bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Prediction Model for Lung Cancer Diagnosis that Integrates Genomic and Clinical Features
Authors: Beane Jennifer , Sebastiani Paola , Whitfield Theodore H. , Steiling Katrina , Dumas Yves-Martine , Lenburg Marc E. , Spira Avrum
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer death due, in part, to lack of early diagnostic tools. Bronchoscopy represents a relatively noninvasive initial diagnostic test in smokers with suspect disease, but it has low sensitivity. We have reported a gene expression profile in cytologically normal large airway epithelium obtained via bronchoscopic brushings, which is a sensitive and specific biomarker for lung cancer. Here, we evaluate the independence of the biomarker from other clinical risk factors and determine the performance of a clinicogenomic model that combines clinical factors and gene expression.

Training (n = 76) and test (n = 62) sets consisted of smokers undergoing bronchoscopy for suspicion of lung cancer at five medical centers. Logistic regression models describing the likelihood of having lung cancer using the biomarker, clinical factors, and these data combined were tested using the independent set of patients with nondiagnostic bronchoscopies. The model predictions were also compared with physicians' clinical assessment.

The gene expression biomarker is associated with cancer status in the combined clinicogenomic model (P < 0.005). There is a significant difference in performance of the clinicogenomic relative to the clinical model (P < 0.05). In the test set, the clinicogenomic model increases sensitivity and negative predictive value to 100% and results in higher specificity (91%) and positive predictive value (81%) compared with other models. The clinicogenomic model has high accuracy where physician assessment is most uncertain.

The airway gene expression biomarker provides information about the likelihood of lung cancer not captured by clinical factors, and the clinicogenomic model has the highest prediction accuracy. These findings suggest that use of the clinicogenomic model may expedite more invasive testing and definitive therapy for smokers with lung cancer and reduce invasive diagnostic procedures for individuals without lung cancer.
Data from Early Changes in Pulmonary Gene Expression following Tobacco Exposure Shed Light on the Role of Estrogen Metabolism in Lung Carcinogenesis
Authors: Siegfried Jill M.
Published: March 2024

Abstract
This perspective on Meireles et al. (beginning on p. 707 in this issue of the journal) discusses the increasing evidence for the role of female steroid hormones in lung cancer development and progression. The novel work of Meireles et al. is the first evidence for the rapid upregulation by tobacco smoke of a key cytochrome P450 gene that can metabolize estrogens such as β-estradiol to potentially carcinogenic catechol and quinine forms, as well as the first evidence for the colocalization of β-estradiol and estrogen receptors in murine airway epithelium. Actions of estrogens that contribute to lung carcinogenesis, especially in the presence of tobacco smoke, may involve both reactive intermediates that damage DNA and steroid hormone receptor signaling that promotes growth. Cancer Prev Res; 3(6); 692–5. ©2010 AACR.
Data from Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention
Authors: Lucia M. Scott , Darke Amy K. , Goodman Phyllis J. , La Rosa Francisco G. , Parnes Howard L. , Ford Leslie G. , Coltman Charles A. , Thompson Ian M.
Published: March 2024

Abstract
The Prostate Cancer Prevention Trial (PCPT) showed a risk of prostate cancer at prostate-specific antigen (PSA) <4.0 ng/mL and that prostate cancer risk is reduced by finasteride. A major concern about early detection by PSA and prevention by finasteride is that they may involve biologically inconsequential tumors. We reviewed the pathologic characteristics of prostate biopsies from men in the placebo and finasteride groups of the PCPT. We examined tumor pathology characteristics stratified by level of PSA for men in the placebo group who underwent radical prostatectomy. Seventy-five percent of all cancers and 62% of Gleason score ≤6 cancers in the PCPT met the biopsy criteria for clinically significant tumors. Surrogate measures for tumor volume (number of cores positive, percent cores positive, linear extent, and bilaterality) and risk of perineural invasion were lower in men who received finasteride. The PSA-associated risks of insignificant cancer were 51.7% (PSA, 0-1.0 ng/mL), 33.7% (1.1-2.5 ng/mL), 17.8% (2.6-4.0 ng/mL), and 11.7% (4.1-10 ng/mL). Conversely, the risks of high-grade (Gleason score ≥7) tumors for the same PSA strata were 15.6%, 37.9%, 49.1%, and 52.4%, respectively. These data highlight the dilemma of PSA when used for screening: Lower cutoff levels increase detection of insignificant disease, but cure is more likely, whereas higher cutoff levels make detection of significant cancer more likely, but cure is less likely. Therefore, the effectiveness of finasteride in preventing prostate cancer, including Gleason score ≤6 cancer, with meaningful rates of significant disease in the PCPT suggests that cutoff values for PSA screening should be individualized and that men undergoing screening should be informed of the opportunity to reduce their risk of disease with finasteride.
Data from Reduction of Ovarian and Oviductal Cancers in Calorie-Restricted Laying Chickens
Authors: Carver Donna K. , Barnes H. John , Anderson Kenneth E. , Petitte James N. , Whitaker Regina , Berchuck Andrew , Rodriguez Gustavo C.
Published: March 2024

Abstract
Epithelial ovarian cancer (OVAC) remains a highly lethal malignancy. It is a leading cause of cancer deaths among women in the United States causing more deaths than all other gynecologic malignancies combined. The pathogenesis of OVAC is not completely understood, but the process of repeated ovulation is believed to lead to genetic damage in the ovarian epithelium. As part of a prospective trial designed to evaluate OVAC chemopreventive strategies using the chicken model, caloric restriction (55% less energy) was used to inhibit ovulation in groups of hens receiving chemopreventives, thereby minimizing the impact of ovulation on the incidence of reproductive tract cancer. A separate group of chickens was maintained concurrently in the same environment, and managed similarly, except that caloric intake was not restricted. Among birds not receiving chemopreventive agents, we compared caloric versus noncaloric restricted birds to determine the relations between calorie restriction and risk of developing adenocarcinoma of the reproductive tract. Mortality in the calorie-restricted group was almost half that of those on full feed. Calorie-restricted chickens maintained body weights averaging 1.423 kg compared with the full-fed birds at 1.892 kg. Ovulation rate varied with the full-fed group producing 64% more eggs than the calorie-restricted group. Total reproductive cancers occurred in 57 (33.3%) birds for the full-fed group and 26 (10.3%) birds for the calorie-restricted group. On the basis of histopathology, 45 (26.3%) birds in the full-fed group had ovarian adenocarcinoma compared with 16 (6.3%) birds in the calorie-restricted group. Calorie restriction in laying hens resulted in a near five-fold reduction in OVAC. Cancer Prev Res; 4(4); 562–7. ©2011 AACR.
Data from Identification of Actively Translated mRNA Transcripts in a Rat Model of Early-Stage Colon Carcinogenesis
Authors: Davidson Laurie A. , Wang Naisyin , Ivanov Ivan , Goldsby Jennifer , Lupton Joanne R. , Chapkin Robert S.
Published: March 2024

Abstract
With respect to functional mapping of gene expression signatures, the steady-state mRNA expression level does not always accurately reflect the status of critical signaling proteins. In these cases, control is exerted at the epigenetic level of recruitment of mRNAs to polysomes, the factories of ribosomes that mediate efficient translation of many cellular messages. However, to date, a genome-wide perspective of the effect of carcinogen and chemoprotective bioactive diets on actively translated (polysomal) mRNA populations has not been done. Therefore, we used an established colon cancer model, i.e., the azoxymethane (AOM)-treated rat, in combination with a chemoprotective diet extensively studied in our laboratory, i.e., n-3 polyunsaturated fatty acids, to characterize the molecular processes underlying the transformation of normal colonic epithelium. The number of genes affected by AOM treatment 10 weeks after carcinogen injection was significantly greater in the polysome RNA fraction compared with the total RNA fraction as determined using a high-density microarray platform. In particular, polysomal loading patterns of mRNAs associated with the Wnt-β catenin, phospholipase A2-eicosanoid and the mitogen-activated protein kinase signaling axes were significantly upregulated at a very early period of tumor development in the colon. These data indicate that translational alterations are far more extensive relative to transcriptional alterations in mediating malignant transformation. In contrast, transcriptional alterations were found to be more extensive relative to translational alterations in mediating the effects of diet. Therefore, during early stage colonic neoplasia, diet and carcinogen seem to predominantly regulate gene expression at multiple levels via unique mechanisms.
Data from Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor–Negative Breast Cancer
Authors: Crew Katherine D. , Brown Powel , Greenlee Heather , Bevers Therese B. , Arun Banu , Hudis Clifford , McArthur Heather L. , Chang Jenny , Rimawi Mothaffar , Vornik Lana , Cornelison Terri L. , Wang Antai , Hibshoosh Hanina , Ahmed Aqeel , Terry Mary Beth , Santella Regina M. , Lippman Scott M. , Hershman Dawn L.
Published: March 2024

Abstract
Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor–negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. Cancer Prev Res; 5(9); 1144–54. ©2012 AACR.
Data from Effects of Physical Activity and Restricted Energy Intake on Chemically Induced Mammary Carcinogenesis
Authors: Jiang Weiqin , Zhu Zongjian , Thompson Henry J.
Published: March 2024

Abstract
In the field of energetics and cancer, little attention has been given to whether energy balance directed interventions designed to regulate body weight by increasing energy expenditure versus reducing energy intake have an equivalent effect on the development of breast cancer. The objective of this experiment was to determine the effects on mammary carcinogenesis of physical activity (PA), achieved via running on an activity wheel, or restricted energy intake (RE). Food intake of PA and RE rats was controlled so that both groups had the same net energy balance determined by growth rate, which was 92% of the sedentary control group (SC). A total of 135 female Sprague-Dawley rats were injected with 1-methyl-1-nitrosourea (50 mg/kg) and 7 days thereafter were randomized to either SC, PA, or RE. Mammary cancer incidence was 97.8%, 88.9%, and 84.4% and cancer multiplicity was 3.66, 3.11, and 2.64 cancers/rat in SC, RE, and PA, respectively (SC versus PA, P = 0.02 for incidence and P = 0.03 for multiplicity). Analyses of mammary carcinomas revealed that cell proliferation–associated proteins were reduced and caspase-3 activity and proapoptotic proteins were elevated by PA or RE relative to SC (P < 0.05). It was observed that these effects may be mediated, in part, by activation of AMP-activated protein kinase and down-regulation of protein kinase B and the mammalian target of rapamycin.
Data from Effects of Chlorophyll and Chlorophyllin on Low-Dose Aflatoxin B1 Pharmacokinetics in Human Volunteers
Authors: Jubert Carole , Mata John , Bench Graham , Dashwood Roderick , Pereira Cliff , Tracewell William , Turteltaub Kenneth , Williams David , Bailey George
Published: March 2024

Abstract
Chlorophyll (Chla) and chlorophyllin (CHL) were shown previously to reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings were partially extended to humans, where CHL reduced excretion of aflatoxin B1 (AFB1)-DNA repair products in Chinese unavoidably exposed to dietary AFB1. However, neither AFB1 pharmacokinetics nor Chla effects were examined. We conducted an unblinded crossover study to establish AFB1 pharmacokinetic parameters among four human volunteers, and to explore possible effects of CHL or Chla cotreatment in three of those volunteers. For protocol 1, fasted subjects received an Institutional Review Board–approved dose of 14C-AFB1 (30 ng, 5 nCi) by capsule with 100 mL water, followed by normal eating and drinking after 2 hours. Blood and cumulative urine samples were collected over 72 hours, and 14C- AFB1 equivalents were determined by accelerator mass spectrometry. Protocols 2 and 3 were similar except capsules also contained 150 mg of purified Chla or CHL, respectively. Protocols were repeated thrice for each volunteer. The study revealed rapid human AFB1 uptake (plasma ka, 5.05 ± 1.10 h−1; Tmax, 1.0 hour) and urinary elimination (95% complete by 24 hours) kinetics. Chla and CHL treatment each significantly impeded AFB1 absorption and reduced Cmax and AUCs (plasma and urine) in one or more subjects. These initial results provide AFB1 pharmacokinetic parameters previously unavailable for humans, and suggest that Chla or CHL co-consumption may limit the bioavailability of ingested aflatoxin in humans, as they do in animal models.
Data from Growth Inhibition and Regression of Lung Tumors by Silibinin: Modulation of Angiogenesis by Macrophage-Associated Cytokines and Nuclear Factor-κB and Signal Transducers and Activators of Transcription 3
Authors: Tyagi Alpna , Singh Rana P. , Ramasamy Kumaraguruparan , Raina Komal , Redente Elizabeth F. , Dwyer-Nield Lori D. , Radcliffe Richard A. , Malkinson Alvin M. , Agarwal Rajesh
Published: March 2024

Abstract
The latency period for lung tumor progression offers a window of opportunity for therapeutic intervention. Herein, we studied the effect of oral silibinin (742 mg/kg body weight, 5 d/wk for 10 weeks) on the growth and progression of established lung adenocarcinomas in A/J mice. Silibinin strongly decreased both tumor number and tumor size, an antitumor effect that correlates with reduced antiangiogenic activity. Silibinin reduced microvessel size (50%, P < 0.01) with no change in the number of tumor microvessels and reduced (by 30%, P < 0.05) the formation of nestin-positive microvessels in tumors. Analysis of several proteins involved in new blood vessel formation showed that silibinin decreased the tumor expression of interleukin-13 (47%) and tumor necrosis factor-α (47%), and increased tissue inhibitor of metalloproteinase-1 (2-fold) and tissue inhibitor of metalloproteinase-2 (7-fold) expression, without significant changes in vascular endothelial growth factor levels. Hypoxia- inducible factor-1α expression and nuclear localization were also decreased by silibinin treatment. Cytokines secreted by tumor cells and tumor-associated macrophages regulate angiogenesis by activating nuclear factor-κB (NF-κB) and signal transducers and activators of transcription (STAT). Silibinin decreased the phosphorylation of p65NF-κB (ser276, 38%; P < 0.01) and STAT-3 (ser727, 16%; P < 0.01) in tumor cells and decreased the lung macrophage population. Angiopoietin-2 (Ang-2) and Ang-receptor tyrosine kinase (Tie-2) expression were increased by silibinin. Therapeutic efficacy of silibinin in lung tumor growth inhibition and regression by antiangiogenic mechanisms seem to be mediated by decreased tumor-associated macrophages and cytokines, inhibition of hypoxia-inducible factor-1α, NF-κB, and STAT-3 activation, and up-regulation of the angiogenic inhibitors, Ang-2 and Tie-2.
Data from Prevalence of Cervical Human Papillomavirus (HPV) Infection in Vanuatu
Authors: Aruhuri Bernadette , Tarivonda Len , Tenet Vanessa , Sinha Rohit , Snijders Peter J.F. , Clifford Gary , Pang James , McAdam Margaret , Meijer Chris J.L.M. , Frazer Ian H. , Franceschi Silvia
Published: March 2024

Abstract
To provide information on human papillomavirus (HPV) prevalence and the distribution of individual HPV types in Pacific Islands, we conducted a population-based survey in Vanuatu, South Pacific. Nine hundred and eighty-seven women between 18 and 64 years of age were included. GP5+/6+-mediated PCR assay was used for HPV testing. The prevalence of 44 HPV types was 28.4% corresponding to an age (world)-standardized prevalence of 25.0% [95% confidence interval (CI), 21.9%–28.0%]. The prevalence of high-risk (HR) HPV types was 21.7% (age-standardized prevalence of 19.2%; 95% CI, 16.4%–22.0%). Among 840 women with adequate cytologic results, 13.6% showed cervical abnormalities, including 3.6% with high-grade squamous intraepithelial lesions (HSIL) and 0.8% with invasive cervical carcinoma. HPV prevalence declined from 46.1% in women aged ≤21 to 15.3% in those ≥45 years. Being single was significantly associated with HPV positivity. HR HPV findings by PCR assay and hybrid capture 2 (HC2; conducted in Vanuatu) were moderately correlated (κ test = 0.59). The positive predictive values of HR HPV positivity for HSIL or worse were 27.6% for PCR and 35.2% for HC2 among women aged ≥30. Nearly half of screening-positive women could not be reevaluated mainly on account of the difficulty to trace back women. The availability of a rapid HPV testing method that allows see-and-treat approaches at the same visit would be, therefore, essential. On account of their high cumulative burden of cervical lesions, also women older than 40 years should be included in at least the first screening round in unscreened populations. Cancer Prev Res; 5(5); 746–53. ©2012 AACR.
Data from The Role of Estrogen Receptor β in Transplacental Cancer Prevention by Indole-3-Carbinol
Authors: Benninghoff Abby D. , Williams David E.
Published: March 2024

Abstract
In the present study, the efficacy of indole-3-carbinol (I3C), a key bioactive component of cruciferous vegetables, for prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[def,p]chrysene (DBC) was evaluated using an estrogen receptor β (ERβ) knockout mouse model. I3C was provided either through the maternal diet coincident with carcinogen exposure during pregnancy or directly to offspring postinitiation with DBC. I3C was effective at reducing T-cell acute lymphoblastic lymphoma/leukemia (T-ALL)–related mortality in offspring only if provided via the maternal diet, although a gender difference in the role of ERβ in mediating this response was evident. In female offspring, chemoprevention of T-ALL by maternal dietary I3C required expression of ERβ; survival in Esr2 wild-type and heterozygous female offspring was more than 90% compared with 66% in Esr2 null females. Alternatively, ERβ status did not significantly impact the transplacental chemoprevention by I3C in males. The possible role of ERβ in mediating lung carcinogenesis or chemoprevention by I3C was similarly complicated. Lung tumor incidence was unaltered by either dietary intervention, whereas lung tumor multiplicity was substantially reduced in Esr2 null females on the control diet and marginally lower in Esr2 null males exposed to I3C via the maternal diet compared with their wild-type and heterozygous counterparts. These findings suggest that I3C may act via ERβ to prevent or suppress DBC-initiated transplacental carcinogenesis but that the involvement of this receptor seems to differ depending on the cancer type and gender of the offspring. Cancer Prev Res; 6(4); 339–48. ©2013 AACR.
Data from Breaking the NF-κB and STAT3 Alliance Inhibits Inflammation and Pancreatic Tumorigenesis
Authors: Surh Young-Joon , Bode Ann M. , Dong Zigang
Published: March 2024

Abstract
This perspective on Liby et al. (beginning on page 1427 in this issue of the journal) discusses the importance of the finding that two synthetic triterpenoids prolonged survival in a pancreatic cancer mouse model. This finding is significant because pancreatic cancer is one of the deadliest human cancers. These compounds inhibited the interaction between NF-κB and signal transducer and activator of transcription 3, and determining the mechanisms underlying this inhibition will help to rapidly move these compounds into phase I clinical trials. Cancer Prev Res; 3(11); 1379–81. ©2010 AACR.
Data from Deregulation of XPC and CypA by Cyclosporin A: An Immunosuppression-Independent Mechanism of Skin Carcinogenesis
Authors: Han Weinong , Soltani Keyoumars , Ming Mei , He Yu-Ying
Published: March 2024

Abstract
Skin cancer is the most common malignancy in organ transplant recipients, causing serious morbidity and mortality. Preventing and treating skin cancer in these individuals has been extraordinarily challenging. Following organ transplantation, cyclosporin A (CsA) has been used as an effective immunosuppressive to prevent rejection. Therefore immunosuppression has been widely assumed to be the major cause for increased skin carcinogenesis. However, the mechanism of skin carcinogenesis in organ transplant recipients has not been understood to date; specifically, it remains unknown whether these cancers are immunosuppression dependent or independent. Here, using both immunocompromised nude mice which are defective in mature T lymphocytes as an in vivo model and human keratinocytes as an in vitro model, we showed that CsA impairs genomic integrity in the response of keratinocytes to ultra violet B (UVB). Following UVB radiation, CsA inhibited UVB-induced DNA damage repair by suppressing the transcription of the DNA repair factor xeroderma pigmentosum C (XPC). In addition, CsA compromised the UVB-induced checkpoint function by upregulating the molecular chaperone protein cyclophilin A (CypA). XPC mRNA levels were lower, whereas CypA mRNA and protein levels were higher in human skin cancers than in normal skin. CsA-induced phosphoinositide 3-kinase(PI3K)/AKT activation was required for both XPC suppression and CypA upregulation. Blocking UVB damage or inhibiting the PI3K/AKT pathway prevented CsA-sensitized skin tumorigenesis. Our findings identified deregulation of XPC and CypA as key targets of CsA, and UVB damage and PI3K/AKT activation as two principal drivers for CsA-sensitized skin tumorigenesis, further supporting an immunosuppression-independent mechanism of CsA action on skin tumorigenesis. Cancer Prev Res; 5(9); 1155–62. ©2012 AACR.
Data from An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion
Authors: Danussi Carla , Petrucco Alessandra , Wassermann Bruna , Modica Teresa Maria Elisa , Pivetta Eliana , Belluz Lisa Del Bel , Colombatti Alfonso , Spessotto Paola
Published: March 2024

Abstract
The evidence that EMILIN1 (Elastic Microfibril Interface Located proteIN) deficiency in Emilin1−/− mice caused dermal and epidermal hyperproliferation and an abnormal lymphatic phenotype prompted us to hypothesize the involvement of this extracellular matrix component in tumor development and in lymphatic metastasis. Using the 12-dimethylbenz(α)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage model of skin carcinogenesis, we found that Emilin1−/− mice presented an accelerated formation, a higher incidence, and the development of a larger number of tumors compared with their wild-type littermates. EMILIN1-negative tumors showed more Ki67-positive proliferating cells and higher levels of pErk1/2. In these tumors, PTEN expression was lower. Emilin1−/− mice displayed enhanced lymphangiogenesis both in the tumor and in the sentinel lymph nodes. Accordingly, tumor growth and lymph node metastasis of transplanted syngenic tumors were also increased in Emilin1−/− mice. In vitro transmigration assays through lymphatic endothelial cells showed that EMILIN1 deficiency greatly facilitated tumor cell trafficking. Overall, these data established that EMILIN1 exerts a protective role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes and reinforced the importance of its presence in the microenvironment to determine the tumor phenotype. Cancer Prev Res; 5(9); 1131–43. ©2012 AACR.
Data from Statins and the Colorectum: Hope for Chemoprevention?
Authors: Baron John A.
Published: March 2024

Abstract
This perspective on Bertagnolli et al. (beginning on p. 588 in this issue of the journal) and Lipkin et al. (beginning on p. 597) considers the likelihood that statins have chemopreventive efficacy in the large bowel. An observational analysis within a clinical trial of celecoxib found no benefit of statin use on the risk of colorectal adenomas (and some suggestions of an adverse effect). On the other hand, variation in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene modified the association of statins with risk of colorectal cancer. The perspective discusses the implications of these data and how they fit into the context of previous investigations. Cancer Prev Res; 3(5); 573–5. ©2010 AACR.
Data from Helicobacter pylori and Esophageal Cancer Risk: A Meta-analysis
Authors: Islami Farhad , Kamangar Farin
Published: March 2024

Abstract
We conducted this meta-analysis to examine the association between Helicobacter pylori and esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma. We searched the PubMed database, the ISI database, and the references of the selected articles. Case-control or nested case-control studies were selected if they used serology or endoscopic methods to detect H. pylori in the stomach and if control subjects were not restricted to upper gastrointestinal tract cancer or peptic ulcer disease patients. A total of 19 studies were used for this analysis. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using the DerSimonian-Laird method. Q statistics and I2 statistics were calculated to examine heterogeneity. Subgroup analyses were conducted by CagA status. For EAC, the summary OR (95% CI) was 0.56 (0.46-0.68). There was little heterogeneity among studies (I2 = 15%). Further analysis showed that colonization with CagA-positive strains was inversely associated with EAC risk (OR, 0.41; 95% CI, 0.28-0.62) but colonization with CagA-negative strains was not (OR, 1.08; 95% CI, 0.76-1.53). For esophageal squamous cell carcinoma, the summary OR (95% CI) was 1.10 (0.78-1.55). However, there was substantial heterogeneity among studies (I2 = 73%), with statistically significant associations in both directions. Our results suggest an inverse association between CagA-positive H. pylori colonization and risk of EAC. The prominent decline of H. pylori colonization in the past few decades may be partly responsible for the recent increase in EAC incidence in Western countries.
Data from Targeting Mammalian Target of Rapamycin by Rapamycin Prevents Tumor Progression in an Oral-Specific Chemical Carcinogenesis Model
Authors: Czerninski Rakefet , Amornphimoltham Panomwat , Patel Vyomesh , Molinolo Alfredo A. , Gutkind J. Silvio
Published: March 2024

Abstract
The increased molecular understanding of cancerous growth may now afford the opportunity to develop novel therapies targeting specific dysregulated molecular mechanisms contributing to the progression of each cancer type. In this regard, the aberrant activation of Akt/mammalian target of rapamycin (mTOR) pathway is a frequent event in head and neck squamous cell carcinomas (HNSCC), thus representing a potential molecular target for the treatment of HNSCC patients. The ability to translate this emerging body of information into effective therapeutic strategies, however, has been hampered by the limited availability of animal models for oral malignancies. Here, we show that the administration in the drinking water to mice of 4-nitroquinoline-1 oxide, a DNA adduct-forming agent that serves as a surrogate of tobacco exposure, leads to the progressive appearance of preneoplastic and tumoral lesions in the tongue and oral mucosa, with 100% incidence after only 16 weeks of carcinogen exposure. Remarkably, many of these lesions evolve spontaneously into highly malignant SCCs few weeks after 4-nitroquinoline-1 oxide withdrawal. In this model, we have observed that the activation of the Akt-mTOR biochemical route represents an early event, which is already detectable in dysplastic lesions. Furthermore, we show that the inhibition of mTOR by the chronic administration of rapamycin halts the malignant conversion of precancerous lesions and promotes the regression of advanced carcinogen-induced SCCs. Together, these findings support the contribution of the mTOR signaling pathway to HNSCC progression and provide a strong rationale for the early evaluation of mTOR inhibitors as a molecular-targeted strategy for HNSCC chemoprevention and treatment.
Data from Oral Cancer Prevention Advances with a Translational Trial of Green Tea
Authors: Shin Dong M.
Published: March 2024

Abstract
This perspective on Tsao et al. (beginning on p. 931 in this issue of the journal) discusses green tea extract, which was shown for the first time to have dose-dependent effects in a clinical chemopreventive setting (oral premalignant lesions). This translational trial provides important data on angiogenesis and other biomarkers on which to base future clinical research, which should include trials of green tea extract or polyphenols combined with other natural or synthetic compounds to enhance chemopreventive effects.
Data from A Novel Look into Estrogen Receptor–Negative Breast Cancer Prevention with the Natural, Multifunctional Signal Transduction Inhibitor Deguelin
Authors: Rodenberg Jennifer M. , Brown Powel H.
Published: March 2024

Abstract
This perspective on Murillo et al. (beginning on page 942 in this issue of the journal) examines the potential of the naturally derived agent deguelin to prevent mammary tumorigenesis. These investigators showed that deguelin inhibits wnt/β-catenin signaling in breast cancer cell lines, in addition to inhibiting other previously reported signaling pathways. Our growing understanding of deguelin mechanisms could lead to important advances in the prevention of estrogen receptor–negative breast and other cancers.
Data from Effects of Ginger Supplementation on Cell-Cycle Biomarkers in the Normal-Appearing Colonic Mucosa of Patients at Increased Risk for Colorectal Cancer: Results from a Pilot, Randomized, and Controlled Trial
Authors: Citronberg Jessica , Bostick Roberd , Ahearn Thomas , Turgeon D. Kim , Ruffin Mack T. , Djuric Zora , Sen Ananda , Brenner Dean E. , Zick Suzanna M.
Published: March 2024

Abstract
To estimate the effects of ginger on apoptosis, proliferation, and differentiation in the normal-appearing colonic mucosa, we randomized 20 people at increased risk for colorectal cancer to 2.0 g of ginger or placebo daily for 28 days in a pilot trial. Overall expression and distributions of Bax, Bcl-2, p21, hTERT, and MIB-1 (Ki-67) in colorectal crypts in rectal mucosa biopsies were measured using automated immunohistochemistry and quantitative image analysis. Relative to placebo, Bax expression in the ginger group decreased 15.6% (P = 0.78) in the whole crypts, 6.6% (P = 0.95) in the upper 40% (differentiation zone) of crypts, and 21.7% (P = 0.67) in the lower 60% (proliferative zone) of crypts; however, there was a 19% increase (P = 0.14) in Bax expression in the upper 40% relative to the whole crypt. While p21 and Bcl-2 expression remained relatively unchanged, hTERT expression in the whole crypts decreased by 41.2% (P = 0.05); the estimated treatment effect on hTERT expression was larger in the upper 40% of crypts (−47.9%; P = 0.04). In the ginger group, MIB-1 expression decreased in the whole crypts, upper 40% of crypts, and lower 60% of crypts by 16.9% (P = 0.39), 46.8% (P = 0.39), and 15.3% (P = 0.41), respectively. These pilot study results suggest that ginger may reduce proliferation in the normal-appearing colorectal epithelium and increase apoptosis and differentiation relative to proliferation—especially in the differentiation zone of the crypts and support a larger study to further investigate these results. Cancer Prev Res; 6(4); 271–81. ©2012 AACR.
Data from Molecular Imaging of Cyclooxygenase-2 in Canine Transitional Cell Carcinomas In Vitro and In Vivo
Authors: Cekanova Maria , Uddin Md. Jashim , Bartges Joseph W. , Callens Amanda , Legendre Alfred M. , Rathore Kusum , Wright Laura , Carter Amanda , Marnett Lawrence J.
Published: March 2024

Abstract
The enzyme COX-2 is induced at high levels in tumors but not in surrounding normal tissues, which makes it an attractive target for molecular imaging of cancer. We evaluated the ability of novel optical imaging agent, fluorocoxib A to detect urinary bladder canine transitional cell carcinomas (K9TCC). Here, we show that fluorocoxib A uptake overlapped with COX-2 expression in primary K9TCC cells in vitro. Using subcutaneously implanted primary K9TCC in athymic mice, we show specific uptake of fluorocoxib A by COX-2–expressing K9TCC xenograft tumors in vivo. Fluorocoxib A uptake by COX-2–expressing xenograft tumors was blocked by 70% (P < 0.005) when pretreated with the COX-2 selective inhibitor, celecoxib (10 mg/kg), 4 hours before intravenous administration of fluorocoxib A (1 mg/kg). Fluorocoxib A was taken up by COX-2–expressing tumors but not by COX-2–negative human UMUC-3 xenograft tumors. UMUC-3 xenograft tumors with no expression of COX-2 showed no uptake of fluorocoxib A. In addition, fluorocoxib A uptake was evaluated in five dogs diagnosed with TCC. Fluorocoxib A specifically detected COX-2–expressing K9TCC during cystoscopy in vivo but was not detected in normal urothelium. Taken together, our findings show that fluorocoxib A selectively bound to COX-2–expressing primary K9TCC cells in vitro, COX-2–expressing K9TCC xenografts tumors in nude mice, and heterogeneous canine TCC during cystoscopy in vivo. Spontaneous cancers in companion animals offer a unique translational model for evaluation of novel imaging and therapeutic agents using primary cancer cells in vitro and in heterogeneous cancers in vivo. Cancer Prev Res; 6(5); 466–76. ©2013 AACR.
Data from Programmable Bio-Nano-Chip Systems for Serum CA125 Quantification: Toward Ovarian Cancer Diagnostics at the Point-of-Care
Authors: Raamanathan Archana , Simmons Glennon W. , Christodoulides Nicolaos , Floriano Pierre N. , Furmaga Wieslaw B. , Redding Spencer W. , Lu Karen H. , Bast Robert C. , McDevitt John T.
Published: March 2024

Abstract
Point-of-care (POC) implementation of early detection and screening methodologies for ovarian cancer may enable improved survival rates through early intervention. Current laboratory-confined immunoanalyzers have long turnaround times and are often incompatible with multiplexing and POC implementation. Rapid, sensitive, and multiplexable POC diagnostic platforms compatible with promising early detection approaches for ovarian cancer are needed. To this end, we report the adaptation of the programmable bio-nano-chip (p-BNC), an integrated, microfluidic, and modular (programmable) platform for CA125 serum quantitation, a biomarker prominently implicated in multimodal and multimarker screening approaches. In the p-BNCs, CA125 from diseased sera (Bio) is sequestered and assessed with a fluorescence-based sandwich immunoassay, completed in the nano-nets (Nano) of sensitized agarose microbeads localized in individually addressable wells (Chip), housed in a microfluidic module, capable of integrating multiple sample, reagent and biowaste processing, and handling steps. Antibody pairs that bind to distinct epitopes on CA125 were screened. To permit efficient biomarker sequestration in a three-dimensional microfluidic environment, the p-BNC operating variables (incubation times, flow rates, and reagent concentrations) were tuned to deliver optimal analytical performance under 45 minutes. With short analysis times, competitive analytical performance (inter- and intra-assay precision of 1.2% and 1.9% and limit of detection of 1.0 U/mL) was achieved on this minisensor ensemble. Furthermore, validation with sera of patients with ovarian cancer (n = 20) showed excellent correlation (R2 = 0.97) with gold-standard ELISA. Building on the integration capabilities of novel microfluidic systems programmed for ovarian cancer, the rapid, precise, and sensitive miniaturized p-BNC system shows strong promise for ovarian cancer diagnostics. Cancer Prev Res; 5(5); 706–16. ©2012 AACR.
Data from Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar Alterations in p53, ras, and HER-2/neu
Authors: Hakim Amy A. , Barry Catherine P. , Barnes H. John , Anderson Kenneth E. , Petitte James , Whitaker Regina , Lancaster Jonathan M. , Wenham Robert M. , Carver Donna K. , Turbov Jane , Berchuck Andrew , Kopelovich Levy , Rodriguez Gustavo C.
Published: March 2024

Abstract
We examined alterations in the p53 tumor suppressor gene and the ras and HER-2/neu oncogenes in chicken ovarian cancers to determine if these tumors have genetic alterations similar to those in human ovarian adenocarcinomas. Mutations in the p53 tumor suppressor gene and the H-ras and K-ras oncogenes were assessed by direct sequencing in 172 ovarian cancers obtained from 4-year-old birds enrolled at age 2 in two separate 2-year chemoprevention trials. Birds in trial B had approximately twice as many lifetime ovulations as those in trial A. Immunohistochemical staining for the HER-2/neu oncogene was done on a subset of avian ovarian and oviductal adenocarcinomas. Alterations in p53 were detected in 48% of chicken ovarian cancers. Incidence of p53 alterations varied according to the number of lifetime ovulations, ranging from 14% in trial A to 96% in trial B (P < 0.01). No mutations were seen in H-ras, and only 2 of 172 (1.2%) tumors had K-ras mutations. Significant HER-2/neu staining was noted in 10 of 19 ovarian adenocarcinomas but in only 1 of 17 oviductal adenocarcinomas. Similar to human ovarian cancers, p53 alterations are common in chicken ovarian adenocarcinomas and correlate with the number of lifetime ovulations. Ras mutations are rare, similar to high-grade human ovarian cancers. HER-2/neu overexpression is common and may represent a marker to exclude an oviductal origin in cancers involving both the ovary and oviduct.
Data from Failure Rates in the Hepatocellular Carcinoma Surveillance Process
Authors: Singal Amit G. , Yopp Adam C. , Gupta Samir , Skinner Celette Sugg , Halm Ethan A. , Okolo Eucharia , Nehra Mahendra , Lee William M. , Marrero Jorge A. , Tiro Jasmin A.
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) surveillance is underutilized among patients with cirrhosis. Understanding which steps in the surveillance process are not being conducted is essential for designing effective interventions to improve surveillance rates. The aim of our study was to characterize reasons for failure in the HCC surveillance process among a cohort of cirrhotic patients with HCC. We conducted a retrospective cohort study of cirrhotic patients diagnosed with HCC at a large urban safety-net hospital between 2005 and 2011. Patients were characterized by receipt of HCC surveillance over a two-year period before HCC diagnosis. Among patients without HCC surveillance, we classified reasons for failure into four categories: failure to recognize liver disease, failure to recognize cirrhosis, failure to order surveillance, and failure to complete surveillance despite orders. Univariate and multivariate analyses were conducted to identify predictors of failures. We identified 178 patients with HCC, of whom 20% had undergone surveillance. There were multiple points of failure—20% had unrecognized liver disease, 19% had unrecognized cirrhosis, 38% lacked surveillance orders, and 3% failed to complete surveillance despite orders. Surveillance was more likely among patients seen by hepatologists [OR, 6.11; 95% confidence interval (CI), 2.5–14.8] and less likely in those with alcohol abuse (OR, 0.14; 95% CI, 0.03–0.65). Although a retrospective analysis in a safety-net hospital, our data suggest that only one in five patients received surveillance before HCC diagnosis. There are multiple points of failure in the surveillance process, with the most common being failure to order surveillance in patients with known cirrhosis. Future interventions must target multiple failure points in the surveillance process to be highly effective. Cancer Prev Res; 5(9); 1124–30. ©2012 AACR.
Data from High Prevalence of Preinvasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers
Authors: Arun Banu , Vogel Kristen J. , Lopez Adriana , Hernandez Mike , Atchley Deann , Broglio Kristine R. , Amos Christopher I. , Meric-Bernstam Funda , Kuerer Henry , Hortobagyi Gabriel N. , Albarracin Constance T.
Published: March 2024

Abstract
Mutations in BRCA1 and BRCA2 increase a woman's lifetime risk of developing breast cancer by 43% to 84%. It was originally postulated that BRCA1/2-associated breast cancers develop more rapidly than sporadic cancers and may lack preinvasive lesions. More recent studies have found preinvasive lesions in prophylactic mastectomy specimens from mutation carriers; however, there is little information on the presence of preinvasive lesions in tissue adjacent to breast cancers. Our aim is to investigate the role of preinvasive lesions in BRCA-associated breast carcinogenesis.

We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of preinvasive lesions [ductal carcinoma in situ (DCIS), lobular carcinoma in situ, and atypical lobular hyperplasia] in tissue adjacent to invasive breast cancers.

Pathology was reviewed for 73 BRCA1/2-associated tumors from patients with breast cancer. We selected 146 patients with mutation-negative breast cancer as age-matched controls. Among the BRCA1/2-associated breast cancers, 59% had at least one associated preinvasive lesion compared with 75% of controls. Preinvasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% versus 52%, respectively). The most common preinvasive lesion in both groups was DCIS; 56% of BRCA1/2-associated breast cancers and 71% of the sporadic breast cancers had adjacent intraductal disease, respectively.

Preinvasive lesions, most notably DCIS, are common in BRCA1/2-associated breast cancers. These findings suggest that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumor spectrum.
Data from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
Authors: Abba Martín C. , Hu Yuhui , Levy Carla C. , Gaddis Sally , Kittrell Frances S. , Hill Jamal , Bissonnette Reid P. , Brown Powel H. , Medina Daniel , Aldaz C. Marcelo
Published: March 2024

Abstract
Genetically engineered mouse cancer models are among the most useful tools for testing the in vivo effectiveness of the various chemopreventive approaches. The p53-null mouse model of mammary carcinogenesis was previously characterized by us at the cellular, molecular, and pathologic levels. In a companion article, Medina et al. analyzed the efficacy of bexarotene, gefitinib, and celecoxib as chemopreventive agents in the same model. Here we report the global gene expression effects on mammary epithelium of such compounds, analyzing the data in light of their effectiveness as chemopreventive agents. SAGE was used to profile the transcriptome of p53-null mammary epithelium obtained from mice treated with each compound versus controls. This information was also compared with SAGE data from p53-null mouse mammary tumors. Gene expression changes induced by the chemopreventive treatments revealed a common core of 87 affected genes across treatments (P < 0.05). The effective compounds, bexarotene and gefitinib, may exert their chemopreventive activity, at least in part, by affecting a set of 34 genes related to specific cellular pathways. The gene expression signature revealed various genes previously described to be associated with breast cancer, such as the activator protein-1 complex member Fos-like antigen 2 (Fosl2), early growth response 1 (Egr1), gelsolin (Gsn), and tumor protein translationally controlled 1 (Tpt1), among others. The concerted modulation of many of these transcripts before malignant transformation seems to be conducive to predominantly decrease cell proliferation. This study has revealed candidate key pathways that can be experimentally tested in the same model system and may constitute novel targets for future translational research.
Data from A Mouse Model for Human Anal Cancer
Authors: Stelzer Marie K. , Pitot Henry C. , Liem Amy , Schweizer Johannes , Mahoney Charles , Lambert Paul F.
Published: March 2024

Abstract
Human anal cancers are associated with high-risk human papillomaviruses (HPV) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including, but not limited to, their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors, whereas none of the like-treated nontransgenic mice showed tumors. Histopathologic analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. Cancer Prev Res; 3(12); 1534–41. ©2010 AACR.