bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Randomized, Double-Blind, Placebo-Controlled Phase 3 Skin Cancer Prevention Study of α-Difluoromethylornithine in Subjects with Previous History of Skin Cancer
Authors: Bailey Howard H. , Kim KyungMann , Verma Ajit K. , Sielaff Karen , Larson Paul O. , Snow Stephen , Lenaghan Theresa , Viner Jaye L. , Douglas Jeff , Dreckschmidt Nancy E. , Hamielec Mary , Pomplun Marcy , Sharata Harry H. , Puchalsky David , Berg Eric R. , Havighurst Thomas C. , Carbone Paul P.
Published: April 2023

Abstract
Preclinical studies have shown that the inhibition of ornithine decarboxylase (ODC) by α-difluoromethylornithine (DFMO) and resultant decreases in tissue concentrations of polyamines (putrescine and spermidine) prevents neoplastic developments in many tissue types. Clinical studies of oral DFMO at 500 mg/m2/day revealed it to be safe and tolerable and resulted in significant inhibition of phorbol ester–induced skin ODC activity. Two hundred and ninety-one participants (mean age, 61 years; 60% male) with a history of prior nonmelanoma skin cancer (NMSC; mean, 4.5 skin cancers) were randomized to oral DFMO (500 mg/m2/day) or placebo for 4 to 5 years. There was a trend toward a history of more prior skin cancers in subjects randomized to placebo, but all other characteristics including sunscreen and nonsteroidal anti-inflammatory drug use were evenly distributed. Evaluation of 1,200 person-years of follow-up revealed a new NMSC rate of 0.5 events/person/year. The primary end point, new NMSCs, was not significantly different between subjects taking DFMO and placebo (260 versus 363 cancers, P = 0.069, two-sample t test). Evaluation of basal cell (BCC) and squamous cell cancers separately revealed very little difference in squamous cell cancer between treatment groups but a significant difference in new BCC (DFMO, 163 cancers; placebo, 243 cancers; expressed as event rate of 0.28 BCC/person/year versus 0.40 BCC/person/year, P = 0.03). Compliance with DFMO was >90% and it seemed to be well tolerated with evidence of mild ototoxicity as measured by serial audiometric examination when compared with placebo subjects. The analysis of normal skin biopsies revealed a significant (P < 0.05) decrease in 12-0-tetradecanoylphorbol-13-acetate–induced ODC activity (month 24, 36, and 48) and putrescine concentration (month 24 and 36 only) in DFMO subjects. Subjects with a history of skin cancer taking daily DFMO had an insignificant reduction (P = 0.069) in new NMSC that was predominantly due to a marked reduction in new BCC. Based on these data, the potential of DFMO, alone or in combination, to prevent skin cancers should be explored further. Cancer Prev Res; 3(1); 35–47
Data from Momordica Charantia Lectin, a Type II Ribosome Inactivating Protein, Exhibits Antitumor Activity toward Human Nasopharyngeal Carcinoma Cells In Vitro and In Vivo
Authors: Fang Evandro Fei , Zhang Chris Zhi Yi , Ng Tzi Bun , Wong Jack Ho , Pan Wen Liang , Ye Xiu Juan , Chan Yau Sang , Fong Wing Ping
Published: April 2023

Abstract
The incidence of nasopharyngeal carcinoma (NPC) remains high in endemic regions, including southern China, northern Africa, and North America. One of the promising therapeutic approaches on NPC is drug screening from natural products, such as components from traditional Chinese medicine. In this study, the antitumor activity of Momordica charantia lectin (MCL), a type II ribosome inactivating protein from bitter gourd, on NPC was investigated. MCL evinced potent cytotoxicity toward NPC CNE-1 (IC50 = 6.9) and CNE-2 (IC50 = 7.4) cells but minimally affected normal NP 69 cells. Further investigation disclosed that MCL induced apoptosis, DNA fragmentation, G1-phase arrest, and mitochondrial injury in both types of NPC cells. The reduction of cyclin D1 and phosphoretinoblastoma (Rb) protein expression contributed to arrest at G1-phase of the cell cycle. These events were associated with regulation of mitogen-activated protein kinases (MAPK; including p38 MAPK, JNK, and ERK) phosphorylation and promoted downstream nitric oxide (NO) production. Concurrent administration of the p38 MAPK inhibitor SB-203580 significantly diminished NO production and lethality of MCL toward NPC cells. Further studies revealed that MCL increased cytochrome c release into the cytosol, activated caspases-8, -9, and -3, and enhanced production of cleaved PARP, subsequently leading to DNA fragmentation and apoptosis. Finally, an intraperitoneal injection of MCL (1.0 mg/kg/d) led to an average of 45% remission of NPC xenograft tumors subcutaneously inoculated in nude mice. This is the first article that unveils the potential of a type II RIP, MCL, for prevention and therapy of NPC. Cancer Prev Res; 5(1); 109–21. ©2011 AACR.
Data from Adulthood Weight Change and Risk of Colorectal Cancer in the Nurses' Health Study and Health Professionals Follow-up Study
Authors: Song Mingyang , Hu Frank B. , Spiegelman Donna , Chan Andrew T. , Wu Kana , Ogino Shuji , Fuchs Charles S. , Willett Walter C. , Giovannucci Edward L.
Published: April 2023

Abstract
We investigated the association between adulthood weight change and colorectal cancer risk in a prospective study with 24 to 34 years of follow-up among 90,988 women and 46,679 men. The primary exposures included weight change from early adulthood (age = 18 years for women, 21 years for men) to baseline enrollment (median age = 43 years for women, 52 years for men), and from baseline to present. In the secondary analyses, we also assessed 4-year weight change during follow-up, and during premenopausal (from age 18 years to menopause) and postmenopausal (from menopause to present) periods in women. Compared to men maintaining their weight from age 21 to baseline, those who gained 20 kg or more were at a higher risk of colorectal cancer (relative risk [RR], 1.64; 95% confidence interval [CI], 1.15–2.35, Ptrend < 0.001), whereas those who lost 8 kg or more had a lower risk (RR, 0.61; 95% CI, 0.30–1.22, Ptrend = 0.003). Similar but weaker associations were found in women and the corresponding RRs were 1.38 (95% CI, 1.13–1.69, Ptrend < 0.001) and 0.80 (95% CI, 0.58–1.09, Ptrend = 0.21). Weight change from baseline to present was not associated with colorectal cancer risk. Four-year weight change during follow-up was positively associated with colorectal cancer risk in men (Ptrend = 0.03) but not in women (Ptrend = 0.42). In addition, in women, weight change before, but not after, menopause was associated with colorectal cancer risk. Our findings provide further scientific rationale for recommendations to maintain a healthy body weight during adulthood. A potential differential association according to sex and timing of weight change warrants further investigation. Cancer Prev Res; 8(7); 620–7. ©2015 AACR.
Data from Evaluation of Clinical Criteria for the Identification of Lynch Syndrome among Unselected Patients with Endometrial Cancer
Authors: Bruegl Amanda S. , Djordjevic Bojana , Batte Brittany , Daniels Molly , Fellman Bryan , Urbauer Diana , Luthra Rajyalakshmi , Sun Charlotte , Lu Karen H. , Broaddus Russell R.
Published: April 2023

Abstract
Clinical criteria, primarily young age of cancer onset and family history of signature cancers, have been developed to identify individuals at elevated risk for Lynch syndrome with the goals of early identification and cancer prevention. In 2007, the Society of Gynecologic Oncology (SGO)–codified criteria for women presenting with gynecologic cancers. These criteria have not been validated in a population-based setting. For 412 unselected endometrial cancers, immunohistochemical expression of DNA mismatch repair proteins and MLH1 methylation were assessed to classify tumors as sporadic or probable Lynch syndrome (PLS). In this cohort, 10.5% of patients were designated as PLS based on tumor testing. The sensitivity and specificity of the SGO criteria to identify these same cases were 32.6% [95% confidence interval (CI), 19.2–48.5] and 77% (95% CI, 72.7–81.8), respectively. With the exception of tumor location in the lower uterine segment, multivariate analysis of clinical features, family history, and pathologic variables failed to identify significant differences between the sporadic and PLS groups. A simplified cost-effectiveness analysis demonstrated that the SGO clinical criteria and universal tissue testing strategies had comparable costs per patient with PLS identified. In conclusion, the SGO criteria successfully identify PLS cases among women with endometrial cancer who are young or have significant family history of signature tumors. However, a larger proportion of patients with PLS who are older and have less significant family history are not detected by this screening strategy. Universal tissue testing may be necessary to capture more individuals at risk for having Lynch syndrome. Cancer Prev Res; 7(7); 686–97. ©2014 AACR.
Data from Estimating the Attributable Fraction for Cancer: A Meta-analysis of Nevi and Melanoma
Authors: Olsen Catherine M. , Carroll Heidi J. , Whiteman David C.
Published: April 2023

Abstract
Epidemiologic research has shown convincingly that certain phenotypic attributes are associated with increased relative risks of melanoma. Although such findings have intrinsic utility, there have been few attempts to translate such knowledge into estimates of disease burden suitable for framing public health policy. We aimed to estimate the population attributable fraction (PAF) for melanoma associated with melanocytic nevi using relative risk estimates derived from a systematic review and meta-analysis. We identified eligible studies using citation databases, followed by manual review of retrieved references. Of 49 studies identified, 25 and 23, respectively, were included in meta-analyses of atypical and common nevi. For people with ≥1 atypical nevi, the summary relative risk was 3.63 (95% confidence interval, 2.85-4.62), with a PAF of 0.25. The relative risk increased by 1.017 (95% confidence interval, 1.014-1.020) for each common nevus; however, significant heterogeneity in risk estimates was observed. We estimated that 42% of melanomas were attributable to having ≥25 common nevi (PAF 25-49 nevi = 0.15; PAF ≥50 nevi = 0.27), whereas PAFs for low nevus counts were modest (PAF 0-10 nevi = 0.04; PAF 11-24 nevi = 0.07). We modeled PAF under scenarios of varying nevus prevalence; the highest melanoma burden was always among those with high nevus counts (PAF range of 0.31-0.62 for ≥25 common nevi). Patients with ≥25 common nevi and/or ≥1 atypical nevi are a high-risk group, which might be targeted for identification, screening, and education. This work is the necessary first step in designing targeted preventive strategies for melanoma, which must now be overlaid with information about cost and utility. Cancer Prev Res; 3(2); 233–45
Data from Examination of Whole Blood DNA Methylation as a Potential Risk Marker for Gastric Cancer
Authors: Tahara Tomomitsu , Maegawa Shinji , Chung Woonbok , Garriga Judith , Jelinek Jaroslav , Estécio Marcos R.H. , Shibata Tomoyuki , Hirata Ichiro , Arisawa Tomiyasu , Issa Jean-Pierre J.
Published: April 2023

Abstract
Whole blood DNA methylation analysis has been proposed to be a risk marker for cancer that can be used to target patients for preventive interventions. To test this, we examined whole blood DNA methylation of 16 CpG island promoters and LINE1 repetitive element in patients with gastric cancer and control subjects. Bisulfite pyrosequencing was used to quantify the methylation of 14 CpG island promoters (MINT25, RORA, GDNF, CDH1, RARAB2, ER, CDH13, MYOD1, SFRP1, P2RX7, SLC16A12, IGF2, DPYS, and N33) and LINE1 from 72 patients with gastric cancer, 67 control, and 52 healthy young individuals. Quantitative methylation-specific real-time PCR was also conducted for 3 CpG island promoters (MINT25, MYO3A, and SOX11). Among all sites tested, only a marginal increase in the methylation of the SFRP1 promoter was observed in the blood of patients with gastric cancer when compared with the control group (11.3 % vs 10.5%; age-adjusted P value: P = 0.009), and this association was also seen in a validation set of 91 patients with gastric cancer (11.5% vs 10.5%; age-adjusted P value: P = 0.001). The methylation of 9 sites (GDNF, CDH1, RARAB2, CDH13, MYOD1, SFRP1, SLC16A12, DPYS, N33, and LINE1) and their mean Z score was correlated with higher age (R = 0.41, P < 0.0001) and marginally with telomere shortening (R = −0.18, P = 0.01) but not with gastric cancer risk (other than SFRP1 methylation). Variability in whole blood DNA methylation of cancer markers is primarily associated with aging, reflecting turnover of white blood cells, and has no direct link to gastric cancer predisposition. SFRP1 methylation in whole blood may be associated with gastric cancer risk. Cancer Prev Res; 6(10); 1093–100. ©2013 AACR.
Data from Gene Expression Changes in Adipose Tissue with Diet- and/or Exercise-Induced Weight Loss
Authors: Campbell Kristin L. , Foster-Schubert Karen E. , Makar Karen W. , Kratz Mario , Hagman Derek , Schur Ellen A. , Habermann Nina , Horton Marc , Abbenhardt Clare , Kuan Ling-Yu , Xiao Liren , Davison Jerry , Morgan Martin , Wang Ching-Yun , Duggan Catherine , McTiernan Anne , Ulrich Cornelia M.
Published: April 2023

Abstract
Adipose tissue plays a role in obesity-related cancers via increased production of inflammatory factors, steroid hormones, and altered adipokines. The impact of weight loss on adipose tissue gene expression may provide insights into pathways linking obesity with cancer risk. We conducted an ancillary study within a randomized trial of diet, exercise, or combined diet + exercise versus control among overweight/obese postmenopausal women. In 45 women, subcutaneous adipose tissue biopsies were conducted at baseline and after 6 months, and changes in adipose tissue gene expression were determined by microarray with an emphasis on prespecified candidate pathways as well as by unsupervised clustering of more than 37,000 transcripts (Illumina). Analyses were conducted first by randomization group and then by degree of weight change at 6-months in all women combined. At 6 months, diet, exercise, and diet + exercise participants lost a mean of 8.8, 2.5, and 7.9 kg (all P < 0.05 vs. no change in controls). There was no significant change in candidate gene expression by intervention group. In analysis by weight change category, greater weight loss was associated a decrease in 17β-hydroxysteroid dehydrogenase-1 (HSD17B1, Ptrend < 0.01) and leptin (LEP, Ptrend < 0.01) expression, and marginally significant increased expression of estrogen receptor-1 (ESR1, Ptrend = 0.08) and insulin-like growth factor–binding protein-3 (IGFBP3, Ptrend = 0.08). Unsupervised clustering revealed 83 transcripts with statistically significant changes. Multiple gene expression changes correlated with changes in associated serum biomarkers. Weight loss was associated with changes in adipose tissue gene expression after 6 months, particularly in two pathways postulated to link obesity and cancer, that is, steroid hormone metabolism and IGF signaling. Cancer Prev Res; 6(3); 217–31. ©2013 AACR.
Data from Orally Active Vitamin D for Potential Chemoprevention of Posttransplant Malignancy
Authors: Obi Yoshitsugu , Ichimaru Naotsugu , Hamano Takayuki , Tomida Kodo , Matsui Isao , Fujii Naohiko , Okumi Masayoshi , Kaimori Jun-ya , Yazawa Koji , Kokado Yukito , Tsubakihara Yoshiharu , Nonomura Norio , Rakugi Hiromi , Takahara Shiro , Isaka Yoshitaka
Published: April 2023

Abstract
Posttransplant malignancy (PTM) is a limiting factor both for patient and allograft survival in kidney transplant recipients (KTRs). We hypothesized that active vitamin D compounds (AVD) could reduce PTM development in KTRs. Ambulatory KTRs in a Japanese prospective cohort were followed from August 2007 to November 2010. The outcome of interest was newly diagnosed PTM. A propensity score (PS) of having received AVDs was estimated using 26 clinically relevant factors. We used the Cox proportional hazards model with stratification by PS tertiles on the assumption that baseline hazard functions differ among tertiles. As sensitivity analyses, we used inverse probability weighting and PS matching. Among 218 participants, the median age was 50 (interquartile range [IQR], 40 to 59) years, 63.3% were male, median time since transplantation was 11.2 (IQR, 5.2 to 17.1) years, and mean estimated GFR was 41.3 (SD, 15.6) mL/min per 1.73 m2. At baseline, 42.2% had been treated with AVDs mainly for glucocorticoid-induced osteoporosis. AVDs used were calcitriol (58.7%) and alfacalcidol (41.3%). During follow-up, PTM developed in 5.4% of 92 AVD users and 8.7% of 126 nonusers. Poor vitamin D status was common in the participants, but the serum 25-hydroxyvitamin D level was not significantly associated with PTM in Cox regression analysis. After stratifying patients by PS tertiles, we found that AVDs were significantly associated with a lower risk of PTM (HR 0.25 [0.07 to 0.82]). Sensitivity analyses yielded similar results. AVDs are potential chemopreventive agents against PTM in KTRs. Cancer Prev Res; 5(10); 1229–35. ©2012 AACR.
Data from Chemopreventive Effects of Dietary Eicosapentaenoic Acid Supplementation in Experimental Myeloid Leukemia
Authors: Finch Emily R. , Kudva Avinash K. , Quickel Michael D. , Goodfield Laura L. , Kennett Mary J. , Whelan Jay , Paulson Robert F. , Prabhu K. Sandeep
Published: April 2023

Abstract
Current therapies for treatment of myeloid leukemia do not eliminate leukemia stem cells (LSC), leading to disease relapse. In this study, we supplemented mice with eicosapentaenoic acid (EPA, C20:5), a polyunsaturated omega-3 fatty acid, at pharmacologic levels, to examine whether the endogenous metabolite, cyclopentenone prostaglandin delta-12 PGJ3 (Δ12-PGJ3), was effective in targeting LSCs in experimental leukemia. EPA supplementation for 8 weeks resulted in enhanced endogenous production of Δ12-PGJ3 that was blocked by indomethacin, a cyclooxygenase (COX) inhibitor. Using a murine model of chronic myelogenous leukemia (CML) induced by bone marrow transplantation of BCR-ABL–expressing hematopoietic stem cells, mice supplemented with EPA showed a decrease in the LSC population, and reduced splenomegaly and leukocytosis, when compared with mice on an oleic acid diet. Supplementation of CML mice carrying the T315I mutation (in BCR-ABL) with EPA resulted in a similar effect. Indomethacin blocked the EPA effect and increased the severity of BCR-ABL–induced CML and decreased apoptosis. Δ12-PGJ3 rescued indomethacin-treated BCR-ABL mice and decreased LSCs. Inhibition of hematopoietic-prostaglandin D synthase (H-PGDS) by HQL-79 in EPA-supplemented CML mice also blocked the effect of EPA. In addition, EPA supplementation was effective in a murine model of acute myeloid leukemia. EPA-supplemented mice exhibited a decrease in leukemia burden and a decrease in the LSC colony-forming unit (LSC-CFU). The decrease in LSCs was confirmed through serial transplantation assays in all disease models. The results support a chemopreventive role for EPA in myeloid leukemia, which is dependent on the ability to efficiently convert EPA to endogenous COX-derived prostanoids, including Δ12-PGJ3. Cancer Prev Res; 8(10); 989–99. ©2015 AACR.
Data from Frequency of Rearrangements in Lynch Syndrome Cases Associated with MSH2: Characterization of a New Deletion Involving both EPCAM and the 5′ Part of MSH2
Authors: Pérez-Cabornero Lucia , Sanz Mar Infante , Sampedro Eladio Velasco , Aras Enrique Lastra , Becares Alberto Acedo , Pino Cristina Miner , Domínguez Mercedes Durán
Published: April 2023

Abstract
Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch repair genes and leads to a high risk of colorectal and endometrial cancer. It was recently shown that constitutional 3′ end deletions of EPCAM could cause Lynch syndrome in tissues with MSH2 deficiency. We aim to establish the spectrum of mutations in MSH2-associated Lynch syndrome cases and their clinical implications. Probands from 159 families suspected of having Lynch syndrome were enrolled in the study. Immunohistochemistry and microsatellite instability (MSI) analyses were used on the probands of all families. Eighteen cases with MSH2 loss were identified: eight had point mutations in MSH2. In 10 Lynch syndrome families without MSH2 mutations, EPCAM-MSH2genomic rearrangement screening was carried out with the use of multiplex ligation–dependent probe amplification and reverse transcriptase PCR. We report that large germline deletions, encompassing one or more exons of the MSH2 gene, cosegregate with the Lynch syndrome phenotype in 23% (8 of 35) of MSI families tested. A new combined deletion EPCAM-MSH2 was identified and characterized by break point analysis, encompassing from the 3′ end region of EPCAM to the 5′ initial sequences of the MSH2 (c.859-1860_MSH2:646-254del). EPCAM-MSH2 fusion transcript was isolated. The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome. Cancer Prev Res; 4(10); 1556–62. ©2011 AACR.
Data from Autoantibody Signatures Combined with Epstein–Barr Virus Capsid Antigen-IgA as a Biomarker Panel for the Detection of Nasopharyngeal Carcinoma
Authors: Peng Yu-Hui , Xu Yi-Wei , Huang Li-Sheng , Zhai Tian-Tian , Dai Li-Hua , Qiu Si-Qi , Yang Yu-Su , Chen Wei-Zheng , Zhang Li-Qun , Li En-Min , Xu Li-Yan
Published: April 2023

Abstract
Nasopharyngeal carcinoma (NPC) is prevalent in Southern China and Southeast Asia, and autoantibody signatures may improve early detection of NPC. In this study, serum levels of autoantibodies against a panel of six tumor-associated antigens (p53, NY-ESO-1, MMP-7, Hsp70, Prx VI, and Bmi-1) and Epstein–Barr virus capsid antigen-IgA (VCA-IgA) were tested by enzyme-linked immunosorbent assay in a training set (220 NPC patients and 150 controls) and validated in a validation set (90 NPC patients and 68 controls). We used receiver-operating characteristics (ROC) to calculate diagnostic accuracy. ROC curves showed that use of these 6 autoantibody assays provided an area under curve (AUC) of 0.855 [95% confidence interval (CI), 0.818–0.892], 68.2% sensitivity, and 90.0% specificity in the training set and an AUC of 0.873 (95% CI, 0.821–0.925), 62.2% sensitivity, and 91.2% specificity in the validation set. Moreover, the autoantibody panel maintained diagnostic accuracy for VCA-IgA–negative NPC patients [0.854 (0.809–0.899), 67.8%, and 90.0% in the training set; 0.879 (0.815–0.942), 67.4%, and 91.2% in the validation set]. Importantly, combination of the autoantibody panel and VCA-IgA improved diagnostic accuracy for NPC versus controls compared with the autoantibody panel alone [0.911 (0.881–0.940), 81.4%, and 90.0% in the training set; 0.919 (0.878–0.959), 78.9%, and 91.2% in the validation set), as well as for early-stage NPC (0.944 (0.894–0.994), 87.9%, and 94.0% in the training set; 0.922 (0.808–1.000), 80.0%, and 92.6% in the validation set]. These results reveal autoantibody signatures in an optimized panel that could improve the identification of VCA-IgA–negative NPC patients, may aid screening and diagnosis of NPC, especially when combined with VCA-IgA. Cancer Prev Res; 8(8); 729–36. ©2015 AACR.
Data from Involvement of Epigenetics and EMT-Related miRNA in Arsenic-Induced Neoplastic Transformation and Their Potential Clinical Use
Authors: Michailidi Christina , Hayashi Masamichi , Datta Sayantan , Sen Tanusree , Zenner Kaitlyn , Oladeru Oluwadamilola , Brait Mariana , Izumchenko Evgeny , Baras Alexander , VandenBussche Christopher , Argos Maria , Bivalacqua Trinity J. , Ahsan Habibul , Hahn Noah M. , Netto George J. , Sidransky David , Hoque Mohammad Obaidul
Published: April 2023

Abstract
Exposure to toxicants leads to cumulative molecular changes that overtime increase a subject's risk of developing urothelial carcinoma. To assess the impact of arsenic exposure at a time progressive manner, we developed and characterized a cell culture model and tested a panel of miRNAs in urine samples from arsenic-exposed subjects, urothelial carcinoma patients, and controls. To prepare an in vitro model, we chronically exposed an immortalized normal human bladder cell line (HUC1) to arsenic. Growth of the HUC1 cells was increased in a time-dependent manner after arsenic treatment and cellular morphology was changed. In a soft agar assay, colonies were observed only in arsenic-treated cells, and the number of colonies gradually increased with longer periods of treatment. Similarly, invaded cells in an invasion assay were observed only in arsenic-treated cells. Withdrawal of arsenic treatment for 2.5 months did not reverse the tumorigenic properties of arsenic-treated cells. Western blot analysis demonstrated decreased PTEN and increased AKT and mTOR in arsenic-treated HUC1 cells. Levels of miR-200a, miR-200b, and miR-200c were downregulated in arsenic-exposed HUC1 cells by quantitative RT-PCR. Furthermore, in human urine, miR-200c and miR-205 were inversely associated with arsenic exposure (P = 0.005 and 0.009, respectively). Expression of miR-205 discriminated cancer cases from controls with high sensitivity and specificity (AUC = 0.845). Our study suggests that exposure to arsenic rapidly induces a multifaceted dedifferentiation program and miR-205 has potential to be used as a marker of arsenic exposure as well as a maker of early urothelial carcinoma detection. Cancer Prev Res; 8(3); 208–21. ©2015 AACR.
Data from Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin
Authors: Bermudez Yira , Stratton Steven P. , Curiel-Lewandrowski Clara , Warneke James , Hu Chengcheng , Bowden George T. , Dickinson Sally E. , Dong Zigang , Bode Ann M. , Saboda Kathylynn , Brooks Christine A. , Petricoin Emanuel F. , Hurst Craig A. , Alberts David S. , Einspahr Janine G.
Published: April 2023

Abstract
The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers. Cancer Prev Res; 8(8); 720–8. ©2015 AACR.
Data from Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model
Authors: Mazzilli Sarah A. , Hershberger Pamela A. , Reid Mary E. , Bogner Paul N. , Atwood Kristopher , Trump Donald L. , Johnson Candace S.
Published: April 2023

Abstract
The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2,000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C; 80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N). After treatment with 15 μmol NTCU, the percentages of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D–deficient + NTCU (DN), 22.7% [P < 0.05 compared with vitamin D–sufficient +NTCU (SN)]; DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared with SN mice, DN mice exhibited a three-fold increase (P < 0.005) in circulating white blood cells (WBC), a 20% (P < 0.05) increase in IL6 levels, and a four-fold (P < 0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted. Cancer Prev Res; 8(10); 895–904. ©2015 AACR.
Data from Effects of Pubertal Exposure to Dietary Soy on Estrogen Receptor Activity in the Breast of Cynomolgus Macaques
Authors: Dewi Fitriya N. , Wood Charles E. , Willson Cynthia J. , Register Thomas C. , Lees Cynthia J. , Howard Timothy D. , Huang Zhiqing , Murphy Susan K. , Tooze Janet A. , Chou Jeff W. , Miller Lance D. , Cline J. Mark
Published: April 2023

Abstract
Endogenous estrogens influence mammary gland development during puberty and breast cancer risk during adulthood. Early-life exposure to dietary or environmental estrogens may alter estrogen-mediated processes. Soy foods contain phytoestrogenic isoflavones (IF), which have mixed estrogen agonist/antagonist properties. Here, we evaluated mammary gland responses over time in pubertal female cynomolgus macaques fed diets containing either casein/lactalbumin (n = 12) or soy protein containing a human-equivalent dose of 120 mg IF/day (n = 17) for approximately 4.5 years spanning menarche. We assessed estrogen receptor (ER) expression and activity, promoter methylation of ERs and their downstream targets, and markers of estrogen metabolism. Expression of ERα and classical ERα response genes (TFF1, PGR, and GREB1) decreased with maturity, independent of diet. A significant inverse correlation was observed between TFF1 mRNA and methylation of CpG sites within the TFF1 promoter. Soy effects included lower ERβ expression before menarche and lower mRNA for ERα and GREB1 after menarche. Expression of GATA-3, an epithelial differentiation marker that regulates ERα-mediated transcription, was elevated before menarche and decreased after menarche in soy-fed animals. Soy did not significantly alter expression of other ER activity markers, estrogen-metabolizing enzymes, or promoter methylation for ERs or ER-regulated genes. Our results demonstrate greater ER expression and activity during the pubertal transition, supporting the idea that this life stage is a critical window for phenotypic modulation by estrogenic compounds. Pubertal soy exposure decreases mammary ERα expression after menarche and exerts subtle effects on receptor activity and mammary gland differentiation. Cancer Prev Res; 9(5); 385–95. ©2016 AACR.
Data from Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Postmenopausal Women
Authors: Fabian Carol J. , Kimler Bruce F. , Phillips Teresa A. , Nydegger Jennifer L. , Kreutzjans Amy L. , Carlson Susan E. , Hidaka Brandon H. , Metheny Trina , Zalles Carola M. , Mills Gordon B. , Powers Kandy R. , Sullivan Debra K. , Petroff Brian K. , Hensing Whitney L. , Fridley Brooke L. , Hursting Stephen D.
Published: April 2023

Abstract
Associational studies suggest higher intakes/blood levels of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) are associated with reduced breast cancer risk. We performed a pilot study of high-dose EPA + DHA in postmenopausal women to assess feasibility before initiating a phase IIB prevention trial. Postmenopausal women with cytologic evidence of hyperplasia in their baseline random periareolar fine needle aspiration (RPFNA) took 1,860 mg EPA +1500 mg DHA ethyl esters daily for 6 months. Blood and breast tissue were sampled at baseline and study conclusion for exploratory biomarker assessment, with P values uncorrected for multiple comparisons. Feasibility was predefined as 50% uptake, 80% completion, and 70% compliance. Trial uptake by 35 study entrants from 54 eligible women was 65%, with 97% completion and 97% compliance. Favorable modulation was suggested for serum adiponectin (P = 0.0027), TNFα (P = 0.016), HOMA 2B measure of pancreatic β cell function (P = 0.0048), and bioavailable estradiol (P = 0.039). Benign breast tissue Ki-67 (P = 0.036), macrophage chemoattractant protein-1 (P = 0.033), cytomorphology index score (P = 0.014), and percent mammographic density (P = 0.036) were decreased with favorable effects in a proteomics array for several proteins associated with mitogen signaling and cell-cycle arrest; but no obvious overall effect on proteins downstream of mTOR. Although favorable risk biomarker modulation will need to be confirmed in a placebo-controlled trial, we have demonstrated feasibility for development of high-dose EPA and DHA ethyl esters for primary prevention of breast cancer. Cancer Prev Res; 8(10); 922–31. ©2015 AACR.

See related article, p. 912.
Data from Enhanced Antitumor Effects of Novel Intracellular Delivery of an Active Form of Menaquinone-4, Menahydroquinone-4, into Hepatocellular Carcinoma
Authors: Setoguchi Shuichi , Watase Daisuke , Matsunaga Kazuhisa , Matsubara Misa , Kubo Yohei , Kusuda Mariko , Nagata-Akaho Nami , Enjoji Munechika , Nakashima Manabu , Takeshita Morishige , Karube Yoshiharu , Takata Jiro
Published: April 2023

Abstract
Reduced cellular uptake of menaquinone-4 (MK-4), a vitamin K2 homolog, in human hepatocellular carcinoma (HCC) limits its usefulness as a safe long-term antitumor agent for recurrent HCC and produces des-γ-carboxy prothrombin (DCP). We hypothesized that effective delivery of menahydroquinone-4 (MKH), the active form of MK-4 for γ-glutamyl carboxylation, into HCC cells is critical for regulating HCC growth, and may enable it to be applied as a safe antitumor agent. In this study, we verified this hypothesis using menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of MKH, and demonstrated its effectiveness. Intracellular delivery of MKH and subsequent growth inhibition of PLC/PRF/5 and Hep3B (DCP-positive) and SK-Hep-1 (DCP-negative) cells after MKH-DMG administration were determined and compared with MK-4. The activity of MKH-DMG against tumor progression in the liver alongside DCP formation was determined in a spleen–liver metastasis mouse model. MKH-DMG exhibited greater intracellular delivery of MKH in vitro (AUC0–72 hour of MKH) and increased growth-inhibitory activity against both DCP-positive and DCP-negative HCC cell lines. The phenomena of MKH delivery into cells in parallel with simultaneous growth inhibition suggested that MKH is the active form for growth inhibition of HCC cells. Cell-cycle arrest was determined to be involved in the growth inhibition mechanisms of MKH-DMG. Furthermore, MKH-DMG showed significant inhibition of tumor progression in the liver, and a substantial decrease in plasma DCP levels in the spleen–liver metastasis mouse model. Our results suggest that MKH-DMG is a promising new candidate antitumor agent for safe long-term treatment of HCC. Cancer Prev Res; 8(2); 129–38. ©2014 AACR.
Data from Selecting High-Risk Individuals for Lung Cancer Screening: A Prospective Evaluation of Existing Risk Models and Eligibility Criteria in the German EPIC Cohort
Authors: Li Kuanrong , Hüsing Anika , Sookthai Disorn , Bergmann Manuela , Boeing Heiner , Becker Nikolaus , Kaaks Rudolf
Published: April 2023

Abstract
Lung cancer risk prediction models are considered more accurate than the eligibility criteria based on age and smoking in identification of high-risk individuals for screening. We externally validated four lung cancer risk prediction models (Bach, Spitz, LLP, and PLCOM2012) among 20,700 ever smokers in the EPIC-Germany cohort. High-risk subjects were identified using the eligibility criteria applied in clinical trials (NELSON/LUSI, DLCST, ITALUNG, DANTE, and NLST) and the four risk prediction models. Sensitivity, specificity, and positive predictive value (PPV) were calculated based on the lung cancers diagnosed in the first 5 years of follow-up. Decision curve analysis was performed to compare net benefits. The number of high-risk subjects identified by the eligibility criteria ranged from 3,409 (NELSON/LUSI) to 1,458 (NLST). Among the eligibility criteria, the DLCST produced the highest sensitivity (64.13%), whereas the NLST produced the highest specificity (93.13%) and PPV (2.88%). The PLCOM2012 model showed the best performance in external validation (C-index: 0.81; 95% CI, 0.76–0.86; E/O: 1.03; 95% CI, 0.87–1.23) and the highest sensitivity, specificity, and PPV, but the superiority over the Bach model and the LLP model was modest. All the models but the Spitz model showed greater net benefit over the full range of risk estimates than the eligibility criteria. We concluded that all of the lung cancer risk prediction models apart from the Spitz model have a similar accuracy to identify high-risk individuals for screening, but in general outperform the eligibility criteria used in the screening trials. Cancer Prev Res; 8(9); 777–85. ©2015 AACR.
Data from Prevention of Tobacco Carcinogen-Induced Lung Tumor Development by a Novel STAT3 Decoy Inhibitor
Authors: Njatcha Christian , Farooqui Mariya , Almotlak Abdulaziz A. , Siegfried Jill M.
Published: April 2023

Abstract
The STAT3 pathway is frequently overactive in non–small cell lung cancer (NSCLC), an often fatal disease with known risk factors including tobacco and chemical exposures. Whether STAT3 can be downmodulated to delay or prevent development of lung cancer resulting from an environmental exposure has not been previously tested. A circular oligonucleotide STAT3 decoy (CS3D) was used to treat mice previously exposed to the tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. CS3D contains a double-stranded STAT3 DNA response element sequence and interrupts STAT3 signaling by binding to STAT3 dimers, rendering them unable to initiate transcription at native STAT3 DNA binding sites. An intermittent course of CS3D decreased the development of airway preneoplasias by 42% at 1 week posttreatment, reduced the progression of preneoplasia to adenomas by 54% at 8 weeks posttreatment, and reduced the size and number of resulting lung tumors by 49.7% and 29.5%, respectively, at 20 weeks posttreatment. No toxicity was detected. A mutant cyclic oligonucleotide with no STAT3 binding ability was used as a control. Chemopreventive effects were independent of the KRAS mutational status of the tumors. In lungs harvested during and after the treatment course with CS3D, airway preneoplasias had reduced STAT3 signaling. Chemopreventive effects were accompanied by decreased VEGFA expression, ablated IL6, COX-2, and p-NF-κB, and decreased pulmonary M2 macrophages and myeloid-derived suppressor cells. Thus, downmodulation of STAT3 activity using a decoy molecule both reduced oncogenic signaling in the airway epithelium and favored a lung microenvironment with reduced immunosuppression.
Data from Breast Cancer Characteristics and Survival among Users versus Nonusers of Raloxifene
Authors: Pinsky Paul F. , Miller Eric A. , Heckman-Stoddard Brandy M. , Minasian Lori
Published: April 2023

Abstract
Raloxifene reduces breast cancer incidence. However, it is unclear whether it also reduces mortality from breast cancer. For raloxifene to reduce incidence but not mortality, breast cancer survival would have to be worse for raloxifene users than nonusers. Surveillance Epidemiology and End Results-Medicare was used to identify women with invasive breast cancer diagnosed from 2007 to 2015 at ages 65–89 who had prior Medicare Part D (prescription drug) enrollment; breast cancer characteristics and survival were assessed among raloxifene regular users (≥180 days in past year) versus nonusers. Logistic regression was used to assess cancer characteristics. Two methods utilizing proportional hazards models were employed to assess breast cancer–specific survival. In method 1, survival was assessed adjusting for demographics, mammography use, and chronic conditions in the subset with Medicare fee-for-service enrollment. In method 2, predicted survival as a function of breast cancer characteristics was modeled in nonusers and the model applied to users to predict survival. A total of 116,317 raloxifene nonusers and 1,223 regular users were identified. Users were significantly more likely to have hormone receptor (HR)-negative cancers, but less likely to have T2+, N1+, and metastatic disease. There were 10,869 and 101 breast cancer–related deaths in nonusers and regular users, respectively. The HR (users vs. nonusers) for breast cancer–specific survival in method 1 was 0.94 (95% confidence interval, 0.73–1.22). In method 2, predicted survival was higher in users than nonusers (8-year survival 84.9% vs. 83.4%). Breast cancer–specific survival in raloxifene users was not worse than in nonusers, providing indirect evidence that raloxifene reduces breast cancer–related mortality.
Data from Hallmark Circulating Tumor-Associated Cell Clusters Signify 230 Times Higher One-Year Cancer Risk
Authors: Ranade Anantbhushan , Bhatt Amit , Page Raymond , Limaye Sewanti , Crook Timothy , Akolkar Dadasaheb , Patil Darshana
Published: April 2023

Abstract
We have previously shown that circulating ensembles of tumor-associated cells (C-ETACs) are a systemic hallmark of cancer based on analysis of blood samples from 16,134 individuals including 10,625 asymptomatic individuals and 5,509 diagnosed cases of cancer. C-ETACs were ubiquitously (90%) detected across all cancer types and were rare (3.6%) among the asymptomatic population. Consequently, we hypothesized that asymptomatic individuals with detectable C-ETACs would have a definitively elevated risk of developing cancer as compared with individuals without C-ETACs. In the present manuscript we present 1-year follow-up data of the asymptomatic cohort which shows that C-ETAC positive individuals have a 230-fold (P < 0.00001) higher 1-year cancer risk as compared with individuals where C-ETACs were undetectable. Simultaneously, we also expanded the study to include 4,419 symptomatic individuals, suspected of cancer, prior to undergoing an invasive biopsy for diagnosis. C-ETACs were detected in 4,101 (92.8%) of these 4,419 cases where cancer was eventually confirmed. We conclude that detection of C-ETACs can identify patients at risk of cancer and can be reliably used to stratify asymptomatic individuals with an elevated 1-year risk of cancer.
Prevention Relevance:
The study evaluated a blood test that can determine if healthy (‘asymptomatic’) individuals without a history of cancer have an increased risk of developing cancer within the next one year. This test can significantly minimize radiological or invasive screening in the majority individuals who do not have any increased risk.
Data from Phase I Dose Escalation Study of Topical Bexarotene in Women at High Risk for Breast Cancer
Authors: Thomas Parijatham S. , Patel Anisha B. , Lee J. Jack , Liu Diane D. , Hernandez Mike , Muzzio Miguel , Contreras Alejandro , Sepeda Valerie , Mays Carrie , Weber Diane , Vornik Lana A. , Khan Seema A. , Dimond Eileen , Heckman-Stoddard Brandy M. , Perloff Marjorie , Brown Powel H.
Published: April 2023

Abstract
Agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene significantly reduced mammary tumor development in preclinical mouse models. Oral bexarotene in BRCA mutation carriers significantly decreased cyclin D1 in breast cells, suggesting biological activity on breast tissue. This study evaluated topical bexarotene 1% gel applied to one unaffected breast in women at high risk for breast cancer for 4 weeks to assess safety and toxicity. Secondary objectives included assessment of bexarotene concentrations in the plasma and breast tissue. In the dose escalation phase, women were assigned to one of three different dose levels: 10 mg (1 mL) every other day, 10 mg (1 mL) daily, 20 mg (2 mL) daily. Dose-limiting toxicity (DLT) was defined as a grade 2 skin adverse event for at least 6 days or any grade 3 or 4 adverse event related to study drug. A total of 14 women were enrolled with 10 participants at the every other day dose level and 4 participants at daily dosing. Two skin DLTs were experienced at daily dosing and therefore further enrollment was discontinued per protocol. An additional 10 participants were enrolled at the MTD as part of the dose expansion phase. These individuals tolerated the treatment with minimal adverse events. Maculopapular rash at the treatment site was the most common adverse event related to study drug and resolved within a few days of discontinuation. Bexarotene was detectable in breast tissue at the 10 mg daily every other day dose.
Prevention Relevance:
Bexarotene is a rexinoid that has been shown to prevent mammary tumors in mouse models but oral dosing has toxicities. This phase I study evaluates topical bexarotene, as a potential chemoprevention agent, for safety and toxicity in high-risk women for breast cancer.