bluuebunny/crossref_metadata_2025 huggingface dataset:
Photocatalysis of WO3 Nanoplates Synthesized by Conventional‐Hydrothermal and Microwave‐Hydrothermal Methods and of Commercial WO3 Nanorods
Authors: Sungpanich Jarupat , Thongtem Titipun , Thongtem Somchai
Published: August 2014

The degradation of methylene blue (MB) dye by tungsten oxide (WO3) photocatalyst synthesized by the 200°C conventional‐hydrothermal (C‐H) and 270 W microwave‐hydrothermal (M‐H) methods and commercial WO3 was studied under UV light irradiation for 360 min. The photocatalysts were characterized by X‐ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, Raman spectrophotometry, and UV visible spectroscopy to determine phase, morphology, vibration mode, and optical property. The BET analysis revealed the specific surface area of 29.74, 37.25, and 33.56 m2/g for the C‐H WO3 nanoplates, M‐H WO3 nanoplates, and commercial WO3 nanorods, respectively. In this research, the M‐H WO3 nanoplates have the highest photocatalytic efficiency of 90.07% within 360 min, comparing to the C‐H WO3 nanoplates and even commercial WO3 nanorods.
Littlewood-Paley Operators on Morrey Spaces with Variable Exponent
Authors: Tao Shuangping , Wang Lijuan
Published: August 2014

By applying the vector-valued inequalities for the Littlewood-Paley operators and their commutators on Lebesgue spaces with variable exponent, the boundedness of the Littlewood-Paley operators, including the Lusin area integrals, the Littlewood-Paleyg-functions andgμ*-functions, and their commutators generated by BMO functions, is obtained on the Morrey spaces with variable exponent.
New Insights in the Mobilization of Hematopoietic Stem Cells in Lymphoma and Multiple Myeloma Patients
Authors: Angelopoulou Maria K. , Tsirkinidis Pantelis , Boutsikas Georgios , Vassilakopoulos Theodoros P. , Tsirigotis Panayiotis
Published: August 2014

Following chemotherapy and/or the administration of growth factors, such as granulocyte-colony stimulated factor (G-CSF), hematopoietic stem cells (HSC) mobilize from bone marrow to peripheral blood. This review aims to systematically present the structure of the HSC “niche” and elucidate the mechanisms of their mobilization. However, this field is constantly evolving and new pathways and molecules have been shown to contribute to the mobilization process. Understanding the importance and the possible primary pathophysiologic role of each pathway is rather difficult, since they share various overlapping components. The primary initiating event for the mobilization of HSC is chemotherapy-induced endogenous G-CSF production or exogenous G-CSF administration. G-CSF induces proliferation and expansion of the myelomonocytic series, which leads to proteolytic enzyme activation. These enzymes result in disruption of various receptor-ligand bonds, which leads to the disanchorage of HSC from the bone marrow stroma. In everyday clinical practice, CXC chemokine receptor-4 (CXCR4) antagonists are now being used as mobilization agents in order to improve HSC collection. Furthermore, based on the proposed mechanisms of HSC mobilization, novel mobilizing agents have been developed and are currently evaluated in preclinical and clinical studies.
Design of a New 4-DOF Haptic Master Featuring Magnetorheological Fluid
Authors: Song Byung-Keun , Oh Jong-Seok , Choi Seung-Bok
Published: August 2014

This work presents a novel 4-degree-of-freedom (4-DOF) haptic master using magnetorheological (MR) fluid which is applicable to a robot-assisted minimally invasive surgery (RMIS) system. By using MR fluid, the proposed haptic device can easily generate bidirectional repulsive torque along the directions of the required motions. The proposed master consists of two actuators: an MR bidirectional clutch associated with a planetary gear system and an MR clutch with a bevel gear system. After demonstrating the configuration, the torque models of MR actuators are mathematically derived based on the field-dependent Bingham model. An optimal design that accounts for spatial-limitation and the desired torque constraint is then undertaken. An optimization procedure based on finite element analysis is proposed to determine optimal geometric dimensions. Based on the design procedure, MR haptic master with the optimal parameters has been manufactured. In order to demonstrate the practical feasibility of the proposed haptic master, the field-dependent generating repulsive force is measured. In addition, a proportional-integral-derivative (PID) controller is empirically implemented to accomplish the desired torque trajectories. It has been shown that the proposed haptic master can track the desired torque trajectory without a significant error.
Identification of Multiple Soluble Fe(III) Reductases in Gram-Positive Thermophilic BacteriumThermoanaerobacter indiensisBSB-33
Authors: Pal Subrata
Published: August 2014

Thermoanaerobacter indiensisBSB-33 has been earlier shown to reduce Fe(III) and Cr(VI) anaerobically at 60°C optimally. Further, the Gram-positive thermophilic bacterium contains Cr(VI) reduction activity in both the membrane and cytoplasm. The soluble fraction prepared fromT. indiensiscells grown at 60°C was found to contain the majority of Fe(III) reduction activity of the microorganism and produced four distinct bands in nondenaturing Fe(III) reductase activity gel. Proteins from each of these bands were partially purified by chromatography and identified by mass spectrometry (MS) with the help ofT. indiensisproteome sequences. Two paralogous dihydrolipoamide dehydrogenases (LPDs), thioredoxin reductase (Trx), NADP(H)-nitrite reductase (Ntr), and thioredoxin disulfide reductase (Tdr) were determined to be responsible for Fe(III) reductase activity. Amino acid sequence and three-dimensional (3D) structural similarity analyses of theT. indiensisFe(III) reductases were carried out with Cr(VI) reducing proteins from other bacteria. The two LPDs and Tdr showed very significant sequence and structural identity, respectively, with Cr(VI) reducing dihydrolipoamide dehydrogenase fromThermus scotoductusand thioredoxin disulfide reductase fromDesulfovibrio desulfuricans. It appears that in addition to their iron reducing activityT. indiensisLPDs and Tdr are possibly involved in Cr(VI) reduction as well.
The Effect of Serine Protease Inhibitors on Airway Inflammation in a Chronic Allergen-Induced Asthma Mouse Model
Authors: Lin Chih-Che , Lin Li-Jen , Wang Shulhn-Der , Chiang Chung-Jen , Chao Yun-Peng , Lin Joseph , Kao Shung-Te
Published: August 2014

Serine protease inhibitors reportedly attenuated airway inflammation and had antioxidant in multiorgan. However, the effects of the serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on a long-term challenged mouse model of chronic asthma are unclear. BALB/c mice (6 mice/group) were intratracheally inoculated with five doses ofDermatophagoides pteronyssinus(Der p; 50 μL, 1 mg/mL) at one-week intervals. Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), or UTI (10,000 U/kg) were, respectively, injected intraperitoneally into these mice. Control mice received sterile PBS. At 3 days after the last challenge, mice were sacrificed to assess airway hyperresponsiveness (AHR), remodeling, and inflammation; lung histological features; and cytokine expression profiles. Compared with untreated controls, mice treated with FUT, FOY, and UTI had decreased AHR and goblet cell hyperplasia, decreased eosinophil and neutrophil infiltration, decreased Der p-induced IL-4 levels in serum and IL-5, IL-6, IL-13, and IL-17 levels in bronchoalveolar lavage fluid, and inhibited nuclear factor (NF)-κB activity in lung tissues. The serine protease inhibitors FUT, FOY, and UTI have potential therapeutic benefits for treating asthma by downregulating Th2 cytokines and Th17 cell function and inhibiting NF-κB activation in lung tissue.
Anthropometry and Dietary Intake before and during a Competition in Mountain Runners
Authors: Carlsohn Anja , Müller Wolfram
Published: August 2014

Mountain running is a non-Olympic sport consisting of uphill or up- and downhill races at moderate-to-high altitude. Special nutritional requirements are anticipated, but no nutritional data of mountain runners are available. In three studies, physique of elite and recreational athletes (N=62), maximum oxygen uptake (N=3), and prerace and race day dietary intake (N=6) were measured (mean ± SD). Mean oxygen uptake was68.7±5.2 mL/kg/min. Energy and carbohydrate intake before a race (29±15 km,1596±556 m HD) was3199±701 kcal/d (13.4±2.9 MJ/d) and497±128 g/d (8.3±1.8 g/kg/d) in German national team members. Fluid intake was calculated as2783±1543 mL/d. During the race, athletes consumed336±364 kcal and927±705 mL of fluids. Substrate intake per hour was calculated as23±22 g of carbohydrates and4.0±3.2 g of proteins. In conclusion, anthropometric and oxygen uptake characteristics of mountain runners were similar to those reported for elite distance runners. Carbohydrate intake before and during the race was below recommendations for endurance athletes. This is of concern when considering the increased reliance on carbohydrates at altitude.
Inverse‐Problem‐Based Accuracy Control for Arbitrary‐Resolution Fairing of Quasiuniform Cubic B‐Spline Curves
Authors: Ji Xiaogang , Xue Jie , Yang Yan , He Xueming
Published: August 2014

In the process of curves and surfaces fairing with multiresolution analysis, fairing accuracy will be determined by final fairing scale. On the basis of Dyadic wavelet fairing algorithm (DWFA), arbitrary resolution wavelet fairing algorithm (ARWFA), and corresponding software, accuracy control of multiresolution fairing was studied for the uncertainty of fairing scale. Firstly, using the idea of inverse problem for reference, linear hypothesis was adopted to predict the corresponding wavelet scale for any given fairing error. Although linear hypothesis has error, it can be eliminated by multiple iterations. So faired curves can be determined by a minimum number of control vertexes and have the best faring effect under the requirement of accuracy. Secondly, in consideration of efficiency loss caused by iterative algorithm, inverse calculation of fairing scale was presented based on the least squares fitting. With the increase of order of curves, inverse calculation accuracy becomes higher and higher. Verification results show that inverse calculation scale can meet the accuracy requirement when fitting curve is sextic. In the whole fairing process, because there is no approximation algorithm such as interpolation and approximation, faired curves can be reconstructed again exactly. This algorithm meets the idea and essence of wavelet analysis well.
Development of a Hybrid Magnetic Resonance and Ultrasound Imaging System
Authors: Sherwood Victoria , Civale John , Rivens Ian , Collins David J. , Leach Martin O. , ter Haar Gail R.
Published: August 2014

A system which allows magnetic resonance (MR) and ultrasound (US) image data to be acquired simultaneously has been developed. B-mode and Doppler US were performed inside the bore of a clinical 1.5 T MRI scanner using a clinical 1–4 MHz US transducer with an 8-metre cable. Susceptibility artefacts and RF noise were introduced into MR images by the US imaging system. RF noise was minimised by using aluminium foil to shield the transducer. A study of MR and B-mode US image signal-to-noise ratio (SNR) as a function of transducer-phantom separation was performed using a gel phantom. This revealed that a 4 cm separation between the phantom surface and the transducer was sufficient to minimise the effect of the susceptibility artefact in MR images. MR-US imaging was demonstratedin vivowith the aid of a 2 mm VeroWhite 3D-printed spherical target placed over the thigh muscle of a rat. The target allowed single-point registration of MR and US images in the axial plane to be performed. The system was subsequently demonstrated as a tool for the targeting and visualisation of high intensity focused ultrasound exposure in the rat thigh muscle.
A Hybrid Mean Value Involving Dedekind Sums and the General Exponential Sums
Authors: Li Jianghua , Wang Tingting
Published: August 2014

The main purpose of this paper is using the analytic method, A. Weil’s classical work for the upper bound estimate of the general exponential sums, and the properties of Gauss sums to study the hybrid mean value problem involving Dedekind sums and the general exponential sums and give a sharp asymptotic formula for it.
Local Fractional Laplace Variational Iteration Method for Nonhomogeneous Heat Equations Arising in Fractal Heat Flow
Authors: Xu Shu , Ling Xiang , Cattani Carlo , Xie Gong-Nan , Yang Xiao-Jun , Zhao Yang
Published: August 2014

The local fractional Laplace variational iteration method is used for solving the nonhomogeneous heat equations arising in the fractal heat flow. The approximate solutions are nondifferentiable functions and their plots are also given to show the accuracy and efficiency to implement the previous method.
Concomitant Transarterial and Transvenous Embolization of a Pelvic Arteriovenous Malformation Using a New Liquid Embolic Agent, Squid-12 and Detachable Coils
Authors: Erbahceci Salik Aysun , Islim Filiz , Akgul Ahmet , Cil Barbaros Erhan
Published: August 2014

We describe a complex congenital pelvic AVM with multiple feeding arteries arising from the side branches of the right internal iliac artery and a single draining vein in a male patient. Concomitant transarterial and transvenous embolization with a new liquid embolic agent Squid-12 and metallic coils enabled a complete embolization at a single session. Squid-12 is composed of ethylene vinyl alcohol copolymers and its lower viscosity makes it a promising agent for the treatment of AVMs. The patient showed prompt resolution of the symptoms and complete devascularization of the AVM lesion was persisted on the 1-month control angiography. The patient was asymptomatic on the 6th month follow-up.
Fading Evaluation in the 60 GHz Band in Line-of-Sight Conditions
Authors: Reig J. , Martínez-Inglés M.-T. , Rubio L. , Rodrigo-Peñarrocha V.-M. , Molina-García-Pardo J.-M.
Published: August 2014

An exhaustive analysis of the small-scale fading amplitude in the 60 GHz band is addressed for line-of-sight conditions (LOS). From a measurement campaign carried out in a laboratory, we have estimated the distribution of the small-scale fading amplitude over a bandwidth of 9 GHz. From the measured data, we have estimated the parameters of the Rayleigh, Rice, Nakagami-m, Weibull, andα-μdistributions for the small-scale amplitudes. The test of Kolmogorov-Smirnov (K-S) for each frequency bin is used to evaluate the performance of such statistical distributions. Moreover, the distributions of the main estimated parameters for such distributions are calculated and approximated for lognormal statistics in some cases. The matching of the above distributions to the experimental distribution has also been analyzed for the lower tail of the cumulative distribution function (CDF). These parameters offer information about the narrowband channel behavior that is useful for a better knowledge of the propagation characteristics at 60 GHz.
AEG-1 Regulates Retinoid X Receptor and Inhibits Retinoid Signaling
Authors: Srivastava Jyoti , Robertson Chadia L. , Rajasekaran Devaraja , Gredler Rachel , Siddiq Ayesha , Emdad Luni , Mukhopadhyay Nitai D. , Ghosh Shobha , Hylemon Phillip B. , Gil Gregorio , Shah Khalid , Bhere Deepak , Subler Mark A. , Windle Jolene J. , Fisher Paul B. , Sarkar Devanand
Published: August 2014

Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)–mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics. Cancer Res; 74(16); 4364–77. ©2014 AACR.
Sentinel Lymph Node Biopsy Revisited: Ultrasound-Guided Photoacoustic Detection of Micrometastases Using Molecularly Targeted Plasmonic Nanosensors
Authors: Luke Geoffrey P. , Myers Jeffrey N. , Emelianov Stanislav Y. , Sokolov Konstantin V.
Published: August 2014

Metastases rather than primary tumors are responsible for killing most patients with cancer. Cancer cells often invade regional lymph nodes (LN) before colonizing other parts of the body. However, due to the low sensitivity and specificity of current imaging methods to detect localized nodal spread, an invasive surgical procedure—sentinel LN biopsy—is generally used to identify metastatic cancer cells. Here, we introduce a new approach for more sensitive in vivo detection of LN micrometastases, based on the use of ultrasound-guided spectroscopic photoacoustic (sPA) imaging of molecularly activated plasmonic nanosensors (MAPS). Using a metastatic murine model of oral squamous cell carcinoma, we showed that MAPS targeted to the epidermal growth factor receptor shifted their optical absorption spectrum to the red-near-infrared region after specific interactions with nodal metastatic cells, enabling their noninvasive detection by sPA. Notably, LN metastases as small as 50 μm were detected at centimeter-depth range with high sensitivity and specificity. Large sPA signals appeared in metastatic LN within 30 minutes of MAPS injection, in support of the clinical utility of this method. Our findings offer a rapid and effective tool to noninvasively identify micrometastases as an alternate to sentinal node biopsy analysis. Cancer Res; 74(19); 5397–408. ©2014 AACR.
Abstract P1-03-02: “Normal” tissue adjacent to breast cancer is not normal
Authors: Clare SE , Pardo I , Mathieson T , Lillemoe HA , Blosser RJ , Choi M , Sauder CAM , Doxey DK , Badve S , Storniolo AMV , Atale R , Radovich M
Published: August 2014

Background: Gene expression data from pancreatic cancer, histologically normal tissue adjacent to the cancer and normal pancreas reveals that adjacent normal has already acquired a number of transcriptional alterations and is not, therefore, an appropriate baseline for comparison with cancers. (Gadaleta et al., 2011) The purpose of this study was to determine if this is also the case for breast cancer and, if so, to identify the differences in gene expression between adjacent normal and normal breast.

Methods: RNA-Seq data from breast cancer and adjacent normal was downloaded from the TCGA (The Cancer Genome Atlas) data portal. The epithelia from 20 frozen tissue cores from healthy premenopausal donors to the Susan G. Komen for the the Cure® Tissue Bank at the IU Simon Cancer Center were microdissected and the RNA isolated. RNA-seqeuncing was carried out using the Life Technologies SOLiD Platform. RPKM gene expression values from TCGA and sequencing of the Komen normal tissues were merged, quantile normalized, and batch effect corrected. Normalization and differential gene expression was performed using Partek Genomics Suite.

Results: Principal component analysis (PCA) reveals complete separation between adjacent normal and healthy normal breast tissue. Setting a maximum FDR (false discover rate) of 5%, 2239 genes are differentially expressed between adjacent normal and healthy normal. Ingenuity pathway analysis reveals that the Fos, Jun and TGFbeta pathways are active in the adjacent normal.

Conclusions: Tissue adjacent to a primary breast cancer is not normal when using healthy breast tissue as a comparator. As RNA-Seq data is digital, it is possible to quantify the changes in gene expression starting from healthy normal to normal adjacent to tumor to tumor. Increasing and decreasing gene expression values provide clues to the fundamental molecular changes occurring in histologically normal appearing adjacent tissue. The differences in gene expression we have identified are some of the earliest changes in breast carcinogenesis and provide insight into the etiology of this disease and, potentially, its prevention.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-03-02.
Abstract P1-05-24: Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis.
Authors: Borges S , Doppler H , Andorfer CA , Perez EA , Sun Z , Anastasiadis PZ , Thompson AE , Geiger XJ , Storz P
Published: August 2014

Epigenetic silencing of tumor suppressing genes by promoter-specific DNA methylation is common in many types of cancer. As an early event, this process has been well shown to promote tumor initiation and progression; however little is known how such epigenetic silencing can contribute to tumor metastasis. The PRKD1 gene encodes Protein Kinase D1 (PKD1), a serine/threonine kinase expressed in epithelial cells of the normal mammary gland that maintains the epithelial phenotype of normal breast cells and prevents epithelial-to-mesenchymal transition (EMT). PKD1 is also a critical suppressor of tumor cell invasion and is silenced in expression and activity during breast tumor progression. Here, we show that aberrant methylation of PRKD1 promoter region is not only correlated with the silencing of its expression but is also associated with invasiveness of breast cancer cell lines and with aggressiveness of breast tumors. Using the highly invasive MDA-MB-231 cells, we show that the inhibition of PRKD1 promoter methylation with the DNA methyltransferase inhibitor decitabine restores PKD1 expression and significantly decreases their invasive abilities in vitro. More importantly, in a tumor xenograft model it dramatically blocks tumor spread and metastasis to the lung in a PKD1-dependent fashion. Our data suggest that the status of epigenetic regulation of the PRKD1 promoter can provide valid information on the invasiveness of breast tumors, and therefore could serve as an early diagnostic marker. Moreover, targeted upregulation of PKD1 expression may be used as a therapeutic approach to reverse the invasive phenotype of breast cancer cells.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-24.
Abstract P4-14-07: Impact of preservation of the intercostobrachial nerve during axillary dissection on sensory change and health-related quality of life two years after breast cancer surgery
Authors: Taira N , Shimozuma K , Ohsumi S , Kuroi K , Shiroiwa T , Watanabe T , Saito M
Published: August 2014

Background: Sensory loss or paresthesia due to division of the intercostobrachial nerve (ICBN) is a complication of axillary lymph node dissection (ALND). Preservation of the ICBN may be of value, but few prospective studies have shown an impact of preservation on sensory changes or health related quality of life (HRQOL) after breast cancer surgery.

Methods: Prospective study was performed to evaluate the association of ICBN preservation with sensory change and HRQOL at 1 (baseline), 6, 12 and 24 months after breast cancer surgery in 140 patients. The sensory examination included dysesthesia, paresthesia, abnormal touch and pain sensation in the upper arm.

Results: Division of the ICBN did not influence the frequency or severity of subjective dysesthesia and paresthesia. There was no marked difference in touch or pain sensation at baseline between patients with a preserved (group P) and divided (group D) ICBN. In group P, the percentage of patients aware of a sensory deficit or loss decreased with time, and that of patients aware of a hypersensitive sensation increased. These changes did not occur in group D, leading to a significant difference between the groups at 24 months. The main difference between the groups was the area with reduced touch or pain sensation. This area decreased with time in group P, but not in group D. ICBN preservation or division did not influence HRQOL.

Conclusion: ICBN preservation in ALND has a benefit of a reduced area with long-term axillary hypoesthesia, but has no influence on improvement of pain and HRQOL.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-14-07.
Abstract P5-18-09: A Phase I Study of MM-302, a HER2-targeted Liposomal Doxorubicin, in Patients with Advanced, HER2- Positive Breast Cancer
Authors: Wickham T , Futch K
Published: August 2014

Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clear-cut efficacy advantages. To address these safety and efficacy limitations, we have designed a pegylated liposomal doxorubicin formulation, MM-302, with anti-HER2 antibody fragments coupled to its surface. MM-302 specifically targets tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. This first-in-human Phase 1 study evaluates the safety of MM-302 in patients with HER2+ advanced breast cancer (ABC).

Methods: Patients aged > 18 years with histologically confirmed HER2+ advanced breast cancer that have progressed or recurred on standard therapy or for which no standard therapy exists who have adequate performance status, bone marrow reserve, and organ function, were eligible for the study. A standard 3 + 3 dose escalation design is used to determine the maximum tolerated dose (MTD) followed by expansion arms to evaluate activity. The primary endpoint is determination of the MTD. Secondary endpoints included determination of dose-limiting toxicity, adverse event(s), and pharmacokinetic and immunogenicity profiles of MM-302, as well as overall response and clinical benefit rates of MM-302. MM-302 is administered intravenously weekly in 4-week cycles.

Results: We report current findings containing data from four cohorts (8, 16, 30 and 40 mg/m2 Q4W). 14 patients have been enrolled in these cohorts; median age 55 (range 34–65), median cycles 2 (range 1–6). The most frequent AEs were constipation (53.8%), Fatigue (69.2%) and decreased appetite (46.2%). Five patients have achieved SD and one patient has achieved a PR. A pharmacokinetic analysis indicates a half-life of approximately 50 hours.

Conclusions: To date, results suggest that single agent MM-302 administered to patients with ABC is tolerable, without cardiotoxicity, in patients up to 40 mg/m2 Q4W. Updated data on additional dosing cohorts and expansion arms will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-09.
Abstract P5-20-04: Eribulin mesylate + trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer: results from a phase 2, multicenter, single-arm study
Authors: Vahdat L , Schwartzberg L , Wilks S , Rege J , Liao J , Cox D , O'Shaughnessy J
Published: August 2014

Background: Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, has been approved for patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for MBC. This study evaluates efficacy and safety of eribulin + trastuzumab (TRAZ) as first-line therapy for human epidermal growth factor receptor 2 positive (HER2+) locally recurrent or MBC.

Methods: Patients received eribulin mesylate at 1.4 mg/m2 IV on days 1, 8 and TRAZ initial dose of 8 mg/kg IV on day 1 every 21 days, followed by 6 mg/kg on day 1 of each subsequent cycle. For study inclusion, patients could have been previously treated with TRAZ, but at least 12 months should have passed since any prior neoadjuvant or adjuvant chemotherapy was used. Endpoints include objective response rate (ORR) (primary), safety, progression free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments are evaluated every 6 weeks for the first 6 cycles and every 6–12 weeks thereafter per RECIST 1.1.

Results: Updated results presented here as of June 1, 2012; 37 of 52 planned patients have been treated. Patient characteristics are as follows: median age: 58 years (range, 31–81), 70% have luminal subtype, 95% are stage IV disease, and 73% have visceral disease, 46% had prior neo/adjuvant, 22% had prior anthracycline and 32% had prior taxane, 35% had original diagnosis of MBC. Patients received median of 7 (1,20) cycles for eribulin and 9 (1,23) cycles for TRAZ. The most common treatment related AEs are reported in Table 1.

Treatment-related serious AEs were reported for 4 (11%) patients; neutropenia 3 (8%) and febrile neutropenia 2 (6%) patients each. Eight patients have discontinued treatment due to disease progression (PD). Best patient responses are found in Table 2.

Conclusions: Based on the updated preliminary results of this Phase II study, the combination of eribulin + trastuzumab as first-line therapy for HER2+ locally recurrent or MBC appears to demonstrate an acceptable safety profile with considerable tumor responses, including in patients with ER/PR+ disease. Accrual is ongoing and study completion is anticipated prior to SABCS 2012.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-04.
Abstract P6-10-01: A randomized phase 2 study of the antibody-drug conjugate CDX-011 in advanced GPNMB-overexpressing breast cancer: The EMERGE study
Authors: Yardley DA , Weaver R , Melisko ME , Saleh MN , Arena FP , Forero A , Cigler T , Stopeck A , Citron D , Oliff I , Bechhold R , Loutfi R , Garcia A , Crowley E , Green J , Yellin MJ , Davis TA , Vahdat LT
Published: August 2014

Background: GPNMB is an internalizable transmembrane glycoprotein overexpressed in multiple tumor types, including breast cancer (BC). GPNMB promotes BC metastases in a murine model and is a poor prognostic marker in patients (pts) (Rose 2010). CDX-011 (glembatumumab vedotin) is a fully human GPNMB-specific monoclonal antibody conjugated to the potent cellular toxin MMAE via a protease-sensitive peptide linker, designed to cleave upon cellular internalization. In Phase I/II studies of CDX-011 in BC (n = 42), an objective response rate (ORR) (including confirmed and unconfirmed response) of 12% overall and 20% for “triple-negative” (ER/PR/HER2−; TN) pts was observed (Saleh, ASCO 2010).

Methods: The Phase II EMERGE study examined the efficacy of CDX-011 by level of GPNMB expression. Refractory BC (2–7 prior cytotoxic regimens in metastatic setting), GPNMB expression in ≥ 5% of tumor or stroma cells (as centrally determined on archival tumor), and no persistent treatment-related toxicity (including neuropathy) of ≥ Grade 2 severity were required for enrollment. Pts were stratified by GPNMB expression pattern (any tumor, low stromal or high stromal) and randomized 2:1 to CDX-011 (1.88 mg/kg IV q 21 days) or “investigator's choice” (IC) single-agent chemotherapy, and treated until progression (PD) or intolerance with IC pt crossover permitted to CDX-011 at PD. Endpoints: ORR (primary), progression-free survival (PFS), safety, pharmacokinetics, pharmacodynamics.

Results: 99% of screened tumor samples expressed GPNMB. 122 treated pts (81 CDX-011 vs. 41 IC) had median age = 56 vs. 56 years; median # prior anticancer regimens = 6 vs. 5; visceral disease (liver/lung) = 83% vs. 80%; TN = 33% vs 27%, respectively. To date, 15 IC pts have crossed over to CDX-011, and 14 pts (8 CDX-011, 6 IC) continue on treatment. CDX-011 was well tolerated with less hematologic toxicity than IC; CDX-011-related toxicity included rash (overall = 38%; Grade 1 = 20%; Grade 2 = 15%; Grade 3 = 3%) and neuropathy (overall = 18%; Grade 1 = 8%; Grade 2 = 7%; Grade 3 = 2%).

Conclusions: CDX-011 was a well-tolerated and active agent in this heavily pre-treated BC pt population. Preliminary analysis of the EMERGE study demonstrates enhanced activity of CDX-011 in TN as well as high GPNMB expressing BC tumors, confirming that CDX-011 is a targeted agent. This noted promising activity in advanced TN and hGPNMB enriched pt populations warrants further evaluation.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-01.
Abstract PD03-08: Statin use and improved outcome in primary inflammatory breast cancer: retrospective cohort study
Authors: Brewer TM , Masuda H , Iwamoto T , Liu P , Shen Y , Liu DD , Kai K , Barnett CM , Woodward WA , Reuben JM , Yang P , Hortobagyi GN , Ueno NT
Published: August 2014

Background Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. HMG-CoA reductase inhibitors (statins) are cholesterol reducing agents with pleiotropic effects, including antitumorigenic and anti-inflammatory properties. We hypothesized that statins reduce the metastatic potential in primary IBC.

Methods We retrospectively reviewed 724 patients diagnosed with and treated for primary IBC at The University of Texas MD Anderson Cancer Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with records indicating statin use at the time of IBC diagnosis on the electronic medical record were compared with those without. We further compared outcomes stratified by statin type (hydrophilic [H] versus lipophilic [L]). We used the Kaplan-Meier method to estimate the median disease-free survival (DFS) after surgery, overall survival (OS), and disease specific survival (DSS), followed by Cox proportional hazards regression model to test statistical significance of several potential prognostic factors.

Results For primary IBC patients who had information on their statin use status at IBC diagnosis, the median DFS time were 4.88 years, 2.47 years and 1.76 years (P= 0.04); the median OS time 5.05 years, 3.79 years and 4.32 years (P= 0.35); and the median DSS time 5.10 years, 3.79 years and 4.52 years (P= 0.37), for patients who took “ H”, “L” and no statin, respectively. In multivariable Cox model stratified by radiation therapy, ER/PR status and HER2 status, statin “H” use was associated with significantly improved DFS compared to no statin use (HR=0.49; 95% CI: 0.28–0.84; p<0.01), adjusted for lymphatic/vascular invasion. Although there is a trend that patients who used statin “H” had a longer time to death compared to patients who did not take statin, it did not reach statistical significance for OS (HR=0.80; 95% CI: 0.43–1.49; p=0.49) and DSS (HR=0.85; 95% CI: 0.46–1.57, p=0.59) after adjustment for lymphatic/vascular invasion, nuclear grade and surgery status within one year.

Conclusions Hydrophilic statin use was associated with improved DFS. There was a trend for reduced HR in OS and DSS among primary IBC patient who used hydrophilic statins. A prospective randomized study to evaluate the potential survival benefits of statins in primary IBC population is warranted.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-08.
Abstract ES01-1: Targeting the DNA damage response in triple negative breast cancer
Authors: Cortez D
Published: August 2014

Triple negative breast cancer (TNBC) comprises approximately 25 percent of breast cancer deaths. There is a critical need to develop better therapeutic options for TNBC patients. We hypothesize that at least a subset of these cancers are especially dependent on DNA repair mechanisms that are coordinated by the ATR kinase-dependent DNA damage response signaling pathway. This hypothesis has been tested using genetic and chemical genetic approaches. We are working to develop small molecule inhibitors of the ATR pathway, understand how they work, and identify when these targeted therapies may provide clinical benefit. Our studies of an ATR selective inhibitor indicate that it kills cells due to a requirement for ATR signaling to complete DNA replication. ATR inhibition is synergistic with other chemotherapeutic agents such as platinum crosslinking drugs. ATR-inhibitor treated cells accumulate toxic DNA double-strand breaks and large stretches of single-stranded DNA through an active process catalyzed by deregulated nucleases and helicases. Effective biomarkers of ATR inhibition include DNA-PK, H2AX, RPA, and ATR phosphorylation. We have also worked with colleagues at Vanderbilt Medical School to identify additional therapeutic targets and develop small molecule inhibitors.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES01-1.
Abstract ES01-2: 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions
Authors: Nussenzweig A , Callen E
Published: August 2014

The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP1(8A), comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP1(8A) recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP1(8A). We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES01-2.
Abstract ES02-2: Who should receive preventive therapy?
Authors: Cuzick J
Published: August 2014

Several options are now becoming available for preventive therapy in women at increased risk for breast cancer. A major challenge is to determine which women are at sufficiently high risk to warrant treatment, and who will benefit from such treatment. Standard risk factors have been combined in several models to develop a risk score, and the spread in 10-year risk associated with these models will be examined. Two new features which offer improved prognostic discrimination are breast density and SNP profiles. The former can be routinely read visually, but there is a substantial inter-reader variability, and a goal is to develop automated testing which is reproducible and highly prognostic for risk. SNP profiles consist of panels (now over 70) of low risk but common genes that individually are not useful, but as a panel may add useful information. A discussion of the relative amount of information in classic models, mammographic density, and SNP scores will be presented along with initial estimates of their combined utility. Lastly we look at markers which may be able to predict response to endocrine prophylactic treatment. Currently change in breast density offers the most promise in this arena.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES02-2.
Abstract ES03-3: Clinical 101: Clinical trial endpoints: Selection, analysis and interpretation
Authors: Garrett-Mayer E
Published: August 2014

The selection of clinical endpoints when designing a clinical trial is critically important to ensure appropriate evaluation of the agent or regimen of interest. Endpoints in early stage clinical trials differ from those in later stage trials, and the nature of the endpoints (e.g., continuou,s categorical) has an impact on both the parameters that can be estimated and the power to detect significant differences. This talk will focus on the selection of continuous (e.g. Ki67, breast density, change in tumor size), categorical (e.g. RECIST response, pathologic complete response), and time to event endpoints (e.g. progression-free survival, overall survival) when designing clinical trials. Discussion will also include interpretation of resulting measures of clinical efficacy (e.g. hazard ratios), approaches for stating trial objectives and implications of endpoint selection on statistical power.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES03-3.
Abstract ES07-2: Inflammatory breast cancer: Diagnosis, treatment and biology
Authors: Woodward WA
Published: August 2014

Inflammatory breast cancer (IBC) is a relatively rare variant of breast cancer accounting for a disproportionate amount of breast cancer mortality. It is histopathologically similar to non-IBC but presents with a very distinct clinical picture: rapid onset of breast redness and swelling often without an obvious lump. Misdiagnosis and delay in diagnosis are common. Although the breast appears “inflamed” obvious inflammatory infiltrates are not detectable in most tissues. Three presentations will focus on the diagnostic challenges, determinants, epidemiology, management and biology of inflammatory breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES07-2.
Abstract ES08-1: Imaging tumor response: Challenges of heterogeneity
Authors: Piwnica-Worms D
Published: August 2014

Large-scale sequencing analyses of solid cancers have identified extensive genetic inter-tumor and intra-tumor heterogeneity, which likely contribute to treatment failure and drug resistance. For example, recent unbiased whole genome sequencing approaches have highlighted the complexity of the mutational landscape of ER+ luminal breast cancers. In 46 breast tumors, 82,000 total somatic mutations and 2,000 tier 1 mutations were identified. While pathway signatures enabled the evaluation of mutations with low recurrence frequency where statistical comparisons conventionally were underpowered, this massive heterogeneity presents an enormous challenge for therapy and prognostic assessment of cancer. Furthermore, cells have evolved complex molecular networks to sense cues from the environment and transmit them throughout the cell to elicit appropriate biological responses. These signaling pathways require certain elemental properties, such as sensitivity, reversibility, a capacity to be regulated, and robustness, that are crucial to reliably maintaining the organization and function of cells within organisms. These molecular networks comprise sets of recurring regulation patterns, manifest as network motifs, which link together in a variety of combinations to create a web of connectivity within a given signaling pathway or between multiple cascades. Using a kB5-IkBα-FLuc bioluminescent reporter as one example, we rigorously evaluated the dynamics of IkBa degradation and subsequent NF-kB transcriptional activity in response to diverse modes of TNFα stimulation in isogenic tumor cells. Tremendous heterogeneity in the transcriptional amplitudes of responding cells was observed, which was greater than the heterogeneity in the transcriptional kinetics of responsive cells. Thus, systems heterogeneity was observed even in isogenic cells, further adding to the complexity of cellular responses and their associated signaling networks. One must conclude that inter-tumor and intra-tumor heterogeneity at the level of cancer genes and systems responses may have important consequences for targeted molecular imaging strategies that commonly lack spatial and temporal resolution in their depiction of tumor phenotypes.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES08-1.
Abstract ES09-1: Update on management of ER positive metastatic breast cancer
Authors: Burstein HJ
Published: August 2014

Patients with ER positive, metastatic breast cancer are candidate for endocrine and chemotherapy treatments in order to prolong survival, alleviate and forestall symptoms, and preserve quality of life. Classical management strategies such as the prompt initiation of ovarian suppression at the time of diagnosis of metastatic disease, the sequential use of treatment with endocrine agents and chemotherapeutic agents, the predilection of ER positive tumors for bone / soft tissue / mucosal and lymph nodes as initial sites of metastatic disease, and the lack of close correlation between clinical benefit and overt treatment response to endocrine agents remain valuable observations. Despite decades of clinical use, important new findings regarding endocrine therapy continue to emerge. Several examples of recent innovation include the following. 1. Dosing of fulvestrant. Because of limited bioavailability in its injectable formulation, higher doses of fulvestrant (500 mg) yield superior clinical outcomes than seen with the lower doses (250 mg) originally used for drug approval. 2. Combinations of aromatase inhibitors and fulvestrant. Historically, single-agent endocrine treatment has been the norm. Recent studies have examined AI therapy given with or without fulvestrant. In the FACT trial, no substantial benefit was observed. However, in the SWOG 0221 study, the combination led to improved overall survival, perhaps because this patient population had received less in the way of prior endocrine treatment. 3. Novel pathways: mTOR inhibitors. Everolimus, the orally available mTOR inhibitor, is now FDA approved for use in AI-refractory breast cancer based on the BOLERO-2 study which showed that adding everolimus improved PFS compared to ongoing AI therapy, alone. To date, genomic biomarkers have not lent themselves to clinical use for patient selection of mTOR inhibitor therapy. 4. Novel pathways: CDK4/6 inhibitors. Novel agents are targeting the CDK4/6 pathway in ER+ metastatic breast cancer, and show early promise in randomized phase II studies. 5. Use of estrogens as treatment for advanced breast cancer. Harkening back to observations from the 1950s and 1960s, investigators have shown in small phase II trials that estrogen therapy itself can achieve tumor regression and clinical benefit in ER+ metastatic breast cancer. 6. Genomic revolution. Full genome sequencing is now available for many ER+ advanced cancers, identifying frequent mtuations in many genes (PIK3CA, FGFR, IGFR, AKT, CCND1 and other genes that may lend themselves to targeted therapeutic approaches. In addition to these innovations in targeted the ER and related pathways, it is also becoming clear chemotherapy outcomes for women with ER+ breast cancer are effective, and often more effective than in the treatment of TNBC which is more often considered a “chemotherapy-treated” tumor. These advances and other insights into ER positive metastatic breast cancer will be discussed.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES09-1.