bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissociable effects of local inhibitory and excitatory theta-burst stimulation on large-scale brain dynamics
Authors: Cocchi Luca , Sale Martin V. , Lord Anton , Zalesky Andrew , Breakspear Michael , Mattingley Jason B.
Published: February 2015

Normal brain function depends on a dynamic balance between local specialization and large-scale integration. It remains unclear, however, how local changes in functionally specialized areas can influence integrated activity across larger brain networks. By combining transcranial magnetic stimulation with resting-state functional magnetic resonance imaging, we tested for changes in large-scale integration following the application of excitatory or inhibitory stimulation on the human motor cortex. After local inhibitory stimulation, regions encompassing the sensorimotor module concurrently increased their internal integration and decreased their communication with other modules of the brain. There were no such changes in modular dynamics following excitatory stimulation of the same area of motor cortex nor were there changes in the configuration and interactions between core brain hubs after excitatory or inhibitory stimulation of the same area. These results suggest the existence of selective mechanisms that integrate local changes in neural activity, while preserving ongoing communication between brain hubs.
Differential Purkinje cell simple spike activity and pausing behavior related to cerebellar modules
Authors: Zhou Haibo , Voges Kai , Lin Zhanmin , Ju Chiheng , Schonewille Martijn
Published: February 2015

The massive computational capacity of the cerebellar cortex is conveyed by Purkinje cells onto cerebellar and vestibular nuclei neurons through their GABAergic, inhibitory output. This implies that pauses in Purkinje cell simple spike activity are potentially instrumental in cerebellar information processing, but their occurrence and extent are still heavily debated. The cerebellar cortex, although often treated as such, is not homogeneous. Cerebellar modules with distinct anatomical connectivity and gene expression have been described, and Purkinje cells in these modules also differ in firing rate of simple and complex spikes. In this study we systematically correlate, in awake mice, the pausing in simple spike activity of Purkinje cells recorded throughout the entire cerebellum, with their location in terms of lobule, transverse zone, and zebrin-identified cerebellar module. A subset of Purkinje cells displayed long (>500-ms) pauses, but we found that their occurrence correlated with tissue damage and lower temperature. In contrast to long pauses, short pauses (<500 ms) and the shape of the interspike interval (ISI) distributions can differ between Purkinje cells of different lobules and cerebellar modules. In fact, the ISI distributions can differ both between and within populations of Purkinje cells with the same zebrin identity, and these differences are at least in part caused by differential synaptic inputs. Our results suggest that long pauses are rare but that there are differences related to shorter intersimple spike intervals between and within specific subsets of Purkinje cells, indicating a potential further segregation in the activity of cerebellar Purkinje cells.
The kinematics of far-near re-fixation saccades
Authors: Hess Bernhard J. M. , Misslisch H.
Published: February 2015

We have analyzed the three-dimensional spatiotemporal characteristics of saccadic refixations between far and near targets in three behaviorally trained rhesus monkeys. The kinematics underlying these rapid eye movements can be accurately described by rotations of the eyes in four different planes, namely, first disconjugate rotations in the horizontal plane of regard converging the eyes toward the near target, followed by rotations in each eye's vertical direction plane, and finally, disconjugate rotations in a common frontoparallel plane. This compounded rotation of the eye was underlying an initially fast-rising variable torsion that typically overshot the final torsion, which the eyes attained at the time of target acquisition. The torsion consisted of a coarse, widely varying component of opposite polarity in the two eyes, which contained a more robust, much smaller modulation that sharply increased toward the end of saccades. The reorientation of the eyes in torsion depended on each eye's azimuth, elevation, and target distance. We conclude that refixation saccades are generated by motor commands that control ocular torsion in concert with the saccade generator, which operates in Donders-Listing kinematics underlying Listing's law.
Inhibition during response preparation is sensitive to response complexity
Authors: Greenhouse Ian , Saks Dylan , Hoang Timothy , Ivry Richard B.
Published: February 2015

Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single-pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors.
Systemic Steroid Treatment for Severe Expanding Pneumococcal Pneumonia
Authors: Lavi Eran , Shoseyov David , Simanovsky Natalia , Brooks Rebecca
Published: February 2015

The treatment of bacterial community-acquired pneumonia (CAP) is based on appropriate antibiotic therapy and supportive care such as intravenous fluids and supplemental oxygen. There is no available data regarding the use of steroids in CAP in children. We present an unusual case of a child with severe respiratory distress, on the brink of mechanical ventilation, due to a rapidly expanding pneumococcal pneumonia. The administration of systemic steroids resulted in a dramatic response with rapid improvement of clinical and radiological abnormalities followed by improvement of laboratory abnormalities. This case report should raise the awareness of the potential benefits of steroids in the treatment of severe pneumonia in children. Prospective randomized trials are needed to confirm the efficacy of steroids in this setting and to determine which patients would benefit most from this.
Correlation of Defect‐Related Optoelectronic Properties in Zn5(OH)6(CO3)2/ZnO Nanostructures with Their Quasi‐Fractal Dimensionality
Authors: Paramo J. Antonio , Strzhemechny Yuri M. , Endo Tamio , Crnjak Orel Zorica
Published: February 2015

Hydrozincite (Zn5(OH)6(CO3)2) is, among others, a popular precursor used to synthesize nanoscale ZnO with complex morphologies. For many existing and potential applications utilizing nanostructures, performance is determined by the surface and subsurface properties. Current understanding of the relationship between the morphology and the defect properties of nanocrystalline ZnO and hydrozincite systems is still incomplete. Specifically, for the latter nanomaterial the structure‐property correlations are largely unreported in the literature despite the extensive use of hydrozincite in the synthesis applications. In our work, we addressed this issue by studying precipitated nanostructures of Zn5(OH)6(CO3)2 with varying quasi‐fractal dimensionalities containing relatively small amounts of a ZnO phase. Crystal morphology of the samples was accurately controlled by the growth time. We observed a strong correlation between the morphology of the samples and their optoelectronic properties. Our results indicate that a substantial increase of the free surface in the nanocrystal samples generates higher relative concentration of defects, consistent with the model of defect‐rich surface and subsurface layers.
The Chaperone Balance Hypothesis: The Importance of the Extracellular to Intracellular HSP70 Ratio to Inflammation‐Driven Type 2 Diabetes, the Effect of Exercise, and the Implications for Clinical Management
Authors: Krause Mauricio , Heck Thiago Gomes , Bittencourt Aline , Scomazzon Sofia Pizzato , Newsholme Philip , Curi Rui , Homem de Bittencourt Paulo Ivo
Published: February 2015

Recent evidence shows divergence between the concentrations of extracellular 70 kDa heat shock protein [eHSP70] and its intracellular concentrations [iHSP70] in people with type 2 diabetes (T2DM). A vital aspect regarding HSP70 physiology is its versatility to induce antagonistic actions, depending on the location of the protein. For example, iHSP70 exerts a powerful anti‐inflammatory effect, while eHSP70 activates proinflammatory pathways. Increased eHSP70 is associated with inflammatory and oxidative stress conditions, whereas decreased iHSP70 levels are related to insulin resistance in skeletal muscle. Serum eHSP70 concentrations are positively correlated with markers of inflammation, such as C‐reactive protein, monocyte count, and TNF‐α, while strategies to enhance iHSP70 (e.g., heat treatment, chemical HSP70 inducers or coinducers, and physical exercise) are capable of reducing the inflammatory profile and the insulin resistance state. Here, we present recent findings suggesting that imbalances in the HSP70 status, described by the [eHSP70]/[iHSP70] ratio, may be determinant to trigger a chronic proinflammatory state that leads to insulin resistance and T2DM development. This led us to hypothesize that changes in this ratio value could be used as a biomarker for the management of the inflammatory response in insulin resistance and diabetes.
3D Palmprint Recognition Using Dempster-Shafer Fusion Theory
Authors: Ni Jianyun , Luo Jing , Liu Wubin
Published: February 2015

This paper proposed a novel 3D palmprint recognition algorithm by combining 3D palmprint features using D-S fusion theory. Firstly, the structured light imaging is used to acquire the 3D palmprint data. Secondly, two types of unique features, including mean curvature feature and Gaussian curvature feature, are extracted. Thirdly, the belief function of the mean curvature recognition and the Gaussian curvature recognition was assigned, respectively. Fourthly, the fusion belief function from the proposed method was determined by the Dempster-shafer (D-S) fusion theory. Finally, palmprint recognition was accomplished according to the classification criteria. A 3D palmprint database with 1000 range images from 100 individuals was established, on which extensive experiments were performed. The results show that the proposed method 3D palmprint recognition is much more robust to illumination variations and condition changes of palmprint than MCR and GCR. Meanwhile, by fusing mean curvature and Gaussian curvature feature, the experimental results are promising (the average equal error rate of 0.404%). In the future, imaging technique needs further improvement for a better recognition performance.
A Radar Wind Analysis System for Nowcast Applications
Authors: Xu Qin , Wei Li , Nai Kang , Liu Shun , Rabin Robert M. , Zhao Qingyun
Published: February 2015

A radar wind analysis system (RWAS) has been developed for nowcast applications. By ingesting real-time wind observations from operational WSR-88D radars and surface mesonet, this system can produce and display real-time vector winds at each selected vertical level or on each conical surface of radar scans superimposed on radar reflectivity or radial-velocity images. An early version of the system has been evaluated and used to provide real-time winds to drive high-resolution emergency response dispersion models. This paper presents the detailed formulations of background error correlation functions used in each of the three steps of vector wind analysis performed in the RWAS and the method of solution used in each step of vector wind analysis. The performances of the RWAS are demonstrated by illustrative examples.
Analysis of Urban Car Owners Commute Mode Choice Based on Evolutionary Game Model
Authors: Gong Huawei , Jin Wenzhou
Published: February 2015

With the aggravation of the traffic congestion in the city, car owners will have to give up commuting with private cars and take the public transportation instead. The paper uses the replication dynamic mechanism to simulate the learning and adjustment mechanism of the automobile owners commuting mode selection. The evolutionary stable strategy is used to describe the long-term evolution of competition game trend. Finally we simulate equilibrium and stability of an evolution of the game under a payoff imbalance situation. The research shows that a certain proportion of car owners will choose public transit under the pressure of public transport development and heavy traffic, and the proportion will be closely related to the initial conditions and urban transportation development policy.
Lutein Has a Protective Effect on Hepatotoxicity Induced by Arsenic via Nrf2 Signaling
Authors: Li Shugang , Ding Yusong , Niu Qiang , Xu Shangzhi , Pang Lijuan , Ma Rulin , Jing Mingxia , Feng Gangling , Tang Jing Xia , Zhang Qian , Ma Xiaomei , Yan Yizhong , Zhang Jingyu , Wei Meng , Wang Hai Xia , Li Feng , Guo Shuxia
Published: February 2015

Arsenic produces liver disease through the oxidative stress. While lutein can alleviate cytotoxic and oxidative injury, nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a critical role in defending oxidative species. However, the mechanisms by which lutein protects the liver against the effect of arsenic are not known. Therefore, this study aims to investigate the mechanisms involved in the action of lutein using mice model in which hepatotoxicity was induced by arsenic. We found that mice treatment with lutein could reverse changes in morphological and liver indexes and result in a significant improvement in hepatic function comparing with arsenic trioxide group. Lutein treatment improved the activities of antioxidant enzymes and attenuated increasing of ROS and MDA induced by arsenic trioxide. Lutein could increase the mRNA and protein expression of Nrf2 signaling related genes (Nrf2, Nqo1, Ho-1, and Gst). These findings provide additional evidence that lutein may be useful for reducing reproductive injury associated with oxidative stress by the activation of Nrf2 signaling. Our findings suggest a possible mechanism of antioxidant lutein in preventing the hepatotoxicity, which implicate that a dietary lutein may be a potential treatment for liver diseases, especially for arsenicosis therapy.
Genome-Wide Identification, Evolutionary, and Expression Analyses of Histone H3 Variants in Plants
Authors: Cui Jinteng , Zhang Zhanlu , Shao Yang , Zhang Kezhong , Leng Pingsheng , Liang Zhe
Published: February 2015

Histone variants alter the nucleosome structure and play important roles in chromosome segregation, transcription, DNA repair, and sperm compaction. Histone H3 is encoded by many genes in most eukaryotic species and is the histone that contains the largest variety of posttranslational modifications. Compared with the metazoan H3 variants, little is known about the complex evolutionary history of H3 variants proteins in plants. Here, we study the identification, evolutionary, and expression analyses of histone H3 variants from genomes in major branches in the plant tree of life. Firstly we identified all the histone three related (HTR) genes from the examined genomes, then we classified the four groups variants: centromeric H3, H3.1, H3.3 and H3-like, by phylogenetic analysis, intron information, and alignment. We further demonstrated that the H3 variants have evolved under strong purifying selection, indicating the conservation of HTR proteins. Expression analysis revealed that the HTR has a wide expression profile in maize and rice development and plays important roles in development.
Bilateral Coordination Strategy of Supply Chain with Bidirectional Option Contracts under Inflation
Authors: Wan Nana , Chen Xu
Published: February 2015

As far as the price increase and the demand contraction caused by inflation are concerned, we establish a Stackelberg game model that incorporates bidirectional option contracts and the effect of inflation and derive the optimal ordering and production policies on a one-period two-stage supply chain composed of one supplier and one retailer. Through using the model of wholesale price contracts as the benchmark, we find that the introduction of bidirectional option contracts can benefit both the supplier and the retailer under inflation scenarios. Based on the conclusions drawn above, we design the bilateral coordination mechanism from the different perspective of two members involved and discuss how bidirectional option contracts should be set to achieve channel coordination under inflation scenarios. Through the sensitivity analysis, we illustrate the effect of inflation on the optimal decision variables and the optimal expected profits of the two parties with bidirectional option contracts.
TAP-Stenting Technique for Bifurcation Stenosis of Celiac Artery
Authors: Colkesen Yucel , Seker Taner , Kuloglu Osman , Çayli Murat
Published: February 2015

We report a clinical course of a patient who developed severe ischemic liver injury and total occlusion of the celiac artery (CA). A 40-year-old man presented with abdominal pain. Computed tomography indicated total occlusion of the CA. Laboratory data demonstrated markedly elevated hepatic enzymes. An exploratory laparotomy was not necessitated due to absence of peritonism. The patient was successfully treated by endovascular recanalization of the CA occlusion via transcatheter balloon angioplasty and TAP-stenting (T-stenting and small protrusion) technique. Endovascular intervention in patients solely with liver failure appears practicable and early treatment is advised.
Descemet Membrane Endothelial Keratoplasty: Intraoperative and Postoperative Imaging Spectral-Domain Optical Coherence Tomography
Authors: Ang Marcus , Dubis Adam M. , Wilkins Mark R.
Published: February 2015

We describe a case report of using the same handheld spectral-domain anterior segment optical coherence tomography (ASOCT) for rapid intraoperative and postoperative imaging in a case of Descemet membrane endothelial keratoplasty (DMEK). A 67-year-old woman, with Fuchs dystrophy and corneal decompensation, underwent DMEK with intraoperative ASOCT imaging using the handheld Envisu spectral domain ASOCT system (Bioptigen, Inc., Morrisville, NC, USA). We found that this easy-to-use portable system with handheld probe allowed for rapid imaging of the anterior segment during donor manipulation to visualize the orientation of the DMEK donor, as well as to confirm the initial adhesion of the DMEK donor. Moreover, the same system may be used for postoperative monitoring of graft adhesion, corneal thickness, and stromal remodeling in the clinic with very high-definition images.
The Electrochemical Stability in NaCl Solution of Nanotubes and Nanochannels Elaborated on a New Ti‐20Zr‐5Ta‐2Ag Alloy
Authors: Manole Claudiu Constantin , Pirvu Cristian , Stoian Andrei Bogdan , Calderon Moreno Jose M. , Stanciu Doina , Demetrescu Ioana
Published: February 2015

Nanotubular and nanochannels structures were fabricated via anodizing on a new alloy Ti‐20Zr‐8Ta‐2Ag. A continuous coating of connected tubes/channels can be observed in the SEM micrographs forming tubular structures with diameters in hundreds of nm, as well as smaller tubes, with diameters in tens of nm. In the case of nanochannels structure, the diameters are smaller and wall thicknesses significantly thinner than in nanotubes. Wettability measurements indicate a decrease of contact angles in both cases of nanotubes and nanochannels, but the increase of hydrophilic character is more significant in the case of nanochannels. The Tafel procedure and electrochemical impedance spectroscopy tests performed in NaCl 0.9% solution indicate a better stability for the nanostructured surfaces compared to untreated alloy, the surface with nanochannels offering higher corrosion resistance. Spectral UV‐VIS determination has confirmed Ag metallic presence, opening the door for applications not only in tissue engineering but for water splitting and the photoreduction of CO2 as well.
Acoustic Self-Calibrating System for Indoor Smart Phone Tracking
Authors: Ens Alexander , Höflinger Fabian , Wendeberg Johannes , Hoppe Joachim , Zhang Rui , Bannoura Amir , Reindl Leonhard M. , Schindelhauer Christian
Published: February 2015

This paper presents an acoustic indoor localization system for commercial smart phones that emit high pitched acoustic signals beyond the audible range. The acoustic signals with an identifier code modulated on the signal are detected by self-built receivers which are placed at the ceiling or on walls in a room. The receivers are connected in a Wi-Fi network, such that they synchronize their clocks and exchange the time differences of arrival (TDoA) of the received chirps. The location of the smart phone is calculated by TDoA multilateration. The precise time measuring of sound enables high precision localization in indoor areas. Our approach enables applications that require high accuracy, such as finding products in a supermarket or guiding blind people through complicated buildings. We have evaluated our system in real-world experiments using different algorithms for calibration-free localization and different types of sound signals. The adaptive GOGO-CFAR threshold enables a detection of 48% of the chirp pulses even at a distance of 30 m. In addition, we have compared the trajectory of a pedestrian carrying a smart phone to reference positions of an optic system. Consequently, the localization error is observed to be less than 30 cm.
Role of Circulating miRNAs as Biomarkers in Idiopathic Pulmonary Arterial Hypertension: Possible Relevance of miR-23a
Authors: Sarrion Irene , Milian Lara , Juan G. , Ramon Mercedes , Furest Idelfonso , Carda Carmen , Cortijo Gimeno Julio , Mata Roig Manuel
Published: February 2015

Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients’ pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1α, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1α, as well as in its well-known regulated genesCYC,SOD,NRF2, andHO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression.
A Simple Approach to Distinguish Classic and Formaldehyde-Free Tannin Based Rigid Foams by ATR FT-IR
Authors: Tondi Gianluca , Link Martin , Oo Chuan Wei , Petutschnigg Alexander
Published: February 2015

Tannin based rigid foams (TBRFs) have been produced with formaldehyde since 1994. Only recently several methods have been developed in order to produce these foams without using formaldehyde. TBRFs with and without formaldehyde are visually indistinguishable; therefore a method for determining the differences between these foams had to be found. The attenuated total reflectance infrared spectroscopy (ATR FT-IR) investigation of the TBRFs presented in this paper allowed discrimination between the formaldehyde-containing (classic) and formaldehyde-free TBRFs. The spectra of the formaldehyde-free TBRFs, indeed, present decreased band intensity related to the C–O stretching vibration of (i) the methylol groups and (ii) the furanic rings. This evidence served to prove the chemical difference between the two TBRFs and explained the slightly higher mechanical properties measured for the classic TBRFs.
Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem–like Cells in an Akt/Foxo3a/TRAIL–Dependent Manner
Authors: Prabhu Varun V. , Allen Joshua E. , Dicker David T. , El-Deiry Wafik S.
Published: February 2015

Self-renewing colorectal cancer stem/progenitor cells (CSC) contribute to tumor maintenance and resistance to therapy. Therapeutic targeting of CSCs could improve treatment response and prolong patient survival. ONC201/TIC10 is a first-in-class antitumor agent that induces TRAIL pathway–mediated cell death in cancer cells without observed toxicity. We have previously described that ONC201/TIC10 exposure leads to transcriptional induction of the TRAIL gene via transcription factor Foxo3a, which is activated by dual inactivation of Akt and ERK. The Akt and ERK pathways serve as important targets in CSCs. Foxo3a is a key mediator of Akt and ERK-mediated CSC regulation. We hypothesized that the potent antitumor effect of ONC201/TIC10 in colorectal cancer involves targeting CSCs and bulk tumor cells. ONC201/TIC10 depletes CD133+, CD44+, and Aldefluor+ cells in vitro and in vivo. TIC10 significantly inhibits colonosphere formation of unsorted and sorted 5-fluorouracil–resistant CSCs. ONC201/TIC10 significantly reduces CSC-initiated xenograft tumor growth in mice and prevents the passage of these tumors. ONC201/TIC10 treatment also decreased xenograft tumor initiation and was superior to 5-fluorouracil treatment. Thus, ONC201/TIC10 inhibits CSC self-renewal in vitro and in vivo. ONC201/TIC10 inhibits Akt and ERK, consequently activating Foxo3a and significantly induces cell surface TRAIL and DR5 expression in both CSCs and non-CSCs. ONC201/TIC10-mediated anti-CSC effect is significantly blocked by the TRAIL sequestering antibody RIK-2. Overexpression of Akt, DR5 knockdown, and Foxo3a knockdown rescues ONC201/TIC10-mediated depletion of CD44+ cells and colonosphere inhibition. In conclusion, ONC201/TIC10 is a promising agent for colorectal cancer therapy that targets both non-CSCs and CSCs in an Akt–Foxo3a–TRAIL–dependent manner. Cancer Res; 75(7); 1423–32. ©2015 AACR.
Usp28 Counteracts Fbw7 in Intestinal Homeostasis and Cancer
Authors: Diefenbacher Markus E. , Chakraborty Atanu , Blake Sophia M. , Mitter Richard , Popov Nikita , Eilers Martin , Behrens Axel
Published: February 2015

The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin-dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a “piggyback” interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity. Unexpectedly, we found that genetic deletion of Usp28 rescued the lethality of Fbw7-deficient primary fibroblasts. Moreover, Usp28 inactivation in the intestine (Usp28ΔIEC) ameliorated the hyperproliferation and the impaired goblet and Paneth cell differentiation observed in Fbw7ΔIEC mice. The aggressive intestinal tumor formation of APCMin/+; Fbw7ΔIEC mice was restrained when Usp28 was inactivated concomitantly. In both fibroblasts and intestinal cells, Usp28 deficiency corrected the accumulation of SCF(Fbw7) substrate proteins, including NICD1, c-Jun, and c-Myc. These findings suggested that Usp28 function does not depend on the presence of Fbw7, but instead independently recognizes and deubiquitylates the same substrates as SCF(Fbw7). Fbw7 binds to a phosphorylated motif termed the phosphodegron and we found that Usp28 also interacted with this same motif, but only when it is unphosphorylated, offering a mechanistic explanation for identical substrate selection by Fbw7 and Usp28. Our results indicate an unusually direct antagonism between an E3 ligase and a deubiquitinase, Fbw7 and Usp28, in modulating intestinal homeostasis and cancer. Cancer Res; 75(7); 1181–6. ©2015 AACR.
MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells
Authors: Koch Adam T. , Love-Homan Laurie , Espinosa-Cotton Madelyn , Stanam Aditya , Simons Andrean L.
Published: February 2015

EGFR is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). However, many patients with HNSCC respond poorly to the EGFR inhibitors (EGFRI) cetuximab and erlotinib, despite tumor expression of EGFR. Gene expression analysis of erlotinib-treated HNSCC cells revealed an upregulation of genes involved in MyD88-dependent signaling compared with their respective vehicle-treated cell lines. We therefore investigated whether MyD88-dependent signaling may reduce the antitumor efficacy of EGFRIs in HNSCC. Erlotinib significantly upregulated IL6 secretion in HNSCC cell lines, which our laboratory previously reported to result in reduced drug efficacy. Suppression of MyD88 expression blocked erlotinib-induced IL6 secretion in vitro and increased the antitumor activity of erlotinib in vivo. There was little evidence of Toll-like receptor or IL18 receptor involvement in erlotinib-induced IL6 secretion. However, suppression of IL1R signaling significantly reduced erlotinib-induced IL6 production. A time-dependent increase of IL1α but not IL1β was observed in response to erlotinib treatment, and IL1α blockade significantly increased the antitumor activity of erlotinib and cetuximab in vivo. A pan-caspase inhibitor reduced erlotinib-induced IL1α secretion, suggesting that IL1α was released because of cell death. Human HNSCC tumors showed higher IL1α mRNA levels compared with matched normal tissue, and IL1α was found to be negatively correlated with survival in patients with HNSCC. Overall, the IL1α/IL1R/MYD88/IL6 pathway may be responsible for the reduced antitumor efficacy of erlotinib and other EGFRIs, and blockade of IL1 signaling may improve the efficacy of EGFRIs in the treatment of HNSCC. Cancer Res; 75(8); 1657–67. ©2015 AACR.
Dietary Microbes Modulate Transgenerational Cancer Risk
Authors: Poutahidis Theofilos , Varian Bernard J. , Levkovich Tatiana , Lakritz Jessica R. , Mirabal Sheyla , Kwok Caitlin , Ibrahim Yassin M. , Kearney Sean M. , Chatzigiagkos Antonis , Alm Eric J. , Erdman Susan E.
Published: February 2015

Environmental factors are suspected in the increase of obesity and cancer in industrialized countries but are poorly understood. Here, we used animal models to test how future generations may be affected by Westernized diets. We discover long-term consequences of grandmothers' in utero dietary exposures, leading to high rates of obesity and frequent cancers of lung and liver in two subsequent generations of mice. Transgenerational effects were transplantable using diet-associated bacteria communities alone. Consequently, feeding of beneficial microbes was sufficient to lower transgenerational risk for cancer and obesity regardless of diet history. Targeting microbes may be a highly effective population-based approach to lower risk for cancer. Cancer Res; 75(7); 1197–204. ©2015 AACR.
PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets
Authors: Scortegagna Marzia , Lau Eric , Zhang Tongwu , Feng Yongmei , Sereduk Chris , Yin Hongwei , De Surya K. , Meeth Katrina , Platt James T. , Langdon Casey G. , Halaban Ruth , Pellecchia Maurizio , Davies Michael A. , Brown Kevin , Stern David F. , Bosenberg Marcus , Ronai Ze'ev A.
Published: February 2015

Melanoma development involves members of the AGC kinase family, including AKT, PKC, and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here, we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in about 70% of human melanomas. The PDK1 substrate SGK3 was determined to be an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacologic inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell-cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify patients with melanoma for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment. Cancer Res; 75(7); 1399–412. ©2015 AACR.
The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28–Costimulated T Cells Prepared for Adoptive Therapy
Authors: Zsiros Emese , Duttagupta Priyanka , Dangaj Denarda , Li Hongzhe , Frank Renee , Garrabrant Thomas , Hagemann Ian S. , Levine Bruce L. , June Carl H. , Zhang Lin , Wang Ena , Marincola Francesco M. , Bedognetti Davide , Powell Daniel J. , Tanyi Janos , Feldman Michael D. , Kandalaft Lana E. , Coukos George
Published: February 2015

Purpose: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)–vaccine primed T cells in the context of cell-based immunotherapy.

Experimental Design: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer.

Results: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer.

Conclusions: DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840–50. ©2015 AACR.
Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation
Authors: Hasegawa Masanori , Sinha Raj Kumar , Kumar Manoj , Alam Maroof , Yin Li , Raina Deepak , Kharbanda Akriti , Panchamoorthy Govind , Gupta Dikshi , Singh Harpal , Kharbanda Surender , Kufe Donald
Published: February 2015

Purpose: The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell-penetrating capabilities.

Experimental Design: Encapsulation of the MUC1-C inhibitor GO-203 in novel polymeric nanoparticles was studied for effects on intracellular targeting of MUC1-C signaling and function.

Results: Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. In addition, we found that release of GO-203 from these nanoparticles is controllable over at least 7 days. GO-203/nanoparticle treatment of MUC1-C–positive breast and lung cancer cells in vitro was more active with less frequent dosing than that achieved with nonencapsulated GO-203. Moreover, treatment with GO-203/nanoparticles blocked MUC1-C homodimerization, consistent with on-target effects. GO-203/nanoparticle treatment was also effective in downregulating TIGAR, disrupting redox balance, and inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/nanoparticles to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable with those found when dosing on a daily basis with GO-203.

Conclusions: These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA-(PEG-PPG-PEG) nanoparticles to target MUC1-C in cancer cells and (ii) the potential delivery of other anticancer peptide drugs. Clin Cancer Res; 21(10); 2338–47. ©2015 AACR.
A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma
Authors: Hansson Markus , Gimsing Peter , Badros Ashraf , Niskanen Titti Martinsson , Nahi Hareth , Offner Fritz , Salomo Morten , Sonesson Elisabeth , Mau-Sorensen Morten , Stenberg Yvonne , Sundberg Annika , Teige Ingrid , Van Droogenbroeck Jan , Wichert Stina , Zangari Maurizio , Frendeus Björn , Korsgren Magnus , Poelman Martine , Tricot Guido
Published: February 2015

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients.

Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses.

Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months.

Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.
Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo
Authors: Barton Valerie N. , D'Amato Nicholas C. , Gordon Michael A. , Lind Hanne T. , Spoelstra Nicole S. , Babbs Beatrice L. , Heinz Richard E. , Elias Anthony , Jedlicka Paul , Jacobsen Britta M. , Richer Jennifer K.
Published: February 2015

Triple-negative breast cancer (TNBC) has the lowest 5-year survival rate of invasive breast carcinomas, and currently there are no approved targeted therapies for this aggressive form of the disease. The androgen receptor (AR) is expressed in up to one third of TNBC and we find that all AR+ TNBC primary tumors tested display nuclear localization of AR, indicative of transcriptionally active receptors. While AR is most abundant in the “luminal AR (LAR)” molecular subtype of TNBC, here, for the first time, we use both the new-generation anti-androgen enzalutamide and AR knockdown to demonstrate that the other non-LAR molecular subtypes of TNBC are critically dependent on AR protein. Indeed, AR inhibition significantly reduces baseline proliferation, anchorage-independent growth, migration, and invasion and increases apoptosis in four TNBC lines (SUM159PT, HCC1806, BT549, and MDA-MB-231), representing three non-LAR TNBC molecular subtypes (mesenchymal-like, mesenchymal stem–like, and basal-like 2). In vivo, enzalutamide significantly decreases viability of SUM159PT and HCC1806 xenografts. Furthermore, mechanistic analysis reveals that AR activation upregulates secretion of the EGFR ligand amphiregulin (AREG), an effect abrogated by enzalutamide in vitro and in vivo. Exogenous AREG partially rescues the effects of AR knockdown on proliferation, migration, and invasion, demonstrating that upregulation of AREG is one mechanism by which AR influences tumorigenicity. Together, our findings indicate that non-LAR subtypes of TNBC are AR dependent and, moreover, that enzalutamide is a promising targeted therapy for multiple molecular subtypes of AR+ TNBC. Mol Cancer Ther; 14(3); 769–78. ©2015 AACR.
Novel Evidence for Curcumin and Boswellic Acid–Induced Chemoprevention through Regulation of miR-34a and miR-27a in Colorectal Cancer
Authors: Toden Shusuke , Okugawa Yoshinaga , Buhrmann Constanze , Nattamai Durgha , Anguiano Esperanza , Baldwin Nicole , Shakibaei Mehdi , Boland C. Richard , Goel Ajay
Published: February 2015

Colorectal cancer is one of the most common causes of cancer-associated mortality worldwide, but it is truly a preventable disease. Both curcumin and boswellic acids are well-established dietary botanicals with potent antitumorigenic properties that have been shown to modulate multiple oncogenic pathways. Recent data suggest that the chemopreventive effects of these botanicals may, in part, be mediated through regulation of key cancer-related microRNAs (miRNA) and their downstream gene targets. Here, we investigated the antitumorigenic effects of curcumin and 3 acetyl-11-keto-β-boswellic acid (AKBA) on modulation of specific cancer-related miRNAs in colorectal cancer cells and validated their protective effects in vivo using a xenograft mouse model. Both curcumin and AKBA inhibited cellular proliferation, induced apoptosis and cell-cycle arrest in colorectal cancer cell lines, and these effects were significantly enhanced with combined treatment. Gene-expression arrays revealed that curcumin and AKBA regulated distinct cancer signaling pathways, including key cell-cycle regulatory genes. Combined bioinformatics and in silico analysis identified apoptosis, proliferation, and cell-cycle regulatory signaling pathways as key modulators of curcumin and AKBA-induced anticancer effects. We discovered that curcumin and AKBA induced upregulation of tumor-suppressive miR-34a and downregulation of miR-27a in colorectal cancer cells. Furthermore, we demonstrated in a mouse xenograft model that both curcumin and AKBA treatments suppressed tumor growth, which corresponded with alterations in the expression of miR-34a and miR-27a, consistent with our in vitro findings. Herein, we provide novel mechanistic evidence for the chemopreventive effects of curcumin and AKBA through regulation of specific miRNAs in colorectal cancer. Cancer Prev Res; 8(5); 431–43. ©2015 AACR.
NOTCH Mutations: Multiple Faces in Human Malignancies
Authors: Mao Li
Published: February 2015

NOTCH proteins have been implicated in multiple cellular functions, such as stem cell maintenance and cell fate determination. Initially identified as proto-oncogenes because they promote the development of certain types of leukemia, inactivating mutations of NOTCH were later reported. Together with the potential distinct functions of NOTCH family members, their ligands and associated niches, the precise roles of NOTCH in human cancers, particularly solid tumors, remain unsettled. In oral squamous cell carcinoma (OSCC), mutations of NOTCH1 are found in 10% to 15% tumors from Caucasian patients, mostly inactivating mutations. Recent studies of OSCC from Chinese patients, however, showed mutation rates of NOTCH1 about 50% with a considerable portion of potential activating mutations. These findings add another twist into the already complex picture of NOTCH alterations in human cancers, calling for further investigation to uncover what role exactly these molecules play in cancer initiation and progression to develop strategies targeting NOTCH signaling for cancer prevention and treatment. Cancer Prev Res; 8(4); 259–61. ©2015 AACR.

See related article by Izumchenko et al., p. 277
Robust Antitumor Effects of Combined Anti–CD4-Depleting Antibody and Anti–PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice
Authors: Ueha Satoshi , Yokochi Shoji , Ishiwata Yoshiro , Ogiwara Haru , Chand Krishant , Nakajima Takuya , Hachiga Kosuke , Shichino Shigeyuki , Terashima Yuya , Toda Etsuko , Shand Francis H.W. , Kakimi Kazuhiro , Ito Satoru , Matsushima Kouji
Published: February 2015

Depletion of CD4+ cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4+ cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti–CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8+ cell depletion. CD4+ cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti–PD-1 or anti–PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti–PD-1 or anti–PD-L1 mAb therapies. Cancer Immunol Res; 3(6); 631–40. ©2015 AACR.