bluuebunny/crossref_metadata_2025 huggingface dataset:
The Results of Search for the Neutrino Magnetic Moment in GEMMA Experiment
Authors: Beda A. G. , Brudanin V. B. , Egorov V. G. , Medvedev D. V. , Pogosov V. S. , Shirchenko M. V. , Starostin A. S.
Published: June 2012

The result of the neutrino magnetic moment measurement at the Kalinin Nuclear Power Plant (KNPP) with GEMMA spectrometer is presented. The antineutrino-electron scattering is investigated. A high-purity germanium detector with a mass of 1.5 kg placed at a distance of 13.9 m from the 3 GWthreactor core is exposed to the antineutrino flux of2.7×10131/cm2/s. The recoil electron spectra taken in 18134 and 4487 hours for the reactor ON and OFF periods are compared. The upper limit for the neutrino magnetic momentμν<  2.9×10−11μBat 90% C.L. is derived from the data processing.
High Gain and High Directive of Antenna Arrays Utilizing Dielectric Layer on Bismuth Titanate Ceramics
Authors: Wee F. H. , Malek F. , Ghani Farid , Sreekantan S. , Al-Amani A. U.
Published: June 2012

A high gain and high directive microstrip patch array antenna formed from dielectric layer stacked on bismuth titanate (BiT) ceramics have been investigated, fabricated, and measured. The antennas are designed and constructed with a combination of two-, four-, and six-BiT elements in an array form application on microwave substrate. For gain and directivity enhancement, a layer of dielectric was stacked on the BiT antenna array. We measured the gain and directivity of BiT array antennas with and without the dielectric layer and found that the gain of BiT array antenna with the dielectric layer was enhanced by about 1.4 dBi of directivity and 1.3 dB of gain over the one without the dielectric layer at 2.3 GHz. The impedance bandwidth of the BiT array antenna both with and without the dielectric layer is about 500 MHz and 350 MHz, respectively, which is suitable for the application of the WiMAX 2.3 GHz system. The utilization of BiT ceramics that covers about 90% of antenna led to high radiation efficiency, and small-size antennas were produced. In order to validate the proposed design, theoretical and measured results are provided and discussed.
Needleless Melt‐Electrospinning of Polypropylene Nanofibres
Authors: Fang Jian , Zhang Li , Sutton David , Wang Xungai , Lin Tong
Published: June 2012

Polypropylene (PP) nanofibres have been electrospun from molten PP using a needleless melt‐electrospinning setup containing a rotary metal disc spinneret. The influence of the disc spinneret (e.g., disc material and diameter), operating parameters (e.g., applied voltage, spinning distance), and a cationic surfactant on the fibre formation and average fibre diameter were examined. It was shown that the metal material used for making the disc spinneret had a significant effect on the fibre formation. Although the applied voltage had little effect on the fibre diameter, the spinning distance affected the fibre diameter considerably, with shorter spinning distance resulting in finer fibres. When a small amount of cationic surfactant (dodecyl trimethyl ammonium bromide) was added to the PP melt for melt‐electrospinning, the fibre diameter was reduced considerably. The finest fibres produced from this system were 400 ± 290 nm. This novel melt‐electrospinning setup may provide a continuous and efficient method to produce PP nanofibres.
Deterministic Kalman Filtering on Semi-Infinite Interval
Authors: Faybusovich L. , Mouktonglang T.
Published: June 2012

We relate a deterministic Kalman filter on semi-infinite interval to linear-quadratic tracking control model with unfixed initial condition.
Regulator of G-Protein Signaling 5 Reduces HeyA8 Ovarian Cancer Cell Proliferation and Extends Survival in a Murine Tumor Model
Authors: Altman Molly K. , Nguyen Duy T. , Patel Santosh B. , Fambrough Jada M. , Beedle Aaron M. , Hardman William J. , Murph Mandi M.
Published: June 2012

The regulator of G-protein signaling 5 (RGS5) belongs to a family of GTPase activators that terminate signaling cascades initiated by extracellular mediators and G-protein-coupled receptors. RGS5 has an interesting dual biological role. One functional RGS5 role is as a pericyte biomarker influencing the switch to angiogenesis during malignant progression. Its other functional role is to promote apoptosis in hypoxic environments. We set out to clarify the extent to which RGS5 expression regulates tumor progression—whether it plays a pathogenic or protective role in ovarian tumor biology. We thus constructed an inducible gene expression system to achieve RGS5 expression in HeyA8-MDR ovarian cancer cells. Through this we observed that inducible RGS5 expression significantly reducesin vitroBrdU-positive HeyA8-MDR cells, although this did not correlate with a reduction in tumor volume observed using anin vivomouse model of ovarian cancer. Interestingly, mice bearing RGS5-expressing tumors demonstrated an increase in survival compared with controls, which might be attributed to the vast regions of necrosis observed by pathological examination. Additionally, mice bearing RGS5-expressing tumors were less likely to have ulcerated tumors. Taken together, this data supports the idea that temporal expression and stabilization of RGS5 could be a valuable tactic within the context of a multicomponent approach for modulating tumor progression.
Multiple Solutions for Degenerate Elliptic Systems Near Resonance at Higher Eigenvalues
Authors: An Yu-Cheng , Suo Hong-Min
Published: June 2012

We study the degenerate semilinear elliptic systems of the form −div(h1(x)∇u) = λ(a(x)u + b(x)v) + Fu(x, u, v), x ∈ Ω, −div(h2(x)∇v) = λ(d(x)v + b(x)u) + Fv(x, u, v), x ∈ Ω, u|∂Ω = v|∂Ω = 0, where Ω ⊂ RN(N ≥ 2) is an open bounded domain with smooth boundary ∂Ω, the measurable, nonnegative diffusion coefficients h1, h2 are allowed to vanish in Ω (as well as at the boundary ∂Ω) and/or to blow up in . Some multiplicity results of solutions are obtained for the degenerate elliptic systems which are near resonance at higher eigenvalues by the classical saddle point theorem and a local saddle point theorem in critical point theory.
Effect of the Random Error on the Radiation Characteristic of the Reflector Antenna Based on Two-Dimensional Fractal
Authors: Li Na , Duan Baoyan , Zheng Fei
Published: June 2012

Influence of the random error due to the distortion of the antenna reflector was discussed by using the two-dimensional fractal model. Firstly, a mathematical model of the random error was presented to investigate its impact on the radiation characteristic of the antenna, which was filtered from the two-dimensional fractal by using the wavelet analysis method. Based on the error model, a density formulation of the far field of the antenna with random error was deduced. Finally, a 3.7 m and a 3 m antennas were used to validate the proposed models, and a novel simulation method was put forward to remedy the deficiencies of existing software tools for the antenna with error. Results of the proposed methods showed a good agreement with the experimental data, and the existence of error broadened the beam width and raised the sidelobe level of the antenna, while it had little influence to the antenna gain. By comparison on results of the different scales error, the main influencing parameter of error was found out, which can provide the theoretical foundation for the control of the antenna surface working.
Subfusion Frames
Authors: Amiri Z. , Dehghan M. A. , Rahimi E.
Published: June 2012

Fusion frames are generalizations of frames in Hilbert spaces which were introduced by Casazza et al. (2008). In the present paper, we study the relations between fusion frames and subfusion frame operators. Specially, we introduce new construction of subfusion frames and derive new results.
Existence and Uniqueness of Solution for a Class of Nonlinear Fractional Order Differential Equations
Authors: Babakhani Azizollah , Baleanu Dumitru
Published: June 2012

We discuss the existence and uniqueness of solution to nonlinear fractional order ordinary differential equations (𝒟α − ρt𝒟β)x(t) = f(t, x(t), 𝒟γx(t)), t ∈ (0, 1) with boundary conditions x(0) = x0,   x(1) = x1 or satisfying the initial conditions x(0) = 0,   x′(0) = 1, where 𝒟α denotes Caputo fractional derivative, ρ is constant, 1 < α < 2, and 0 < β + γ ≤ α. Schauder′s fixed‐point theorem was used to establish the existence of the solution. Banach contraction principle was used to show the uniqueness of the solution under certain conditions on f.
Radial Basis Function Neural Network Application to Power System Restoration Studies
Authors: Sadeghkhani Iman , Ketabi Abbas , Feuillet Rene
Published: June 2012

One of the most important issues in power system restoration is overvoltages caused by transformer switching. These overvoltages might damage some equipment and delay power system restoration. This paper presents a radial basis function neural network (RBFNN) to study transformer switching overvoltages. To achieve good generalization capability for developed RBFNN, equivalent parameters of the network are added to RBFNN inputs. The developed RBFNN is trained with the worst-case scenario of switching angle and remanent flux and tested for typical cases. The simulated results for a partial of 39-bus New England test system show that the proposed technique can estimate the peak values and duration of switching overvoltages with good accuracy.
Efavirenz Conceptions and Regimen Management in a Prospective Cohort of Women on Antiretroviral Therapy
Authors: Schwartz Sheree , Taha Taha E. , Venter Willem Daniel Francois , Mehta Shruti , Rees Helen , Black Vivian
Published: June 2012

Use of the antiretroviral drug efavirenz (EFV) is not recommended by the WHO or South African HIV treatment guidelines during the first trimester of pregnancy due to potential fetal teratogenicity; there is little evidence of how clinicians manage EFV-related fertility concerns. Women on antiretroviral therapy (ART) were enrolled into a prospective cohort in four public clinics in Johannesburg, South Africa. Fertility intentions, ART regimens, and pregnancy testing were routinely assessed during visits. Women reporting that they were trying to conceive while on EFV were referred for regimen changes. Kaplan-Meier estimators were used to assess incidence across ART regimens. From the 822 women with followup visits between August 2009–March 2011, 170 pregnancies were detected during study followup, including 56 EFV conceptions. Pregnancy incidence rates were comparable across EFV, nevirapine, and lopinavir/ritonavir person-years (95% 100/users (P=0.25)); incidence rates on EFV were 18.6 Confidence Interval: 14.2–24.2). Treatment substitution from EFV was made for 57 women, due to pregnancy intentions or actual pregnancy; however, regimen changes were not systematically applied across women. High rates of pregnancy on EFV and inconsistencies in treatment management suggest that clearer guidelines are needed regarding how to manage fertility-related issues in. women on EFV-based regimens.
Detecting Optic Disc on Asians by Multiscale Gaussian Filtering
Authors: Zhang Bob , You Jane , Karray Fakhri
Published: June 2012

The optic disc (OD) is an important anatomical feature in retinal images, and its detection is vital for developing automated screening programs. Currently, there is no algorithm designed to automatically detect the OD in fundus images captured from Asians which are larger and have thicker vessels compared to Caucasians. In this paper, we propose such a method to complement current algorithms using two steps: OD vessel candidate detection and OD vessel candidate matching. The first step is achieved with multiscale Gaussian filtering, scale production, and double thresholding to initially extract the vessels' directional map of various thicknesses. The map is then thinned before another threshold is applied to remove pixels with low intensities. This result forms the OD vessel candidates. In the second step, a Vessels' Directional Matched Filter (VDMF) of various dimensions is applied to the candidates to be matched, and the pixel with the smallest difference designated the OD center. We tested the proposed method on a new database consisting of 402 images from a diabetic retinopathy (DR) screening programme consisting of Asians. The OD center was successfully detected with an accuracy of 99.25% (399/402).
Fabrication of Nonenzymatic Glucose Sensors Based on Multiwalled Carbon Nanotubes with Bimetallic Pt-M (M = Ru and Sn) Catalysts by Radiolytic Deposition
Authors: Kwon Sun-Young , Kwen Hai-Doo , Choi Seong-Ho
Published: June 2012

Nonenzymatic glucose sensors employing multiwalled carbon nanotubes (MWNTs) with highly dispersed Pt-M (M = Ru and Sn) nanoparticles (Pt-M@PVP-MWNTs) were fabricated by radiolytic deposition. The Pt-M nanoparticles on the MWNTs were characterized by transmittance electron microscopy, elemental analysis, and X-ray diffraction. They were found to be well dispersed and to exhibit alloy properties on the MWNT support. Electrochemical testing showed that these nonenzymatic sensors had larger currents (mA) than that of a bare glassy carbon (GC) electrode and one modified with MWNTs. The sensitivity (A mM−1), linear range (mM), and detection limit (mM) (S/N = 3) of the glucose sensor with the Pt-Ru catalyst in NaOH electrolyte were determined as 18.0, 1.0–2.5, 0.7, respectively. The corresponding data of the sensor with Pt-Sn catalyst were 889.0, 1.00–3.00, and 0.3, respectively. In addition, these non-enzymatic sensors can effectively avoid interference arising from the oxidation of the common interfering species ascorbic acid and uric acid in NaOH electrolyte. The experimental results show that such sensors can be applied in the detection of glucose in commercial red wine samples.
Dietary Phenolic Acids Act as Effective Antioxidants in Membrane Models and in Cultured Cells, Exhibiting Proapoptotic Effects in Leukaemia Cells
Authors: Zambonin Laura , Caliceti Cristiana , Vieceli Dalla Sega Francesco , Fiorentini Diana , Hrelia Silvana , Landi Laura , Prata Cecilia
Published: June 2012

Caffeic, syringic, and protocatechuic acids are phenolic acids derived directly from food intake or come from the gut metabolism of polyphenols. In this study, the antioxidant activity of these compounds was at first evaluated in membrane models, where caffeic acid behaved as a very effective chain-breaking antioxidant, whereas syringic and protocatechuic acids were only retardants of lipid peroxidation. However, all three compounds acted as good scavengers of reactive species in cultured cells subjected to exogenous oxidative stress produced by low level of H2O2. Many tumour cells are characterised by increased ROS levels compared with their noncancerous counterparts. Therefore, we investigated whether phenolic acids, at low concentrations, comparable to those present in human plasma, were able to decrease basal reactive species. Results show that phenolic acids reduced ROS in a leukaemia cell line (HEL), whereas no effect was observed in normal cells, such as HUVEC. The compounds exhibited no toxicity to normal cells while they decreased proliferation in leukaemia cells, inducing apoptosis. In the debate on optimal ROS-manipulating strategies in cancer therapy, our work in leukaemia cells supports the antioxidant ROS-depleting approach.
Impact of Enzymatic Degradation of the Endothelial Glycocalyx on Vascular Permeability in an Awake Hamster Model
Authors: Landsverk S. A. , Tsai A. G. , Cabrales P. , Intaglietta M.
Published: June 2012

Background. The inside of the endothelium is covered by a glycocalyx layer, and enzymatic degradation of this layer induces vascular leakageex vivo. We hypothesized that enzymatic degrading of the glycocalyx in anin vivo, whole body model, would induce plasma leakage and affect the microcirculation.Methods. Golden Syrian hamsters were divided into an enzyme (hyaluronidase) and a control group. Mean arterial pressure (MAP), heart rate (HR), hematocrit (Hct), base excess (BE), and plasma volume were obtained before, 45 and 120 min after enzyme/saline treatment. Plasma volume was evaluated by the distribution volume of indocyanine green and the microcirculation by functional capillary density (FCD). The enzymatic effect was determined by measuring plasma levels of hyaluronan (HA).Results. There were no differences in MAP, HR, Hct, and BE between the two groups. Enzyme treatment did not induce changes in plasma volume but reduced FCD. There was a 50–100-fold increase in plasma HA, but no relationship was found between HA levels and plasma volume or FCD.Conclusion. Vascular leakage was not confirmed in anin vivo, whole body model after degradation of the endothelial glycocalyx. The microcirculation was affected, but no relationship between plasma levels of HA and FCD was seen.
Hippocampal Neurogenesis, Cognitive Deficits and Affective Disorder in Huntington's Disease
Authors: Ransome Mark I. , Renoir Thibault , Hannan Anthony J.
Published: June 2012

Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases.
GABA through the Ages: Regulation of Cortical Function and Plasticity by Inhibitory Interneurons
Authors: Lehmann Konrad , Steinecke André , Bolz Jürgen
Published: June 2012

Inhibitory interneurons comprise only about 20% of cortical neurons and thus constitute a clear minority compared to the vast number of excitatory projection neurons. They are, however, an influential minority with important roles in cortical maturation, function, and plasticity. In this paper, we will highlight the functional importance of cortical inhibition throughout brain development, starting with the embryonal formation of the cortex, proceeding by the regulation of sensory cortical plasticity in adulthood, and finishing with the GABA involvement in sensory information processing in old age.
Assessment of the Variation Associated with Repeated Measurement of Gastrointestinal Transit Times and Assessment of the Effect of Oral Ranitidine on Gastrointestinal Transit Times Using a Wireless Motility Capsule System in Dogs
Authors: Lidbury Jonathan A. , Suchodolski Jan S. , Ivanek Renata , Steiner Jörg M.
Published: June 2012

This study aimed to evaluate the variation associated with repeated measurement of gastrointestinal (GI) transit times and the effect of oral ranitidine on GI transit times in healthy dogs using a wireless motility capsule (WMC) system. Eight privately owned healthy adult dogs were enrolled, and one developed diarrhea and was removed from the study. For the first 3 repetitions, each dog was fed a standard meal followed by oral administration of a WMC. For the 4th repetition, each dog was given ranitidine hydrochloride (75 mg PO every 12 hours) prior to and during assessment of GI transit times. Mean between-subject coefficients of variation for gastric emptying time (GET), small and large bowel transit time (SLBTT), and total transit time (TTT) were 26.9%, 32.3%, and 19.6%, respectively. Mean within-subject coefficients of variation for GET, SLBTT, and TTT were 9.3%, 19.6%, and 15.9%, respectively. Median GET, SLBTT, and TTT without ranitidine were 719, 1,636, and 2,735 minutes, respectively. Median GET, SLBTT, and TTT with ranitidine were 757, 1,227, and 2,083 minutes, respectively. No significant differences in GI transit times were found between any of the 4 repetitions. Under these experimental conditions, no significant effects of oral ranitidine on GI transit times were observed.
ES8-3: Measuring Outcomes in Breast Reconstruction: The Patient Perspective.
Authors: Pusic A
Published: June 2012

In breast reconstruction, understanding patients’ perceptions of surgical results is of primary importance. As new reconstructive techniques continue to advance, surgeons and patients require high quality information on key outcomes such as patient satisfaction and quality of life. The need for meaningful data is further accentuated by concerns over healthcare expenditures and the increasing involvement of patients in their own surgical decision-making.

Patient-reported outcome (PRO) measures are questionnaires specifically designed to quantify aspects of outcome such as patient satisfaction and health-related quality of life. When developed and validated according to internationally recognized standards, PRO measures can provide reliable and valid assessment of patient outcomes. Traditionally, PRO measures were used in clinical research alone; however, advances in psychometric methods have now facilitated the development of a new generation of PRO measures that are also useful in clinical care.

This presentation will provide an overview of PRO research in breast reconstruction. The BREAST-Q, a new PRO measure for breast surgery patients, will be highlighted. Physicians will gain the necessary critical appraisal skills to interpret and apply evidence from PRO studies in their own clinical practice. Approaches to routine use of PRO measures in clinical care will also be described.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr ES8-3.
OT1-01-02: A Multicentre Study Assessing 12-Weekly Intravenous Bisphosphonate Therapy in Women with Low Risk Bone Metastases from Breast Cancer – The TRIUMPH Trial.
Authors: Bouganim N , Hilton J , Vandermeer L , Hopkins S , Spencer P , Robbins D , Amir E , Dent S , Milano C , Ooi D , Dranitsaris G , Clemons M
Published: June 2012

Background: Metastatic bone disease is a major cause of morbidity and mortality for breast cancer patients. Bisphosphonates (BP) have been shown to significantly delay the onset and frequency of skeletal related events (SREs), improve pain control and overall quality of life. Most patients receive intravenous BP every 3–4 weeks regardless of their individual risk for a SRE. This “one size fits all” strategy could expose those patients at a relatively low risk of SREs to an increased chance of adverse drug effects, as well as to the financial and quality of life burden of multiple visits to the cancer centre for treatments. This study aimed to assess whether IV BP can be safely given at reduced frequency.

Methods: The primary objective of this study is to demonstrate in women with biochemically defined low-risk bone metastases that the administration of IV BP every 12 weeks is sufficient to maintain biochemical stability for one year. Eligibility criteria include; bone metastases from breast cancer, have received at least three months of regular 3–4 weekly IV BP, satisfactory renal function, adequate dental health, no systemic treatment change or recent SRE within 4 weeks of study entry. Low risk disease will be defined as serum CTx levels <600 ng/L Biochemical failure is defined as CTx levels >600 ng/L measured at predefined time points (6, 12, 24, 36 and 48th). Secondary objectives are to evaluate the palliative benefit of 12-weekly IV BP therapy as reflected by occurrence of SREs, analgesic use, self-reported pain using the validated BP and FACT-BP questionnaires. Sample size was calculated at 68 patients. Given the small sample size, nonparametric Bootstrapping will be employed to calculate point estimates, standard deviations and 95% confidence intervals (CIs). An exploratory multivariable analysis will also be undertaken to determine baseline factors that were associated with patient's maintaining their telopeptide levels in the low risk range. Conclusion: TRIUMPH opened in October 2010 and as of June 2011, has quickly accrued 54/68 patients (79%). This trial has the potential to allow lower risk women to receive less frequent dosing of bisphosphonates, thus improving their quality of life with less cancer center visits and reducing their chance of drug induced adverse events.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-01-02.
OT2-03-03: Spectroscopic Feature of Breast Cancer.
Authors: Ogura H , Yamashita D , Nasu H , Hosokawa Y , Koizumi K , Yamaki E , Yoshimoto K , Suzuki T , Ueda Y , Oda M , Yamashita Y , Sakahara H
Published: June 2012

Objectives: To examine optical properties of breast cancer by time-resolved spectroscopy.

Materials and Methods: We irradiated a pulsed laser of 760, 800, and 830 nm wave-length lights at multiple sites of both breasts including the site just above the cancer and detected the light transmitted through the breast with TRS-20SH (Hamamatsu Photonics K.K.). Absorption coefficient (μa), reduced scattering coefficient (μs'), total hemoglobin (tHb), and oxygen saturation (SO2) of the breast were calculated by photon diffusion equation. The clinical trial started in January 2007. A total of one hundred nine breast cancer patients participated in the trial and written informed consent were obtained from all of the patients. Results: In 800 nm wave-length, absorption coefficient (μa) of breast cancer tissue was significantly high, compared with contra-lateral normal breast (cancer:0.0677± 0.0293, normal breast;0.0479± 0.0161, p<0.001).

The result was the same in 760, and 830 nm. There was no difference in reduced scattering coefficient (μs') between breast cancer tissue and contra-lateral normal breast (800 nm cancer:9.070±1.217, normal breast;9.348±1.243, p=0.10). The tHb of breast cancer tissue was significantly high, compared with normal breast (cancer:31.0± 14.7, normal breast;21.0±8.2, p<0.001). There was no difference in oxygen saturation (SO2) between breast cancer tissue and contra-lateral normal breast (cancer:72.8±4.1, normal breast;73.8±4.5, p=0.08).

Conclusion: Absorption coefficient (μa) and tHb increased in breast cancer, whereas reduced scattering coefficient (μs') did not.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-03-03.
OT2-05-03: ACRIN 6688 Phase II Study of Fluorine-18 3′-Deoxy-3′ Fluorothymidine (FLT) in Invasive Breast Cancer.
Authors: Jolles PJ , Kostakoglu L , Bear HD , Idowu MO , Kurdziel K , Shankar L , Mankoff DA , Duan F , L'Heureux DZ
Published: June 2012

Background

Neoadjuvant chemotherapy (NAC) prior to surgery provides enhanced options for locoregional management and has become an integral component of primary breast cancer management. Initial tumor response in patients receiving NAC is generally determined at therapy completion. This evaluation is determined by either the presence/absence of palpable tumor as a clinical response and/or presence/absence of invasive tumor cells in the breast and nodes as a pathological response. The ability to evaluate the effectiveness of neoadjuvant therapy early during treatment would be of significant importance. FDG PET imaging has been shown to be predictive of subsequent tumor response, but the tendency of FDG to accumulate in inflammatory tissues can complicate image interpretation. MRI changes have also been touted as predictors of response. Preliminary data suggest that early FLT PET is better able to predict response to therapy, as FLT uptake has been shown to correlate with cellular proliferation, and does not significantly accumulate in inflammatory tissue (Kenny et al, Eur J Nucl Med Mol Imaging 2007:1339–1347). The analysis of these data may provide a better understanding of early treatment response and improve the clinical management of breast cancer in the future.

Trial design and eligibility: In this phase II multi-institutional study, breast cancer patients with locally advanced disease with a tumor size ≥2cm (measured on imaging or estimated by physical exam) are eligible. Participants will receive standard of care NAC at their respective institutions. Participants will have 3 FLT imaging sessions to evaluate therapy response: at baseline, early-treatment (5-10 days after initiating treatment), and post-treatment prior to surgery.

Specific aims: The primary objective is to correlate the percentage change in the standardized uptake value between baseline and early therapy FLT in the primary tumor with pathologic response. Correlatively, FLT PET parameters will be compared with proliferative indices from the initial biopsy and residual tumor surgical samples using Ki-67 staining, mitotic index, and residual cancer burden. Potential safety issues and the physiologic effects associated with FLT administration will also be evaluated.

Statistical methods: To evaluate the relationship between an uptake parameter and pathologic complete response, a ROC curve will be estimated and the area under the curve, along with its 95% confidence interval, will be determined.

Accrual: Currently, 45/67 patients have accrued to the study.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-03.
OT2-06-01: A Phase III Randomized Multicentric French Study To Evaluate the Impact of a Localized 16-Gy Boost after Conservative Surgery and a 50-Gy Whole-Breast Irradiation in Breast Ductal Carcinoma In Situ (The BONBIS Trial).
Authors: Azria D , Cowen D , De La Lande B , Bourgier C , Latorzeff I , Leblanc-Onfroy M , Douadi-Gaci Z , Pradier O , Peignaux K , Levy C , Ellis S , Lecouillard I , Racadot S , Bontemps P , Benyoucef A , Lagarde P , Laharie-Mineur H , Cretin J , Marchal C , Serin D , Lemanski C
Published: June 2012

Background

Ductal carcinoma in situ is defined as breast cancer confined to the ducts of the breast without evidence of penetration of the basement membrane. Local treatment quality represents one of the most prognostic factors as half of recurrences are invasive diseases. The main goal of adjuvant radiotherapy after conservative surgery is to decrease local recurrences and to permit breast conservation with low treatment-induced sequelae. Several randomized trials have established the impact of 50 Gy to the whole breast (WB) in terms of local control. Nevertheless, no randomized trial is still available concerning the role of the boost in this disease. The phase III randomized trial “BONBIS” is elaborated to evaluate the impact of a 16-Gy boost after 50 Gy delivered to the whole breast in 25 fractions and 33 days.

Methods: A total of 1950 patients DCIS breast cancer patients are planned to be enrolled in this trial. Patients will receive the following treatment: (A) WB radiotherapy of 50 Gy in 25 fractions vs. (B) WB radiotherapy of 50 Gy in 25 fractions plus a localized 16-Gy boost in 8 fractions. The primary endpoint is local-relapse free survival (LRFS). This trial is designed to detect an expected rate in control arm of 7% and 4 % in experimental arm. With 90% power and a=0.05, 137 events are necessary to achieve the main goal. An interim analysis is planned after 50% of observed event. Stratifications are made based on recognized prognostic factors: age, hormonal treatment, differentiation, circumstance of diagnosis, surgical margin, centre. Secondary endpoints are relapse free survival, overall survival, acute and late toxicities, cosmetic results, and quality of life. Translational researches are also planned to identify intrinsic radiosensitivity of normal tissues (radiation-induced apoptosis assay, genome-wide association study) but also predictive models of tumor recurrences. Inclusions have started in November 2008 and are not so far than the planned estimation.

This trial is granted by the French National Cancer Institute (PHRC 2008) and supported by the French National Society of Radiation Oncology (SFRO).

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-06-01.
OT3-01-01: Randomized Phase II Study of Fulvestrant Versus Fulvestrant Plus Bortezomib in Postmenopausal Women with Estrogen Receptor (ER) Positive, Aromatase-Inhibitor (AI) Resistant Metastatic Breast Cancer (MBC): New York Cancer Consortium Trial P8457.
Authors: Adelson KB , Raptis G , Sparano J , Germain D
Published: June 2012

Background: Bortezomib ia proteasome inhibitor that enhances fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking ER degradation in the nucleus in ER+ human breast cancer cell lines, thereby promoting cytoplasmic ER aggresomes which activate a sustained unfolded protein response leading to apoptotic cell death; the combination also induces tumor regression in a tamoxifen resistant T47D-cyclin D1 xenograft model more effectively than either agent alone (Clin Cancer Res 2011; 17: 2292–2300).

Hypothesis: We hpothesize that the combination of fulvestrant and bortezomib will be more effective than fulvestrant alone in ER+, AI-resistant MBC.

Trial design: This is an open-label randomized phase II design in which patients with MBC are randomized to receive fulvestrant alone (500 mg IM day −14, day +1, and day +14 during cycle 1, then 500 mg every 4 weeks on day +1 during cycle 2 and thereafter) or in combination with bortezomib (1.6 mg/m2 IV days +1, +8, +15 every cycle). Stratification factors for randomization include performance status (ECOG 0 vs. 1–2), measurable disease (yes vs. no), and prior chemotherapy for MBC (yes vs. no). Patients who progress on fulvestrant alone may cross over to the combination.

Eligibility criteria: Postmenopausal women with ER+, Her2-negative, MBC who have progressive disease during AI therapy for metastatic disease, or relapse while receiving adjuvant AI therapy. Up to one prior chemotherapy regimen for metastatic disease is permitted.

Specific aims: Primary Objective: To determine if the addition of bortezomib to fulvestrant significantly improves median progression-free survival (PFS), defined as the time from cycle 1, day 1 of therapy until disease progression or death from any cause.

Secondary Objectives: To determine: (1) adverse event rates in both arms, (2) the clinical benefit rate (CBR — objective response [by RECIST 1.1] and/or progression free at 24 weeks), (3) the objective response and CBR after crossover from fulvestrant to fulvestrant plus bortezomib.

Translational Objectives: To perform an exploratory analysis of the effects of the combination on intratumoral nuclear/cytoplasmic ER ratio, unfolded protein response (BiP), apoptotis (cleaved caspase 3, Bc1-2 phospho JNK.)

Statistical methods: he median PFS for patients receiving fulvestrant alone is expected to be approximately 5.4 months based upon patients with AI-resistant disease enrolled on the CONFIRM trial ( J Clin Oncol 2010; 28: 4594–4600). The trial is designed to detect a 70% improved in median PFS to 9.0 months (alpha=0.10, beta =0.10), which will require 59 eligible patients in each arm.

Present accrual and target accrual: 24/118

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-01.
P1-03-05: Fibrocystic Changes Have Different Age-Dependent Patterns in Benign, In Situ, and Invasive Breast Cancer Patients.
Authors: Bekhash A , Kovatich AJ , Chen Y , Hooke JA , Kvecher L , Mural RJ , Shriver CD , Hu H
Published: June 2012

Background: Fibrocystic changes (FCCs) have been known to develop in the aging process. Breast cancers in younger and elderly women are known to have different characteristics. Less is known about alterations in the microenvironment for disease development in middle-aged women who undergo menopausal changes. The Walter Reed Army Medical Center, through the Clinical Breast Care Project, has enrolled over 2000 subjects undergoing a biopsy; all the pathology was reviewed by a single pathologist. These subjects provide an opportunity to study the age-dependent pattern of FCC across benign, in situ (IS) and invasive breast carcinoma (IBC) patient populations.

Methods: Subjects were enrolled following IRB-approved protocols. A total of 2060 subjects were identified for this study, including 1226 benign/atypical, 193 IS, and 641 IBC patients. Patients were divided into three age groups: <=45 years, 46–65 years, and >=66 years. Chi-Square test in the SAS was used for statistical analysis across the age groups for the occurrence of FCCs. For IS and IBC patients, additional analysis was performed on high grade (grade 3) and non-high grade (grades 1 and 2 combined) cancers. For IS, grade analysis was performed on ductal carcinoma (DCIS).

Results: As shown in the Table, FCC occurrence rate is significantly lower in younger patients in the benign population. In the IBC population, this rate is significantly higher in middle-aged patients. This higher rate is significant in the non-high grade patients but disappears in the high grade patients. In the IS population, the same trend exists that the FCC rate is higher in middle-aged patients. This trend is retained in non-high grade DCIS but again lost in high grade DCIS.

Discussion: The observation that FCC increases with age in the benign population, but is bell-shaped in IBC and IS populations, supports a hypothesis that physiological changes in the middle-aged women may alter the microenvironment for disease development. The observation that the bell-shaped pattern is due to non-high grade DCIS but not due to high-grade DCIS suggests that changes in the microenvironment contribute to breast disease development.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-05.
P1-03-09: Significance of FAP, SMA and CD31 Expression in the Stroma of Breast Cancer.
Authors: Tchou J , Satija C , Zhang P , Bi Y , Davuluri R , Chen H , Majumdar R , Mies C , Herlyn M , Pure E
Published: June 2012

Breast cancer stroma heterogeneity has been demonstrated in various gene expression profile analyses. Whether there is any association between stroma heterogeneity and the molecular phenotype of breast cancer has yet to be established. Therefore, we performed immunohistochemical analyses (IHC) to evaluate the expression of the following stromal cell markers (fibroblast activation protein (FAP), smooth muscle actin (SMA), and CD31, an endothelial cell marker) in tumor tissues from a contemporary cohort of 52 patients comprising of all four molecular subtypes (luminal A (n=25); luminal B (n=2); Her2-neu (+) (n=5); and basal (n=20)). We hypothesize that stroma heterogeneity as reflected by the proportion of stromal cells staining (+) for FAP and SMA may correlate with their molecular epithelial phenotype. Furthermore, studying the distribution of these stromal cell markers in IHC sections may evaluate their spatial relationship with tumor cells, immune cells, and tumor microvasculature which may have strategic significance within the tumor/microenvironment.

As shown in Table 1, FAP is a more robust stromal cell marker staining 85±14% of stromal cells compared to SMA which stains only 28±29% of stromal cells (p<0.05). However, the distribution of FAP, SMA and microvessel density appears to be similar in all four subtypes. Multivariate analyses to correlate molecular subtype, tumor grade, tumor size, the no. of (+) nodes, and age with the% stromal cells staining (+) for FAP, SMA and CD31 yielded a significant correlation between the intensity of FAP(+) cells with tumor size, tumor grade, and the no. of positive nodes (p=0.00134, 0.0044, and 0.01141 respectively). We conclude that 1) stroma heterogeneity on IHC does not differ significantly across molecular subtypes; 2) FAP is a robust stromal cell marker; and 3) a higher FAP expression intensity on IHC may correlate with poor prognosis. Recent reports on the role of FAP in promoting tumor growth plus the abundance of FAP expression in breast cancer stroma underscore a significant role of FAP in breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-09.
P1-04-03: The Effect of Survivin Downregulation on Radiosensitization of Breast Cancer Cell Lines Grown under Adherent and Stem Cell Promoting Culture Conditions.
Authors: Debeb BG , Larson R , Xu W , Lacerda L , Reuben JM , Buchholz TA , Ueno NT , Woodward WA
Published: June 2012

Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is a bifunctional protein that has been implicated in both control of cell division and inhibition of apoptosis. Survivin has been shown to be involved in radiation resistance of various cancer types and its expression is increased by sublethal doses of irradiation in both differentiated and cancer stem cell (CSC) population. However, it is unknown whether suppression of survivin radiosensitizes the CSC population or diminishes its self renewal ability. Herein, we cloned the survivin dominant-negative mutant lacking a phosphorylation site (T34A) (Mesri et al., 2001 JCI) into the lentiviral LeGo vectors and assessed mammosphere formation and radiosensitization in MCF7, SUM149 and SUM159 cell lines grown under adherent or stem cell promoting conditions. We found an induction of survivin by western blotting in the dominant negative mutant (T34A)-transfected cell lines. Moreover, we observed a higher than two-fold increase in the Sub-G1 population as well as an increased Caspase 3 activity in the T34A-transfected SUM149 and SUM159 cells compared to control cells indicating an anti-apoptotic function of survivin. We also found that T34A-transfected cells showed a 1.5 to 2-fold decrease in the number of mammospheres compared to the control-transfected cells. Furthermore, T34A-transfected cells showed radiosensitization in adherent cells from SUM149 and SUM159 cells but no effect was observed in MCF7 cells. However, no radiosensitization was observed in stem cell promoting culture conditions with increasing doses of radiation in all tested cell lines. This indicates that the widely used standard clonogenic assays do not optimally select anti-CSC agents and that targeted therapies should be specifically tested for their activity against the CSC population. Further functional endpoint studies will be conducted to validate the in vitro findings.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-03.
P1-04-06: Ionizing Radiation Reprograms Non-Tumorigenic Cancer Cells into Cancer Stem Cells.
Authors: Chann L , Vlashi E , Lorenza DD , Dekmezian C , Pajonk F
Published: June 2012

Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells (BCSCs) able to re-grow a tumor while their progeny lack this feature. BCSCs in breast cancer have been found to be relatively resistant to radiation and several groups reported enrichment for BCSCs when breast cancers are subjected to classical anticancer treatment. Differentiation of BCSCs is thought to be unidirectional but an alternative model assumes that stemness can be obtained by clonal evolution.

In this study, we quantified the number of BCSCs surviving after radiation treatment. We compared the number of surviving BCSCs to the expected number and found an increase in BCSCs after irradiation that could not be explained by current models. We propose that radiation induces a BCSC phenotype in previously non-BCSCs and show that this transition is Notch-dependent and coincided with up-regulation of the transcription factors Oct4, Sox-2, Nanog, and Klf4.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-06.
P1-06-24: Nuclear Localization of Stat5a Predicts Response to Antiestrogen Therapy and Prognosis of Clinical Breast Cancer Outcome.
Authors: Peck AR , Witkiewicz AK , Liu C , Klimowicz AC , Stringer GA , Pequignot E , Freydin B , Yang N , Tran TH , Rosenberg AL , Hooke JA , Kovatich AJ , Shriver CD , Rimm DL , Magliocco AM , Hyslop T , Rui H
Published: June 2012

Nuclear-localized and tyrosine-phosphorylated Stat5 has been reported as a favorable prognostic marker and predictor of response to antiestrogen therapy in breast cancer. Phospho-Stat5 antibodies do not distinguish between phosphorylated Stat5a and the closely related Stat5b, but Stat5a is considered more critical for normal mammary development than Stat5b. The purpose of this study was to determine whether levels of nuclear-localized Stat5a protein (Nuc-Stat5a) were prognostic of clinical outcome or predictive of antiestrogen response. Stat5a was detected by traditional diaminobenzidine-chromogen immunohistochemistry (IHC) and pathologist scoring or by quantitative immunofluorescence in five archival cohorts of breast cancer. Levels of nuclear-localized Stat5a (Nuc-Stat5a) were evaluated by pathologist scoring of whole tissue sections detected by IHC or automated quantitative analysis (AQUA) of immunofluorescently-labeled tissue microarrays. Levels of Nuc-Stat5a were reduced in invasive breast cancer tissues and lymph node metastases compared to normal tissue and ductal carcinoma in situ when quantified by AQUA (Material I; n=180). Tissues from patients not treated with adjuvant therapy or treated with antiestrogen monotherapy were analyzed according to Nuc-Stat5a status for breast cancer-specific survival (CSS) and time to recurrence (TTR) using univariate and multivariate statistical models, adjusting for clinical features including tumor grade, size, lymph node and ER, PR and Her2 status. In two prognostic cohorts of node-negative breast cancer patients, low expression of Nuc-Stat5a, detected by standard IHC (Material II; n=223) or quantitative analysis (Material III; n=198), was prognostic of poor breast cancer outcome as measured by univariate and multivariate CSS (Material II/III) and TTR (Material II). CSS and TTR analysis of two independent materials of tumors from patients treated with antiestrogen monotherapy and analyzed by standard IHC (Material IV; n=73) or quantitative immunofluorescence (Material V; n=97) indicated that patients whose tumors expressed low levels of Nuc-Stat5a were at a greater than 4-fold risk of antiestrogen therapy failure when adjusted for hormone receptor status and clinical features (multivariate CSS: Material IV HR=4.3 (1.2,15.6), p=0.03; Material V HR=5.0 (1.87,13.06), p=0.001). In conclusion, loss of Nuc-Stat5a is a promising independent marker of poor breast cancer prognosis in node-negative, non-adjuvant treated breast cancer patients. Additionally, Nuc-Stat5a may be a useful clinical tool to predict tumor response to antiestrogen therapy.

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