammation versus none (95% CI), 0.35 (0.14–0.89)] and docosahexaenoic acid [OR (95% CI), 0.42 (0.17–1.02)] were inversely associated with, whereas linoleic acid [OR (95% CI), 3.85 (1.41–10.55)] was positively associated with intraprostatic inflammation. Serum trans fatty acids were not associated with intraprostatic inflammation. No significant associations were observed in cases; however, we could not rule out a positive association with linoleic acid and an inverse association with arachidonic acid. Thus, in the PCPT, we found that serum n-3 fatty acids were inversely, n-6 fatty acids were positively, and trans fatty acids were not associated with intraprostatic inflammation in controls. Although, in theory, inflammation could mediate associations of serum fatty acids with prostate cancer risk, our findings cannot explain the epidemiologic associations observed with n-3 and n-6 fatty acids. Cancer Prev Res; 8(7); 590–6. ©2015 AACR.
Data from Genetic Variants Associated with the Risk of Chronic Obstructive Pulmonary Disease with and without Lung Cancer
Authors: de Andrade Mariza , Li Yan , Marks Randolph S. , Deschamps Claude , Scanlon Paul D. , Olswold Curtis L. , Jiang Ruoxiang , Swensen Stephen J. , Sun Zhifu , Cunningham Julie M. , Wampfler Jason A. , Limper Andrew H. , Midthun David E. , Yang Ping
Published: April 2023

Abstract
Chronic obstructive pulmonary disease (COPD) is a strong risk factor for lung cancer. Published studies about variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive. We evaluated 470 single-nucleotide polymorphisms (SNP) from 56 genes of these three pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established. Twenty-one SNPs were found to be significantly associated with risk of COPD (P < 0.01); gene-based analyses confirmed two genes (GCLC and GSS) and identified three additional genes (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; eight SNPs altered COPD risk without lung cancer by 3.1-fold and 4 SNPs altered the risk with lung cancer by 2.3-fold. Our findings indicate that multiple genetic variations in the three selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both. Cancer Prev Res; 5(3); 365–73. ©2011 AACR.
Data from Targeting Ornithine Decarboxylase for the Prevention of Nonmelanoma Skin Cancer in Humans
Authors: Elmets Craig A. , Athar Mohammad
Published: April 2023

Abstract
Bailey et al. report in this issue of the journal (beginning on page 35) one of the first successful trials of basal cell carcinoma (BCC) prevention. Oral α-difluoromethyl-dl-ornithine (DFMO) reduced new BCCs in patients with a prior history of nonmelanoma skin cancer. DFMO is an inhibitor of ornithine decarboxylase, a key enzyme in the polyamine biosynthetic pathway. This perspective on Bailey et al. discusses our knowledge of the contribution of polyamines to BCC pathogenesis, how this knowledge advanced the development of a new method to prevent BCCs, and prospects for future studies of DFMO in BCC prevention. Cancer Prev Res; 3(1); 8–11
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: April 2023

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 Cucurbitacin B Alters the Expression of Tumor-Related Genes by Epigenetic Modifications in NSCLC and Inhibits NNK-Induced Lung Tumorigenesis
Authors: Shukla Samriddhi , Khan Sajid , Kumar Sudhir , Sinha Sonam , Farhan Mohd. , Bora Himangsu K. , Maurya Rakesh , Meeran Syed Musthapa
Published: April 2023

Abstract
Non–small cell lung cancer (NSCLC) represents almost 85% of total diagnosed lung cancer. Studies have shown that combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors is effective against various cancers, including lung cancer. However, optimizing the synergistic dose regime is very difficult and involves adverse side effects. Therefore, in this study, we have shown that cucurbitacin B (CuB), a single bioactive triterpenoid compound, inhibits both DNMTs and HDACs starting at a very low dose of 60 nmol/L in NSCLC H1299 cells. The CuB-mediated inhibition of DNMTs and HDACs in H1299 cells leads to the reactivation of key tumor suppressor genes (TSG) such as CDKN1A and CDKN2A, as well as downregulation of oncogenes c-MYC and K-RAS and key tumor promoter gene (TPG), human telomerase reverse transcriptase (hTERT). The upregulation of TSGs and downregulation of TPG were consistently correlated with the alterations in their promoter methylation and histone modifications. This altered expression of TPG and TSGs is, at least in part, responsible for the inhibition of cellular proliferation and induction of cellular apoptosis in NSCLC. Furthermore, CuB treatment significantly inhibited the tumor incidence and multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, which was associated with the induction of apoptosis and inhibition of hyperproliferation in the lung tissues. Together, our study provides new insight into the CuB-mediated epigenetic alterations and its chemotherapeutic effects on lung cancer. Cancer Prev Res; 8(6); 552–62. ©2015 AACR.
Data from Chronic Social Isolation Is Associated with Metabolic Gene Expression Changes Specific to Mammary Adipose Tissue
Authors: Volden Paul A. , Wonder Erin L. , Skor Maxwell N. , Carmean Christopher M. , Patel Feenalie N. , Ye Honggang , Kocherginsky Masha , McClintock Martha K. , Brady Matthew J. , Conzen Suzanne D.
Published: April 2023

Abstract
Chronic social isolation is linked to increased mammary tumor growth in rodent models of breast cancer. In the C3(1)/SV40 T-antigen FVB/N (TAg) mouse model of “triple-negative” breast cancer, the heightened stress response elicited by social isolation has been associated with increased expression of metabolic genes in the mammary gland before invasive tumors develop (i.e., during the in situ carcinoma stage). To further understand the mechanisms underlying how accelerated mammary tumor growth is associated with social isolation, we separated the mammary gland adipose tissue from adjacent ductal epithelial cells and analyzed individual cell types for changes in metabolic gene expression. Specifically, increased expression of the key metabolic genes Acaca, Hk2, and Acly was found in the adipocyte, rather than the epithelial fraction. Surprisingly, metabolic gene expression was not significantly increased in visceral adipose depots of socially isolated female mice. As expected, increased metabolic gene expression in the mammary adipocytes of socially isolated mice coincided with increased glucose metabolism, lipid synthesis, and leptin secretion from this adipose depot. Furthermore, application of media that had been cultured with isolated mouse mammary adipose tissue (conditioned media) resulted in increased proliferation of mammary cancer cells relative to group-housed–conditioned media. These results suggest that exposure to a chronic stressor (social isolation) results in specific metabolic reprogramming in mammary gland adipocytes that in turn contributes to increased proliferation of adjacent preinvasive malignant epithelial cells. Metabolites and/or tumor growth-promoting proteins secreted from adipose tissue could identify biomarkers and/or targets for preventive intervention in breast cancer. Cancer Prev Res; 6(7); 634–45. ©2013 AACR.
Data from Personalized Immune-Interception of Cancer and the Battle of Two Adaptive Systems—When Is the Time Right?
Authors: Dhodapkar Madhav V.
Published: April 2023

Abstract
A growing body of evidence points to a coevolutionary model of cancer, wherein the cross-talk between tumor cells (or their subclones) and the host determine the malignant potential of individual tumors. Most of this natural history is clinically invisible and includes preneoplastic states. The capacity of the immune system to recognize these incipient lesions provides the basis for targeting them immunologically to arrest the development of preneoplasia toward clinical cancer. Kimura and colleagues provide evidence of immunogenicity of a potential cancer vaccine in patients with a history of advanced colon adenomas. These studies provide proof-of-principle or feasibility of such an approach in the clinic. Here, we discuss emerging opportunities and challenges in harnessing the immune system to “intercept” the precursor or preneoplastic lesions. Both cancer cells as well as the immune system represent independent and complex systems with plasticity and adaptive potential. It is therefore likely that specific aspects of the cross-talk between tumor cells and host may differ between individual tumors and determine the evolution of both tumors and the host response. We try to make the case to consider individualized approaches based on the genetic make-up of tumor cells and properties of the host response. Such strategies may be needed to optimally position the immune system to prevent cancers. Cancer Prev Res; 6(3); 173–6. ©2013 AACR.
Data from Chemoprevention of Endometrial Cancer in Lynch Syndrome: A Step Forward
Authors: Stoffel Elena M. , Walsh Christine
Published: April 2023

Abstract
Lynch syndrome is one of the most common hereditary cancer syndromes. Although Lynch syndrome is associated with increased risk for developing colorectal, endometrial, and other cancers specialized screening, risk-reducing surgery, and chemoprevention offer promise for reducing morbidity and mortality. Frequent colonoscopic surveillance has proven effective for early detection and prevention of Lynch syndrome-associated colorectal cancer; however, the optimal strategy for managing endometrial cancer risks in women with germline mutations in DNA mismatch repair genes has yet to be determined. In this issue of Cancer Prevention Research, Lu and colleagues report their findings of a phase II prospective, multicenter randomized trial comparing the effects of oral contraceptive pills and Depo-Provera on endometrial proliferation in women with Lynch syndrome. Although short-term hormonal treatment with either modality altered endometrial proliferation indices, it remains unknown whether hormonal suppression actually reduces endometrial cancer risk in women with Lynch syndrome. This trial represents the first of its kind in evaluating agents which might offer protection against Lynch syndrome-associated endometrial cancer and provides preliminary data regarding potential biomarkers for early detection of endometrial neoplasia. The investigators' experience with this trial also offers insights regarding the various technical and scientific challenges inherent in chemoprevention research. Cancer Prev Res; 6(8); 755–9. ©2013 AACR.
Data from Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat
Authors: Skibinski Christine G. , Thompson Henry J. , Das Arunangshu , Manni Andrea , Bortner James D. , Stanley Anne , Stanley Bruce A. , El-Bayoumy Karam
Published: April 2023

Abstract
We used a proteomic approach to gain insights into the mechanisms of protection at the protein level by a high n-3:n-6 ratio in the absence and presence of Tamoxifen. Four groups were treated with 1-methyl-1-nitrosourea (MNU) and fed the following diets with varied n-3:n-6 ratios; group 1 = 1:1; groups 2 and 3 = 10:1 and 25:1, respectively; group 4: (25:1) plus Tamoxifen (1 mg/kg diet). The plasma from six rats/group was pooled and analyzed with the isobaric tags for relative and absolute quantitation method; 148 proteins were identified with 95% confidence by ProteinPilot 4.0. In plasma of rats fed 10:1, 25:1 n-3:n-6, and 25:1 plus Tamoxifen, the number of proteins that met our criteria (P ≤ 0.05, error factor ≤ 2) were 10, 14, and 19 proteins, respectively. Selected proteins were further validated by Western blotting. Compared to 1:1, both 10:1 and 25:1 diets upregulated vitamin D binding protein, gelsolin, and 14-3-3 sigma, reported to have tumor suppressive effects, whereas alpha-1B-glycoprotein, which has been reported to be elevated in the serum of breast cancer patients was decreased. Compared to 25:1, the 25:1 plus Tamoxifen diet downregulated apolipoprotein E, haptoglobin, and inter-α-inhibitor H4 heavy chain. Ingenuity pathway analysis determined that the trends of specific proteins were related to lipid metabolism in the 25:1 n-3:n-6 group, whereas the 25:1 n-3:n-6 plus Tamoxifen group included proteins involved in cancer and inflammation. Our results show that several proteins were altered in a manner consistent with chemoprevention. Such proteins may serve as biomarkers to monitor efficacy of n-3 and Tamoxifen in future clinical chemoprevention trials. Cancer Prev Res; 6(9); 979–88. ©2013 AACR.
Data from Genetic Manipulation of Homologous Recombination In Vivo Attenuates Intestinal Tumorigenesis
Authors: McIlhatton Michael A. , Murnan Kevin , Carson Daniel , Boivin Gregory P. , Croce Carlo M. , Groden Joanna
Published: April 2023

Abstract
Although disruption of DNA repair capacity is unquestionably associated with cancer susceptibility in humans and model organisms, it remains unclear if the inherent tumor phenotypes of DNA repair deficiency syndromes can be regulated by manipulating DNA repair pathways. Loss-of-function mutations in BLM, a member of the RecQ helicase family, cause Bloom's syndrome (BS), a rare, recessive genetic disorder that predisposes to many types of cancer. BLM functions in many aspects of DNA homeostasis, including the suppression of homologous recombination (HR) in somatic cells. We investigated whether BLM overexpression, in contrast with loss-of-function mutations, attenuated the intestinal tumor phenotypes of ApcMin/+ and ApcMin/+;Msh2−/− mice, animal models of familial adenomatous polyposis coli (FAP). We constructed a transgenic mouse line expressing human BLM (BLM-Tg) and crossed it onto both backgrounds. BLM-Tg decreased adenoma incidence in a dose-dependent manner in our ApcMin/+ model of FAP, although levels of GIN were unaffected and concomitantly increased animal survival over 50%. It did not reduce intestinal tumorigenesis in ApcMin/+;Msh2−/− mice. We used the pink-eyed unstable (pun) mouse model to demonstrate that increasing BLM dosage in vivo lowered endogenous levels of HR by 2-fold. Our data suggest that attenuation of the Min phenotype is achieved through a direct effect of BLM-Tg on the HR repair pathway. These findings demonstrate that HR can be manipulated in vivo to modulate tumor formation at the organismal level. Our data suggest that lowering HR frequencies may have positive therapeutic outcomes in the context of specific hereditary cancer predisposition syndromes, exemplified by FAP. Cancer Prev Res; 8(7); 650–6. ©2015 AACR.
Data from Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention
Authors: Thomasset Sarah , Berry David P. , Cai Hong , West Kevin , Marczylo Tim H. , Marsden Debbie , Brown Karen , Dennison Ashley , Garcea Giuseppe , Miller Andrew , Hemingway David , Steward William P. , Gescher Andreas J.
Published: April 2023

Abstract
Naturally occurring anthocyanins possess colorectal cancer chemopreventive properties in rodent models. We investigated whether mirtocyan, an anthocyanin-rich standardized bilberry extract, causes pharmacodynamic changes consistent with chemopreventive efficacy and generates measurable levels of anthocyanins in blood, urine, and target tissue. Twenty-five colorectal cancer patients scheduled to undergo resection of primary tumor or liver metastases received mirtocyan 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) daily for 7 days before surgery. Bilberry anthocyanins were analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. Proliferation was determined by immunohistochemistry of Ki-67 in colorectal tumor. Concentrations of insulin-like growth factor (IGF)-I were measured in plasma. Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, colorectal tissue, and urine, but not in liver. Anthocyanin concentrations in plasma and urine were roughly dose-dependent, reaching ∼179 ng/gram in tumor tissue at the highest dose. In tumor tissue from all patients on mirtocyan, proliferation was decreased by 7% compared with preintervention values. The low dose caused a small but nonsignificant reduction in circulating IGF-I concentrations. In conclusion, repeated administration of bilberry anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in humans resembling those seen in ApcMin mice, a model of FAP adenomas sensitive to the chemopreventive properties of anthocyanins. Studies of doses containing <0.5 gram bilberry anthocyanins are necessary to adjudge whether they may be appropriate for development as colorectal cancer chemopreventive agents.
Data from Esculetin Suppresses Proliferation of Human Colon Cancer Cells by Directly Targeting β-Catenin
Authors: Lee Sung-Young , Lim Tae-Gyu , Chen Hanyong , Jung Sung Keun , Lee Hyo-Jeong , Lee Mee-Hyun , Kim Dong Joon , Shin Aram , Lee Ki Won , Bode Ann M. , Surh Young-Joon , Dong Zigang
Published: April 2023

Abstract
The Wnt pathway is a promising therapeutic and preventive target in various human cancers. The transcriptional complex of β-catenin–T-cell factor (Tcf), a key mediator of canonical Wnt signaling, has been implicated in human colon cancer development. Current treatment of colon cancer depends on traditional cytotoxic agents with limited effects. Therefore, the identification of natural compounds that can disrupt the β-catenin–TcF complex to suppress cancer cell growth with fewer adverse side effects is needed. To identify compounds that inhibit the association between β-catenin and Tcf, we used computer docking to screen a natural compound library. Esculetin, also known as 6,7-dihydroxycoumarin, is a derivative of coumarin and was identified as a potential small-molecule inhibitor of the Wnt–β-catenin pathway. We then evaluated the effect of esculetin on the growth of various human colon cancer cell lines and its effect on Wnt–β-catenin signaling in cells and in an embryonic model. Esculetin disrupted the formation of the β-catenin–Tcf complex through direct binding with the Lys312, Gly307, Lys345, and Asn387 residues of β-catenin in colon cancer cells. In addition, esculetin effectively decreased viability and inhibited anchorage-independent growth of colon cancer cells. Esculetin potently antagonized the cellular effects of β-catenin–dependent activity, and in vivo treatment with esculetin suppressed tumor growth in a colon cancer xenograft mouse model. Our data indicate that the interaction between esculetin and β-catenin inhibits the formation of the β-catenin–Tcf complex, which could contribute to esculetin's positive therapeutic and preventive effects against colon carcinogenesis. Cancer Prev Res; 6(12); 1356–64. ©2013 AACR.
Data from Combination of Chemopreventive Agents in Nanoparticles for Cancer Prevention
Authors: Yang Chung S. , Wang Hong , Hu Bing
Published: April 2023

Abstract
Carcinogenesis involves multiple genetic and epigenetic alterations, and a single chemopreventive agent may not be sufficient to prevent these events. Therefore, the use of a combination of agents is an attractive approach for cancer chemoprevention. In this issue of the journal, Prabhu and colleagues examined a combination of aspirin, curcumin, and sulforaphane for the prevention of pancreatic cancer in hamsters (beginning page 1015). The novelty of this work is that when aspirin and curcumin were incorporated in nanoparticles and administered orally, in combination with sulforaphane, the effective dosages were decreased by 10-fold in comparison with the free form mixture. In this commentary, the possible mechanisms of synergistic action among multiple chemopreventive agents and the use of stable nanoparticles for oral delivery are discussed. Also discussed is the importance of measuring tissue levels of the chemopreventive agents to understand the mode of action of these nanoparticles and to avoid toxicity. Cancer Prev Res; 6(10); 1011–4. ©2013 AACR.
Data from Regulation of Colorectal Cancer Cell Apoptosis by the n-3 Polyunsaturated Fatty Acids Docosahexaenoic and Eicosapentaenoic
Authors: Giros Anna , Grzybowski Mike , Sohn Vanessa R. , Pons Elisenda , Fernandez-Morales Jessica , Xicola Rosa M. , Sethi Puja , Grzybowski Jessica , Goel Ajay , Boland C. Richard , Gassull Miquel A. , Llor Xavier
Published: April 2023

Abstract
Several studies have suggested that the n-3 fatty acids Docosahexaenoic (DHA) and Eicosapentaenoic (EPA) have an important protective effect on colorectal cancer, and this could be at least partly due to their proapoptotic activity. It is unclear, however, how this phenomenon is triggered and what mechanisms are implicated. Here, we show that both DHA and EPA have an important proapoptotic effect on colorectal cancer cells with different molecular phenotypes but not in noncancerous cells. Apoptosis is caspase dependent, and both intrinsic and extrinsic pathways are implicated. The dimerization of Bax and Bak, the depolarization of the mitochondrial membrane, and the subsequent release of cytochrome c and Smac/Diablo to the cytosol evidence the activation of the intrinsic pathway. The implication of the extrinsic pathway is shown by the activation of caspase-8, along with the down-regulation of FLIP. The timing of caspase-8 activation, and the oligomerization of Bid with Bax, suggest a cross-talk with the intrinsic pathway. None of the death receptors that commonly initiate the extrinsic pathway: FAS, TNF-R1, and TRAIL-R2 are found to be responsible for triggering the apoptosis cascade induced by DHA and EPA. Neither PPARγ nor cyclooxygenase-2, two likely candidates to regulate this process, play a significant role. Our findings suggest that the down-regulation of two key regulatory elements of the extrinsic and intrinsic pathways, FLIP and XIAP, respectively, is determinant in the induction of apoptosis by DHA and EPA. These fatty acids could potentially be useful adjuvant anticancer agents in combination with other chemotherapeutic elements.
Data from Mapping of Three Genetic Determinants of Susceptibility to Estrogen-Induced Mammary Cancer within the Emca8 Locus on Rat Chromosome 5
Authors: Schaffer Beverly S. , Leland-Wavrin Kristin M. , Kurz Scott G. , Colletti John A. , Seiler Nicole L. , Warren Christopher L. , Shull James D.
Published: April 2023

Abstract
The ACI rat model of 17β-estradiol (E2)-induced mammary cancer has gained wide use in the study of breast cancer etiology, prevention, and genetics. Emca8, a QTL that determines susceptibility to E2-induced mammary cancer, was previously mapped to rat chromosome 5 (RNO5) in an intercross between resistant Brown Norway (BN) and susceptible ACI rats. In this study, a panel of congenic rat strains, each of which carries BN alleles across a defined segment of RNO5 on the ACI genetic background, was generated and used to map more precisely the Emca8 determinants of mammary cancer susceptibility. Three distinct genetic determinants were localized within Emca8, and two of these were mapped to intervals of less than 15 megabases. Emca8.1 harbors Cdkn2a, Cdkn2b, and other genes and is orthologous to the 9p21 breast cancer locus identified in genome-wide and candidate gene association studies. Emca8.2 harbors Cdkn2c and other genes and is orthologous to the 1p32 locus in humans that is frequently deleted in breast cancers. Both Emca8.1 and Emca8.2 harbor copy number variants that are orthologous to copy number variant regions in humans. Gene expression profiles were defined for mammary tissues from E2-treated ACI and ACI.BN-Emca8 rats to define the impact of Emca8 on gene expression and identify differentially expressed genes residing within Emca8.1 and Emca8.2. This study further illustrates the relevance of the ACI rat model of E2-induced mammary cancer for identifying novel genetic determinants of breast cancer susceptibility and defining the mechanisms through which estrogens contribute to breast cancer development. Cancer Prev Res; 6(1); 59–69. ©2012 AACR.
Data from Curcumin Implants, Not Curcumin Diet, Inhibit Estrogen-Induced Mammary Carcinogenesis in ACI Rats
Authors: Bansal Shyam S. , Kausar Hina , Vadhanam Manicka V. , Ravoori Srivani , Pan Jianmin , Rai Shesh N. , Gupta Ramesh C.
Published: April 2023

Abstract
Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17β-estradiol (E2)–mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached >80% (∼6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm3 vs. 280 ± 141 mm3; P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered. Cancer Prev Res; 7(4); 456–65. ©2014 AACR.
Data from A Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial of Lovastatin for Various Endpoints of Melanoma Pathobiology
Authors: Linden Kenneth G. , Leachman Sancy A. , Zager Jonathan S. , Jakowatz James G. , Viner Jaye L. , McLaren Christine E. , Barr Ronald J. , Carpenter Philip M. , Chen Wen-Pin , Elmets Craig A. , Tangrea Joseph A. , Lim Sung-Jig , Cochran Alistair J. , Meyskens Frank L.
Published: April 2023

Abstract
On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed. Cancer Prev Res; 7(5); 496–504. ©2014 AACR.
Data from Microscopic and Early-Stage Ovarian Cancers in BRCA1/2 Mutation Carriers: Building a Model for Early BRCA-Associated Tumorigenesis
Authors: Yates Melinda S. , Meyer Larissa A. , Deavers Michael T. , Daniels Molly S. , Keeler Elizabeth R. , Mok Samuel C. , Gershenson David M. , Lu Karen H.
Published: April 2023

Abstract
Risk-reducing salpingo-oophorectomy (RRSO) is the cornerstone of ovarian cancer prevention in BRCA1/2 mutation carriers. Occult fallopian tube and ovarian cancers have been reported in a small percentage of BRCA1/2 mutation carriers undergoing RRSO. Here, we review our single-institution experience with RRSO in BRCA1/2 mutation carriers to characterize cases of microscopic cancers in these patients. At the time of RRSO, 7.9% of BRCA1 mutation carriers were diagnosed with microscopic fallopian tube or ovarian cancers and no cases were diagnosed in BRCA2 mutation carriers. The majority of the microscopic cancers include cases that were confined to the fallopian tubes, although there were also cases involving ovaries only or peritoneal washings only. This suggests that the site of origin may be in the ovary, fallopian tube, or peritoneum for BRCA-associated serous cancers. However, an analysis of early-stage (stages I and II) ovarian and fallopian tube cancers diagnosed in BRCA1/2 mutation carriers confirms that the ovary is a preferred site for tumor growth with 11 of 14 early-stage cancers having a dominant ovarian mass. Overall, these data suggest that cancer initiation may occur in the ovary, fallopian tube, or peritoneum, but tumor growth and progression are favored in the ovary. We present an updated model for BRCA1/2 mutation–associated ovarian and fallopian tube carcinogenesis, which may aid in identifying improved prevention strategies for high-risk women who delay or decline RRSO. Cancer Prev Res; 4(3); 463–70. ©2011 AACR.
Data from Kava Blocks 4-(Methylnitrosamino)-1-(3-pyridyl)-1-Butanone–Induced Lung Tumorigenesis in Association with Reducing O6-methylguanine DNA Adduct in A/J Mice
Authors: Leitzman Pablo , Narayanapillai Sreekanth C. , Balbo Silvia , Zhou Bo , Upadhyaya Pramod , Shaik Ahmad Ali , O'Sullivan M. Gerard , Hecht Stephen S. , Lu Junxuan , Xing Chengguo
Published: April 2023

Abstract
We previously reported the chemopreventive potential of kava against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP)–induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of kava, the potential active compounds, and the underlying mechanisms in NNK-induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated kava's chemopreventive efficacy, whereas kavalactone-free fractions A and C were much less effective. Mechanistically, kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O6-methylguanine (O6-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O6-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in kava. Cancer Prev Res; 7(1); 86–96. ©2013 AACR.
Data from Cancer Chemoprevention Locks onto a New Polyamine Metabolic Target
Authors: Gerner Eugene W.
Published: April 2023

Abstract
Ornithine decarboxylase has a relatively long history as a target for cancer chemoprevention and chemotherapy. Plym Forshell et al. report new evidence (beginning on p. 140 in this issue of the journal) indicating that spermidine synthase, a fellow enzyme of ornithine decarboxylase in polyamine metabolism, is transactivated in part by the MYC gene and is a potential target for chemoprevention of B-cell lymphomas. Cancer Prev Res; (3)2; 125–7
Data from Diagnosing Lynch Syndrome: More Light at the End of the Tunnel
Authors: Burt Randall W.
Published: April 2023

Abstract
Since the recognition of Lynch syndrome, which confers a high risk of colorectal, uterine, and other cancers, approaches to its diagnosis have included a family history of associated cancers and web-based algorithms. Identification of causative genes now allows a precise diagnosis, thus focusing present efforts on who should have genetic testing. Testing for cancer tissue changes can determine who should have germline genetic testing. Indeed, such tumor testing is now generally recommended for all newly diagnosed colorectal cancer cases. As reported in this issue of the journal by Yurgelun and colleagues (beginning on page 574), large colorectal adenomatous polyps (≥10 mm) from patients with Lynch syndrome exhibit findings similar to those in Lynch syndrome colorectal cancer tissues. This finding indicates that testing larger adenomas in persons at a significant risk for Lynch syndrome can now determine the need for germline genetic testing. Although further study is needed for general application, the present study justifies large polyp testing in high-risk families when cancer tissue is unavailable, albeit negative polyp tissue would not rule out Lynch syndrome, as would negative cancer tissue. Cancer Prev Res; 5(4); 507–10. ©2012 AACR.
Data from Comparative Effects of Two Different Forms of Selenium on Oxidative Stress Biomarkers in Healthy Men: A Randomized Clinical Trial
Authors: Richie John P. , Das Arun , Calcagnotto Ana M. , Sinha Raghu , Neidig Wanda , Liao Jiangang , Lengerich Eugene J. , Berg Arthur , Hartman Terryl J. , Ciccarella Amy , Baker Aaron , Kaag Matthew G. , Goodin Susan , DiPaola Robert S. , El-Bayoumy Karam
Published: April 2023

Abstract
Epidemiologic and laboratory studies indicate that dietary selenium protects against prostate cancer. Results from clinical trials suggest that selenium-enriched yeast (SY) but not selenomethionine (SeMet) may be effective at reducing prostate cancer risk. Our objectives were to directly compare for the first time the effects of SeMet and SY on prostate cancer relevant biomarkers in men. We performed a randomized double blind, placebo-controlled trial of SY (200 or 285 μg/day) and SeMet (200 μg/day) administered for 9 months in 69 healthy men. Primary endpoints included blood levels of selenium-containing compounds and oxidative stress biomarkers [urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α) and blood glutathione (GSH)]. Secondary endpoints included plasma glucose and PSA levels. Compliance was high in all groups (>95%). Plasma selenium levels were increased 93%, 54%, and 86% after 9 months in SeMet and low- and high-dose SY groups, respectively, and returned to baseline levels after a 3-month washout (P < 0.05). Levels of 8-OHdG and 8-iso-PGF2α were decreased 34% and 28%, respectively, after 9 months in the high-dose SY group (P < 0.05). These decreases were greatest in individuals with low baseline plasma levels of selenium (<127 ng/mL). No changes in serum PSA or blood glucose and GSH were observed. Overall, we showed for the first time, reductions in biomarkers of oxidative stress following supplementation with SY but not SeMet in healthy men. These findings suggest that selenium-containing compounds other than SeMet may account for the decrease in oxidative stress. Cancer Prev Res; 7(8); 796–804. ©2014 AACR.
Data from Screening for Oral Premalignancy and Cancer: What Platform and Which Biomarkers?
Authors: Lingen Mark W.
Published: April 2023

Abstract
This perspective on the report by Pattani et al. in this issue of the journal (beginning on page 1093) examines the utility of detecting hypermethylation of the candidate tumor suppressor genes endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) as a means of oral cancer or premalignancy screening. The data discussed here raise the possibility that saliva-based hypermethylation studies may hold promise as a cancer screening platform. This perspective also discusses some of the challenges and current limitations of developing biomarkers to screen not only for oral premalignancy and early cancer but for human papillomavirus–related oropharyngeal neoplasia as well. Cancer Prev Res; 3(9); 1056–9. ©2010 AACR.
Data from Hepatitis B Virus Combo Mutations Improve the Prediction and Active Prophylaxis of Hepatocellular Carcinoma: A Clinic-Based Cohort Study
Authors: Yin Jianhua , Wang Junxue , Pu Rui , Xin Haiguang , Li Zixiong , Han Xue , Ding Yibo , Du Yan , Liu Wenbin , Deng Yang , Ji Xiaowei , Wu Ming , Yu Min , Zhang Hongwei , Wang Hongyang , Thompson Timothy C. , Ni Wu , Cao Guangwen
Published: April 2023

Abstract
We aimed to evaluate whether hepatitis B virus (HBV) mutations at the core promoter region could improve the prediction and specific prophylaxis of hepatocellular carcinoma (HCC) in chronic HBV-infected patients. A total of 2,114 HBV-infected patients enrolled between August 1998 and December 2007 were followed-up for 18,406 person-years. Of those, 612 received ≥48 week treatments with nucleos(t)ide analogue (NA) and/or IFNα. Baseline HBV mutations were identified by sequencing. Propensity score matching was applied to reduce baseline differences between antiviral and control cohorts. Multivariate Cox regression analyses, including baseline characteristics of 2,114 patients, showed that age, male, cirrhosis, and HBV mutations (C1653T, T1753V, and A1762T/G1764A) independently increased HCC risk. In control patients carrying A1762T/G1764A, addition of C1653T and/or T1753V significantly increased HCC risk (HR, 1.57; P = 0.038); combo mutations with C1653T, T1753V, and A1762T/G1764A improved the validity of HCC prediction by age, male, and cirrhosis (P = 0.002). In the matched cohorts, antiviral treatment reduced HCC incidence (13.90/1,000 vs. 7.70/1,000 person-years, P = 0.005); NA treatment for ≥60 months was required for the prophylaxis of HCC in cirrhotic patients (P = 0.03); antiviral treatment reduced HCC risk in patients carrying A1762T/G1764A (HR, 0.40; P = 0.002) or C1653T (HR, 0.45; P = 0.04) and in those without T1753V (HR, 0.42; P = 0.005), but could not reduce HCC risk in patients without A1762T/G1764A or C1653T and in those with T1753V. In summary, HBV mutation A1762T/G1764A, C1653T, and T1753V in combination improve HCC prediction in HBV-infected patients. To prevent HCC, patients infected with HBV carrying A1762T/G1764A or C1653T, but not T1753V, should be given priority of receiving antiviral treatments. Cancer Prev Res; 8(10); 978–88. ©2015 AACR.
Data from A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum α-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP
Authors: Morgan Timothy R. , Osann Kathryn , Bottiglieri Teodoro , Pimstone Neville , Hoefs John C. , Hu Ke-Qin , Hassanein Tarek , Boyer Thomas D. , Kong Lorene , Chen Wen-Pin , Richmond Ellen , Gonzalez Rachel , Rodriguez Luz M. , Meyskens Frank L.
Published: April 2023

Abstract
In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential. Cancer Prev Res; 8(9); 864–72. ©2015 AACR.