bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype
Authors: Li Ling , Li Chao , Wang Shaoxin , Wang Zhaohui , Jiang Jian , Wang Wei , Li Xiaoxia , Chen Jin , Liu Kun , Li Chunhua , Zhu Guiquan
Published: April 2023

Abstract
Hypoxia is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. Exosomes, initially considered to be cellular “garbage dumpsters,” are now implicated in mediating interactions with the cellular environment. However, the mechanisms underlying the association between exosomes and hypoxia during cancer progression remain poorly understood. In this study, we found that exosomes derived from hypoxic oral squamous cell carcinoma (OSCC) cells increased the migration and invasion of OSCC cells in a HIF-1α and HIF-2α–dependent manner. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we performed miRNA sequencing of normoxic and hypoxic OSCC-derived exosomes. Of the 108 miRNAs that were differentially expressed, miR-21 stood out as one of the most significantly upregulated miRNAs under hypoxic conditions. miR-21 depletion in hypoxic OSCC cells led to decreased miR-21 levels in exosomes and significantly reduced cell migration and invasion. Conversely, restoration of miR-21 expression in HIF-1α and HIF-2α–depleted exosomes rescued OSCC cell migration and invasion. Moreover, exosomal miR-21 markedly enhanced snail and vimentin expression, while significantly decreasing E-cadherin levels in OSCC cells, in vitro and in vivo. Finally, circulating exosomal miR-21 levels were closely associated with HIF-1α/HIF-2α expression, T stage, and lymph node metastasis in patients with OSCC. In conclusion, our findings suggest that the hypoxic microenvironment may stimulate tumor cells to generate miR-21–rich exosomes that are delivered to normoxic cells to promote prometastatic behaviors and prompt further investigation into the therapeutic value of exosome inhibition for cancer treatment. Cancer Res; 76(7); 1770–80. ©2016 AACR.
Data from TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy
Authors: Zhang Han , Chen Zheng , Miranda Roberto N. , Medeiros L. Jeffrey , McCarty Nami
Published: April 2023

Abstract
Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-κB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-κB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the current study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-κB/IL6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-κB and IL6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy. Cancer Res; 76(21); 6410–23. ©2016 AACR.
Data from Antitumor Properties of an IgG2-Enhanced Next-Generation MET Monoclonal Antibody That Degrades Wild-Type and Mutant MET Receptors
Authors: Yang Yan , Mandiyan Sreekala , Robinson Brett S. , McMahon Gerald
Published: April 2023

Abstract
A sound rationale exists for antibody targeting of the MET receptor tyrosine kinase, but therapeutic agents that can broadly block HGF ligand binding and exon 14–mutated or amplified MET to induce receptor degradation have yet to be reported. Here we report the identification of several MET monoclonal antibodies (mAb) that block MET-dependent signaling and tumor growth. In particular, the MET mAb KTN0073 and KTN0074 bind the Sema/PSI domain, at overlapping but distinct epitopes, preventing HGF interaction with MET and triggering receptor ubiquitination and degradation. Notably, both mAbs also triggered degradation of oncogenic MET exon 14 mutants, which propagate more durable MET signals due to a defect in receptor degradation. Mechanistic investigations showed that both mAbs engaged a pathway distinct from HGF-induced receptor degradation and protease-mediated shedding, independently of signaling driven by the exon 14–encoded sequences in the intracellular juxtamembrane region of the MET receptor. Grafting the mAb variable regions onto the IgG2 constant region dramatically enhanced the tumor inhibitory activities of KTN0073 but not KTN0074, suggesting a specific influence of antibody isotype of the epitopes for these two MET mAbs. Overall, our results highlight KTN0073 as a novel IgG2-based MET mAb that acts through exon 14–independent mechanisms to degrade the MET receptor, potentially offering a therapeutic tool to treat a broader range of human tumors where MET is exon 14 mutated or amplified. Cancer Res; 76(19); 5788–97. ©2016 AACR.
Data from HuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis
Authors: Lang Michaela , Berry David , Passecker Katharina , Mesteri Ildiko , Bhuju Sabin , Ebner Florian , Sedlyarov Vitaly , Evstatiev Rayko , Dammann Kyle , Loy Alexander , Kuzyk Orest , Kovarik Pavel , Khare Vineeta , Beibel Martin , Roma Guglielmo , Meisner-Kober Nicole , Gasche Christoph
Published: April 2023

Abstract
HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3′ untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia. Intraperitoneal injection of the HuR small-molecule inhibitor MS-444 in AOM/DSS mice, a model of IBD and inflammatory colon cancer, augmented DSS-induced weight loss and increased tumor multiplicity, size, and invasiveness. MS-444 treatment also abrogated tumor cell apoptosis and depleted tumor-associated eosinophils, accompanied by a decrease in IL18 and eotaxin-1. In contrast, HuR inhibition in APCMin mice, a model of FAP and colon cancer, diminished the number of small intestinal tumors generated. In this setting, fecal microbiota, evaluated by 16S rRNA gene amplicon sequencing, shifted to a state of reduced bacterial diversity, with an increased representation of Prevotella, Akkermansia, and Lachnospiraceae. Taken together, our results indicate that HuR activation is an early event in FAP-adenoma but is not present in IBD-dysplasia. Furthermore, our results offer a preclinical proof of concept for HuR inhibition as an effective means of FAP chemoprevention, with caution advised in the setting of IBD. Cancer Res; 77(9); 2424–38. ©2017 AACR.
Data from Measurement of Endogenous versus Exogenous Formaldehyde–Induced DNA–Protein Crosslinks in Animal Tissues by Stable Isotope Labeling and Ultrasensitive Mass Spectrometry
Authors: Lai Yongquan , Yu Rui , Hartwell Hadley J. , Moeller Benjamin C. , Bodnar Wanda M. , Swenberg James A.
Published: April 2023

Abstract
DNA–protein crosslinks (DPC) arise from a wide range of endogenous and exogenous chemicals, such as chemotherapeutic drugs and formaldehyde. Importantly, recent identification of aldehydes as endogenous genotoxins in Fanconi anemia has provided new insight into disease causation. Because of their bulky nature, DPCs pose severe threats to genome stability, but previous methods to measure formaldehyde-induced DPCs were incapable of discriminating between endogenous and exogenous sources of chemical. In this study, we developed methods that provide accurate and distinct measurements of both exogenous and endogenous DPCs in a structurally specific manner. We exposed experimental animals to stable isotope–labeled formaldehyde ([13CD2]-formaldehyde) by inhalation and performed ultrasensitive mass spectrometry to measure endogenous (unlabeled) and exogenous (13CD2-labeled) DPCs. We found that exogenous DPCs readily accumulated in nasal respiratory tissues but were absent in tissues distant to the site of contact. This observation, together with the finding that endogenous formaldehyde–induced DPCs were present in all tissues examined, suggests that endogenous DPCs may be responsible for increased risks of bone marrow toxicity and leukemia. Furthermore, the slow rate of DPC repair provided evidence for the persistence of DPCs. In conclusion, our method for measuring endogenous and exogenous DPCs presents a new perspective for the potential health risks inflicted by endogenous formaldehyde and may inform improved disease prevention and treatment strategies. Cancer Res; 76(9); 2652–61. ©2016 AACR.
Data from Oncogenic Mutation of AIMP2/p38 Inhibits Its Tumor-Suppressive Interaction with Smurf2
Authors: Kim Dae Gyu , Lee Jin Young , Lee Ji-Hyun , Cho Ha Yeon , Kang Beom Sik , Jang Song-Yee , Kim Myung Hee , Guo Min , Han Jung Min , Kim Seong-Jin , Kim Sunghoon
Published: April 2023

Abstract
AIMP2/p38 is a multifunctional tumor suppressor that normally resides in the cytosol as a scaffold protein of the multi-tRNA synthetase complex (MSC). One of the tumor-suppressive functions of AIMP2 is to facilitate ubiquitin-mediated degradation of FUSE-binding protein (FBP, FUBP1), a transcriptional activator of c-Myc. However, the mechanism by which AIMP2 functions within this pathway and its significance in tumorigenesis are uncertain. Here, we report that Smurf2 is responsible for AIMP2-mediated ubiquitination of FBP, and a mutation in AIMP2 that inhibited its nuclear interaction with Smurf2 enhanced cellular transformation and tumorigenesis in vivo. Treatment of HeLa cells with TGFβ resulted in the phosphorylation of AIMP2 on S156, a residue that is exposed on the embedded GST domain of AIMP2. We further found that phospho-AIMP2 dissociated from the MSC and translocated to the nucleus, where it bound to Smurf2, enhancing ubiquitination of FBP. AIMP2 also inhibited nuclear export of Smurf2 to sustain TGFβ signaling. Collectively, these findings present a novel tumor-suppressive interaction between AIMP2 and Smurf2 and suggest that the disruption of this interaction can lead to oncogenic transformation. Cancer Res; 76(11); 3422–36. ©2016 AACR.
Data from Snail Up-regulates Proinflammatory Mediators and Inhibits Differentiation in Oral Keratinocytes
Authors: Lyons J. Guy , Patel Vyomesh , Roue Naomi C. , Fok Sandra Y. , Soon Lilian L. , Halliday Gary M. , Gutkind J. Silvio
Published: April 2023

Abstract
The transcriptional repressor Snail2 is overexpressed in head and neck squamous cell carcinomas (HNSCC) relative to nonmalignant head and neck mucosal epithelium, and in locally recurrent relative to nonrecurrent HNSCCs. We investigated the mechanisms by which Snails might contribute to the pathogenesis of HNSCCs using cell biological and molecular analyses. Oral keratinocytes that expressed Snails acquired an enhanced ability to attract monocytes and to invade a dense interstitial collagen matrix. They were also found to up-regulate production of proinflammatory cytokines and cyclooxygenase-2 (COX2), which have previously been shown to correlate with malignancy. Induction of nuclear factor-κB transcriptional activity by Snails was weak and not sufficient to account for the elevated levels of COX2, interleukin (IL)-6, IL8, or CXCL1. In addition, expression of Snails in oral keratinocytes impaired desquamation in vitro and strongly repressed expression of both ELF3 and matriptase-1, which play important roles in the terminal differentiation of keratinocytes. Reexpression of matriptase-1 in Snail-expressing cells partially rescued desquamation. This implicates Snails as contributing to malignancy both at the early stages, by impeding terminal differentiation, and at later stages, when invasion and inflammation are important. [Cancer Res 2008;68(12):4525–30]
Data from Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance
Authors: Liu Jianglan , Rebecca Vito W. , Kossenkov Andrew V. , Connelly Thomas , Liu Qin , Gutierrez Alexis , Xiao Min , Li Ling , Zhang Gao , Samarkina Anastasia , Zayasbazan Delaine , Zhang Jie , Cheng Chaoran , Wei Zhi , Alicea Gretchen M. , Fukunaga-Kalabis Mizuho , Krepler Clemens , Aza-Blanc Pedro , Yang Chih-Cheng , Delvadia Bela , Tong Cynthia , Huang Ye , Delvadia Maya , Morias Alice S. , Sproesser Katrin , Brafford Patricia , Wang Joshua X. , Beqiri Marilda , Somasundaram Rajasekharan , Vultur Adina , Hristova Denitsa M. , Wu Lawrence W. , Lu Yiling , Mills Gordon B. , Xu Wei , Karakousis Giorgos C. , Xu Xiaowei , Schuchter Lynn M. , Mitchell Tara C. , Amaravadi Ravi K. , Kwong Lawrence N. , Frederick Dennie T. , Boland Genevieve M. , Salvino Joseph M. , Speicher David W. , Flaherty Keith T. , Ronai Ze'ev A. , Herlyn Meenhard
Published: April 2023

Abstract
Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell–like pathways hijacked by tumor cells.
Significance:
This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.
Supplementary Figure S4. Distinct HPV methylation in genic regions between CIN and ICC and CIN3 and SCC from Targeted, Deep Sequencing Reveals Full Methylation Profiles of Multiple HPV Types and Potential Biomarkers for Cervical Cancer Progression
Authors: Liu Pengyuan , Iden Marissa , Fye Samantha , Huang Yi-Wen , Hopp Elizabeth , Chu Chen , Lu Yan , Rader Janet S.
Published: April 2023

Methylation differences among genic regions between (A) CIN and ICC or (B) CIN3 and SCC in all HPV types. Methylation difference (%) was calculated by subtracting the mean methylation rate of CIN or CIN3 from the mean methylation rate of ICC or SCC at a specific genic region. Dashed lines imply p values = 0.05.
Supplemental Table 1 from Opportunities and Challenges for the Use of Large-Scale Surveys in Public Health Research: A Comparison of the Assessment of Cancer Screening Behaviors
Authors: Hamilton Jada G. , Breen Nancy , Klabunde Carrie N. , Moser Richard P. , Leyva Bryan , Breslau Erica S. , Kobrin Sarah C.
Published: April 2023

Supplemental Table 1. Details regarding cancer screening constructs in the National Health Interview Survey (NHIS), Health Information National Trends Survey (HINTS), Behavioral Risk Factor Surveillance System (BRFSS), and California Health Interview Survey (CHIS), 2005
Supplementary Methods from Fine-Mapping of IL16 Gene and Prostate Cancer Risk in African Americans
Authors: Batai Ken , Shah Ebony , Murphy Adam B. , Newsome Jennifer , Ruden Maria , Ahaghotu Chiledum , Kittles Rick A.
Published: April 2023

PDF file, 93K, Assessment of imputation accuracy and results of imputation.
Data from Depressive Symptoms and Short Telomere Length Are Associated with Increased Mortality in Bladder Cancer Patients
Authors: Lin Jie , Blalock Janice A. , Chen Meng , Ye Yuanqing , Gu Jian , Cohen Lorenzo , Cinciripini Paul M. , Wu Xifeng
Published: April 2023

Abstract
Background: Depression is associated with an increased risk of mortality in patients with cancer; it has been hypothesized that depression-associated alterations in cell aging mechanisms, in particular, the telomere/telomerase maintenance system, may underlie this increased risk. We evaluated the association of depressive symptoms and telomere length to mortality and recurrence/progression in 464 patients with bladder cancer.

Methods: We used the Center for Epidemiologic Studies Depression Scale (CES-D) and Structured Clinical Interview for DSM-IV Disorder (SCID) to assess current depressive symptoms and lifetime major depressive disorder (MDD), respectively, and telomere length was assessed from peripheral blood lymphocytes. Multivariate Cox regression was used to assess the association of depression and telomere length to outcomes and the joint effect of both. Kaplan–Meier plots and log-rank tests were used to compare survival time of subgroups by depression variables and telomere length.

Results: Patients with depressive symptoms (CES-D ≥ 16) had a 1.83-fold [95% confidence interval (CI), 1.08–3.08; P = 0.024] increased risk of mortality compared with patients without depressive symptoms (CES-D < 16) and shorter disease-free survival time (P = 0.004). Patients with both depressive symptoms and lifetime history of MDD were at 4.88-fold (95% CI, 1.40–16.99; P = 0.013) increased risk compared with patients with neither condition. Compared to patients without depressive symptoms and long telomere length, patients with depressive symptoms and short telomeres exhibited a 4-fold increased risk of mortality (HR, 3.96; 95% CI, 1.86–8.41; P = 0.0003) and significantly shorter disease-free survival time (P < 0.001).

Conclusion: Short telomere length and depressive symptoms are associated with bladder cancer mortality individually and jointly.

Impact: Further investigation of interventions that impact depression and telomere length may be warranted in patients with cancer. Cancer Epidemiol Biomarkers Prev; 24(2); 336–43. ©2014 AACR.
Data from Inflammatory Markers and Risk of Epithelial Ovarian Cancer by Tumor Subtypes: The EPIC Cohort
Authors: Ose Jennifer , Schock Helena , Tjønneland Anne , Hansen Louise , Overvad Kim , Dossus Laure , Clavel-Chapelon Françoise , Baglietto Laura , Boeing Heiner , Trichopolou Antonia , Benetou Vassiliki , Lagiou Pagona , Masala Giovanna , Tagliabue Giovanna , Tumino Rosario , Sacerdote Carlotta , Mattiello Amalia , Bueno-de-Mesquita H. B(as). , Peeters Petra H. M. , Onland-Moret N. Charlotte , Weiderpass Elisabete , Gram Inger T. , Sánchez Soledad , Obon-Santacana Mireia , Sànchez-Pérez Maria-José , Larrañaga Nerea , Castaño José María Huerta , Ardanaz Eva , Brändstedt Jenny , Lundin Eva , Idahl Annika , Travis Ruth C. , Khaw Kay-Tee , Rinaldi Sabina , Romieu Isabelle , Merritt Melissa A. , Gunter Marc J. , Riboli Elio , Kaaks Rudolf , Fortner Renée T.
Published: April 2023

Abstract
Background: Evidence suggests an etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Prospective studies on circulating inflammatory markers and epithelial invasive ovarian cancer (EOC) have predominantly investigated overall risk; data characterizing risk by tumor characteristics (histology, grade, stage, dualistic model of ovarian carcinogenesis) and anthropometric indices are sparse.

Methods: We conducted a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate C-reactive protein (CRP), IL6, and EOC risk by tumor characteristics. A total of 754 eligible EOC cases were identified; two controls (n = 1,497) were matched per case. We used multivariable conditional logistic regression to assess associations.

Results: CRP and IL6 were not associated with overall EOC risk. However, consistent with prior research, CRP >10 versus CRP ≤1 mg/L was associated with higher overall EOC risk [OR, 1.67 (1.03–2.70)]. We did not observe significant associations or heterogeneity in analyses by tumor characteristics. In analyses stratified by waist circumference, inflammatory markers were associated with higher risk among women with higher waist circumference; no association was observed for women with normal waist circumference [e.g., IL6: waist ≤80: ORlog2, 0.97 (0.81–1.16); waist >88: ORlog2, 1.78 (1.28–2.48), Pheterogeneity ≤ 0.01].

Conclusions: Our data suggest that high CRP is associated with increased risk of overall EOC, and that IL6 and CRP may be associated with EOC risk among women with higher adiposity.

Impact: Our data add to global evidence that ovarian carcinogenesis may be promoted by an inflammatory milieu. Cancer Epidemiol Biomarkers Prev; 24(6); 951–61. ©2015 AACR.
Data from Glomerular Function Time Trends in Long-Term Survivors of Childhood Cancer: A Longitudinal Study
Authors: Mulder Renée L. , Knijnenburg Sebastiaan L. , Geskus Ronald B. , van Dalen Elvira C. , van der Pal Helena J.H. , Koning Caro C.E. , Bouts Antonia H. , Caron Huib N. , Kremer Leontien C.M.
Published: April 2023

Abstract
Background: Impaired glomerular function is one of the health problems affecting childhood cancer survivors (CCS). It is unclear whether glomerular function deteriorates or recovers. We investigated time trends and predictors of glomerular function in CCS.

Methods: We evaluated repeated observations of estimated glomerular filtration rate (GFR) and glomerular dysfunction (GFR <90 mL/min/1.73 m2) among adult five-year CCS treated in the EKZ/AMC between 1966 and 2003. Ifosfamide, cisplatin, carboplatin, high-dose (HD) methotrexate, HD-cyclophosphamide, radiotherapy to the kidney region, and nephrectomy (i.e., potentially nephrotoxic therapy) were investigated as predictors of glomerular function patterns over time in multivariable longitudinal analyses.

Results: At a median follow-up of 21 years after diagnosis, glomerular function was assessed in 1,122 CCS aged ≥18 years. CCS treated with potentially nephrotoxic therapy had a significantly lower GFR and higher glomerular dysfunction probability up to 35 years after cancer diagnosis compared with CCS treated without nephrotoxic therapy (P < 0.001). Especially ifosfamide, cisplatin, and nephrectomy were associated with worse glomerular function that persisted during the entire follow-up period (P < 0.001). Glomerular function deteriorated over time in all CCS (P < 0.001). CCS treated with higher doses of cisplatin seem to have a higher deterioration rate as compared with other CCS (P < 0.005).

Conclusions: The loss in glomerular function starts early, especially for CCS treated with ifosfamide, higher doses of cisplatin, and nephrectomy, and seems to be persistent. We have an indication that CCS treated with higher doses of cisplatin experience faster decline than other CCS.

Impact: As glomerular function continues to deteriorate, CCS are at risk for premature chronic renal failure. Cancer Epidemiol Biomarkers Prev; 22(10); 1736–46. ©2013 AACR.
Data from Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium
Authors: Kane Eleanor , Skibola Christine F. , Bracci Paige M. , Cerhan James R. , Costas Laura , Smedby Karin Ekström , Holly Elizabeth A. , Maynadié Marc , Novak Anne J. , Lightfoot Tracy J. , Ansell Stephen M. , Smith Alex G. , Liebow Mark , Melbye Mads , Morton Lindsay , de Sanjosé Silvia , Slager Susan L. , Wang Sophia S. , Zhang Yawei , Zheng Tongzhang , Roman Eve
Published: April 2023

Abstract
Background: Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported.

Method: Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988–2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI).

Results: Obesity (BMI ≥ 30 kg/m2) was associated with DLBCL risk [OR = 1.33; 95% confidence interval (CI), 1.02–1.73], as was TNF-308GA+AA (OR = 1.24; 95% CI, 1.07–1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost 2-fold relative to those of normal weight and TNF-308GG (OR = 1.93; 95% CI, 1.27–2.94), with a RERI of 0.41 (95% CI, −0.05–0.84; Pinteraction = 0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected.

Conclusions: Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk.

Impact: Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma. Cancer Epidemiol Biomarkers Prev; 24(7); 1061–70. ©2015 AACR.
Data from Single-Nucleotide Polymorphisms in Genes Encoding for CC Chemokines were Not Associated with the Risk of Non-Hodgkin Lymphoma
Authors: Chen Qiong , Zheng Tongzhang , Lan Qing , Lerro Catherine , Zhao Nan , Qin Qin , Hu Xiaobin , Huang Huang , Liang Jiaxin , Holford Theodore , Leaderer Brian , Boyle Peter , Chanock Stephen J. , Rothman Nathaniel , Zhang Yawei
Published: April 2023

Abstract
Background: Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and non-Hodgkin lymphoma (NHL).

Methods: We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8, and CCR9) encoding for the CC chemokines using data from a population-based case–control study of NHL conducted in Connecticut women.

Results:CCR8 was associated with diffuse large B-cell lymphoma (DLBCL; P = 0.012), and CCL13 was associated with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; P = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or single-nucleotide polymorphisms (SNP) were associated with risk of overall NHL or NHL subtypes.

Conclusions: Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings.

Impact: Our data indicate that CC chemokine genes were not associated with NHL risk. Cancer Epidemiol Biomarkers Prev; 22(7); 1332–5. ©2013 AACR.
Data from Telomere Length Varies By DNA Extraction Method: Implications for Epidemiologic Research
Authors: Cunningham Julie M. , Johnson Ruth A. , Litzelman Kristin , Skinner Halcyon G. , Seo Songwon , Engelman Corinne D. , Vanderboom Russell J. , Kimmel Grace W. , Gangnon Ronald E. , Riegert-Johnson Douglas L. , Baron John A. , Potter John D. , Haile Robert , Buchanan Daniel D. , Jenkins Mark A. , Rider David N. , Thibodeau Stephen N. , Petersen Gloria M. , Boardman Lisa A.
Published: April 2023

Abstract
Background: Both shorter and longer telomeres in peripheral blood leukocyte (PBL) DNA have been associated with cancer risk. However, associations remain inconsistent across studies of the same cancer type. This study compares DNA preparation methods to determine telomere length from patients with colorectal cancer.

Methods: We examined PBL relative telomere length (RTL) measured by quantitative PCR (qPCR) in 1,033 patients with colorectal cancer and 2,952 healthy controls. DNA was extracted with phenol/chloroform, PureGene, or QIAamp.

Results: We observed differences in RTL depending on DNA extraction method (P < 0.001). Phenol/chloroform-extracted DNA had a mean RTL (T/S ratio) of 0.78 (range 0.01–6.54) compared with PureGene-extracted DNA (mean RTL of 0.75; range 0.00–12.33). DNA extracted by QIAamp yielded a mean RTL of 0.38 (range 0.02–3.69). We subsequently compared RTL measured by qPCR from an independent set of 20 colorectal cancer cases and 24 normal controls in PBL DNA extracted by each of the three extraction methods. The range of RTL measured by qPCR from QIAamp-extracted DNA (0.17–0.58) was less than from either PureGene or phenol/chloroform (ranges, 0.04–2.67 and 0.32–2.81, respectively).

Conclusions: RTL measured by qPCR from QIAamp-extracted DNA was less than from either PureGene or phenol/chloroform (P < 0.001).

Impact: Differences in DNA extraction method may contribute to the discrepancies between studies seeking to find an association between the risk of cancer or other diseases and RTL. Cancer Epidemiol Biomarkers Prev; 22(11); 2047–54. ©2013 AACR.
Data from Human Papillomavirus Load in Eyebrow Hair Follicles and Risk of Cutaneous Squamous Cell Carcinoma
Authors: Neale Rachel E. , Weissenborn Soenke , Abeni Damiano , Bavinck Jan Nico Bouwes , Euvrard Sylvie , Feltkamp Mariet C.W. , Green Adele C. , Harwood Catherine , de Koning Maurits , Naldi Luigi , Nindl Ingo , Pawlita Michael , Proby Charlotte , Quint Wim G. , Waterboer Tim , Wieland Ulrike , Pfister Herbert
Published: April 2023

Abstract
Background: Beta-human papillomavirus (betaPV) may play a role in the development of cutaneous squamous cell carcinoma (SCC). However betaPV is highly prevalent, and it may only be people with a higher viral load who have increased risk of SCCs. We therefore examined the association between betaPV load and SCCs.

Methods: We recruited 448 immunocompetent cases with SCCs and 464 controls from Italy and Australia and 497 immunosuppressed organ transplant recipients (OTR; 179 cases and 318 controls) from Europe. We used reverse hybridization to genotype 25 betaPV types in eyebrow hair follicles and determined the viral load for eight selected types using quantitative PCR. We used logistic regression to assess associations between type-specific and cumulative viral load and SCCs.

Results: Australian and OTR participants in the highest cumulative load tertile were at significantly higher risk of SCCs than those in the lowest tertile. Those with more than four betaPV types in the high load tertile were at approximately three-fold increased risk of SCCs. In Australia, HPV23 and 36 loads were significantly associated with SCCs, with borderline associations for HPV5 and 38. In OTR, HPV8 and 38 loads were significantly associated and HPV20 and 36 were borderline. We found little evidence for an association between load and SCCs in Italy.

Conclusions: High viral load may be associated with risk of cutaneous SCCs, with total load seemingly more important than the load of any specific type.

Impact: Our findings lend weight to the hypothesis that HPV plays a role in skin carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(4); 719–27. ©2013 AACR.
Data from MicroRNA Profiles of Barrett's Esophagus and Esophageal Adenocarcinoma: Differences in Glandular Non-native Epithelium
Authors: Drahos Jennifer , Schwameis Katrin , Orzolek Linda D. , Hao Haiping , Birner Peter , Taylor Phillip R. , Pfeiffer Ruth M. , Schoppmann Sebastian F. , Cook Michael B.
Published: April 2023

Abstract
Background: The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus.

Methods: In a case–control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using NanoString miRNA v2. We tested differences in detection by case group using the χ2 test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E−05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation.

Results: We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but <20% of Barrett's esophagus. Seven miRNAs (miR-4286, miR-630, miR-575, miR-494, miR-320e, miR-4488, and miR-4508) exhibited the most extreme differences in expression with >5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case–control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity.

Conclusion: This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma.

Impact: These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance. Cancer Epidemiol Biomarkers Prev; 25(3); 429–37. ©2015 AACR.
Data from Organizational Predictors of Colonoscopy Follow-up for Positive Fecal Occult Blood Test Results: An Observational Study
Authors: Partin Melissa R. , Burgess Diana J. , Burgess James F. , Gravely Amy , Haggstrom David , Lillie Sarah E. , Nugent Sean , Powell Adam A. , Shaukat Aasma , Walter Louise C. , Nelson David B.
Published: April 2023

Abstract
Background: This study assessed the contribution of organizational structures and processes identified from facility surveys to follow-up for positive fecal occult blood tests [FOBT-positive (FOBT+)].

Methods: We identified 74,104 patients with FOBT+ results from 98 Veterans Health Administration (VHA) facilities between August 16, 2009 and March 20, 2011, and followed them until September 30, 2011, for completion of colonoscopy. We identified patient characteristics from VHA administrative records, and organizational factors from facility surveys completed by primary care and gastroenterology chiefs. We estimated predictors of colonoscopy completion within 60 days and six months using hierarchical logistic regression models.

Results: Thirty percent of patients with FOBT+ results received colonoscopy within 60 days and 49% within six months. Having gastroenterology or laboratory staff notify gastroenterology providers directly about FOBT+ cases was a significant predictor of 60-day [odds ratio (OR), 1.85; P = 0.01] and six-month follow-up (OR, 1.25; P = 0.008). Additional predictors of 60-day follow-up included adequacy of colonoscopy appointment availability (OR, 1.43; P = 0.01) and frequent individual feedback to primary care providers about FOBT+ referral timeliness (OR, 1.79; P = 0.04). Additional predictors of six-month follow-up included using guideline-concordant surveillance intervals for low-risk adenomas (OR, 1.57; P = 0.01) and using group appointments and combined verbal–written methods for colonoscopy preparation instruction (OR, 1.48; P = 0.0001).

Conclusion: Directly notifying gastroenterology providers about FOBT+ results, using guideline-concordant adenoma surveillance intervals, and using colonoscopy preparations instruction methods that provide both verbal and written information may increase overall follow-up rates. Enhancing follow-up within 60 days may require increased colonoscopy capacity and feedback to primary care providers.

Impact: These findings may inform organizational-level interventions to improve FOBT+ follow-up. Cancer Epidemiol Biomarkers Prev; 24(2); 422–34. ©2014 AACR.
Data from Increased and Mistimed Sex Hormone Production in Night Shift Workers
Authors: Papantoniou Kyriaki , Pozo Oscar J. , Espinosa Ana , Marcos Josep , Castaño-Vinyals Gemma , Basagaña Xavier , Juanola Pagès Elena , Mirabent Joan , Martín Jordi , Such Faro Patricia , Gascó Aparici Amparo , Middleton Benita , Skene Debra J. , Kogevinas Manolis
Published: April 2023

Abstract
Background: Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes.

Methods: We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers.

Results: Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17–2.32] and androgens (GMR: 1.44; 95% CI, 1.03–2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46).

Conclusions: We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers.

Impact: The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers. Cancer Epidemiol Biomarkers Prev; 24(5); 854–63. ©2015 AACR.
Data from Medical Care Cost of Oropharyngeal Cancer among Texas Patients
Authors: Lairson David R. , Wu Chi-Fang , Chan Wenyaw , Dahlstrom Kristina R. , Tam Samantha , Sturgis Erich M.
Published: April 2023

Abstract
Background: The incidence of oropharyngeal cancer is rising rapidly, with the majority of cases being attributable to human papillomavirus (HPV). Despite the availability of a vaccine, rates of HPV vaccination among Texas youth are low. The healthcare cost of oropharyngeal cancer in Texas is unknown. The aims of this study were to estimate the first 2-year cost of treating new cases of oropharyngeal cancer and determine the predictors of oropharyngeal cancer treatment cost in Texas.

Methods: This study included a retrospective cohort of 467 Texas patients with commercial insurance claims data with oropharyngeal cancer diagnosed from 2011 to 2014 and a control group of 467 noncancer patients obtained with propensity score matching. Total healthcare cost during the first 2 years after the index date was measured. A generalized linear model was used to identify predictors of monthly cost during the 2 years after the index date.

Results: The mean differential adjusted healthcare cost for oropharyngeal cancer cases was $139,749 in the first 2 years. The mean adjusted monthly cost in the first 2 years was $6,693 for cases and $870 for controls. Age, comorbidity, mental health, prediagnostic healthcare cost, and time index were significant predictors of monthly cost.

Conclusions: Medical care cost was about $140,000 in the first 2 years after diagnosis of oropharyngeal cancer among commercially insured patients in Texas.

Impact: The cost estimates provide important parameters for development of decision-analytic models to inform decision makers about the potential value of initiatives for increasing the HPV immunization rate in the state. Cancer Epidemiol Biomarkers Prev; 26(9); 1443–9. ©2017 AACR.
Data from Intermediate- and Low-Methylation Epigenotypes Do Not Correspond to CpG Island Methylator Phenotype (Low and -Zero) in Colorectal Cancer
Authors: Karpinski Pawel , Walter Michael , Szmida Elzbieta , Ramsey David , Misiak Blazej , Kozlowska Joanna , Bebenek Marek , Grzebieniak Zygmunt , Blin Nikolaus , Laczmanski Lukasz , Sasiadek Maria M.
Published: April 2023

Abstract
Background: Most recent genome-wide studies on the CpG island methylation in colorectal cancer (CRC) have led to the discovery of at least 3 distinct methylation clusters. However, there remains an uncertainty whether the CRC clusters identified in these studies represent compatible phenotypes.

Methods: We carried out comprehensive genome-scale DNA methylation profiling by Illumina Infinium HumanMethylation27 of 21 DNA pools that represent 84 CRC samples divided according to their high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively) and 70 normal-adjacent colonic tissues. We have also examined the relationship among 3 epigenotypes and chromosomal gains and deletions (assessed by Comparative Genomic Hybridization) in a group of 100 CRC samples.

Results: The HME subgroup showed features associated with CpG island methylator phenotype – high (CIMP-high) including methylation of specific CpG sites (CpGs) as well as significantly lower mean number of chromosomal imbalances when compared with other epigenotypes. The IME subgroup displayed the lowest number of methylated CpGs (717 vs. 2,399 and 2,679 in HME and LME, respectively) and highest mean number of chromosomal imbalances when compared with HME (P, 0.001) and LME (P, 0.004). A comparison between the methylation profiles of 3 epigenotypes revealed more similarities between the HME and LME (1,669 methylated CpGs overlapped) than HME and IME (673 methylated CpGs overlapped).

Conclusion: Our results provide evidence that IME and LME CRCs show opposite features to those that have been previously attributed to CIMP-low and CIMP-0 CRCs.

Impact: These discrepancies should be considered when interpreting the data from a particular epigenotyping method. Cancer Epidemiol Biomarkers Prev; 22(2); 201–8. ©2012 AACR.
Data from Cellular Expression of PD-L1 in the Peripheral Blood of Lung Cancer Patients is Associated with Worse Survival
Authors: Boffa Daniel J. , Graf Ryon P. , Salazar Michelle C. , Hoag Jessica , Lu David , Krupa Rachel , Louw Jessica , Dugan Lyndsey , Wang Yipeng , Landers Mark , Suraneni Mahipal , Greene Stephanie B. , Magaña Marisa , Makani Samir , Bazhenova Lyudmila , Dittamore Ryan V. , Nieva Jorge
Published: April 2023

Abstract
Background: Lung cancer treatment has become increasingly dependent upon invasive biopsies to profile tumors for personalized therapy. Recently, tumor expression of programmed death-ligand 1 (PD-L1) has gained interest as a potential predictor of response to immunotherapy. Circulating biomarkers present an opportunity for tumor profiling without the risks of invasive procedures. We characterized PD-L1 expression within populations of nucleated cells in the peripheral blood of lung cancer patients in hopes of expanding the role of liquid biopsy in this setting.

Methods: Peripheral blood samples from a multi-institutional prospective study of patients with clinical diagnosis of lung cancer were subjected to cytomorphometric and immunohistochemical evaluation using single-cell, automated slide-based, digital pathology. PD-L1 expression was determined by immunofluorescence.

Results: PD-L1 expression was detected within peripheral circulating cells associated with malignancy (CCAM) in 26 of 112 (23%) non–small cell lung cancer patients. Two distinct populations of nucleated, nonhematolymphoid, PD-L1–expressing cells were identified; cytokeratin positive (CK+, PD-L1+, CD45−) and cytokeratin negative (CK−, PD-L1+, CD45−) cells, both with cytomorphometric features (size, nuclear-to-cytoplasm ratio) consistent with tumor cells. Patients with >1.1 PD-L1(+) cell/mL (n = 14/112) experienced worse overall survival than patients with ≤1.1 PD-L1(+) cell/mL (2-year OS: 31.2% vs. 78.8%, P = 0.00159). In a Cox model adjusting for stage, high PD-L1(+) cell burden remained a significant predictor of mortality (HR = 3.85; 95% confidence interval, 1.64–9.09; P = 0.002).

Conclusions: PD-L1 expression is detectable in two distinct cell populations in the peripheral blood of lung cancer patients and is associated with worse survival.

Impact: These findings could represent a step forward in the development of minimally invasive liquid biopsies for the profiling of tumors. Cancer Epidemiol Biomarkers Prev; 26(7); 1139–45. ©2017 AACR.
Data from Adult Stature and Risk of Cancer at Different Anatomic Sites in a Cohort of Postmenopausal Women
Authors: Kabat Geoffrey C. , Anderson Matthew L. , Heo Moonseong , Hosgood H. Dean , Kamensky Victor , Bea Jennifer W. , Hou Lifang , Lane Dorothy S. , Wactawski-Wende Jean , Manson JoAnn E. , Rohan Thomas E.
Published: April 2023

Abstract
Background: Prospective studies in Western and Asian populations suggest that height is a risk factor for various cancers. However, few studies have explored potential confounding or effect modification of the association by other factors.

Methods: We examined the association between height measured at enrollment in 144,701 women participating in the Women's Health Initiative and risk of all cancers combined and cancer at 19 specific sites. Over a median follow-up of 12.0 years, 20,928 incident cancers were identified. We used Cox proportional hazards models to estimate HR and 95% confidence intervals (CI) per 10 cm increase in height, with adjustment for established risk factors. We also examined potential effect modification of the association with all cancer and specific cancers.

Results: Height was significantly positively associated with risk of all cancers (HR = 1.13; 95% CI, 1.11–1.16), as well as with cancers of the thyroid, rectum, kidney, endometrium, colorectum, colon, ovary, and breast, and with multiple myeloma and melanoma (range of HRs: 1.13 for breast cancer to 1.29 for multiple myeloma and thyroid cancer). These associations were generally insensitive to adjustment for confounders, and there was little evidence of effect modification.

Conclusions: This study confirms the positive association of height with risk of all cancers and a substantial number of cancer sites.

Impact: Identification of single-nucleotide polymorphisms associated both with height and with increased cancer risk may help elucidate the association. Cancer Epidemiol Biomarkers Prev; 22(8); 1353–63. ©2013 AACR.