bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Dynamics in Cancer and Neurodegenerative and Neuroinflammatory Diseases
Authors: Corrado Mauro , Scorrano Luca , Campello Silvia
Published: June 2012

Mitochondria are key organelles in the cell, hosting essential functions, from biosynthetic and metabolic pathways, to oxidative phosphorylation and ATP production, from calcium buffering to red-ox homeostasis and apoptotic signalling pathways. Mitochondria are also dynamic organelles, continuously fusing and dividing, and their localization, size and trafficking are finely regulated. Moreover, in recent decades, alterations in mitochondrial function and dynamics have been implicated in an increasing number of diseases. In this review, we focus on the relationship clarified hitherto between mitochondrial dynamics and cancer, neurodegenerative and neuroinflammatory diseases.
Signorini Cylindrical Waves and Shannon Wavelets
Authors: Cattani Carlo
Published: June 2012

Hyperelastic materials based on Signorini’s strain energy density are studied by using Shannon wavelets. Cylindrical waves propagating in a nonlinear elastic material from the circular cylindrical cavity along the radius are analyzed in the following by focusing both on the main nonlinear effects and on the method of solution for the corresponding nonlinear differential equation. Cylindrical waves’ solution of the resulting equations can be easily represented in terms of this family of wavelets. It will be shown that Hankel functions can be linked with Shannon wavelets, so that wavelets can have some physical meaning being a good approximation of cylindrical waves. The nonlinearity is introduced by Signorini elastic energy density and corresponds to the quadratic nonlinearity relative to displacements. The configuration state of elastic medium is defined through cylindrical coordinates but the deformation is considered as functionally depending only on the radial coordinate. The physical and geometrical nonlinearities arising from the wave propagation are discussed from the point of view of wavelet analysis.
Control of In Vivo Transport and Toxicity of Nanoparticles by Tea Melanin
Authors: Chen Yu-Shiun , Hung Yao-Ching , Hong Meng-Yeng , Onischuk Andrei Aleksandrovich , Chiou Jin Chern , Sorokina Irina V. , Tolstikova Tatiana , Steve Huang G.
Published: June 2012

Nanoparticles are unfamiliar to researchers in toxicology. Toxicity may be generated simply due to the reduction in size. Compounds that prevent or cure toxic materials may not work on nanoparticles. Furthermore, as there are more and more applications of nanoparticles in drug delivery and in vivo imaging, controlling the transport and toxicity will be primary concerns for medical application of nanoparticles. Gold nanoparticles (GNPs) if injected intraperitoneally into mice can enter hippocampus and induce cognitive impairment. GNPs caused a global imbalance of monoamine levels, specifically affecting the dopaminergic and serotonergic neurons. Pretreatment of tea melanin significantly prevented the deposition of GNPs in mouse brains, especially in the hippocampus. Pretreatment of melanin completely alleviated GNP‐induced impairment of cognition. Pre‐administration of melanin stably maintained monoamines at normal profiles. Melanin completely prevented the invasion of GNPs into the Cornu Ammonis region of the hippocampus shown by coherent anti‐Stoke Raman scattering microscopy. Here we show that the administration of tea melanin prevented the accumulation of Au in brain, the imbalance of monoamines, and the impairment of cognition in mice. The current study provides a therapeutic approach to toxicity of nanoparticles and a novel strategy to control the transport of GNP in mouse brain.
Effect of Manganese Content on the Fabrication of Porous Anodic Alumina
Authors: Voon C. H. , Derman M. N. , Hashim U.
Published: June 2012

The influence of manganese content on the formation of well‐ordered porous anodic alumina was studied. Porous anodic alumina has been produced on aluminium substrate of different manganese content by single‐step anodizing at 50 V in 0.3 M oxalic acid at 15°C for 60 minutes. The well‐ordered pore and cell structure was revealed by subjecting the porous anodic alumina to oxide dissolution treatment in a mixture of chromic acid and phosphoric acid. It was found that the manganese content above 1 wt% impaired the regularity of the cell and pore structure significantly, which can be attributed to the presence of secondary phases in the starting material with manganese content above 1 wt%. The pore diameter and interpore distance decreased with the addition of manganese into the substrates. The time variation of current density and the thickness of porous anodic alumina also decreased as a function of the manganese content in the substrates.
Particle-Filter-Based WiFi-Aided Reduced Inertial Sensors Navigation System for Indoor and GPS-Denied Environments
Authors: Atia M. M. , Korenberg M. J. , Noureldin A.
Published: June 2012

Indoor navigation is challenging due to unavailability of satellites-based signals indoors. Inertial Navigation Systems (INSs) may be used as standalone navigation indoors. However, INS suffers from growing drifts without bounds due to error accumulation. On the other side, the IEEE 802.11 WLAN (WiFi) is widely adopted which prompted many researchers to use it to provide positioning indoors using fingerprinting. However, due to WiFi signal noise and multipath errors indoors, WiFi positioning is scattered and noisy. To benefit from both WiFi and inertial systems, in this paper, two major techniques are applied. First, a low-cost Reduced Inertial Sensors System (RISS) is integrated with WiFi to smooth the noisy scattered WiFi positioning and reduce RISS drifts. Second, a fast feature reduction technique is applied to fingerprinting to identify the WiFi access points with highest discrepancy power to be used for positioning. The RISS/WiFi system is implemented using a fast version of Mixture Particle Filter for state estimation as nonlinear non-Gaussian filtering algorithm. Real experiments showed that drifts of RISS are greatly reduced and the scattered noisy WiFi positioning is significantly smoothed. The proposed system provides smooth indoor positioning of 1 m accuracy 70% of the time outperforming each system individually.
Effects of a Preconditioning Oral Nutritional Supplement on Pig Livers after Warm Ischemia
Authors: Nickkholgh Arash , Li Zhanqing , Yi Xue , Mohr Elvira , Liang Rui , Mikalauskas Saulius , Gross Marie-Luise , Zorn Markus , Benzing Steffen , Schneider Heinz , Büchler Markus W. , Schemmer Peter
Published: June 2012

Background. Several approaches have been proposed to pharmacologically ameliorate hepatic ischemia/reperfusion injury (IRI). This study was designed to evaluate the effects of a preconditioning oral nutritional supplement (pONS) containing glutamine, antioxidants, and green tea extract on hepatic warm IRI in pigs. Methods. pONS (70 g per serving, Fresenius Kabi, Germany) was dissolved in 250 mL tap water and given to pigs 24, 12, and 2 hrs before warm ischemia of the liver. A fourth dose was given 3 hrs after reperfusion. Controls were given the same amount of cellulose with the same volume of water. Two hours after the third dose of pONS, both the portal vein and the hepatic artery were clamped for 40 min. 0.5, 3, 6, and 8 hrs after reperfusion, heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), portal venous flow (PVF), hepatic arterial flow (HAF), bile flow, and transaminases were measured. Liver tissue was taken 8 hrs after reperfusion for histology and immunohistochemistry. Results. HR, MAP, CVP, HAF, and PVF were comparable between the two groups. pONS significantly increased bile flow 8 hrs after reperfusion. ALT and AST were significantly lower after pONS. Histology showed significantly more severe necrosis and neutrophil infiltration in controls. pONS significantly decreased the index of immunohistochemical expression for TNF-α, MPO, and cleaved caspase-3 (). Conclusion. Administration of pONS before and after tissue damage protects the liver from warm IRI via mechanisms including decreasing oxidative stress, lipid peroxidation, apoptosis, and necrosis.
Prostate Carcinogenesis with Diabetes and Androgen-Deprivation-Therapy-Related Diabetes: An Update
Authors: Hara Noboru
Published: June 2012

Prostate cancer and the androgen deprivation therapy (ADT) thereof are involved in diabetes in terms of diabetes-associated carcinogenesis and ADT-related metabolic disorder, respectively. The aim of this study is to systematically review relevant literature. About 218,000 men are estimated to be newly diagnosed with prostate cancer every year in the United States. Approximately 10% of them are still found with metastasis, and in addition to them, about 30% of patients with nonmetastatic prostate cancer recently experience ADT. Population-based studies have shown that dissimilar to other malignancies, type 2 diabetes is associated with a lower incidence of prostate cancer, whereas recent large cohort studies have reported the association of diabetes with advanced high-grade prostate cancer. Although the reason for the lower prevalence of prostate cancer among diabetic men remains unknown, the lower serum testosterone and PSA levels in them can account for the increased risk of advanced disease at diagnosis. Meanwhile, insulin resistance already appears in 25–60% of the patients 3 months after the introduction of ADT, and long-term ADT leads to a higher incidence of diabetes (reported hazard ratio of 1.28–1.44). Although the possible relevance of cytokines such as Il-6 and TNF-αto ADT-related diabetes has been suggested, its mechanism is poorly understood.
Strain-Specific Transfer of Antibiotic Resistance from an Environmental Plasmid to Foodborne Pathogens
Authors: Van Meervenne Eva , Van Coillie Els , Kerckhof Frederiek-Maarten , Devlieghere Frank , Herman Lieve , De Gelder Leen S. P. , Top Eva M. , Boon Nico
Published: June 2012

Pathogens resistant to multiple antibiotics are rapidly emerging, entailing important consequences for human health. This study investigated if the broad-host-range multiresistance plasmid pB10, isolated from a wastewater treatment plant, harbouring amoxicillin, streptomycin, sulfonamide, and tetracycline resistance genes, was transferable to the foodborne pathogensSalmonellaspp. orE. coliO157:H7 and how this transfer alters the phenotype of the recipients. The transfer ratio was determined by both plating and flow cytometry. Antibiotic resistance profiles were determined for both recipients and transconjugants using the disk diffusion method. For 14 of the 15 recipient strains, transconjugants were detected. Based on plating, transfer ratios were between6.8×10−9and3.0×10−2while using flow cytometry, transfer ratios were between <1.0×10−5and1.9×10−2. With a few exceptions, the transconjugants showed phenotypically increased resistance, indicating that most of the transferred resistance genes were expressed. In summary, we showed that an environmental plasmid can be transferred into foodborne pathogenic bacteria at high transfer ratios. However, the transfer ratio seemed to be recipient strain dependent. Moreover, the newly acquired resistance genes could turn antibiotic susceptible strains into resistant ones, paving the way to compromise human health.
Osteotome-Mediated Sinus Lift without Grafting Material: A Review of Literature and a Technique Proposal
Authors: Taschieri Silvio , Corbella Stefano , Saita Massimo , Tsesis Igor , Del Fabbro Massimo
Published: June 2012

Implant rehabilitation of the edentulous posterior maxilla may be a challenging procedure in the presence of insufficient bone volume for implant placement. Maxillary sinus augmentation with or without using grafting materials aims to provide adequate bone volume. The aim of the present study was to systematically review the existing literature on transalveolar maxillary sinus augmentation without grafting materials and to propose and describe an osteotome-mediated approach in postextraction sites in combination with platelet derivative. The systematic review showed that high implant survival rate (more than 96% after 5 years) can be achieved even without grafting the site, with a low rate of complications. Available alveolar bone height before surgery was not correlated to survival rate. In the described case report, three implants were placed in posterior maxilla after extraction of two teeth. An osteotome-mediated sinus lifting technique was performed with the use of platelet derivative (PRGF); a synthetic bone substitute was used to fill the gaps between implant and socket walls. No complications occurred, and implants were successfully in site after 1 year from prosthetic loading. The presented technique might represent a viable alternative for the treatment of edentulous posterior maxilla with atrophy of the alveolar bone though it needs to be validated by studies with a large sample size.
Identification ofCandidaSpecies Associated with Vulvovaginal Candidiasis by Multiplex PCR
Authors: Mahmoudi Rad Mahnaz , Zafarghandi Ameneh Sh , Amel Zabihi Maryam , Tavallaee Mahkam , Mirdamadi Yasaman
Published: June 2012

Background. Vulvovaginal candidiasis is a common infection. The aim of this study was to identify the species of vaginalCandidaisolates by using multiplex PCR technique.Methods. 191 isolates from patients admitted to Mahdieh hospital were identified. The vaginal swab specimens were cultured on Sabouraud Dextrose Agar. The ITS1 region between the 18S and 5.8S rRNA genes and a specific DNA fragment within the ITS2 region were amplified. The multiplex PCR products were separated by electrophoresis in 2% agarose gel, visualized by staining with ethidium bromide, and photographed. Descriptive statistics, Chi-square test, and Spearman correlation were used to summarize the findings.Results.C. albicansandC. glabratawere the most common species isolated from the specimens. A mix ofC. glabrataandC. albicanswas the most common mixed infection isolated from the samples. The analysis revealed a significant positive association between older age and infection withC. glabrataisolates (Spearman’s rho = 0.89,P=0.015).Conclusion. Multiplex PCR is a fast, yet reliable method to identifyCandidaspecies.C. albicansand thenC. glabrataare the two most common causes of vulvovaginal candidiasis. The number of mixed fungal infections is higher among Iranian population compared to international reports.
Adult-Onset Still’s Disease: From Pathophysiology to Targeted Therapies
Authors: Mavragani Clio P. , Spyridakis Evangelos G. , Koutsilieris Michael
Published: June 2012

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder affecting primarily young individuals. The diagnosis is primarily clinical and necessitates the exclusion of a wide range of mimicking disorders. Given the lack of solid data in regard to the underlying pathogenetic mechanisms, treatment of AOSD has been for years largely empirical. Recent advances have revealed a pivotal role of several proinflammatory cytokines such as tumor necrosis factor-α(TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) in disease pathogenesis, giving rise to the development of new targeted therapies aiming at optimal disease control.
Interventions to Promote an Integrated Approach to Public Health Problems: An Application to Childhood Obesity
Authors: Hendriks Anna-Marie , Gubbels Jessica S. , De Vries Nanne K. , Seidell Jaap C. , Kremers Stef P. J. , Jansen Maria W. J.
Published: June 2012

Experts stress the need to bring the childhood obesity epidemic under control by means of an integrated approach. The implementation of such an approach requires the development of integrated enabling policies on public health by local governments. A prerequisite for developing such integrated public health policies is intersectoral collaboration. Since the development of integrated policies is still in its early stages, this study aimed to answer the following research question: “What interventions can promote intersectoral collaboration and the development of integrated health policies for the prevention of childhood obesity?” Data were collected through a literature search and observations of and interviews with stakeholders. Based on a theoretical framework, we categorized potential interventions that could optimize an integrated approach regarding children's physical activity and diet. The intervention categories included education, persuasion, incentivization, coercion, training, restriction, environmental restructuring, modeling, and enablement.
Exfoliated Graphite Reinforced PMMA Composite: A Study on Nanoindentation and Scratch Behavior
Authors: Chakraborty Himel , Sinha Arijit , Mukherjee Nillohit , Chattopadhyay Partha Protim
Published: June 2012

The present work aims to compare the scratch hardness (Hs) with the indentation hardness (HIT) obtained from nanoindentation measurements of exfoliated graphite/poly (methyl methacrylate) (EG/PMMA) composites. EG/PMMA composites with thickness 50 μm each were produced by in situ melt mixing method. Scratch hardness was measured from the scratch width formed at low applied load during the course of the scratch measurements. The measured scratch hardness values were compared with the indentation hardness. There is a good correlation between the scratch hardness and the indentation hardness at low indentation depths, with a linear relationship between hardness and the reinforcement content of exfoliated graphite.
Melanonychia
Authors: Jefferson Julie , Rich Phoebe
Published: June 2012

Melanonychia, or melanin-derived brown-to-black nail pigmentation, is a diagnostic challenge for clinicians. The most serious disease of the nail unit, melanoma, primarily presents with melanonychia. However, melanonychia most often occurs as a result of benign etiologies such as nail matrix melanocytic activation, nail matrix melanocytic hyperplasia, and nail invasion by melanin-producing pathogens. Regrettably, patients with nail apparatus melanoma are often initially misdiagnosed, and due to diagnostic delays of an average of 2 years, melanoma of the nail unit carries a poor prognosis. Having a thorough knowledge of the various causes of melanonychia and using a systematic approach when evaluating brown-to-black nail pigmentation may help prevent misdiagnosis and thereby improve prognosis.
Enhancement of Photoluminescence Lifetime of ZnO Nanorods Making Use of Thiourea
Authors: Sönmez Erdal , Meral Kadem
Published: June 2012

We have investigated correlation of photoluminescence lifetime between zinc oxide (ZnO) nanorods and thiourea‐doped ZnO nanorods (tu: CH4N2S). Aqueous solutions of ZnO nanorods were deposited on glass substrate by using pneumatic spray pyrolysis technique. The as‐prepared specimens were characterized by X‐ray diffraction (XRD), scanning electron microscopy (SEM), and time‐resolved photoluminescence spectroscopy (TRPL). The photoluminescence lifetime of ZnO nanorods and ZnO nanorods containing thiourea was determined as τ = 1.56 ± 0.05 ns (χ2 = 0.9) and τ = 2.12 ± 0.03 ns (χ2 = 1.0), respectively. The calculated lifetime values of ZnO nanorods revealed that the presence of thiourea in ZnO nanorods resulted in increasing the exciton lifetime. In addition to the optical quality of ZnO nanorods, their exciton lifetime is comparable to the longest lifetimes reported for ZnO nanorods. The structural improvement of ZnO nanorods, containing thiourea, was also elucidated by taking their SEM images which show the thinner and longer ZnO nanorods compared to those without thiourea.
MS1-1: Imaging Cancer Invasion In Vivo: Mechanisms and Implications for Therapy.
Authors: Friedl P
Published: June 2012

The tumor microenvironment contributes to cancer invasion, growth and survival and thereby impacts tumor responses to therapy. Using infrared-excited multiphoton microscopy in orthotopic fibrosarcoma and melanoma xenografts, we here identify a novel radio- and chemoresistance niche consisting of invading tumor cell strands consisting of several hundred connected cells located within collagen-rich stroma nearby blood and lymph vessels. Despite normoxia, perivascular invasion strands were resistant to high-dose hypofractionated irradiation which otherwise was sufficient to induce regression of the tumor main mass. This invasion-associated chemo-and radioresistance was sensitive to the simultaneous inhibition of β1 and β3 integrins by RNA interference or combined anti-β1/aV integrin antibody treatment leading to proliferation arrest, anoikis induction and subtotal to complete regression of both tumor lesion and invasion strands. Thus, collective invasion is an important invasion mode in solid tumors into a microenvironmentally priviledged perivascular survival niche which conveys radioresistance by integrin-dependent signals.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS1-1.
MS2-2: Environmental Exposures, Epigenetics, and Epidemiology: Influence of Environmental Factors on Pubertal Maturation and Breast Cancer Etiology.
Authors: Hiatt RA
Published: June 2012

Although much of breast cancer etiology can be explained on the basis of reproductive and family histories, there remains concern among both the public and scientific communities about the possible role of environmental factors. Several well-established observations suggest a role of external environmental factors including the 5-fold international differences in incidence rates and the rapid inter-generational increases in incidence with migration from low to high incidence countries. Although epidemiologic studies in adult populations have generally failed to discover a strong role for environmental factors in breast cancer etiology, emerging data suggests that relevant exposures may have effects in early life during so-called “windows of susceptibility” and be missed by attempted measurement in adulthood. Exposures to ionizing radiation and to diethylstilbestrol during pubertal development and in utero, respectively, are two examples. Recently, more attention has been directed to other environmental exposures, especially endocrine disrupting chemicals (EDCs) during early development and the pubertal period in particular. Many EDCs can now be measured in biospecimens from young prepubertal girls and in pregnant women, and animal studies suggest that some of these may cause changes in reproductive systems.

Early menarche is a well-established risk factor for breast cancer and increases risk approximately 2-fold compared to later menarche. The average age at menarche has also dramatically decreased in developed countries over the last 100 years, likely as the result of environmental factors including diet. However, the relevant exposures and their mode and timing of action are not well understood. An on-going epidemiologic cohort study of 1239 pre-pubertal girls from diverse race/ethnic and socioeconomic backgrounds has documented still earlier ages of pubertal onset and is offering insights into the potential role of EDCs and other chemicals, diet, physical activity, psychosocial and genetic factors on pubertal onset, the age of menarche and other markers of early development. This research on early environmental exposures in humans is proving both exciting and challenging and requires consideration of the complex nature of breast cancer etiology.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS2-2.
OT2-01-02: First-Line Bevacizumab in Combination with Capecitabine or Paclitaxel for HER2−Negative Locally Recurrent or Metastatic Breast Cancer (LR/MBC): A Randomized Phase III Trial.
Authors: Beslija S , Brodowicz T , Greil R , Inbar MJ , Kahán Z , Kaufman B , Lang I , Steger GG , Stemmer SM , Zielinski C , Zvirbule Z
Published: June 2012

Background

A number of phase III studies have shown significant progression-free survival (PFS) benefits with the combination of bevacizumab (Bev) and either first-line capecitabine (X) or taxane therapy in LR/MBC. The ongoing open-label, randomized, phase III CECOG-sponsored TURANDOT study (CECOG/BC.1.3.005) is investigating the efficacy and safety of first-line Bev plus paclitaxel (P) versus Bev plus X in this setting.

Materials and methods: Eligible patients (pts) are aged ≥18 years with HER2−negative, chemonaïve LR/MBC, an ECOG performance status of 0–2 and a life expectancy >12 weeks. Prior chemotherapy and concomitant hormonal therapy for LR/MBC are not permitted, but prior (neo)adjuvant chemotherapy is allowed if completed ≥6 months before randomization or ≥12 months if taxane based. Pts are randomized to receive Bev 10mg/kg days 1, 15 plus P 90mg/m2 days 1, 8, 15, q28d (Arm A) or Bev 15mg/kg day 1 plus X 1,000mg/m2 bid days 1–14, q21d (Arm B) until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to demonstrate non-inferiority in overall survival (OS) with Bev plus P versus Bev plus X (upper limit ≤1.33 for the two-sided confidence interval for hazard ratio [HR]). Secondary objectives are: comparison of overall response rate (RECIST criteria); PFS; time to response; duration of response; time to treatment failure; safety (CTCAE version 3); and quality of life (EORTC QLQ-30). The recruitment target is 560 pts. A sample size of 490 pts in the per-protocol population will be required to provide 80% power to reject the null hypothesis of inferiority at a one-sided significance level of 0.025, assuming a 24-month median OS with Bev plus P and an alternative hypothesis of HR=1. Data cut-off for adverse event reports was 12 Apr 2010. Interim and final efficacy analyses will be triggered after 175 and 389 events, respectively.

Results: Recruitment to the study began in Sep 2008 and was completed in Aug 2010, with 561 pts randomized. Follow-up is ongoing.

Conclusions: TURANDOT is the first study to examine the efficacy and safety of Bev plus P versus Bev plus X as first-line treatment for pts with LR/MBC.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-01-02.
P1-01-07: ErbB-2 Peptide Vaccination Suppresses Spontaneous Tumorigenesis and Tumor Stem Cell Expansion in MMTV-PyVT Transgenic Mouse.
Authors: Park KH , Gil EY , Choi YJ , Kim ST , Cho KR , Seo JH , Lee ES , Kim IS , Disis ML
Published: June 2012

Immunization targeting ErbB-2 could have considerable therapeutic potential by controlling growth and metastasis of highly aggressive tumor cells in the earlier preclinical and clinical studies. Just a few studies have examined preventive potential of ErbB-2 vaccines in preclinical studies. However, animal model systems used in the previous studies were tumor transplantation or neu-transgenic mouse, which were not relevant to human HER-2 positive breast tumorigenesis. In this study, active immunotherapy against tumor antigen ErbB-2/neu for primary prevention of breast cancer was tested using FVB/N-Tg (MMTV-PyVT) transgenic mice model. Mice were grouped to receive either ErbB-2 peptide vaccine, immune adjuvant only, tetanus toxoid, or PBS every 2 weeks for 3 times and monthly thereafter. The MMTV-PyVT transgenic mice in control groups (PBS, immune adjuvant only, or tetanus toxoid peptide) developed spontaneous mammary adenocarcinomas in 12 to 15 weeks, but vaccination against ErbB-2 strongly suppressed tumor formation by 30 weeks of observation. Further pathologic examination showed complete prevention of tumorigenesis was observed in ErbB-2 vaccinated mice, whereas the mice in control groups developed highly aggressive ErbB-2 overexpressing tumors similar to human breast cancer. The tumor protective effect of peptide vaccination was associated with induction of ErbB-2-specific humoral immune responses as well as T cell responses. Additionally, role of signal through ErbB-2 pathway and the relationship with stemness of cancer cells were determined by Aldefluor assay, mammosphere formation assay using Mouse mammary carcinoma (MMC) cells in vitro, and level of nestin expression determined by Western blot analysis. Further analysis of mammosphere formation capacity of MMC cells using immune sera showed that sera from ErbB2 vaccinated mice had a significant inhibitory effect on mammosphere formation in ErbB-2 overexpressing MMC cells. These results suggest that ErbB-2 targeting by cancer vaccination might be useful adjuvant to standard therapy, helping to prevent relapse in patients with ErbB-2-overexpressing tumors by suppressing stem/progenitor cell population.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-07.
P1-01-14: Gene Expression of Immune Mediators within Nipple Aspirate Fluid and Ductal Lavage from Normal and Cancerous Breasts.
Authors: Love SM , Ruffell B , Nguyen T , Mills D , Coussens LM
Published: June 2012

The majority of breast cancers are thought to initiate in the lining of the 6 to 8 ducts that exit the nipple. Evidence suggests that the presence of nipple aspirate fluid (NAF), and in particular NAF containing atypical epithelial cells, in the ducts is predictive of future breast cancer risk. Although NAF fluid and cells may be representative of a preneoplastic state, use of NAF has not proven to represent a robust indicator for future malignancy. Chronic infiltration of tissues by immune cells predisposes them to future malignancy. Since macrophages can represent up to half of the total cells recovered from NAF, and their presence within malignant breast tumors has predictive value in terms of survival, we hypothesized that changes in the inflammatory microenvironment of breast ducts may foster future malignancy and/or provide an early indicator of future neoplasia. To test this hypothesis, we conducted an exploratory study to investigate gene expression in NAF and ductal lavage fluid. We first used real-time PCR to quantitatively measure mRNA expression of select genes within the cellular milieu of NAF to determine if that microenvironment correlated with a tumor-promoting state. Expression of multiple genes was observed in 15 samples collected from healthy volunteers, with robust expression of myeloid-associated genes including CD14, CD68, CCL3, CSF1 and IL1B observed in the majority of samples. To determine whether similar inflammatory microenvironments were found within each duct, and whether they were comparable to those in NAF-containing ducts, ductal lavage (DL) samples were obtained from 4 different ducts at the same time as NAF collection. Out of 7 volunteers, 4 provided samples allowing comparison between NAF and DL, and between multiple ducts. Analysis of gene expression from these healthy volunteers indicated that gene expression differed between NAF samples and each DL sample. More importantly, unique gene expression was found for each duct sampled, indicating that the immune microenvironment within each duct is distinct from other ducts within the same breast. In order to identify a potential inflammatory gene signature, we then obtained NAF samples from patients with breast cancer that had not received neoadjuvant chemotherapy prior to surgery, from both the cancerous and contralateral breasts. With 4 patients analyzed, no consistent expression difference has thus far been observed, indicating either that the relevant genes have not been identified, or that analysis of inflammatory genes within NAF may not be a predictive method with which to evaluate risk of future malignancy in women that produce NAF. A larger study is warranted to further investigate the significance of inflammatory gene expression in breast ductal fluid.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-14.
P1-01-15: Do Serum Cytokines Predict Breast Cancer Behavior?
Authors: Lush E , Dedert E , Daup M , Dhabhar F , Spiegel D , Tillie J , McMasters K , Sephton SE , Chagpar A
Published: June 2012

Introduction: The role of inflammation in breast cancer development and progression is poorly understood. The potential for serum cytokines to predict breast cancer behavior is an intriguing hypothesis, and data to date, has been conflicting. We sought to determine if serum inflammatory cytokines could predict clinicopathologic factors in breast cancer patients.

Methods: Fifty-seven women with newly diagnosed breast cancer (stage 0–4) were accrued to this IRB-approved study. Serum cytokine levels were obtained in 50 of these women; this was the cohort of interest. All patients underwent surgical therapy, and log serum cytokine levels were correlated to final pathologic results. Results: The median patient age was 51 (range; 21–79) with a median tumor size was 19.5 mm (range; 2.3−95.0 mm). A variety of cytokines were evaluated. None were found to correlate with tumor size, lymph node status, presence of metastases, tumor grade, or lymphovascular invasion (all p's > .05). While most of the cytokines evaluated did not correlate with hormone receptor status, a significant correlation was seen between serum IFN-gamma and estrogen receptor (p = .011) and progesterone receptor (p = .013) status. No correlation was seen with her-2-neu status (p > .05).

Conclusions: Serum cytokine levels do not seem to correlate with tumor size, lymph node status or grade. However, the strong correlation between IFN-gamma serum levels and hormone receptor status is hypothesis-generating and requires further study.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-15.
P1-02-09: Epigenetics-Regulated microRNAs Related with Epithelial-Mesenchymal Transition of Breast Cancer Cells.
Authors: Sato F , Ito T , Tsuchiya S , Kawaguchi-Sakita N , Shimizu K , Tsujimoto G , Toi M
Published: June 2012

Background: Epithelial-mesenchymal transition (EMT) is a program in which biological cells change morphologically and functionally from an epithelial phenotype to a mesenchymal phenotype. The EMT is involved in the process of cancer metastasis. On the other hand, accumulated evidence showed epigenetics and microRNA plays important roles in breast cancer. However, to date, biological networks between epigenetics and microRNAs regarding EMT remains largely unclear. Thus, the aim of this study is to identify epigenetics-regulated microRNAs related with EMT of breast cancer.

Materials / Methods and Results: MicroRNA expression profiles of 11 breast cancer cell lines (8 epithelial-phenotype (E-type) cells and 3 mesenchymal-phenotype (M-type) cells) were obtained by microarray method. Unsupervised clustering analysis showed that E- and M-type breast cancer cells had different microRNA expression profiles. On the other hand, we obtained a genomewide methylation status of these breast cancer cell lines by a MeDIP-seq method. An integrated in silico analysis identified microRNAs which microRNA and DNA methylation were inversely correlated. All of miR-200b/a/429 cluster members were listed in top5 differentially expressed miRs between E-and M-type cells, and also in top 5 epigenetics-regulated microRNAs. In the further study, we focused upon the miR-200b/a/429 cluster. A COBRA assay revealed that promoter regions of miR-200b/a/429 cluster in M-type breast cancer cells were more frequently methylated than that in E-type cells (65.1% vs 6.8%, p<0.0001, respectively). The methylation levels were inversely associated with miR-200b/a/429 cluster expression (Taqman assay, p<0.01). In addition, demethylating treatment using 5-aza-dC unmasked miR-200b/a/429 expression in M-typed breast cancer cell lines. Taken together, the finding indicated that the expression of miR-200b/a/429 cluster is epigenetically regulated. Next, we investigated an effect of the miR-200b/a/429 cluster upon cell motility as a function of the EMT. A transfection of exogenous miR-200b/429 inhibited 24% of cell migration ability (Transwell assay). Utilizing microRNA target prediction algorithm, we identified fibronectin as a target gene of miR-200b/429. Utilizing several prediction algorithms for microRNA target genes, we identified fibronectin as a target gene of miR-200b/429. A luciferase-based reporter assay demonstrated that miR-200b/429 were directly associated with fibronectin-3'UTR and repressed 21% (p<0.0001) of the reporter gene expression post-transcriptionally. Conclusion: The promoter hypermethylation of miR-200b cluster is associated with epithelial-mesenchymal transition, and stimulates cell motility by upregulating fibronectin expression in mesenchymal-phenotype breast cancer cells.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-09.
P1-03-07: Subtype-Specific Gene Expression Signatures in Peritumoral Non-Neoplastic Breast Tissue.
Authors: Williams T , Roman-Perez E , Rein JL , Amos KD , Troester MA
Published: June 2012

Tumors and histologically normal-tissue adjacent to cancer share many biological features with healing wounds. We previously described that the majority of cancer-adjacent normal (CN) tissues show activation of wound response gene expression signatures. However, CN tissue also shows considerable heterogeneity across patients. Therefore, to characterize interindividual variation in CN tissues, we performed unsupervised clustering on gene expression data from women with invasive breast cancer or ductal carcinoma in situ of the breast. Two distinct classes of CN tissue were identified, one of which showed gene expression consistent with epithelial-to-mesenchymal transition (EMT), a process that is well known to be activated in healing wounds. Activation of this signature was present in ∼40% of cancer-adjacent normal specimens and it was also correlated with poor outcome among ER-positive patients. We next hypothesized that gene expression changes in cancer-adjacent normal tissue would be associated with breast cancer subtype and/or estrogen receptor status. To test this, we performed supervised analysis to identify subtype-associated gene expression profiles in CN. We observed that more aggressive tumor subtypes had distinct gene expression profiles in the adjacent normal tissue in supervised analysis. Specifically, Basal-like and luminal B tumors were characterized by reduced expression of claudins and cell adhesion genes, while also exhibiting higher expression of transcription factors associated with migration. These characteristic changes were validated in independent datasets by evaluating the ability of these signatures to predict subtype. It is possible to predict tumor subtype using just adjacent normal gene expression. Thus, our findings show that cancer-adjacent tissue may have value in identifying tumor subtype for cases where tumors are too small to allow genomic analyses. Furthermore, genomic field effects may have clinical implications if, as our data suggests, subtypes with higher local recurrence rates (e.g. basal-like and luminal B breast cancers) have widespread genomic alterations, even in non-neoplastic tissue. Widespread genomic changes may indicate a need for mastectomy rather than breast conserving therapy. Ongoing work is (1) assessing these signatures in association with relapse outcomes in the Polish Women's Breast Cancer Study, where more than 10 years of follow up data have been accrued on more than 200 patients, and (2) using co-culture models systems to study paracrine communication between breast cancer cells and stroma according to breast cancer subtypes.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-07.
P1-06-06: The Importance of CXCL10 and CXCR3-A in Breast Cancer.
Authors: Hilborn E , Sivik T , Kot A , Fornander T , Skoog L , Nordenskjöld B , Stål O , Jansson A
Published: June 2012

Background: CXCL10 is a chemokine with chemo attractant properties which signals through G protein-coupled receptor CXCR3. At least two reported isoforms exists; CXCR3-A and CXCR3-B. CXCL10 is involved in the recruitment of leucocytes, immune modulation and angiogenesis. In animal models CXCL10 inhibits tumour growth, metastase formation and inhibits angiogenesis. The receptors have opposite features; CXCR3-A mediates proliferative or anti-apoptotic response and CXCR3-B mediates growth inhibition and apoptosis in response to ligand binding. The aim of this study was to investigate the role of CXCL10 and CXCR3-A as prognostic or tamoxifen treatment predictive factors in breast cancer.

Material and Methods: A randomized tamoxifen trial comprising 1,780 breast cancer patients was conducted in Stockholm, Sweden, 1976–1990. All patients had lymph node negative primary breast cancer and were postmenopausal at the time of diagnosis. The patients were randomized to tamoxifen or no endocrine treatment. We analyzed the protein expression of CXCL10 and the receptor CXCR3A with immunohistochemistry using tissue microarrays, which were constructed from paraffin blocks originating from 912 patients. CXCL10 and CXCR3A could be scored in 793 (87%) and 735 (81%), respectively.

Results: High expression of CXCL10 was associated with significant benefit of tamoxifen treatment concerning local recurrence and breast cancer survival (P=0.02 and P=0.008). For patients with high CXCL10 expression, tamoxifen decreased the risk concerning local recurrence (rate ratio (RR) = 0.56, 95% C.I. 0.33−0.97, P=0.0029) and breast cancer survival (RR 0.6 95% C.I. 0.39−0.97, P=0.023). High expression of CXCR3-A was associated with significant benefit of tamoxifen treatment concerning total recurrence and breast cancer survival (P=0.00001 and P=0.004, respectively). For patients with high CXCR3-A expression, tamoxifen decreased the risk of total recurrence (RR 0.54 95% C.I. 0.35−0.83, P=0.005) and breast cancer survival (RR 0.49 95% C.I. 0.35−0.69, P=0.00003). On the opposite, in the cohort of patients with no endocrine treatment and high CXCR3-A expression, there was an increased risk of total recurrence (P=0.003). (RR 2.07 95% C.I. 1.18−3.61, P=0.011).

Conclusions: This study indicates that high expression of CXCL10 can be used as predictive markers for tamoxifen treatment. Further, high expression of CXCR3-A is related to bad prognosis and predicts tamoxifen treatment in breast cancer patients. This needs to be further evaluated.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-06.
P1-06-07: TIMP-1 in Combination with HER2 and TOP2A for Prediction of Benefit from Adjuvant Anthracyclines in High Risk Breast Cancer Patients.
Authors: Hertel PB , Tu D , Ejlertsen B , Jensen M-B , Balslev E , Jiang S , O'Malley FP , Pritchard KI , Shepherd LE , Bartels A , Brünner N , Nielsen TO
Published: June 2012

Purpose: HER2 amplification, TOP2A aberrations and absence of TIMP-1 (Tissue Inhibitor of Metalloproteinase-1) expression in breast carcinomas have been associated with incremental benefit from anthracycline-containing adjuvant chemotherapy in several reports. In the DBCG 89D trial, we demonstrated that the predictive value of these markers improved when they were combined in a profile and the present study was undertaken to validate these findings in NCIC CTG MA.5, a similar but independent clinical trial.

Design: TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to CEF or CMF in the MA.5 trial. Patients were classified according to 2 predefined marker profiles — the HT profile (HER2, TIMP-1) and the 2T profile (TOP2A, TIMP-1) and the statistical analyses were performed as closely as possible to the analytical approach used previously in the MA.5 trial and when analysing the biomarker profiles in the DBCG 89D trial.

Results: 98 (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. 44% of patients were classified as HT responsive (HER2-positive and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT responsive patients, CEF was superior to CMF with improved RFS (adjusted HR, 0.64; 95% CI, 0.42 to 0.98) and a borderline-significant improvement in OS (adjusted HR, 0.66; 95% CI, 0.42 to 1.04). A significant HT profile versus treatment interaction was detected for OS (P=0.03). In 2T responsive patients, CEF was superior to CMF with borderline significant improvement in RFS (adjusted HR, 0.67; 95% CI, 0.43 to 1.03), and with improvement in OS (adjusted HR, 0.58; 95% CI, 0.36 to 0.93). A significant 2T profile versus treatment interaction was detected for OS (P=0.01).

Conclusion: In the MA.5 trial, we have validated the HT and 2T profiles as predictors of incremental benefit from anthracycline-containing chemotherapy. The proportion of patients categorized as anthracycline responsive increases from 18–27% using individual markers to 37–44% when combining TIMP-1 with either HER2 or TOP2A. Patients with responsive profiles had a 34–42% relative reduction in mortality when treated with CEF. In contrast, patients with non-responsive profiles (56-63% of patients) had no incremental benefit from CEF compared with CMF. All 3 biomarkers are easily applied in the pathology lab and as such could be used in daily clinical practice to select patients for anthracycline or non-anthracycline containing adjuvant chemotherapy.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-07.
P1-06-26: The EndoPredict Score Is a Response Predictor for Neoadjuvant Chemotherapy in ER-Positive, HER2−Negative Breast Cancer.
Authors: Brase JC , Gehrmann MC , Petry C , Weber KE , Schmidt M , Kölbl H , Brauch H , Schwab M , Müller V , Jänicke F , Rody A , Kaufmann M , Filipits M , Gnant M , Denkert C , Loibl S , von Minckwitz G , Kronenwett R
Published: June 2012

Background:

The EndoPredict (EP) score is a multigene classifier to predict the likelihood of distant recurrence in ER-positive, HER2−negative breast cancer patients treated with adjuvant endocrine therapy. Two large randomized phase III trials involving endocrine therapy only (n > 1700) demonstrated additional prognostic information of the EP score independent from clinicopathological parameters by classifying 49% as low risk. However, the predictive role of the EP is not clear. Therefore, we examined whether the EP Score also predicts sensitivity towards neoadjuvant chemotherapy in ER-positive, HER2−negative breast cancer patients.

Methods: Four publicly available gene expression data sets (Affymetrix HG-U133A) were retrieved from the gene expression omnibus (GEO) data repository. All analyzed breast cancer patients were treated with anthracycline or taxane/anthracycline-based neoadjuvant chemotherapy. Microarray cel files were MAS5 normalized with a global scaling procedure and a target intensity of 500. The analysis was restricted to ER-positive, HER2−negative breast cancer patients according to pre-specified cut-off levels for the respective ESR1/ERBB2 Affymetrix probesets. The EP score was calculated and patients were classified as having low or high risk according to the pre-specified validated cut-off value. Pathological complete response (pCR) — defined as no residual invasive cancer in the breast or lymph nodes — was used as the primary endpoint for the assessment of treatment response.

Results: The EP Score was examined in 221 ER-positive, HER2−negative breast cancer patients treated with neoadjuvant therapy. Among the 221 patients, 61 tumors (27.6%) were classified as EP-low-risk, whereas 160 tumors (72.4%) were EP-high-risk. Only one of the EP-low-risk tumors achieved a pCR after neoadjuvant therapy, whereas 24 of the 25 pCR events were classified as EP high risk. The sensitivity of the EP score was 96% and the negative predictive value 98% with an area under the receiver operating characteristic curve of 0.73.

Conclusions: The EP Score is a predictor of chemosensitivity in the neoadjuvant setting. The test correctly identified all but one of the patients achieving a pCR suggesting that the benefit of cytotoxic chemotherapy is limited to the EP high risk group.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-26.