bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Adding Multiwall Carbon Nanotubes on Performance of Polyvinyl Acetate and Urea‐Formaldehyde Adhesives in Tropical Timber Species
Authors: Moya Róger , Rodríguez-Zúñiga Ana , Vega-Baudrit José
Published: August 2015

Multiwall carbon nanotubes (MWCNTs) functionalized with hydroxyl groups (MWCNTs‐OH) have been incorporated into polyvinyl acetate (PVAc) and urea‐formaldehyde (UF) adhesives utilized in tropical wood gluing. The Raman spectroscopy, the atomic force microscopy (AFM), and transmission electron microscopy (TEM) were used to describe the MWCNTs‐OH. The adhesives were evaluated in three concentrations of MWCNTs‐OH: 0% (control), 0.05%, and 0.1%. The evaluation included color, the distribution of MWCNTs‐OH by TEM and AFM, thermal stability and viscosity of the adhesives, and shear strength (SS) of the glue line for nine tropical woods. AFM and TEM confirmed interaction of MWCNTs‐OH with adhesives. The viscosity of the PVAc adhesive increases with added MWCNTs‐OH. The incorporation of MWCNTs‐OH in PVAc and UF resin produces wood adhesives with less brightness, less yellowness, and increased redness. The nanotubes in the adhesive improved the thermal stability of the composites and increased the entropy factor and energy of activation in the kinetic decomposition of the resin. In relation to SS, MWCNTs‐OH in any of the two concentrations had no significant effect on SS in dry condition in half of the species studied glued with PVAc adhesive, whereas, for UF‐adhesive, the SS and percentage of wood failure improved in most of the 9 species studied.
Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts
Authors: Bieniasz Magdalena , Radhakrishnan Parvathi , Faham Najme , De La O Jean-Paul , Welm Alana L.
Published: August 2015

Purpose: Recent studies have demonstrated that short-form Ron (sfRon) kinase drives breast tumor progression and metastasis through robust activation of the PI3K pathway. We reasoned that upfront, concurrent inhibition of sfRon and PI3K might enhance the antitumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKI).

Experimental Design: We used patient-derived breast tumor xenografts (PDX) as high-fidelity preclinical models to determine the efficacy of single-agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without coadministration of the PI3K inhibitor NVP-BKM120 in hormone receptor–positive [estrogen receptor (ER)+/progesterone receptor (PR)+] breast PDXs with and without PIK3CA gene mutation.

Results: Breast PDX tumors harboring wild-type PIK3CA showed a robust response to ASLAN002 as a single agent. In contrast, PDX tumors harboring mutated PIK3CA demonstrated partial resistance to ASLAN002, which was overcome with addition of NVP-BKM120 to the treatment regimen. We further demonstrated that concurrent inhibition of sfRon and PI3K in breast PDX tumors with wild-type PIK3CA provided durable tumor stasis after therapy cessation, whereas discontinuation of either monotherapy facilitated tumor recurrence.

Conclusions: Our work provides preclinical rationale for targeting sfRon in patients with breast cancer, with the important stipulation that tumors harboring PIK3CA mutations may be partially resistant to Ron inhibitor therapy. Our data also indicate that tumors with wild-type PIK3CA are most effectively treated with an upfront combination of Ron and PI3K inhibitors for the most durable response. Clin Cancer Res; 21(24); 5588–600. ©2015 AACR.
Preclinical Assessment of Efficacy of Radiation Dose Painting Based on Intratumoral FDG-PET Uptake
Authors: Trani Daniela , Yaromina Ala , Dubois Ludwig , Granzier Marlies , Peeters Sarah G.J.A. , Biemans Rianne , Nalbantov Georgi , Lieuwes Natasja , Reniers Brigitte , Troost Esther E.G.C. , Verhaegen Frank , Lambin Philippe
Published: August 2015

Purpose: We tested therapeutic efficacy of two dose painting strategies of applying higher radiation dose to tumor subvolumes with high FDG uptake (biologic target volume, BTV): dose escalation and dose redistribution. We also investigated whether tumor response was determined by the highest dose in BTV or the lowest dose in gross tumor volume (GTV).

Experimental Design: FDG uptake was evaluated in rat rhabdomyosarcomas prior to irradiation. BTV was defined as 30% of GTV with the highest (BTVhot) or lowest (BTVcold) uptake. To test efficacy of dose escalation, tumor response (time to reach two times starting tumor volume, TGTV2) to Hot Boost irradiation (40% higher dose to BTVhot) was compared with Cold Boost (40% higher dose to BTVcold), while mean dose to GTV remained 12 Gy. To test efficacy of dose redistribution, TGTV2 after Hot Boost was compared with uniform irradiation with the same mean dose (8 or 12 Gy).

Results: TGTV2 after 12 Gy delivered heterogeneously (Hot and Cold Boost) or uniformly were not significantly different: 20.2, 19.5, and 20.6 days, respectively. Dose redistribution (Hot Boost) with 8 Gy resulted in faster tumor regrowth as compared with uniform irradiation (13.3 vs. 17.1 days; P = 0.026). Further increase in dose gradient to 60% led to a more pronounced decrease in TGTV2 (10.9 days; P < 0.0001).

Conclusions: Dose escalation effect was independent of FDG uptake in target tumor volume, while dose redistribution was detrimental in this tumor model for dose levels applied here. Our data are consistent with the hypothesis that tumor response depends on the minimum intratumoral dose. Clin Cancer Res; 21(24); 5511–8. ©2015 AACR.
Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis–Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer
Authors: Kimbung Siker , Johansson Ida , Danielsson Anna , Veerla Srinivas , Egyhazi Brage Suzanne , Frostvik Stolt Marianne , Skoog Lambert , Carlsson Lena , Einbeigi Zakaria , Lidbrink Elisabet , Linderholm Barbro , Loman Niklas , Malmström Per-Olof , Söderberg Martin , Walz Thomas M. , Fernö Mårten , Hatschek Thomas , Hedenfalk Ingrid
Published: August 2015

Purpose: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis–selective genes of prognostic importance following primary tumor diagnosis.

Experimental Design: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis–selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis–selective genes in primary breast cancer was tested.

Results: Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by downregulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis–selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors.

Conclusions: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer. Clin Cancer Res; 22(1); 146–57. ©2015 AACR.
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

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

Associational 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

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

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 < 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 < 0.005) in circulating white blood cells (WBC), a 20% (P < 0.05) increase in IL6 levels, and a four-fold (P < 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

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

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

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

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 (>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

Soy 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

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 < 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

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 < 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.
Noninvasive Molecular Screening for Oral Precancer in Fanconi Anemia Patients
Authors: Smetsers Stephanie E. , Velleuer Eunike , Dietrich Ralf , Wu Thijs , Brink Arjen , Buijze Marijke , Deeg Dorly J.H. , Soulier Jean , Leemans C. René , Braakhuis Boudewijn J.M. , Brakenhoff Ruud H.
Published: August 2015

LOH at chromosome arms 3p, 9p, 11q, and 17p are well-established oncogenetic aberrations in oral precancerous lesions and promising biomarkers to monitor the development of oral cancer. Noninvasive LOH screening of brushed oral cells is a preferable method for precancer detection in patients at increased risk for head and neck squamous cell carcinoma (HNSCC), such as patients with Fanconi anemia. We determined the prevalence of LOH in brushed samples of the oral epithelium of 141 patients with Fanconi anemia and 144 aged subjects, and studied the association between LOH and HNSCC. LOH was present in 14 (9.9%) nontransplanted patients with Fanconi anemia, whereas LOH was not detected in a low-risk group (n = 50, >58 years, nonsmoking/nonalcohol history) and a group with somewhat increased HNSCC risk (n = 94, >58 years, heavy smoking/excessive alcohol use); Fisher exact test, P = 0.023 and P = 0.001, respectively. Most frequent genetic alteration was LOH at 9p. Age was a significant predictor of LOH (OR, 1.13, P = 0.001). Five patients with Fanconi anemia developed HNSCC during the study at a median age of 39.6 years (range, 24.8–53.7). LOH was significantly associated with HNSCC (Fisher exact test, P = 0.000). Unexpectedly, the LOH assay could not be used for transplanted patients with Fanconi anemia because donor DNA in brushed oral epithelium, most likely from donor leukocytes present in the oral cavity, disturbed the analysis. Noninvasive screening using a LOH assay on brushed samples of the oral epithelium has a promising outlook in patients with Fanconi anemia. However, assays need to be adapted in case of stem cell transplantation, because of contaminating donor DNA. Cancer Prev Res; 8(11); 1102–11. ©2015 AACR.
Development and Characterization of an Engraftable Tissue-Cultured Skin Autograft: Alternative Treatment for Severe Electrical Injuries?
Authors: Golinski Peter , Menke Henrik , Hofmann Matthias , Valesky Eva , Butting Manuel , Kippenberger Stefan , Bereiter-Hahn Jürgen , Bernd August , Kaufmann Roland , Zoeller Nadja N.
Published: August 2015

Background/Aims: Optimizing the treatment regimens of extensive or nonhealing defects is a constant challenge. Tissue-cultured skin autografts may be an alternative to mesh grafts and keratinocyte suspensions that are applied during surgical defect coverage. Methods: Autologous epidermal and dermal cells were isolated, in vitro expanded and seeded on collagen-elastin scaffolds. The developed autograft was immunohistochemically and electron microscopically characterized. Subsequently, it was transplanted onto lesions of a severely burned patient. Results: Comparability of the skin equivalent to healthy human skin could be shown due to the epidermal strata, differentiation, proliferation markers and development of characteristics of a functional basal lamina. Approximately 2 weeks after skin equivalent transplantation the emerging new skin correlated closely to the adjacent normal skin. Conclusion: The present study demonstrates the comparability of the developed organotypic skin equivalent to healthy human skin and its versatility for clinical applications.
One of the Mechanisms to Increase HSV-1 Uptake in HSV-1-Infected, Activated T Lymphocytes Is the Formation of Filopodia
Authors: Bhattarakosol Parvapan , Donchai Pornnapa
Published: August 2015

Objectives: To explore the host transcription factor E2F-1 and/or any mechanisms that may support viral entry and its effect on the HSV-1 production in anti-CD3-activated Jurkat cells. Methods: The expressions of ICP4, HVEM and E2F-1 were studied using reverse transcription-PCR and Western blot. HSV-1 production was determined by plaque titration assay and HSV-1 DNA load was quantified by real-time PCR. The viral uptake was observed by electron microscopy. Results: In anti-CD3-activated Jurkat cells, there was a significant increase in the HSV-1 production. The expression of ICP4 mRNA after HSV-1 infection occurred 2 h prior to the synthesis of the ICP4 protein, which was significantly higher in activated than nonactivated T cells. There were no significant differences in the expressions of E2F-1 mRNA. The HVEM expression was positively correlated with the HSV-1 DNA in the activated T cells. From the electron micrograph, the formations of filopodia were observed only in HSV-1-infected, activated cells. Conclusions: High expressions of viral receptor protein and filopodia formations are the key factors that enhance the HSV-1 entry into activated T lymphocytes, resulting in an increased production of the virus.
Time Course of Atrial Fibrillation in Patients With Congenital Heart Defects
Authors: Teuwen Christophe P. , Ramdjan Tanwier T.T.K. , Götte Marco , Brundel Bianca J.J.M. , Evertz Reinder , Vriend Joris W.J. , Molhoek Sander G. , Dorman Henderikus G.R. , van Opstal Jurren M. , Konings Thelma C. , van der Voort Pepijn , Delacretaz Etienne , Houck Charlotte , Yaksh Ameeta , Jansz Luca. J. , Witsenburg Maarten , Roos-Hesselink Jolien W. , Triedman John K. , Bogers Ad J.J.C. , de Groot Natasja M.S.
Published: August 2015

Background—

The incidence of atrial fibrillation (AF) is rising in the aging patients with congenital heart defects (CHD). However, studies reporting on AF in patients with CHD are scarce. The aim of this multicenter study was to examine in a large cohort of patients with a variety of CHD: (1) the age of onset and initial treatment of AF, coexistence of atrial tachyarrhythmia and (2) progression of paroxysmal to (long-standing) persistent/permanent AF during long-term follow-up.

Methods and Results—

Patients (n=199) with 15 different CHD and documented AF episodes were studied. AF developed at 49±17 years. Regular atrial tachycardia (AT) coexisting with AF occurred in 65 (33%) patients; 65% initially presented with regular AT. At the end of a follow-up period of 5 (0–24) years, the ECG showed AF in 81 patients (41%). In a subgroup of 114 patients, deterioration from paroxysm of AF to (long-standing) persistent/permanent AF was observed in 29 patients (26%) after only 3 (0–18) years of the first AF episode. Cerebrovascular accidents/transient ischemic attacks occurred in 26 patients (13%), although a substantial number (n=16) occurred before the first documented AF episode.

Conclusions—

Age at development of AF in patients with CHD is relatively young compared with the patients without CHD. Coexistence of episodes of AF and regular AT occurred in a considerable number of patients; most of them initially presented with regular AT. The fast and frequent progression from paroxysmal to (long-standing) persistent or permanent AF episodes justifies close follow-up and early, aggressive therapy of both AT and AF.
Functional Analysis of a Carotid Intima-Media Thickness Locus Implicates
BCAR1
and Suggests a Causal Variant
Authors: Boardman-Pretty Freya , Smith Andrew J.P. , Cooper Jackie , Palmen Jutta , Folkersen Lasse , Hamsten Anders , Catapano Alberico L. , Melander Olle , Price Jacqueline F. , Kumari Meena , Deanfield John E. , Kivimäki Mika , Gertow Karl , Baragetti Andrea , Norata Giuseppe Danilo , Humphries Steve E.
Published: August 2015

Background—

Carotid intima-media thickness (IMT) is a marker of subclinical atherosclerosis that can predict cardiovascular disease events over traditional risk factors. This study examined the
BCAR1-CFDP1-TMEM170A
locus on chromosome 16, associated with carotid IMT and coronary artery disease in the IMT and IMT-Progression as Predictors of Vascular Events (IMPROVE) cohort, to identify the functional variant.

Methods and Results—

In analysis of the locus lead single nucleotide polymorphism (SNP; rs4888378, intronic in
CFDP1
) in Progressione della Lesione Intimale Carotidea (PLIC), the protective AA genotype was associated with slower IMT progression in women (
P
=0.04) but not in men. Meta-analysis of 5 cohort studies also supported a protective effect of the A allele on common carotid IMT in women only (women: β=−0.0047,
P
=1.63×10
–4
; men: β=−0.0029,
P
=0.0678). Two hundred fourteen noncoding variants in strong linkage disequilibrium (
r
2
≥0.8) with rs4888378 were identified from 1000 Genome Project. ENCODE regulatory chromatin marks were used to create a shortlist of 6 possible regulatory variants. Electrophoretic mobility shift assays on the shortlist detected allele-specific protein binding to the lead SNP rs4888378; multiplexed competitor electrophoretic mobility shift assays implicated FOXA as the protein. Luciferase reporter assays on rs4888378 showed a significant 35% to 92% (
P
=0.0057;
P
=4.0×10
–22
) decrease in gene expression with the A allele. Expression quantitative trait loci analysis confirmed previously reported associations of rs4888378 with
BCAR1
in vascular tissues.

Conclusions—

Molecular studies suggest the lead SNP as a potentially causal SNP at the
BCAR1
-
CFDP1
-
TMEM170A
locus, and expression quantitative trait loci studies implicate
BCAR1
as the causal gene. This variant showed stronger effects on common carotid IMT in women, raising questions about the mechanism of the causal SNP on atherosclerosis.
Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure
Authors: Kennedy David J. , Shrestha Kevin , Sheehey Brendan , Li Xinmin S. , Guggilam Anuradha , Wu Yuping , Finucan Michael , Gabi Alaa , Medert Charles M. , Westfall Kristen , Borowski Allen , Fedorova Olga , Bagrov Alexei Y. , Tang W.H. Wilson
Published: August 2015

Background—

Plasma levels of cardiotonic steroids are elevated in volume-expanded states, such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the cardiotonic steroids marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes.

Methods and Results—

We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with HF. All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median (interquartile range) MBG was 583 (383–812) pM. Higher MBG was associated with higher myeloperoxidase (
r
=0.42,
P
<0.0001), B-type natriuretic peptide (
r
=0.25,
P
=0.001), and asymmetrical dimethylarginine (
r
=0.32,
P
<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV
s
′,
r
=−0.39,
P
<0.0001) and predicted increased risk of adverse clinical outcomes (MBG≥574 pmol/L: hazard ratio 1.58 [1.10–2.31],
P
=0.014) even after adjustment for age, sex, diabetes mellitus, and ischemic pathogenesis. In mice, a left anterior descending coronary artery ligation model of HF lead to increases in MBG, whereas infusion of MBG into mice for 4 weeks lead to significant increases in myeloperoxidase, asymmetrical dimethylarginine, and cardiac fibrosis.

Conclusions—

In the setting of HF, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG seems to directly contribute to increased nitrative stress and cardiac fibrosis.
Risk of Cardiomyopathy in Younger Persons With a Family History of Death from Cardiomyopathy
Authors: Ranthe Mattis F. , Carstensen Lisbeth , Øyen Nina , Jensen Morten K. , Axelsson Anna , Wohlfahrt Jan , Melbye Mads , Bundgaard Henning , Boyd Heather A.
Published: August 2015

Background—

Recommendations for presymptomatic screening of relatives of cardiomyopathy patients are based on findings from tertiary centers. Cardiomyopathy inheritance patterns are fairly well understood, but how cardiomyopathy in younger persons (<50 years) aggregates in families at the population level is unclear. In a nationwide cohort, we examined the risk of cardiomyopathy by family history of premature death (<60 years) from cardiomyopathy.

Methods and Results—

By linking Danish national register data, we constructed a cohort of 3.9 million persons born from 1950 to 2008. We ascertained family history of premature (<60 years) death from cardiomyopathy or other conditions, and cohort members were followed from 1977 to 2008 for cardiomyopathy diagnosed at <50 years. We identified 3890 cardiomyopathies in 89 million person-years of follow-up. Using Poisson regression, we estimated incidence rate ratios for cardiomyopathy by family history of premature death. Premature cardiomyopathy deaths in first- and second-degree relatives were associated with 29- and 6-fold increases in the rate of cardiomyopathy, respectively. If the first-degree relative died aged <35 years, the rate of cardiomyopathy increased 100-fold; given ≥2 premature deaths in first-degree relatives, the rate increased more than 400-fold. In contrast, a family history of premature death from other cardiac or noncardiac conditions increased the rate of cardiomyopathy 3-fold at most.

Conclusions—

A family history of premature cardiomyopathy death was associated with an increase in risk of cardiomyopathy ranging from 6- to 400-fold, depending on age, kinship, gender and number of affected family members. Our general population-based results support recommendations for presymptomatic screening of relatives of cardiomyopathy patients.
Improving the Diagnosis of Infective Endocarditis in Prosthetic Valves and Intracardiac Devices With
18
F-Fluordeoxyglucose Positron Emission Tomography/Computed Tomography Angiography
Authors: Pizzi María N. , Roque Albert , Fernández-Hidalgo Nuria , Cuéllar-Calabria Hug , Ferreira-González Ignacio , Gonzàlez-Alujas María T. , Oristrell Gerard , Gracia-Sánchez Laura , González Juan J. , Rodríguez-Palomares José , Galiñanes Manuel , Maisterra-Santos Olga , Garcia-Dorado David , Castell-Conesa Joan , Almirante Benito , Aguadé-Bruix Santiago , Tornos Pilar
Published: August 2015

Background—

The diagnosis of infective endocarditis (IE) in prosthetic valves and intracardiac devices is challenging because both the modified Duke criteria (DC) and echocardiography have limitations in this population. The added value of
18
F-fluorodeoxyglucose (
18
F-FDG) positron emission tomography (PET)/computed tomography (CT) and
18
F-FDG PET/CT angiography (PET/CTA) was evaluated in this complex scenario at a referral center with a multidisciplinary IE unit.

Methods and Results—

Ninety-two patients admitted to our hospital with suspected prosthetic valve or cardiac device IE between November 2012 and November 2014 were prospectively included. All patients underwent echocardiography and PET/CT, and 76 had cardiac CTA. PET/CT and echocardiography findings were evaluated and compared, with concordant results in 54% of cases (κ=0.23). Initial diagnoses with DC at admission, PET/CT, and DC+PET/CT were compared with the final diagnostic consensus reached by the IE Unit. DC+PET/CT enabled reclassification of 90% of cases initially classified as possible IE with DC and provided a conclusive diagnosis (definite/rejected) in 95% of cases. Sensitivity, specificity, and positive and negative predictive values were 52%, 94.7%, 92.9%, and 59.7% for DC; 87%, 92.1%, 93.6%, and 84.3% for PET/CT; and 90.7%, 89.5%, 92%, and 87.9% for DC+PET/CT. Use of PET/CTA yielded even better diagnostic performance values than PET/nonenhanced CT (91%, 90.6%, 92.8%, and 88.3% versus 86.4%, 87.5%, 90.2%, and 82.9%) and substantially reduced the rate of doubtful cases from 20% to 8% (
P
<0.001). DC+PET/CTA reclassified an additional 20% of cases classified as possible IE with DC+PET/nonenhanced CT. In addition, PET/CTA enabled detection of a significantly larger number of anatomic lesions associated with active endocarditis than PET/nonenhanced CT (
P
=0.006) or echocardiography (
P
<0.001).

Conclusions—

18
F-FDG PET/CT improves the diagnostic accuracy of the modified DC in patients with suspected IE and prosthetic valves or cardiac devices. PET/CTA yielded the highest diagnostic performance and provided additional diagnostic benefits.