bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma
Authors: Kadariya Yuwaraj , Menges Craig W. , Talarchek Jacqueline , Cai Kathy Q. , Klein-Szanto Andres J. , Pietrofesa Ralph A. , Christofidou-Solomidou Melpo , Cheung Mitchell , Mossman Brooke T. , Shukla Arti , Testa Joseph R.
Published: March 2024

Abstract
Exposure to asbestos is causally associated with the development of malignant mesothelioma, a cancer of cells lining the internal body cavities. Malignant mesothelioma is an aggressive cancer resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including malignant mesothelioma. The NALP3/NLRP3 inflammasome, including the component ASC, is thought to be an important mediator of inflammation in cells that sense extracellular insults, such as asbestos, and activate a signaling cascade resulting in release of mature IL1β and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to asbestos and evaluated differences in tumor incidence and latency. The Asc-deficient mice showed significantly delayed tumor onset and reduced malignant mesothelioma incidence compared with wild-type animals. We also tested whether inflammation-related release of IL1β contributes to tumor development in an accelerated mouse model of asbestos-induced malignant mesothelioma. Nf2+/−;Cdkn2a+/− mice exposed to asbestos in the presence of anakinra, an IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL1β/IL1R signaling and the development of asbestos-induced malignant mesothelioma. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL1β/IL1R signaling in high-risk, asbestos-exposed populations. Cancer Prev Res; 9(5); 406–14. ©2016 AACR.
Data from Sociocultural Factors, Access to Healthcare, and Lifestyle: Multifactorial Indicators in Association with Colorectal Cancer Risk
Authors: Warren Andersen Shaneda , Zheng Wei , Steinwandel Mark , Murff Harvey J. , Lipworth Loren , Blot William J.
Published: March 2024

Abstract
Black Americans of low socioeconomic status (SES) have higher colorectal cancer incidence than other groups in the United States. However, much of the research that identifies colorectal cancer risk factors is conducted in cohorts of high SES and non-Hispanic White participants. Adult participants of the Southern Community Cohort Study (N = 75,182) were followed for a median of 12.25 years where 742 incident colorectal cancers were identified. The majority of the cohort are non-Hispanic White or Black and have low household income. Cox models were used to estimate HRs for colorectal cancer incidence associated with sociocultural factors, access to and use of healthcare, and healthy lifestyle scores to represent healthy eating, alcohol intake, smoking, and physical activity. The association between Black race and colorectal cancer was consistent and not diminished by accounting for SES, access to healthcare, or healthy lifestyle [HR = 1.34; 95% confidence interval (CI),1.10–1.63]. Colorectal cancer screening was a strong, risk reduction factor for colorectal cancer (HR = 0.65; 95% CI, 0.55–0.78), and among colorectal cancer-screened, Black race was not associated with risk. Participants with high school education were at lower colorectal cancer risk (HR = 0.81; 95% CI, 0.67–0.98). Income and neighborhood-level SES were not strongly associated with colorectal cancer risk. Whereas individual health behaviors were not associated with risk, participants that reported adhering to ≥3 health behaviors had a 19% (95% CI, 1–34) decreased colorectal cancer risk compared with participants that reported ≤1 behaviors. The association was consistent in fully-adjusted models, although HRs were no longer significant. Colorectal cancer screening, education, and a lifestyle that includes healthy behaviors lowers colorectal cancer risk. Racial disparities in colorectal cancer risk may be diminished by colorectal cancer screening.
Prevention Relevance:
Colorectal cancer risk may be reduced through screening, higher educational attainment and performing more health behaviors. Importantly, our data show that colorectal cancer screening is an important colorectal cancer prevention strategy to eliminate the racial disparity in colorectal cancer risk.

See related Spotlight, p. 561
Data from Physical Activity and Long-term Quality of Life among Colorectal Cancer Survivors—A Population-based Prospective Study
Authors: Eyl Ruth Elisa , Koch-Gallenkamp Lena , Jansen Lina , Walter Viola , Carr Prudence R. , Hoffmeister Michael , Chang-Claude Jenny , Brenner Hermann , Arndt Volker
Published: March 2024

Abstract
Evidence suggests that physical activity (PA) is positively associated with (health-related) quality of life (QOL) in colorectal cancer survivors. However, little is known regarding long-term effects of PA on QOL and if prediagnosis PA is associated with QOL in the years after diagnosis. Our study aimed to investigate the association of prediagnosis and postdiagnosis PA with long-term QOL in colorectal cancer survivors.

This study is based on a population-based cohort from Germany of 1,781 newly diagnosed colorectal cancer survivors over a 5-year period. PA was assessed at diagnosis and at 5-year follow-up (5YFU). Quality of life was assessed by the European Organisation for Research and Treatment of Cancer C Quality of Life Questionnaire QLQ-C30 at 5YFU. Multivariable linear regression was used to explore associations between prediagnosis and postdiagnosis PA and QOL at 5YFU.

No evidence of a positive association between higher levels of prediagnosis PA and better long-term QOL was found. Higher levels of prediagnosis work-related PA and vigorous PA were even associated with decreased QOL in domains such as cognitive [Beta(β) = −2.52, 95% confidence interval (CI) = −3.77, −1.27; β = −1.92, CI = −3.17, −0.67) and emotional functioning (β = −2.52, CI = −3.84, −1.19; β = −2.12, CI = −3.44, −0.80). In cross-sectional analyses, higher postdiagnosis PA was strongly associated with higher QOL. Survivors physically active at both prediagnosis and postdiagnosis as well as survivors who increased their PA between prediagnosis and postdiagnosis reported significantly higher long-term QOL compared with survivors who remained inactive at prediagnosis and postdiagnosis. In this study, higher prediagnosis PA does not appear to be associated with higher QOL among long-term colorectal cancer survivors but our results support the importance of ongoing PA throughout survivorship.
Data from A Multi-Institutional Cohort of Therapy-Associated Polyposis in Childhood and Young Adulthood Cancer Survivors
Authors: Biller Leah H. , Ukaegbu Chinedu , Dhingra Tara G. , Burke Carol A. , Chertock Yana , Chittenden Anuradha , Church James M. , Koeppe Erika S. , Leach Brandie H. , Levinson Elana , Lim Ramona M. , Lutz Megan , Salo-Mullen Erin , Sheikh Rania , Idos Gregory , Kastrinos Fay , Stoffel Elena , Weiss Jennifer M. , Hall Michael J. , Kalady Matthew F. , Stadler Zsofia K. , Syngal Sapna , Yurgelun Matthew B.
Published: March 2024

Abstract
Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20–33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair–deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.
Data from Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype
Authors: Kanth Priyanka , Bronner Mary P. , Boucher Kenneth M. , Burt Randall W. , Neklason Deborah W. , Hagedorn Curt H. , Delker Don A.
Published: March 2024

Abstract
Sessile serrated colon adenoma/polyps (SSA/P) are found during routine screening colonoscopy and may account for 20% to 30% of colon cancers. However, differentiating SSA/Ps from hyperplastic polyps (HP) with little risk of cancer is challenging and complementary molecular markers are needed. In addition, the molecular mechanisms of colon cancer development from SSA/Ps are poorly understood. RNA sequencing (RNA-Seq) was performed on 21 SSA/Ps, 10 HPs, 10 adenomas, 21 uninvolved colon, and 20 control colon specimens. Differential expression and leave-one-out cross-validation methods were used to define a unique gene signature of SSA/Ps. Our SSA/P gene signature was evaluated in colon cancer RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify a subtype of colon cancers that may develop from SSA/Ps. A total of 1,422 differentially expressed genes were found in SSA/Ps relative to controls. Serrated polyposis syndrome (n = 12) and sporadic SSA/Ps (n = 9) exhibited almost complete (96%) gene overlap. A 51-gene panel in SSA/P showed similar expression in a subset of TCGA colon cancers with high microsatellite instability. A smaller 7-gene panel showed high sensitivity and specificity in identifying BRAF-mutant, CpG island methylator phenotype high, and MLH1-silenced colon cancers. We describe a unique gene signature in SSA/Ps that identifies a subset of colon cancers likely to develop through the serrated pathway. These gene panels may be utilized for improved differentiation of SSA/Ps from HPs and provide insights into novel molecular pathways altered in colon cancer arising from the serrated pathway. Cancer Prev Res; 9(6); 456–65. ©2016 AACR.
Data from Aspirin and the Risk of Colorectal Cancer According to Genetic Susceptibility among Older Individuals
Authors: Bakshi Andrew , Cao Yin , Orchard Suzanne G. , Carr Prudence R. , Joshi Amit D. , Manning Alisa K. , Buchanan Daniel D. , Umar Asad , Winship Ingrid M. , Gibbs Peter , Zalcberg John R. , Macrae Finlay , McNeil John J. , Lacaze Paul , Chan Andrew T.
Published: March 2024

Abstract
Although aspirin has been considered a promising agent for prevention of colorectal cancer, recent data suggest a lack of benefit among older individuals. Whether some individuals with higher risk of colorectal cancer may benefit from aspirin remains unknown. We used a 95-variant colorectal cancer polygenic risk score (PRS) to explore the association between genetic susceptibility to colorectal cancer and aspirin use in a prospective study of 12,609 individuals of European descent ages ≥70 years, enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) double-blinded, placebo-controlled randomized trial (randomized controlled trial; RCT). Cox proportional hazards models were used to assess the association of aspirin use on colorectal cancer, as well as the interaction between the PRS and aspirin treatment on colorectal cancer. Over a median of 4.7 years follow-up, 143 participants were diagnosed with incident colorectal cancer. Aspirin assignment was not associated with incidence of colorectal cancer overall [HR = 0.94; 95% confidence interval (CI), 0.68–1.30] or within strata of PRS (P for interaction = 0.97). However, the PRS was associated with an increased risk of colorectal cancer (HR = 1.28 per SD; 95% CI, 1.09–1.51). Individuals in the top quintile of the PRS distribution had an 85% higher risk compared with individuals in the bottom quintile (HR = 1.85; 95% CI, 1.08–3.15). In a prospective RCT of older individuals, a PRS is associated with incident colorectal cancer risk, but aspirin use was not associated with a reduction of incident colorectal cancer, regardless of baseline genetic risk.
Prevention Relevance:
There is strong evidence to support prophylactic aspirin use for the prevention of colorectal cancer. However recent recommendations suggest the risk of bleeding in older individuals outweighs the benefit. We sought to determine whether some older individuals might still benefit from aspirin based on their genetic susceptibility.
Data from Spatial Variation of the Native Colon Microbiota in Healthy Adults
Authors: Flynn Kaitlin J. , Ruffin Mack T. , Turgeon D. Kim , Schloss Patrick D.
Published: March 2024

Abstract
The microbiome has been implicated in the development of colorectal cancer and inflammatory bowel diseases. The specific traits of these diseases vary along the axis of the digestive tract. Further, variation in the structure of the gut microbiota has been associated with both diseases. We profiled the microbiota of the healthy proximal and distal mucosa and lumen to better understand how bacterial populations vary along the colon. We used a two-colonoscope approach to sample proximal and distal mucosal and luminal contents from the colons of 20 healthy subjects that had not undergone any bowel preparation procedure. The biopsies and home-collected stool were subjected to 16S rRNA gene sequencing, and random forest classification models were built using taxa abundance and location to identify microbiota specific to each site. The right mucosa and lumen had the most similar community structures of the five sites we considered from each subject. The distal mucosa had higher relative abundance of Finegoldia, Murdochiella, Peptoniphilus, Porphyromonas, and Anaerococcus. The proximal mucosa had more of the genera Enterobacteriaceae, Bacteroides, and Pseudomonas. The classification model performed well when classifying mucosal samples into proximal or distal sides (AUC = 0.808). Separating proximal and distal luminal samples proved more challenging (AUC = 0.599), and specific microbiota that differentiated the two were hard to identify. By sampling the unprepped colon, we identified distinct bacterial populations native to the proximal and distal sides. Further investigation of these bacteria may elucidate if and how these groups contribute to different disease processes on their respective sides of the colon. Cancer Prev Res; 11(7); 393–402. ©2018 AACR.
Data from Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia
Authors: Khandelwal Alok R. , Rong Xiaohua , Moore-Medlin Tara , Ekshyyan Oleksandr , Abreo Fleurette , Gu Xin , Nathan Cherie-Ann O.
Published: March 2024

Abstract
Aggressive cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common type of skin cancer in the United States due to high exposure to ultraviolet B (UVB) radiation. In our previous studies, Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed UVB-induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling that play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against acute UVB-induced hyperproliferation by targeting the mTOR and FGFR signaling pathways. Pretreatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2–induced cell proliferation, progression and colony formation, mTORC1 and mTORC2 activation, and FGFR2 phosphorylation in the promotion-sensitive JB6 cells epithelial cells. Further, FGFR was critical for UVB-induced mTOR activation, suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pretreated with C3 (15 mg/kg/b.w.) for 2 weeks followed by a single exposure to UVB (180 mj/cm2) significantly attenuated UVB-induced mTORC1, mTORC2, and FGFR2 activation. To further assess the role of FGFR in UVB-induced hyperproliferation, SKH-1 mice were pretreated with AZD4547 (5 mg/kg/b.w.); a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (180 mj/cm2). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyperproliferation. Our studies underscore the importance of FGFR signaling in UVB-induced acute skin changes and the role of FGFR/mTOR signaling in mediating the effects of C3 complex in the pathogenesis of skin cancer. Cancer Prev Res; 9(4); 296–304. ©2016 AACR.
Data from HIST1H2BB and MAGI2 Methylation and Somatic Mutations as Precision Medicine Biomarkers for Diagnosis and Prognosis of High-grade Serous Ovarian Cancer
Authors: Valle Blanca L. , Rodriguez-Torres Sebastian , Kuhn Elisabetta , Díaz-Montes Teresa , Parrilla-Castellar Edgardo , Lawson Fahcina P. , Folawiyo Oluwasina , Ili-Gangas Carmen , Brebi-Mieville Priscilla , Eshleman James R. , Herman James , Shih Ie-Ming , Sidransky David , Guerrero-Preston Rafael
Published: March 2024

Abstract
Molecular alterations that contribute to long-term (LT) and short-term (ST) survival in ovarian high-grade serous carcinoma (HGSC) may be used as precision medicine biomarkers. DNA promoter methylation is an early event in tumorigenesis, which can be detected in blood and urine, making it a feasible companion biomarker to somatic mutations for early detection and targeted treatment workflows. We compared the methylation profile in 12 HGSC tissue samples to 30 fallopian tube epithelium samples, using the Infinium Human Methylation 450K Array. We also used 450K methylation arrays to compare methylation among HGSCs long-term survivors (more than 5 years) and short-term survivors (less than 3 years). We verified the array results using bisulfite sequencing and methylation-specific PCR (qMSP). in another cohort of HGSC patient samples (n = 35). Immunoblot and clonogenic assays after pharmacologic unmasking show that HIST1H2BB and MAGI2 promoter methylation downregulates mRNA expression levels in ovarian cancer cells. We then used qMSP in paired tissue, ascites, plasma/serum, vaginal swabs, and urine from a third cohort of patients with HGSC cancer (n = 85) to test the clinical potential of HIST1H2BB and MAGI2 in precision medicine workflows. We also performed next-generation exome sequencing of 50 frequently mutated in human cancer genes, using the Ion AmpliSeqCancer Hotspot Panel, to show that the somatic mutation profile found in tissue and plasma can be quantified in paired urine samples from patients with HGSC. Our results suggest that HIST1H2BB and MAGI2 have growth-suppressing roles and can be used as HGSC precision medicine biomarkers.
Data from DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation
Authors: Sheaffer Karyn L. , Elliott Ellen N. , Kaestner Klaus H.
Published: March 2024

Abstract
Intestinal cancer is a heterogeneous disease driven by genetic mutations and epigenetic changes. Approximately 80% of sporadic colorectal cancers are initiated by mutation and inactivation of the adenomatous polyposis coli (APC) gene, which results in unrestrained intestinal epithelial growth and formation of adenomas. Aberrant DNA methylation promotes cancer progression by the inactivation of tumor suppressor genes via promoter methylation. In addition, global DNA hypomethylation is often seen before the formation of adenomas, suggesting that it contributes to neoplastic transformation. Previous studies employed mice with a hypomorphic mutation in DNA methyltransferase 1 (Dnmt1), which exhibited constitutive global DNA hypomethylation and decreased tumorigenesis in the ApcMin/+ mouse model of intestinal cancer. However, the consequences of intestinal epithelial-specific acute hypomethylation during ApcMin/+ tumor initiation have not been reported. Using temporally controlled intestinal epithelial-specific gene ablation, we show that total loss of Dnmt1 in the ApcMin/+ mouse model of intestinal cancer causes accelerated adenoma initiation. Deletion of Dnmt1 precipitates an acute response characterized by hypomethylation of repetitive elements and genomic instability, which surprisingly is followed by remethylation with time. Two months post-Dnmt1 ablation, mice display increased macroadenoma load, consistent with a role for Dnmt1 and DNA methylation in maintaining genomic stability. These data suggest that DNA hypomethylation plays a previously unappreciated role in intestinal adenoma initiation. Cancer Prev Res; 9(7); 534–46. ©2016 AACR.

See related article by Lee and Laird, p. 509
Data from Reversing the Genomic, Epigenetic, and Triple-Negative Breast Cancer–Enhancing Effects of Obesity
Authors: Bowers Laura W. , Doerstling Steven S. , Shamsunder Meghana G. , Lineberger Claire G. , Rossi Emily L. , Montgomery Stephanie A. , Coleman Michael F. , Gong Weida , Parker Joel S. , Howell Anthony , Harvie Michelle , Hursting Stephen D.
Published: March 2024

Abstract
The reversibility of the procancer effects of obesity was interrogated in formerly obese C57BL/6 mice that lost weight via a nonrestricted low-fat diet (LFD) or 3 distinct calorie-restricted (CR) regimens (low-fat CR, Mediterranean-style CR, or intermittent CR). These mice, along with continuously obese mice and lean control mice, were orthotopically injected with E0771 cells, a mouse model of triple-negative breast cancer. Tumor weight, systemic cytokines, and incidence of lung metastases were elevated in the continuously obese and nonrestricted LFD mice relative to the 3 CR groups. Gene expression differed between the obese and all CR groups, but not the nonrestricted LFD group, for numerous tumoral genes associated with epithelial-to-mesenchymal transition as well as several genes in the normal mammary tissue associated with hypoxia, reactive oxygen species production, and p53 signaling. A high degree of concordance existed between differentially expressed mammary tissue genes from obese versus all CR mice and a microarray dataset from overweight/obese women randomized to either no intervention or a CR diet. Assessment of differentially methylated regions in mouse mammary tissues revealed that obesity, relative to the 4 weight loss groups, was associated with significant DNA hypermethylation. However, the anticancer effects of the CR interventions were independent of their ability to reverse obesity-associated mammary epigenetic reprogramming. Taken together, these preclinical data showing that the procancer effects of obesity are reversible by various forms of CR diets strongly support translational exploration of restricted dietary patterns for reducing the burden of obesity-associated cancers.
Prevention Relevance:
Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC). Given rising global rates of obesity and TNBC, strategies to reduce the burden of obesity-driven TNBC are urgently needed. We report the genomic, epigenetic, and procancer effects of obesity are reversible by various calorie restriction regimens.
Data from Primary Care Provider Beliefs and Recommendations About Colorectal Cancer Screening in Four Healthcare Systems
Authors: Ghai Nirupa R. , Jensen Christopher D. , Merchant Sophie A. , Schottinger Joanne E. , Lee Jeffrey K. , Chubak Jessica , Kamineni Aruna , Halm Ethan A. , Skinner Celette Sugg , Haas Jennifer S. , Green Beverly B. , Cannizzaro Nancy T. , Schneider Jennifer L. , Corley Douglas A.
Published: March 2024

Abstract
Primary care provider's (PCP) perceptions of colorectal cancer screening test effectiveness and their recommendations for testing intervals influence patient screening uptake. Few large studies have examined providers’ perceptions and recommendations, including their alignment with evidence suggesting comparable test effectiveness and guideline recommendations for screening frequency. Providers (n = 1,281) within four healthcare systems completed a survey in 2017–2018 regarding their perceptions of test effectiveness and recommended intervals for colonoscopy and fecal immunochemical testing (FIT) for patients ages 40–49, 50–74, and ≥75 years. For patients 50–74 (screening eligible), 82.9% of providers rated colonoscopy as very effective versus 59.6% for FIT, and 26.3% rated colonoscopy as more effective than FIT. Also, for this age group, 77.9% recommended colonoscopy every 10 years and 92.4% recommended FIT annually. For patients ages 40–49 and ≥75, more than one-third of providers believed the tests were somewhat or very effective, although >80% did not routinely recommend screening by either test for these age groups. Provider screening test interval recommendations generally aligned with colorectal cancer guidelines; however, 25% of providers believed colonoscopy was more effective than FIT for mortality reduction, which differs from some modeling studies that suggest comparable effectiveness. The latter finding may have implications for health systems where FIT is the dominant screening strategy. Only one-third of providers reported believing these screening tests were effective in younger and older patients (i.e., <50 and ≥75 years). Evidence addressing these beliefs may be relevant if cancer screening recommendations are modified to include older and/or younger patients.
Data from The Acceptability and Preference of Vaginal Self-sampling for Human Papillomavirus (HPV) Testing among a Multi-ethnic Asian Female Population
Authors: Khoo Su Pei , Lim Wen Tzien , Rajasuriar Reena , Nasir Nazrila Hairizan , Gravitt Patti , Woo Yin Ling
Published: March 2024

Abstract
Vaginal self-sampling for human papillomavirus (HPV) testing can potentially increase cervical screening coverage. This study aimed to investigate the acceptability of vaginal self-sampling for HPV testing and factors that might influence a woman's preference for this as a cervical screening method. This was a cross-sectional study that recruited 725 women from the urban and suburban areas of Selangor, Malaysia. All study participants were instructed to self-collect vaginal sample using a dry flocked swab before responding to a detailed questionnaire documenting their experience and preference for self-sampling. Most of the study participants (>80%) perceived vaginal self-sampling as easy, convenient, not embarrassing, comfortable, and were confident in performing the test. This suggests high acceptability toward vaginal self-sampling for HPV testing. Of the 725 women, 83% preferred self-sampling HPV testing over healthcare personnel sampling HPV testing and Pap test. Women with higher household income and full-time employment status were more likely to prefer self-sampling. Those who had not undergone Pap test also expressed preference for self-sampling HPV testing. Convenience and women's confidence in performing a vaginal self-sampling for HPV testing were the independent key factors that influenced the preference for self-sampling method. Vaginal self-sampling for HPV testing is highly acceptable among Malaysian women. It is the preferred choice as a primary cervical screening method and serves as an alternative to healthcare-acquired sample for Pap test.
Prevention Relevance:
Organized cervical cancer screening remains unachievable in many countries. Self-sampling HPV testing is an evidence-based method that can remove barriers to cervical screening. This is particularly important for developing countries in order to achieve the WHO global strategy to accelerate cervical cancer elimination.
Data from Effect of Aspirin on Melanoma Incidence in Older Persons: Extended Follow-up of a Large Randomized Double-blind Placebo-controlled Trial
Authors: Yan Mabel K. , Orchard Suzanne G. , Adler Nikki R. , Wolfe Rory , McLean Catriona , Rodriguez Luz María. , Woods Robyn L. , Gibbs Peter , Chan Andrew T. , Haydon Andrew , Mar Victoria J.
Published: March 2024

Abstract
The effects of aspirin on melanoma are unclear, with studies reporting conflicting results. Data from two periods of the ASPirin in Reducing Events in the Elderly (ASPREE) study; the randomized placebo-controlled trial period examining daily 100 mg aspirin in older adults with a median follow-up of 4.7 years, and the second period, an additional 2 years of observational follow-up, were utilized in this secondary analysis to examine whether aspirin exposure is associated with a reduced cutaneous melanoma incidence. All melanoma cases were adjudicated and Cox proportional hazards models were used to compare incidence between randomized treatment groups. ASPREE recruited 19,114 participants with a median age of 74 years. During the trial period, 170 individuals (76 aspirin, 94 placebo) developed an invasive melanoma, and no significant effect of aspirin was observed on incident melanoma [HR = 0.81; 95% confidence interval (CI), 0.60–1.10]. Including the additional 2 years of observational follow-up (median follow-up of 6.3 years), 268 individuals (119 aspirin, 149 placebo) developed an invasive melanoma, and similar results were observed (HR = 0.81; 95% CI, 0.63–1.03). A reduced number of events was observed with aspirin among females in a subgroup analysis (HR = 0.65; 95% CI, 0.44–0.92); however, the interaction effect with males (HR = 0.92; 95% CI, 0.68–1.25) was nonsignificant (P = 0.17). Our findings from this randomized trial do not provide strong support that aspirin is associated with a reduced risk of invasive melanoma in older individuals. Additional studies are required to further explore this relationship.
Prevention Relevance:
Melanoma prevention is an important strategy to improve outcomes and while preventive efforts have largely focused on sun protection, the role of potential chemopreventive agents such as aspirin warrants investigation.
Data from Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study
Authors: Fabian Carol J. , Nye Lauren , Powers Kandy R. , Nydegger Jennifer L. , Kreutzjans Amy L. , Phillips Teresa A. , Metheny Trina , Winblad Onalisa , Zalles Carola M. , Hagan Christy R. , Goodman Merit L. , Gajewski Byron J. , Koestler Devin C. , Chalise Prabhakar , Kimler Bruce F.
Published: March 2024

Abstract
Interventions that relieve vasomotor symptoms while reducing risk for breast cancer would likely improve uptake of chemoprevention for perimenopausal and postmenopausal women. We conducted a pilot study with 6 months of the tissue selective estrogen complex bazedoxifene (20 mg) and conjugated estrogen (0.45 mg; Duavee) to assess feasibility and effects on risk biomarkers for postmenopausal breast cancer. Risk biomarkers included fully automated mammographic volumetric density (Volpara), benign breast tissue Ki-67 (MIB-1 immunochemistry), and serum levels of progesterone, IGF-1, and IGFBP3, bioavailable estradiol and testosterone. Twenty-eight perimenopausal and postmenopausal women at increased risk for breast cancer were enrolled: 13 in cohort A with baseline Ki-67 < 1% and 15 in cohort B with baseline Ki-67 of 1% to 4%. All completed the study with > 85% drug adherence. Significant changes in biomarkers, uncorrected for multiple comparisons, were a decrease in mammographic fibroglandular volume (P = 0.043); decreases in serum progesterone, bioavailable testosterone, and IGF-1 (P < 0.01), an increase in serum bioavailable estradiol (P < 0.001), and for women from cohort B a reduction in Ki-67 (P = 0.017). An improvement in median hot flash score from 15 at baseline to 0 at 6 months, and menopause-specific quality-of-life total, vasomotor, and sexual domain scores were also observed (P < 0.001). Given the favorable effects on risk biomarkers and patient reported outcomes, a placebo-controlled phase IIB trial is warranted.
Data from Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts
Authors: Zhou Cindy Ke , Daugherty Sarah E. , Liao Linda M. , Freedman Neal D. , Abnet Christian C. , Pfeiffer Ruth , Cook Michael B.
Published: March 2024

Abstract
Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer–specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75–0.90) and 15% (HR = 0.85; 95% CI = 0.77–0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72–0.95) and 25% (HR = 0.75; 95% CI = 0.66–0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410–20. ©2017 AACR.
Data from Breast Cancer Risk and Use of Nonsteroidal Anti-inflammatory Agents After a Benign Breast Biopsy
Authors: Sherman Mark E. , Vierkant Robert A. , Kaggal Suneetha , Hoskin Tanya L. , Frost Marlene H. , Denison Lori , Visscher Daniel W. , Carter Jodi M. , Winham Stacey J. , Jensen Matthew R. , Radisky Derek C. , Vachon Celine M. , Degnim Amy C.
Published: March 2024

Abstract
Over one million women in the United States receive biopsy diagnoses of benign breast disease (BBD) each year, which confer a 1.5–4.0-fold increase in breast cancer risk. Studies in the general population suggest that nonsteroidal anti-inflammatory agents (NSAID) lower breast cancer risk; however, associations among women with BBD are unknown. We assessed whether NSAID use among women diagnosed with BBD is associated with lower breast cancer risk. Participants included 3,080 women (mean age = 50.3 ± 13.5 years) in the Mayo BBD surgical biopsy cohort diagnosed between January 1, 1992 and December 31, 2001 who completed breast cancer risk factor questionnaires that assessed NSAID use, and whose biopsies underwent detailed pathology review, masked to outcome. Women were followed from date of BBD biopsy to breast cancer diagnosis (main outcome) or censoring (death, prophylactic mastectomy, reduction mammoplasty, lobular carcinoma in situ or last contact). Median follow-up time was 16.4 ± 6.0 years. Incident breast cancer was diagnosed among 312 women over a median follow-up of 9.9 years. Regular non-aspirin NSAID use was associated with lower breast cancer risk [HR = 0.63; 95% confidence interval (CI) = 0.46–0.85; P = 0.002] with trends of lower risk (highest tertiles of use vs. nonuse) for greater number of years used [HR = 0.55; 95% CI = 0.31–0.97; Ptrend = 0.003), days used per month (HR = 0.51; 95% CI = 0.33–0.80; Ptrend = 0.001) and lifetime number of doses taken (HR = 0.53; 95% CI = 0.31–0.89; Ptrend = 0.003). We conclude that nonaspirin NSAID use is associated with statistically significant lower breast cancer risk after a BBD biopsy, including a dose–response effect, suggesting a potential role for NSAIDs in breast cancer prevention among patients with BBD.
Data from Risk of De Novo Hepatocellular Carcinoma Following Use of Direct Acting Antiviral Medications for Treatment of Chronic Hepatitis C
Authors: Antwi Samuel O. , Van Houten Holly K. , Sangaralingham Lindsey R. , Patel Tushar
Published: March 2024

Abstract
Direct-acting antivirals (DAA) are now the mainstay of treatment for patients with chronic hepatitis C virus (HCV); however, there is some controversy over whether use of DAAs for HCV, as compared with IFN-based regimens, leads to an increased risk for hepatocellular carcinoma (HCC) development. We investigated the association between use of DAAs and subsequent development of HCC in longitudinal data from patients with HCV from diverse backgrounds (various ages, ethnicities, and geographic regions) across the United States. The design was a retrospective study performed using medical and pharmacy claims from OptumLabs. HCV treatment exposure was categorized as DAA-only, DAA + IFN, any-DAA, or IFN-only. To account for confounding by indication, inverse probability of treatment weighting was performed. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). We identified 5,781 patients with HCV with no history of HCC at baseline. Compared with IFN-only regimen, no significant increase in HCC risk was found for use of DAA-only (HR, 1.53; 95% CI, 0.73–3.23), DAA + IFN (HR, 1.02; 95% CI, 0.51–2.06), or any-DAA (HR, 1.04; 95% CI, 0.65–1.65). When stratified by sustained virological response (SVR), we noted a higher HCC risk for DAA-only among patients who achieved SVR post-treatment (HR, 7.53; 95% CI, 1.48–38.34), but the CIs were wide, which might be due to the small sample size of the subgroups. Among those who did not achieve SVR, no association was found for use of DAA-only (HR, 0.59; 95% CI, 0.19–1.91). These findings do not provide compelling evidence for the conception that use of DAAs for HCV is associated with increased risk of HCC development.
Data from Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis
Authors: Boutaud Olivier , Sosa I. Romina , Amin Taneem , Oram Denise , Adler David , Hwang Hyun S. , Crews Brenda C. , Milne Ginger , Harris Bradford K. , Hoeksema Megan , Knollmann Bjorn C. , Lammers Philip E. , Marnett Lawrence J. , Massion Pierre P. , Oates John A.
Published: March 2024

Abstract
Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)–derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE2 biosynthesis. We show that low-dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet–tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855–65. ©2016 AACR.
Data from Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development
Authors: Chu Nina J. , Anders Robert A. , Fertig Elana J. , Cao Minwei , Hopkins Alexander C. , Keenan Bridget P. , Popovic Aleksandra , Armstrong Todd D. , Jaffee Elizabeth M. , Zimmerman Jacquelyn W.
Published: March 2024

Abstract
Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. In vivo miR-21 inhibition improved survival in established PDA. Importantly, early systemic miR-21 inhibition completely intercepted premalignant progression. Finally, an evaluation of miR-21 expression in the PDA cohort of The Cancer Genome Atlas identified a correlation between tumor epithelial cell content and miR-21 expression in human tumors providing further rationale for conducting human studies. Thus, miR-21 may be useful for early PanIN detection, and for intercepting developing premalignant pancreatic lesions and other KRAS-driven premalignancies.
Data from The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice
Authors: Cao Martine , Royce Darlene B. , Risingsong Renee , Williams Charlotte R. , Sporn Michael B. , Liby Karen T.
Published: March 2024

Abstract
LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1β, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology. Cancer Prev Res; 9(1); 105–14. ©2015 AACR.
Data from Risk of Prostate Cancer–related Death Following a Low PSA Level in the PLCO Trial
Authors: Landy Rebecca , Houghton Lauren C. , Berg Christine D. , Grubb Robert L. , Katki Hormuzd A. , Black Amanda
Published: March 2024

Abstract
Longer-than-annual screening intervals have been suggested to improve the balance of benefits and harms in prostate cancer screening. Many researchers, societies, and guideline committees have suggested that screening intervals could depend on the prostate-specific antigen (PSA) result. We analyzed data from men (N = 33,897) ages 55–74 years with a baseline PSA test in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial (United States, 1993–2001). We estimated 5- and 10-year risks of aggressive cancer (Gleason ≥8 and/or stage III/IV) and 15-year risks of prostate cancer–related mortality for men with baseline PSA ≤ 0.5 ng/mL (N = 4,862), ≤1 ng/mL (N = 15,110), and 1.01–2.5 ng/mL (N = 12,422). A total of 217 men died from prostate cancer through 15 years, although no men with PSA ≤ 1 ng/mL died from prostate cancer within 5 years [95% confidence interval (CI), 0.00%–0.03%]. The 5-year incidence of aggressive disease was low (0.08%; 95% CI, 0.03%–0.12%) for men with PSA ≤ 1 ng/mL, and higher for men with baseline PSA 1.01–2.5 ng/mL (0.51%; 95% CI, 0.38%–0.74%). No men aged ≥65 years with PSA ≤ 0.5 ng/mL died from prostate cancer within 15 years (95% CI, 0.00%–0.32%), and their 10-year incidence of aggressive disease was low (0.25%; 95% CI, 0.00%–0.53%). Compared with white men, black men with PSA ≤ 1 ng/mL had higher 10-year rates of aggressive disease (1.6% vs. 0.4%; P < 0.01). Five-year screening intervals may be appropriate for the 45% of men with PSA ≤ 1 ng/mL. Men ages ≥65 years with PSA ≤ 0.5 ng/mL could consider stopping screening. Substantial risk disparities suggest appropriate screening intervals could depend on race/ethnicity.