bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel, noninvasive transdermal fluid sampling methodology: IGF-I measurement following exercise
Authors: Scofield D. E. , McClung H. L. , McClung J. P. , Kraemer W. J. , Rarick K. R. , Pierce J. R. , Cloutier G. J. , Fielding R. A. , Matheny R. W. , Young A. J. , Nindl B. C.
Published: March 2011

This study tested the hypothesis that transdermal fluid (TDF) provides a more sensitive and accurate measure of exercise-induced increases in insulin-like growth factor-I (IGF-I) than serum, and that these increases are detectable proximal, but not distal, to the exercising muscle. A novel, noninvasive methodology was used to collect TDF, followed by sampling of total IGF-I (tIGF-I) and free IGF-I (fIGF-I) in TDF and serum following an acute bout of exercise. Experiment 1: eight men (23 ± 3 yrs, 79 ± 7 kg) underwent two conditions (resting and 60 min of cycling exercise at 60% V̇o2peak) in which serum and forearm TDF were collected for comparison. There were no significant changes in tIGF-I or fIGF-I in TDF obtained from the forearm or from serum following exercise ( P > 0.05); however, the proportion of fIGF-I to tIGF-I in TDF was approximately fourfold greater than that of serum ( P ≤ 0.05). These data suggest that changes in TDF IGF-I are not evident when TDF is sampled distal from the working tissue. To determine whether exercise-induced increases in local IGF-I could be detected when TDF was sampled directly over the active muscle group, we performed a second experiment. Experiment 2: fourteen subjects (22 ± 4 yr, 68 ± 11 kg) underwent an acute plyometric exercise condition consisting of 10 sets of 10 plyometric jumps with 2-min rest between sets. We observed a significant increase in TDF tIGF-I following exercise ( P ≤ 0.05) but no change in serum tIGF-I ( P > 0.05). Overall, these data suggest that TDF may provide a noninvasive means of monitoring acute exercise-induced changes in local IGF-I when sampled in proximity to exercising muscles. Moreover, our finding that the proportion of free to tIGF-I was greater in TDF than in serum suggests that changes in local IGF-I may be captured more readily using this system.
IGF-I/PI3K/Akt and IGF-I/MAPK/ERK pathways in vivo in skeletal muscle are regulated by nutrition and contribute to somatic growth in the fine flounder
Authors: Fuentes Eduardo N. , Björnsson Björn Thrandur , Valdés Juan Antonio , Einarsdottir Ingibjörg Eir , Lorca Belen , Alvarez Marco , Molina Alfredo
Published: March 2011

The insulin-like growth factor-I (IGF-I) is a key regulator of skeletal muscle growth in vertebrates, promoting mitogenic and anabolic effects through the activation of the MAPK/ERK and the PI3K/Akt signaling pathways. Nutrition also affects skeletal muscle growth, activating intracellular pathways and inducing protein synthesis and accretion. Thus, both hormonal and nutritional signaling regulate muscle mass. In this context, plasma IGF-I levels and the activation of both pathways in response to food were evaluated in the fine flounder using fasting and refeeding trials. The present study describes for the first time in a nonmammalian species that the MAPK/ERK and PI3K/Akt are activated by exogenous circulating IGF-I, as well as showing that the MAPK/ERK pathway activation is modulated by the nutritional status. Also, these results show that there is a time-dependent regulation of IGF-I plasma levels and its signaling pathways in muscle. Together, these results suggest that the nutritionally managed IGF-I could be regulating the activation of the MAPK/ERK and the PI3K/Akt signaling pathways differentially according to the nutritional status, triggering different effects in growth parameters and therefore contributing to somatic growth in fish. This study contributes to the understanding of the nutrient regulation of IGF-I and its signaling pathways in skeletal muscle growth in nonmammalian species, therefore providing insight concerning the events controlling somatic growth in vertebrates.
Ventrolateral medullary functional connectivity and the respiratory and central chemoreceptor-evoked modulation of retrotrapezoid-parafacial neurons
Authors: Ott Mackenzie M. , Nuding Sarah C. , Segers Lauren S. , Lindsey Bruce G. , Morris Kendall F.
Published: March 2011

The medullary ventral respiratory column (VRC) of neurons is essential for respiratory motor pattern generation; however, the functional connections among these cells are not well understood. A rostral extension of the VRC, including the retrotrapezoid nucleus/parafacial region (RTN-pF), contains neurons responsive to local perturbations of CO2/pH. We addressed the hypothesis that both local RTN-pF interactions and functional connections from more caudal VRC compartments—extending from the Bötzinger and pre-Bötzinger complexes to the ventral respiratory group (Böt-VRG)—influence the respiratory modulation of RTN-pF neurons and their responses to central chemoreceptor and baroreflex activation. Spike trains from 294 RTN-pF and 490 Böt-VRG neurons were monitored with multielectrode arrays along with phrenic nerve activity in 14 decerebrate, vagotomized cats. Overall, 214 RTN-pF and 398 Böt-VRG neurons were respiratory modulated; 124 and 95, respectively, were cardiac modulated. Subsets of these neurons were tested with sequential, selective, transient stimulation of central chemoreceptors and arterial baroreceptors; each cell's response was evaluated and categorized according to the change in firing rate (if any) following the stimulus. Cross-correlation analysis was applied to 2,884 RTN-pF↔RTN-pF and 8,490 Böt-VRG↔RTN-pF neuron pairs. In total, 174 RTN-pF neurons (59.5%) had significant features in short-time scale correlations with other RTN-pF neurons. Of these, 49 neurons triggered cross-correlograms with offset peaks or troughs ( n = 99) indicative of paucisynaptic excitation or inhibition of the target. Forty-nine Böt-VRG neurons (10.0%) were triggers in 74 Böt-VRG→RTN-pF correlograms with offset features, suggesting that Böt-VRG trigger neurons influence RTN-pF target neurons. The results support the hypothesis that local RTN-pF neuron interactions and inputs from Böt-VRG neurons jointly contribute to respiratory modulation of RTN-pF neuronal discharge patterns and promotion or limitation of their responses to central chemoreceptor and baroreceptor stimulation.
Mesopic background lights enhance dark-adapted cone ERG flash responses in the intact mouse retina: a possible role for gap junctional decoupling
Authors: Heikkinen H. , Vinberg F. , Nymark S. , Koskelainen A.
Published: March 2011

The cone-driven flash responses of mouse electroretinogram (ERG) increase as much as twofold over the course of several minutes during adaptation to a rod-compressing background light. The origins of this phenomenon were investigated in the present work by recording preflash-isolated (M-)cone flash responses ex vivo in darkness and during application of various steady background lights. In this protocol, the cone stimulating flash was preceded by a preflash that maintains rods under saturation (hyperpolarized) to allow selective stimulation of the cones at varying background light levels. The light-induced growth was found to represent true enhancement of cone flash responses with respect to their dark-adapted state. It developed within minutes, and its overall magnitude was a graded function of the background light intensity. The threshold intensity of cone response growth was observed with lights in the low mesopic luminance region, at which rod responses are partly compressed. Maximal effect was reached at intensities sufficient to suppress ∼90% of the rod responses. Light-induced enhancement of the cone photoresponses was not sensitive to antagonists and agonists of glutamatergic transmission. However, applying gap junction blockers to the dark-adapted retina produced qualitatively similar changes in the cone flash responses as did background light and prevented further growth during subsequent light-adaptation. These results are consistent with the idea that cone ERG photoresponses are suppressed in the dark-adapted mouse retina by gap junctional coupling between rods and cones. This coupling would then be gradually and reversibly removed by mesopic background lights, allowing larger functional range for the cone light responses.
Two aspects of feedforward postural control: anticipatory postural adjustments and anticipatory synergy adjustments
Authors: Klous Miriam , Mikulic Pavle , Latash Mark L.
Published: March 2011

We used the framework of the uncontrolled manifold hypothesis to explore the relations between anticipatory synergy adjustments (ASAs) and anticipatory postural adjustments (APAs) during feedforward control of vertical posture. ASAs represent a drop in the index of a multimuscle-mode synergy stabilizing the coordinate of the center of pressure in preparation to an action. ASAs reflect early changes of an index of covariation among variables reflecting muscle activation, whereas APAs reflect early changes in muscle activation levels averaged across trials. The assumed purpose of ASAs is to modify stability of performance variables, whereas the purpose of APAs is to change magnitudes of those variables. We hypothesized that ASAs would be seen before APAs and that this finding would be consistent with regard to the muscle-mode composition defined on the basis of different tasks and phases of action. Subjects performed a voluntary body sway task and a quick, bilateral shoulder flexion task under self-paced and reaction time conditions. Surface muscle activity of 12 leg and trunk muscles was analyzed to identify sets of 4 muscle modes for each task and for different phases within the shoulder flexion task. Variance components in the muscle-mode space and indexes of multimuscle-mode synergy stabilizing shift of the center of pressure were computed. ASAs were seen ∼100–150 ms prior to the task initiation, before APAs. The results were consistent with respect to different sets of muscle modes defined over the two tasks and different shoulder flexion phases. We conclude that the preparation for a self-triggered postural perturbation is associated with two types of anticipatory adjustments, ASAs and APAs. They reflect different feedforward processes within the hypothetical hierarchical control scheme, resulting in changes in patterns of covariation of elemental variables and in their patterns averaged across trials, respectively. The results show that synergies quantified using dissimilar sets of muscle modes show similar feedforward changes in preparation to action.
Responses of spinal dorsal horn neurons to foot movements in rats with a sprained ankle
Authors: Kim Jae Hyo , Kim Hee Young , Chung Kyungsoon , Chung Jin Mo
Published: March 2011

Acute ankle injuries are common problems and often lead to persistent pain. To investigate the underlying mechanism of ankle sprain pain, the response properties of spinal dorsal horn neurons were examined after ankle sprain. Acute ankle sprain was induced manually by overextending the ankle of a rat hindlimb in a direction of plantarflexion and inversion. The weight-bearing ratio (WBR) of the affected foot was used as an indicator of pain. Single unit activities of dorsal horn neurons in response to plantarflexion and inversion of the foot or ankle compression were recorded from the medial part of the deep dorsal horn, laminae IV-VI, in normal and ankle-sprained rats. One day after ankle sprain, rats showed significantly reduced WBRs on the affected foot, and this reduction was partially restored by systemic morphine. The majority of deep dorsal horn neurons responded to a single ankle stimulus modality. After ankle sprain, the mean evoked response rates were significantly increased, and afterdischarges were developed in recorded dorsal horn neurons. The ankle sprain-induced enhanced evoked responses were significantly reduced by morphine, which was reversed by naltrexone. The data indicate that movement-specific dorsal horn neuron responses were enhanced after ankle sprain in a morphine-dependent manner, thus suggesting that hyperactivity of dorsal horn neurons is an underlying mechanism of pain after ankle sprain.
Relation of ordinal position signals to the expectation of reward and passage of time in four areas of the macaque frontal cortex
Authors: Berdyyeva Tamara K. , Olson Carl R.
Published: March 2011

Neurons in several areas of the monkey frontal cortex exhibit rank selectivity, firing differentially as a function of the stage attained during the performance of a serial order task. The activity of these neurons is commonly thought to represent ordinal position within the trial. However, they might also be sensitive to factors correlated with ordinal position including time elapsed during the trial (which is greater for each successive stage) and the degree of anticipation of reward (which probably increases at each successive stage). To compare the influences of these factors, we monitored neuronal activity in the supplementary motor area (SMA), presupplementary motor area (pre-SMA), supplementary eye field (SEF), and dorsolateral prefrontal cortex during the performance of a serial order task (requiring a series of saccades in three specified directions), a variable reward task (in which a cue displayed early in the trial indicated whether the reward received at the end of the trial would be large or small), and a long delay task (in which the monkey had simply to maintain fixation during a period of time approximating the duration of an average trial in the serial order task). We found that rank signals were partially correlated with sensitivity to elapsed time and anticipated reward. The connection to elapsed time was strongest in the pre-SMA. The connection to anticipated reward was most pronounced in the SMA and SEF. However, critically, these factors could not fully explain rank selectivity in any of the areas tested.
The cortical response to the oral perception of fat emulsions and the effect of taster status
Authors: Eldeghaidy Sally , Marciani Luca , McGlone Francis , Hollowood Tracey , Hort Joanne , Head Kay , Taylor Andrew J. , Busch Johanneke , Spiller Robin C. , Gowland Penny A. , Francis Susan T.
Published: March 2011

The rewarding attributes of foods containing fat are associated with the increase in fat consumption, but little is known of how the complex physical and chemical properties of orally ingested fats are represented and decoded in the brain nor how this impacts feeding behavior within the population. Here, functional MRI (fMRI) is used to assess the brain response to isoviscous, isosweet fat emulsions of increasing fat concentration and to investigate the correlation of behavioral and neuroimaging responses with taster status (TS). Cortical areas activated in response to fat, and those areas positively correlated with fat concentration, were identified. Significant responses that positively correlated with increasing fat concentration were found in the anterior insula, frontal operculum and secondary somatosensory cortex (SII), anterior cingulate cortex, and amygdala. Assessing the effect of TS revealed a strong correlation with self-reported preference of the samples and with cortical response in somatosensory areas [primary somatosensory cortex (SI), SII, and midinsula] and the primary taste area (anterior insula) and a trend in reward areas (amygdala and orbitofrontal cortex). This finding of a strong correlation with TS in somatosensory areas supports the theory of increased mechanosensory trigeminal innervation in high 6- n-propyl-2-thiouracil (PROP) tasters and has been linked to a higher risk of obesity. The interindividual differences in blood oxygenation level-dependent (BOLD) amplitude with TS indicates that segmenting populations by TS will reduce the heterogeneity of BOLD responses, improving signal detection power.
Vasoactive intestinal polypeptide requires parallel changes in adenylate cyclase and phospholipase C to entrain circadian rhythms to a predictable phase
Authors: An Sungwon , Irwin Robert P. , Allen Charles N. , Tsai Connie , Herzog Erik D.
Published: March 2011

Circadian oscillations in the suprachiasmatic nucleus (SCN) depend on transcriptional repression by Period (PER)1 and PER2 proteins within single cells and on vasoactive intestinal polypeptide (VIP) signaling between cells. Because VIP is released by SCN neurons in a circadian pattern, and, after photic stimulation, it has been suggested to play a role in the synchronization to environmental light cycles. It is not known, however, if or how VIP entrains circadian gene expression or behavior. Here, we tested candidate signaling pathways required for VIP-mediated entrainment of SCN rhythms. We found that single applications of VIP reset PER2 rhythms in a time- and dose-dependent manner that differed from light. Unlike VIP-mediated signaling in other cell types, simultaneous antagonism of adenylate cyclase and phospholipase C activities was required to block the VIP-induced phase shifts of SCN rhythms. Consistent with this, VIP rapidly increased intracellular cAMP in most SCN neurons. Critically, daily VIP treatment entrained PER2 rhythms to a predicted phase angle within several days, depending on the concentration of VIP and the interval between VIP applications. We conclude that VIP entrains circadian timing among SCN neurons through rapid and parallel changes in adenylate cyclase and phospholipase C activities.
Throughput Capacity of Opportunistic Routing in Wireless Sensor Networks
Authors: Niu Xiaoguang , Cui Li
Published: March 2011

Recently, the idea of opportunistic routing (OR) has been widely explored to cope with the unreliable transmissions by exploiting the broadcast nature and spatial diversity of the wireless medium in order to improve the performance of wireless sensor networks. However, there are few theoretical analyses on the maximum throughput of OR WSNs. This paper is the first attempt to conduct a theoretical analysis on aggregate throughput capacity of OR in multihop many-to-one WSNs with consideration for lossy link and transmission fairness. By capturing the key characteristics of forwarding candidate set in OR networks, we propose the cumulative delivery transmission model. Then we introduce the concept of concurrent schedulable set to represent the constraints imposed by the transmission conflicts of OR, and formulate the optimal aggregate throughput problem as a maximum concurrent flow linear programming problem. Simulation results demonstrate that the OR design derived from our analysis model often yields noticeably better throughput than traditional unicast routing protocols and the OR design derived from existing analysis model under a range of scenarios.
Immune Suppression in Head and Neck Cancers: A Review
Authors: Duray Anaëlle , Demoulin Stéphanie , Hubert Pascale , Delvenne Philippe , Saussez Sven
Published: March 2011

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancer in the world. Despite significant advances in the treatment modalities involving surgery, radiotherapy, and concomitant chemoradiotherapy, the 5‐year survival rate remained below 50% for the past 30 years. The worse prognosis of these cancers must certainly be link to the fact that HNSCCs strongly influence the host immune system. We present a critical review of our understanding of the HNSCC escape to the antitumor immune response such as a downregulation of HLA class I and/or components of APM. Antitumor responses of HNSCC patients are compromised in the presence of functional defects or apoptosis of T‐cells, both circulating and tumor‐infiltrating. Langerhans cells are increased in the first steps of the carcinogenesis but decreased in invasive carcinomas. The accumulation of macrophages in the peritumoral areas seems to play a protumoral role by secreting VEGF and stimulating the neoangiogenesis.
The Fixed Point Theory for Some Generalized Nonexpansive Mappings
Authors: Llorens Fuster Enrique , Moreno Gálvez Elena
Published: March 2011

We study some aspects of the fixed point theory for a class of generalized nonexpansive mappings, which among others contain the class of generalized nonexpansive mappings recently defined by Suzuki in 2008.
Legionnaires' Disease with Facial Nerve Palsy
Authors: Basani Shailesh R. , Ahmed Salwa Mohamed , Habte-Gabr Eyassu
Published: March 2011

Legionnaires' disease is primarily a pneumonic process caused byLegionella pneumophilia, a gram-negative aerobic bacillus but also has multiple system involvement. The most common manifestation is encephalopathy suggesting a generalized brain dysfunction but focal neurological manifestations have been reported. We report a patient with Legionella pneumonia associated with cerebellar dysfunction and unilateral facial nerve weakness. 51-year-old previously healthy male presented with shortness of breath, cough, slurred speech, and unsteadiness on feet associated with malaise, fevers and myalgias. Patient's family reported facial asymmetry for 2 days. Patient had no significant medical history and was not on any medication. He denied smoking, alcohol or illicit drug use. Chest X-ray showed bilateral lower lobe infiltrates. Urinary antigen assay forLegionella pneumophiliaserogroup 1 was positive. Patient was started on intravenous moxifloxacin. On day 5 the patient was discharged home and continued oral moxifloxacin for two weeks. After the two weeks, his respiratory symptoms, gait ataxia and dysarthria resolved. We report the first case of Legionnaires' disease with cerebellar dysfunction and seventh nerve palsy. Legionnaires' disease should be considered in patients with any neurological symptoms in the setting of pneumonia. Failure to recognize and treat the infection may lead to poor outcomes.
Phosphoglucose Isomerase/Autocrine Motility Factor Mediates Epithelial-Mesenchymal Transition Regulated by miR-200 in Breast Cancer Cells
Authors: Ahmad Aamir , Aboukameel Amro , Kong Dejuan , Wang Zhiwei , Sethi Seema , Chen Wei , Sarkar Fazlul H. , Raz Avraham
Published: March 2011

Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) plays an important role in glycolysis and gluconeogenesis and is associated with invasion and metastasis of cancer cells. We have previously shown its role in the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells, which led to increased aggressiveness; however, the molecular mechanism by which PGI/AMF regulates EMT is not known. Here we show, for the first time, that PGI/AMF overexpression led to an increase in the DNA-binding activity of NF-κB, which, in turn, led to increased expression of ZEB1/ZEB2. The microRNA-200s (miR-200s) miR-200a, miR-200b, and miR-200c are known to negatively regulate the expression of ZEB1/ZEB2, and we found that the expression of miR-200s was lost in PGI/AMF overexpressing MCF-10A cells and in highly invasive MDA-MB-231 cells, which was consistent with increased expression of ZEB1/ZEB2. Moreover, silencing of PGI/AMF expression in MDA-MB-231 cells led to overexpression of miR-200s, which was associated with reversal of EMT phenotype (i.e., mesenchymal-epithelial transition), and these findings were consistent with alterations in the relative expression of epithelial (E-cadherin) and mesenchymal (vimentin, ZEB1, ZEB2) markers and decreased aggressiveness as judged by clonogenic, motility, and invasion assays. Moreover, either reexpression of miR-200 or silencing of PGI/AMF suppressed pulmonary metastases of MDA-MB-231 cells in vivo, and anti-miR-200 treatment in vivo resulted in increased metastases. Collectively, these results suggest a role of miR-200s in PGI/AMF-induced EMT and thus approaches for upregulation of miR-200s could be a novel therapeutic strategy for the treatment of highly invasive breast cancer. Cancer Res; 71(9); 3400–9. ©2011 AACR.
Combined Promoter Methylation Analysis of CADM1 and MAL: An Objective Triage Tool for High-Risk Human Papillomavirus DNA–Positive Women
Authors: Hesselink Albertus T. , Heideman Daniëlle AM , Steenbergen Renske DM , Coupé Veerle M.H. , Overmeer Renee M. , Rijkaart Dorien , Berkhof Johannes , Meijer Chris J.L.M. , Snijders Peter J.F.
Published: March 2011

Purpose: Screening women for high-grade cervical intraepithelial neoplasia or cervical cancer (CIN3+) by high-risk human papillomavirus (hrHPV) testing has as side-effect the detection of hrHPV-positive women without clinically relevant lesions. Here, we developed an objective assay assessing the methylation status of the promoter regions of CADM1 and MAL to triage hrHPV-positive women for CIN3+.

Experimental Design: In a training set (51 women with CIN3+ and 224 without CIN2+), panels consisting of one to four quantitative methylation-specific PCR (qMSP) assays (CADM1-m12,CADM1-m18,MAL-m1,MAL-m2) were analyzed. Cross-validated receiver-operating characteristics (ROC) curves were constructed and the panel with highest partial cross-validated area under the curve (AUC) was used for validation in an independent set of 236 consecutive hrHPV-positive women from a screening cohort. In the validation set, the ROC curve of the panel was compared with CIN3+ sensitivity and specificity of cytology and of cytology combined with HPV16/18 genotyping.

Results: In the training set, CADM1-m18 combined with MAL-m1 was the best panel (cross-validated partial AUC = 0.719). In the validation set, this panel revealed CIN3+ sensitivities ranging from 100% (95% CI: 92.4–100) to 60.5% (95% CI: 47.1–74.6), with corresponding specificities ranging from 22.7% (95% CI: 20.2–25.2) to 83.3% (95% CI: 78.4–87.4). For cytology these were 65.8% (95% CI: 52.3–79.0) and 78.8% (95% CI: 73.7–83.1) and for cytology/HPV16/18, these were 84.2% (95% CI: 72.0–92.7) and 54.0% (95% CI: 49.2–58.7), respectively. The point estimates of both cytology and cytology/HPV16/18 were equal to the values of the ROC curve of CADM1-m18/MAL-m1.

Conclusions: We developed an objective methylation marker panel that was equally discriminatory for CIN3+ as cytology or cytology with HPV16/18 genotyping in hrHPV-positive women. This opens the possibility for complete cervical screening by objective, nonmorphological molecular methods. Clin Cancer Res; 17(8); 2459–65. ©2011 AACR.
Local Activation of CD8 T Cells and Systemic Tumor Eradication without Toxicity via Slow Release and Local Delivery of Agonistic CD40 Antibody
Authors: Fransen Marieke F. , Sluijter Marjolein , Morreau Hans , Arens Ramon , Melief Cornelis J.M.
Published: March 2011

Purpose: Immunotherapy against tumors with anti-CD40 agonistic antibodies has been extensively studied in preclinical animal models and recently also in clinical trials. Although promising results have been obtained, antibody (Ab)-related toxicity has been a limiting factor. We reasoned that strict local activation of tumor-specific CD8 T cells through stimulation of CD40 on the dendritic cells (DC) in the tumor area while excluding systemic stimulation might be sufficient for effective tumor eradication and can limit systemic toxicity.

Experimental Design: Preclinical in vivo models for immunogenic tumors were used to investigate the potential of delivering a nontoxic dose of agonistic anti-CD40 Ab to the tumor region, including draining lymph node, in a slow-release formulation (montanide).

Results: The delivery of anti-CD40 monoclonal Ab, formulated in slow-release Montanide ISA-51, reprograms CTLs by inducing local but not systemic DC activation, resulting in effective tumor-specific CTL responses that eradicate local and distant tumors. Adverse side effects, assayed by organ histology and liver enzymes in the blood, were much lower after local anti-CD40 Ab delivery than systemic administration. The local delivery of anti-CD40 Ab activates only CTLs against antigens presented in the tumor-draining area, because unrelated distant tumors expressing different tumor antigens were not eradicated.

Conclusions: These results establish a novel therapeutic principle that local delivery and slow release of agonistic anti-CD40 Ab to the tumor-draining area effectively activates local tumor-specific CD8 T cells to become systemic effectors without causing systemic toxicity or nonspecific CTL activation. These findings have important implications for the use of anti-CD40 therapies in patients. Clin Cancer Res; 17(8); 2270–80. ©2011 AACR.
Internalization of Oncolytic Reovirus by Human Dendritic Cell Carriers Protects the Virus from Neutralization
Authors: Ilett Elizabeth J. , Bárcena Montserrat , Errington-Mais Fiona , Griffin Stephen , Harrington Kevin J. , Pandha Hardev S. , Coffey Matthew , Selby Peter J. , Limpens Ronald W.A.L. , Mommaas Mieke , Hoeben Rob C. , Vile Richard G. , Melcher Alan A.
Published: March 2011

Purpose: Dendritic cells (DC) may be the most effective way of delivering oncolytic viruses to patients. Reovirus, a naturally occurring oncolytic virus, is currently undergoing early clinical trials; however, intravenous delivery of the virus is hampered by pre-existing antiviral immunity. Systemic delivery via cell carriage is a novel approach currently under investigation and initial studies have indicated its feasibility by using a variety of cell types and viruses. This study addressed the efficacy of human DC to transport virus in the presence of human neutralizing serum.

Experimental Design: Following reovirus-loading, DC or T cells were cocultured with melanoma cells with or without neutralizing serum; the melanoma cells were then analyzed for cell death. Following reovirus loading, cells were examined by electron microscopy to identify mechanisms of delivery. The phagocytic function of reovirus-loaded DC was investigated by using labeled tumor cells and the ability of reovirus-loaded DC to prime T cells was also investigated.

Results: In the presence of human neutralizing serum DC, but not T cells, were able to deliver reovirus for melanoma cell killing in vitro. Electron microscopy suggested that DC protected the virus by internalization, whereas with T cells it remained bound to the surface and hence accessible to neutralizing antibodies. Furthermore, DC loaded with reovirus were fully functional with regard to phagocytosis and priming of specific antitumor immune responses.

Conclusions: The delivery of reovirus via DC could be a promising new approach offering the possibility of combining systemic viral therapy for metastatic disease with induction of an antitumor immune response. Clin Cancer Res; 17(9); 2767–76. ©2011 AACR.
Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor
Authors: Soung Young Hwa , Chung Jun
Published: March 2011

The functional interaction between integrin α6β4 and growth factor receptors has been implicated in key signaling pathways important for cancer cell function. However, few attempts have been made to selectively target this interaction for therapeutic intervention. Previous studies showed that curcumin, a yellow pigment isolated from turmeric, inhibits integrin α6β4 signaling important for breast carcinoma cell motility and invasion, but the mechanism is not currently known. To address this issue, we tested the hypothesis that curcumin inhibits the functional interaction between α6β4 and the epidermal growth factor receptor (EGFR). In this study, we found that curcumin disrupts functional and physical interactions between α6β4 and EGFR, and blocks α6β4/EGFR-dependent functions of carcinoma cells expressing the signaling competent form of α6β4. We further showed that curcumin inhibits EGF-dependent mobilization of α6β4 from hemidesmosomes to the leading edges of migrating cells such as lammelipodia and filopodia, and thereby prevents α6β4 distribution to lipid rafts where functional interactions between α6β4 and EGFR occur. These data suggest a novel paradigm in which curcumin inhibits α6β4 signaling and functions by altering intracellular localization of α6β4, thus preventing its association with signaling receptors such as EGFR. Mol Cancer Ther; 10(5); 883–91. ©2011 AACR.
Suppression of the uPAR–uPA System Retards Angiogenesis, Invasion, and In Vivo Tumor Development in Pancreatic Cancer Cells
Authors: Gorantla Bharathi , Asuthkar Swapna , Rao Jasti S. , Patel Jitendra , Gondi Christopher S.
Published: March 2011

Despite existing chemotherapy and surgical resection strategies, pancreatic cancer is one of the major causes of mortality in the United States with a 5-year mean survival rate of less than 5%. The activation of the urokinase-type plasminogen activator receptor–urokinase-type plasminogen activator (uPAR–uPA) system in the development of pancreatic ductal adenocarcinoma has been well established. In the present study, we used 2 pancreatic cancer cell lines, MIA PaCa-2 and PANC-1 to show the effects of uPAR and uPA downregulation. From the results, we observed that RNAi expressing plasmids efficiently downregulated mRNA and protein expression of uPAR and uPA. In vitro and in vivo angiogenic assays revealed a significant decrease in the angiogenic potential of MIA PaCa-2 and PANC-1 cells that were downregulated for both uPAR and uPA. From the angiogenesis antibody array analysis, we observed that the simultaneous downregulation of uPAR and uPA resulted in the downregulation of angiogenin and overexpression of RANTES. Further, FACS analysis showed that the simultaneous downregulation of uPAR and uPA caused the accumulation of cells in the sub-G0/1 phase in both MIA PaCa-2 and PANC-1 cells. In addition, Western blot analysis revealed that downregulation of uPAR and uPA caused the activation of caspase 8 and CAD, which is indicative of apoptosis, and in vivo TUNEL assay confirmed these results. Finally, we observed the nuclear localization of uPA and that uPA interacts with the transcription factor Lhx-2. Taken together, the results of the present study show that the targeting of the uPAR–uPA system has therapeutic potential. Mol Cancer Res; 9(4); 377–89. ©2011 AACR.
Postoperative Adjuvant Therapy after Transoral Robotic Resection for Oropharyngeal Carcinomas: Rationale and Current Treatment Approach
Authors: Quon Harry , O’Malley, Jr. Bert W. , Weinstein Gregory S.
Published: March 2011

The advancement of transoral surgical techniques for the management of oropharyngeal carcinomas has raised questions about how adjuvant therapy can best be integrated. Some of these questions have come from the application of established oncologic principles of adjuvant therapy, and some are unique to the evolving experience with transoral surgery and in particular with the recent advancement of robotic surgery. It is important for all members of the multidisciplinary treatment team to have a clear understanding of the foundation for adjuvant therapy and the issues unique to transoral robotic surgery to provide optimal patient care as this new treatment paradigm gains popularity for its safe application.
Sporadic Intramedullary Spinal Cord Hemangioblastoma in a Newborn
Authors: Campos Wuilker Knoner , Linhares Marcelo Neves
Published: March 2011

Background: Hemangioblastomas (HB) are rare lesions accounting for 2% of all spinal cord tumors. They are highly vascular, benign tumors that occur either sporadically or in the presence of von Hippel-Lindau disease. Spinal cord HB are usually diagnosed in adult patients and their incidence in early infancy is an extreme rarity. Methods: We present a case of a 1-month-old male with a back deformity and left leg hypomotility. MRI of the spine revealed an intramedullary tumor extending from level T6 to T12. Results: The tumor was excised completely, using standard microsurgical techniques via a posterior approach. The histological diagnosis was spinal cord HB. Conclusion: A review of the literature revealed that this neoplasm is composed of 3 major cell types: endothelial cells, pericytes and stromal cells. Complete microsurgical removal is the treatment of choice for spinal cord HB because the tumor is benign. To the best of our knowledge, sporadic spinal cord HB at this age has not been reported so far.
Luminal Amino Acid-Sensing Cells in Gastric Mucosa
Authors: Nakamura Eiji , Hasumura Mai , Uneyama Hisayuki , Torii Kunio
Published: March 2011

Chemosensing of nutrients in the gastrointestinal tract plays physiologically important roles in the regulation of food intake behaviors, including digestion, absorption, metabolism and other subsequently occurring body functions via brain activation. Free amino acids, liberated from ingested foods, are of course essential nutrients which compose the body proteins and sometimes determine the taste of the food. Glutamate, one of the most abundant amino acids in the foods and the liberated free form, critically contributes to the ‘umami’ taste perception. Recently, it has been revealed that dietary glutamate has many beneficial functions in the gastrointestinal tract. However, the precise mechanism of glutamate sensing still remains unclear. Using primary rat gastric mucosal cell cultures, we demonstrated that somatostatin-secreting D cells are candidate cells for glutamate sensing in the stomach through inhibition of somatostatin release. Considering that somatostatin is one of the major negative regulators of gastric functions, it is suggested that some parts of glutamate’s beneficial effects could be explained by suppression of the inhibitory somatostatin effects, i.e. stimulation, by glutamate.
Effects of ad libitum Ingestion of Monosodium Glutamate on Weight Gain in C57BL6/J Mice
Authors: Ren Xueying , Ferreira Jozélia G. , Yeckel Catherine W. , Kondoh Takashi , de Araujo Ivan E.
Published: March 2011

Although the umami compound monosodium glutamate (MSG) is a widely used flavor enhancer, controversy still persists regarding the effects of MSG intake on body weight. It has been claimed, in particular, that chronic MSG intake may result in excessive body weight gain and obesity. In this study we assessed the effects of chronic (16 weeks) ad libitum MSG on body weight and metabolism of C57BL6/J mice. Adult male mice were divided in four experimental groups and fed with either a low-fat (LF) or high-fat (HF) diet and with either two bottles of plain water or one bottle containing 1% MSG and another one containing water according to a factorial design. Mice were monitored weekly for body weight and food/fluid intake for 15 weeks. At the end of the experiments, the circulating levels of leptin, insulin, total protein, total cholesterol, triglyceride, blood urea nitrogen, and non-esterified fatty acids were also analyzed. Our results show that MSG intake did not influence body weight in either LF or HF groups. Interestingly, although animals overall displayed strong preferences for MSG against water, preferences were relatively higher in LF compared to HF group. Consistent with the body weight data, while significant differences in leptin, insulin, total cholesterol, and non-esterified fatty acids were found between HF and LF groups, such an effect was not influenced by MSG intake. Finally, indirect calorimetry measurements revealed similar energy expenditure levels between animals being presented water only and MSG only. In summary, our data does not support the notion that ad libitum MSG intake should trigger the development of obesity or other metabolic abnormalities.
Biological Significance of Glutamate Signaling during Digestion of Food through the Gut-Brain Axis
Authors: Kitamura Akihiko , Tsurugizawa Tomokazu , Torii Kunio
Published: March 2011

Monosodium L-glutamate (MSG) elicits a unique taste termed umami and is widely used as a flavor enhancer in various cuisines. In addition, recent studies suggest the existence of sensors for L-glutamate (Glu) and transduction molecules in the gut mucosa as well as in the oral cavity. The vagal gastric afferent responds specifically to the luminal stimulation of Glu in the stomach and regulates the autonomic reflexes. The intragastric infusion of Glu also activates several brain areas (insular cortex, limbic system, and hypothalamus) and is able to induce flavor-preference learning in rats. These results suggest that umami signaling via gustatory and visceral pathways plays an important role in the processes of digestion, absorption, metabolism, and other physiological functions via activation of the brain.
Application of the Optimal Discovery Procedure to Genetic Case-Control Studies: Comparison with p Values and Asymptotic Bayes Factors
Authors: Tachmazidou Ioanna , De Iorio Maria , Dudbridge Frank
Published: March 2011

Objectives: The power of genetic association studies is limited by stringent levels of statistical significance. To improve power, Bayes factors (BFs) have been suggested as an alternative measure to the p value, and Storey recently introduced an optimal discovery procedure (ODP) for multiple testing. We aimed to adapt the ODP to genetic case-control studies and to compare its power to p values and asymptotic BFs (ABFs). Methods: We propose estimators of the ODP based on prospective and retrospective likelihoods. We performed simulations based on independent common SNPs and on sequence data including rare variants. Effects of causal SNPs were simulated under various distributions of effect size. Results: The true ODP is never outperformed, but the estimated ODP has similar power to p values and ABFs. For common SNPs the ODP offers power advantages only in extreme scenarios. However, for rare variants the ODP and ABF detect more associations at low false-positive rates than do p values. Conclusions: The ODP can provide higher power than p values for genetic case-control studies of common variants. However, as the ABF has similar power to the ODP and is computed more rapidly, it is our currently preferred method.
Vascular Endothelial Growth Factor Attenuates Neurodegenerative Changes in the NSC-34 Motor Neuron Cell Line Induced by Cerebrospinal Fluid of Sporadic Amyotrophic Lateral Sclerosis Patients
Authors: Kulshreshtha Dinkar , Vijayalakshmi K. , Alladi Phalguni Anand , Sathyaprabha T.N. , Nalini Atchayaram , Raju T.R.
Published: March 2011

Background: Motor neuron disease or amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord as well as motor cortex. Recently, vascular endothelial growth factor (VEGF) has been identified as a neurotrophic factor in animal models of familial ALS and other neurological diseases. Objective: The present study was designed to investigate the neuroprotective role of VEGF in the more prevalent sporadic form of ALS. Methods: We studied the effect of VEGF on the NSC-34 cell line exposed to cerebrospinal fluid (CSF) from sporadic ALS patients (ALS-CSF) in terms of lactate dehydrogenase (LDH) assay as well as choline acetyltransferase (ChAT) and phosphorylated neurofilament expression by immunocytochemistry and confocal microscopy. NSC-34 cells were exposed to CSF from patients with definite ALS and compared to controls. LDH activity was assessed in the growth media, prior to and 24 h after the addition of VEGF to the cells. At similar time points, the cells were fixed and processed for immunocytochemistry to evaluate ChAT and phosphorylated neurofilament expression. Results: Exposure to ALS-CSF caused morphological changes of NSC-34 cells like reduced differentiation and aggregation of phosphorylated neurofilaments. Enhanced LDH activity and reduced ChAT immunoreactivity were also observed. Addition of VEGF to NSC-34 cells exposed to ALS-CSF was protective in terms of reduced LDH activity and restoration of ChAT expression. Conclusion: The present study confirms that VEGF exerts a neuroprotective effect on the NSC-34 cell line by attenuating the degenerative changes induced by ALS-CSF. It thus has therapeutic potential in sporadic ALS.
Glutathione S-Transferase Gene Polymorphism as a Susceptibility Factor for Acute Myocardial Infarction and Smoking in the North Indian Population
Authors: Singh Neha , Sinha Nakul , Kumar Sudeep , Pandey Chandra M. , Agrawal Suraksha
Published: March 2011

Objectives: Glutathione S-transferase (GST) plays a key role in the detoxification of xenobiotic atherogens generated by smoking. We investigated whether functional GST gene polymorphism might be associated with acute myocardial infarction (AMI) and smoking. No such investigation has previously been conducted among North Indians. Methods: 230 patients with AMI and 300 healthy controls of North Indian ethnicity were enrolled in the study. GSTM1/T1/P1 gene polymorphisms were examined using restriction fragment length polymorphism. Results: When GST polymorphism was analyzed in patients with AMI, GSTM1 null genotype frequencies were 0.24 and 0.21 among cases with coronary artery disease and controls, respectively. The respective GSTT1 null genotype frequencies were 0.10 and 0.20 (p = 0.001). GSTP1 variant Val/Val allele frequencies were 0.02 and 0.07 with p = 0.03. After risk factor adjustment, only GSTP1Val/Val was found to be protective against disease. Considering the effect of GST (T1, M1, and P1) gene polymorphism on smoking, subjects were further divided into smokers and nonsmokers. However, GSTT1 null as well as GSTP Val/Val genotypes were protective only in nonsmokers (p = 0.01 and p = 0.04). Conclusions: A significant protective effect of GSTT1 null and GSTP1 Val genotype against disease was observed in patients with AMI although protection was limited to nonsmokers.
Effects of Different Types of Anesthetic Agents on Cellular Protein Kinase C-γ Dynamics in Mouse Brain
Authors: Takeda Akiko , Miyashita Ryoichi , Nagura Takeo , Sekine Shusuke , Murozono Michihiro , Matsumoto Shohei , Uchino Hiroyuki
Published: March 2011

Background/Aims: Although protein kinase C-γ (PKC-γ) is a target for the effects of volatile anesthetics, the molecular mechanisms of the kinase function during their action remain unclear. We examined the effects of different types of anesthetics on PKC-γ knockout mice. Furthermore, we investigated the dynamics of the kinase in brain cells obtained from mice anesthetized with these anesthetics. Methods: We measured the required times for loss of righting reflex (rtfLORR) after administration of isoflurane, sevoflurane, or propofol on PKC-γ knockout mice and compared the times with those of wild-type mice. We also used immunoblotting to investigate the intracellular distribution of PKC-γ and phosphorylated PKC-γ (p-PKC-γ) in brain cell fractions obtained from wild-type mice during the loss of righting reflex induced by these anesthetics. Results: Isoflurane (2.6%) and sevoflurane (3.4%) used at twice the minimum alveolar concentration significantly prolonged the rtfLORRs in PKC-γ knockout mice compared to those in wild-type mice. On the other hand, no significant difference was observed between knockout and wild-type mice treated with propofol (200 mg/kg). Examination of the cellular fractions isolated from volatile anesthetic-treated mouse brains showed that PKC-γ was significantly decreased in the synaptic membrane fraction (P2), whereas p-PKC-γ was significantly increased in P2. There was no significant change in the supernatant fraction (S). In propofol-treated mice, PKC-γ and p-PKC-γ showed no significant changes in P2 or S. Conclusion: Our results provide new evidence to support the possibility of the involvement of PKC-γ in the actions of volatile anesthetics.
Camptocormia in Parkinson’s Disease: A Review of the Literature
Authors: Ponfick Matthias , Gdynia Hans-Juergen , Ludolph Albert C. , Kassubek Jan
Published: March 2011

Camptocormia (CC) is defined as a trunkal flexion which worsens while standing, sitting and walking and disappears in the supine position. CC is a well-known clinical phenomenon in patients with generalized neuromuscular disorders like polymyositis, myasthenia gravis or motor neuron diseases, and it is also described in the context of movement disorders like Parkinson’s disease (PD) or multiple system atrophy. In association with PD, CC seems to be a rare symptom which occurs preferentially in late stages of the disease. Currently, there are 3 main hypotheses on the pathogenesis of CC in PD, i.e. a focal myopathy of the trunk muscles, axial dystonia and a drug-induced etiology. This review gives a synopsis and critical acclaim of these 3 etiologies and refers to the current study data and possible treatment strategies.