bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Piperlongumine Induces Reactive Oxygen Species (ROS)-Dependent Downregulation of Specificity Protein Transcription Factors
Authors: Karki Keshav , Hedrick Erik , Kasiappan Ravi , Jin Un-Ho , Safe Stephen
Published: April 2023

Abstract
Piperlongumine is a natural product found in the plant species Piper longum, and this compound exhibits potent anticancer activity in multiple tumor types and has been characterized as an inducer of reactive oxygen species (ROS). Treatment of Panc1 and L3.6pL pancreatic, A549 lung, 786-O kidney, and SKBR3 breast cancer cell lines with 5 to 15 μmol/L piperlongumine inhibited cell proliferation and induced apoptosis and ROS, and these responses were attenuated after cotreatment with the antioxidant glutathione. Piperlongumine also downregulated expression of Sp1, Sp3, Sp4, and several pro-oncogenic Sp-regulated genes, including cyclin D1, survivin, cMyc, EGFR and hepatocyte growth factor receptor (cMet), and these responses were also attenuated after cotreatment with glutathione. Mechanistic studies in Panc1 cells showed that piperlongumine-induced ROS decreased expression of cMyc via an epigenetic pathway, and this resulted in downregulation of cMyc-regulated miRNAs miR-27a, miR-20a, and miR-17 and induction of the transcriptional repressors ZBTB10 and ZBTB4. These repressors target GC-rich Sp-binding sites to decrease transactivation. This pathway observed for piperlongumine in Panc1 cells has previously been reported for other ROS-inducing anticancer agents and shows that an important underlying mechanism of action of piperlongumine is due to downregulation of Sp1, Sp3, Sp4, and pro-oncogenic Sp-regulated genes. Cancer Prev Res; 10(8); 467–77. ©2017 AACR.
Data from Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer
Authors: Fabian Carol J. , Khan Seema A. , Garber Judy E. , Dooley William C. , Yee Lisa D. , Klemp Jennifer R. , Nydegger Jennifer L. , Powers Kandy R. , Kreutzjans Amy L. , Zalles Carola M. , Metheny Trina , Phillips Teresa A. , Hu Jinxiang , Koestler Devin C. , Chalise Prabhakar , Yellapu Nanda Kumar , Jernigan Cheryl , Petroff Brian K. , Hursting Stephen D. , Kimler Bruce F.
Published: April 2023

Abstract
We conducted a multiinstitutional, placebo-controlled phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was −1.8% in the SDG arm (P = 0.001) and −1.2% for placebo (P = 0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median = −2.2%; P = 0.002) but not placebo (median = −1.0%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (<0.5 or >2.0) with 7 of 10 increases in placebo and 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.
Data from Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis
Authors: Bowen Charles M. , Walter Lewins , Borras Ester , Wu Wenhui , Ozcan Zuhal , Chang Kyle , Bommi Prashant V. , Taggart Melissa W. , Thirumurthi Selvi , Lynch Patrick M. , Reyes-Uribe Laura , Scheet Paul A. , Sinha Krishna M. , Vilar Eduardo
Published: April 2023

Abstract
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP.
Prevention Relevance:
This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.
Data from β-Cryptoxanthin Reduced Lung Tumor Multiplicity and Inhibited Lung Cancer Cell Motility by Downregulating Nicotinic Acetylcholine Receptor α7 Signaling
Authors: Iskandar Anita R. , Miao Benchun , Li Xinli , Hu Kang-Quan , Liu Chun , Wang Xiang-Dong
Published: April 2023

Abstract
Despite the consistent association between a higher intake of the provitamin A carotenoid β-cryptoxanthin (BCX) and a lower risk of lung cancer among smokers, potential mechanisms supporting BCX as a chemopreventive agent are needed. We first examined the effects of BCX on 4-[methyl nitrosamino]-1-[3-pyridyl]-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. BCX supplementation was given daily to the mice starting 2 weeks prior to the injection of NNK and continued 16 weeks after NNK injection. BCX supplementation resulted in a dose-dependent increase of BCX concentration in both serum and lungs of the mice without a significant alteration of vitamin A (retinol and retinyl palmitate) concentration. BCX significantly reduced the multiplicity of the NNK-induced lung tumor by 52% to 63% compared with the NNK-treated mice without BCX supplementation. The protective effect of BCX in the lungs was associated with reductions of both mRNA and protein of the homopentameric neuronal nicotinic acetylcholine receptor α7 (α7-nAChR), which has been implicated in lung tumorigenesis. We then conducted an in vitro cell culture study and found that BCX treatment suppressed α7-nAChR expression and inhibited the migration and invasion of α7-nAChR-positive lung cancer cells but not in cells lacking α7-nAChR. The activities of BCX were significantly attenuated by activators of α7-nAChR/PI3K signaling or by overexpression of constitutively active PI3K. Collectively, the results suggest that BCX inhibits lung tumorigenesis and cancer cell motility through the downregulation of α7-nAChR/PI3K signaling, independent of its provitamin A activity. Therefore, BCX can be used as a chemopreventive agent or a chemotherapeutic compound against lung cancer. Cancer Prev Res; 9(11); 875–86. ©2016 AACR.
Data from Evaluation of Cancer-Associated DNA Copy Number Events in Colorectal (Advanced) Adenomas
Authors: Carvalho Beatriz , Diosdado Begoña , Terhaar Sive Droste Jochim S. , Bolijn Anne S. , Komor Malgorzata A. , de Wit Meike , Bosch Linda J.W. , van Burink Myrthe , Dekker Evelien , Kuipers Ernst J. , Coupé Veerle M.H. , van Grieken Nicole C.T. , Fijneman Remond J.A. , Meijer Gerrit A.
Published: April 2023

Abstract
About 5% of colorectal adenomas are estimated to progress to colorectal cancer. However, it is important to identify which adenomas actually carry a high risk of progression, because these serve as intermediate endpoints, for example, in screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression. We set out to determine the prevalence of cancer-associated events (CAE) in advanced and nonadvanced adenomas. DNA copy number analysis was performed on archival tissues from three independent series of, in total, 297 adenomas (120 nonadvanced and 177 advanced) using multiplex ligation-dependent probe amplification or low-coverage whole-genome DNA sequencing. Alterations in two or more CAEs were considered to mark adenomas as high risk. Two or more CAEs were overall present in 25% (95% CI, 19.0–31.8) of advanced adenomas; 23% (11/48), 36% (12/33), and 23% (22/96) of the advanced adenomas in series 1, 2, and 3, respectively, and 1.7% (1/58) and 4.8% (3/62) of the nonadvanced adenomas, in series 1 and 2, respectively. The majority of advanced adenomas do not show CAEs, indicating that only a subset of these lesions is to be considered high risk. Nonadvanced adenomas have very low prevalence of CAEs, although those with CAEs should be considered high risk as well. Specific DNA copy number alterations may better reflect the true progression risk than the advanced adenoma phenotype. Cancer Prev Res; 11(7); 403–12. ©2018 AACR.
Data from Genome-Wide Gene Expression Changes in the Normal-Appearing Airway during the Evolution of Smoking-Associated Lung Adenocarcinoma
Authors: Kantrowitz Jacob , Sinjab Ansam , Xu Li , McDowell Tina L. , Sivakumar Smruthy , Lang Wenhua , Nunomura-Nakamura Sayuri , Fukuoka Junya , Nemer Georges , Darwiche Nadine , Chami Hassan , Tfayli Arafat , Wistuba Ignacio I. , Scheet Paul , Fujimoto Junya , Spira Avrum E. , Kadara Humam
Published: April 2023

Abstract
Smoking perpetuates in cytologically normal airways a molecular “field of injury” that is pertinent to lung cancer and early detection. The evolution of airway field changes prior to lung oncogenesis is poorly understood largely due to the long latency of lung cancer in smokers. Here, we studied airway expression changes prior to lung cancer onset in mice with knockout of the Gprc5a gene (Gprc5a−/−) and tobacco carcinogen (NNK) exposure and that develop the most common type of lung cancer, lung adenocarcinoma, within 6 months following exposure. Airway epithelial brushings were collected from Gprc5a−/− mice before exposure and at multiple times post-NNK until time of lung adenocarcinoma development and then analyzed by RNA sequencing. Temporal airway profiles were identified by linear models and analyzed by comparative genomics in normal airways of human smokers with and without lung cancer. We identified significantly altered profiles (n = 926) in the NNK-exposed mouse normal airways relative to baseline epithelia, a subset of which were concordantly modulated with smoking status in the human airway. Among airway profiles that were significantly modulated following NNK, we found that expression changes (n = 22) occurring as early as 2 months following exposure were significantly associated with lung cancer status when examined in airways of human smokers. Furthermore, a subset of a recently reported human bronchial gene classifier (Percepta; n = 56) was enriched in the temporal mouse airway profiles. We underscore evolutionarily conserved profiles in the normal-appearing airway that develop prior to lung oncogenesis and that comprise viable markers for early lung cancer detection in suspect smokers. Cancer Prev Res; 11(4); 237–48. ©2018 AACR.
Data from EUS-based Pancreatic Cancer Surveillance in BRCA1/BRCA2/PALB2/ATM Carriers Without a Family History of Pancreatic Cancer
Authors: Katona Bryson W. , Long Jessica M. , Ahmad Nuzhat A. , Attalla Sara , Bradbury Angela R. , Carpenter Erica L. , Clark Dana F. , Constantino Gillain , Das Koushik K. , Domchek Susan M. , Dudzik Christina , Ebrahimzadeh Jessica , Ginsberg Gregory G. , Heiman Jordan , Kochman Michael L. , Maxwell Kara N. , McKenna Danielle B. , Powers Jacquelyn , Shah Payal D. , Wangensteen Kirk J. , Rustgi Anil K.
Published: April 2023

Abstract
Carriers of a pathogenic/likely pathogenic (P/LP) BRCA1/BRCA2/ATM/PALB2 variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)–based PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS at a tertiary care center. Of 194 P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS, 64 (33%) had no family history of PDAC and had at least 1 EUS for PDAC surveillance. These individuals underwent 143 total EUSs, were predominantly female (72%), and BRCA2 carriers (73%), with the majority having a personal history of cancer other than PDAC (67%). The median age at time of first EUS was 62 years [interquartile range (IQR), 53–67 years] and a median of 2 EUSs (IQR 1–3) were performed per patient, with a median of 3 years (IQR 2–4.5 years) between the first and last EUS for those with more than 1 EUS. Pancreatic abnormalities were detected in 44%, including cysts in 27%, and incidental luminal abnormalities in 41%. Eight percent developed a new pancreatic mass or cyst during surveillance, 2 individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC; however, the effectiveness of PDAC surveillance in this population requires further study.
Prevention Relevance:
BRCA1/BRCA2/ATM/PALB2 carriers have increased pancreatic ductal adenocarcinoma (PDAC) risk, yet are typically not eligible for PDAC surveillance in the absence of PDAC family history. Herein we describe outcomes of PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC, showing that PDAC surveillance can be considered in this high-risk group.
Data from Individual and Joint Associations of Genetic Risk and Healthy Lifestyle Score with Colorectal Neoplasms Among Participants of Screening Colonoscopy
Authors: Erben Vanessa , Carr Prudence R. , Guo Feng , Weigl Korbinian , Hoffmeister Michael , Brenner Hermann
Published: April 2023

Abstract
Genetic and lifestyle factors contribute to colorectal cancer risk. We investigated their individual and joint associations with various stages of colorectal carcinogenesis. We assessed associations of a polygenic risk score (PRS) and a healthy lifestyle score (HLS) with presence of nonadvanced adenomas and advanced neoplasms among 2,585 participants of screening colonoscopy from Germany. The PRS and HLS individually showed only weak associations with presence of nonadvanced adenomas; stronger associations were observed with advanced neoplasms (ORs, 95% CI, for highest vs. lowest risk tertile: PRS 2.27, 1.78–2.88; HLS 1.96, 1.53–2.51). The PRS was associated with higher odds of advanced neoplasms among carriers of any neoplasms (1.65, 1.23–2.22). Subjects in the highest risk tertile (vs. lowest tertile) of both scores had higher risks for nonadvanced adenomas (1.77, 1.09–2.86), for advanced neoplasms (3.95, 2.53–6.16) and, among carriers of any neoplasms, for advanced versus nonadvanced neoplasms (2.26, 1.31–3.92). Both scores were individually associated with increased risk of nonadvanced adenomas and, much more pronounced, advanced neoplasms. The similarly strong association in relative terms across all levels of genetic risk implies that a healthy lifestyle may be particularly beneficial in those at highest genetic risk, given that the same relative risk reduction in this group would imply a stronger absolute risk reduction. Genetic factors may be of particular relevance for the transition of nonadvanced to advanced adenomas.
Prevention Relevance:
Genetic factors have strong impact on the risk of colorectal neoplasms, which may be reduced by healthy lifestyle. Similarly strong associations in relative terms across all levels of genetic risk imply that a healthy lifestyle may be beneficial due to higher absolute risk reduction in those at highest genetic risk.
Data from Diagnosing Cervical Neoplasia in Rural Brazil Using a Mobile Van Equipped with In Vivo Microscopy: A Cluster-Randomized Community Trial
Authors: Hunt Brady , Fregnani José Humberto Tavares Guerreiro , Schwarz Richard A. , Pantano Naitielle , Tesoni Suelen , Possati-Resende Júlio César , Antoniazzi Marcio , de Oliveira Fonseca Bruno , de Macêdo Matsushita Graziela , Scapulatempo-Neto Cristovam , Kerr Ligia , Castle Philip E. , Schmeler Kathleen , Richards-Kortum Rebecca
Published: April 2023

Abstract
Cervical cancer is a leading cause of death in underserved areas of Brazil. This prospective randomized trial involved 200 women in southern/central Brazil with abnormal Papanicolaou tests. Participants were randomized by geographic cluster and referred for diagnostic evaluation either at a mobile van upon its scheduled visit to their local community, or at a central hospital. Participants in both arms underwent colposcopy, in vivo microscopy, and cervical biopsies. We compared rates of diagnostic follow-up completion between study arms, and also evaluated the diagnostic performance of in vivo microscopy compared with colposcopy. There was a 23% absolute and 37% relative increase in diagnostic follow-up completion rates for patients referred to the mobile van (102/117, 87%) compared with the central hospital (53/83, 64%; P = 0.0001; risk ratio = 1.37, 95% CI, 1.14–1.63). In 229 cervical sites in 144 patients, colposcopic examination identified sites diagnosed as cervical intraepithelial neoplasia grade 2 or more severe (CIN2+; 85 sites) with a sensitivity of 94% (95% CI, 87%–98%) and specificity of 50% (95% CI, 42%–58%). In vivo microscopy with real-time automated image analysis identified CIN2+ with a sensitivity of 92% (95% CI, 84%–97%) and specificity of 48% (95% CI, 40%–56%). Women referred to the mobile van were more likely to complete their diagnostic follow-up compared with those referred to a central hospital, without compromise in clinical care. In vivo microscopy in a mobile van provides automated diagnostic imaging with sensitivity and specificity similar to colposcopy. Cancer Prev Res; 11(6); 359–70. ©2018 AACR.
Data from Inflammatory and Insulinemic Dietary Patterns: Influence on Circulating Biomarkers and Prostate Cancer Risk
Authors: Aroke Desmond , Folefac Edmund , Shi Ni , Jin Qi , Clinton Steven K. , Tabung Fred K.
Published: April 2023

Abstract
Prostate cancer is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. In the Prostate, Lung, Colorectal, and Ovarian cancer cohort, we calculated the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores from food frequency questionnaire data among 3,517 men and women who provided a blood sample at enrollment. We used these scores in multivariable-adjusted linear regression to validate EDIH and EDIP against relevant circulating biomarkers. In a separate sample of 49,317 men, we used multivariable-adjusted Cox regression to evaluate associations of EDIH and EDIP with prostate cancer (total and subtypes) risk. Participants consuming the most hyperinsulinemic diets (EDIH quintile 5) had significantly higher concentrations of C-peptide, insulin, c-reactive protein, TNFα-R2, and lower adiponectin, than those in quintile 1. Similarly, participants consuming the most proinflammatory diets had significantly higher concentrations of IL6, TNFα-R2, C-peptide, insulin, and lower adiponectin. Men consuming hyperinsulinemic diets were at higher total prostate cancer risk: HRquintile5vs1, 1.11; 95% confidence interval (CI), 1.01–1.23; P trend = 0.03, especially high-grade cancer: HRquintile5vs1, 1.18; 95% CI, 1.02–1.37; P trend = 0.06. The EDIP was not associated with prostate cancer risk. In summary, EDIH and EDIP predicted concentrations of known insulinemic and inflammatory biomarkers, and EDIH further predicted risk of future prostate cancer. Interventions to reduce the adverse role of hyperinsulinemic diets may be a means of prostate cancer prevention.
Data from Evaluating the Utility and Prevalence of HPV Biomarkers in Oral Rinses and Serology for HPV-related Oropharyngeal Cancer
Authors: D'Souza Gypsyamber , Clemens Gwendolyn , Troy Tanya , Castillo Rachel G. , Struijk Linda , Waterboer Tim , Bender Noemi , Pierorazio Phillip M. , Best Simon R. , Strickler Howard , Wiley Dorothy J. , Haddad Robert I. , Posner Marshall , Fakhry Carole
Published: April 2023

Abstract
Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 “at-risk” people (screening) and 133 “high-risk” people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each P < 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88% for DEIA, Cobas, and E6 antibodies, respectively), but specificity was reduced (93%–97%). Aptima had poor sensitivity (23%). Sensitivity decreased when cotesting HPV16 oral rinse DNA and E6 antibodies (37%–48%), or multiple E antibodies (69%–72%). HPV16 DNA were detected in ∼2% of the at-risk by either DEIA or Cobas and up to 15% of the high-risk population. HPV16 E6 seroprevalence was 2.3% and 2.4% in the at-risk and high-risk populations, respectively. Oral rinse HPV testing had moderate-to-poor sensitivity for HPV-OPC, suggesting many true positives would be missed in a potential screening scenario. HPV16 E6 serum antibody was the most promising biomarker evaluated.
Data from Effects of Supplemental Calcium and Vitamin D on Expression of Toll-Like Receptors and Phospho-IKKα/β in the Normal Rectal Mucosa of Colorectal Adenoma Patients
Authors: Hodge Rebecca , Mandle Hannah B. , Ray Stephen , Tandon Sonia , Peterson Meaghan , Henry Abigail , Jahan Ferdous A. , Bostick Roberd M. , Baron John A. , Barry Elizabeth L. , Yacoub Rami , Rutherford Robin E. , Seabrook March E. , Fedirko Veronika
Published: April 2023

Abstract
Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/β (pIKKα/β), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/β expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/β. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/β expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707–16. ©2018 AACR.
Data from Phase I Trial of Encapsulated Rapamycin in Patients with Prostate Cancer Under Active Surveillance to Prevent Progression
Authors: Kemp Bohan Phillip M. , Chick Robert C. , O'Shea Anne E. , Vreeland Timothy J. , Hickerson Annelies T. , Cindass Jessica L. , Ensley Daniel C. , Hale Diane , Clifton Guy T. , Sohn Vance Y. , Thompson Ian M. , Peoples George E. , Liss Michael A.
Published: April 2023

Abstract
No approved medical therapies prevent progression of low-grade prostate cancer. Rapamycin inhibits cell proliferation and augments immune responses, producing an antitumor effect. Encapsulated rapamycin (eRapa) incorporates rapamycin into a pH-sensitive polymer, ensuring consistent dosing. Here, we present results from a phase I trial evaluating the safety and tolerability of eRapa in patients with prostate cancer. Patients with Gleason ≤7 (3+4) disease (low and intermediate risk) under active surveillance were enrolled in a 3+3 study with three eRapa dosing cohorts (cohort 1, 0.5 mg/week; cohort 2, 1 mg/week; and cohort 3, 0.5 mg/day). Patients were treated for 3 months and followed for an additional 3 months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1, n = 3; cohort 2, n = 3; and cohort 3, n = 8) were enrolled. In cohort 3, one dose-limiting toxicity (DLT; neutropenia) and two non-DLT grade 1–2 adverse events (AE) occurred that resulted in patient withdrawal. All AEs in cohorts 1 and 2 were grade 1. Peak serum rapamycin concentration was 7.1 ng/mL after a 1 mg dose. Stable trough levels (∼2 ng/mL) developed after 48–72 hours. Daily dosing mildly worsened QoL, although QoL recovered after treatment cessation in all categories, except fatigue. Weekly dosing increased naïve T-cell populations. Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability.

Prevention Relevance: There is an unmet medical need for a well-tolerated treatment capable of delaying progression of newly diagnosed low-grade prostate cancer. This treatment would potentially obviate the need for future surgical intervention and improve the perception of active surveillance as a more acceptable option among this patient population.
Data from Cost Effectiveness of Lung Cancer Screening With Low-Dose CT in Heavy Smokers in China
Authors: Yuan Jingmin , Sun Yan , Wang Ke , Wang Zhiyi , Li Duo , Fan Meng , Bu Xiang , Chen Mingwei , Ren Hui
Published: April 2023

Abstract
Although lung cancer screening with low-dose CT (LDCT) can reduce lung cancer mortality by 20%, without an appropriate eligibility criteria, it may result in a waste of medical resources and a degree of unnecessary damage to participants' health. This study aims to give the optimal screening strategy in China based on cost-effectiveness analysis on pros and cons of different situations. From the perspective of primary healthcare system, a Markov model was built to simulate LDCT screening of 100,000 heavy smokers (>30 pack years) aged 40 in different situations. Model parameters mainly came from screening programs conducted in China and other countries, official public data, and published literature. Two indicators of primary outcome, incremental cost-effectiveness ratio (ICER) and net health benefits (NHB), were compared with those of no screening. Sensitivity analysis was conducted to evaluate model uncertainties. We defined the optimal strategy as the one with both acceptable cost effectiveness and maximal NHB. Base-case analysis results showed that for all screening strategies, ICERs were less than three times of GDP per capita. As for NHB results, it showed that when the willingness to pay for screening was less than three times of GPD per capita, the largest NHB was obtained in the strategy which started screening at 50 years old and this strategy showed stable performance in univariate and probabilistic sensitivity as well.
Prevention Relevance:
LDCT screening is cost effective in heavy smokers in China, and the optimal age to start screening is suggested to be 50 years old.
Data from Evaluation of the Associations Between Cervical Microbiota and HPV Infection, Clearance, and Persistence in Cytologically Normal Women
Authors: Ritu Wu , Enqi Wu , Zheng Siriguleng , Wang Jiandong , Ling Yaqin , Wang Yan
Published: April 2023

Abstract
The aim of this study was to investigate the associations between cervical microbiota and different human papillomavirus (HPV) infection statuses in cytologically normal women. The cervical microbiota of HPV-positive or -negative women with a normal cytologic diagnosis was characterized and compared using 16S rDNA-based high-throughput sequencing, and the differences in cervical microbiota associated with new acquisition, persistence, and clearances of HPV genotypes were analyzed via one-year follow-up. The results showed that the cervical microbial richness of HPV-positive women was lower than for HPV-negative women, and the difference was more significant in the postmenopausal group relative to the premenopausal group. Ureaplasma parvum and related taxa were associated with baseline HPV positivity, while Brochothrix, Diplorickettsia, Ezakiella, Faecalibacterium, and Fusobacterium genera and their related taxa and Pseudomonas aeruginosa were associated with baseline HPV negativity. For HPV-positive women, the baseline abundance of Actinomyces was negatively associated with new HPV infection, Alloprevotella tannerae, Prevotella nigrescens, and Prevotella oulorum; and Dialister invisus were positively associated with new HPV-type infection within the year of follow-up. Lactobacillus delbrueckii was found to be negatively associated with persistent HPV infection and 9 taxa belonging to Prevotella, Dialister, and Lachnospiraceae were found to be positively associated with persistence, and/or negatively associated with clearance of HPV types. We also observed 10 novel taxa associated with the clearance/persistence of HPV that had not been reported elsewhere. Those taxa associated with different infection statuses of HPV could be used as a biomarker to help predict the risk of developing persistent HPV infection.
Data from Economic Evaluation of Tailored Web versus Tailored Telephone-Based Interventions to Increase Colorectal Cancer Screening among Women
Authors: Lairson David R. , Chung Tong Han , Huang Danmeng , Stump Timothy E. , Monahan Patrick O. , Christy Shannon M. , Rawl Susan M. , Champion Victoria L.
Published: April 2023

Abstract
Screening for colorectal cancer is cost-effective, but many U.S. women are nonadherent, and the cost-effectiveness of web-based tailored screening interventions is unknown. A randomized controlled trial, COBRA (Increasing Colorectal and Breast Cancer Screening), was the source of information for the economic evaluation. COBRA compared screening among a Usual Care group to: (i) tailored Phone Counseling intervention; (ii) tailored Web intervention; and (iii) tailored Web + Phone intervention groups. A sample of 1,196 women aged 50 to 75 who were nonadherent to colorectal cancer screening were recruited from Indiana primary care clinics during 2013 to 2015. Screening status was obtained through medical records at recruitment with verbal confirmation at consent, and at 6-month follow-up via medical record audit and participant self-report. A "best sample" analysis and microcosting from the patient and provider perspectives were applied to estimate the costs and effects of the interventions. Statistical uncertainty was analyzed with nonparametric bootstrapping and net benefit regression analysis. The per participant cost of implementing the Phone Counseling, Web-based, and Web + Phone Counseling interventions was $277, $314, and $336, respectively. The incremental cost per person screened for the Phone Counseling compared with no intervention was $995, while the additional cost of Web and the Web + Phone compared with Phone Counseling did not yield additonal persons screened. Tailored Phone Counseling significantly increased colorectal cancer screening rates compared with Usual Care. Tailored Web interventions did not improve the screening rate compared with the lower cost Phone Counseling intervention.
Data from Post Genome-Wide Gene–Environment Interaction Study Using Random Survival Forest: Insulin Resistance, Lifestyle Factors, and Colorectal Cancer Risk
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Zhang Zuo-Feng
Published: April 2023

Abstract
Molecular and genetic pathways of insulin resistance (IR) connecting colorectal cancer and obesity factors in postmenopausal women remain inconclusive. We examined the IR pathways on both genetic and phenotypic perspectives at the genome-wide level. We further constructed colorectal cancer risk profiles with the most predictive IR SNPs and lifestyle factors. In our earlier genome-wide association gene–environmental interaction study, we used data from a large cohort of postmenopausal women in the Women's Health Initiative Database for Genotypes and Phenotypes Study and identified 58 SNPs in relation to IR phenotypes. In this study, we evaluated the identified IR SNPs and selected 34 lifestyles for their association with colorectal cancer risk in a total of 11,078 women (including 736 women with colorectal cancer) using a 2-stage multimodal random survival forest analysis. In overall and subgroup (defined via body mass index, exercise, and dietary-fat intake) analyses, we identified 2 SNPs (LINC00460 rs1725459 and MTRR rs722025) and lifetime cumulative exposure to estrogen (oral contraceptive use) and cigarette smoking as the most common and strongest predictive markers for colorectal cancer risk across the analyses. The combinations of genetic and lifestyle factors had much greater impact on colorectal cancer risk than any individual risk factors, and a possible synergism existed to increase colorectal cancer risk in a gene-behavior dose-dependent manner. Our findings may inform research on the role of IR in the etiology of colorectal cancer and contribute to more accurate prediction of colorectal cancer risk, suggesting potential intervention strategies for women with specific genotypes and lifestyles to reduce their colorectal cancer risk.
Data from Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762
Authors: Zhang Di , Leal Ana S. , Carapellucci Sarah , Zydeck Kayla , Sporn Michael B. , Liby Karen T.
Published: April 2023

Abstract
Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143–56. ©2017 AACR.
Data from Dietary Weight Loss, Exercise, and Oxidative Stress in Postmenopausal Women: A Randomized Controlled Trial
Authors: Duggan Catherine , Tapsoba Jean de Dieu , Wang Ching-Yun , Campbell Kristin L. , Foster-Schubert Karen , Gross Myron D. , McTiernan Anne
Published: April 2023

Abstract
Oxidative stress, a potential mechanism linking obesity and cancer, results from an imbalance between activation/inactivation of reactive oxygen species, byproducts of cellular metabolism. In a randomized controlled trial, we investigated effects of diet and/or exercise on biomarkers of oxidative stress. A total of 439 overweight/obese [body mass index (BMI) > 25 kg/m2] postmenopausal women, ages 50 of 75 years, were randomized to 12 months of (i) reduced-calorie weight loss diet (“diet”; n = 118); (ii) moderate-to-vigorous intensity aerobic exercise (“exercise”; n = 117); (iii) combined diet and exercise intervention (“diet + exercise”; n = 117); or (iv) control (n = 87). Outcomes were circulating markers of oxidative stress, including fluorescent oxidation products (FOP), F2-isoprostanes, and oxidized low-density lipoprotein (LDL). On average, participants were 57.9 years, with a BMI of 30.9 kg/m2. F2-isprostanes were significantly reduced in the diet (−22.7%, P = 0.0002) and diet + exercise (−23.5%, P < 0.0001) arms versus controls (−2.99%) and nonsignificantly reduced in the exercise arm (−14.5%, P = 0.01). Participants randomized to the diet and diet + exercise arms had significant increases in levels of FOP [control −5.81%; diet +14.77% (P = 0.0001); diet + exercise +17.45%, (P = 0.0001)]. In secondary analyses, increasing weight loss was statistically significantly associated with linear trends of greater reductions in oxidized LDL and in F2-isoprostanes and increases in FOP. Compared with controls, exercise participants whose maximal oxygen consumption increased had significant decreases in levels of F2-isoprostanes and in oxidized LDL and increases in FOP. Dietary weight loss, with or without exercise, significantly reduced some markers of oxidative stress in postmenopausal women. Cancer Prev Res; 9(11); 835–43. ©2016 AACR.
Data from Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers
Authors: Hall Michael J. , Bernhisel Ryan , Hughes Elisha , Larson Katie , Rosenthal Eric T. , Singh Nanda A. , Lancaster Johnathan M. , Kurian Allison W.
Published: April 2023

Abstract
Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24–5.47), prostate (OR, 2.58; 95% CI, 1.93–3.44), gastric (OR, 2.97; 95% CI, 1.66–5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89–2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76–5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61–2.02), male breast cancer (OR, 1.72; 95% CI, 1.08–2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35–1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24–1.79), and melanoma (OR, 1.46; 95% CI, 1.18–1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection.
Prevention Relevance:
This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.
Data from Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells
Authors: Yang Wanshui , Liu Li , Keum NaNa , Qian Zhi Rong , Nowak Jonathan A. , Hamada Tsuyoshi , Song Mingyang , Cao Yin , Nosho Katsuhiko , Smith-Warner Stephanie A. , Zhang Sui , Masugi Yohei , Ng Kimmie , Kosumi Keisuke , Ma Yanan , Garrett Wendy S. , Wang Molin , Nan Hongmei , Giannakis Marios , Meyerhardt Jeffrey A. , Chan Andrew T. , Fuchs Charles S. , Nishihara Reiko , Wu Kana , Giovannucci Edward L. , Ogino Shuji , Zhang Xuehong
Published: April 2023

Abstract
Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36–0.84; Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.
Data from IKZF1 Gene in Childhood B-cell Precursor Acute Lymphoblastic Leukemia: Interplay between Genetic Susceptibility and Somatic Abnormalities
Authors: Lopes Bruno A. , Barbosa Thayana C. , Souza Bruna K.S. , Poubel Caroline P. , Pombo-de-Oliveira Maria S. , Emerenciano Mariana
Published: April 2023

Abstract
SNPs in IKZF1 are associated with inherited susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Besides, somatic copy number abnormalities (CNA) in genes related to lymphopoiesis (e.g., IKZF1, CDKN2A/B, BTG1) impact patient's outcome. Therefore, this study aimed to investigate an association between germline susceptibility and CNAs in BCP-ALL. The IKZF1 SNPs (rs11978267 and rs4132601) were genotyped in 276 cases and 467 controls. Bone marrow samples were used to determine the presence of somatic abnormalities. The IKZF1 transcript levels were quantified and associated with the SNPs and CNAs. Categorical variables were compared by χ2 test. ORs were estimated with unconditional logistic regression with 95% confidence interval (CI). The variant allele of IKZF1 rs4132601 conferred increased risk of BCP-ALL (OR, 2.09; 95% CI, 1.16–3.74). Individuals with either rs11978267 or rs4132601 had an increased risk for harboring IKZF1 deletion (OR, 2.80; 95% CI, 1.25–6.23 and OR, 2.88; 95% CI, 1.24–6.69, respectively). Increased risks were observed for individuals harboring both IKZF1 and BTG1 deletions (OR, 4.90; 95% CI, 1.65–14.55, rs11978267 and OR, 5.80; 95% CI, 1.94–17.41, rs4132601). Germline genetic variation increases the risk for childhood ALL in general, but also acts as a susceptibility factor bound for risk of specific somatic alterations. These findings provide new insight into the development of childhood ALL regarding causal variants and the biological basis of the risk association, offering the opportunity for future tailored research. Cancer Prev Res; 10(12); 738–44. ©2017 AACR.