bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table 7 from A DRD1 Polymorphism Predisposes to Lung Cancer among Those Exposed to Secondhand Smoke during Childhood
Authors: Robles Ana I. , Yang Ping , Jen Jin , McClary Andrew C. , Calhoun Kara , Bowman Elise D. , Vähäkangas Kirsi , Greathouse K. Leigh , Wang Yi , Olivo-Marston Susan , Wenzlaff Angela S. , Deng Bo , Schwartz Ann G. , Ryan Bríd M.
Published: April 2023

Test for departure from additivity for rs686 and exposure to secondhand smoke during childhood.
Supplementary Figure 2 from Breast Cancer Cell Apoptosis with Phytoestrogens Is Dependent on an Estrogen-Deprived State
Authors: Obiorah Ifeyinwa E. , Fan Ping , Jordan V. Craig
Published: April 2023

PDF file - 101K, Differential apoptotic effects of E2 equilin and phytoestrogens MCF7:5C cells were treated with control or E2(1nM), equilin (1nM), phytoestrogens (1microM) for 72h and then stained with YO-PRO-1 and propidium iodide and analysed by flow cytometry.
Supplementary Figure-2 from Novel Evidence for Curcumin and Boswellic Acid–Induced Chemoprevention through Regulation of miR-34a and miR-27a in Colorectal Cancer
Authors: Toden Shusuke , Okugawa Yoshinaga , Buhrmann Constanze , Nattamai Durgha , Anguiano Esperanza , Baldwin Nicole , Shakibaei Mehdi , Boland C. Richard , Goel Ajay
Published: April 2023

Supplementary Figure-2. Curcumin and AKBA exert cytotoxicity and suppress colony formation on CRC cell lines.
Supplementary Figure 1 from Isoangustone A, A Novel Licorice Compound, Inhibits Cell Proliferation by Targeting PI3K, MKK4, and MKK7 in Human Melanoma
Authors: Song Nu Ry , Lee Eunjung , Byun Sanguine , Kim Jong-Eun , Mottamal Madhusoodanan , Park Jung Han Yoon , Lim Soon Sung , Bode Ann M. , Lee Hyong Joo , Lee Ki Won , Dong Zigang
Published: April 2023

PDF file - 30K, The cytotoxicity of IAA against normal melanocytes.
Supplementary Table 2 from Gene Expression Patterns in the Human Breast after Pregnancy
Authors: Asztalos Szilard , Gann Peter H. , Hayes Meghan K. , Nonn Larisa , Beam Craig A. , Dai Yang , Wiley Elizabeth L. , Tonetti Debra A.
Published: April 2023

Supplementary Table 2 from Gene Expression Patterns in the Human Breast after Pregnancy
Supplementary Figure 2 from Preventive Effects of NSAIDs, NO-NSAIDs, and NSAIDs Plus Difluoromethylornithine in a Chemically Induced Urinary Bladder Cancer Model
Authors: Nicastro Holly L. , Grubbs Clinton J. , Margaret Juliana M. , Bode Ann M. , Kim Mi-Sung , Lu Yan , You Ming , Milne Ginger L. , Boring Daniel , Steele Vernon E. , Lubet Ronald A.
Published: April 2023

PDF - 982K, Supplementary figure 2. Common gene network for NO-naproxen and naproxen treated rat liver.
Supplementary Figure Legends from Eflornithine (DFMO) Prevents Progression of Pancreatic Cancer by Modulating Ornithine Decarboxylase Signaling
Authors: Mohammed Altaf , Janakiram Naveena B. , Madka Venkateshwar , Ritchie Rebekah L. , Brewer Misty , Biddick Laura , Patlolla Jagan Mohan R. , Sadeghi Michael , Lightfoot Stan , Steele Vernon E. , Rao Chinthalapally V.
Published: April 2023

Supplementary Figure Legends
Supplementary Table 1 from Epigallocatechin-gallate Suppresses Tumorigenesis by Directly Targeting Pin1
Authors: Urusova Darya V. , Shim Jung-Hyun , Kim Dong Joon , Jung Sung Keun , Zykova Tatyana A. , Carper Andria , Bode Ann M. , Dong Zigang
Published: April 2023

PDF file - 27K
Fig S7 from Loss of BRCA1 in the Cells of Origin of Ovarian Cancer Induces Glycolysis: A Window of Opportunity for Ovarian Cancer Chemoprevention
Authors: Chiyoda Tatsuyuki , Hart Peter C. , Eckert Mark A. , McGregor Stephanie M. , Lastra Ricardo R. , Hamamoto Ryuji , Nakamura Yusuke , Yamada S. Diane , Olopade Olufunmilayo I. , Lengyel Ernst , Romero Iris L.
Published: April 2023

Fig S7 shows drug screen of candidate chemopreventive agents for effects on HK2 expression and glycolytic metabolism in IOSE cells.
Suppl. Figure 1 from Voluntary Wheel Running Reduces the Acute Inflammatory Response to Liver Carcinogen in a Sex-specific Manner
Authors: Bay M.L. , Gehl Julie , Pedersen Bente Klarlund , Hojman Pernille
Published: April 2023

Supplementary Figure 1. Serum concentrations of pro-inflammatory cytokines in male and female mice.
Figure S2 from Fixed-Dose Combinations of Pioglitazone and Metformin for Lung Cancer Prevention
Authors: Seabloom Donna E. , Galbraith Arthur R. , Haynes Anna M. , Antonides Jennifer D. , Wuertz Beverly R. , Miller Wendy A. , Miller Kimberly A. , Steele Vernon E. , Miller Mark Steven , Clapper Margie L. , O'Sullivan M. Gerard , Ondrey Frank G.
Published: April 2023

Supplementary Figure 2
Supplementary Figure 3 from JAK3 Variant, Immune Signatures, DNA Methylation, and Social Determinants Linked to Survival Racial Disparities in Head and Neck Cancer Patients
Authors: Guerrero-Preston Rafael , Lawson Fahcina , Rodriguez-Torres Sebastian , Noordhuis Maartje G. , Pirini Francesca , Manuel Laura , Valle Blanca L. , Hadar Tal , Rivera Bianca , Folawiyo Oluwasina , Baez Adriana , Marchionni Luigi , Koch Wayne M. , Westra William H. , Kim Young J. , Eshleman James R. , Sidransky David
Published: April 2023

Aircraft Tracking Analogy that integrates Contextual, Bio-psychosocial and Molecular Determinants of Population Health in a Patient Centered Trajectory that can be used in Personalized Medicine workflows.
Supplementary Figure 2 from JAK3 Variant, Immune Signatures, DNA Methylation, and Social Determinants Linked to Survival Racial Disparities in Head and Neck Cancer Patients
Authors: Guerrero-Preston Rafael , Lawson Fahcina , Rodriguez-Torres Sebastian , Noordhuis Maartje G. , Pirini Francesca , Manuel Laura , Valle Blanca L. , Hadar Tal , Rivera Bianca , Folawiyo Oluwasina , Baez Adriana , Marchionni Luigi , Koch Wayne M. , Westra William H. , Kim Young J. , Eshleman James R. , Sidransky David
Published: April 2023

Data Integration modules and systems interface.s
Supplemental Figure 2 from β-Carotene 9′,10′ Oxygenase Modulates the Anticancer Activity of Dietary Tomato or Lycopene on Prostate Carcinogenesis in the TRAMP Model
Authors: Tan Hsueh-Li , Thomas-Ahner Jennifer M. , Moran Nancy E. , Cooperstone Jessica L. , Erdman John W. , Young Gregory S. , Clinton Steven K.
Published: April 2023

Lycopene precursor concentrations in mouse serum.
Supplementary Table 7 from Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention
Authors: Weinberg David S. , Lin Jieru E. , Foster Nathan R. , Della'Zanna Gary , Umar Asad , Seisler Drew , Kraft Walter K. , Kastenberg David M. , Katz Leo C. , Limburg Paul J. , Waldman Scott A.
Published: April 2023

Post intervention colonoscopy/endoscopy results.
Supplementary Table 6 from Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention
Authors: Weinberg David S. , Lin Jieru E. , Foster Nathan R. , Della'Zanna Gary , Umar Asad , Seisler Drew , Kraft Walter K. , Kastenberg David M. , Katz Leo C. , Limburg Paul J. , Waldman Scott A.
Published: April 2023

Incidence of adverse events by study age.
Supplementary Table 5 from Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention
Authors: Weinberg David S. , Lin Jieru E. , Foster Nathan R. , Della'Zanna Gary , Umar Asad , Seisler Drew , Kraft Walter K. , Kastenberg David M. , Katz Leo C. , Limburg Paul J. , Waldman Scott A.
Published: April 2023

Cyclic GMP responses in rectal biopsies in subjects receiving linaclotide (Active) or placebo.
Legends for supplemental data from Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression
Authors: Pettapiece-Phillips Rachael , Kotlyar Max , Chehade Rania , Salmena Leonardo , Narod Steven A. , Akbari Mohammad , Jurisica Igor , Kotsopoulos Joanne
Published: April 2023

Attached are the legends for the 4 supplemental figures.
Supplementary Table from Genetically Predicted Circulating Levels of Antioxidants and Risk of Breast and Ovarian Cancer
Authors: Zhao Huanling , Zhu Jiahao , TSE Lap Ah , Kinra Sanjay , Li Yingjun
Published: April 2023

Supplementary Table from Genetically Predicted Circulating Levels of Antioxidants and Risk of Breast and Ovarian Cancer
Supplementary Tables from Combination of Erlotinib and Naproxen Employing Pulsatile or Intermittent Dosing Profoundly Inhibits Urinary Bladder Cancers
Authors: Mohammed Altaf , Miller Mark Steven , Lubet Ronald A. , Suen Chen S. , Sei Shizuko , Shoemaker Robert H. , Juliana Margaret M. , Moeinpour Fariba L. , Grubbs Clinton J.
Published: April 2023

Supplementary Tables
Supplementary Table 7 from Molecular Triage of Premalignant Lesions in Liquid-Based Cervical Cytology and Circulating Cell-Free DNA from Urine, Using a Panel of Methylated Human Papilloma Virus and Host Genes
Authors: Guerrero-Preston Rafael , Valle Blanca L. , Jedlicka Anne , Turaga Nitesh , Folawiyo Oluwasina , Pirini Francesca , Lawson Fahcina , Vergura Angelo , Noordhuis Maartje , Dziedzic Amanda , Pérez Gabriela , Renehan Marisa , Guerrero-Diaz Carolina , De Jesus Rodríguez Edgar , Diaz-Montes Teresa , Rodríguez Orengo José , Méndez Keimari , Romaguera Josefina , Trock Bruce J. , Florea Liliana , Sidransky David
Published: April 2023

Primer and probe list of genes used for quantitative Methylation Specific PCR.
Table S5 from Post Genome-Wide Gene–Environment Interaction Study Using Random Survival Forest: Insulin Resistance, Lifestyle Factors, and Colorectal Cancer Risk
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Zhang Zuo-Feng
Published: April 2023

Overall analysis: combined effect
Supplementary Table 4 from Molecular Triage of Premalignant Lesions in Liquid-Based Cervical Cytology and Circulating Cell-Free DNA from Urine, Using a Panel of Methylated Human Papilloma Virus and Host Genes
Authors: Guerrero-Preston Rafael , Valle Blanca L. , Jedlicka Anne , Turaga Nitesh , Folawiyo Oluwasina , Pirini Francesca , Lawson Fahcina , Vergura Angelo , Noordhuis Maartje , Dziedzic Amanda , Pérez Gabriela , Renehan Marisa , Guerrero-Diaz Carolina , De Jesus Rodríguez Edgar , Diaz-Montes Teresa , Rodríguez Orengo José , Méndez Keimari , Romaguera Josefina , Trock Bruce J. , Florea Liliana , Sidransky David
Published: April 2023

Mapping efficiency of cervical cancer cell lines, head and neck squamous cell carcinoma cell lines and clinical samples to HPV16-L1.
Table S2 from Post Genome-Wide Gene–Environment Interaction Study Using Random Survival Forest: Insulin Resistance, Lifestyle Factors, and Colorectal Cancer Risk
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Zhang Zuo-Feng
Published: April 2023

Second RSF by PA
Figure S6 from Post Genome-Wide Gene–Environment Interaction Study Using Random Survival Forest: Insulin Resistance, Lifestyle Factors, and Colorectal Cancer Risk
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Zhang Zuo-Feng
Published: April 2023

Two-stage RSF
Figure S1 from Post Genome-Wide Gene–Environment Interaction Study Using Random Survival Forest: Insulin Resistance, Lifestyle Factors, and Colorectal Cancer Risk
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Zhang Zuo-Feng
Published: April 2023

Diagrams of pathways of SNPs
Supplementary Figure 2A from Molecular Triage of Premalignant Lesions in Liquid-Based Cervical Cytology and Circulating Cell-Free DNA from Urine, Using a Panel of Methylated Human Papilloma Virus and Host Genes
Authors: Guerrero-Preston Rafael , Valle Blanca L. , Jedlicka Anne , Turaga Nitesh , Folawiyo Oluwasina , Pirini Francesca , Lawson Fahcina , Vergura Angelo , Noordhuis Maartje , Dziedzic Amanda , Pérez Gabriela , Renehan Marisa , Guerrero-Diaz Carolina , De Jesus Rodríguez Edgar , Diaz-Montes Teresa , Rodríguez Orengo José , Méndez Keimari , Romaguera Josefina , Trock Bruce J. , Florea Liliana , Sidransky David
Published: April 2023

GenoScape - HPV genotype profiling from high-throughput sequencing samples consists of four analytic steps: (1) High-throughput sequencing (454, MiSeq) of HPV TrDNA; (2) Profiling by comparing sequences against several databases such as Human genome (bowtie), HPV databases -GenBank, PaVE, Enterix-HPV Hi-lo risk (sim4db) and RefSeq bacterial genomes (blast); (3) Assembly into contigs, for AlignScape visualization (newbler,minimus, trinity); and SNP discovery (samtools + filter).
Supplementary Figure 1D from Molecular Triage of Premalignant Lesions in Liquid-Based Cervical Cytology and Circulating Cell-Free DNA from Urine, Using a Panel of Methylated Human Papilloma Virus and Host Genes
Authors: Guerrero-Preston Rafael , Valle Blanca L. , Jedlicka Anne , Turaga Nitesh , Folawiyo Oluwasina , Pirini Francesca , Lawson Fahcina , Vergura Angelo , Noordhuis Maartje , Dziedzic Amanda , Pérez Gabriela , Renehan Marisa , Guerrero-Diaz Carolina , De Jesus Rodríguez Edgar , Diaz-Montes Teresa , Rodríguez Orengo José , Méndez Keimari , Romaguera Josefina , Trock Bruce J. , Florea Liliana , Sidransky David
Published: April 2023

Description of cervical cancer screening and triage method workflow using HPV and host methylation markers. The method consists of 7 steps: 1) Liquid-based cytology or urine sample collection; 2) DNA isolation; 3) Human and HPV DNA sequence capture (optional); 4) Bisulfite treatment of Human and HPV DNA (or enzymatic restriction with CG sensitive enzymes) to interrrogate DNA methylation of host and viral genes. Bisulfite treatment is not needed if only genomic HPV-DNA identification is needed; 5) PCR or Sequencing based analysis of genomic HPV DNA for genotyping (top panel) or for identification of differentially methylated regions (DMRs) in bisulfite treated host and viral DNA (bottom panel); 6) HPV genotyping to identify high risk (oncogenic) strains (top panel) or assessment of progression risk to CIN2+ (bottom panel); 7) Deliverables: Cervical cancer screening and/or triage results, together with optional personalized web-based alignment and visualization.
Supplementary Legends from A Calcium-Rich Multimineral Intervention to Modulate Colonic Microbial Communities and Metabolomic Profiles in Humans: Results from a 90-Day Trial
Authors: Aslam Muhammad N. , Bassis Christine M. , Bergin Ingrid L. , Knuver Karsten , Zick Suzanna M. , Sen Ananda , Turgeon D. Kim , Varani James
Published: April 2023

Supplemental Tables/Figures legends
Supplementary Figure from Retention and Evaluation of Precision and Generic Prevention Materials for Melanoma: A Qualitative Study Comparing Young Adults and Adults
Authors: Crowder Sylvia L. , Buro Acadia W. , Lacson John Charles A. , Kim Youngchul , Sutton Steven K. , Roetzheim Richard G. , Vadaparampil Susan T. , Stern Marilyn , Kanetsky Peter A.
Published: April 2023

Supplementary Figure from Retention and Evaluation of Precision and Generic Prevention Materials for Melanoma: A Qualitative Study Comparing Young Adults and Adults
Supplementary Table 4 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: April 2023

Frequency of pre-diagnostic aspirin and non-aspirin NSAID use in relation to mortality restricted to exclusive users in the past year.
Supplementary Table 3 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: April 2023

Four-level frequency of pre-diagnostic NSAID use in relation to mortality.
Supplementary Table 1 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: April 2023

Study-specific characteristics of prostate cancer cases in the pre-diagnostic NIH-AARP and PLCO cohorts.
Supplementary Table 3 from Long-Term Glucocorticoid Use and Cancer Risk: A Population-Based Cohort Study in South Korea
Authors: Oh Tak Kyu , Song In-Ae
Published: April 2023

Multivariable Cox regression analysis of development of cancer during 2012-2015 in the 2010 sample cohort of South Korea (n=770,880)
List of cationic metabolites detected using CE-TOFMS from Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model
Authors: Qin Xian-Yang , Tatsukawa Hideki , Hitomi Kiyotaka , Shirakami Yohei , Ishibashi Naoto , Shimizu Masahito , Moriwaki Hisataka , Kojima Soichi
Published: April 2023

Relative intensity of 254 cationic metabolites detected using CE-TOFMS.
Effect of ACR on AA-induced cell growth of JHH7 cells from Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model
Authors: Qin Xian-Yang , Tatsukawa Hideki , Hitomi Kiyotaka , Shirakami Yohei , Ishibashi Naoto , Shimizu Masahito , Moriwaki Hisataka , Kojima Soichi
Published: April 2023

The cells were seeded in 96 well plates 24 h before treatment with AA in the presence and absence of 10 μM ACR in DMEM containing 5% FBS. After 48 h, cell viability was determined using the Cell Counting Kit-8. Quantitative data normalized to EtOH control were expressed as the means {plus minus} SD. *P<0.05 identified using two-tailed Student's t-test. n.s., not significant.
Supplementary 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: April 2023

Supplementary Tables and Figures
Supplementary 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: April 2023

Supplementary data
Supplementary Figure 1 from Cost Effectiveness of Whole Population BRCA Genetic Screening for Cancer Prevention in Israel
Authors: Michaan Nadav , Leshno Moshe , Safra Tamar , Sonnenblick Amir , Laskov Ido , Grisaru Dan
Published: April 2023

Supplementary Figure 1 Tornado diagram
Supplementary Text 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: April 2023

Supplementary text
Supplementary Table S1 from Chemopreventive Effect of Cinnamon and Its Bioactive Compounds in a Rat Model of Premalignant Prostate Carcinogenesis
Authors: Gopalakrishnan Srividya , Dhaware Mahamaya , Sudharma Athira Anilkumar , Mullapudi Surekha Venkata , Siginam Siva Ramakrishna , Gogulothu Ramesh , Mir Irfan Ahmad , Ismail Ayesha
Published: April 2023

Supplementary Table S1: Rat primer sequences used for qPCR in prostate tissue of the different groups
Data from Brush-based Cytology Screening in the Tonsils and Cervix: There Is a Difference!
Authors: Lingen Mark W.
Published: April 2023

Abstract
This perspective on the report by Fakhry and colleagues in this issue of the journal (beginning on page 1378) examines the diagnostic accuracy of a “Pap-test equivalent” for screening for human papillomavirus (HPV)-associated cancers in the tonsils. HPV infection is strongly associated with cancer development in the oropharynx (tonsils and base of tongue) and cervix; the data discussed here underscore the differences in screening for cervical versus oropharyngeal malignancies and discuss some of the challenges and limitations associated with screening for tonsillar premalignancy and early cancers. Cancer Prev Res; 4(9); 1350–2. ©2011 AACR.
Data from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Authors: Wu Xifeng , Spitz Margaret R. , Lee J. Jack , Lippman Scott M. , Ye Yuanqing , Yang Hushan , Khuri Fadlo R. , Kim Edward , Gu Jian , Lotan Reuben , Hong Waun K.
Published: April 2023

Abstract
This study was aimed to identify novel susceptibility variants for second primary tumor (SPT) or recurrence in curatively treated early-stage head and neck squamous cell carcinoma (HNSCC) patients.

We constructed a custom chip containing a comprehensive panel of 9,645 chromosomal and mitochondrial single nucleotide polymorphisms (SNP) representing 998 cancer-related genes selected by a systematic prioritization schema. Using this chip, we genotyped 150 early-stage HNSCC patients with and 300 matched patients without SPT/recurrence from a prospectively conducted randomized trial and assessed the association of these SNPs with risk of SPT/recurrence.

Individually, six chromosomal SNPs and seven mitochondrial SNPs were significantly associated with risk of SPT/recurrence after adjustment for multiple comparisons. A strong gene-dosage effect was observed when these SNPs were combined, as evidenced by a progressively increasing SPT/recurrence risk as the number of unfavorable genotypes increased (P for trend < 1.00 × 10−20). Several polygenic analyses suggest an important role of interconnected functional network and gene-gene interaction in modulating SPT/recurrence. Furthermore, incorporation of these genetic markers into a multivariate model improved significantly the discriminatory ability over the models containing only clinical and epidemiologic variables.

This is the first large-scale systematic evaluation of germ-line genetic variants for their roles in HNSCC SPT/recurrence. The study identified several promising susceptibility loci and showed the cumulative effect of multiple risk loci in HNSCC SPT/recurrence. Furthermore, this study underscores the importance of incorporating germ-line genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes.
Data from Effects of Human Oral Mucosal Tissue, Saliva, and Oral Microflora on Intraoral Metabolism and Bioactivation of Black Raspberry Anthocyanins
Authors: Mallery Susan R. , Budendorf Deric E. , Larsen Matthew P. , Pei Ping , Tong Meng , Holpuch Andrew S. , Larsen Peter E. , Stoner Gary D. , Fields Henry W. , Chan Kenneth K. , Ling Yonghua , Liu Zhongfa
Published: April 2023

Abstract
Our oral cancer chemoprevention trial data implied that patient-specific differences in local retention and metabolism of freeze-dried components of black raspberries (BRB) affected therapeutic responsiveness. Subsequent studies have confirmed that anthocyanins are key contributors to BRB's chemopreventive effects. Consequently, functional assays, immunoblotting, and immunohistochemical analyses to evaluate levels and distribution of BRB anthocyanin-relevant metabolic enzymes in human oral tissues were conducted. Liquid chromatography/tandem mass spectrometry (LC/MS-MS) analyses of time course saliva samples collected following BRB rinses were conducted to assess local pharmacokinetics and compare the capacities of three different BRB rinse formulations to provide sustained intraoral levels of anthocyanins. Protein profiles showed the presence of key metabolic enzymes in all 15 oral mucosal tissues evaluated, whereas immunohistochemistry confirmed these enzymes were distributed within surface oral epithelia and terminal salivary ducts. β-Glucosidase assays confirmed that whole and microflora-reduced saliva can deglycosylate BRB anthocyanins, enabling generation of the bioactive aglycone, cyanidin. LC/MS-MS analyses showed retention of parent anthocyanins and their functional, stable metabolite, protocatechuic acid, in saliva for up to 4 hours after rinsing. Furthermore, postrinse saliva samples contained glucuronidated anthocyanin conjugates, consistent with intracellular uptake and phase II conversion of BRB anthocyanins into forms amenable to local recycling. Our data show that comparable to the small intestine, the requisite hydrolytic, phase II and efflux transporting enzymes necessary for local enteric recycling are present and functional in human oral mucosa. Notably, interpatient differences in anthocyanin bioactivation and capacities for enteric recycling would impact treatment as retention of bioactivated chemopreventives at the target site would sustain therapeutic effectiveness. Cancer Prev Res; 4(8); 1209–21. ©2011 AACR.
Data from Identification of Gene Signatures and Molecular Markers for Human Lung Cancer Prognosis using an In vitro Lung Carcinogenesis System
Authors: Kadara Humam , Lacroix Ludovic , Behrens Carmen , Solis Luisa , Gu Xuemin , Lee J. Jack , Tahara Eiji , Lotan Dafna , Hong Waun Ki , Wistuba Ignacio I. , Lotan Reuben
Published: April 2023

Abstract
Lung cancer continues to be a major deadly malignancy. The mortality of this disease could be reduced by improving the ability to predict cancer patients' survival. We hypothesized that genes differentially expressed among cells constituting an in vitro human lung carcinogenesis model consisting of normal, immortalized, transformed, and tumorigenic bronchial epithelial cells are relevant to the clinical outcome of non–small cell lung cancer (NSCLC). Multidimensional scaling, microarray, and functional pathways analyses of the transcriptomes of the above cells were done and combined with integrative genomics to incorporate the microarray data with published NSCLC data sets. Up-regulated (n = 301) and down-regulated genes (n = 358) displayed expression level variation across the in vitro model with progressive changes in cancer-related molecular functions. A subset of these genes (n = 584) separated lung adenocarcinoma clinical samples (n = 361) into two clusters with significant survival differences. Six genes, UBE2C, TPX2, MCM2, MCM6, FEN1, and SFN, selected by functional array analysis, were also effective in prognosis. The mRNA and protein levels of one these genes—UBE2C—were significantly up-regulated in NSCLC tissue relative to normal lung and increased progressively in lung lesions. Moreover, stage I NSCLC patients with positive UBE2C expression exhibited significantly poorer overall and progression-free survival than patients with negative expression. Our studies with this in vitro model have lead to the identification of a robust six-gene signature, which may be valuable for predicting the survival of lung adenocarcinoma patients. Moreover, one of those genes, UBE2C, seems to be a powerful biomarker for NSCLC survival prediction.
Data from Effects of Energy Restriction and Wheel Running on Mammary Carcinogenesis and Host Systemic Factors in a Rat Model
Authors: Zhu Zongjian , Jiang Weiqin , Zacher Jarrod H. , Neil Elizabeth S. , McGinley John N. , Thompson Henry J.
Published: April 2023

Abstract
Limiting energy availability via diet or physical activity has health benefits; however, it is not known whether these interventions have similar effects on the development of cancer. Two questions were addressed as follows: (i) Does limiting energy availability by increasing physical activity have the same effect on mammary carcinogenesis as limiting caloric intake? and (ii) Are host systemic factors, implicated as risk biomarkers for breast cancer, similarly affected by these interventions? Female Sprague Dawley rats were injected with 50-mg 1-methyl-1-nitrosourea per kg body weight at 21 days of age and randomized to one of five groups (30 rats per group) as follows: (i) sham running wheel control; (ii) restricted fed to 85% of the sham control; (iii and iv) voluntary running in a motorized activity wheel (37 m/min) to a maximum of 3,500 m/d or 1,750 m/d; and (v) sedentary ad libitum fed control with no access to a running wheel. The three energetics interventions inhibited the carcinogenic response, reducing cancer incidence (P = 0.01), cancer multiplicity (P < 0.001), and cancer burden (P < 0.001) whereas prolonging cancer latency (P = 0.004) although differences among energetics interventions were not significant. Of the plasma biomarkers associated with the development of cancer, the energetics interventions reduced bioavailable insulin-like growth factor-1 (IGF-1), insulin, interleukin-6, serum amyloid protein, TNF-α, and leptin and increased IGF-binding protein 3 (IGFBP-3) and adiponectin. Plasma-fasting glucose, C-reactive protein, estradiol, and progesterone were unaffected. The plasma biomarkers of greatest value in predicting the carcinogenic response were adiponectin > IGF-1/IGFBP-3 > IGFBP-3 > leptin > IGF-1. Cancer Prev Res; 5(3); 414–22. ©2012 AACR.
Data from Dietary Resveratrol Prevents Development of High-Grade Prostatic Intraepithelial Neoplastic Lesions: Involvement of SIRT1/S6K Axis
Authors: Li Guiming , Rivas Paul , Bedolla Roble , Thapa Dinesh , Reddick Robert L. , Ghosh Rita , Kumar Addanki P.
Published: April 2023

Abstract
SIRT1 (mammalian ortholog of the yeast silent information regulator 2) is a NAD-dependent histone deacetylase belonging to the multigene family of sirtuins. Anecdotal and epidemiologic observations provide evidence for beneficial effects of the calorie restriction mimetic resveratrol (RES), a SIRT1 activator in preventing cardiovascular diseases and cancer. Although SIRT1 possesses both tumorigenic and antitumorigenic potential, the molecular mechanisms underlying SIRT1-mediated tumor progression or inhibition are poorly understood. In this study, we investigated the role of SIRT1 in multiple human prostate cancer cell lines and prostate-specific PTEN knockout mouse model using resveratrol. Androgen-independent prostate cancer cell lines (C42B, PC3, and DU145) express higher levels of SIRT1 than androgen-responsive (LNCaP) and nontumorigenic prostate cells (RWPE-1). Resveratrol enhanced this expression without any significant effect on SIRT1 enzymatic activity. Inhibition of SIRT1 expression using shRNA enhanced cell proliferation and inhibited autophagy by repressing phosphorylation of S6K and 4E-BP1. These biologic correlates were reversed in the presence of resveratrol. Analysis of prostates from dietary intervention with resveratrol showed a significant reduction in prostate weight and reduction in the incidence of high-grade prostatic intraepithelial neoplastic (HGPIN) lesions by approximately 54% with no significant change in body weight. Consistent with the in vitro findings, resveratrol intervention in the PTEN knockout mouse model was associated with reduction in the prostatic levels of mTOR complex 1 (mTORC1) activity and increased expression of SIRT1. These data suggest that SIRT1/S6K-mediated inhibition of autophagy drives prostate tumorigenesis. Therefore, modulation of SIRT1/S6K signaling represents an effective strategy for prostate cancer prevention. Cancer Prev Res; 6(1); 27–39. ©2012 AACR.
Data from The Antidepressant Desipramine and α2-Adrenergic Receptor Activation Promote Breast Tumor Progression in Association with Altered Collagen Structure
Authors: Szpunar Mercedes J. , Burke Kathleen A. , Dawes Ryan P. , Brown Edward B. , Madden Kelley S.
Published: April 2023

Abstract
Emotional stress activates the sympathetic nervous system (SNS) and release of the neurotransmitter norepinephrine to promote breast tumor pathogenesis. We demonstrate here that the metastatic mammary adenocarcinoma cell line 4T1 does not express functional adrenergic receptors (AR), the receptors activated by norepinephrine, yet stimulation of adrenergic receptor in vivo altered 4T1 tumor progression in vivo. Chronic treatment with the antidepressant desipramine (DMI) to inhibit norepinephrine reuptake increased 4T1 tumor growth but not metastasis. Treatment with a highly selective α2-adrenergic receptor agonist, dexmedetomidine (DEX), increased tumor growth and metastasis. Neither isoproterenol (ISO), a β-AR agonist, nor phenylephrine, an α1-AR agonist, altered tumor growth or metastasis. Neither DMI- nor DEX-induced tumor growth was associated with increased angiogenesis. In DMI-treated mice, tumor VEGF, IL-6, and the prometastatic chemokines RANTES, M-CSF, and MIP-2 were reduced. Tumor collagen microstructure was examined using second harmonic generation (SHG), a nonabsorptive optical scattering process to highlight fibrillar collagen. In DMI- and DEX-treated mice, but not ISO-treated mice, tumor SHG was significantly altered without changing fibrillar collagen content, as detected by immunofluorescence. These results demonstrate that α2-AR activation can promote tumor progression in the absence of direct sympathetic input to breast tumor cells. The results also suggest that SNS activation may regulate tumor progression through alterations in the extracellular matrix, with outcome dependent on the combination of adrenergic receptor activated. These results underscore the complexities underlying SNS regulation of breast tumor pathogenesis, and suggest that the therapeutic use of adrenergic receptor blockers, tricyclic antidepressants, and adrenergic receptor agonists must be approached cautiously in patients with breast cancer. Cancer Prev Res; 6(12); 1262–72. ©2013 AACR.
Data from Benign Breast Disease and the Risk of Subsequent Breast Cancer in African American Women
Authors: Cote Michele L. , Ruterbusch Julie J. , Alosh Barra , Bandyopadhyay Sudeshna , Kim Elizabeth , Albashiti Bassam , Sharaf Aldeen Bashar , Radisky Derek C. , Frost Marlene H. , Visscher Daniel W. , Hartmann Lynn C. , Nassar Warzecha Hind , Ali-Femhi Rouba
Published: April 2023

Abstract
Benign breast disease (BBD) is an established risk factor for breast cancer among Caucasian women but less is known about BBD in African American women. As African American women suffer from disproportionate mortality due to breast cancer, special focus on pathologic characteristics that may influence disease risk is warranted.

Benign breast biopsies from African American women were identified by the University Pathology Group (Detroit, MI). African American women of ages 20 to 84 years, who underwent a breast biopsy from 1997 to 2000, were eligible for the study. Subsequent breast cancers were identified through a linkage with the Detroit Surveillance Epidemiology and End Results (SEER) program. The first biopsy was reviewed by the pathologist, and lesions were classified following Dupont and Page criteria along with involution and other histologic features. Logistic regression was used to estimate the risk of developing a subsequent breast cancer with the histologic characteristics of BBD.

A total of 1,406 BBD biopsies from African American women were included in this study with a median follow-up of 10.1 years. The majority (68%) showed nonproliferative disease, 29% had proliferative disease without atypia, and 3% had proliferative disease with atypia. Subsequent incident breast cancers occurred in 55 women (3.9%). Women whose biopsies showed proliferative disease with atypia were more than three-fold more likely to develop breast cancer as compared with women who had nonproliferative disease [relative risk (RR) 3.29, 95% confidence interval (CI) 1.21–8.93].

Better characterization of the risk of breast cancer among women with BBD, considering both ethnicity and detailed molecular findings, can lead to better surveillance, earlier diagnosis, and potentially improved survival. Cancer Prev Res; 5(12); 1375–80. ©2012 AACR.
Data from HPV-associated Oropharyngeal Cancers—Are They Preventable?
Authors: Kreimer Aimée R. , Chaturvedi Anil K.
Published: April 2023

Abstract
It is not known whether a human papillomavirus (HPV)-induced oropharyngeal precancerous lesion could be identified by screening with a pap test equivalent or whether one even exists. In this issue of the journal (beginning on page 1378), Fakhry and colleagues report their results showing that cytologic evaluation of the oropharynx, although useful in detecting invasive oropharyngeal cancers, may have limited utility as a screening modality for detecting precancer. These findings argue against the potential for secondary prevention of HPV-associated oropharyngeal cancers through screening for and preventing the progression of precancer and highlight the opportunity for primary prevention through prophylactic HPV vaccination, if proven efficacious and cost-effective. Cancer Prev Res; 4(9); 1346–9. ©2011 AACR.
Data from Biomarkers of Dietary Energy Restriction in Women at Increased Risk of Breast Cancer
Authors: Ong Kai Ren , Sims Andrew H. , Harvie Michelle , Chapman Mary , Dunn Warwick B. , Broadhurst David , Goodacre Royston , Wilson Mary , Thomas Nicola , Clarke Robert B. , Howell Anthony
Published: April 2023

Abstract
Dietary energy restriction (DER) reduces risk of spontaneous mammary cancer in rodents. In humans, DER in premenopausal years seems to reduce risk of postmenopausal breast cancer. Markers of DER are required to develop acceptable DER regimens for breast cancer prevention. We therefore examined markers of DER in the breast, adipose tissue, and serum.

Nineteen overweight or obese women at moderately increased risk of breast cancer (lifetime risk, 1 in 6 to 1 in 3) ages between 35 and 45 were randomly allocated to DER [liquid diet, 3,656 kJ/d (864 kcal/d); n = 10] or asked to continue their normal eating patterns (n = 9) for one menstrual cycle. Biopsies of the breast and abdominal fat were taken before and after the intervention. RNA was extracted from whole tissues and breast epithelium (by laser capture microdissection) and hybridized to Affymetrix GeneChips. Longitudinal plasma and urine samples were collected before and after intervention, and metabolic profiles were generated using gas chromatography-mass spectrometry.

DER was associated with significant reductions in weight [−7.0 (±2.3) kg] and in alterations of serum biomarkers of breast cancer risk (insulin, leptin, total and low-density lipoprotein cholesterol, and triglycerides). In both abdominal and breast tissues, as well as isolated breast epithelial cells, genes involved in glycolytic and lipid synthesis pathways (including stearoyl-CoA desaturase, fatty acid desaturase, and aldolase C) were significantly down-regulated.

We conclude that reduced expressions of genes in the lipid metabolism and glycolytic pathways are detectable in breast tissue following DER, and these may represent targets for DER mimetics as effective chemoprophylactic agents.
Data from Metformin Reduces Endogenous Reactive Oxygen Species and Associated DNA Damage
Authors: Algire Carolyn , Moiseeva Olga , Deschênes-Simard Xavier , Amrein Lilian , Petruccelli Luca , Birman Elena , Viollet Benoit , Ferbeyre Gerardo , Pollak Michael N.
Published: April 2023

Abstract
Pharmacoepidemiologic studies provide evidence that use of metformin, a drug commonly prescribed for type II diabetes, is associated with a substantial reduction in cancer risk. Experimental models show that metformin inhibits the growth of certain neoplasms by cell autonomous mechanisms such as activation of AMP kinase with secondary inhibition of protein synthesis or by an indirect mechanism involving reduction in gluconeogenesis leading to a decline in insulin levels and reduced proliferation of insulin-responsive cancers. Here, we show that metformin attenuates paraquat-induced elevations in reactive oxygen species (ROS), and related DNA damage and mutations, but has no effect on similar changes induced by H202, indicating a reduction in endogenous ROS production. Importantly, metformin also inhibited Ras-induced ROS production and DNA damage. Our results reveal previously unrecognized inhibitory effects of metformin on ROS production and somatic cell mutation, providing a novel mechanism for the reduction in cancer risk reported to be associated with exposure to this drug. Cancer Prev Res; 5(4); 536–43. ©2012 AACR.
Data from In Vivo Longitudinal Imaging of Experimental Human Papillomavirus Infection in Mice with a Multicolor Fluorescence Mini-Endoscopy System
Authors: Mitsunaga Makoto , Kosaka Nobuyuki , Kines Rhonda C. , Roberts Jeffrey N. , Lowy Douglas R. , Schiller John T. , Ishihara Yasushige , Hasegawa Akira , Choyke Peter L. , Kobayashi Hisataka
Published: April 2023

Abstract
Human papillomavirus (HPV) infection is the most common sexually transmitted infection. Vaccines for HPV infection can reduce the risk of developing cervical cancer. To further improve such vaccines and to explore other methods of preventing or treating viral infection, longitudinal studies in experimental animals are desirable. Here, we describe a newly developed multicolor endoscopic fluorescence imaging system to visualize early HPV infection with fluorescent protein–encoded pseudoviruses (PsV) in the female genital tract of living mice. With this imaging method, the course of HPV PsV infection and the effects of intervention to prevent infection can be monitored in a single mouse over time. Female immunocompetent or athymic mice were pretreated with a vaginal spermicide and then HPV PsV composed of an authentic viral capsid and encapsidating green or red fluorescent protein (GFP or RFP) reporter gene was intravaginally instilled. Expression of GFP or RFP was detected 1 day after PsV challenge, which peaked after 2 or 3 days and decreasing thereafter. No fluorescence was detected in vaccine-treated immunocompetent mice. By using serial infection of the same PsV type (HPV16) encoding either GFP or RFP, different infection patterns of repeated exposure can be monitored. This method offers the ability to monitor experimental virus infections before and after intervention, thereby accelerating the development of appropriate prevention and therapy. Cancer Prev Res; 4(5); 767–73. ©2011 AACR.
Data from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer
Authors: Carmona F. Javier , Azuara Daniel , Berenguer-Llergo Antonio , Fernández Agustin F. , Biondo Sebastiano , de Oca Javier , Rodriguez-Moranta Francisco , Salazar Ramón , Villanueva Alberto , Fraga Mario F. , Guardiola Jordi , Capellá Gabriel , Esteller Manel , Moreno Victor
Published: April 2023

Abstract
DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer (CRC) and precursor lesions have been extensively studied. Different panels have been reported attempting to improve current protocols in clinical practice, although no definite biomarkers have been established.

In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes aiming to select the best performing candidates informative for CRC diagnosis in stool samples.

Five selected markers were considered for subsequent analyses in independent biologic cohorts and in silico data sets. Among the five selected genes, three of them (AGTR1, WNT2 and SLIT2) were validated in stool DNA of affected patients with a detection sensitivity of 78% [95% confidence interval (CI), 56%–89%]. As a reference, DNA methylation of VIM and SEPT9 was evaluated in a subset of stool samples yielding sensitivities of 55% and 20%, respectively. Moreover, our panel may complement histologic and endoscopic diagnosis of inflammatory bowel disease (IBD)-associated neoplasia, as it was also efficient detecting aberrant DNA methylation in non-neoplastic tissue samples from affected patients.

This novel panel of specific methylation markers can be useful for early diagnosis of CRC using stool DNA and may help in the follow-up of high-risk patients with IBD. Cancer Prev Res; 6(7); 656–65. ©2013 AACR.
Data from TFAP2A Regulates Nasopharyngeal Carcinoma Growth and Survival by Targeting HIF-1α Signaling Pathway
Authors: Shi Dingbo , Xie Fangyun , Zhang Yun , Tian Yun , Chen Wangbing , Fu Lingyi , Wang Jingshu , Guo Wei , Kang Tiebang , Huang Wenlin , Deng Wuguo
Published: April 2023

Abstract
TFAP2A is a transcription factor that orchestrates a variety of cell processes, including cell growth and tissue differentiation. However, the regulation of TFAP2A in human nasopharyngeal carcinoma tumorigenesis and its precise mechanism of action remain largely unknown. In this study, we investigated the biologic role and clinical significance of TFAP2A in nasopharyngeal carcinoma growth and progression and identified the underlying molecular mechanisms. We found that TFAP2A was highly expressed in various nasopharyngeal carcinoma cell lines and tumor tissue specimens and was significantly correlated with hypoxia-inducible factor-1α (HIF-1α) expression. A positive correlation of TFAP2A overexpression with advanced tumor stage, local invasion, clinical progression, and poor prognosis of patients with nasopharyngeal carcinomas were also observed. Moreover, we found that knockdown of TFAP2A expression by siRNA significantly inhibited tumor cell growth in nasopharyngeal carcinoma cell lines and in a subcutaneous xenograft mouse model by targeting the HIF-1α–mediated VEGF/pigment epithelium–derived factor (PEDF) signaling pathway. Treatment of nasopharyngeal carcinoma cells with TFAP2A siRNA dramatically inhibited the expression and the release of VEGF protein but did not change the level of PEDF protein, resulting in a significant reduction of the ratio of VEGF/PEDF. Pretreatment with a HIF-1α siRNA did not significantly change the TFAP2A siRNA-mediated inhibition in cell viability. Our results indicate that TFAP2A regulates nasopharyngeal carcinoma growth and survival through the modulation of the HIF-1α–mediated VEGF/PEDF signaling pathway, and suggest that TFAP2A could be a potential prognostic biomarker and therapeutic target for nasopharyngeal carcinoma treatment. Cancer Prev Res; 7(2); 266–77. ©2013 AACR.
Data from eRapa Restores a Normal Life Span in a FAP Mouse Model
Authors: Hasty Paul , Livi Carolina B. , Dodds Sherry G. , Jones Diane , Strong Randy , Javors Martin , Fischer Kathleen E. , Sloane Lauren , Murthy Kruthi , Hubbard Gene , Sun Lishi , Hurez Vincent , Curiel Tyler J. , Sharp Zelton Dave
Published: April 2023

Abstract
Mutation of a single copy of the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), which confers an extremely high risk for colon cancer. ApcMin/+ mice exhibit multiple intestinal neoplasia (MIN) that causes anemia and death from bleeding by 6 months. Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors were shown to improve ApcMin/+ mouse survival when administered by oral gavage or added directly to the chow, but these mice still died from neoplasia well short of a natural life span. The National Institute of Aging Intervention Testing Program showed that enterically targeted rapamycin (eRapa) extended life span for wild-type genetically heterogeneous mice in part by inhibiting age-associated cancer. We hypothesized that eRapa would be effective in preventing neoplasia and extend survival of ApcMin/+ mice. We show that eRapa improved survival of ApcMin/+ mice in a dose-dependent manner. Remarkably, and in contrast to previous reports, most of the ApcMin/+ mice fed 42 parts per million eRapa lived beyond the median life span reported for wild-type syngeneic mice. Furthermore, chronic eRapa did not cause detrimental immune effects in mouse models of cancer, infection, or autoimmunity, thus assuaging concerns that chronic rapamycin treatment suppresses immunity. Our studies suggest that a novel formulation (enteric targeting) of a well-known and widely used drug (rapamycin) can dramatically improve its efficacy in targeted settings. eRapa or other mTORC1 inhibitors could serve as effective cancer preventatives for people with FAP without suppressing the immune system, thus reducing the dependency on surgery as standard therapy. Cancer Prev Res; 7(1); 169–78. ©2013 AACR.