bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Hepatitis B Virus Combo Mutations Improve the Prediction and Active Prophylaxis of Hepatocellular Carcinoma: A Clinic-Based Cohort Study
Authors: Yin Jianhua , Wang Junxue , Pu Rui , Xin Haiguang , Li Zixiong , Han Xue , Ding Yibo , Du Yan , Liu Wenbin , Deng Yang , Ji Xiaowei , Wu Ming , Yu Min , Zhang Hongwei , Wang Hongyang , Thompson Timothy C. , Ni Wu , Cao Guangwen
Published: March 2024

Abstract
We aimed to evaluate whether hepatitis B virus (HBV) mutations at the core promoter region could improve the prediction and specific prophylaxis of hepatocellular carcinoma (HCC) in chronic HBV-infected patients. A total of 2,114 HBV-infected patients enrolled between August 1998 and December 2007 were followed-up for 18,406 person-years. Of those, 612 received ≥48 week treatments with nucleos(t)ide analogue (NA) and/or IFNα. Baseline HBV mutations were identified by sequencing. Propensity score matching was applied to reduce baseline differences between antiviral and control cohorts. Multivariate Cox regression analyses, including baseline characteristics of 2,114 patients, showed that age, male, cirrhosis, and HBV mutations (C1653T, T1753V, and A1762T/G1764A) independently increased HCC risk. In control patients carrying A1762T/G1764A, addition of C1653T and/or T1753V significantly increased HCC risk (HR, 1.57; P = 0.038); combo mutations with C1653T, T1753V, and A1762T/G1764A improved the validity of HCC prediction by age, male, and cirrhosis (P = 0.002). In the matched cohorts, antiviral treatment reduced HCC incidence (13.90/1,000 vs. 7.70/1,000 person-years, P = 0.005); NA treatment for ≥60 months was required for the prophylaxis of HCC in cirrhotic patients (P = 0.03); antiviral treatment reduced HCC risk in patients carrying A1762T/G1764A (HR, 0.40; P = 0.002) or C1653T (HR, 0.45; P = 0.04) and in those without T1753V (HR, 0.42; P = 0.005), but could not reduce HCC risk in patients without A1762T/G1764A or C1653T and in those with T1753V. In summary, HBV mutation A1762T/G1764A, C1653T, and T1753V in combination improve HCC prediction in HBV-infected patients. To prevent HCC, patients infected with HBV carrying A1762T/G1764A or C1653T, but not T1753V, should be given priority of receiving antiviral treatments. Cancer Prev Res; 8(10); 978–88. ©2015 AACR.
Data from Chemoprevention of Colon Cancer in a Rat Carcinogenesis Model Using a Novel Nanotechnology-Based Combined Treatment System
Authors: Chaudhary Abhishek , Sutaria Dhruvitkumar , Huang Ying , Wang Jeffrey , Prabhu Sunil
Published: March 2024

Abstract
Colorectal cancer (CRC) is the third most common cause of cancer death in the United States, accounting for approximately 51,000 deaths each year. We have previously shown in vitro chemopreventive effects of mixtures of aspirin, folic acid, and calcium (AFAC) on colon cancer cell lines. The objective of the present study was to evaluate the in vivo effects of orally administered, colon targeted chemopreventive combination regimens on the inhibition of aberrant crypt foci (ACF) in a rat model of colon carcinogenesis using (i) unmodified (free drug) combinations of AFAC and (ii) nanoparticle-encapsulated combinations of the same agents. A 14-week animal study was conducted in three phases to determine an optimal effective dose from AFAC combinations and evaluate the efficacy of nanotechnology-based chemopreventive regimens administered in combined (mixtures) and individual (single entity) forms. ACF inhibition when compared with azoxymethane-treated rat control group was significant in both the unmodified and the modified nanoparticle-mediated chemopreventive regimens, showing a range of 31% to 38% (P < 0.05) and 50% to 75% (P < 0.001) reduction, respectively, in the number of ACFs. In addition, the nanoparticulate combination regimens of AFAC showed a 2-fold increase in suppression of ACF compared with free drug mixtures. Individual administration of nanoparticle-encapsulated drugs showed no significant effect on the reduction of ACF. Histochemical analysis provided further confirmation of chemopreventive effects, showing a significant reduction in cell nuclear proliferation. Overall, our results provide a strong proof of concept using nanoparticle-mediated combination treatment in the chemoprevention of colon cancer. Cancer Prev Res; 4(10); 1655–64. ©2011 AACR.
Data from Alterations in Bronchial Airway miRNA Expression for Lung Cancer Detection
Authors: Pavel Ana B. , Campbell Joshua D. , Liu Gang , Elashoff David , Dubinett Steven , Smith Kate , Whitney Duncan , Lenburg Marc E. , Spira Avrum
Published: March 2024

Abstract
We have previously shown that gene expression alterations in normal-appearing bronchial epithelial cells can serve as a lung cancer detection biomarker in smokers. Given that miRNAs regulate airway gene expression responses to smoking, we evaluated whether miRNA expression is also altered in the bronchial epithelium of smokers with lung cancer. Using epithelial brushings from the mainstem bronchus of patients undergoing bronchoscopy for suspected lung cancer (as part of the AEGIS-1/2 clinical trials), we profiled miRNA expression via small-RNA sequencing from 347 current and former smokers for which gene expression data were also available. Patients were followed for one year postbronchoscopy until a final diagnosis of lung cancer (n = 194) or benign disease (n = 153) was made. Following removal of 6 low-quality samples, we used 138 patients (AEGIS-1) as a discovery set to identify four miRNAs (miR-146a-5p, miR-324-5p, miR-223-3p, and miR-223-5p) that were downregulated in the bronchial airway of lung cancer patients (ANOVA P < 0.002, FDR < 0.2). The expression of these miRNAs is significantly more negatively correlated with the expression of their mRNA targets than with the expression of other nontarget genes (K-S P < 0.05). Furthermore, these mRNA targets are enriched among genes whose expression is elevated in cancer patients (GSEA FDR < 0.001). Finally, we found that the addition of miR-146a-5p to an existing mRNA biomarker for lung cancer significantly improves its performance (AUC) in the 203 samples (AEGIS-1/2) serving an independent test set (DeLong P < 0.05). Our findings suggest that there are miRNAs whose expression is altered in the cytologically normal bronchial epithelium of smokers with lung cancer, and that they may regulate cancer-associated gene expression differences. Cancer Prev Res; 10(11); 651–9. ©2017 AACR.
Data from Inhibitory Effects of γ- and δ-Tocopherols on Estrogen-Stimulated Breast Cancer In Vitro and In Vivo
Authors: Bak Min Ji , Das Gupta Soumyasri , Wahler Joseph , Lee Hong Jin , Li Xiaowei , Lee Mao-Jung , Yang Chung S. , Suh Nanjoo
Published: March 2024

Abstract
Estrogens have been implicated as complete carcinogens for breast and other tissues through mechanisms involving increased cell proliferation, oxidative stress, and DNA damage. Because of their potent antioxidant activity and other effects, tocopherols have been shown to exert antitumor activities in various cancers. However, limited information is available on the effect of different forms of tocopherols in estrogen-mediated breast cancer. To address this, we examined the effects of α-, γ-, and δ-tocopherols as well as a natural γ-tocopherol–rich mixture of tocopherols, γ-TmT, on estrogen-stimulated MCF-7 cells in vitro and in vivo. For the in vivo studies, MCF-7 cells were injected into the mammary fat pad of immunodeficient mice previously implanted with estrogen pellets. Mice were then administered diets containing 0.2% α-, γ-, δ-tocopherol, or γ-TmT for 5 weeks. Treatment with α-, γ-, δ-tocopherols, and γ-TmT reduced tumor volumes by 29% (P < 0.05), 45% (P < 0.05), 41% (P < 0.05), and 58% (P < 0.01), as well as tumor weights by 20%, 37% (P < 0.05), 39% (P < 0.05), and 52% (P < 0.05), respectively. γ- and δ-tocopherols and γ-TmT inhibited the expression of cell proliferation–related genes such as cyclin D1 and c-Myc, and estrogen-related genes such as TFF/pS2, cathepsin D, and progesterone receptor in estrogen-stimulated MCF-7 cells in vitro. Further, γ- and δ-tocopherols decreased the levels of estrogen-induced oxidative stress and nitrosative stress markers, 8-hydroxy-2′-deoxyguanosine and nitrotyrosine, as well as the DNA damage marker, γ-H2AX. Our results suggest that γ- and δ-tocopherols and the γ-tocopherol–rich mixture are effective natural agents for the prevention and treatment of estrogen-mediated breast cancer. Cancer Prev Res; 10(3); 188–97. ©2017 AACR.
Data from Sleep Duration across the Adult Lifecourse and Risk of Lung Cancer Mortality: A Cohort Study in Xuanwei, China
Authors: Wong Jason Y. , Bassig Bryan A. , Vermeulen Roel , Hu Wei , Ning Bofu , Seow Wei Jie , Ji Bu-Tian , Downward George S. , Katki Hormuzd A. , Barone-Adesi Francesco , Rothman Nathaniel , Chapman Robert S. , Lan Qing
Published: March 2024

Abstract
Sufficient sleep duration is crucial for maintaining normal physiological function and has been linked to cancer risk; however, its contribution to lung cancer mortality is unclear. Therefore, we evaluated the relationship between average sleep duration in various age-periods across the adult lifecourse, and risk of lung cancer mortality in Xuanwei, China. An ambidirectional cohort study was conducted in 42,422 farmers from Xuanwei, China. Participants or their surrogates were interviewed in 1992 to assess average sleep hours in the age periods of 21–30, 31–40, 41–50, 51–60, 61–70, and ≥71 years, which were categorized as ≤7, 8 (reference), 9, and ≥10 hours/day. Vital status was followed until 2011. Sex-specific Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lung cancer mortality in 1994–2011, adjusted for demographic, anthropometric, medical, and household characteristics. J-shaped relationships were found between average sleep duration and lung cancer mortality. The patterns were consistent across sex, age periods, and fuel usage. Compared with sleeping 8 hours/day on average, ≤7 hours/day was associated with significantly increased HRs ranging from 1.39 to 1.58 in ages ≥41 years in men, and 1.29 to 2.47 in ages ≥51 years in women. Furthermore, sleeping ≥10 hours/day was associated with significantly increased HRs ranging from 2.44 to 3.27 in ages ≥41 year in men, and 1.31 to 2.45 in ages ≤60 years in women. Greater and less than 8 hours/day of sleep in various age-periods may be associated with elevated risk of lung cancer mortality in Xuanwei, China. Cancer Prev Res; 10(6); 327–35. ©2017 AACR.
Data from PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions
Authors: Wang Jin , Xie Tongxin , Wang Bingbing , William William N. , Heymach John V. , El-Naggar Adel K. , Myers Jeffrey N. , Caulin Carlos
Published: March 2024

Abstract
Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPL). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti–PD-1 treatment significantly reduced the number of oral lesions that developed in these mice and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8+ and CD4+ T cells and the accumulation of CTLA-4+ T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of IFNγ, STAT1 activation and the production of the T-cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T-cell activation mediates the immunopreventive effects of anti–PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti–PD-1. Cancer Prev Res; 10(12); 684–93. ©2017 AACR.

See related editorial by Gutkind et al., p. 681
Data from Evaluation of Biodistribution of Sulforaphane after Administration of Oral Broccoli Sprout Extract in Melanoma Patients with Multiple Atypical Nevi
Authors: Tahata Shawn , Singh Shivendra V. , Lin Yan , Hahm Eun-Ryeong , Beumer Jan H. , Christner Susan M. , Rao Uma N. , Sander Cindy , Tarhini Ahmad A. , Tawbi Hussein , Ferris Laura K. , Wilson Melissa , Rose Amy , Dietz Catherine M. , Hughes Ellen , Fahey Jed W. , Leachman Sancy A. , Cassidy Pamela B. , Butterfield Lisa H. , Zarour Hassane M. , Kirkwood John M.
Published: March 2024

Abstract
Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation–induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 μmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 μmol, 206 ng/mL for 100 μmol, and 655 ng/mL for 200 μmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 μmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 μmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 μmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. Cancer Prev Res; 11(7); 429–38. ©2018 AACR.
Data from Transcriptome-wide In Vitro Effects of Aspirin on Patient-derived Normal Colon Organoids
Authors: Devall Matthew A.M. , Drew David A. , Dampier Christopher H. , Plummer Sarah J. , Eaton Stephen , Bryant Jennifer , Díez-Obrero Virginia , Mo Jiancheng , Kedrin Dmitriy , Zerjav Dylan C. , Takacsi-Nagy Oliver , Jennelle Lucas T. , Ali Mourad W. , Yilmaz Ömer H. , Moreno Victor , Powell Steven M. , Chan Andrew T. , Peters Ulrike , Casey Graham
Published: March 2024

Abstract
Mechanisms underlying aspirin chemoprevention of colorectal cancer remain unclear. Prior studies have been limited because of the inability of preclinical models to recapitulate human normal colon epithelium or cellular heterogeneity present in mucosal biopsies. To overcome some of these obstacles, we performed in vitro aspirin treatment of colon organoids derived from normal mucosal biopsies to reveal transcriptional networks relevant to aspirin chemoprevention. Colon organoids derived from 38 healthy individuals undergoing endoscopy were treated with 50 μmol/L aspirin or vehicle control for 72 hours and subjected to bulk RNA sequencing. Paired regression analysis using DESeq2 identified differentially expressed genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin treatment was associated with 1,154 significant (q < 0.10) DEGs prior to deconvolution. We provide replication of these findings in an independent population-based RNA-sequencing dataset of mucosal biopsies (BarcUVa-Seq), where a significant enrichment for overlap of DEGs was observed (P < 2.2E−16). Single-cell deconvolution revealed changes in cell composition, including a decrease in transit-amplifying cells following aspirin treatment (P = 0.01). Following deconvolution, DEGs included novel putative targets for aspirin such as TRABD2A (q = 0.055), a negative regulator of Wnt signaling. Weighted gene co-expression network analysis identified 12 significant modules, including two that contained hubs for EGFR and PTGES2, the latter being previously implicated in aspirin chemoprevention. In summary, aspirin treatment of patient-derived colon organoids using physiologically relevant doses resulted in transcriptome-wide changes that reveal altered cell composition and improved understanding of transcriptional pathways, providing novel insight into its chemopreventive properties.
Prevention Relevance:
Numerous studies have highlighted a role for aspirin in colorectal cancer chemoprevention, though the mechanisms driving this association remain unclear. We addressed this by showing that aspirin treatment of normal colon organoids diminished the transit-amplifying cell population, inhibited prostaglandin synthesis, and dysregulated expression of novel genes implicated in colon tumorigenesis.
Data from DNA Methylation of Telomere-Related Genes and Cancer Risk
Authors: Joyce Brian T. , Zheng Yinan , Nannini Drew , Zhang Zhou , Liu Lei , Gao Tao , Kocherginsky Masha , Murphy Robert , Yang Hushan , Achenbach Chad J. , Roberts Lewis R. , Hoxha Mirjam , Shen Jincheng , Vokonas Pantel , Schwartz Joel , Baccarelli Andrea , Hou Lifang
Published: March 2024

Abstract
Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (β = 1.0–6.93) and one protective CpG in MAD1L1 (β = −0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction. Cancer Prev Res; 11(8); 511–22. ©2018 AACR.
Data from Vaccination with Polyclonal Antibody Stimulator (PAS) Prevents Pancreatic Carcinogenesis in the KRAS Mouse Model
Authors: Smith Jill P. , Cao Hong , Chen Wenqiang , Kallakury Bhaskar , Phillips Teresa , Sutton Lynda , Cato Allen
Published: March 2024

Abstract
The incidence of pancreatic cancer is increasing significantly and will soon become the second leading cause of cancer-related deaths in the United States. We have previously shown that the gastrointestinal peptide gastrin, which is only expressed in the fetal pancreas and not in the adult pancreas, is activated during pancreatic carcinogenesis where it stimulates growth in an autocrine fashion. In this investigation, we used transgenic LSL-KrasG12D/+; P48-Cre mice that develop precancerous pancreatic intraepithelial neoplasia (PanIN) lesions and pancreatic cancer over time. Starting at 3 months of age, mice were either left untreated (control) or were treated with a gastrin-targeted vaccine, polyclonal antibody stimulator (PAS 250 μg) followed by a monthly booster until the mice reached 8 months of age when pancreata were excised, and analyzed by histology for PanIN grade in a blinded fashion. High-grade PanIN-3 lesions were significantly less in PAS-treated mice (P = 0.0077), and cancers developed in 33% of the control mice but only in 10% of the PAS-treated mice. Compared with the control mice, fibrosis was reduced by >50%, arginase positive M2 macrophages were reduced by 74%, and CD8+ T cells were increased by 73% in the pancreas extracellular matrix in PAS-treated mice.
Prevention Relevance:
PAS vaccination significantly decreased high-grade PanIN lesions and altered the pancreas microenvironment, rendering it less carcinogenic.
Data from Blood Supply of Early Lung Adenocarcinomas in Mice and the Tumor-supplying Vessel Relationship: A Micro-CT Angiography Study
Authors: Deng Lin , Tang Hanzhou , Qiang Jinwei , Wang Jie , Xiao Shiman
Published: March 2024

Abstract
This study aimed to investigate the blood supply of early lung adenocarcinomas in mice and the relationship between tumors and their supplying vessels by using micro-CT. An early lung adenocarcinoma model was established in 10 female mice with subcutaneous injections of a 1-methyl-3-nitro-1-nitrosoguanidine solution. Micro-CT pulmonary and bronchial arteriography were performed to demonstrate the blood supply of early lung adenocarcinomas, especially the tumor–vessel relationships, and the findings were correlated with the pathology results. The quantitative and texture changes in the tumor-supplying vessels were analyzed. Micro-CT showed that the pulmonary artery was densely distributed in and around tumors in 141 (84%) of 167 early lung adenocarcinomas, the bronchial artery was not related to tumors, and there were four patterns of tumor–pulmonary artery relationships that correlated well with pathologic findings. Quantitative and texture analyses showed that the tumor size had positive correlations with vessel volume (VV), VV fraction (VVF), vessel thickness (VT), vessel number (VN), inverse difference moment, long run emphasis, gray level nonuniformity (GLN), and run length nonuniformity (RLN) and negative correlations with vessel separation (VS), inertia, and short run emphasis (SRE); the size of the solid component had positive correlations with VV, VVF, VT, VN, GLN, and RLN and negative correlations with VS, cluster shade, and SRE. This study concluded that early lung adenocarcinomas are mainly supplied by the pulmonary arteries in mice, and micro-CT angiography can clearly demonstrate the morphologic changes of pulmonary arteries and their relationships with tumors.
Data from Circulating RANKL and RANKL/OPG and Breast Cancer Risk by ER and PR Subtype: Results from the EPIC Cohort
Authors: Sarink Danja , Schock Helena , Johnson Theron , Overvad Kim , Holm Marianne , Tjønneland Anne , Boutron-Ruault Marie-Christine , His Mathilde , Kvaskoff Marina , Boeing Heiner , Lagiou Pagona , Papatesta Eleni-Maria , Trichopoulou Antonia , Palli Domenico , Pala Valeria , Mattiello Amalia , Tumino Rosario , Sacerdote Carlotta , Bueno-de-Mesquita H.B(as). , van Gils Carla H. , Peeters Petra H. , Weiderpass Elisabete , Agudo Antonio , Sánchez Maria-José , Chirlaque Maria-Dolores , Ardanaz Eva , Amiano Pilar , Khaw Kay Tee , Travis Ruth , Dossus Laure , Gunter Mark , Rinaldi Sabina , Merritt Melissa , Riboli Elio , Kaaks Rudolf , Fortner Renée T.
Published: March 2024

Abstract
Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case–control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1,976 incident invasive breast cancer cases [estrogen receptor positive (ER+), n = 1,598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (Phet = 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01–1.63); Ptrend = 0.20], but not ER− disease. For both ER+ and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER−PR− disease [5th vs. 1st quintile RR = 0.60 (0.31–1.14); Ptrend = 0.03]. This study provides the first large-scale prospective data on circulating sRANKL and breast cancer. We observed limited evidence for an association between sRANKL and breast cancer risk. Cancer Prev Res; 10(9); 525–34. ©2017 AACR.
Data from Bisphosphonates Zometa and Fosamax Synergize with Metformin to Prevent AOM-Induced Colon Cancer in F344 Rat Model
Authors: Madka Venkateshwar , Kumar Gaurav , Pathuri Gopal , Zhang Yuting , Lightfoot Stanley , Asch Adam S. , Mohammed Altaf , Steele Vernon E. , Rao Chinthalapally V.
Published: March 2024

Abstract
Recent observational studies suggest that bisphosphonates (BP) and antidiabetic drugs are associated with colorectal cancer risk reduction. Hence, we evaluated the colorectal cancer preventive effects of BPs (zometa and fosamax), individually and when combined with metformin, in azoxymethane-induced rat colon cancer model. Rat (30/group) were randomized and treated subcutaneously with azoxymethane to induce colorectal cancer. Dietary intervention with zometa or fosamax (0, 20, or 100 ppm) or metformin (1,000 ppm) or the combinations (zometa/fosamax 20 ppm plus metformin 1,000 ppm) began 4 weeks after azoxymethane treatment, at premalignant lesions stage. Rats were killed 40 weeks post drug intervention to assess colorectal cancer preventive efficacy. Dietary zometa (20 ppm) inhibited noninvasive adenocarcinomas multiplicity by 37% (P < 0.03) when compared with control diet fed group. Fosamax at 20 ppm and 100 ppm significantly reduced adenocarcinoma incidence (P < 0.005) and inhibited the noninvasive adenocarcinoma multiplicities by 43.8% (P < 0.009) and 60.8% (P < 0.004), respectively, compared with the group fed control diet. At 1,000 ppm dose, metformin failed to suppress colon adenocarcinoma formation. However, the lower dose combinations of zometa or fosamax with metformin resulted in significant inhibition of noninvasive adenocarcinoma by 48% (P < 0.006) and 64% (P < 0.0002), and invasive adenocarcinoma by 49% (P < 0.0005) and 38% (P < 0.006), respectively. Biomarker analysis of combination drug–treated tumors showed a decrease in cell proliferation with increased apoptosis when compared with untreated tumors. Overall, our results suggest that the combination of low doses of zometa or fosamax with metformin showed synergistic effect and significantly inhibited colon adenocarcinoma incidence and multiplicity.
Data from Reducing Fatty Acid Oxidation Improves Cancer-free Survival in a Mouse Model of Li-Fraumeni Syndrome
Authors: Wang Ping-Yuan , Ma Jin , Li Jie , Starost Matthew F. , Wolfgang Michael J. , Singh Komudi , Pirooznia Mehdi , Kang Ju-Gyeong , Hwang Paul M.
Published: March 2024

Abstract
Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid β-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knock-in mutation (p53172H/H, homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout (MB−/−) mice known to have decreased FAO. MB−/− p53172H/H double-mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with an approximately 40% improvement in cancer-free survival time. RNA sequencing profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of p53172H/H mice using a Cre-loxP–mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention.
Prevention Relevance:
Mildly inhibiting the increased fatty acid oxidation observed in a mouse model of Li-Fraumeni syndrome, a cancer predisposition disorder caused by inherited mutations of TP53, dampens aberrant pro-tumorigenic cell signaling and improves the survival time of these mice, thereby revealing a potential strategy for cancer prevention in patients.
Data from Sex-Specific Association between Family History of Diabetes and Risk of Colorectal Cancer: Two Prospective Cohort Studies
Authors: Ma Wenjie , Song Mingyang , Kværner Ane Sørlie , Prescott Jennifer , Chan Andrew , Giovannucci Edward , Zhang Xuehong
Published: March 2024

Abstract
Type 2 diabetes (T2D) is associated with increased risk of colorectal cancer. It remains unclear whether family history of diabetes influences colorectal cancer risk and relevant biomarkers. We followed 101,323 women from the Nurses’ Health Study (1982–2012) and 48,542 men from the Health Professionals Follow-up Study (1988–2012), free of cancer and inflammatory bowel disease at baseline. Participants reported whether any of their first-degree family members ever had diabetes in multiple questionnaires administered biennially. Plasma levels of colorectal cancer–related biomarkers were measured in subsets of participants from previous nested case–control studies. We documented 1,950 colorectal cancer cases in women and 1,173 colorectal cancer cases in men. After adjustment for potential confounders including obesity and diabetes, the hazard ratio (HR) for colorectal cancer among men who had family history of diabetes was 1.19 [95% confidence interval (CI), 1.04–1.36) as compared with those who did not. The corresponding HR was 1.06 among women (95% CI, 0.96–1.17). Interestingly, for individuals younger than 60 years, these associations appeared stronger among men (HR, 1.65; 95% CI, 1.15–2.38) and possibly among women (HR, 1.23; 95% CI, 0.99–1.54). Moreover, family history of diabetes was related to reduced levels of estradiol, sex hormone binding globulin (SHBG), and adiponectin in men, with a greater reduction of SHBG for those younger than 60 years (P for interaction = 0.03). In conclusion, family history of diabetes was associated with increased colorectal cancer risk in men, which may be partly mediated by altered sex hormones and adiponectin. The possible positive association in younger women needs further confirmation. Cancer Prev Res; 11(9); 535–44. ©2018 AACR.
Data from Analgesic Use and Circulating Estrogens, Androgens, and Their Metabolites in the Women's Health Initiative Observational Study
Authors: Hurwitz Lauren M. , Shadyab Aladdin H. , Tabung Fred K. , Anderson Garnet L. , Saquib Nazmus , Wallace Robert B. , Wild Robert A. , Pfeiffer Ruth M. , Xu Xia , Trabert Britton
Published: March 2024

Abstract
Though studies have observed inverse associations between use of analgesics (aspirin, NSAIDs, and acetaminophen) and the risk of several cancers, the potential biological mechanisms underlying these associations are unclear. We investigated the relationship between analgesic use and serum concentrations of estrogens, androgens, and their metabolites among postmenopausal women to provide insights on whether analgesic use might influence endogenous hormone levels, which could in turn influence hormone-related cancer risk. The study included 1,860 postmenopausal women from two case–control studies nested within the Women's Health Initiative Observational Study. Analgesic use was reported at study baseline. Fifteen estrogens and estrogen metabolites and 12 androgens and androgen metabolites were quantified in baseline serum by LC/MS-MS. Linear regression with inverse probability weighting, stratified by menopausal hormone therapy (MHT) use, was used to estimate adjusted geometric mean concentrations of each hormone by analgesic use. Among women not currently using MHT (n = 951), low-dose aspirin (<100 mg) use was associated with a higher serum concentration of estrone, estradiol, and 2, 4, and 16 hydroxylated metabolites. Use of regular-dose aspirin (≥100 mg), non-aspirin NSAIDs, and acetaminophen was not associated with serum concentrations of estrogens, androgens, or their metabolites. This study highlights the importance of examining aspirin use by dose and suggests that low-dose aspirin may influence endogenous estrogen concentrations.
Prevention relevance:
This study explores a potential pathway by which analgesic medications such as aspirin may prevent hormone-related cancers. The findings support a positive association between low-dose aspirin use and endogenous estrogens, indicating that further elucidation of the interplay between low-dose aspirin, estrogen concentrations, and cancer risk is needed.
Data from Adiposity, Adulthood Weight Change, and Risk of Incident Hepatocellular Carcinoma
Authors: Simon Tracey G. , Kim Mi Na , Luo Xiao , Liu Xing , Yang Wanshui , Ma Yanan , Chong Dawn Q. , Fuchs Charles S. , Stampfer Meir , Giovannucci Edward L. , Chan Andrew T. , Zhang Xuehong
Published: March 2024

Abstract
Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980–2012) and 48,026 men (1986–2012), who recalled young-adult weight [age 18 years (women); 21 years (men)], and provided biennially updated information regarding weight, body mass index (BMI), and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable adjusted HRs (aHR) and 95% confidence intervals (CI). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood [continuous aHRs per each 1 unit = 1.05; 95% CI = 1.02–1.09 (Ptrend = 0.019), and 1.08; 95% CI = 1.06–1.10 (Ptrend = 0.004), respectively]. Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase = 1.03; 95% CI = 1.01–1.08; Ptrend = 0.010), including after further adjusting for young-adult BMI (Ptrend = 0.010) and later-adult BMI (Ptrend = 0.008). Compared with adults with stable weight (±5 kg), the multivariable-aHRs with weight gain of 5–<10 kg, 10–<20 kg, and ≥20 kg were, 1.40 (95% CI = 0.67–2.16), 2.09 (95% CI = 1.11–3.95), and 2.61 (95% CI = 1.42–5.22), respectively. In two prospective, nationwide cohorts, adulthood weight gain was significantly associated with increased HCC risk.
Prevention Relevance:
Our data suggest that maintaining a stable weight during adulthood, specifically by preventing weight gain, could represent an important public health strategy for the prevention of hepatocellular carcinoma.
Data from Upper Gastrointestinal Cancer in China: Spatial Epidemiologic Evidence from Screening Areas
Authors: Li Peng , Jing Jing , Li Rui , Ge Miao , Jia Peng , Hu Wenbiao , Qi Xin , Wei Wen-Qiang , Zhuang Guihua
Published: March 2024

Abstract
Upper gastrointestinal cancer (UGIC) including esophageal cancer and gastric cancer, which has been a significant burden in China. Few studies have explored the spatial pattern and association of incidence and mortality using nationwide data. This study aims to explore the spatial pattern and association of incidence and mortality between esophageal cancer and gastric cancer, and identify high-risk areas of the cancers to provide scientific evidence for tailoring endoscopic screening programs. We collected UGIC data in 2014 from a National Cancer Report, and then adopted methods of correlation analysis and spatial statistics to identify high-risk areas on the cancers and to explore the pattern. The results show a spatial autocorrelation on the spatial distribution of incidence and mortality of esophageal and gastric cancers, and the relative risks were from 2.52 (95% CI (confidence interval), 2.37–2.67; P < 0.001) to 3.80 (95% CI, 3.46–4.18; P < 0.001) in primary risk areas, respectively. Moreover, esophageal cancer shows an upward and then downward trend from west to east, and from south to north, yet gastric cancer exhibits an upward and then downward trend only from south to north. This study indicates habitants in overlapping risk areas have heavier cancer burdens, and suggests esophageal cancer and gastric cancer have a significant correlation. Therefore, more endoscopic screening attention should focus on overlapping risk areas.
Data from Physical Activity and Risk of Hepatocellular Carcinoma Among U.S. Men and Women
Authors: Luo Xiao , Yang Wanshui , Ma Yanan , Simon Tracey G. , Meyerhardt Jeffrey A. , Chan Andrew T. , Giovannucci Edward L. , Zhang Xuehong
Published: March 2024

Abstract
Mounting evidence indicates a potential beneficial effect of vigorous-intensity physical activity on hepatocellular carcinoma (HCC). However, the association between moderate-intensity physical activity, such as brisk walking, and the risk of HCC remains largely unknown. Two prospective cohorts of 77,535 women from the Nurses' Health Study and 44,540 men from the Health Professionals Follow-up Study were included. Weekly time spent on physical activities were updated biennially. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HR) and 95% confidence intervals (95% CI). After an average 23-year follow-up, we identified 138 incident HCC cases. A higher amount of total physical activity was not significantly associated with a reduced risk of HCC (top tertile vs. bottom tertile; HR = 0.78; 95% CI, 0.51–1.18; Ptrend = 0.33). For the same comparison, there was an inverse association between moderate-intensity activity and HCC risk (HR = 0.60; 95% CI, 0.38–0.94; Ptrend = 0.04), whereas no statistically significant association with vigorous-intensity activity (HR = 0.88; 95% CI, 0.56–1.37; Ptrend = 0.74). Engaging in brisk walking was significantly associated with a lower risk of HCC (over 1 hour/week vs. non-brisk walking; HR = 0.50; 95% CI, 0.31–0.78; Ptrend = 0.006). The association between brisk walking and HCC risk was generally present across all subgroups, including age, body mass index, type 2 diabetes mellitus, smoking status, aspirin use, and alcohol consumption (all Pinteraction ≥ 0.05). In conclusion, moderate-intensity activity, especially brisk walking, was associated with reduced risk of HCC among U.S. men and women. If confirmed, brisk walking might serve a feasible way for HCC prevention.
Data from Interaction Between Susceptibility Loci in MAVS and TRAF3 Genes, and High-risk HPV Infection on the Risk of Cervical Precancerous Lesions in Chinese Population
Authors: Xiao Di , Liu Dandan , Wen Zihao , Huang Xiuxia , Zeng Chengli , Zhou Zixing , Han Yajing , Ye Xiaohong , Wu Jing , Wang Yao , Guo Congcong , Ou Meiling , Huang Shiqi , Huang Chuican , Wei Xiangcai , Yang Guang , Jing Chunxia
Published: March 2024

Abstract
Persistent high-risk HPV infection is considered as a major cause of cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The RIG-I pathway in innate immunity plays an important role in antivirus response. Here, we hypothesized that altered function of mitochondrial antiviral signaling protein (MAVS) and mitochondrial TNF receptor–associated factor 3(TRAF3), key molecules downstream of the viral sensors RIG-I, may impair their ability of clearing HPV and thereby influence the risk for cervical precancerous lesions. To investigate the effects of MAVS and TRAF3 polymorphisms on susceptibility to cervical precancerous lesions, 8 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene–environment interactions were also calculated. We found that CA genotype of rs6052130 in MAVS gene were at 1.48 times higher risk of developing cervical precancerous lesion than individuals with CC genotype (CA vs. CC: ORadjusted = 1.48, 95% CI, 1.02–2.16). In addition, a significant synergetic interaction between high-risk HPV infection and rs6052130 was found on an additive scale. A significantly decreased risk of cervical precancerous lesions for the TC genotype of rs12435483 in the TRAF3 gene (ORadjusted = 0.67, 95% CI, 0.45–0.98) was also found. Moreover, MDR analysis identified a significant three-locus interaction model, involving high-risk HPV infection, TRAF3 rs12435483 and number of full-term pregnancies. Our results indicate that the MAVS rs6052130 and TRAF3 rs12435483 confer genetic susceptibility to cervical precancerous lesions. Moreover, MAVS rs6052130–mutant individuals have an increased vulnerability to high-risk HPV-induced cervical precancerous lesions.
Data from Risk of Liver Cirrhosis in HBV/HCV-Infected Individuals with First-Degree Relatives Who Have Liver Cancer: Development and Validation of a Simple Model
Authors: Liu Yin , Guo Lan-Wei , Xu Hui-Fang , Kang Rui-Hua , Zheng Li-Yang , Zhang Lu-Yao , Chen Qiong , Sun Xi-Bin , Zhang Shao-Kai , Qiao You-Lin
Published: March 2024

Abstract
Identification of high-risk population among hepatitis B virus (HBV)/hepatitis C virus (HCV)-infected individuals with first-degree relatives (FDR) who have liver cancer is important to implement precise intervention. A cross-sectional study was conducted under the framework of a population-based Cancer Screening Program in Urban China (CanSPUC), aimed to develop and validate a simple noninvasive model that could assess and stratify cirrhosis risk, in HBV/HCV-infected individuals with FDRs who have liver cancer. People who participated in liver cancer screening in Henan province were enrolled. Using the data set consisting of participants admitted from October 1, 2013, to December 31, 2016, a 24-point scale risk score model was developed through logistic regression, based on educational background, dietary habit, smoking index, cooking oil fume exposure, history of severe trauma, HBV/HCV infection status, history of diabetes, history of hyperlipidemia, and parent history of liver cancer. The model showed excellent discrimination with area under the receiver operator characteristic curve (AUROC) of 0.875 [95% confidence interval (CI), 0.853–0.896] and fair calibration with a Hosmer–Lemeshow test P = 0.106. The prevalence rates in the medium- and high-risk groups were 2.87 (95% CI, 1.94–4.25) and 47.57 (95% CI, 31.59–71.63) times of low-risk group, respectively. After internal validation, bias-corrected AUROC was 0.874 (95% CI, 0.873–0.875). In the external validation data set consisting of participants admitted from January 1, 2017, to October 31, 2018, the model had achieved similar discrimination, calibration, and risk stratification ability. In conclusion, the risk score model we developed can be a practical tool for the screening and prevention of liver cirrhosis among HBV/HCV-infected individuals with FDRs who have liver cancer.
Prevention Relevance:
We created a simple and noninvasive cirrhosis risk model for individuals infected by HBV/HCV who have FDRs with liver cancer. This model is useful not only for the prognosis of HBV/HCV infection, but also for the prevention of hepatocellular carcinoma.
Data from Comparison of Different HPV-based Strategies and Cytology in Routine Cervical Cancer Screening Programme in China: A Population-based Study
Authors: Wang Shi , Li Ling , Yang Jie , Han Na , Bao Heling , Wang Hai-Jun
Published: March 2024

Abstract
The study aimed to compare the performance of human papillomavirus (HPV)-based strategies to cytology for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in routine program in China. The study included 50,434 women ages 30–64 years from January 2015 to December 2019, to assess four strategies: cytology with HPV triage (strategy 1), primary HPV testing with reflex cytology (strategy 2), primary HPV testing with HPV-16/18 genotyping and reflex cytology for non-16–18 high-risk HPV genotypes (strategy 3), and co-testing (strategy 4). The main outcomes were sensitivity for CIN3+ and colposcopy referral rate. Overall, the rates of HPV positivity and cytologic abnormality were 7.0% [95% confidential interval (CI), 6.8–7.2] and 3.5% (95% CI, 3.3–3.6], respectively. The sensitivity for CIN3+ were 88.5% for strategy 4, 83.2% for strategy 3, 64.6% for strategy 1, and 60.1% for strategy 2. The relative sensitivity of strategy 4 and strategy 3 compared with strategy 1 for detecting CIN3+ were 1.38 (95% CI, 1.24–1.54) and 1.29 (95% CI, 1.14–1.46), respectively. The colposcopy referral rates of strategies 4 and 3 were significantly higher than that of strategy 1 (2.4% and 2.2% vs. 1.4%, P < 0.001). In conclusion, co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology improved the sensitivity for CIN3+ compared with cytology but increased the colposcopy referral rate. Long-term negative predicted value for HPV-negative women should be studied to determine the screening interval. Our study provides further evidence to the introduction of HPV-based strategies in China.
Prevention Relevance:
Both co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology triage provided higher sensitivity for detecting CIN3+; however, the number of colposcopy referrals also increased compared with cytology in a routine program. It has great public health implications for the introduction of HPV-based screening strategies in China.