bluuebunny/crossref_metadata_2025 huggingface dataset:
Choosing Money over Drugs: The Neural Underpinnings of Difficult Choice in Chronic Cocaine Users
Authors: Wesley Michael J. , Lohrenz Terry , Koffarnus Mikhail N. , McClure Samuel M. , De La Garza Richard , Salas Ramiro , Thompson-Lake Daisy G. Y. , Newton Thomas F. , Bickel Warren K. , Montague P. Read
Published: August 2014

Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs) who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC.
Magnetic Fluid Hyperthermia of Rodent Tumors Using Manganese Perovskite Nanoparticles
Authors: Bubnovskaya Larissa , Belous Anatolij , Solopan Sergej , Kovelskaya Antonina , Bovkun Lyudmila , Podoltsev Alexander , Kondtratenko Igor , Osinsky Sergej
Published: August 2014

Purpose. To test the antitumor activity of magnetic fluid (MF) on the basis of substituted lanthanum-strontium manganite nanoparticles combined with alternating magnetic field (AMF) in experiments with transplanted tumors. Materials and Methods. MF with a size of nanoparticles of 30–40 nm in aqueous agarose solution was investigated. The ability of MF to heat tumor under AMF (300 kHz, 7.7 kA/m) was tested in vivo with rodent tumors (Guerin carcinoma, Walker-256 carcinosarcoma, and Lewis lung carcinoma (3LL)). Results. Single administration of MF into the tumor at a dose of 150 mg/kg (rats) or 200 mg/kg (mice) followed by AMF within 20–30 min (treatment was repeated 3-4-fold) has resulted in the complete regression of tumor in the 35% of rats and 57% of mice. Administration of MF alone or action of AMF alone has not resulted in tumor growth inhibition. The chemomodifying effect of nanohyperthermia was determined, in particular for cisplatinum: thermal enhancement ratio was 2.0. It was also observed that nanohyperthermia has resulted in the absence of 3LL metastases in 43% of mice. Conclusions. MF on the basis of lanthanum-strontium manganite may be considered as an effective inductor of tumor local hyperthermia.
A New Mathematical Inventory Model with Stochastic and Fuzzy Deterioration Rate under Inflation
Authors: Naserabadi Bahar , Mirzazadeh Abolfazl , Nodoust Sara
Published: August 2014

This paper develops an inventory model for items with uncertain deterioration rate, time-dependent demand rate with nonincreasing function, and allowable shortage under fuzzy inflationary situation. The goods are not deteriorating upon reception, but the deteriorating starts after elapsing a specified time. The lead time and inflation rate are both uncertain in the model. The resultant effect of inflation and time value of money is assumed to be fuzzy in nature and also we consider lead time as a fuzzy function of order quantity. Furthermore the following different deterioration rates have been considered: for the first case we consider fuzzy deterioration rate and for the second case we assume that the deterioration rate is time dependent and follows Weibull distribution with three known parameters. Since the inflation rate, deterioration rate, and the lead time are fuzzy numbers, the objective function becomes fuzzy. Therefore the estimate of total costs for each case is derived using signed distance technique for defuzzification. The optimal replenishment policy for the model is to minimize the total present value of inventory system costs, derived for both the above mentioned policies. Numerical examples are then presented to illustrate how the proposed model is applied.
A Medical Manipulator System with Lasers in Photodynamic Therapy of Port Wine Stains
Authors: Wang Xingtao , Tian Chunlai , Duan Xingguang , Gu Ying , Huang Naiyan
Published: August 2014

Port wine stains (PWS) are a congenital malformation and dilation of the superficial dermal capillary. Photodynamic therapy (PDT) with lasers is an effective treatment of PWS with good results. However, because the laser density is uneven and nonuniform, the treatment is carried out manually by a doctor thus providing little accuracy. Additionally, since the treatment of a single lesion can take between 30 and 60 minutes, the doctor can become fatigued after only a few applications. To assist the medical staff with this treatment method, a medical manipulator system (MMS) was built to operate the lasers. The manipulator holds the laser fiber and, using a combination of active and passive joints, the fiber can be operated automatically. In addition to the control input from the doctor over a human-computer interface, information from a binocular vision system is used to guide and supervise the operation. Clinical results are compared in nonparametric values between treatments with and without the use of the MMS. The MMS, which can significantly reduce the workload of doctors and improve the uniformity of laser irradiation, was safely and helpfully applied in PDT treatment of PWS with good therapeutic results.
Anticancer, Anti-Inflammatory, and Analgesic Activities of Synthesized 2-(Substituted phenoxy) Acetamide Derivatives
Authors: Rani Priyanka , Pal Dilipkumar , Hegde Rahul Rama , Hashim Syed Riaz
Published: August 2014

The aphorism was to develop new chemical entities as potential anticancer, anti-inflammatory, and analgesic agents. The Leuckart synthetic pathway was utilized in development of novel series of 2-(substituted phenoxy)-N-(1-phenylethyl)acetamide derivatives. The compounds containing 1-phenylethylamine as basic moiety attached to substituted phenols were assessed for their anticancer activity against MCF-7 (breast cancer), SK-N-SH (neuroblastoma), anti-inflammatory activity, and analgesic activity. These investigations revealed that synthesized products3a–jwith halogens on the aromatic ring favors as the anticancer and anti-inflammatory activity. Among all, compound3cN-(1-(4-chlorophenyl)ethyl)-2-(4-nitrophenoxy)acetamide exhibited anticancer, anti-inflammatory, and analgesic activities. In conclusion,3cmay have potential to be developed into a therapeutic agent.
NK Cells in Mucosal Defense against Infection
Authors: Ivanova Daria , Krempels Ryan , Ryfe Jennyfer , Weitzman Kaitlyn , Stephenson David , Gigley Jason P.
Published: August 2014

Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγproduction against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.
Proteinases in Excretory-Secretory Products ofToxocara canisSecond-Stage Larvae: Zymography and Modeling Insights
Authors: González-Páez Gonzalo Ernesto , Alba-Hurtado Fernando , García-Tovar Carlos Gerardo , Argüello-García Raúl
Published: August 2014

Components released in excretory-secretory products ofToxocara canislarvae (TES) include phosphatidylethanolamine-binding proteins (TES26), mucins (TES120, MUC2-5), and C-type lectins (TES32, TES70) and their biochemical, immunological, and diagnostic properties have been extensively studied albeit proteinase activities towards physiological substrates are almost unknown. Proteolytic activities in TES samples were first analyzed by gel electrophoresis with gelatin as substrate. Major activities of ~400, 120, and 32 kDa in TES were relatively similar over a broad pH range (5.5–9.0) and all these were of the serine-type as leupeptin abolished gelatinolysis. Further, the ~400 kDa component degraded all physiological substrates tested (laminin, fibronectin, albumin, and goat IgG) and the 120 kDa component degraded albumin and goat IgG while proteinases of lower MW (45, 32, and 26 kDa) only degraded laminin and fibronectin, preferentially at alkaline pH (9.0). By protein modeling approaches using the known sequences of TES components, only TES26 and MUC4 displayed folding patterns significantly related to reference serine proteinases. These data suggest that most of serine proteinase activities secretedin vitroby infective larvae ofT. canishave intriguing nature but otherwise help the parasite to affect multiple components of somatic organs and bodily fluids within the infected host.
Extension of Cherenkov Light LDF Approximation for Yakutsk EAS Array
Authors: Al-Rubaiee A. A. , Al-Douri Y. , Hashim U.
Published: August 2014

The simulation of the Cherenkov light lateral distribution function (LDF) in extensive air showers (EAS) was performed using CORSIKA code for configuration of Yakutsk EAS array at high energy range for different primary particles (p, Fe, and O2) and different zenith angles. Depending on Breit-Wigner function a parameterization of Cherenkov light LDF was reconstructed on the basis of this simulation as a function of primary energy. A comparison of the calculated Cherenkov light LDF with that measured on the Yakutsk EAS array gives the possibility of identification of the particle initiating the shower and determination of its energy in the knee region of the cosmic ray spectrum. The extrapolation of approximated Cherenkov light LDF for high energies was obtained for primary proton and iron nuclei.
Predictors of Response to 24-Week Telaprevir-Based Triple Therapy for Treatment-Naïve Genotype 1b Chronic Hepatitis C Patients
Authors: Abe Hiroshi , Tsubota Akihito , Shimada Noritomo , Atsukawa Masanori , Kato Keizo , Takaguchi Koichi , Asano Toru , Chuganji Yoshimichi , Sakamoto Choitsu , Toyoda Hidenori , Kumada Takashi , Ide Tatsuya , Sata Michio , Aizawa Yoshio
Published: August 2014

We evaluated the genetic variation in rs8099917, substitutions in core amino acid (aa) 70, and the number of aa substitutions in the interferon sensitivity-determining region (ISDR) on the prediction of sustained virological response (SVR) in treatment-naïve hepatitis C virus (HCV) genotype 1b (G1b) patients. This multicenter study involved 150 Asian treatment-naïve patients infected with HCV G1b who received 12 weeks of telaprevir in combination with 24 weeks of peginterferon-α-2b and ribavirin. The baseline and treatment-related factors potentially associated with SVR were determined by multivariate logistic regression analysis. Virological response was analyzed on an intent-to-treat basis. Cessation of the therapy due to adverse effects occurred in only 2 patients, who discontinued the trial at 10 weeks and at 2 weeks due to cerebral infarction and renal impairment, respectively. Among the 150 patients in whom the final virological response was determined, only genotype TT in rs8099917 was identified as a pretreatment predictor (P= 7.38 × 10−4). Achievement of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 of treatment, was identified as an after-starting-treatment predictor (P= 2.47 × 10−5). However, neither a substitution in core aa 70 nor the number of substitutions in the ISDR affected treatment outcome.
Variability in Myosteatosis and Insulin Resistance Induced by High-Fat Diet in Mouse Skeletal Muscles
Authors: Collino Massimo , Mastrocola Raffaella , Nigro Debora , Chiazza Fausto , Aragno Manuela , D’Antona Giuseppe , Minetto Marco A.
Published: August 2014

Nutrient overload leads to impaired muscle oxidative capacity and insulin sensitivity. However, comparative analyses of the effects of dietary manipulation on skeletal muscles with different fiber composition are lacking. This study aimed to investigate the selective adaptations in the soleus and tibialis anterior muscles evoked by administration of high-fat diet for 12 weeks in 10 mice (HFD mice) compared to 10 animals fed with a normal chow diet (control mice). Mice fed with the HFD diet exhibited hyperlipidemia, hyperinsulinemia, hyperglycemia, and lower exercise capacity in comparison to control mice. In control mice, soleus fibers showed higher lipid content than tibialis anterior fibers. In contrast, the lipid content was similar between the two muscles in HFD mice. Significant differences in markers of muscle mitochondrial production and/or activity as well as of lipid synthesis were detected between HFD mice and control mice, especially in the tibialis anterior. Moreover, translocation of GLUT-4 transporter to the plasma membrane and activation of the insulin signaling pathway were markedly inhibited in the tibialis and slightly reduced in the soleus of HFD mice compared to control mice. Overall, these results show that adaptive responses to dietary manipulation occur in a muscle-specific pattern.
Damage Identification of Bridge Based on Modal Flexibility and Neural Network Improved by Particle Swarm Optimization
Authors: Liu Hanbing , Song Gang , Jiao Yubo , Zhang Peng , Wang Xianqiang
Published: August 2014

An approach to identify damage of bridge utilizing modal flexibility and neural network optimized by particle swarm optimization (PSO) is presented. The method consists of two stages; modal flexibility indices are applied to damage localizing and neural network optimized by PSO is used to identify the damage severity. Numerical simulation of simply supported bridge is presented to demonstrate feasibility of the proposed method, while comparative analysis with traditional BP network is for its superiority. The results indicate that curvature of flexibility changes can identify damages with both single and multiple locations. The optimization of bias and weight for neural network by fitness function of PSO algorithm can realize favorable damage severity identification and possesses more satisfactory accuracy than traditional BP network.
DNA Damage and Its Cellular Response in Mother and Fetus Exposed to Hyperglycemic Environment
Authors: Moreli Jusciele Brogin , Santos Janine Hertzog , Rocha Clarissa Ribeiro , Damasceno Débora Cristina , Morceli Glilciane , Rudge Marilza Vieira , Bevilacqua Estela , Calderon Iracema Mattos Paranhos
Published: August 2014

The increased production of reactive oxygen species (ROS) plays a key role in pathogenesis of diabetic complications. ROS are generated by exogenous and endogenous factors such as during hyperglycemia. When ROS production exceeds the detoxification and scavenging capacity of the cell, oxidative stress ensues. Oxidative stress induces DNA damage and when DNA damage exceeds the cellular capacity to repair it, the accumulation of errors can overwhelm the cell resulting in cell death or fixation of genome mutations that can be transmitted to future cell generations. These mutations can lead to and/or play a role in cancer development. This review aims at (i) understanding the types and consequences of DNA damage during hyperglycemic pregnancy; (ii) identifying the biological role of DNA repair during pregnancy, and (iii) proposing clinical interventions to maintain genome integrity. While hyperglycemia can damage the maternal genetic material, the impact of hyperglycemia on fetal cells is still unclear. DNA repair mechanisms may be important to prevent the deleterious effects of hyperglycemia both in mother and in fetus DNA and, as such, prevent the development of diseases in adulthood. Hence, in clinical practice, maternal glycemic control may represent an important point of intervention to prevent the deleterious effects of maternal hyperglycemia to DNA.
A Rapid Extractive Spectrophotometric Method for the Determination of Tin with 6-Chloro-3-hydroxy-2-(2′-thienyl)-4-oxo-4H-1-benzopyran
Authors: Kataria Ramesh , Sharma Harish Kumar
Published: August 2014

An extractive spectrophotometric method for the determination of the trace amounts of tin has been carried out by employing 6-chloro-3-hydroxy-2-(2′-thienyl)-4-oxo-4H-1-benzopyran (in acetone) (CHTB) for the complexation of the metal ion in HCl medium. The colored species thus produced is quantitatively extracted into dichloromethane and shows the maximum absorbance at 432–437 nm. The method obeys Beer’s law in the range 0.0–1.3 μg mL−1 of tin with molar absorptivity and Sandell’s sensitivity of 5.81×104 L mol−1 cm−1 and 0.0020 μg Sn cm−2, respectively, at 435 nm. The method is highly selective and free from the interference of a large number of elements including platinum metals. The ratio of metal to ligand in the extracted species is 1 : 2. Utilizing this method, the analysis of various synthetic and technical samples including gun metal and tin can have been carried out satisfactorily.
The Treatment of PPCP-Containing Sewage in an Anoxic/Aerobic Reactor Coupled with a Novel Design of Solid Plain Graphite-Plates Microbial Fuel Cell
Authors: Chang Yi-Tang , Yang Chu-Wen , Chang Yu-Jie , Chang Ting-Chieh , Wei Da-Jiun
Published: August 2014

Synthetic sewage containing high concentrations of pharmaceuticals and personal care products (PPCPs, mg/L level) was treated using an anoxic/aerobic (A/O) reactor coupled with a microbial fuel cell (MFC) at hydraulic retention time (HRT) of 8 h. A novel design of solid plain graphite plates (SPGRPs) was used for the high surface area biodegradation of the PPCP-containing sewage and for the generation of electricity. The averageCODCrand total nitrogen removal efficiencies achieved were 97.20% and 83.75%, respectively. High removal efficiencies of pharmaceuticals, including acetaminophen, ibuprofen, and sulfamethoxazole, were also obtained and ranged from 98.21% to 99.89%. A maximum power density of 532.61 mW/cm2and a maximum coulombic efficiency of 25.20% were measured for the SPGRP MFC at the anode. Distinct differences in the bacterial community were presented at various locations including the mixed liquor suspended solids and biofilms. The bacterial groups involved in PPCP biodegradation were identified asDechloromonasspp.,Sphingomonassp., andPseudomonas aeruginosa. This design, which couples an A/O reactor with a novel design of SPGRP MFC, allows the simultaneous removal of PPCPs and successful electricity production.
Nonparetic Knee Extensor Strength Is the Determinant of Exercise Capacity of Community-Dwelling Stroke Survivors
Authors: Wang Wei-Te , Huang Ling-Tzu , Chou Ya-Hui , Wei Ta-Sen , Lin Chung-Che
Published: August 2014

Objective.To investigate the relationship among walking speed, exercise capacity, and leg strength in community dwelling stroke subjects and to evaluate which one was the leading determinant factor of them.Design.This is a descriptive, cross-sectional study. Thirty-five chronic stroke patients who were able to walk independently in their community were enrolled. Walking speed was evaluated by using the 12-meter walking test. A maximal exercise test was used to determine the stroke subjects’ exercise capacity. Knee extensor strength, measured as isokinetic torque, was assessed by isokinetic dynamometer.Results.The main walking speed of our subjects was 0.52 m/s. Peak oxygen uptake (VO2peak) was1.21±0.43 L/min. Knee extensor strength, no matter whether paretic or nonparetic side, was significantly correlated to 12-meter walking speed and exercise capacity. Linear regression also showed the strength of the affected knee extensor was the determinant of walking speed and that of the nonparetic knee extensor was the determinant of exercise capacity in community dwelling stroke subjects.Conclusions.Walking speed and peak oxygen uptake were markedly decreased after stroke. Knee extensor strength of nonparetic leg was the most important determinant of exercise capacity of the community-dwelling stroke subjects. Knee extensor strengthening should be emphasized to help stroke patient to achieve optimal community living.
MicroRNAs: Promising New Antiangiogenic Targets in Cancer
Authors: Gallach Sandra , Calabuig-Fariñas Silvia , Jantus-Lewintre Eloisa , Camps Carlos
Published: August 2014

MicroRNAs are one class of small, endogenous, non-coding RNAs that are approximately 22 nucleotides in length; they are very numerous, have been phylogenetically conserved, and involved in biological processes such as development, differentiation, cell proliferation, and apoptosis. MicroRNAs contribute to modulating the expression levels of specific proteins based on sequence complementarity with their target mRNA molecules and so they play a key role in both health and disease. Angiogenesis is the process of new blood vessel formation from preexisting ones, which is particularly relevant to cancer and its progression. Over the last few years, microRNAs have emerged as critical regulators of signalling pathways in multiple cell types including endothelial and perivascular cells. This review summarises the role of miRNAs in tumour angiogenesis and their potential implications as therapeutic targets in cancer.
Early Glottic Cancer: Role of MRI in the Preoperative Staging
Authors: Allegra Eugenia , Ferrise Pierpaolo , Trapasso Serena , Trapuzzano Orazio , Barca Antonio , Tamburrini Stefania , Garozzo Aldo
Published: August 2014

Introduction.Clinical staging is the most important time in management of glottic cancer in early stage (I-II). We have conducted a prospective study to evaluate if magnetic resonance imaging (MRI) is more accurate than computed tomography (CT) about tumoral extension, to exactly choose the most appropriate surgical approach, from organ preservation surgery to demolitive surgery.Materials and Methods.This prospective study was conducted on 26 male patients, with suspected laryngeal neoplasia of glottic region. The images of MRI and CT were analyzed to define the expansion of glottic lesion to anterior commissure, laryngeal cartilages, subglottic and/or supraglottic site, and paraglottic space. The results of MRI and CT were compared with each other and with the pathology report.Results.CT accuracy was 70% with low sensitivity but with high specific value. MRI showed a diagnostic accuracy in 80% of cases, with a sensitivity of 100% and high specificity. Statistical analysis showed that MRI has higher correlation than CT with the pathology report.Conclusion.Our study showed that MRI is more sensitive than CT in the preoperative staging of early glottic cancer, to select exactly the eligible patients in conservative surgery of the larynx, as supracricoid laryngectomy and cordectomy by CO2laser.
A Modified Strip-Yield-Saturation-Induction Model Solution for Cracked Piezoelectromagnetic Plate
Authors: Bhargava R. R. , Verma Pooja Raj
Published: August 2014

A strip-yield-saturation-induction model is proposed for an impermeable crack embedded in piezoelectromagnetic plate. The developed slide-yield, saturation, and induction zones are arrested by distributing, respectively, mechanical, electrical, and magnetic loads over their rims. Two cases are considered: when saturation zone exceeds induction zone and vice-versa. It is assumed that developed slide-yield zone is the smallest because of the brittle nature of piezoelectromagnetic material. Fourier integral transform technique is employed to obtain the solution. Closed form analytic expressions are derived for developed zones lengths, crack sliding displacement, crack opening potential drop, crack opening induction drop, and energy release rate. Case study presented for BaTiO3–CoFe2O4 shows that crack arrest is possible under small-scale mechanical, electrical, and magnetic yielding.
Determination of the Thermal Insulation for the Model Building Approach and the Global Effects in Turkey
Authors: Onan Cenk
Published: August 2014

One of the most important considerations to be considered in the design of energy efficient buildings is the thickness of the insulation to be applied to the building. In this study the existing building stock in Turkey has been investigated depending on parameters such as the height and the area. A model building has been created covering all of these buildings. Fuel emission reduction of combustion system was calculated in the case of insulation applied to this model building. Heat loss of the existing building stock and exhaust emissions and the contribution to the country's economy with the model building methodology are also determined. The results show that the optimum insulation thicknesses vary between 3.21 and 7.12 cm, the energy savings vary between 9.23 US$/m2 and43.95 US$/m2, and the payback periods vary between 1 and 8.8 years depending on the regions. As a result of the study when the optimum insulation thickness is applied in the model building, the total energy savings for the country are calculated to be 41.7 billion US$. And also total CO2 emissions for the country are calculated to be 57.2 billion kg CO2 per year after insulation.
Delay Differential Model for Tumour-Immune Response with Chemoimmunotherapy and Optimal Control
Authors: Rihan F. A. , Abdelrahman D. H. , Al-Maskari F. , Ibrahim F. , Abdeen M. A.
Published: August 2014

We present a delay differential model with optimal control that describes the interactions of the tumour cells and immune response cells with external therapy. The intracellular delay is incorporated into the model to justify the time required to stimulate the effector cells. The optimal control variables are incorporated to identify the best treatment strategy with minimum side effects by blocking the production of new tumour cells and keeping the number of normal cells above 75% of its carrying capacity. Existence of the optimal control pair and optimality system are established. Pontryagin’s maximum principle is applicable to characterize the optimal controls. The model displays a tumour-free steady state and up to three coexisting steady states. The numerical results show that the optimal treatment strategies reduce the tumour cells load and increase the effector cells after a few days of therapy. The performance of combination therapy protocol of immunochemotherapy is better than the standard protocol of chemotherapy alone.
NSAID Use Reduces Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin–Aromatase Interactions
Authors: Bowers Laura W. , Maximo Ilane X.F. , Brenner Andrew J. , Beeram Muralidhar , Hursting Stephen D. , Price Ramona S. , Tekmal Rajeshwar R. , Jolly Christopher A. , deGraffenried Linda A.
Published: August 2014

Obesity is associated with a worse breast cancer prognosis and elevated levels of inflammation, including greater cyclooxygenase-2 (COX-2) expression and activity in adipose-infiltrating macrophages. The product of this enzyme, the proinflammatory eicosanoid prostaglandin E2 (PGE2), stimulates adipose tissue aromatase expression and subsequent estrogen production, which could promote breast cancer progression. This study demonstrates that daily use of a nonsteroidal anti-inflammatory drug (NSAID), which inhibits COX-2 activity, is associated with reduced estrogen receptor α (ERα)–positive breast cancer recurrence in obese and overweight women. Retrospective review of data from ERα-positive patients with an average body mass index of >30 revealed that NSAID users had a 52% lower recurrence rate and a 28-month delay in time to recurrence. To examine the mechanisms that may be mediating this effect, we conducted in vitro studies that utilized sera from obese and normal-weight patients with breast cancer. Exposure to sera from obese patients stimulated greater macrophage COX-2 expression and PGE2 production. This was correlated with enhanced preadipocyte aromatase expression following incubation in conditioned media (CM) collected from the obese-patient, sera-exposed macrophages, an effect neutralized by COX-2 inhibition with celecoxib. In addition, CM from macrophage/preadipocyte cocultures exposed to sera from obese patients stimulated greater breast cancer cell ERα activity, proliferation, and migration compared with sera from normal-weight patients, and these differences were eliminated or reduced by the addition of an aromatase inhibitor during CM generation. Prospective studies designed to examine the clinical benefit of NSAID use in obese patients with breast cancer are warranted. Cancer Res; 74(16); 4446–57. ©2014 AACR.
Abstract BL-1: Brinker Award Lecture: How Does HER2 Contribute to Breast Cancer Progression?
Authors: Yarden Y
Published: August 2014

HER2 (also called NEU and ERBB2), a receptor tyrosine kinase frequently overexpressed in breast cancer, is one of the most oncogenic kinases of the human kinome. Multiple mechanisms contribute to the transforming potential of HER2. Although HER2 is structurally similar to the receptors for EGF (EGFR) and neuregulins (ERBB3 and ERBB4), the cytoplasm-facing kinase domain of HER2 is characterized by relatively high basal activity, and unlike the ectodomains of EGFR and ERBB3/ERBB4, HER2?s extracellular part cannot bind any known growth factor with high affinity. Nevertheless, HER2 acts as the preferred partner of the other three receptors, and the heterodimers it forms display not only high kinase activity but also increased binding affinity toward a broad spectrum of growth factors. In addition, HER2-containing heterodimers typically interact with a relatively wide set of cytoplasmic effector proteins, such as the phosphoinositol 3-kinase and SHC, which recruits the mitogen-activated protein kinase pathway. The collective outcome of these functional features translates to prolonged and enhanced signaling capacity.

One way to comprehend HER2 is offered by the evolutionary history of the family of receptor tyrosine kinases. Accordingly, HER2 and EGFR share a common precursor, but genome duplications denied a growth factor from HER2, and in parallel inactivated the catalytic function of ERBB3, to achieve a layered signaling network, whose autonomy and steady state are maintained by a dense web of feedback regulatory loops. In line with this scenario, HER2 cannot signal in isolation, but requires an activating growth factor receptor. Once recruited, HER2 enables evasion of negative feedback regulation, such as receptor ubiquitination and intracellular degradation: Unlike homodimers of EGFRs, which are targeted to lysosomes for degradation, HER2-containing heterodimers are targeted to a recycling pathway that replenishes the surface pool of HER2 molecules and further prolongs signaling.

In-depth understanding of HER2?s oncogenic functions holds promise for therapy of a fraction of breast cancer patients. For example, the relatively high basal activation of the kinase domain means that HER2 relies on a chaperone called HSP90, hence blocking HSP90 might retard HER2-overexpressing tumors. Likewise, it is predictable that agents able to block either recycling of HER2 or its ability to form heterodimers, would curtail tumor growth.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BL-1.
Abstract BS1-1: Essential Role for Wnt Signaling in Metastatic Colonization
Authors: Huelsken J
Published: August 2014

Metastatic growth in distant organs is the major cause of cancer mortality. Formation of metastasis is a multi-step process with several rate-limiting steps: while dissemination of tumour cells appears to be an early and frequent event, successful initiation of metastatic growth, a process termed metastatic colonization, is rather inefficient and accomplished only by a minority of cancer cells that reach distant sites. We now identify two key mechanisms essential for the initiation of metastasis: first, a small population of cancer stem cells that are critical for metastatic colonization, i.e. the initial expansion of cancer cells at the secondary site. Second, we find stromal niche signals to be crucial for this process. This niche is required to promote Wnt signaling in infiltrating cancer stem cells and thereby this pathway plays an essential role in metastatic colonization. We suggest that interfering with this stromal support may represent a novel treatment strategy against metastatic disease.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BS1-1.
Abstract BS3-2: Molecular Imaging of Breast Cancer: Visualizing In Vivo Breast Cancer Biology
Authors: Mankoff DA , Chodosh LA
Published: August 2014

The ability to measure biochemical and molecular processes underlies progress in breast cancer biology and treatment. These assays have traditionally been performed by analysis of cell culture or tissue samples. More recently, functional and molecular imaging allows in vivo assay of biochemistry and molecular biology that is highly complementary to tissue-based assay. Molecular imaging can serve and number of roles, from characterization of pre-clinical models, to testing the ability of novel drugs to interact with their intended targets, to characterizing entire burden of disease for patients with breast cancer, to helping direct therapeutic choices and assign their efficacy.

This talk will review basic principals of molecular imaging, with an emphasis on those methods of greatest translational potential. The session will discuss the use of pre-clinical models of breast disease to help test and validate new molecular imaging methods, and in turn, the use of molecular imaging to characterize the disease process in the animal models. The session will then review the current state of molecular imaging in breast cancer patients, including methods in routine clinical use, those undergoing advanced clinical trials, and those in early-phase testing.

The session is designed for a broad audience, ranging from breast cancer translational scientists to practicing physicians caring for breast cancer patients.

References

1. Vernon AE, Bakewell SJ, Chodosh LA. Deciphering the molecular basis of breast cancer metastasis with mouse models. Rev Endocr Metab Disord. 2007 Sep;8(3):199–213. 2. Mankoff DA. Molecular imaging as a tool for translating breast cancer science. Breast Cancer Res. 2008;10 Suppl 1:S3. 3. Specht JM, Mankoff DA. Advances in molecular imaging for breast cancer detection and characterization. Breast Cancer Res. 2012 Mar 16;14(2):206.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BS3-2.
Abstract ES1-1: Molecular Profiling for In Situ Carcinoma of the Breast
Authors: Solin LJ
Published: August 2014

The management of in situ carcinoma of the breast represents a clinical dilemma. Such a non-invasive lesion places the patient at risk for subsequent development of an invasive lesion, and various treatments have been shown to reduce this risk. However, most patients are asymptomatic at initial presentation, and standard treatments are associated with the risk of side effects. It can be difficult for the individual patient to find the most appropriate balance between the risks and benefits of adding treatment. Although many patients elect for all treatments to minimize risk of progression regardless of potential side effects, other patients elect against treatment, often because of the potential risk of associated side effects.

Standard approaches to managing the patient with in situ disease have employed various clinical and pathologic characteristics to assess and stratify risk. Models for determining risk have used a number of clinical and pathologic characteristics, including patient age, lesion size, and grade. Ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have different risk profiles. For example, LCIS is well known to have subsequent risk that is more frequently bilateral than DCIS.

Prospective randomized clinical trials for DCIS have demonstrated a substantial reduction in the risk of recurrence associated with adding radiation treatment and tamoxifen after lumpectomy. Five randomized DCIS trials have shown that adding radiation treatment after lumpectomy lowers the risk of local recurrence and invasive local recurrence in the ipsilateral breast by approximately 50%. Two randomized DCIS trials have demonstrated that adding tamoxifen reduces the risk of all breast cancer events (combined ipsilateral plus contralateral) by approximately 30–40%. No survival benefit has been shown for adding either radiation or tamoxifen. For LCIS, hormonal treatment has been shown to reduce subsequent risk.

More recent efforts have focused on the value of molecular markers to individualize and tailor risk profiling for the individual patient. Using such molecular risk profiling, adding treatment can be selected for higher risk patients, and omitting treatment can be chosen for lower risk patients. To be clinically useful, molecular profiling should demonstrate value beyond that seen using standard clinical and pathologic factors. While current efforts have focused on using molecular profiling as a prognostic factor, future efforts will evaluate molecular profiling as a predictive factor.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES1-1.
Abstract ES3-1: Early Phase Trials – What Are They For?
Authors: Hilsenbeck SG
Published: August 2014

Early in drug development, there are lots of things we need to learn about new agents or new combinations of agents in order to make ‘good’ decisions about whether and how to proceed. The landscape of clinical trials is changing, with greater focus on targeted therapies and biomarker defined patient populations. Trial design, as we will hear in this session, must adapt to these new challenges. However, fundamentals still apply. We still need to demonstrate that drugs are safe and effective. As an introduction to the session, we will review the basic steps in drug development, especially early development, and the basic questions that must be answered at each step, in order to develop evidence for safety and efficacy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES3-1.
Abstract ES3-4: Clinical Trial Designs for New Therapies: When Should We Randomize?
Authors: Hunsberger S
Published: August 2014

There is a tension in clinical trial study design between the desire to keep the number of patients in a study small (so that as few patients as possible are exposed to potentially harmful agents, resources are minimized, and an answer is obtained as early as possible) and how much certainty is needed in the conclusion of the study. Different phases of drug development require different levels of certainty. Single arm studies require fewer patients than randomized studies but an observed improvement in the study defined endpoint in a single arm study may be observed for reasons unrelated to the experimental treatment. In randomized studies factors (known and unknown) that influence the endpoint of interest should be balanced between groups therefore any improvement in the endpoint of interest can be attributed to the experimental agent. In this talk I discuss circumstances that would be appropriate to perform single arms studies and circumstances that require randomized studies.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES3-4.
Abstract ES4-2: Cognitive Changes and Breast Cancer Treatments
Authors: Ganz PA
Published: August 2014

Cognitive difficulties after cancer treatment are among the most feared outcomes voiced by patients who are approaching the start of chemotherapy. This phenomenon, sometimes referred to as “chemo brain” or “chemo fog,” is quite common during the acute course of chemotherapy treatment. This may result from direct antieneoplastic drug toxicity, use of premedications and anxiolytics to prevent nausea and vomiting, as well as the expected anxiety, depression, and sleep deprivation that accompanies a new diagnosis of cancer and initiation of treatment. For most patients, this fog clears after the completion of acute treatments, and as with many physical symptoms, resolves in the following months. However, 15–25% of post-treatment patients, cognitive complaints persist long after treatment ends. Reports of difficulty concentrating, remembering recent events, multi-tasking, and paying attention are frequent in such patients. For those used to carrying on demanding executive function activities prior to cancer treatment, this can lead to substantial disruption in work and home life. Most of the studies conducted to date with early stage breast cancer have not accounted for the impact of adjuvant endocrine therapy alone or added to adjuvant chemotherapy. This presentation will review emerging data regarding self-reported cognitive complaints, neuropsychological testing, and brain imaging as they related to adjuvant therapies for breast cancer. In addition, some of the developing information about potential mechanisms associated with this late effect will be discussed.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES4-2.
Abstract ES9-1: Adjuvant Treatment of HER2 Positive Breast Cancer: The Next Installment
Authors: Pietenpol JA
Published: August 2014

The treatment of HER2 positive breast cancer radically changed in 2005; at ASCO that year adjuvant trials reported that the addition of trastuzumab consistently showed a major improvement in progression free survival in the treatment of early breast cancer that was HER2 positive. A benefit was seen when trastuzumab was given either concurrently with chemotherapy or sequentially. The trials generally studied one year of trastuzumab although data from Finland showed a benefit for 3 months of treatment. Additional, yet to be reported studies, have explored durations of 6 months and 2 years. Initially there was concern about cardio toxicity and the potential for significant long-term harm, but the rate of cardio toxicity remains low and usually is seen early in the treatment. To further improve outcomes, new agents have been studied in the neo and adjuvant settings. The large ALTTO study randomized patients to either chemotherapy with either a year of trastuzumab, a year of lapatinib (the TKI inhibitor with efficacy in the metastatic arena), the combination of both agents or sequential use of each agent. The lapatinib monotherapy arm was shown to be inferior in an interim analysis and discontinued. Final data is pending although extrapolating from the NEOALTTO study, one may expect heightened activity from dual blockade. The BETH study added bevacizumab to trastuzumab in a 2-arm study trying to combat angiogenesis with HER2 blockade; this study has not reported. Although the same combination studied in the AVEREL study in the advanced setting did not show a benefit, this may not be the case in earlier disease and we need to wait for data. Dual blockade with two antiHER2 agents has been beneficial in the advanced setting and this has led to the APHINITY study, which is comparing chemotherapy with standard trastuzumab or trastuzumab with another antiHER2 antibody, pertuzumab. This study is accruing well and will provide evidence for whether dual blockade with two antibodies is of benefit. It will also provide some clinical trial data for small tumors, as these are eligible for enrollment in this trial. Other new agents, including TDM 1, are being taken into the neoadjuvant setting and will be in adjuvant trials soon. Subcutaneous trastuzumab may provide easier treatment for women over their year of adjuvant therapy. A big question is whether all HER2 tumors are the same or whether we can begin tailoring treatment according to molecular features. Are there some cancers that will be cured with a short course of chemotherapy and trastuzumab while others may need multiple antiHER2 agents combined to acquire the same result? With the collection of tumor samples we can hopefully begin to further understand this. Tailored treatment has the potential to decrease toxicity and improve quality of life issues, provide more rational use of costly resources, and finally develop more intensive therapy for resistant tumors thus improving outcomes overall.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES9-1.
Abstract MS3-3: Navigating the Genome: Quandaries and Approaches to Dealing with Genomic Information
Authors: Evans JP
Published: August 2014

Recent technological advances have made large-scale DNA sequencing, including whole genome sequencing, a practical reality. The ability to sequence tumor genomes as well as the germ-line genome of individuals holds considerable promise for the practice of oncology. Broad assessment of cancer risk in individuals, identification of those at extreme risk for cancer who might benefit from specific interventions and pharmacogenomic guidance regarding therapy are possible benefits of assessing an individual's genome. Likewise, analysis of genomic information in tumors is poised to begin helping to guide highly specific treatment of cancer in an increasingly individualized manner.

However, as the field of oncology begins to use genomic queries to assess patient risk, characterize disease and guide treatment, many challenges must be addressed. Purely technical issues include the suboptimal accuracy of current platforms for massively parallel sequencing, tumor heterogeneity and difficulties interpreting genomic risk information in a clinically relevant manner. Systemic challenges include how to interpret, store and present massive amounts of genomic data in the currently highly fragmented (and limited) electronic medical record. Finally, in the process of genome-scale sequencing vast numbers of incidental results are inevitably generated, which may have important ramifications for patients and providers but may be unwelcome. Such ethical, legal and social implications of whole genome sequencing raise significant questions about patient autonomy, the physician's duty to warn and the laboratory's duty to report a wide variety of highly heterogeneous genomic findings. In this presentation some of these salient issues and possible solutions will be explored.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS3-3.