bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal transport, thermomechanical, and dielectric properties of chalcogenide Se98–xAg2Inx (x = 0, 2, 4, 6) system
Authors: Dohare C. , Mehta N.
Published: February 2014

The present work reports a detailed study of some physical properties of some novel glasses of Se98–xAg2Inx (x = 0, 2, 4, 6) system. Measurements of thermal transport properties (i.e., thermal conductivity, κ, and thermal diffusivity, χe) have been carried out using the transient plane source technique. Specific heat measurements have been done by differential scanning calorimetry. Thermomechanical properties (i.e., Vickers hardness, Hv, and modulus of elasticity, E) have been evaluated by the indenter test. The minimal energy for formation of microvoids, Eh, and microvoids volume, Vh, of the previously mentioned glassy system are discussed in terms of microhardness, Hv. Temperature and frequency dependence of dielectric constant, ε1, and dielectric loss, ε2, for the same system were measured in the frequency (50 Hz – 1000 kHz) and temperature (303–338 K) range. The experimental results illustrate that the values of dielectric constant, ε1, and dielectric loss, ε2, are decreased with frequency and increased with temperature. The maximum barrier height, Wb, is calculated using the dielectric measurements according to the Guintini equation. The morphology and microstructural analysis of as-prepared alloys are confirmed by X-ray diffraction, scanning electron microscope, and transmission electron microscope.
Nutritional implications of increased shrub cover for caribou (Rangifer tarandus) in the Arctic
Authors: Thompson D.P. , Barboza P.S.
Published: February 2014

Shrubs are increasing in the annual range of arctic caribou (Rangifer tarandus (L., 1758)), but it is unknown how much summer browse caribou could consume. We measured instantaneous intakes of resin birch (Betula glandulosa Michx.) and feltleaf willow (Salix alaxensis (Andersson) Coville) by caribou during summer. Daily intake of a formulated diet without toxins was measured during the same period to monitor appetite. Caribou appetite increased from 64.1 to 86.7 g DM·kg–0.75·day−1 as animals gained body mass from 96.8 to 113.5 kg. We estimated that caribou required 645 kJ·kg–0.75·day−1 of digestible energy to maintain body mass and 1113 kJ·kg–0.75·day−1 to gain body mass for autumn reproduction. Caribou had the same bite mass (9.7 mg·bite−1·kg–0.75) and instantaneous intake rate (0.17 g DM·min−1·kg–0.75) on both forages; however, birch contained more phenols (3.3% vs. 1.5%) and less available protein (6.2% vs. 10.2%) than willow. A 100 kg female caribou would need to consume 2.4–8.7 kg of fresh browse, requiring 3.1–8.5 h·day−1 of eating time to meet daily energy requirements. Birch is unlikely to provide enough nitrogen for maintenance of body protein. Therefore, caribou may depend on abundance and diversity of plants to offset toxin loads and low protein intake from shrubs during summer.
RECOVERING STRINGS IN ORACLES: QUANTUM AND CLASSIC
Authors: IWAMA KAZUO , NISHIMURA HARUMICHI
Published: February 2014

Recovering unknown inputs in oracles with as few queries as possible is one of the most basic problems in theoretical computer science. In this paper, we survey the classical and quantum query complexity of this problem for various types of oracles with different types of queries.
P AND dP AUTOMATA: UNCONVENTIONAL VERSUS CLASSICAL AUTOMATA
Authors: CSUHAJ-VARJÚ ERZSÉBET
Published: February 2014

In this paper we provide a summary on important results concerning P automata and their distributed systems, dP automata. Since these constructs combine properties of classical automata and membrane systems being in interaction with their environments, we also discuss their non-standard features, compared them to characteristics of classical automata.
INSIDE THE CLASS OF REGEX LANGUAGES
Authors: SCHMID MARKUS L.
Published: February 2014

We study different possibilities of combining the concept of homomorphic replacement with regular expressions in order to investigate the class of languages given by extended regular expressions with backreferences (REGEX). It is shown in which regard existing and natural ways to do this fail to reach the expressive power of REGEX. Furthermore, the complexity of the membership problem for REGEX with a bounded number of backreferences is considered.
Mortein: Finalizing the Theme and Creative Idea
Authors: Pradhan Debasis , Agrawal Divya
Published: February 2014

Mortein, one of the top pest repellant brands in India, was facing a stagnant market share for the past three years. Although the brand in itself stood for “power”, consumers did not perceive the vaporizer to have the same power as competitors' products. Deepak Sinha, the brand manager for Mortein, had formulated a business strategy to capture share from competition through a brand relaunch with an improved and more effective product, Mortein PowerGard. Deepak had come up with the proposal for a 360-degree activation for Mortein.

Deepak had to approve the advertising copy designed and developed by a management trainee. He wanted to be doubly-sure about the target audience for the communication campaign and the decision-making units for the purchase of a mosquito repellent. There was a debate on this at Reckitt-Benckiser (hereafter referred to as RB). He wanted to be scientific about decisions like target audience selection and the appropriateness of the message strategy which was also part of the copy strategy. Deepak and the trainee had to convince the top management at RB on certain decisions that were taken and some others that were being contemplated upon.
Beams for the Intensity Frontier of Particle Physics
Authors: Tschirhart Robert S.
Published: February 2014

Advances in high intensity beams have driven particle physics forward since the inception of the field. State-of-the-art and next generation high intensity beams will drive experiments searching for ultrarare processes sensitive through quantum corrections to new particle states far beyond the reach of direct production in foreseeable beam colliders. The recent discovery of the ultrarare B meson decay Bs → μμ, with a branching fraction of 3 × 10-9 for example, has set stringent limits on new physics within direct reach of the Large Hadron Collider. Today, even in the context of the Higgs boson discovery, observation of finite neutrino masses is the only laboratory evidence of physics beyond the Standard Model of particle physics. The tiny mass scale of neutrinos may foretell and one day expose physics that connects quarks and leptons together at the "grand unification" scale and may be the portal through which our world came to the matter-dominated state so different from conditions we expect in the early universe. Here we describe next generation neutrino and rare processes experiments that will deeply probe these and other questions central to the field of particle physics.
Particle Beam Radiography
Authors: Peach Ken , Ekdahl Carl
Published: February 2014

Particle beam radiography, which uses a variety of particle probes (neutrons, protons, electrons, gammas and potentially other particles) to study the structure of materials and objects noninvasively, is reviewed, largely from an accelerator perspective, although the use of cosmic rays (mainly muons but potentially also high-energy neutrinos) is briefly reviewed. Tomography is a form of radiography which uses multiple views to reconstruct a three-dimensional density map of an object. There is a very wide range of applications of radiography and tomography, from medicine to engineering and security, and advances in instrumentation, specifically the development of electronic detectors, allow rapid analysis of the resultant radiographs. Flash radiography is a diagnostic technique for large high-explosive-driven hydrodynamic experiments that is used at many laboratories. The bremsstrahlung radiation pulse from an intense relativistic electron beam incident onto a high-Z target is the source of these radiographs. The challenge is to provide radiation sources intense enough to penetrate hundreds of g/cm2 of material, in pulses short enough to stop the motion of high-speed hydrodynamic shocks, and with source spots small enough to resolve fine details. The challenge has been met with a wide variety of accelerator technologies, including pulsed-power-driven diodes, air-core pulsed betatrons and high-current linear induction accelerators. Accelerator technology has also evolved to accommodate the experimenters' continuing quest for multiple images in time and space. Linear induction accelerators have had a major role in these advances, especially in providing multiple-time radiographs of the largest hydrodynamic experiments.
Fingerprints of hSGLT5 sugar and cation selectivity
Authors: Ghezzi Chiara , Gorraitz Edurne , Hirayama Bruce A. , Loo Donald D. F. , Grempler Rolf , Mayoux Eric , Wright Ernest M.
Published: February 2014

Sodium glucose cotransporters (SGLTs) mediate the translocation of carbohydrates across the brush border membrane of different organs such as intestine, kidney, and brain. The human SGLT5 (hSGLT5), in particular, is localized in the kidney were it is responsible for mannose and fructose reabsorption from the glomerular filtrate as confirmed by more recent studies on hSGLT5 knockout mice. Here we characterize the functional properties of hSGLT5 expressed in a stable T-Rex-HEK-293 cell line using biochemical and electrophysiological assays. We confirmed that hSGLT5 is a sodium/mannose transporter that is blocked by phlorizin. Li+ and H+ ions were also able to drive mannose transport, and transport was electrogenic. Our results moreover indicate that substrates require a pyranose ring with an axial hydroxyl group (–OH) on carbon 2 (C-2). Compared with Na+/glucose cotransport, the level of function of Na+/mannose cotransport in rat kidney slices was low.
Even an old technique is suitable in the molecular world of science: the everted sac preparation turns 60 years old
Authors: Hamilton Kirk L.
Published: February 2014

An old proverb states “necessity is the mother of invention.” This certainly holds true in science as one pursues research questions. Experimental techniques have evolved as scientists have asked more specific research questions. Indeed, techniques such as the Ussing chamber, the perfused renal tubule preparation, patch-clamp, polymerase chain reaction, and site-directed mutagenesis have been developed over the past 60 years. However, sometimes, simple techniques may be useful and still very informative, and this certainly applies to intestinal physiology. Indeed, Gerald Wiseman and Thomas Hastings Wilson described the intestinal everted sac preparation some 60 years ago. Since then, this technique has been used for numerous research purposes including determining ion, amino acid, water and solute transport across the intestinal epithelium; and drug metabolism, absorption, and interactions in pharmaceutical/pharmacological research and even in education. This article provides a historical review of the development of the in vitro intestinal preparation that led to the everted sac preparation and its use in science.
Activation of Notch signaling by short-term treatment with Jagged-1 enhances store-operated Ca2+ entry in human pulmonary arterial smooth muscle cells
Authors: Yamamura Hisao , Yamamura Aya , Ko Eun A. , Pohl Nicole M. , Smith Kimberly A. , Zeifman Amy , Powell Frank L. , Thistlethwaite Patricia A. , Yuan Jason X.-J.
Published: February 2014

Notch signaling plays a critical role in controlling proliferation and differentiation of pulmonary arterial smooth muscle cells (PASMC). Upregulated Notch ligands and Notch3 receptors in PASMC have been reported to promote the development of pulmonary vascular remodeling in patients with pulmonary arterial hypertension (PAH) and in animals with experimental pulmonary hypertension. Activation of Notch receptors by their ligands leads to the cleavage of the Notch intracellular domain (NICD) to the cytosol by γ-secretase; NICD then translocates into the nucleus to regulate gene transcription. In this study, we examined whether short-term activation of Notch functionally regulates store-operated Ca2+ entry (SOCE) in human PASMC. Treatment of PASMC with the active fragment of human Jagged-1 protein (Jag-1) for 15–60 min significantly increased the amplitude of SOCE induced by passive deletion of Ca2+ from the intracellular stores, the sarcoplasmic reticulum (SR). The Jag-1-induced enhancement of SOCE was time dependent: the amplitude was maximized at 30 min of treatment with Jag-1, which was closely correlated with the time course of Jag-1-mediated increase in NICD protein level. The scrambled peptide of Jag-1 active fragment had no effect on SOCE. Inhibition of γ-secretase by N-[ N-(3,5-difluorophenacetyl-l-alanyl)]- S-phenylglycine t-butyl ester (DAPT) significantly attenuated the Jag-1-induced augmentation of SOCE. In addition to the short-term effect, prolonged treatment of PASMC with Jag-1 for 48 h also markedly enhanced the amplitude of SOCE. These data demonstrate that short-term activation of Notch signaling enhances SOCE in PASMC; the NICD-mediated functional interaction with store-operated Ca2+ channels (SOC) may be involved in the Jag-1-mediated enhancement of SOCE in human PASMC.
Label-free quantitative proteomic analysis of the YAP/TAZ interactome
Authors: Kohli Priyanka , Bartram Malte P. , Habbig Sandra , Pahmeyer Caroline , Lamkemeyer Tobias , Benzing Thomas , Schermer Bernhard , Rinschen Markus M.
Published: February 2014

The function of an individual protein is typically defined by protein-protein interactions orchestrating the formation of large complexes critical for a wide variety of biological processes. Over the last decade the analysis of purified protein complexes by mass spectrometry became a key technique to identify protein-protein interactions. We present a fast and straightforward approach for analyses of interacting proteins combining a Flp-in single-copy cellular integration system and single-step affinity purification with single-shot mass spectrometry analysis. We applied this protocol to the analysis of the YAP and TAZ interactome. YAP and TAZ are the downstream effectors of the mammalian Hippo tumor suppressor pathway. Our study provides comprehensive interactomes for both YAP and TAZ and does not only confirm the majority of previously described interactors but, strikingly, revealed uncharacterized interaction partners that affect YAP/TAZ TEAD-dependent transcription. Among these newly identified candidates are Rassf8, thymopoetin, and the transcription factors CCAAT/enhancer-binding protein (C/EBP)β/δ and core-binding factor subunit β (Cbfb). In addition, our data allowed insights into complex stoichiometry and uncovered discrepancies between the YAP and TAZ interactomes. Taken together, the stringent approach presented here could help to significantly sharpen the understanding of protein-protein networks.
Remembering to eat: hippocampal regulation of meal onset
Authors: Parent Marise B. , Darling Jenna N. , Henderson Yoko O.
Published: February 2014

A wide variety of species, including vertebrate and invertebrates, consume food in bouts (i.e., meals). Decades of research suggest that different mechanisms regulate meal initiation (when to start eating) versus meal termination (how much to eat in a meal, also known as satiety). There is a very limited understanding of the mechanisms that regulate meal onset and the duration of the postprandial intermeal interval (ppIMI). In the present review, we examine issues involved in measuring meal onset and some of the limited available evidence regarding how it is regulated. Then, we describe our recent work indicating that dorsal hippocampal neurons inhibit meal onset during the ppIMI and describe the processes that may be involved in this. We also synthesize recent evidence, including evidence from our laboratory, suggesting that overeating impairs hippocampal functioning and that impaired hippocampal functioning, in turn, contributes to the development and/or maintenance of diet-induced obesity. Finally, we identify critical questions and challenges for future research investigating neural controls of meal onset.
Development of attenuated baroreflexes in obese Zucker rats coincides with impaired activation of nucleus tractus solitarius
Authors: Guimaraes Priscila S. , Huber Domitila A. , Campagnole-Santos Maria J. , Schreihofer Ann M.
Published: February 2014

Adult obese Zucker rats (OZR; >12 wk) develop elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) with impaired baroreflexes compared with adult lean Zucker rats (LZR) and juvenile OZR (6–7 wk). In adult OZR, baroreceptor afferent nerves respond normally to changes in MAP, whereas electrical stimulation of baroreceptor afferent fibers produces smaller reductions in SNA and MAP compared with LZR. We hypothesized that impaired baroreflexes in OZR are linked to reduced activation of brain stem sites that mediate baroreflexes. In conscious adult rats, a hydralazine (HDZ)-induced reduction in MAP evoked tachycardia that was initially blunted in OZR, but equivalent to LZR within 5 min. In agreement, HDZ-induced expression of c-Fos in the rostral ventrolateral medulla (RVLM) was comparable between groups. In contrast, phenylephrine (PE)-induced rise in MAP evoked markedly attenuated bradycardia with dramatically reduced c-Fos expression in the nucleus tractus solitarius (NTS) of adult OZR compared with LZR. However, in juvenile rats, PE-induced hypertension evoked comparable bradycardia in OZR and LZR with similar or augmented c-Fos expression in NTS of the OZR. In urethane-anesthetized rats, microinjections of glutamate into NTS evoked equivalent decreases in SNA, heart rate (HR), and MAP in juvenile OZR and LZR, but attenuated decreases in SNA and MAP in adult OZR. In contrast, microinjections of glutamate into the caudal ventrolateral medulla, a target of barosensitive NTS neurons, evoked comparable decreases in SNA, HR, and MAP in adult OZR and LZR. These data suggest that OZR develop impaired glutamatergic activation of the NTS, which likely contributes to attenuated baroreflexes in adult OZR.
Human podocytes perform polarized, caveolae-dependent albumin endocytosis
Authors: Dobrinskikh Evgenia , Okamura Kayo , Kopp Jeffrey B. , Doctor R. Brian , Blaine Judith
Published: February 2014

The renal glomerulus forms a selective filtration barrier that allows the passage of water, ions, and small solutes into the urinary space while restricting the passage of cells and macromolecules. The three layers of the glomerular filtration barrier include the vascular endothelium, glomerular basement membrane (GBM), and podocyte epithelium. Podocytes are capable of internalizing albumin and are hypothesized to clear proteins that traverse the GBM. The present study followed the fate of FITC-labeled albumin to establish the mechanisms of albumin endocytosis and processing by podocytes. Confocal imaging and total internal reflection fluorescence microscopy of immortalized human podocytes showed FITC-albumin endocytosis occurred preferentially across the basal membrane. Inhibition of clathrin-mediated endocytosis and caveolae-mediated endocytosis demonstrated that the majority of FITC-albumin entered podocytes through caveolae. Once internalized, FITC-albumin colocalized with EEA1 and LAMP1, endocytic markers, and with the neonatal Fc receptor, a marker for transcytosis. After preloading podocytes with FITC-albumin, the majority of loaded FITC-albumin was lost over the subsequent 60 min of incubation. A portion of the loss of albumin occurred via lysosomal degradation as pretreatment with leupeptin, a lysosomal protease inhibitor, partially inhibited the loss of FITC-albumin. Consistent with transcytosis of albumin, preloaded podocytes also progressively released FITC-albumin into the extracellular media. These studies confirm the ability of podocytes to endocytose albumin and provide mechanistic insight into cellular mechanisms and fates of albumin handling in podocytes.
BDNF Val66Met polymorphism is associated with abnormal interhemispheric transfer of a newly acquired motor skill
Authors: Morin-Moncet Olivier , Beaumont Vincent , de Beaumont Louis , Lepage Jean-Francois , Théoret Hugo
Published: February 2014

Recent data suggest that the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene can alter cortical plasticity within the motor cortex of carriers, which exhibits abnormally low rates of cortical reorganization after repetitive motor tasks. To verify whether long-term retention of a motor skill is also modulated by the presence of the polymorphism, 20 participants (10 Val66Val, 10 Val66Met) were tested twice at a 1-wk interval. During each visit, excitability of the motor cortex was measured by transcranial magnetic stimulations (TMS) before and after performance of a procedural motor learning task (serial reaction time task) designed to study sequence-specific learning of the right hand and sequence-specific transfer from the right to the left hand. Behavioral results showed a motor learning effect that persisted for at least a week and task-related increases in corticospinal excitability identical for both sessions and without distinction for genetic group. Sequence-specific transfer of the motor skill from the right hand to the left hand was greater in session 2 than in session 1 only in the Val66Met genetic group. Further analysis revealed that the sequence-specific transfer occurred equally at both sessions in the Val66Val genotype group. In the Val66Met genotype group, sequence-specific transfer did not occur at session 1 but did at session 2. These data suggest a limited impact of Val66Met polymorphism on the learning and retention of a complex motor skill and its associated changes in corticospinal excitability over time, and a possible modulation of the interhemispheric transfer of procedural learning.
Equalization and decorrelation in primary visual cortex
Authors: Haak Koen V. , Fast Elizabeth , Baek Yihwa , Mesik Juraj
Published: February 2014

There are many theories on the purpose of neural adaptation, but evidence remains elusive. Here, we discuss the recent work by Benucci et al. ( Nat Neurosci 16: 724–729, 2013), who measured for the first time the immediate effects of adaptation on the overall activity of a neuronal population. These measurements confirm two long-standing hypotheses about the purpose of adaptation, namely that adaptation counteracts biases in the statistics of the environment, and that it maintains decorrelation in neuronal stimulus selectivity.
Organization and trade-off of spectro-temporal tuning properties of duration-tuned neurons in the mammalian inferior colliculus
Authors: Morrison James A. , Farzan Faranak , Fremouw Thane , Sayegh Riziq , Covey Ellen , Faure Paul A.
Published: February 2014

Neurons throughout the mammalian central auditory pathway respond selectively to stimulus frequency and amplitude, and some are also selective for stimulus duration. First found in the auditory midbrain or inferior colliculus (IC), these duration-tuned neurons (DTNs) provide a potential neural mechanism for encoding temporal features of sound. In this study, we investigated how having an additional neural response filter, one selective to the duration of an auditory stimulus, influences frequency tuning and neural organization by recording single-unit responses and measuring the dorsal-ventral position and spectral-temporal tuning properties of auditory DTNs from the IC of the awake big brown bat ( Eptesicus fuscus). Like other IC neurons, DTNs were tonotopically organized and had either V-shaped, U-shaped, or O-shaped frequency tuning curves (excitatory frequency response areas). We hypothesized there would be an interaction between frequency and duration tuning in DTNs, as electrical engineering theory for resonant filters dictates a trade-off in spectral-temporal resolution: sharp tuning in the frequency domain results in poorer resolution in the time domain and vice versa. While the IC is a more complex signal analyzer than an electrical filter, a similar operational trade-off could exist in the responses of DTNs. Our data revealed two patterns of spectro-temporal sensitivity and spatial organization within the IC: DTNs with sharp frequency tuning and broad duration tuning were located in the dorsal IC, whereas cells with wide spectral tuning and narrow temporal tuning were found in the ventral IC.
BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma
Authors: Breunig Christian , Mueller Bernadett J. , Umansky Ludmila , Wahl Kristin , Hoffmann Katrin , Lehner Frank , Manns Michael P. , Bantel Heike , Falk Christine S.
Published: February 2014

Purpose: Small molecule inhibitors of the mitogen-activated protein kinase (MAPK) pathway, such as sorafenib, represent novel treatment options for advanced hepatocellular carcinoma. The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in hepatocellular carcinoma and correlate with inhibition of this pathway by multikinase inhibitors.

Experimental Design: Hepatocellular carcinoma cell lines and fresh tumor and tumor-free liver tissues from patients with hepatocellular carcinoma were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation, proliferation, induction of apoptosis, and chemokine secretion.

Results: Hepatocellular carcinoma cell lines responded differentially to these inhibitors in a dose-dependent manner, even those targeting the same kinase. Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations. Similarly, PLX4720 increased MEK/ERK signaling independently from mutations in BRaf or NRas. MEK inhibitors decreased ERK1/2 phosphorylation in a dose-dependent manner. These signaling characteristics correlated with inhibition of proliferation, induction of apoptosis, and chemokine secretion. Fresh tissues derived from patients diagnosed with primary hepatocellular carcinoma responded to these inhibitors with changes in their microenvironment following the patterns observed in hepatocellular carcinoma cells.

Conclusions: Oncogenic signaling of the MAPK pathway influences hepatocellular carcinoma sensitivity to treatment with BRaf and MEK inhibitors about cell fate independently from mutations in BRaf and NRas. MAPK inhibitors have a strong impact on chemokine secretion as a consequence of interference with oncogenic signaling. Therefore, novel biomarker candidates associated with the hepatocellular carcinoma microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors. Clin Cancer Res; 20(9); 2410–23. ©2014 AACR.
A Peptide-Based Positron Emission Tomography Probe for In Vivo Detection of Caspase Activity in Apoptotic Cells
Authors: Hight Matthew R. , Cheung Yiu-Yin , Nickels Michael L. , Dawson Eric S. , Zhao Ping , Saleh Samir , Buck Jason R. , Tang Dewei , Washington M. Kay , Coffey Robert J. , Manning H. Charles
Published: February 2014

Purpose: Apoptosis, or programmed cell death, can be leveraged as a surrogate measure of response to therapeutic interventions in medicine. Cysteine aspartic acid–specific proteases, or caspases, are essential determinants of apoptosis signaling cascades and represent promising targets for molecular imaging. Here, we report development and in vivo validation of [18F]4-fluorobenzylcarbonyl–Val–Ala–Asp(OMe)–fluoromethylketone ([18F]FB-VAD-FMK), a novel peptide-based molecular probe suitable for quantification of caspase activity in vivo using positron emission tomography (PET).

Experimental Design: Supported by molecular modeling studies and subsequent in vitro assays suggesting probe feasibility, the labeled pan-caspase inhibitory peptide, [18F]FB-VAD-FMK, was produced in high radiochemical yield and purity using a simple two-step, radiofluorination. The biodistribution of [18F]FB-VAD-FMK in normal tissue and its efficacy to predict response to molecularly targeted therapy in tumors was evaluated using microPET imaging of mouse models of human colorectal cancer.

Results: Accumulation of [18F]FB-VAD-FMK was found to agree with elevated caspase-3 activity in response to Aurora B kinase inhibition as well as a multidrug regimen that combined an inhibitor of mutant BRAF and a dual PI3K/mTOR inhibitor in V600EBRAF colon cancer. In the latter setting, [18F]FB-VAD-FMK PET was also elevated in the tumors of cohorts that exhibited reduction in size.

Conclusions: These studies illuminate [18F]FB-VAD-FMK as a promising PET imaging probe to detect apoptosis in tumors and as a novel, potentially translatable biomarker for predicting response to personalized medicine. Clin Cancer Res; 20(8); 2126–35. ©2014 AACR.
High-Throughput Detection of Clinically Relevant Mutations in Archived Tumor Samples by Multiplexed PCR and Next-Generation Sequencing
Authors: Bourgon Richard , Lu Shan , Yan Yibing , Lackner Mark R. , Wang Weiru , Weigman Victor , Wang David , Guan Yinghui , Ryner Lisa , Koeppen Hartmut , Patel Rajesh , Hampton Garret M. , Amler Lukas C. , Wang Yulei
Published: February 2014

Purpose: Tailoring cancer treatment to tumor molecular characteristics promises to make personalized medicine a reality. However, reliable genetic profiling of archived clinical specimens has been hindered by limited sensitivity and high false-positive rates. Here, we describe a novel methodology, MMP-seq, which enables sensitive and specific high-throughput, high-content genetic profiling in archived clinical samples.

Experimental Design: We first validated the technical performance of MMP-seq in 66 cancer cell lines and a Latin square cross-dilution of known somatic mutations. We next characterized the performance of MMP-seq in 17 formalin-fixed paraffin-embedded (FFPE) clinical samples using matched fresh-frozen tissue from the same tumors as benchmarks. To demonstrate the potential clinical utility of our methodology, we profiled FFPE tumor samples from 73 patients with endometrial cancer.

Results: We demonstrated that MMP-seq enabled rapid and simultaneous profiling of a panel of 88 cancer genes in 48 samples, and detected variants at frequencies as low as 0.4%. We identified DNA degradation and deamination as the main error sources and developed practical and robust strategies for mitigating these issues, and dramatically reduced the false-positive rate. Applying MMP-seq to a cohort of endometrial tumor samples identified extensive, potentially actionable alterations in the PI3K (phosphoinositide 3-kinase) and RAS pathways, including novel PIK3R1 hotspot mutations that may disrupt negative regulation of PIK3CA.

Conclusions: MMP-seq provides a robust solution for comprehensive, reliable, and high-throughput genetic profiling of clinical tumor samples, paving the way for the incorporation of genomic-based testing into clinical investigation and practice. Clin Cancer Res; 20(8); 2080–91. ©2014 AACR.
Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation
Authors: Yu Yongjiang , Zhang Yu , Guan Wenbin , Huang Tao , Kang Jian , Sheng Xujun , Qi Jun
Published: February 2014

The Jagged1, a Notch signaling pathway ligand, had been shown to have a positive correlation with prostate cancer development. Our study for Jagged1 expression in 218 prostate cancer tissue samples also supports this conclusion. However, the detailed molecular mechanism of Jagged1 in promoting the progression of prostate cancer is still unclear. Through cell proliferation examination, androgen receptor (AR) was found to promote the oncogenic function of Jagged1 to enhance the cell proliferation rate by comparing four prostate cancer cell lines, LNCaP, LAPC4, DU145, and PC3, which was further validated through analyzing the survival of 118 patients treated with androgen-deprivation therapy (ADT) with different expression levels of Jagged1 and AR. More importantly, our data showed that Jagged1 combined with AR could increase the phosphorylation level of Akt and, in turn, phosphorylated Akt plays an important role in regulating the expression level of cyclin B1 by interacting with AR and increasing the transcriptional activity of AR. These data indicate that prostate cancer progression regulated by Jagged1 can be dramatically enhanced by combining with AR through promoting Akt activity.

Implications: This study could benefit our clinical treatments for patients with prostate cancer with overexpressed Jagged1 by targeting AR and Akt. Mol Cancer Res; 12(6); 830–42. ©2014 AACR.
DDB2 Suppresses Tumorigenicity by Limiting the Cancer Stem Cell Population in Ovarian Cancer
Authors: Han Chunhua , Zhao Ran , Liu Xingluo , Srivastava Amit , Gong Li , Mao Hsiaoyin , Qu Meihua , Zhao Weiqiang , Yu Jianhua , Wang Qi-En
Published: February 2014

Ovarian cancer is an extremely aggressive disease associated with a high percentage of tumor recurrence and chemotherapy resistance. Understanding the underlying mechanism of tumor relapse is crucial for effective therapy of ovarian cancer. DNA damage-binding protein 2 (DDB2) is a DNA repair factor mainly involved in nucleotide excision repair. Here, a novel role was identified for DDB2 in the tumorigenesis of ovarian cancer cells and the prognosis of patients with ovarian cancer. Overexpressing DDB2 in human ovarian cancer cells suppressed its capability to recapitulate tumors in athymic nude mice. Mechanistic investigation demonstrated that DDB2 is able to reduce the cancer stem cell (CSC) population characterized with high aldehyde dehydrogenase activity in ovarian cancer cells, probably through disrupting the self-renewal capacity of CSCs. Low DDB2 expression correlates with poor outcomes among patients with ovarian cancer, as revealed from the analysis of publicly available gene expression array datasets. Given the finding that DDB2 protein expression is low in ovarian tumor cells, enhancement of DDB2 expression is a promising strategy to eradicate CSCs and would help to halt ovarian cancer relapse.

Implications: DDB2 status has prognostic potential, and elevating its expression eradicates CSCs and could reduce ovarian cancer relapse. Mol Cancer Res; 12(5); 784–94. ©2014 AACR.
NEDD9 Regulates Actin Dynamics through Cortactin Deacetylation in an AURKA/HDAC6–Dependent Manner
Authors: Kozyreva Varvara K. , McLaughlin Sarah L. , Livengood Ryan H. , Calkins Robin A. , Kelley Laura C. , Rajulapati Anuradha , Ice Ryan J. , Smolkin Matthew B. , Weed Scott A. , Pugacheva Elena N.
Published: February 2014

The prometastatic protein NEDD9 (neural precursor cell expressed, developmentally downregulated 9) is highly expressed in many cancers and is required for mesenchymal individual cell migration and progression to the invasive stage. Nevertheless, the molecular mechanisms of NEDD9-driven migration and the downstream targets effecting metastasis are not well defined. In the current study, knockdown of NEDD9 in highly metastatic tumor cells drastically reduces their migratory capacity due to disruption of actin dynamics at the leading edge. Specifically, NEDD9 deficiency leads to a decrease in the persistence and stability of lamellipodial protrusions similar to knockdown of cortactin (CTTN). Mechanistically, it was shown that NEDD9 binds to and regulates acetylation of CTTN in an Aurora A kinase (AURKA)/HDAC6–dependent manner. The knockdown of NEDD9 or AURKA results in an increase in the amount of acetylated CTTN and a decrease in the binding of CTTN to F-actin. Overexpression of the deacetylation mimicking (9KR) mutant of CTTN is sufficient to restore actin dynamics at the leading edge and migration proficiency of the tumor cells. Inhibition of AURKA and HDAC6 activity by alisertib and Tubastatin A in xenograft models of breast cancer leads to a decrease in the number of pulmonary metastases. Collectively, these findings identify CTTN as the key downstream component of NEDD9-driven migration and metastatic phenotypes.

Implications: This study provides a mechanistic platform for therapeutic interventions based on AURKA and HDAC6 inhibition for patients with metastatic breast cancer to prevent and/or eradicate metastases. Mol Cancer Res; 12(5); 681–93. ©2014 AACR.
Monotherapy with Intravenous Vinflunine in Patients with Advanced or Metastatic Urothelial Cancer after Failure of a Platinum-Containing Regimen: A Retrospective Analysis of German Routine Data
Authors: Hegele Axel , Goebell Peter , Matz Ullrich , Neuhaus Thomas
Published: February 2014

Objective: The objective of this retrospective study was to investigate the efficacy and safety of vinflunine monotherapy and the utility of second-line prognostic factors in patients with advanced or metastatic urothelial cancer relapsing/progressing during or after a prior platinum-containing regimen under daily routine clinical conditions in Germany. Methods: The selection was based on the marketing authorization indication and recommendations as well as on the evaluation of second-line prognostic factors issued from prior pivotal trials. Results: Eight centers across Germany provided a total of 21 patient records. Demographic and clinical characteristics were similar to the data previously reported in pivotal trials. Complete and partial response to vinflunine treatment was observed in 1 (4.8%) and 3 (14.3%) patients, respectively, resulting in an overall response rate of 19.1%. The disease control rate reached 47.7%. The median progression-free survival amounted to 4.4 months (95% CI 2.6-6.6), with a median overall survival of 6.2 months (95% CI 3.9-10.7). The observed toxicity profile was manageable and consistent with prior clinical trials: leukopenia (33.3%), neutropenia (9.5%), anemia (9.5%) and hyperglycemia (4.8%). The reported satisfaction rate with the treatment was 90.5 and 61.9% among patients and physicians, respectively. Conclusions: This retrospective study confirms that the clinical outcomes obtained from routine medical practice in Germany with vinflunine in the treatment of advanced/metastatic urothelial cancer are in line with the data observed in prior clinical trials.
THADA Gene Polymorphism and Prostate Cancer Risk: A Meta-Analysis
Authors: Zhao Fan , Xu Yong , Yang Kuo , Liu Ming , Wei Dong , Zhang Yaoguang , Shi Xiaohong , Yang Fan , Wang Xin , Liang Siying , Zhao Chengxiao , Chen Xin , Sun Liang , Zhu Xiaoquan , Wang Nana , Hui Juan , Zhang Yurong , Zhu Ling , Yang Yige , Tang Lei , Wang Jianye , Yang Ze
Published: February 2014

Background: The single nucleotide polymorphism (SNP) rs1465618 in THADA at 2p21 has been identified as being associated with prostate cancer (PCa) risk in Europeans; however, it is not clear whether the SNP is related to PCa risk in multiple populations. We investigated the association of rs1465618 in THADA with PCa in a Chinese population and carried out a meta-analysis in multiple populations, testing the relevance of this SNP for PCa risk. Patients and Methods: We genotyped the SNP using high resolution melting (HRM) analysis and assessed its association with PCa risk in a case-control study of 289 PCa patients and 288 controls in a Chinese population. A meta-analysis was carried out with 36,313 PCa patients and 36,485 controls to evaluate the association of rs1465618 with PCa risk in multiple populations. Results: rs1465618 in THADA was significantly associated with PCa risk (p = 0.026; odds ratio (OR) 1.327, 95% confidence interval (CI) 1.035-1.700). Furthermore, the rs1465618 variant genotype was associated with PCa aggressiveness (p = 0.044; OR = 2.053, 95% CI = 1.015-6.602) in the Chinese population. The meta-analysis showed that rs1465618 was significantly associated with PCa risk in multiple populations (p = 1.0×10-8; OR = 1.127, 95% CI = 1.085-1.171). Conclusion: Our results showed that rs1465618 in THADA may be a shared susceptibility variant for PCa in multiple populations. THADA gene polymorphisms may impact PCa susceptibility and progression.
Investigation of Using Diffusion-Weighted Magnetic Resonance Imaging to Evaluate the Therapeutic Effect of Esophageal Carcinoma Treatment
Authors: Wang Lan , Han Chun , Zhu Shuchai , Shi Gaofeng , Wang Qi , Tian Hua , Kong Jie , Zhang Andu
Published: February 2014

Aim: To explore the associations of diffusion-weighted magnetic resonance imaging (DWI) measurements with the therapeutic effect (TE) on and survival of esophageal carcinoma patients treated with chemoradiotherapy (CRT). Methods: From March 2010 to December 2011, 77 patients were prospectively enrolled into a cohort study. DWI was performed at the beginning and 1-3 months after CRT. The immediate post-CRT TE was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). The associations between the disappearance status of hyperintense expression (HE) in DWI and the apparent diffusion coefficient (ADC) of DWI with the complete response (CR) as TE and survival were analyzed. Results: 3 patients were excluded due to the absence of HE in DWI. Analysis of the remaining 74 patients indicated that their ADC values were significantly improved from 1.64 ± 0.48 to 2.65 ± 0.58 mm2/s from pre-CRT to post-CRT (p = 0.000). Both univariate and multivariate Cox model analyses showed that high post-CRT ADC values and the disappearance status of HE associated significantly with the TE (CR rate) and survival. Conclusions: DWI examination could afford useful markers to predict the treatment response as well as the survival of patients with esophageal squamous cell carcinoma. The non-disappearance of HE in DWI and low ADC values after CRT were risk factors.
Proteome-Based Systems Biology Analysis of the Diabetic Mouse Aorta Reveals Major Changes in Fatty Acid Biosynthesis as Potential Hallmark in Diabetes Mellitus–Associated Vascular Disease
Authors: Husi Holger , Van Agtmael Tom , Mullen William , Bahlmann Ferdinand H. , Schanstra Joost P. , Vlahou Antonia , Delles Christian , Perco Paul , Mischak Harald
Published: February 2014

Background—

Macrovascular complications of diabetes mellitus are a major risk factor for cardiovascular morbidity and mortality. Currently, studies only partially described the molecular pathophysiology of diabetes mellitus–associated effects on vasculature. However, better understanding of systemic effects is essential in unraveling key molecular events in the vascular tissue responsible for disease onset and progression.

Methods and Results—

Our overall aim was to get an all-encompassing view of diabetes mellitus–induced key molecular changes in the vasculature. An integrative proteomic and bioinformatics analysis of data from aortic vessels in the low-dose streptozotocin-induced diabetic mouse model (10 animals) was performed. We observed pronounced dysregulation of molecules involved in myogenesis, vascularization, hypertension, hypertrophy (associated with thickening of the aortic wall), and a substantial reduction of fatty acid storage. A novel finding is the pronounced downregulation of glycogen synthase kinase-3β (Gsk3β) and upregulation of molecules linked to the tricarboxylic acid cycle (eg, aspartate aminotransferase [Got2] and hydroxyacid-oxoacid transhydrogenase [Adhfe1]). In addition, pathways involving primary alcohols and amino acid breakdown are altered, potentially leading to ketone-body production. A number of these findings were validated immunohistochemically. Collectively, the data support the hypothesis that in this diabetic model, there is an overproduction of ketone-bodies within the vessels using an alternative tricarboxylic acid cycle-associated pathway, ultimately leading to the development of atherosclerosis.

Conclusions—

Streptozotocin-induced diabetes mellitus in animals leads to a reduction of fatty acid biosynthesis and an upregulation of an alternative ketone-body formation pathway. This working hypothesis could form the basis for the development of novel therapeutic intervention and disease management approaches.
Molecular Imaging of the Cardiac Extracellular Matrix
Authors: de Haas Hans J. , Arbustini Eloisa , Fuster Valentin , Kramer Christopher M. , Narula Jagat
Published: February 2014

In almost all cardiac diseases, an increase in extracellular matrix (ECM) deposition or fibrosis occurs, mostly consisting of collagen I. Whereas replacement fibrosis follows cardiomyocyte loss in myocardial infarction, reactive fibrosis is triggered by myocardial stress or inflammatory mediators and often results in ventricular stiffening, functional deterioration, and development of heart failure. Given the importance of ECM deposition in cardiac disease, ECM imaging could be a valuable clinical tool. Molecular imaging of ECM may help understand pathology, evaluate impact of novel therapy, and may eventually find a role in predicting the extent of ECM expansion and development of personalized treatment. In the current review, we provide an overview of ECM imaging including the assessment of ECM volume and molecular targeting of key players involved in ECM deposition and degradation. The targets comprise myofibroblasts, intracardiac renin-angiotensin axis, matrix metalloproteinases, and matricellular proteins.
Translating Koch’s Postulates to Identify Matrix Metalloproteinase Roles in Postmyocardial Infarction Remodeling
Authors: Iyer Rugmani Padmanabhan , de Castro Brás Lisandra E. , Jin Yu-Fang , Lindsey Merry L.
Published: February 2014

The first matrix metalloproteinase (MMP) was described in 1962; and since the 1990s, cardiovascular research has focused on understanding how MMPs regulate many aspects of cardiovascular pathology from atherosclerosis formation to myocardial infarction and stroke. Although much information has been gleaned by these past reports, to a large degree MMP cardiovascular biology remains observational, with few studies homing in on cause and effect relationships. Koch's postulates were first developed in the 19th century as a way to establish microorganism function and were modified in the 20th century to include methods to establish molecular causality. In this review, we outline the concept for establishing a similar approach to determine causality in terms of MMP functions. We use left ventricular remodeling postmyocardial infarction as an example, but this approach will have broad applicability across both the cardiovascular and the MMP fields.
Dynamic Changes in Myocardial Matrix and Relevance to Disease
Authors: Li Ai-Hsien , Liu Peter P. , Villarreal Francisco J. , Garcia Ricardo A.
Published: February 2014

The cardiac extracellular matrix (ECM) provides the architectural scaffold to support efficient contraction and relaxation of cardiomyocytes. The elegant design of the ECM facilitates optimal force transduction, electric transmission, intercellular communication, and metabolic exchange within the myocardial microenvironment. In the setting of increased wall stress, injury, or disease, the ECM can undergo a series of dynamic changes that lead to favorable chamber remodeling and functional adaptation. Over time, sustained matrix remodeling can impair diastolic and systolic function caused by excess deposition of interstitial fibrous tissue. These pathological alterations in ECM structure/function are considered central to the evolution of adverse cardiac remodeling and the development of heart failure. This review discusses the complex dynamics of the cardiac ECM in the setting of myocardial infarction, pressure overload, and volume overload. We also summarize the current status of ECM biomarkers that may have clinical value in prognosticating cardiac disease progression in patients. Finally, we discuss the most current status of drugs under evaluation for use in cardiac fibrosis.