bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Mitochondrial DNA Content as Risk Factor for Bladder Cancer and Its Association with Mitochondrial DNA Polymorphisms
Authors: Williams Stephen B. , Ye Yuanqing , Huang Maosheng , Chang David W. , Kamat Ashish M. , Pu Xia , Dinney Colin P. , Wu Xifeng
Published: April 2023

Abstract
Mitochondrial DNA (mtDNA) content has been shown to be associated with cancer susceptibility. We identified 926 bladder cancer patients and compared these with 926 healthy controls frequency matched on age, gender, and ethnicity. Patients diagnosed with bladder cancer had significantly decreased mtDNA content when compared with control subjects (median, 0.98 vs. 1.04, P < 0.001). Low mtDNA content (i.e., less than the median in control subjects) was associated with a statistically significant increased risk of bladder cancer, when compared with high mtDNA content [Odds ratio (OR), 1.37; 95% confidence interval (CI), 1.13–1.66; P < 0.001). In a trend analysis, a statistically significant dose–response relationship was detected between lower mtDNA content and increasing risk of bladder cancer (Ptrend <0.001). When stratified by host characteristics, advanced age (>65 years), male sex and positive smoking history were significantly associated with low mtDNA content and increased risk of bladder cancer. We identified two unique mtDNA polymorphisms significantly associated with risk of bladder cancer: mitot10464c (OR, 1.39; 95% CI, 1.00–1.93; P = 0.048) and mitoa4918g (OR, 1.40; 95% CI, 1.00–1.95; P = 0.049). Analysis of the joint effect of low mtDNA content and unfavorable mtDNA polymorphisms revealed a 2.5-fold increased risk of bladder cancer (OR, 2.50; 95% CI, 1.60–3.94; P < 0.001). Significant interaction was observed between mitoa4918g and mtDNA content (Pinteraction = 0.028). Low mtDNA content was associated with increased risk of bladder cancer and we identified new susceptibility mtDNA alleles associated with increased risk that require further investigation into the biologic underpinnings of bladder carcinogenesis. Cancer Prev Res; 8(7); 607–13. ©2015 AACR.
Data from Application of SNP Microarrays to the Genome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions
Authors: Nakachi Ichiro , Rice Jessica L. , Coldren Christopher D. , Edwards Michael G. , Stearman Robert S. , Glidewell Steven C. , Varella-Garcia Marileila , Franklin Wilbur A. , Keith Robert L. , Lewis Marina T. , Gao Bifeng , Merrick Daniel T. , Miller York E. , Geraci Mark W.
Published: April 2023

Abstract
Chromosomal instability is central to the process of carcinogenesis. The genome-wide detection of somatic chromosomal alterations (SCA) in small premalignant lesions remains challenging because sample heterogeneity dilutes the aberrant cell information. To overcome this hurdle, we focused on the B allele frequency data from single-nucleotide polymorphism microarrays (SNP arrays). The difference of allelic fractions between paired tumor and normal samples from the same patient (delta-θ) provides a simple but sensitive detection of SCA in the affected tissue. We applied the delta-θ approach to small, heterogeneous clinical specimens, including endobronchial biopsies and brushings. Regions identified by delta-θ were validated by FISH and quantitative PCR in heterogeneous samples. Distinctive genomic variations were successfully detected across the whole genome in all invasive cancer cases (6 of 6), carcinoma in situ (3 of 3), and high-grade dysplasia (severe or moderate; 3 of 11). Not only well-described SCAs in lung squamous cell carcinoma, but also several novel chromosomal alterations were frequently found across the preinvasive dysplastic cases. Within these novel regions, losses of putative tumor suppressors (RNF20 and SSBP2) and an amplification of RASGRP3 gene with oncogenic activity were observed. Widespread sampling of the airway during bronchoscopy demonstrated that field cancerization reflected by SCAs at multiple sites was detectable. SNP arrays combined with delta-θ analysis can detect SCAs in heterogeneous clinical sample and expand our ability to assess genomic instability in the airway epithelium as a biomarker of lung cancer risk. Cancer Prev Res; 7(2); 255–65. ©2013 AACR.
Data from Dietary Soy Effects on Mammary Gland Development during the Pubertal Transition in Nonhuman Primates
Authors: Dewi Fitriya N. , Wood Charles E. , Lees Cynthia J. , Willson Cynthia J. , Register Thomas C. , Tooze Janet A. , Franke Adrian A. , Cline J. Mark
Published: April 2023

Abstract
While epidemiologic studies suggest that soy intake early in life may reduce breast cancer risk, there are also concerns that exposure to soy isoflavones during childhood may alter pubertal development and hormonal profiles. Here, we assessed the effect of a high-soy diet on pubertal breast development, sex hormones, and growth in a nonhuman primate model. Pubertal female cynomolgus monkeys were randomized to receive a diet modeled on a typical North American diet with one of two protein sources for approximately 4.5 years: (i) casein/lactalbumin (CL, n = 12, as control) or (ii) soy protein isolate with a human equivalent dose of 120 mg/d isoflavones (SOY, n = 17), which is comparable to approximately four servings of soy foods. Pubertal exposure to the SOY diet did not alter onset of menarche, indicators of growth and pubertal progression, or circulating estradiol and progesterone concentrations. Greater endometrial area was seen in the SOY group on the first of four postmenarchal ultrasound measurements (P < 0.05). There was a subtle effect of diet on breast differentiation whereby the SOY group showed higher numbers of differentiated large-sized lobular units and a lower proportion with immature ducts following menarche (P < 0.05). Numbers of small lobules and terminal end buds and mammary epithelial cell proliferation did not differ by diet. Expression of progesterone receptor was lower in immature lobules of soy-fed animals (P < 0.05). Our findings suggest that consumption of soy starting before menarche may result in modest effects consistent with a more differentiated breast phenotype in adulthood. Cancer Prev Res; 6(8); 832–42. ©2013 AACR.
Data from Global Assessment of Genetic Variation Influencing Response to Retinoid Chemoprevention in Head and Neck Cancer Patients
Authors: Lee J. Jack , Wu Xifeng , Hildebrandt Michelle A.T. , Yang Hushan , Khuri Fadlo R. , Kim Edward , Gu Jian , Ye Yuanqing , Lotan Reuben , Spitz Margaret R. , Hong Waun Ki
Published: April 2023

Abstract
Head and neck squamous cell carcinoma (HNSCC) patients are at an increased risk of developing a second primary tumor (SPT) or recurrence following curative treatment. 13-cis-retinoic acid (13-cRA) has been tested in chemoprevention clinical trials, but the results have been inconclusive. We genotyped 9,465 single nucleotide polymorphisms (SNP) in 450 patients from the Retinoid Head and Neck Second Primary Trial. SNPs were analyzed for associations with SPT/recurrence in patients receiving placebo to identify prognosis markers and further analyzed for effects of 13-cRA in patients with these prognostic loci. Thirteen loci identified a majority subgroup of patients at a high risk of SPT/recurrence and in whom 13-cRA was protective. Patients carrying the common genotype of rs3118570 in the retinoid X receptor (RXRA) were at a 3.33-fold increased risk (95% CI, 1.67–6.67) and represented more than 70% of the study population. This locus also identified individuals who received benefit from chemoprevention with a 38% reduced risk (95% CI, 0.43–0.90). Analyses of cumulative effect and potential gene–gene interactions also implicated CDC25C:rs6596428 and JAK2:rs1887427 as 2 other genetic loci with major roles in prognosis and 13-cRA response. Patients with all 3 common genotypes had a 76% reduction in SPT/recurrence (95% CI, 0.093–0.64) following 13-cRA chemoprevention. Carriers of these common genotypes constituted a substantial percentage of the study population, indicating that a pharmacogenetic approach could help select patients for 13-cRA chemoprevention. The lack of any alternatives for reducing risk in these patients highlights the need for future clinical trials to prospectively validate our findings. Cancer Prev Res; 4(2); 185–93. ©2011 AACR.
Data from Liver Fatty Acid-Binding Protein (L-Fabp) Modifies Intestinal Fatty Acid Composition and Adenoma Formation in ApcMin/+ Mice
Authors: Dharmarajan Sekhar , Newberry Elizabeth P. , Montenegro Grace , Nalbantoglu ILKe , Davis Victoria R. , Clanahan Michael J. , Blanc Valerie , Xie Yan , Luo Jianyang , Fleshman James W. , Kennedy Susan , Davidson Nicholas O.
Published: April 2023

Abstract
Evidence suggests a relationship between dietary fat intake, obesity, and colorectal cancer, implying a role for fatty acid metabolism in intestinal tumorigenesis that is incompletely understood. Liver fatty acid-binding protein (L-Fabp), a dominant intestinal fatty acid-binding protein, regulates intestinal fatty acid trafficking and metabolism, and L-Fabp deletion attenuates diet-induced obesity. Here, we examined whether changes in intestinal fatty acid metabolism following L-Fabp deletion modify adenoma development in ApcMin/+ mice. Compound L-Fabp−/−ApcMin/+ mice were generated and fed a 10% fat diet balanced equally between saturated, monounsaturated, and polyunsaturated fat. L-Fabp−/−ApcMin/+ mice displayed significant reductions in adenoma number and total polyp area compared with ApcMin/+controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp−/−ApcMin/+ mice exhibited reductions in cellular proliferation, high-grade dysplasia, and nuclear β-catenin translocation. Intestinal fatty acid content was increased in L-Fabp−/−ApcMin/+ mice, and lipidomic profiling of intestinal mucosa revealed significant shifts to polyunsaturated fatty acid species with reduced saturated fatty acid species. L-Fabp−/−ApcMin/+ mice also showed corresponding changes in mRNA expression of enzymes involved in fatty acid elongation and desaturation. Furthermore, adenomas from L-Fabp−/−ApcMin/+ mice displayed significant reductions in mRNA abundance of nuclear hormone receptors involved in cellular proliferation and in enzymes involved in lipogenesis. These findings collectively implicate L-Fabp as an important genetic modifier of intestinal tumorigenesis, and identify fatty acid trafficking and metabolic compartmentalization as an important pathway linking dietary fat intake, obesity, and intestinal tumor formation. Cancer Prev Res; 6(10); 1026–37. ©2013 AACR.
Data from Accurate Reconstruction of the Temporal Order of Mutations in Neoplastic Progression
Authors: Sprouffske Kathleen , Pepper John W. , Maley Carlo C.
Published: April 2023

Abstract
The canonical route from normal tissue to cancer occurs through sequential acquisition of somatic mutations. Many studies have constructed a linear genetic model for tumorigenesis using the genetic alterations associated with samples at different stages of neoplastic progression from cross-sectional data. The common interpretation of these models is that they reflect the temporal order within any given tumor. Linear genetic methods implicitly neglect genetic heterogeneity within a neoplasm; each neoplasm is assumed to consist of one dominant clone. We modeled neoplastic progression of colorectal cancer using an agent-based model of a colon crypt and found clonal heterogeneity within our simulated neoplasms, as observed in vivo. Just 7.3% of cells within neoplasms acquired mutations in the same order as the linear model. In 41% of the simulated neoplasms, no cells acquired mutations in the same order as the linear model. We obtained similarly poor results when comparing the temporal order with oncogenetic tree models inferred from cross-sectional data. However, when we reconstructed the cell lineage of mutations within a neoplasm using several biopsies, we found that 99.7% cells within neoplasms acquired their mutations in an order consistent with the cell lineage mutational order. Thus, we find that using cross-sectional data to infer mutational order is misleading, whereas phylogenetic methods based on sampling intratumor heterogeneity accurately reconstructs the evolutionary history of tumors. In addition, we find evidence that disruption of differentiation is likely the first lesion in progression for most cancers and should be one of the few regularities of neoplastic progression across cancers. Cancer Prev Res; 4(7); 1135–44. ©2011 AACR.
Data from Urinary ADAM12 and MMP-9/NGAL Complex Detect the Presence of Gastric Cancer
Authors: Shimura Takaya , Dagher Adelle , Sachdev Monisha , Ebi Masahide , Yamada Tamaki , Yamada Tomonori , Joh Takashi , Moses Marsha A.
Published: April 2023

Abstract
Although the early diagnosis of gastric cancer provides the opportunity for curative endoscopic resection, comprehensive screening endoscopy would be invasive and expensive. To date, there is a complete absence of clinically useful gastric cancer biomarkers. With the goal of discovering noninvasive biomarkers for the early diagnosis of gastric cancer, we have conducted a case–control study using urine samples from individuals with gastric cancer versus healthy control samples. Of the enrolled 106 patients from September, 2012 to April, 2013, a cohort of 70 patients composed of 35 patients with gastric cancer and 35 age- and sex-matched healthy controls was analyzed. The gastric cancer group was composed of stage IA of 62.9% (22/35). The urinary levels of MMP-9/NGAL complex (uMMP-9/NGAL) and ADAM12 (uADAM12) were significantly higher in the gastric cancer group compared with the healthy control group as determined by monospecific ELISAs (uMMP-9/NGAL: median, 85 pg/mL vs. 0 pg/mL; P = 0.020; uADAM12: median, 3.35 ng/mL vs. 1.44 ng/mL; P < 0.001). Multivariate analysis demonstrated that both uMMP-9/NGAL and uADAM12 were significant, independent diagnostic biomarkers for gastric cancer. Moreover, MMP-9/NGAL activity was significantly elevated as determined by gelatin zymography. The combination of uMMP-9/NGAL with uADAM12 distinguished between control samples and gastric cancer samples with an AUC of 0.825 (P < 0.001) in an ROC analysis. Significantly, immunohistochemical analyses demonstrated a high coexpression of MMP-9 and NGAL (P < 0.001) and high expression of ADAM12 (P < 0.001) in gastric cancer tissues compared with adjacent normal tissues (N = 35). In summary, uMMP-9/NGAL and uADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease. Cancer Prev Res; 8(3); 240–8. ©2015 AACR.
Data from Gonadal Tumor in Frasier Syndrome: A Review and Classification
Authors: Ezaki Jiro , Hashimoto Kazunori , Asano Tatsuo , Kanda Shoichiro , Akioka Yuko , Hattori Motoshi , Yamamoto Tomoko , Shibata Noriyuki
Published: April 2023

Abstract
Frasier syndrome is a rare inherited disease characterized by steroid-resistant nephrotic syndrome, gonadal tumor, and male pseudohermaphroditism (female external genitalia with sex chromosomes XY), which is based on a splice site mutation of Wilms tumor-suppressor gene 1 (WT1). Several unusual Frasier syndrome cases have been reported in which male pseudohermaphroditism was absent. We reviewed 88 Frasier syndrome cases in the literature and classified them into three types (type 1–3) according to external genitalia and sex chromosomes, and described their clinical phenotypes. Type 1 Frasier syndrome is characterized by female external genitalia with 46,XY (n = 72); type 2 by male external genitalia with 46,XY (n = 8); and type 3 by female external genitalia with 46,XX (n = 8). Clinical course differs markedly among the types. Although type 1 is noticed at the mean age of 16 due to mainly primary amenorrhea, type 2 and 3 do not present delayed secondary sex characteristics, making diagnosis difficult. The prevalence of gonadal tumor is high in type 1 (67%) and also found in 3 of the 8 type 2 cases, but not in any type 3 cases, which emphasize that preventive gonadectomy is unnecessary in type 3. On the basis of our findings, we propose a new diagnostic algorithm for Frasier syndrome. Cancer Prev Res; 8(4); 271–6. ©2015 AACR.
Data from Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma
Authors: Wikoff William R. , Grapov Dmitry , Fahrmann Johannes F. , DeFelice Brian , Rom William N. , Pass Harvey I. , Kim Kyoungmi , Nguyen UyenThao , Taylor Sandra L. , Gandara David R. , Kelly Karen , Fiehn Oliver , Miyamoto Suzanne
Published: April 2023

Abstract
Adenocarcinoma, a type of non–small cell lung cancer, is the most frequently diagnosed lung cancer and the leading cause of lung cancer mortality in the United States. It is well documented that biochemical changes occur early in the transition from normal to cancer cells, but the extent to which these alterations affect tumorigenesis in adenocarcinoma remains largely unknown. Herein, we describe the application of mass spectrometry and multivariate statistical analysis in one of the largest biomarker research studies to date aimed at distinguishing metabolic differences between malignant and nonmalignant lung tissue. Gas chromatography time-of-flight mass spectrometry was used to measure 462 metabolites in 39 malignant and nonmalignant lung tissue pairs from current or former smokers with early stage (stage IA–IB) adenocarcinoma. Statistical mixed effects models, orthogonal partial least squares discriminant analysis and network integration, were used to identify key cancer-associated metabolic perturbations in adenocarcinoma compared with nonmalignant tissue. Cancer-associated biochemical alterations were characterized by (i) decreased glucose levels, consistent with the Warburg effect, (ii) changes in cellular redox status highlighted by elevations in cysteine and antioxidants, alpha- and gamma-tocopherol, (iii) elevations in nucleotide metabolites 5,6-dihydrouracil and xanthine suggestive of increased dihydropyrimidine dehydrogenase and xanthine oxidoreductase activity, (iv) increased 5′-deoxy-5′-methylthioadenosine levels indicative of reduced purine salvage and increased de novo purine synthesis, and (v) coordinated elevations in glutamate and UDP-N-acetylglucosamine suggesting increased protein glycosylation. The present study revealed distinct metabolic perturbations associated with early stage lung adenocarcinoma, which may provide candidate molecular targets for personalizing therapeutic interventions and treatment efficacy monitoring. Cancer Prev Res; 8(5); 410–8. ©2015 AACR.
Data from Regulation of VDR Expression in Apc-Mutant Mice, Human Colon Cancers and Adenomas
Authors: Giardina Charles , Nakanishi Masako , Khan Awaad , Kuratnik Anton , Xu Wanli , Brenner Bruce , Rosenberg Daniel W.
Published: April 2023

Abstract
One variable that may affect the ability of vitamin D to reduce colon cancer risk is the expression of its high-affinity receptor, VDR. Here, we show that vitamin D does not reduce tumor formation in ApcΔ14/+ mice and that VDR expression is lost in the majority of the colon tumor cells. The extent of VDR loss corresponded inversely to the level of β-catenin nuclear localization and could be observed in early lesions composed of just a few crypts. Analysis of reported VDR regulators showed that the repressing class I histone deacetylases (HDAC) were significantly elevated in the tumors (up to 4-fold), whereas the VDR-activating retinoid X receptors (RXR) were downregulated (∼50%). Expression of the Slug repressor was also increased, but was found primarily in stromal cells. Analysis of epigenetically active compounds on colon cell lines and intestinal organoids showed that HDAC inhibitors were particularly adept at stimulating VDR expression. Treatment of tumor-bearing ApcΔ14/+ mice with the HDAC inhibitor panobinostat increased VDR expression in the tumors and normal mucosa. The RXR agonist bexarotene failed to activate VDR expression, indicating that RXR ligands were not limiting. Analysis of human microarray data indicated that VDR mRNA is frequently downregulated in colon adenomas, which correlated positively with RXRA expression and inversely with HDAC 2 and 8 expression. Human adenomas showed variable VDR protein expression levels, both between and within individual lesions. Determining the mechanisms of VDR regulation in colon neoplasms may significantly enhance our ability to use vitamin D as a cancer prevention agent. Cancer Prev Res; 8(5); 387–99. ©2015 AACR.
Data from TFF2–CXCR4 Axis Is Associated with BRAF V600E Colon Cancer
Authors: Gala Manish K. , Austin Thomas , Ogino Shuji , Chan Andrew T.
Published: April 2023

Abstract
Oncogene-induced senescence (OIS), a tumor-suppressive mechanism that is induced by the replicative and metabolic stress of oncogene activation, is a key barrier in the development of BRAF V600E colon cancer. Inhibition of this mechanism has been observed through epigenetic changes observed in sporadic serrated polyps, as well as through the germline mutations associated with those who develop serrated polyposis. We hypothesize that upregulated autocrine factors exist that are specific to the serrated pathway and also promote bypass of oncogene-induced senescence. To identify such autocrine factors, we integrate analyses of microarrays of sessile serrated polyps and two large colon cancer cohorts, the Cancer Genome Atlas (TCGA; n = 153), and French national Cartes d'Identité des Tumeurs (CIT) program (n = 462), with enhanced gene annotation through natural language processing techniques of the existing medical corpus. We reproducibly associate higher expression of the ligand–receptor axis of TFF2 and CXCR4 with BRAF V600E-mutant colon cancer (P = 3.0 × 10−3 and 0.077, respectively for TCGA; P = 3.0 × 10−8 and 5.1 × 10−7 for CIT). Given well-described oncogenic roles of TFF2 and CXCR4 in colon cancer, and availability of CXCR4 inhibitors for other clinical indications, this ligand–receptor axis may represent an actionable target for prevention and treatment of this molecular subtype of colorectal cancer. Cancer Prev Res; 8(7); 614–9. ©2015 AACR.
Data from Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non–Small Cell Lung Cancer and Its Potential as a Circulating Biomarker
Authors: Lou Tzu-Fang , Sethuraman Deepa , Dospoy Patrick , Srivastva Pallevi , Kim Hyun Seok , Kim Joongsoo , Ma Xiaotu , Chen Pei-Hsuan , Huffman Kenneth E. , Frink Robin E. , Larsen Jill E. , Lewis Cheryl , Um Sang-Won , Kim Duk-Hwan , Ahn Jung-Mo , DeBerardinis Ralph J. , White Michael A. , Minna John D. , Yoo Hyuntae
Published: April 2023

Abstract
In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non–small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA), in cancer cells—undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA's cancer specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N = 577), with minimal expression in all nonmalignant lung tissues (N = 74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA's clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N = 13) in comparison with age-matched healthy controls (N = 21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression, and its extracellular secretion can be detected in blood. Cancer Prev Res; 9(1); 43–52. ©2015 AACR.
Data from Boxing Bladder Cancer with COX-2–specific Inhibition
Authors: Kelly John D. , Hall Emma
Published: April 2023

Abstract
Preventing recurrence of non–muscle-invasive bladder cancer (NMIBC) is important for improving patient well-being and reducing the health economic burden of this disease. To date, no oral agent has shown sufficient benefit to be adopted in clinical practice, where current strategies rely on topical (intravesical) administration of chemotherapy and immunotherapy. In this issue of the journal (beginning on page 1580), Sabichi and colleagues report the first phase II randomized controlled trial of the COX-2 inhibitor celecoxib in bladder cancer. The trial set out to measure an overly ambitious effect size but nevertheless showed encouraging signs of celecoxib activity. It lends support to COX-2 inhibition in NMIBC, which is being tested in several subsequent trials, and to the need for conclusive evidence. Cancer Prev Res; 4(10); 1534–5. ©2011 AACR.
Data from Effect of Low-Fat Diets on Plasma Levels of NF-κB–Regulated Inflammatory Cytokines and Angiogenic Factors in Men with Prostate Cancer
Authors: Heymach John V. , Shackleford Terry J. , Tran Hai T. , Yoo Suk-Young , Do Kim-Anh , Wergin Melanie , Saintigny Pierre , Vollmer Robin T. , Polascik Thomas J. , Snyder Denise C. , Ruffin Mack T. , Yan Shaoyu , Dewhirst Mark , Kunnumakkara Ajaikumar B. , Aggarwal Bharat B. , Demark-Wahnefried Wendy
Published: April 2023

Abstract
Diet, nutritional status, and certain dietary supplements are postulated to influence the development and progression of prostate cancer. Angiogenesis and inflammation are central to tumor growth and progression, but the effect of diet on these processes remains uncertain. We explored changes in 50 plasma cytokines and angiogenic factors (CAF) in 145 men with prostate cancer enrolled in a preoperative, randomized controlled phase II trial with four arms: control (usual diet), low-fat (LF) diet, flaxseed-supplemented (FS) diet, and FS+LS diet. The mean duration of dietary intervention was 30 to 31 days. Among the individual arms, the largest number of significant changes (baseline vs. preoperative follow-up) was observed in the LF arm, with 19 CAFs decreasing and one increasing (P < 0.05). Compared with the control arm, 6 CAFs—including proangiogenic factors (stromal-cell derived-1α) and myeloid factors (granulocyte-colony-stimulating factor, macrophage colony-stimulating factor)—all decreased in the LF arm compared with controls; three and four CAFs changed in the FS and FS+LF arms, respectively. Weight loss occurred in the LF arms and significantly correlated with VEGF decreases (P < 0.001). The CAFs that changed in the LF arm are all known to be regulated by NF-κB, and a pathway analysis identified NF-κB as the most likely regulatory network associated with these changes in the LF arm but not in the FS-containing arms. These results suggest that a LF diet without flaxseed may reduce levels of specific inflammatory CAFs and suggests that the NF-κB pathway may be a mediator of these changes. Cancer Prev Res; 4(10); 1590–8. ©2011 AACR.
Data from Physical Activity from Early Adulthood and Risk of Prostate Cancer: A 24-Year Follow-Up Study among Icelandic Men
Authors: Hrafnkelsdóttir Soffia M. , Torfadóttir Jóhanna E. , Aspelund Thor , Magnusson Kristjan T. , Tryggvadóttir Laufey , Gudnason Vilmundur , Mucci Lorelei A. , Stampfer Meir , Valdimarsdóttir Unnur A.
Published: April 2023

Abstract
Physical activity in adult life may reduce prostate cancer risk. Data are scarce on the role of activity during early adulthood, as well as combined recreational and occupational physical activity on prostate cancer risk and mortality. We undertook a prospective study of 8,221 Icelandic men (born 1907 to 1935) in the population-based Reykjavik Study. At enrollment, between 1967 and 1987, the men provided information on regular recreational physical activity since the age of 20 years as well as current occupational activity. Through linkage to nationwide cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality through 2009. We used Cox models to calculate the relative risk of prostate cancer by level of physical activity. During a mean follow-up of 24.8 years, 1,052 men were diagnosed with prostate cancer, of whom 349 had advanced disease (stage 3+ or prostate cancer death). Neither recreational nor occupational physical activity was, independently or combined, associated with overall or localized prostate cancer. Compared with physically inactive men, we observed a nonsignificant lower risk of advanced prostate cancer [HR, 0.67; 95% confidence interval (CI), 0.42–1.07] among men reporting both recreational and occupational physical activities (P value for interaction = 0.03). Awaiting confirmation in larger studies with detailed assessment of physical activity, our data suggest that extensive physical activity beginning in early adulthood may reduce the risk of advanced prostate cancer. Cancer Prev Res; 8(10); 905–11. ©2015 AACR.
Data from Plasma MicroRNAs as Novel Biomarkers for Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Permuth-Wey Jennifer , Chen Dung-Tsa , Fulp William J. , Yoder Sean J. , Zhang Yonghong , Georgeades Christina , Husain Kazim , Centeno Barbara Ann , Magliocco Anthony M. , Coppola Domenico , Malafa Mokenge
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers worldwide, partly because methods are lacking to detect disease at an early, operable stage. Noninvasive PDAC precursors called intraductal papillary mucinous neoplasms (IPMN) exist, and strategies are needed to aid in their proper diagnosis and management. Data support the importance of miRNAs in the progression of IPMNs to malignancy, and we hypothesized that miRNAs may be shed from IPMN tissues and detected in blood. Our primary goals were to measure the abundance of miRNAs in archived preoperative plasma from individuals with pathologically confirmed IPMNs and healthy controls and discover plasma miRNAs that distinguish between IPMN patients and controls and between “malignant” and “benign” IPMNs. Using novel nCounter technology to evaluate 800 miRNAs, we showed that a 30-miRNA signature distinguished 42 IPMN cases from 24 controls [area underneath the curve (AUC) = 74.4; 95% confidence interval (CI), 62.3–86.5, P = 0.002]. The signature contained novel miRNAs and miRNAs previously implicated in pancreatic carcinogenesis that had 2- to 4-fold higher expression in cases than controls. We also generated a 5-miRNA signature that discriminated between 21 malignant (high-grade dysplasia and invasive carcinoma) and 21 benign (low- and moderate-grade dysplasia) IPMNs (AUC = 73.2; 95% CI, 57.6–88.9, P = 0.005), and showed that paired plasma and tissue samples from patients with IPMNs can have distinct miRNA expression profiles. This study suggests feasibility of using new cost-effective technology to develop a miRNA-based blood test to aid in the preoperative identification of malignant IPMNs that warrant resection while sparing individuals with benign IPMNs the morbidity associated with overtreatment. Cancer Prev Res; 8(9); 826–34. ©2015 AACR.
Data from Omega-3-Acid Ethyl Esters Block the Protumorigenic Effects of Obesity in Mouse Models of Postmenopausal Basal-like and Claudin-Low Breast Cancer
Authors: Ford Nikki A. , Rossi Emily L. , Barnett Kelsey , Yang Peiying , Bowers Laura W. , Hidaka Brandon H. , Kimler Bruce F. , Carlson Susan E. , Shureiqi Imad , deGraffenried Linda A. , Fabian Carol J. , Hursting Stephen D.
Published: April 2023

Abstract
Obesity induces chronic inflammation and is an established risk and progression factor for triple-negative breast cancers, including basal-like (BL) and claudin-low (CL) subtypes. We tested the effects of dietary supplementation with ethyl esters of the marine-derived anti-inflammatory omega-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA+DHA; Lovaza) on growth of murine BL and CL mammary tumors. Female ovariectomized C57BL/6 mice were fed a control diet or a diet-induced obesity (DIO) diet with or without EPA+DHA (0.025%, resulting in blood levels of EPA and DHA comparable with women taking Lovaza 4 g/d) for 6 weeks. All mice were then orthotopically injected with Wnt-1 cells (a BL tumor cell suspension derived from MMTV-Wnt-1 transgenic mouse mammary tumors) or M-Wnt cells (a CL tumor cell line cloned from the Wnt-1 tumor cell suspension). Mice were killed when tumors were 1 cm in diameter. EPA+DHA supplementation did not significantly affect Wnt-1 or M-Wnt mammary tumor growth in normoweight control mice. However, EPA+DHA supplementation in DIO mice reduced growth of Wnt-1 and M-Wnt tumors; reduced leptin:adiponectin ratio and proinflammatory eicosanoids in the serum; improved insulin sensitivity; and decreased tumoral expression of COX-2 and phospho-p65. Thus, EPA+DHA supplementation in mouse models of postmenopausal BL and CL breast cancer offsets many of the protumorigenic effects of obesity. These preclinical findings, in combination with results from parallel biomarker studies in women, suggest that EPA+DHA supplementation may reduce the burden of BL and CL breast cancer in obese women. Cancer Prev Res; 8(9); 796–806. ©2015 AACR.
Data from Mammary Gland Density Predicts the Cancer Inhibitory Activity of the N-3 to N-6 Ratio of Dietary Fat
Authors: Zhu Zongjian , Jiang Weiqin , McGinley John N. , Prokopczyk Bogden , Richie John P. , El Bayoumy Karam , Manni Andrea , Thompson Henry J.
Published: April 2023

Abstract
This study investigated the effect of a broad range of dietary ratios of n-3:n-6 fatty acids on mammary gland density and mammary cancer risk. Cancer was induced in female rats by N-methyl-N-nitrosourea. Purified diet that provided 30% of dietary kilocalories from fat was formulated to contain ratios of n-3:n-6 fatty acids from 25:1 to 1:25. Mammary gland density was determined by digital analysis, fatty acids by gas chromatography/flame ionization detection, and other plasma analytes via ELISA. Mammary gland density was reduced dose dependently at n-3:n-6 ratios from 1:1 to 25:1 (r = −0.477, P = 0.038), with a 20.3% decrease of mammary gland density between n-3:n-6 of 1:1 versus 25:1, P < 0.001. Mammary carcinogenesis was inhibited in the absence or presence of tamoxifen (1 mg/kg diet) in a manner predicted by mammary gland density. Plasma n-3 fatty acid concentrations failed to increase above an n-3:n-6 ratio of 5:1, and changes in specific plasma n-3 or n-6 fatty acids were not predictive of mammary gland density or cancer inhibitory activity. A strong reciprocal effect of the n-3:n-6 ratio on plasma leptin (decreased, P = 0.005) and adiponectin (increased, P < 0.001) was observed indicating adipose tissue function was modulated. However, neither cytokine was predictive of mammary gland density. Plasma insulin-like growth factor I (IGF-I) decreased with increasing dietary n-3:n-6 ratio (P = 0.004) and was predictive of the changes in mammary gland density (r = 0.362, P < 0.005). These findings indicate that (i) mammary gland density predicted the carcinogenic response, (ii) the n-3:n-6 ratio exerts effects in the presence or absence of hormonal regulation of carcinogenesis, and (iii) signaling pathways regulated by IGF-I are potential targets for further mechanistic investigation. Cancer Prev Res; 4(10); 1675–85. ©2011 AACR.
Data from Chemopreventive and Antitumor Efficacy of Curcumin in a Spontaneously Developing Hen Ovarian Cancer Model
Authors: Sahin Kazim , Orhan Cemal , Tuzcu Mehmet , Sahin Nurhan , Tastan Hakkı , Özercan İbrahim Hanifi , Güler Osman , Kahraman Nermin , Kucuk Omer , Ozpolat Bulent
Published: April 2023

Abstract
We investigated the effect of daily dietary curcumin intake on the development and progression of spontaneous ovarian cancer in a galline (hen) model, as the chicken is the only nonhuman animal in which ovarian cancer spontaneously develops with a high prevalence. At the end of 12 months, ovarian cancer had spontaneously developed in 39% (35/90) of control hens not fed curcumin (n = 90). In comparison, it spontaneously developed in 27% (24/90) and 17% (15/90) of hens given curcumin at 25.8 (n = 90) and 53.0 mg/day (n = 90), respectively (P = 0.004). This represented significant dose-dependent reductions in overall ovarian cancer incidence in the 25.8 and 53.0 mg/day curcumin-fed groups (31% and 57%, respectively). Daily curcumin intake also reduced ovarian tumor sizes (P = 0.04) and number of tumors (P = 0.006). Evaluation of the molecular mechanisms underlying the chemopreventive and antitumor effects of curcumin revealed that NF-κB and STAT3 signaling pathways were significantly inhibited but that the nuclear factor erythroid 2/heme oxygenase 1 antioxidant pathway was induced by curcumin intake in a dose-dependent manner in ovarian tissues (P < 0.05). Sequencing of the Ras family genes (KRAS, NRAS, and HRAS) revealed less frequent KRAS and HRAS mutations in ovarian tumors in the curcumin-fed animals. In conclusion, our results demonstrated for the first time that daily curcumin intake leads to a significant and dose-dependent reduction in spontaneous ovarian cancer incidence and tumor growth, indicating a tremendous role for curcumin as a chemopreventive strategy for ovarian cancer. Cancer Prev Res; 11(1); 59–67. ©2017 AACR.
Data from β-Carotene 9′,10′ Oxygenase Modulates the Anticancer Activity of Dietary Tomato or Lycopene on Prostate Carcinogenesis in the TRAMP Model
Authors: Tan Hsueh-Li , Thomas-Ahner Jennifer M. , Moran Nancy E. , Cooperstone Jessica L. , Erdman John W. , Young Gregory S. , Clinton Steven K.
Published: April 2023

Abstract
The hypothesis that dietary tomato consumption or the intake of the carotenoid lycopene inhibits prostate cancer arose from epidemiologic studies and is supported by preclinical rodent experiments and in vitro mechanistic studies. We hypothesize that variation in activity of carotenoid cleavage enzymes, such as β-carotene 9′,10′-oxygenase (BCO2), may alter the impact of dietary tomato and lycopene on prostate carcinogenesis and therefore examined this relationship in the TRAMP model. Starting at 3 weeks of age, TRAMP:Bco2+/+ and TRAMP:Bco2−/− mice were fed either AIN-93G control, or semipurified diets containing 10% tomato powder or 0.25% lycopene beadlets until 18 weeks of age. Both tomato- and lycopene-fed TRAMP:Bco2−/− mice had significantly greater serum concentrations of total, 5-cis, other cis, and all-trans lycopene than TRAMP:Bco2+/+ mice. Tomato- and lycopene-fed mice had a lower incidence of prostate cancer compared with the control-fed mice. Although Bco2 genotype alone did not significantly change prostate cancer outcome in the control AIN-93G-fed mice, the abilities of lycopene and tomato feeding to inhibit prostate carcinogenesis were significantly attenuated by the loss of Bco2 (Pinteraction = 0.0004 and 0.0383, respectively). Overall, dietary tomato and lycopene inhibited the progression of prostate cancer in TRAMP in a Bco2 genotype-specific manner, potentially implicating the anticancer activity of lycopene cleavage products. This study suggests that genetic variables impacting carotenoid metabolism and accumulation can impact anticancer activity and that future efforts devoted to understanding the interface between tomato carotenoid intake, host genetics, and metabolism will be necessary to clearly elucidate their interactive roles in human prostate carcinogenesis. Cancer Prev Res; 10(2); 161–9. ©2016 AACR.
Data from Bacterial Vaginosis Decreases the Risk of Cervical Cytological Abnormalities
Authors: Long Tengfei , Zhang Chao , He Gui , Hu Yue , Lin Zhongqiu , Long Lingli
Published: April 2023

Abstract
Genital tract infections, including vulvovaginal candidiasis and bacterial vaginosis, have emerged as potential modulators of persistent human papillomavirus (HPV) infections causing cervical cytologic abnormalities and cervical cancer. This study aimed to investigate whether vulvovaginal candidiasis or bacterial vaginosis had an additional effect on HPV infection and thus caused such abnormalities. ThinPrep cytologic tests were used to detect cytologic abnormalities, vulvovaginal candidiasis, and bacterial vaginosis in 14,679 women. Cytologic abnormalities included atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, atypical squamous cells-cannot exclude HSIL, and squamous cell carcinoma. Logistic regression Model 1 (univariate regression) and Model 2 (multivariate logistic regression analysis adjusted for age combined with HPV infection) were used to analyze the association between bacterial vaginosis and cytologic abnormalities, or vulvovaginal candidiasis and cytologic abnormalities, alone or in the presence of HPV infection. Bacterial vaginosis infection rates were found to be significantly higher in the cytology-negative group among all participants and those with HPV infection (P = 0.003, P < 0.001, respectively). Analyses using Model 1 and Model 2 both pointed to bacterial vaginosis as a protective factor against cytologic abnormalities for all participants (OR = 0.36, 0.17, respectively, P < 0.05) and for HPV-infected participants (OR = 0.17, 0.16, respectively, P < 0.05). Neither vulvovaginal candidiasis nor vulvovaginal candidiasis + HPV was significantly associated with the incidence of cytologic abnormalities based on Model 1 (OR = 0.94, 0.71, respectively, P > 0.05) and Model 2 (OR = 0.91, 0.74, respectively, P > 0.05). Furthermore, neither vulvovaginal candidiasis nor bacterial vaginosis increased the incidence of cytologic abnormalities regardless of HPV infection status, while bacterial vaginosis might possibly prevent cytologic abnormalities in women coinfected by HPV.
Prevention Relevance:
Neither vulvovaginal candidiasis nor bacterial vaginosis was found to increase the incidence of cervical cytologic abnormalities with or without the presence of HPV. On the contrary, bacterial vaginosis may play a role in preventing cytologic abnormalities in women with HPV coinfection.
Data from A Randomized Phase II Trial of Pioglitazone for Lung Cancer Chemoprevention in High-Risk Current and Former Smokers
Authors: Keith Robert L. , Blatchford Patrick J. , Merrick Daniel T. , Bunn Paul A. , Bagwell Brandi , Dwyer-Nield Lori D. , Jackson Mary K. , Geraci Mark W. , Miller York E.
Published: April 2023

Abstract
Lung cancer chemoprevention, especially in high-risk former smokers, has great potential to reduce lung cancer incidence and mortality. Thiazolidinediones prevent lung cancer in preclinical studies, and diabetics receiving thiazolidinediones have lower lung cancer rates which led to our double-blind, randomized, phase II placebo-controlled trial of oral pioglitazone in high-risk current or former smokers with sputum cytologic atypia or known endobronchial dysplasia. Bronchoscopy was performed at study entry and after completing 6 months of treatment. Biopsies were histologically scored, and primary endpoint analysis tested worst biopsy scores (Max) between groups; Dysplasia index (DI) and average score (Avg) changes were secondary endpoints. Biopsies also received an inflammation score. The trial accrued 92 subjects (47 pioglitazone, 45 placebo), and 76 completed both bronchoscopies (39 pioglitazone, 37 placebo). Baseline dysplasia was significantly worse for current smokers, and 64% of subjects had mild or greater dysplasia at study entry. Subjects receiving pioglitazone did not exhibit improvement in bronchial dysplasia. Former smokers treated with pioglitazone exhibited a slight improvement in Max, while current smokers exhibited slight worsening. While statistically significant changes in Avg and DI were not observed in the treatment group, former smokers exhibited a slight decrease in both Avg and DI. Negligible Avg and DI changes occurred in current smokers. A trend toward decreased Ki-67 labeling index occurred in former smokers with baseline dysplasia receiving pioglitazone. While pioglitazone did not improve endobronchial histology in this high-risk cohort, specific lesions showed histologic improvement, and further study is needed to better characterize responsive dysplasia.
Data from Association of Common Use Pharmaceuticals in Reducing Risk of Esophageal Adenocarcinoma: A SEER–Medicare Analysis
Authors: Loomans-Kropp Holli A. , Chaloux Matthew , Richmond Ellen , Umar Asad
Published: April 2023

Abstract
Barrett's esophagus (BE), a recognized risk factor for esophageal adenocarcinoma (EAC), is routinely managed with proton pump inhibitors (PPIs) when symptomatic. Several lines of evidence suggest that PPIs may prevent malignant transformation. Chronic use of other common drugs, namely, statins nonsteroidal anti-inflammatory drugs (NSAIDs) and metformin, may also interfere with BE carcinogenesis, but confirmatory evidence is lacking. We identified 1,943 EAC cases and 19,430 controls (matched 10:1) between 2007 and 2013 that met our specified inclusion criteria in the SEER–Medicare database. Conditional logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (95% CI). Wald χ2 tests were used to assess significance of covariates. Compared with controls, EAC cases had a higher prevalence of BE (26.2%). Use of PPIs, NSAIDs, statins, or metformin reduced the odds of EAC (PPIs: 0.10; 95% CI, 0.09–0.12; NSAIDs: 0.62; 95% CI, 0.51–0.74; statins: 0.15; 95% CI, 0.13–0.17; metformin: 0.76; 95% CI, 0.62–0.93). When stratified by BE, these associations persisted, though no association was found between NSAID use and EAC risk for participants with BE. Dual use of PPIs with NSAIDs or statins, and NSAID, statin, or metformin use alone also showed significant EAC risk reduction among all participants and those without BE. Use of PPIs alone and with NSAIDs, statins, or metformin was associated with reduced risk of EAC; however, a history of BE may diminish drug efficacy. These results indicate that common pharmacologic agents alone or in combination may decrease EAC development.

Prevention Relevance: The use of common drugs, such as proton pump inhibitors, statins, non-steroidal anti-inflammatory drugs, or metformin, may reduce one's risk of developing esophageal adenocarcinoma. These results suggest that repurposing agents often used for common chronic conditions may be a new strategy for cancer prevention efforts.