bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab
Authors: Gebhardt Christoffer , Sevko Alexandra , Jiang Huanhuan , Lichtenberger Ramtin , Reith Maike , Tarnanidis Kathrin , Holland-Letz Tim , Umansky Ludmila , Beckhove Philipp , Sucker Antje , Schadendorf Dirk , Utikal Jochen , Umansky Viktor 
Published: August 2015

Abstract
Purpose: Immunotherapy with ipilimumab improves the survival of patients with metastatic melanoma. Because only around 20% of patients experience long-term benefit, reliable markers are needed to predict a clinical response. Therefore, we sought to determine if some myeloid cells and related inflammatory mediators could serve as predictive factors for the patients' response to ipilimumab.
Experimental Design: We performed an analysis of myeloid cells in the peripheral blood of 59 stage IV melanoma patients before the treatment and at different time points upon the therapy using a clinical laboratory analysis and multicolor flow cytometry. In addition, the production of related inflammatory factors was evaluated by ELISA or Bio-Plex assays.
Results: An early increase in eosinophil count during the treatment with ipilimumab was associated with an improved clinical response. In contrast, elevated amounts of monocytic myeloid-derived suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders (n = 36) as compared with basal levels and with responding patients (n = 23). Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.
Conclusions: These findings highlight additional mechanisms of ipilimumab effects and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453–9. ©2015 AACR.
Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Postmenopausal Women
Authors: Fabian Carol J. , Kimler Bruce F. , Phillips Teresa A. , Nydegger Jennifer L. , Kreutzjans Amy L. , Carlson Susan E. , Hidaka Brandon H. , Metheny Trina , Zalles Carola M. , Mills Gordon B. , Powers Kandy R. , Sullivan Debra K. , Petroff Brian K. , Hensing Whitney L. , Fridley Brooke L. , Hursting Stephen D. 
Published: August 2015

AbstractAssociational studies suggest higher intakes/blood levels of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) are associated with reduced breast cancer risk. We performed a pilot study of high-dose EPA + DHA in postmenopausal women to assess feasibility before initiating a phase IIB prevention trial. Postmenopausal women with cytologic evidence of hyperplasia in their baseline random periareolar fine needle aspiration (RPFNA) took 1,860 mg EPA +1500 mg DHA ethyl esters daily for 6 months. Blood and breast tissue were sampled at baseline and study conclusion for exploratory biomarker assessment, with P values uncorrected for multiple comparisons. Feasibility was predefined as 50% uptake, 80% completion, and 70% compliance. Trial uptake by 35 study entrants from 54 eligible women was 65%, with 97% completion and 97% compliance. Favorable modulation was suggested for serum adiponectin (P = 0.0027), TNFα (P = 0.016), HOMA 2B measure of pancreatic β cell function (P = 0.0048), and bioavailable estradiol (P = 0.039). Benign breast tissue Ki-67 (P = 0.036), macrophage chemoattractant protein-1 (P = 0.033), cytomorphology index score (P = 0.014), and percent mammographic density (P = 0.036) were decreased with favorable effects in a proteomics array for several proteins associated with mitogen signaling and cell-cycle arrest; but no obvious overall effect on proteins downstream of mTOR. Although favorable risk biomarker modulation will need to be confirmed in a placebo-controlled trial, we have demonstrated feasibility for development of high-dose EPA and DHA ethyl esters for primary prevention of breast cancer. Cancer Prev Res; 8(10); 922–31. ©2015 AACR.See related article, p. 912.
Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
Authors: Ren Xian-Yue , Zhou Guan-Qun , Jiang Wei , Sun Ying , Xu Ya-Fei , Li Ying-Qin , Tang Xin-Ran , Wen Xin , He Qing-Mei , Yang Xiao-Jing , Liu Na , Ma Jun 
Published: August 2015

Abstract
Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/β-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36–3.94; P = 0.002], disease-free survival (HR, 1.98; 95% CI, 1.23–3.18; P = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19–3.59; P = 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. β-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/β-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment. Cancer Prev Res; 8(10); 968–77. ©2015 AACR.
Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model
Authors: Mazzilli Sarah A. , Hershberger Pamela A. , Reid Mary E. , Bogner Paul N. , Atwood Kristopher , Trump Donald L. , Johnson Candace S. 
Published: August 2015

Abstract
The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2,000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C; 80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N). After treatment with 15 μmol NTCU, the percentages of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D–deficient + NTCU (DN), 22.7% [P &lt; 0.05 compared with vitamin D–sufficient +NTCU (SN)]; DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared with SN mice, DN mice exhibited a three-fold increase (P &lt; 0.005) in circulating white blood cells (WBC), a 20% (P &lt; 0.05) increase in IL6 levels, and a four-fold (P &lt; 0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted. Cancer Prev Res; 8(10); 895–904. ©2015 AACR.
Consumption of Soy Isoflavone Enriched Bread in Men with Prostate Cancer Is Associated with Reduced Proinflammatory Cytokines and Immunosuppressive Cells
Authors: Lesinski Gregory B. , Reville Patrick K. , Mace Thomas A. , Young Gregory S. , Ahn-Jarvis Jennifer , Thomas-Ahner Jennifer , Vodovotz Yael , Ameen Zeenath , Grainger Elizabeth , Riedl Kenneth , Schwartz Steven , Clinton Steven K. 
Published: August 2015

Abstract
We hypothesized that soy phytochemicals may have immunomodulatory properties that may affect prostate carcinogenesis and progression. A randomized, phase II trial was conducted in 32 patients with prostate cancer with asymptomatic biochemical recurrence but no measurable disease on standard staging studies. Patients were randomized to two slices of soy bread (34 mg isoflavones/slice) or soy bread containing almond powder daily as a source of β-glucosidase. Flow cytometry and bioplex assays were used to measure cytokines or immune cell phenotype in blood at baseline (day 0) and following intervention (day 56). Adequate blood samples were available at enrollment and day 56 and evaluated. Multiple plasma cytokines and chemokines were significantly decreased on day 56 versus baseline. Subgroup analysis indicated reduced TH1 (P = 0.028) and myeloid-derived suppressor cell (MDSC)-associated cytokines (P = 0.035). TH2 and TH17 cytokines were not significantly altered. Phenotypic analysis revealed no change in CD8+ or CD4+ T cells but showed increased CD56+ natural killer (NK) cells (P = 0.038). The percentage of cells with a T regulatory cell phenotype (CD4+CD25+FoxP3+) was significantly decreased after 56 days of soy bread (P = 0.0136). Significantly decreased monocytic (CD33+HLADRnegCD14+) MDSC were observed in patients consuming soy bread (P = 0.0056). These data suggest that soy bread modulates systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of MDSCs. Additional studies to elucidate impact on the carcinogenic process or as a complement to immune-based therapy are required. Cancer Prev Res; 8(11); 1036–44. ©2015 AACR.
Isoflavone Pharmacokinetics and Metabolism after Consumption of a Standardized Soy and Soy–Almond Bread in Men with Asymptomatic Prostate Cancer
Authors: Ahn-Jarvis Jennifer H. , Clinton Steven K. , Grainger Elizabeth M. , Riedl Kenneth M. , Schwartz Steven J. , Lee Mei-Ling T. , Cruz-Cano Raul , Young Gregory S. , Lesinski Gregory B. , Vodovotz Yael 
Published: August 2015

Abstract
Epidemiologic associations suggest that populations consuming substantial amounts of dietary soy exhibit a lower risk of prostate cancer. A 20-week randomized, phase II, crossover trial was conducted in 32 men with asymptomatic prostate cancer. The crossover involved 8 weeks each of soy bread (SB) and soy–almond bread (SAB). The primary objective was to investigate isoflavone bioavailability and metabolite profile. Secondary objectives include safety, compliance, and assessment of biomarkers linked to prostate carcinogenesis. Two distinct SBs were formulated to deliver approximately 60 mg aglycone equivalents of isoflavones per day. The isoflavones were present as aglycones (∼78% as aglycones) in the SAB whereas in the standard SB predominantly as glucosides (18% total isoflavones as aglycones). Compliance to SB (97% ± 4%) and SAB (92% ± 18%) was excellent; toxicity was rare and limited to grade 1 gastrointestinal complaints. Pharmacokinetic studies between SB and SAB showed modest differences. Peak serum concentration time (Tmax) was significantly faster with SAB meal compared with SB in some isoflavonoids, and AUC0 to 24 h of dihydrodaidzein and O-desmethylangolensin was significantly greater after an SB meal. An exploratory cluster analysis was used to identify four isoflavone-metabolizing phenotypes. Insulin-like growth factor–binding protein increased significantly by 41% (P = 0.024) with soy intervention. Findings from this study provide the necessary framework to study isoflavone-metabolizing phenotypes as a strategy for identification of individuals that might benefit or show resistance to cancer preventive strategies using dietary soy. A standardized SB used for future large-scale randomized clinical trials to affect human prostate carcinogenesis is feasible. Cancer Prev Res; 8(11); 1045–54. ©2015 AACR.
Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence
Authors: Hadac Jamie N. , Leystra Alyssa A. , Paul Olson Terrah J. , Maher Molly E. , Payne Susan N. , Yueh Alexander E. , Schwartz Alexander R. , Albrecht Dawn M. , Clipson Linda , Pasch Cheri A. , Matkowskyj Kristina A. , Halberg Richard B. , Deming Dustin A. 
Published: August 2015

Abstract
Human colorectal cancers often possess multiple mutations, including three to six driver mutations per tumor. The timing of when these mutations occur during tumor development and progression continues to be debated. More advanced lesions carry a greater number of driver mutations, indicating that colon tumors might progress from adenomas to carcinomas through the stepwise accumulation of mutations following tumor initiation. However, mutations that have been implicated in tumor progression have been identified in normal-appearing epithelial cells of the colon, leaving the possibility that these mutations might be present before the initiation of tumorigenesis. We utilized mouse models of colon cancer to investigate whether tumorigenesis still occurs through the adenoma-to-carcinoma sequence when multiple mutations are present at the time of tumor initiation. To create a model in which tumors could concomitantly possess mutations in Apc, Kras, and Pik3ca, we developed a novel minimally invasive technique to administer an adenovirus expressing Cre recombinase to a focal region of the colon. Here, we demonstrate that the presence of these additional driver mutations at the time of tumor initiation results in increased tumor multiplicity and an increased rate of progression to invasive adenocarcinomas. These cancers can even metastasize to retroperitoneal lymph nodes or the liver. However, despite having as many as three concomitant driver mutations at the time of initiation, these tumors still proceed through the adenoma-to-carcinoma sequence. Cancer Prev Res; 8(10); 952–61. ©2015 AACR.
Effect of Metformin on Breast Ductal Carcinoma In Situ Proliferation in a Randomized Presurgical Trial
Authors: DeCensi Andrea , Puntoni Matteo , Guerrieri-Gonzaga Aliana , Cazzaniga Massimiliano , Serrano Davide , Lazzeroni Matteo , Vingiani Andrea , Gentilini Oreste , Petrera Marilena , Viale Giuseppe , Cuzick Jack , Bonanni Bernardo , Pruneri Giancarlo 
Published: August 2015

Abstract
Metformin is associated with lower breast cancer risk in epidemiologic studies and showed decreased proliferation in HER2-positive breast cancer in a presurgical trial. To provide insight into its preventive potential, we measured proliferation by Ki-67 labeling index (LI) of intraepithelial lesions surrounding breast cancer. We randomly assigned 200 nondiabetic patients diagnosed with invasive breast cancer in core biopsies to metformin, 1,700 mg or placebo once daily for 28 days before surgery. Upon surgery, five to seven specimens of cancer adjacent (≤1 cm) and distant (&gt;1 cm) tissue were screened for LCIS, ductal carcinoma in situ (DCIS), and ductal hyperplasia (DH). The prevalence of LCIS, DCIS, and DH was 4.5% (9/200), 67% (133/200), and 35% (69/200), respectively. Overall, metformin did not affect Ki-67 LI in premalignant disorders. The median posttreatment Ki-67 LI (IQR) in the metformin and placebo arm was, respectively, 15% (5–15) versus 5% (4–6) in LCIS (P = 0.1), 12% (8–20) versus 10% (7–24) in DCIS (P = 0.9), and 3% (1–4) versus 3% (1–4) in DH (P = 0.5). However, posttreatment Ki-67 in HER2-positive DCIS lesions was significantly lower in women randomized to metformin especially when ER was coexpressed: 22% (11–32) versus 35% (30–40) in HER2-positive DCIS (n = 22, P = .06); 12% (7–18) versus 32% (27–42) in ER-positive/HER2-positive DCIS (n = 15, P = .004). Eight of 22 (36%) HER2-positive DCIS were adjacent to HER2-negative invasive breast cancer. In tissue samples obtained following 4 weeks of study drug, proliferation was lower in HER2-positive DCIS for women randomized to metformin versus placebo. An adjuvant trial incorporating metformin in HER2-positive DCIS is warranted. Cancer Prev Res; 8(10); 888–94. ©2015 AACR.
Double-Blind Randomized 12-Month Soy Intervention Had No Effects on Breast MRI Fibroglandular Tissue Density or Mammographic Density
Authors: Wu Anna H. , Spicer Darcy , Garcia Agustin , Tseng Chiu-Chen , Hovanessian-Larsen Linda , Sheth Pulin , Martin Sue Ellen , Hawes Debra , Russell Christy , MacDonald Heather , Tripathy Debu , Su Min-Ying , Ursin Giske , Pike Malcolm C. 
Published: August 2015

AbstractSoy supplementation by patients with breast cancer remains controversial. No controlled intervention studies have investigated the effects of soy supplementation on mammographic density in patients with breast cancer. We conducted a double-blind, randomized, placebo-controlled intervention study in previously treated patients with breast cancer (n = 66) and high-risk women (n = 29). We obtained digital mammograms and breast MRI scans at baseline and after 12 months of daily soy (50 mg isoflavones per day; n = 46) or placebo (n = 49) tablet supplementation. The total breast area (MA) and the area of mammographic density (MD) on the mammogram were measured using a validated computer-assisted method, and mammographic density percent (MD% = 100 × MD/MA) was determined. A well-tested computer algorithm was used to quantitatively measure the total breast volume (TBV) and fibroglandular tissue volume (FGV) on the breast MRI, and the FGV percent (FGV% = 100 × FGV/TBV) was calculated. On the basis of plasma soy isoflavone levels, compliance was excellent. Small decreases in MD% measured by the ratios of month 12 to baseline levels were seen in the soy (0.95) and the placebo (0.87) groups; these changes did not differ between the treatments (P = 0.38). Small decreases in FGV% were also found in both the soy (0.90) and the placebo (0.92) groups; these changes also did not differ between the treatments (P = 0.48). Results were comparable in patients with breast cancer and high-risk women. We found no evidence that soy supplementation would decrease mammographic density and that MRI might be more sensitive to changes in density than mammography. Cancer Prev Res; 8(10); 942–51. ©2015 AACR.
Physical Activity and Prostate Tumor Vessel Morphology: Data from the Health Professionals Follow-up Study
Authors: Van Blarigan Erin L. , Gerstenberger John P. , Kenfield Stacey A. , Giovannucci Edward L. , Stampfer Meir J. , Jones Lee W. , Clinton Steven K. , Chan June M. , Mucci Lorelei A. 
Published: August 2015

Abstract
Vigorous activity is associated with lower risk of prostate cancer progression, but the biologic mechanisms are unknown. Exercise affects vascularization of tumors in animal models, and small, irregularly shaped vessels in prostate tumors are associated with fatal prostate cancer. We hypothesized that men who engaged in vigorous activity or brisk walking would have larger, more regularly shaped vessels in their prostate tumors. We prospectively examined whether physical activity was associated with prostate tumor microvessel morphology among 571 men in the Health Professionals Follow-up Study using ordinal logistic regression. Vessel size (μm2), vessel lumen regularity (perimeter2/4 · Π · area), and microvessel density (number/high-powered field) were ascertained in tumor sections stained for endothelial cell marker CD34. Vigorous activity [metabolic equivalent task (MET) ≥ 6], nonvigorous activity (MET &lt; 6), and walking pace were assessed a median of 14 months before diagnosis. Prostate tumors from men who reported a brisk walking pace (3+ mph) had larger, more regularly shaped blood vessels compared with those of men who walked at a less than brisk pace [vessel regularity OR, 1.59; 95% confidence interval (CI), 1.11–2.27; P value, 0.01; vessel size OR, 1.48; 95% CI, 1.04–2.12; P value, 0.03]. Brisk walking was not associated with microvessel density; total vigorous and nonvigorous activities were not associated with vessel size, shape, or number. Brisk walking may be associated with larger, more regularly shaped vessels in prostate tumors. Additional research elucidating the effect of physical activity on prostate tumor biology is needed. Cancer Prev Res; 8(10); 962–7. ©2015 AACR.
ERβ Expression and Breast Cancer Risk Prediction for Women with Atypias
Authors: Hieken Tina J. , Carter Jodi M. , Hawse John R. , Hoskin Tanya L. , Bois Melanie , Frost Marlene , Hartmann Lynn C. , Radisky Derek C. , Visscher Daniel W. , Degnim Amy C. 
Published: August 2015

Abstract
Estrogen receptor (ER) β is highly expressed in normal breast epithelium and a putative tumor suppressor. Atypical hyperplasia substantially increases breast cancer risk, but identification of biomarkers to further improve risk stratification is needed. We evaluated ERβ expression in breast tissues from women with atypical hyperplasia and association with subsequent breast cancer risk. ERβ expression was examined by immunohistochemistry in a well-characterized 171-women cohort with atypical hyperplasia diagnosed 1967–1991. Nuclear ERβ percent and intensity was scored in the atypia and adjacent normal lobules. An ERβ sum score (percent + intensity) was calculated and grouped as low, moderate, or high. Competing risks regression was used to assess associations of ERβ expression with breast cancer risk. After 15-year median follow-up, 36 women developed breast cancer. ERβ expression was lower in atypia lobules in than normal lobules, by percent staining and intensity (both P &lt; 0.001). Higher ERβ expression in the atypia or normal lobules, evaluated by percent staining, intensity or sum score, decreased the risk of subsequent breast cancer by 2-fold (P = 0.04) and 2.5-fold (P = 0.006). High normal lobule ERβ expression conferred the strongest protective effect in premenopausal women: the 20-year cumulative incidence of breast cancer was 0% for women younger than 45 years with high versus 31% for low–moderate ERβ expression (P = 0.0008). High ERβ expression was associated with a significantly decreased risk of breast cancer in women with atypical hyperplasia. These data suggest that ERβ may be a useful biomarker for risk stratification and a novel therapeutic target for breast cancer risk reduction. Cancer Prev Res; 8(11); 1084–92. ©2015 AACR.