bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel paraplegia model in awake behaving macaques
Authors: Krucoff Max O. , Zhuang Katie , MacLeod David , Yin Allen , Byun Yoon Woo , Manson Roberto Jose , Turner Dennis A. , Oliveira Laura , Lebedev Mikhail A.
Published: July 2017

Lower limb paralysis from spinal cord injury (SCI) or neurological disease carries a poor prognosis for recovery and remains a large societal burden. Neurophysiological and neuroprosthetic research have the potential to improve quality of life for these patients; however, the lack of an ethical and sustainable nonhuman primate model for paraplegia hinders their advancement. Therefore, our multidisciplinary team developed a way to induce temporary paralysis in awake behaving macaques by creating a fully implantable lumbar epidural catheter-subcutaneous port system that enables easy and reliable targeted drug delivery for sensorimotor blockade. During treadmill walking, aliquots of 1.5% lidocaine with 1:200,000 epinephrine were percutaneously injected into the ports of three rhesus macaques while surface electromyography (EMG) recorded muscle activity from their quadriceps and gastrocnemii. Diminution of EMG amplitude, loss of voluntary leg movement, and inability to bear weight were achieved for 60–90 min in each animal, followed by a complete recovery of function. The monkeys remained alert and cooperative during the paralysis trials and continued to take food rewards, and the ports remained functional after several months. This technique will enable recording from the cortex and/or spinal cord in awake behaving nonhuman primates during the onset, maintenance, and resolution of paraplegia for the first time, thus opening the door to answering basic neurophysiological questions about the acute neurological response to spinal cord injury and recovery. It will also negate the need to permanently injure otherwise high-value research animals for certain experimental paradigms aimed at developing and testing neural interface decoding algorithms for patients with lower extremity dysfunction.

NEW & NOTEWORTHY A novel implantable lumbar epidural catheter-subcutaneous port system enables targeted drug delivery and induction of temporary paraplegia in awake, behaving nonhuman primates. Three macaques displayed loss of voluntary leg movement for 60–90 min after injection of lidocaine with epinephrine, followed by a full recovery. This technique for the first time will enable ethical live recording from the proximal central nervous system during the acute onset, maintenance, and resolution of paraplegia.
Altered visual strategies and attention are related to increased force fluctuations during a pinch grip task in older adults
Authors: Keenan Kevin G. , Huddleston Wendy E. , Ernest Bradley E.
Published: July 2017

The purpose of the study was to determine the visual strategies used by older adults during a pinch grip task and to assess the relations between visual strategy, deficits in attention, and increased force fluctuations in older adults. Eye movements of 23 older adults (>65 yr) were monitored during a low-force pinch grip task while subjects viewed three common visual feedback displays. Performance on the Grooved Pegboard test and an attention task (which required no concurrent hand movements) was also measured. Visual strategies varied across subjects and depended on the type of visual feedback provided to the subjects. First, while viewing a high-gain compensatory feedback display (horizontal bar moving up and down with force), 9 of 23 older subjects adopted a strategy of performing saccades during the task, which resulted in 2.5 times greater force fluctuations in those that exhibited saccades compared with those who maintained fixation near the target line. Second, during pursuit feedback displays (force trace moving left to right across screen and up and down with force), all subjects exhibited multiple saccades, and increased force fluctuations were associated ( rs = 0.6; P = 0.002) with fewer saccades during the pursuit task. Also, decreased low-frequency (<4 Hz) force fluctuations and Grooved Pegboard times were significantly related ( P = 0.033 and P = 0.005, respectively) with higher (i.e., better) attention z scores. Comparison of these results with our previously published results in young subjects indicates that saccadic eye movements and attention are related to force control in older adults.

NEW & NOTEWORTHY The significant contributions of the study are the addition of eye movement data and an attention task to explain differences in hand motor control across different visual displays in older adults. Older participants used different visual strategies across varying feedback displays, and saccadic eye movements were related with motor performance. In addition, those older individuals with deficits in attention had impaired motor performance on two different hand motor control tasks, including the Grooved Pegboard test.
Influence of envelope waveform on ITD sensitivity of neurons in the auditory midbrain
Authors: Greenberg David , Monaghan Jessica J. M. , Dietz Mathias , Marquardt Torsten , McAlpine David
Published: July 2017

Interaural time differences (ITDs) conveyed by the modulated envelopes of high-frequency sounds can serve as a cue for localizing a sound source. Klein-Hennig et al. ( J Acoust Soc Am 129: 3856, 2011) demonstrated the envelope attack (the rate at which stimulus energy in the envelope increases) and the duration of the pause (the interval between successive envelope pulses) as important factors affecting sensitivity to envelope ITDs in human listeners. Modulated sounds with rapid attacks and long pauses produce the lowest ITD discrimination thresholds. The duration of the envelope’s sustained component (sustain) and the rate at which stimulus energy falls at the offset of the envelope (decay) are only minor factors. We assessed the responses of 71 single neurons, recorded from the midbrains of 15 urethane-anesthetized tri-colored guinea pigs, to envelope shapes in which the four envelope components, i.e., attack, sustain, decay, and pause, were systematically varied. We confirmed the importance of the attack and pause components in generating ITD-sensitive responses. Analysis of neural firing rates demonstrated more neurons (49/71) show ITD sensitivity in response to “damped” stimuli (fast attack and slow decay) compared with “ramped” stimuli (slow attack and fast decay) (14/71). Furthermore, the lowest threshold for the damped stimulus (91 μs) was lower by a factor of 4 than that for the temporally reversed ramped envelope shape (407 μs). The data confirm the importance of fast attacks and optimal pause durations in generating sensitivity to ITDs conveyed in the modulated envelopes of high-frequency sounds and are incompatible with models of ITD processing based on the integration of sound energy over time.

NEW & NOTEWORTHY Using single-neuron electrophysiology, we show that the precise shape of a sound’s “energy envelope” is a critical factor in determining how well midbrain neurons are able to convey information about auditory spatial cues. Consistent with human behavioral performance, sounds with rapidly rising energy and relatively long intervals between energy bursts are best at conveying spatial information. The data suggest specific sound energy patterns that might best be applied to hearing devices to aid spatial listening.
Secondary Syphilis Presenting as Glossodynia, Plaques en Prairie Fauchée, and a Split Papule at the Oral Commissure: Case Report and Review
Authors: Eyer-Silva Walter de Araujo , Freire Maria Alessandra Leite , Horta-Araujo Cecília Angelina , Almeida Rosa da Silva Guilherme , Francisco da Cunha Pinto Jorge , Raphael de Almeida Ferry Fernando
Published: July 2017

Syphilis has been coined “the great imitator” due to its extreme heterogeneity of presentation and mimicry of other conditions. Therefore, it is essential that physicians be familiar with the full spectrum of its manifestations. Syphilis may also lead to oral lesions that, occasionally, are unaccompanied by concomitant tegumentary findings. Such patients will pose unique diagnostic challenges. We report the case of a 45-year-old HIV-infected male patient in whom secondary syphilis presented with burning mouth and dysgeusia that progressed to glossodynia and odynophagia. Examination revealed painful, shallow erosions on the posterior aspect of the tongue, in a pattern of plaques en prairie fauchée. A painful split papule (fausse perlèche or false angular cheilitis) was also present in the left commissure. There were no cutaneous lesions. The oral lesions were considered highly suggestive of secondary syphilis. A novel VDRL assay (which was previously negative) yielded a titer of 1/128. Complete clinical remission was rapidly achieved after initiation of penicillin therapy. A comprehensive review of the literature on oral manifestations of syphilis is offered.
Dynamic Characterization of Rubber O-Rings: Squeeze and Size Effects
Authors: Al-Bender Farid , Colombo Federico , Reynaerts Dominiek , Villavicencio Rodrigo , Waumans Tobias
Published: July 2017

This paper concerns the dynamic characterization of rubber O-rings used to introduce damping in high speed gas bearing systems. O-shaped rubber rings composed of high temperature rubber compounds are characterized in terms of stiffness and damping coefficients in the frequency range 100–800 Hz. Simple formulas with frequency independent coefficients were identified to express the viscoelastic properties of the O-rings. The formulas proposed approximate the stiffness and damping coefficients of O-rings of general size.
A Role for CD154, the CD40 Ligand, in Granulomatous Inflammation
Authors: Villeneuve Julien , Desmoulière Alexis , Dewitte Antoine , Bordeau Nelly , Costet Pierre , Bassaganyas Laia , Fricain Jean-Christophe , Ripoche Jean , Lepreux Sébastien
Published: July 2017

Granulomatous inflammation is a distinctive form of chronic inflammation in which predominant cells include macrophages, epithelioid cells, and multinucleated giant cells. Mechanisms regulating granulomatous inflammation remain ill-understood. CD154, the ligand of CD40, is a key mediator of inflammation. CD154 confers a proinflammatory phenotype to macrophages and controls several macrophagic functions. Here, we studied the contribution of CD154 in a mouse model of toxic liver injury with carbon tetrachloride and a model of absorbable suture graft. In both models, granulomas are triggered in response to endogenous persistent liver calcified necrotic lesions or by grafted sutures. CD154-deficient mice showed delayed clearance of carbon tetrachloride-induced liver calcified necrotic lesions and impaired progression of suture-induced granuloma. In vitro, CD154 stimulated phagocytosis of opsonized erythrocytes by macrophages, suggesting a potential mechanism for the altered granulomatous inflammation in CD154KO mice. These results suggest that CD154 may contribute to the natural history of granulomatous inflammation.
Exploiting Delay-Aware Load Balance for Scalable 802.11 PSM in Crowd Event Environments
Authors: Zhang Yu , Wei Mingfei , Cheng Chen , Xia Xianjin , Gu Tao , Li Zhigang , Li Shining
Published: July 2017

This paper presents ScaPSM (i.e., Scalable Power-Saving Mode Scheduler), a design that enables scalable competing background traffic scheduling in crowd event 802.11 deployments with Power-Saving Mode (PSM) radio operation. ScaPSM prevents the packet delay proliferation of previous study, if applied in the crowd events scenario, by introducing a new strategy of adequate competition among multiple PSM clients to optimize overall energy saving without degrading packet delay performance. The key novelty behind ScaPSM is that it exploits delay-aware load balance to control judiciously the qualification and the number of competing PSM clients before every beacon frame’s transmission, which helps to mitigate congestion at the peak period with increasing the number of PSM clients. With ScaPSM, the average packet delay is bounded and fairness among PSM clients is simultaneously achieved. ScaPSM is incrementally deployable due to only AP-side changes and does not require any modification to the 802.11 protocol or the clients. We theoretically analyze the performance of ScaPSM. Our experimental results show that the proposed design is practical, effective, and featuring with significantly improved scalability for crowd events.
Research of Simulation in Character Animation Based on Physics Engine
Authors: Yu Yang , Yang Jucheng , Zan Xiaofei , Huang Jiangang , Zhang Xiangbo
Published: July 2017

Computer 3D character animation essentially is a product, which is combined with computer graphics and robotics, physics, mathematics, and the arts. It is based on computer hardware and graphics algorithms and related sciences rapidly developed new technologies. At present, the mainstream character animation technology is based on the artificial production of key technologies and capture frames based on the motion capture device technology. 3D character animation is widely used not only in the production of film, animation, and other commercial areas but also in virtual reality, computer-aided education, flight simulation, engineering simulation, military simulation, and other fields. In this paper, we try to study physics based character animation to solve these problems such as poor real-time interaction that appears in the character, low utilization rate, and complex production. The paper deeply studied the kinematics, dynamics technology, and production technology based on the motion data. At the same time, it analyzed ODE, PhysX, Bullet, and other variety of mainstream physics engines and studied OBB hierarchy bounding box tree, AABB hierarchical tree, and other collision detection algorithms. Finally, character animation based on ODE is implemented, which is simulation of the motion and collision process of a tricycle.
Projection Surfaces Detection and Image Correction for Mobile Robots in HRI
Authors: Fernández-Rodicio Enrique , González-Pacheco Víctor , Castillo José Carlos , Castro-González Álvaro , Malfaz María , Salichs Miguel A.
Published: July 2017

Projectors have become a widespread tool to share information in Human-Robot Interaction with large groups of people in a comfortable way. Finding a suitable vertical surface becomes a problem when the projector changes positions when a mobile robot is looking for suitable surfaces to project. Two problems must be addressed to achieve a correct undistorted image: (i) finding the biggest suitable surface free from obstacles and (ii) adapting the output image to correct the distortion due to the angle between the robot and a nonorthogonal surface. We propose a RANSAC-based method that detects a vertical plane inside a point cloud. Then, inside this plane, we apply a rectangle-fitting algorithm over the region in which the projector can work. Finally, the algorithm checks the surface looking for imperfections and occlusions and transforms the original image using a homography matrix to display it over the area detected. The proposed solution can detect projection areas in real-time using a single Kinect camera, which makes it suitable for applications where a robot interacts with other people in unknown environments. Our Projection Surfaces Detector and the Image Correction module allow a mobile robot to find the right surface and display images without deformation, improving its ability to interact with people.
Intrinsic Optimal Control for Mechanical Systems on Lie Group
Authors: Liu Chao , Tang Shengjing , Guo Jie
Published: July 2017

The intrinsic infinite horizon optimal control problem of mechanical systems on Lie group is investigated. The geometric optimal control problem is built on the intrinsic coordinate-free model, which is provided with Levi-Civita connection. In order to obtain an analytical solution of the optimal problem in the geometric viewpoint, a simplified nominal system on Lie group with an extra feedback loop is presented. With geodesic distance and Riemann metric on Lie group integrated into the cost function, a dynamic programming approach is employed and an analytical solution of the optimal problem on Lie group is obtained via the Hamilton-Jacobi-Bellman equation. For a special case on SO(3), the intrinsic optimal control method is used for a quadrotor rotation control problem and simulation results are provided to show the control performance.
Ginkgolide B Suppresses TLR4‐Mediated Inflammatory Response by Inhibiting the Phosphorylation of JAK2/STAT3 and p38 MAPK in High Glucose‐Treated HUVECs
Authors: Chen Kun , Sun Wenjia , Jiang Yun , Chen Beidong , Zhao Yanyang , Sun Jie , Gong Huan , Qi Ruomei
Published: July 2017

Aim. Ginkgolide B is a Ginkgo biloba leaf extract that has been identified as a natural platelet‐activating factor receptor (PAFR) antagonist. We investigated the effect of ginkgolide B on high glucose‐induced TLR4 activation in human umbilical vein endothelial cells (HUVECs). Methods. Protein expression was analyzed by immunoblotting. Small‐interfering RNA (siRNA) was used to knock down PAFR and TLR4 expression. Results. Ginkgolide B suppressed the expression of TLR4 and MyD88 that was induced by high glucose. Ginkgolide B also reduced the levels of platelet endothelial cell adhesion molecule‐1, interleukin‐6, and monocyte chemotactic protein 1. Further, we examined the association between PAFR and TLR4 by coimmunoprecipitation. The result showed that high glucose treatment caused the binding of PAFR and TLR4, whereas ginkgolide B abolished this binding. The functional analysis indicated that PAFR siRNA treatment reduced TLR4 expression, and TLR4 siRNA treatment decreased PAFR expression in high glucose‐treated HUVECs, further supporting the coimmunoprecipitation data. Ginkgolide B inhibited the phosphorylation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and p38 mitogen‐activated protein kinase (MAPK). Conclusion. Ginkgolide B exerted protective effects by inhibiting the TLR4‐mediated inflammatory response in high glucose‐treated endothelial cells. The mechanism of action of ginkgolide B might be associated with inhibition of the JAK2/STAT3 and p38 MAPK phosphorylation.
Variable-Time-Domain Online Neighboring Optimal Trajectory Modification for Hypersonic Interceptors
Authors: Li Ningbo , Lei Humin , Zhou Jin , Shao Lei , Wang Bin
Published: July 2017

The predicted impact point (PIP) of hypersonic interception changes continually; therefore the midcourse guidance law must have the ability of online trajectory optimization. In this paper, an online trajectory generation algorithm is designed based on neighboring optimal control (NOC) theory and improved indirect Radau pseudospectral method (IRPM). A trajectory optimization model is designed according to the features of operations in near space. Two-point boundary value problems (TPBVPs) are obtained based on NOC theory. The second-order linear form of transversality conditions is deduced backward to express the modifications of terminal states, costates, and flight time in terms of current state errors and terminal constraints modifications. By treating the current states and the optimal costates modifications as initial constraints and perturbations, the feedback control variables are obtained based on improved IRPM and nominal trajectory information. The simulation results show that when the changes of terminal constraints are not relatively large, this method can generate a modified trajectory effectively with high precision of terminal modifications. The design concept can provide a reference for the design of the online trajectory generation system of hypersonic vehicles.
APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition
Authors: Buisson Rémi , Lawrence Michael S. , Benes Cyril H. , Zou Lee
Published: July 2017

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic sites at replication forks. In contrast to cells under other types of replication stress, APOBEC3A-expressing cells were selectively sensitive to ATR inhibitors (ATRi), but not to a variety of DNA replication inhibitors and DNA-damaging drugs. In proliferating cells, APOBEC3A modestly elicited ATR but not ATM. ATR inhibition in APOBEC3A-expressing cells resulted in a surge of abasic sites at replication forks, revealing an ATR-mediated negative feedback loop during replication. The surge of abasic sites upon ATR inhibition associated with increased accumulation of single-stranded DNA, a substrate of APOBEC3A, triggering an APOBEC3A-driven feed-forward loop that ultimately drove cells into replication catastrophe. In a panel of cancer cell lines, ATRi selectively induced replication catastrophe in those harboring high APOBEC3A and/or APOBEC3B activities, showing that APOBEC3A and APOBEC3B activities conferred susceptibility to ATRi. Our results define an APOBEC-driven replication stress in cancer cells that may offer an opportunity for ATR-targeted therapy. Cancer Res; 77(17); 4567–78. ©2017 AACR.
Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer
Authors: Argirion Ilona , Weinstein Stephanie J. , Männistö Satu , Albanes Demetrius , Mondul Alison M.
Published: July 2017

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk.

Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer.

Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12–3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99–3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio (Ptrend = 0.55 and Ptrend = 0.27, respectively).

Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development.

Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519–24. ©2017 AACR.
Sorafenib in Patients with Hepatocellular Carcinoma—Results of the Observational INSIGHT Study
Authors: Ganten Tom M. , Stauber Rudolf E. , Schott Eckardt , Malfertheiner Peter , Buder Robert , Galle Peter R. , Göhler Thomas , Walther Matthias , Koschny Ronald , Gerken Guido
Published: July 2017

Purpose: Sorafenib is the only currently approved systemic therapy for advanced hepatocellular carcinoma (HCC). We aimed to evaluate the safety and efficacy of sorafenib therapy in patients with HCC under real-life conditions regarding patient, tumor characteristics, and any adverse events at study entry and at follow-up visits every 2 to 4 months.

Experimental Design: The current INSIGHT study is a noninterventional, prospective, multicenter, observational study performed in 124 sites across Austria and Germany between 2008 and 2014.

Results: Median overall survival and time to progression (RECIST) were found to be dependent on baseline Barcelona Clinic Liver Cancer (BCLC) tumor stage (A: 29.2, B: 19.6, C: 13.6, D: 3.1 and A: 6.0, B: 5.5, C: 3.9, and D: 1.7 months, respectively), Child–Pugh liver function (A: 17.6, B: 8.1, C: 5.6 and A: 5.3, B: 3.3, C: 2.5 months, respectively), and performance status of the patient; however, age did not affect prognosis. Sorafenib-related adverse events at any grade occurred in 64.9% of patients, with diarrhea (35.4%), hand–foot–skin reaction (16.6%), nausea (10.3%), and fatigue (11.2%) occurring most frequently.

Conclusions: Sorafenib treatment was shown to be effective in a real-life setting, in agreement with previously reported clinical trial data. The therapy was found to have an acceptable safety profile, with predominantly mild to moderate side effects. Clin Cancer Res; 23(19); 5720–8. ©2017 AACR.
Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma
Authors: Orillion Ashley , Hashimoto Ayumi , Damayanti Nur , Shen Li , Adelaiye-Ogala Remi , Arisa Sreevani , Chintala Sreenivasulu , Ordentlich Peter , Kao Chingai , Elzey Bennett , Gabrilovich Dmitry , Pili Roberto
Published: July 2017

Purpose: Recent advances in immunotherapy highlight the antitumor effects of immune checkpoint inhibition despite a relatively limited subset of patients receiving clinical benefit. The selective class I histone deacetylase inhibitor entinostat has been reported to have immunomodulatory activity including targeting of immune suppressor cells in the tumor microenvironment. Thus, we decided to assess whether entinostat could enhance anti–PD-1 treatment and investigate those alterations in the immunosuppressive tumor microenvironment that contribute to the combined antitumor activity.

Experimental Design: We utilized syngeneic mouse models of lung (LLC) and renal cell (RENCA) carcinoma and assessed immune correlates, tumor growth, and survival following treatment with entinostat (5 or 10 mg/kg, p.o.) and a PD-1 inhibitor (10 and 20 mg/kg, s.c.).

Results: Entinostat enhanced the antitumor effect of PD-1 inhibition in two syngeneic mouse tumor models by reducing tumor growth and increasing survival. Entinostat inhibited the immunosuppressive function of both polymorphonuclear (PMN)- and monocytic-myeloid derived suppressor cell (M-MDSC) populations. Analysis of MDSC response to entinostat revealed significantly reduced arginase-1, iNOS, and COX-2 levels, suggesting potential mechanisms for the altered function. We also observed significant alterations in cytokine/chemokine release in vivo with a shift toward a tumor-suppressive microenvironment.

Conclusions: Our results demonstrate that entinostat enhances the antitumor effect of PD-1 targeting through functional inhibition of MDSCs and a transition away from an immune-suppressive tumor microenvironment. These data provide a mechanistic rationale for the clinical testing and potential markers of response of this novel combination in solid tumor patients. Clin Cancer Res; 23(17); 5187–201. ©2017 AACR.
ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer
Authors: Lombard Alan P. , Liu Chengfei , Armstrong Cameron M. , Cucchiara Vito , Gu Xinwei , Lou Wei , Evans Christopher P. , Gao Allen C.
Published: July 2017

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC. Mol Cancer Ther; 16(10); 2257–66. ©2017 AACR.
Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC
Authors: Horie Masafumi , Kaczkowski Bogumil , Ohshima Mitsuhiro , Matsuzaki Hirotaka , Noguchi Satoshi , Mikami Yu , Lizio Marina , Itoh Masayoshi , Kawaji Hideya , Lassmann Timo , Carninci Piero , Hayashizaki Yoshihide , Forrest Alistair R.R. , Takai Daiya , Yamaguchi Yoko , Micke Patrick , Saito Akira , Nagase Takahide
Published: July 2017

Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of cancer driver mutations have been identified; however, relevant epigenetic regulation involved in tumorigenesis has only been fragmentarily analyzed. Epigenetically regulated genes have a great theranostic potential, especially in tumors with no apparent driver mutations. Here, epigenetically regulated genes were identified in lung cancer by an integrative analysis of promoter-level expression profiles from Cap Analysis of Gene Expression (CAGE) of 16 non–small cell lung cancer (NSCLC) cell lines and 16 normal lung primary cell specimens with DNA methylation data of 69 NSCLC cell lines and 6 normal lung epithelial cells. A core set of 49 coding genes and 10 long noncoding RNAs (lncRNA), which are upregulated in NSCLC cell lines due to promoter hypomethylation, was uncovered. Twenty-two epigenetically regulated genes were validated (upregulated genes with hypomethylated promoters) in the adenocarcinoma and squamous cell cancer subtypes of lung cancer using The Cancer Genome Atlas data. Furthermore, it was demonstrated that multiple copies of the REP522 DNA repeat family are prominently upregulated due to hypomethylation in NSCLC cell lines, which leads to cancer-specific expression of lncRNAs, such as RP1-90G24.10, AL022344.4, and PCAT7. Finally, Myeloma Overexpressed (MYEOV) was identified as the most promising candidate. Functional studies demonstrated that MYEOV promotes cell proliferation, survival, and invasion. Moreover, high MYEOV expression levels were associated with poor prognosis.

Implications: This report identifies a robust list of 22 candidate driver genes that are epigenetically regulated in lung cancer; such genes may complement the known mutational drivers.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/10/1354/F1.large.jpg. Mol Cancer Res; 15(10); 1354–65. ©2017 AACR.
Strain Differences and Effects of Environmental Manipulation on Astrocytes (Glial Fibrillary Acidic Protein), Glucocorticoid Receptor, and Microglia (Iba1) Immunoreactivity between Wistar-Kyoto and Wistar Females
Authors: Mileva Guergana R. , Moyes Carinna , Syed Shaezeen , Bielajew Catherine
Published: July 2017

Background: Depression is often associated with an increase in hypothalamic-pituitary-adrenal (HPA) axis reactivity and immune response. To investigate this relationship, we examined the consequences of environmental manipulation on the neural correlates of the HPA axis and immune response in an animal model of depression, the Wistar-Kyoto (WKY) rat. Additionally, female animals are often overlooked in preclinical research because of the hormone fluctuations inherent in the estrous cycle. Methods: Female rats were randomly assigned to 1 of 3 environments for 30 days: (1) environmental enrichment (EE), (2) standard housing (SH), and (3) isolated housing (IH). Immunoreactivity of astrocytes (glial fibrillary acidic protein [GFAP]), glucocorticoid receptors (GRs), and microglia (Iba1) in the hippocampus and amygdala were measured using immunohistochemistry. Results: WKY animals had significantly more GR staining area and Iba1 staining intensity and area in the CA1 of the hippocampus. In enriched Wistar rats, GFAP staining intensity and area were greater in the CA1. A trend towards a greater percent of area stained with GR was found in WKY animals as compared to that of the Wistar animals. This was due to WKY females in EE having significantly higher GR staining intensity and area in the amygdala as compared to that of animals in SH. Discussion: These strain differences lend support to the use of WKY animals as an animal model of depression. Furthermore, due to the effects of EE on GFAP and GR staining in WKY females, we suggest that EE can be used as an intervention to potentially alleviate the negative effects of depression.
DoriTool: A Bioinformatics Integrative Tool for Post-Association Functional Annotation
Authors: Martín-Antoniano Isabel , Alonso Lola , Madrid Miguel , López de Maturana Evangelina , Malats Núria
Published: July 2017

The emergence of high-throughput data in biology has increased the need for functional in silico analysis and prompted the development of integrative bioinformatics tools to facilitate the obtainment of biologically meaningful data. In this paper, we present DoriTool, a comprehensive, easy, and friendly pipeline integrating biological data from different functional tools. The tool was designed with the aim to maximize reproducibility and reduce the working time of the researchers, especially of those with limited bioinformatics skills, and to help them with the interpretation of the results. DoriTool is based upon an integrative strategy implemented following a modular design pattern. Using scripts written in Bash, Perl and R, it performs a functional in silico analysis annotation at mutation/variant level, gene level, pathway level and network level by combining up-to-date functional and genomic data and integrating also third-party bioinformatics tools in a pipeline. DoriTool uses GRCh37 human assembly and online mode. DoriTool provides nice visual reports including variant annotation, linkage disequilibrium proxies, gene annotation, gene ontology analysis, expression quantitative trait loci results from Genotype-Tissue Expression (GTEx) and coloured pathways. Here, we also show DoriTool functionalities by applying it to a dataset of 13 variants associated with prostate cancer. Project development, released code libraries, GitHub repository (https://github.com/doritool) and documentation are hosted at https://doritool.github.io/. DoriTool is, to our knowledge, the most complete bioinformatics tool offering functional in silico annotation of variants previously associated with a trait of interest, shedding light on the underlying biology and helping the researchers in the interpretation and discussion of the results.
The Relationship between Hypertriglyceridemic Waist Phenotype and Early Diabetic Nephropathy in Type 2 Diabetes
Authors: Ma Chun-Ming , Wang Rui , Liu Xiao-Li , Lu Na , Lu Qiang , Yin Fu-Zai
Published: July 2017

Background/Aims: The aim of this study was to explore the relationship between hypertriglyceridemic waist (HW) phenotype and early diabetic nephropathy in type 2 diabetes. Methods: A cross-sectional study was conducted on 538 type 2 diabetes patients in Qinhuangdao. The HW phenotype was defined as serum triglyceride concentrations ≥1.7 mmol/L and waist circumference ≥90 cm (males) and ≥85 cm (females). Results: The prevalence of the HW phenotype was 34.9%. The prevalence of early diabetic nephropathy was 10.6% in type 2 diabetes patients with normal waist circumference and triglycerides and 24.5% in type 2 diabetes patients with HW phenotype. After adjustment for sex, age, body mass index, hypertension, history of diabetes, and glycosylated hemoglobin A1c, the prevalence of early diabetic nephropathy among type 2 diabetes patients with the HW phenotype was 2.81 (95% confidence interval 1.36-5.80, p = 0.005) times higher than that among type 2 diabetes patients with normal waist circumference and triglycerides. Conclusion: There was a significant correlation between HW phenotype and early diabetic nephropathy in type 2 diabetes.
Extended Pancreatectomy: Does It Have a Role in the Contemporary Management of Pancreatic Adenocarcinoma?
Authors: Kaiser Joerg , Hackert Thilo , Büchler Markus W.
Published: July 2017

Background: Pancreatic cancer is a low-incident but highly mortal disease. Surgery is still the preferred treatment option for resectable pancreatic cancer as it offers the only realistic chance for cure. As many patients present with locally advanced disease, which is generally considered as not amenable to surgical treatment, it is important to know the limits of surgical therapy in this disease. Methods: In this review, the indication and outcomes of extended pancreatectomies as well as the alternative treatment options for locally advanced pancreatic cancer are described. Furthermore, controversies as well as ongoing and future directions for the treatment options of locally advanced pancreatic cancer are discussed. Results: Extended pancreatectomy can be performed with higher morbidity and mortality rates in patients with locally advanced pancreatic cancer compared to patients undergoing formal pancreatic resections. These procedures offer significant advantages with respect to both perioperative results and to long-term outcome when compared to chemotherapy. Conclusion: Due to the higher morbidity and mortality rates, these operations should be limited to specialist units with great experience in pancreatic surgery as well as experience in peri- and post-operative management of patients with pancreatic diseases.
A Decrease of Histone Deacetylase 6 Expression Caused by Helicobacter Pylori Infection is Associated with Oncogenic Transformation in Gastric Cancer
Authors: He Qing , Li Guoqiang , Wang Xin , Wang Shubin , Hu Jiang , Yang Lang , He Yuqi , Pan Yuanming , Yu Dedong , Wu Yun
Published: July 2017

Background: Histone deacetylase 6 (HDAC6) plays a role in the progression of many tumors. However, the relationship between the level of HDAC6 expression and gastric tumorigenesis is still unclear. Here, we illustrate the potential correlation between Helicobacter pylori (HP) infection and the variation of HDAC6 expression in different gastric lesions, as well as the clinical significance of HDAC6 expression in gastric cancer (GC) patients. Materials and Methods: Between 2011 and 2016, 364 patients with different types of gastric lesions were enrolled in Baotou City Central Hospital. Immunostaining of HDAC6 expression and HP infection were performed in the following cohort including 21 normal tissues (Normal); 40 samples with chronic superficial gastritis (CSG); 106 with chronic atrophic gastritis (CAG); 94 with intestinal metaplasia (IM); 64 with dysplasia (DYS) and 39 with gastric cancer (GC). Survival analysis was performed in another 80 GC patients using the Kaplan-Meier method and multivariate Cox regression analyses. The level of HDAC6 expression was determined by Real-time PCR, Western blotting and IHC staining in gastric cell lines and tissues. Furthermore, the correlation between HDAC6 expression and clinicopathological features and prognosis was analyzed in the GC cohort. HP strains were lavaged into Kunming mice to investigate the effects of HP infection on the expression of different HDAC members in this mouse model. Results: Higher levels of HDAC6 expression were detected in normal and premalignant lesions than in the GC tissues (p<0.01), and decreased HDAC6 expression was associated with HP infection and TNM stage (p<0.01 and p=0.048, respectively). Multivariate analysis revealed that HDAC6 expression was an independent predictor of the outcome of GC patients (p=0.04). HP mediated HDAC6 expression in the cell lines and KM mice. HP infection could promote HDAC1 and HDAC4 expression as determined by Western blotting. Conclusions: HDAC6 is a promising biomarker for early diagnosis and prognosis during the oncogenic transformation of gastric cancer.
MORPHOLOGICAL RESEARCH ON FREE-RESIDUE OXIDATION PROCESSES IN CASES OF DECIDUAL CELLS OF PLACENTA IN CHORIOAMNIONOTIS AND BASAL DECIDUITIS COMBINED WITH IRON-DEFICIENCY ANEMIA IN THE PREGNANT
Authors: Ilika V. V.
Published: July 2017

Background. The oxidative modification of proteins is lately pivotal to pathologists and it is a new way of research on different pathological conditions, as well as the diagnostics of inflammation processes in placenta.Objective. The study was aimed at the research of nitro peroxides and establishing the specific features of oxidative modification of proteins in inflammation of placenta with iron deficient anaemia in the pregnant.Methods. Сhemiluminescent and histochemical technique (with bromphenol blue on ‘acidic’ and ‘basic’ proteins according to Mikel Calvo) was applied.Results. The intensity of nitro peroxides glow in chorioamnionitis and basal deciduitis increased in comparison with the samples of physiological and iron deficient anaemia gestation. At the same time in chorioamnionitis the glow intensity is higher than in basal deciduitis.Due to the results of immune histochemical technique held while analysing the samples, together with chorioamnionitis and basal deciduitis the R/B increases and in basal deciduitis the rate, is probably, higher, than in chorioamnionitis. At the same time, the extent of oxidative modification of proteins in cases of inflammation with iron deficient anaemia in the pregnant is on the average higher than with no iron deficient anaemia in the pregnant.Conclusions. High level of nitro peroxides in placentae basal plate in secundines inflammation, the increase in R/B rate, in other words the prevalence of ‘acidic’ proteins over ‘basic’ ones, is evidenced due to the increase of the intensity of oxidative modification processes of proteins in cases of deciduitis.
Sujeito, objeto e linguagem no brincar
Authors: Pisetta Maria Angélica Augusto de Mello
Published: July 2017

Brincar é uma atividade tão corriqueira na infância que sua teorização resvala em certa obviedade. Todos podem testemunhar, cotidianamente, a necessidade que a criança tem de brincar e os avanços socioculturais que ela demonstra, quando tem seu tempo de fantasiar e brincar respeitado e potencializado. Um olhar mais atento à estrutura do brincar deixa a descoberto o processo da construção da subjetividade da criança, suas relações com o Outro da cultura de seu tempo histórico e a construção do objeto com o qual se produz um embate. Como a análise do brincar pode auxiliar na compreensão dos limites necessários ao fomento da subjetividade e da socialização na infância? É o que pretendemos discutir neste artigo.
Encontros e desencontros: do nascimento à constituição do psiquismo
Authors: Komniski Paula Cristina Nogueira Vieira , Chatelard Daniela Scheinkman , Carvalho Isalena Santos
Published: July 2017

Este artigo tem como objetivo discutir aspectos relacionados ao encontro mãe-bebê no pós-parto. O nascimento e a recepção do bebê que chega são, em geral, descritos pela mãe como um momento de profunda alegria e sensação de completude. Partindo do princípio de que raramente as dificuldades vividas aparecem no discurso materno, temos como proposta discutir o que está por trás da negação da dor e das dificuldades, que também se fazem presentes nesse momento. Assim, pretende-se retomar aspectos do pensamento psicanalítico relacionados à constituição e à organização do psiquismo do bebê, no intuito de compreender mais profundamente a complexidade presente no nascimento, tanto do ponto de vista da mãe quanto do bebê.
Reflexões acerca da possibilidade de prevenção do autismo
Authors: Adurens Fernanda Delai Lucas , Melo Maribél De Salles de
Published: July 2017

Este texto tem como objetivo estu- dar e investigar a possibilidade de identificação dos traços autísticos em bebês. O cuidado precoce quan- to às questões psíquicas possibilita a prevenção de psicopatologias na infância. A análise é de caráter teórico, ilustrada por recortes de casos clínicos; a fundamentação teórica é pautada por uma revisão crítica da literatura especializada, por meio de artigos científicos e livros. Os resultados assinalam avanço científico de pesquisas que apontaram a importância e a eficácia da detecção precoce de risco psíquico, incluindo o autismo.
Expectativas parentais na temporalidade contemporânea
Authors: Féres-Carneiro Terezinha , Mello Renata Machado de , Machado Rebeca Nonato , Magalhães Andrea Seixas
Published: July 2017

Este trabalho tem como objetivo avaliar as expectativas parento-filiais na temporalidade contemporânea. Foram realizadas entrevistas com 132 membros de famílias heteroparentais e homo-parentais, dos segmentos médios da população carioca, com diferentes configurações. As entrevistas foram analisadas pelo método de análise de conteúdo. Observamos que os ideais da sociedade engendram mudanças no modo de se pensar os projetos de vida da geração seguinte. Constatamos que a maioria dos pais e dos filhos apresenta expectativas voltadas para a profissão, apontando para a representação de um futuro trabalhador. Tal representação torna equivalente, muitas vezes, o processo de desen- volvimento humano ao processo de crescimento profissional.
Mechanism and Implications of the Tricuspid Regurgitation
Authors: Mangieri Antonio , Montalto Claudio , Pagnesi Matteo , Jabbour Richard J. , Rodés-Cabau Josep , Moat Neil , Colombo Antonio , Latib Azeem
Published: July 2017

The tricuspid valve was virtually ignored for a long time in the past. However, significant tricuspid regurgitation (TR) often accompanies left-side heart valve pathology and does not always reverse with its correction. If left untreated, TR can progress and result in progressive right ventricular failure. Current guideline recommendations still hold minor differences. Nevertheless, there is a consensus to operate on patients with severe TR undergoing left-sided valve surgery (class I) or those with mild to moderate TR with a dilated annulus (≥40 or ≥21 mm
2
, Class IIa). However, in case of the primary TR, surgical options is limited by a relatively high risk of mortality and morbidity. For these patients, new percutaneous approaches are becoming available but no long-term data are still available. In this review, we provide a comprehensive overview of the epidemiological and pathophysiological aspects of TR, and the current and future directions of therapy.