bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitric oxide promotes GABA release by activating a voltage-independent Ca2+ influx pathway in retinal amacrine cells
Authors: Maddox J. Wesley , Gleason Evanna
Published: January 2017

Retinal amacrine cells express nitric oxide (NO) synthase and produce NO, making NO available to regulate the function of amacrine cells. Here we test the hypothesis that NO can alter the GABAergic synaptic output of amacrine cells. We investigate this using whole cell voltage clamp recordings and Ca2+ imaging of cultured chick retinal amacrine cells. When recording from amacrine cells receiving synaptic input from other amacrine cells, we find that NO increases GABAergic spontaneous postsynaptic current (sPSC) frequency. This increase in sPSC frequency does not require the canonical NO receptor, soluble guanylate cyclase, or presynaptic action potentials. However, removal of extracellular Ca2+ and buffering of cytosolic Ca2+ both inhibit the response to NO. In Ca2+ imaging experiments, we confirm that NO increases cytosolic Ca2+ in amacrine cell processes by activating a Ca2+ influx pathway. Neither the increase in sPSC frequency nor the cytosolic Ca2+ elevations are dependent upon Ca2+ release from stores. NO also enhances evoked GABAergic responses. Because voltage-gated Ca2+ channel function is not altered by NO, the increased evoked response is likely due to the combined effect of voltage-dependent Ca2+ influx adding to the NO-dependent, voltage-independent, Ca2+ influx. Insight into the identity of the Ca2+ influx pathway is provided by the transient receptor potential canonical (TRPC) channel inhibitor clemizole, which prevents the NO-dependent increase in sPSC frequency and cytosolic Ca2+ elevations. These data suggest that NO production in the inner retina will enhance Ca2+-dependent GABA release from amacrine cells by activating TRPC channel(s).

NEW & NOTEWORTHY Our research provides evidence that nitric oxide (NO) promotes GABAergic output from retinal amacrine cells by activating a likely transient receptor potential canonical-mediated Ca2+ influx pathway. This NO-dependent mechanism promoting GABA release can be voltage independent, suggesting that, in the retina, local NO production can bypass the formal retinal circuitry and increase local inhibition.
Distinct neural circuits for control of movement vs. holding still
Authors: Shadmehr Reza
Published: January 2017

In generating a point-to-point movement, the brain does more than produce the transient commands needed to move the body part; it also produces the sustained commands that are needed to hold the body part at its destination. In the oculomotor system, these functions are mapped onto two distinct circuits: a premotor circuit that specializes in generating the transient activity that displaces the eyes and a “neural integrator” that transforms that transient input into sustained activity that holds the eyes. Different parts of the cerebellum adaptively control the motor commands during these two phases: the oculomotor vermis participates in fine tuning the transient neural signals that move the eyes, monitoring the activity of the premotor circuit via efference copy, whereas the flocculus participates in controlling the sustained neural signals that hold the eyes, monitoring the activity of the neural integrator. Here, I review the oculomotor literature and then ask whether this separation of control between moving and holding is a design principle that may be shared with other modalities of movement. To answer this question, I consider neurophysiological and psychophysical data in various species during control of head movements, arm movements, and locomotion, focusing on the brain stem, motor cortex, and hippocampus, respectively. The review of the data raises the possibility that across modalities of motor control, circuits that are responsible for producing commands that change the sensory state of a body part are distinct from those that produce commands that maintain that sensory state.
Heterogeneous effects of norepinephrine on spontaneous and stimulus-driven activity in the male accessory olfactory bulb
Authors: Doyle Wayne I. , Meeks Julian P.
Published: January 2017

Norepinephrine (NE) release has been linked to experience-dependent plasticity in many model systems and brain regions. Among these is the rodent accessory olfactory system (AOS), which is crucial for detecting and processing socially relevant environmental cues. The accessory olfactory bulb (AOB), the first site of chemosensory information processing in the AOS, receives dense centrifugal innervation by noradrenergic fibers originating in the locus coeruleus. Although NE release has been linked to behavioral plasticity through its actions in the AOB, the impacts of noradrenergic modulation on AOB information processing have not been thoroughly studied. We made extracellular single-unit recordings of AOB principal neurons in ex vivo preparations of the early AOS taken from adult male mice. We analyzed the impacts of bath-applied NE (10 μM) on spontaneous and stimulus-driven activity. In the presence of NE, we observed overall suppression of stimulus-driven neuronal activity with limited impact on spontaneous activity. NE-associated response suppression in the AOB came in two forms: one that was strong and immediate (21%) and one other that involved gradual, stimulus-dependent monotonic response suppression (47%). NE-associated changes in spontaneous activity were more modest, with an overall increase in spontaneous spike frequency observed in 25% of neurons. Neurons with increased spontaneous activity demonstrated a net decrease in chemosensory discriminability. These results reveal that noradrenergic signaling in the AOB causes cell-specific changes in chemosensory tuning, even among similar projection neurons.

NEW & NOTEWORTHY Norepinephrine (NE) is released throughout the brain in many behavioral contexts, but its impacts on information processing are not well understood. We studied the impact of NE on chemosensory tuning in the mouse accessory olfactory bulb (AOB). Electrophysiological recordings from AOB neurons in ex vivo preparations revealed that NE, on balance, inhibited mitral cell responses to chemosensory cues. However, NE’s effects were heterogeneous, indicating that NE signaling reshapes AOB output in a cell- and stimulus-specific manner.
An Enhanced Factor Analysis of Performance Degradation Assessment on Slurry Pump Impellers
Authors: Sun Shilong , Tse Peter W. , Tse Y. L.
Published: January 2017

Slurry pumps, such as oil sand pumps, are widely used in industry to convert electrical energy to slurry potential and kinetic energy. Because of adverse working conditions, slurry pump impellers are prone to suffer wear, which may result in slurry pump breakdowns. To prevent any unexpected breakdowns, slurry pump impeller performance degradation assessment should be immediately conducted to monitor the current health condition and to ensure the safety and reliability of slurry pumps. In this paper, to provide an alternative to the impeller health indicator, an enhanced factor analysis based impeller indicator (EFABII) is proposed. Firstly, a low-pass filter is employed to improve the signal to noise ratios of slurry pump vibration signals. Secondly, redundant statistical features are extracted from the filtered vibration signals. To reduce the redundancy of the statistic features, the enhanced factor analysis is performed to generate new statistical features. Moreover, the statistic features can be automatically grouped and developed a new indicator called EFABII. Data collected from industrial oil sand pumps are used to validate the effectiveness of the proposed method. The results show that the proposed method is able to track the current health condition of slurry pump impellers.
CRLH Transmission Lines for Telecommunications: Fast and Effective Modeling
Authors: Gao Juanjuan , Lu Guizhen
Published: January 2017

A different parameter extraction approach based on zero immittances for composite right/left-handed (CRLH) structure is presented. For lossless unit cell equivalent circuit model, LC parameters of series and parallel branches are extracted according to series resonance frequency and parallel resonance frequency, respectively. This approach can be applied to symmetric and unbalanced CRLH structures. The parameter extraction procedure is provided and validated by T-type unit cell model. The responses of distributed prototype and extracted equivalent LC circuit model are in good agreement. The equivalent circuit modeling can improve the degree of freedom in the CRLH TLs design. This parameter extraction method provides an effective and straightforward way in CRLH metamaterials design and applications in telecommunication systems.
Upregulation of PDZK1 by Calculus Bovis Sativus May Play an Important Role in Restoring Biliary Transport Function in Intrahepatic Cholestasis
Authors: Xiang Dong , Wu Tao , Feng Cheng-Yang , Li Xi-Ping , Xu Yan-Jiao , He Wen-Xi , Lei Kai , Cai Hong-Jiao , Zhang Cheng-Liang , Liu Dong
Published: January 2017

Intrahepatic cholestasis is a main cause of hepatic accumulation of bile acids leading to liver injury, fibrosis, and liver failure. Our previous studies proved that Calculus Bovis Sativus (CBS) can restore biliary transport function through upregulating the multidrug resistance‐associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) in 17α‐ethynylestradiol‐ (EE‐) induced intrahepatic cholestasis rats. The regulation mechanism of CBS on these transporters, however, remains unclear. This study was designed to evaluate the possible relationship between the effect of CBS on transport activities and the regulation of CBS on the expression of PDZK1, a mainly scaffold protein which can regulate MRP2 and BCRP. Intrahepatic cholestasis model was induced in rats with injection of EE for five consecutive days and then the biliary excretion rates and cumulative biliary excretions were measured. The mRNA and protein expression levels of PDZK1 were detected by reverse transcription‐quantitative real‐time polymerase chain reaction, western blot, and immunohistochemical analysis. When treated with CBS, cumulative biliary excretions and mRNA and protein expressions of PDZK1 were significantly increased in intrahepatic cholestasis rats. This study demonstrated that CBS exerted a beneficial effect on EE‐induced intrahepatic cholestasis rats by restoring biliary transport function, which may result from the upregulation of PDZK1 expression.
Adipose-Derived Stem Cells Cocultured with Chondrocytes Promote the Proliferation of Chondrocytes
Authors: Shi Jie , Liang Jiulong , Guo Bingyu , Zhang Yu , Hui Qiang , Chang Peng , Tao Kai
Published: January 2017

Articular cartilage injury and defect caused by trauma and chronic osteoarthritis vascularity are very common, while the repair of injured cartilage remains a great challenge due to its limited healing capacity. Stem cell-based tissue engineering provides a promising treatment option for injured articular cartilage because of the cells potential for multiple differentiations. However, its application has been largely limited by stem cell type, number, source, proliferation, and differentiation. We hypothesized that (1) adipose-derived stem cells are ideal seed cells for articular cartilage repair because of their accessibility and abundance and (2) the microenvironment of articular cartilage could induce adipose-derived stem cells (ADSCs) to differentiate into chondrocytes. In order to test our hypotheses, we isolated stem cells from rabbit adipose tissues and cocultured these ADSCs with rabbit articular cartilage chondrocytes. We found that when ADSCs were cocultured with chondrocytes, the proliferation of articular cartilage chondrocytes was promoted, the apoptosis of chondrocytes was inhibited, and the osteogenic and chondrogenic differentiation of ADSCs was enhanced. The study on the mechanism of this coculture system indicated that the role of this coculture system is similar to the function of TGF-β1 in the promotion of chondrocytes.
Transcriptional and Genomic Targets of Neural Stem Cells for Functional Recovery after Hemorrhagic Stroke
Authors: Zhang Le , Tao Wenjing , Feng Hua , Chen Yujie
Published: January 2017

Hemorrhagic stroke is a life-threatening disease characterized by a sudden rupture of cerebral blood vessels, and it is widely believed that neural cell death occurs after exposure to blood metabolites or subsequently damaged cells. Neural stem cells (NSCs), which maintain neurogenesis and are found in subgranular zone and subventricular zone, are thought to be an endogenous neuroprotective mechanism for these brain injuries. However, due to the complexity of NSCs and their microenvironment, current strategies cannot satisfactorily enhance functional recovery after hemorrhagic stroke. It is well known that transcriptional and genomic pathways play important roles in ensuring the normal functions of NSCs, including proliferation, migration, differentiation, and neural reconnection. Recently, emerging evidence from the use of new technologies such as next-generation sequencing and transcriptome profiling has provided insight into our understanding of genomic function and regulation of NSCs. In the present article, we summarize and present the current data on the control of NSCs at both the transcriptional and genomic levels. Using bioinformatics methods, we sought to predict novel therapeutic targets of endogenous neurogenesis and exogenous NSC transplantation for functional recovery after hemorrhagic stroke, which could also advance our understanding of its pathophysiology.
Effect of Annealing Temperature and Spin Coating Speed on Mn-Doped ZnS Nanocrystals Thin Film by Spin Coating
Authors: Mohd Arif Noor Azie Azura , Jiun Chong Chee , Shaari Sahbudin
Published: January 2017

ZnS:Mn nanocrystals thin film was fabricated at 300°C and 500°C via the spin coating method. Its sol-gel was spin coated for 20 s at 3000 rpm and 4000 rpm with metal tape being used to mold the shape of the thin film. A different combination of these parameters was used to investigate their influences on the fabrication of the film. Optical and structural characterizations have been performed. Optical characterization was analyzed using UV-visible spectroscopy and photoluminescence spectrophotometer while the structural and compositional analysis of films was measured via field emission scanning electron microscopy and energy dispersive X-ray. From UV-vis spectra, the wavelength of the ZnS:Mn was 250 nm and the band gap was within the range 4.43 eV–4.60 eV. In room temperature PL spectra, there were two emission peaks centered at 460 nm and 590 nm. Under higher annealing temperature and higher speed used in spin coating, an increase of 0.05 eV was observed. It was concluded that the spin coating process is able to synthesize high quality spherical ZnS:Mn nanocrystals. This conventional process can replace other high technology methods due to its synthesis cost.
The Effect of Commercial Rice Husk Ash Additives on the Porosity, Mechanical Properties, and Microstructure of Alumina Ceramics
Authors: Ali Mohammed Sabah , Hanim M. A. Azmah , Tahir S. M. , Jaafar C. N. A. , Mazlan Norkhairunnisa , Amin Matori Khamirul
Published: January 2017

A porous ceramic is made from composite materials which consist of alumina and commercial rice husk ash. This type of ceramics is obtained by mixing the commercial rice husk ash as a source of silica (SiO2) and a pore forming agent with alumina (Al2O3) powder. To obtain this type of ceramic, a solid-state technique is used with sintering at high temperature. This study also investigated the effects of the rice husk ash ratios on the mechanical properties, porosity, and microstructure. The results showed that, by increasing the content of the rice husk ash from 10 to 50 wt%, there is an increase in the porosity from 42.92% to 49.04%, while the mechanical properties decreased initially followed by an increase at 30 wt% and 50 wt%; the hardness at 20 wt% of the ash content was recorded at 101.90 HV1. When the ash content was increased to 30 wt% and 50 wt%, the hardness was raised to 150.92 HV1and 158.93 HV1, respectively. The findings also revealed that the tensile and compressive strengths experienced a decrease at 10 wt% of the ash content and after that increase at 30 wt% and 50 wt% of rice husk ash. XRD analysis found multiple phases of ceramic formation after sintering for the different rice husk ash content.
Wayside Bearing Fault Diagnosis Based on Envelope Analysis Paved with Time-Domain Interpolation Resampling and Weighted-Correlation-Coefficient-Guided Stochastic Resonance
Authors: Liu Yongbin , Qian Qiang , Liu Fang , Lu Siliang , He Qingbo , Zhao Jiwen
Published: January 2017

Envelope spectrum analysis is a simple, effective, and classic method for bearing fault identification. However, in the wayside acoustic health monitoring system, owing to the high relative moving speed between the railway vehicle and the wayside mounted microphone, the recorded signal is embedded with Doppler effect, which brings in shift and expansion of the bearing fault characteristic frequency (FCF). What is more, the background noise is relatively heavy, which makes it difficult to identify the FCF. To solve the two problems, this study introduces solutions for the wayside acoustic fault diagnosis of train bearing based on Doppler effect reduction using the improved time-domain interpolation resampling (TIR) method and diagnosis-relevant information enhancement using Weighted-Correlation-Coefficient-Guided Stochastic Resonance (WCCSR) method. First, the traditional TIR method is improved by incorporating the original method with kinematic parameter estimation based on time-frequency analysis and curve fitting. Based on the estimated parameters, the Doppler effect is removed using the TIR easily. Second, WCCSR is employed to enhance the diagnosis-relevant period signal component in the obtained Doppler-free signal. Finally, paved with the above two procedures, the local fault is identified using envelope spectrum analysis. Simulated and experimental cases have verified the effectiveness of the proposed method.
Thoracoscopic Surgery for Glomus Tumor: An Uncommon Mediastinal Neoplasm and Iatrogenic Tracheal Rupture
Authors: Fang Zhongjie , Ma Dehua , Chen Baofu , Luo Huarong
Published: January 2017

Mediastinal glomus tumors are rarely recognized, and only seven cases have been reported in the literature. Here, we describe a rare mediastinal glomus tumor and review the characteristics of this rare clinical case. The patient was a 50-year-old female who presented with coughing for 3 months. Her chest computed tomography scan demonstrated a localized tumor in the posterior superior mediastinum. Intraoperatively, we found a longitudinal rupture of the membranous trachea above the carina. We completely resected the tumor and repaired the tracheal rupture under a thoracoscopy using a pedicled muscle flap. The tissue was diagnosed as a mediastinal glomus tumor according to its histological and immunophenotypic characteristics.
Early Diagnosis of Helicobacter pylori Infection in Vietnamese Patients with Acute Peptic Ulcer Bleeding: A Prospective Study
Authors: Quach Duc Trong , Luu Mai Ngoc , Hiyama Toru , To Thuy-HuongThi , Bui Quy Nhuan , Tran Tuan Anh , Tran Binh Duy , Vo Minh-Cong Hong , Tanaka Shinji , Uemura Naomi
Published: January 2017

Aims. To investigate H. pylori infection rate and evaluate a combined set of tests for H. pylori diagnosis in Vietnamese patients with acute peptic ulcer bleeding (PUD). Methods. Consecutive patients with acute PUB were enrolled prospectively. Rapid urease test (RUT) with 3 biopsies was carried out randomly. Patients without RUT or with negative RUT received urea breath test (UBT) and serological and urinary H. pylori antibody tests. H. pylori was considered positive if RUT or any noninvasive test was positive. Patients were divided into group A (RUT plus noninvasive tests) and group B (only noninvasive tests). Results. The overall H. pylori infection rate was 94.2% (161/171). Groups A and B had no differences in demographic characteristics, bleeding severity, endoscopic findings, and proton pump inhibitor use. H. pylori-positive rate in group A was significantly higher than that in group B (98.2% versus 86.7%, p=0.004). The positive rate of RUT was similar at each biopsy site but significantly increased if RUT results from 2 or 3 sites were combined (p<0.05). Conclusions. H. pylori infection rate in Vietnamese patients with acute PUB is high. RUT is an excellent test if at least 2 biopsies are taken.
Mice with Catalytically Inactive Cathepsin A Display Neurobehavioral Alterations
Authors: Calhan O. Y. , Seyrantepe V.
Published: January 2017

The lysosomal carboxypeptidase A, Cathepsin A (CathA), is a serine protease with two distinct functions. CathA protectsβ-galactosidase and sialidase Neu1 against proteolytic degradation by forming a multienzyme complex and activates sialidase Neu1. CathA deficiency causes the lysosomal storage disease, galactosialidosis. These patients present with a broad range of clinical phenotypes, including growth retardation, and neurological deterioration along with the accumulation of the vasoactive peptide, endothelin-1, in the brain. Previous in vitro studies have shown that CathA has specific activity against vasoactive peptides and neuropeptides, including endothelin-1 and oxytocin. A mutant mouse with catalytically inactive CathA enzyme (CathAS190A) shows increased levels of endothelin-1. In the present study, we elucidated the involvement of CathA in learning and long-term memory in 3-, 6-, and 12-month-old mice. Hippocampal endothelin-1 and oxytocin accumulated inCathAS190Amice, which showed learning impairments as well as long-term and spatial memory deficits compared with wild-type littermates, suggesting that CathA plays a significant role in learning and in memory consolidation through its regulatory role in vasoactive peptide processing.
R&D in Vaccines Targeting Neglected Diseases: An Exploratory Case Study Considering Funding for Preventive Tuberculosis Vaccine Development from 2007 to 2014
Authors: Costa Barbosa Bessa Theolis , Santos de Aragão Erika , Medeiros Guimarães Jane Mary , de Araújo Almeida Bethânia
Published: January 2017

Based on an exploratory case study regarding the types of institutions funding the research and development to obtain new tuberculosis vaccines, this article intends to provoke discussion regarding the provision of new vaccines targeting neglected disease. Although our findings and discussion are mainly relevant to the case presented here, some aspects are more generally applicable, especially regarding the dynamics of development in vaccines to prevent neglected diseases. Taking into account the dynamics of innovation currently seen at work in the vaccine sector, a highly concentrated market dominated by few multinational pharmaceutical companies, we feel that global PDP models can play an important role throughout the vaccine development cycle. In addition, the authors call attention to issues surrounding the coordination of actors and resources in the research, development, manufacturing, and distribution processes of vaccine products arising from PDP involvement.
Medical Image Segmentation Using Independent Component Analysis‐Based Kernelized Fuzzy c‐Means Clustering
Authors: Chen Yao-Tien
Published: January 2017

Segmentation of brain tissues is an important but inherently challenging task in that different brain tissues have similar grayscale values and the intensity of a brain tissue may be confused with that of another one. The paper accordingly develops an ICKFCM method based on kernelized fuzzy c‐means clustering with ICA analysis for extracting regions of interest in MRI brain images. The proposed method first removes the skull region using a skull stripping algorithm. Through ICA, three independent components are then extracted from multimodal medical images containing T1‐weighted, T2‐weighted, and PD‐weighted MRI images. As MRI signals can be regarded as a combination of the signals from brain matters, ICA can be used for contrast enhancement of MRI images. Finally, the three independent components are utilized as inputs by KFCM algorithm to extract different brain tissues. Relying on the decomposition of a multivariate signal into independent non‐Gaussian components and using a more appropriate kernel‐induced distance for fuzzy clustering, the proposed method is capable of achieving greater reliability in both theory and practice than other segmentation approaches. According to the experiment results, the proposed method is capable of accurately extracting the complicated shapes of brain tissues and still remaining robust against various types of noises.
Isolation and Characterization of 1,3-Bis(vinylbenzyl)thymine: Copolymerization with Vinylbenzyl Thymine Ammonium Chloride
Authors: Vy Ngoc Chau H. , Chen Nina Bin , Martino Debora M. , Warner John C. , Lee Nancy
Published: January 2017

A novel bioinspired molecule, 1,3-bis(vinylbenzyl)thymine (bisVBT), was isolated as a by-product during the synthesis of 1-(4-vinylbenzyl)thymine (VBT) and analyzed with various techniques: NMR, IR, and Single-Crystal X-ray Diffraction. In addition to embodying all the desired characteristics of VBT (i.e., having the ability to undergo a 2π+2π photodimerization reaction upon UV irradiation, a derivatization site, hydrogen bonding sites, and aromatic stacking ability) the bisVBT monomer has the added benefit of having two vinyl groups for cross-polymerization. Copolymerizing the bisVBT monomer with the charged monomer vinylbenzyl triethylammonium (VBA) chloride, different copolymers/terpolymers/cross-linked network were obtained, as it was shown by the absence of the vinyl resonance in the NMR spectra. Thermal Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) showed an indication of materials with low degree of cross-linking. A Gel Permeation Chromatography (GPC) method was improved to better characterize the molecular weight distributions of the cationic structures. Preliminary qualitative cross-linking studies were performed on bisVBT-VBA copolymers, and a comparison with VBT-VBA copolymers is presented.
Uniqueness of the Minimal l1‐Norm Solution to the Monotone Linear Complementarity Problem
Authors: Zhang Ting , Jiang Xiaoqin
Published: January 2017

The linear complementarity problem (LCP) has wide applications in economic equilibrium, operations research, and so on, which attracted a lot of interest of experts. Finding the sparsest solution to the LCP has real applications in the field of portfolio selection and bimatrix game. Motivated by the approach developed in compressive sensing, we may try to solve an l1‐minimization problem to obtain the sparsest solution to the LCP, where an important theoretical problem is to investigate uniqueness of the solution to the concerned l1‐minimization problem. In this paper, we investigate the problem of finding the minimal l1‐norm solution to the monotone LCP and propose a sufficient and necessary condition for the uniqueness of the minimal l1‐norm solution to the monotone LCP, which provides an important theoretical basis for finding the sparsest solution to the monotone LCP via solving the corresponding l1‐minimization problem. Furthermore, several examples are given to confirm our theoretical finding.
Tang-Luo-Ning Improves Mitochondrial Antioxidase Activity in Dorsal Root Ganglia of Diabetic Rats: A Proteomics Study
Authors: Zhang Taojing , Gao Yanbin , Gong Yanbin , Zhou Hui , Xie Peifeng , Guan Song , Yi Wenming
Published: January 2017

Tang-luo-ning (TLN) is a traditional Chinese herbal recipe for treating diabetic peripheral neuropathy (DPN). In this study, we investigated mitochondrial protein profiles in a diabetic rat model and explored the potential protective effect of TLN. Diabetic rats were established by injection of streptozocin (STZ) and divided into model, alpha lipoic acid (ALA), and TLN groups. Mitochondrial proteins were isolated from dorsal root ganglia and proteomic analysis was used to quantify the differentially expressed proteins. Tang-luo-ning mitigated STZ-induced diabetic symptoms and blood glucose level, including response time to cold or hot stimulation and nerve conductive velocity. As compared to the normal, there were 388 differentially expressed proteins in the TLN group, 445 in ALA group, and 451 in model group. As compared to the model group, there were 275 differential proteins in TLN group and 251 in ALA group. As compared to model group, mitochondrial complex III was significantly decreased, while glutathione peroxidase and peroxidase were increased in TLN group. When compared with ALA group, the mitochondrial complex III was increased, and mitochondrial complex IV was decreased in TLN group. Together, TLN should have a strong antioxidative activity, which appears to be modulated through regulation of respiratory complexes and antioxidases.
Congenital Diaphragmatic Hernia Presenting in a 7-Day-Old Infant
Authors: Rouse Christopher , Schmidt Luke , Brock Lee , Fagiana Angela
Published: January 2017

A 7-day-old male infant presented to the emergency room after respiratory distress was noted at an outpatient well child check. On exam, he was observed to have tachypnea, increased work of breathing, and decreased breath sounds on the left side of the chest. On chest X-ray, he was found to have a left-sided congenital diaphragmatic hernia. The infant was transported to a tertiary care facility where the defect was repaired without complication. Interestingly, the mother had a history of a normal antenatal ultrasound, completed at 19 + 2 weeks of gestational age. This case report summarizes the challenges of diagnosing late-presenting congenital diaphragmatic hernia, associated malformations, possible etiologies, and prognosis.
Pregnancy during Adolescence and Associated Risks: An 8-Year Hospital-Based Cohort Study (2007–2014) in Romania, the Country with the Highest Rate of Teenage Pregnancy in Europe
Authors: Socolov Demetra-Gabriela , Iorga Magdalena , Carauleanu Alexandru , Ilea Ciprian , Blidaru Iolanda , Boiculese Lucian , Socolov Razvan-Vladimir
Published: January 2017

Aim. To determine pregnancy and delivery outcomes among teenagers.Materials and Methods. An 8-year retrospective comparative hospital-based cohort study is analysing singleton pregnancy comorbidities and delivery parameters of a teenage group under the age of 20 compared with a young adult group 20–24 years of age in a university hospital.Results. Teenage is a risk factor for preterm birth <37 weeks (1.21 [1.08–1.35]), foetal growth restriction (1.34 [1.21–1.48]), episiotomy (1.27 [1.21–1.34]), uterine revision (1.15 [1.06–1.25]), APGAR <7 at 1 min (2.42 [1.21–1.67]), cephalopelvic disproportion (1.26 [1.07–1.48]), and postpartum haemorrhage (1.42 [1.25–1.62]); however, caesarean delivery occurs less frequently in teenagers than in adults (0.75 [0.70–0.80]). The following comorbidities are risk factors for teenage pregnancy (risk ratio [CI 95%]): anaemia (1.13 [1.10–1.17]), low urinary tract infection (1.10 [1.03–1.18]), pediculosis (2.42 [1.90–3.00]), anogenital condyloma (1.50 [1.04–2.17]), and trichomoniasis (1.74 [1.12–2.68]). The risks for hepatitis B and hepatitis C, premature rupture of membranes, and placenta praevia were lower compared with those in the young adult group, respectively, 0.43 (0.26–0.71), 0.90 (0.85–0.96), and 0.29 (0.20–0.41), while the risk for gestational diabetes and preeclampsia were the same in both groups.Conclusion. Considering the high risks for teenage pregnancy, this information should be provided to pregnant adolescent women and their caregivers.
Regular Voluntary Exercise Potentiates Interleukin-1βand Interleukin-18 Secretion by Increasing Caspase-1 Expression in Murine Macrophages
Authors: Shirato Ken , Imaizumi Kazuhiko , Sakurai Takuya , Ogasawara Junetsu , Ohno Hideki , Kizaki Takako
Published: January 2017

Moderate-intensity regular exercise improves proinflammatory responses of lipopolysaccharide- (LPS-) stimulated macrophages. However, intracellular events that mediate the beneficial effects of exercise were unclear. This study aimed to clarify the mechanism by which regular voluntary exercise (VE) improves proinflammatory cytokine production by macrophages challenged with LPS. Peritoneal macrophages from VE mice secreted considerably higher amounts of interleukin- (IL-) 1βand IL-18 than did cells from sedentary control (SC) mice in the presence and absence of LPS, although tumor necrosis factor-αand IL-10 secretion were comparable between both groups. The mRNA levels of these cytokines increased significantly in response to LPS; similar levels were noted in macrophages from both SC and VE mice. Moreover, LPS evoked similar levels of degradation of inhibitor ofκB (IκB)αand phosphorylation of IκB kinaseβ, c-Jun N-terminal kinase, and p38 in macrophages from SC and VE mice. These results indicate that the increased IL-1βand IL-18 secretion in VE mice are regulated posttranscriptionally. On the other hand, macrophages from VE mice showed higher amounts of caspase-1 protein than did cells from SC mice. These results suggest that regular VE potentiates IL-1βand IL-18 secretion in LPS-challenged macrophages by increasing caspase-1 levels.
Abstract A10: Redox regulation of the Wnt/β-catenin pathway in colorectal cancer
Authors: Campos Alex , James Brian , Jong Petrus De , Powis Garth
Published: January 2017

Colorectal cancer (CRC) is the third most newly diagnosed cancer, and the third most frequent cause of cancer related death in the United States. Thus, there is an urgent unmet need for the development of new therapies for the treatment of CRC. Loss of function mutations in adenomatous polyposis coli (APC), a critical member of the β-catenin destruction complex, lead to elevated protein levels of β-Catenin, and are found in 85% of CRCs, where they are associated with decreased CRC patient survival. Increased levels of β-catenin protein augment the nuclear accumulation of β-catenin where it interacts with transcription factors to induce transcription of target genes promoting cell proliferation, survival, and migration. Currently, there is still no effective therapy targeting aberrant β-catenin transcriptional activity. Here we report on the redox dependency of the Wnt/β-catenin signaling pathway, identified through a forward genetic screen in Drosophila, and identify TxnR1 as a potential target for the inhibition of aberrant β-catenin transcriptional activity through in vivo studies with the APCmin/+ mouse model. Drosophila harboring a mutation in the thioredoxin reductase (txnr1) gene that have a partial lethality phenotype were used in an enhancer/suppressor forward genetic screen. Increased lethality was observed when the txnr1 mutation (Txnr1481) was combined with heterozygous mutations and deletions in dwnt2, while dwnt2 deletion and mutations alone had no effect (on lethality). In addition, β-Catenin mediated transcription, as measured by TOP Flash luciferase assay, was diminished when TxnR1 was silenced by siRNA. To test the translational value of these findings, APCmin/+ mice were treated with PX-12, a human TxnR1 inhibitor, daily by gavage from day 40 to time of death. We observed a dose dependent reduction in the number and size of intestinal polyps by PX-12 treatment, and an increased survival in treated mice. Also, human colorectal cancer cell lines treated with PX-12 displayed attenuated phosphorylation of β-catenin serine residues 552 and 675. These results suggest a conserved mechanism for the redox regulation of the Wnt/β-catenin pathway involving TxnR1; furthermore, inhibition of TxnR1 can inhibit intestinal neoplasia development in an experimental model of CRC.

Citation Format: Alex Campos, Brian James, Petrus De Jong, Garth Powis. Redox regulation of the Wnt/β-catenin pathway in colorectal cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A10.
Abstract A12: Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide
Authors: Chen Wenshu , Padilla Mabel T. , Xu Xuling , Desai Dhimant , Krzeminski Jacek , Amin Shantu , Lin Yong
Published: January 2017

The interaction between epithelial and stromal cells through soluble factors such as cytokines plays an important role in carcinogenesis. Breaking this cancer-promoting interaction poses an opportunity for cancer prevention. The tumor-promoting function of interleukin 6 (IL-6) has been documented; however, the underlying mechanisms of this function in lung carcinogenesis are not well elucidated. Here, we show that benzo[a]pyrene diol epoxide (BPDE, the active metabolite of cigarette smoke carcinogen benzo[a]pyrene)-induced human bronchial epithelial cell (HBEC) transformation was enhanced by IL-6 in vitro. The carcinogen/IL-6-transformed cells exhibited higher expression of STAT3 (signal transducer and activator of transcription 3) when compared with cells transformed by BPDE alone. Constitutive STAT3 activation drove cell proliferation and survival through anti-apoptosis gene expression. We further show that quercetin, a dietary compound having preventive properties for lung cancer, decreased BPDE-stimulated IL-6 secretion from human lung fibroblasts through inhibition of the NF-κB and ERK pathways. The inhibition was accomplished at clinically achievable concentrations of the compound. Finally, quercetin blocked IL-6-induced STAT3 activation in HBECs, and IL-6 enhancement of HBEC transformation by BPDE was abolished by quercetin treatment. Altogether, our data reveal novel mechanisms for IL-6 in lung carcinogenesis and for the preventive role of quercetin in the process.

Citation Format: Wenshu Chen, Mabel T. Padilla, Xuling Xu, Dhimant Desai, Jacek Krzeminski, Shantu Amin, Yong Lin. Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A12.
Abstract A17: Abiraterone metabolism and a novel therapeutic strategy for castration resistant prostate cancer
Authors: Li Zhenfei , Alyamani Mohammad , Li Jianneng , Taplin Mary-Ellen , Sharifi Nima
Published: January 2017

Prostate cancer is the most common cancer in men in the United States. Abiraterone (abi) is approved by the FDA for treatment of castration resistant prostate cancer (CRPC). However, ~30% of patients have limited or no response to abi. The underlying mechanism of resistance is elusive in these cases, and the best treatment plan for such patients is not clear. Thus we sought to determine a potential mechanism of resistance by analyzing abi metabolism. We found that abi undergoes metabolism catalyzed by steroidogenic enzymes. Abi is converted sequentially to delta-4-abi (D4A), then undergoes C5 reduction to produce several metabolites, including 5α-abi and 5 other metabolites. D4A has more potent anti-tumor activity than abi itself because it inhibits multiple enzymes and antagonizes the androgen receptor (AR) directly. D4A inhibits cell proliferation and xenograft growth better than Abi. However, 5α-Abi has more limited effects on steroidogenic enzymes and is a modest AR agonist, which might promote abi resistance. We suggest that abi metabolism could be a biomarker for abi response, and patients with limited or no response to abi might have less D4A or more 5α-Abi. Furthermore, we demonstrate that dutasteride, a 5α-reductase inhibitor, suppresses the conversion from D4A to 5α-Abi in both prostate cancer cell lines and patients, which might enhance the clinical response to abi. Taken together, these data reveal a novel metabolic pathway of abi that can be exploited for treatment, specifically as a biomarker. It is achievable in clinic to fine tune abi metabolism to obtain greater concentrations of D4A, the most potent anti-tumor abi metabolite, in patients by supplementing abi treatment with dutasteride.

Citation Format: Zhenfei Li, Mohammad Alyamani, Jianneng Li, Mary-Ellen Taplin, Nima Sharifi. Abiraterone metabolism and a novel therapeutic strategy for castration resistant prostate cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A17.
Abstract A20: The DNA damage-induced phosphoproteome is modulated by inhibition of the MET receptor
Authors: Bensimon Ariel , Zimmer Yitzhak , Francica Paola , Koch Jonas P. , Glück Astrid A. , Aebersold Daniel M. , Aebersold Ruedi , Medova Michaela
Published: January 2017

Ionizing radiation (IR) is frequently used in the treatment of a variety of malignant tumors of different origins and stages. In recent years, numerous studies have demonstrated that interfering with signaling via growth factor receptor tyrosine kinases (RTKs) can increase the sensitivity of certain tumors to IR. The RTK for hepatocyte growth factor MET is aberrantly activated in numerous types of human malignancies. MET inhibition has been shown to synergize with DNA damaging agents in generation of DNA damage and to interfere with damage repair. In this study, we aimed to explore how the cellular response to ionizing radiation is modulated by MET inhibition.

We have conducted an immunoaffinity-based LC-MS/MS phosphoproteomics survey study to explore the cellular phosphoproteome following exposure of MET-addicted cancer cells to MET inhibition alone and in combination with IR. Phosphorylation sites of interest have been examined using selected reaction monitoring (SRM) and further validated in vitro and in vivo by Western blotting and immunohistochemistry, respectively.

Analysis of the survey data has identified more than 300 phosphopeptides which have changed in one experimental condition or more. Several of these phosphorylation changes have been confirmed and further investigated by targeted proteomics. These results have pointed to a sub-network of the DNA damage response (DDR) that is modulated in MET-addicted cancer cells upon DNA damage and MET inhibition. The resulting molecular signature present solely in MET-addicted systems could be responsible for the synergism observed between MET inhibition and DNA-damaging agents. We believe that these results will aid in understanding as how MET signaling crosstalks with the DDR with subsequent translational therapeutic clinical applications.

Citation Format: Ariel Bensimon, Yitzhak Zimmer, Paola Francica, Jonas P. Koch, Astrid A. Glück, Daniel M. Aebersold, Ruedi Aebersold, Michaela Medova. The DNA damage-induced phosphoproteome is modulated by inhibition of the MET receptor. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A20.
Abstract A32: Upregulation of the Notch signaling pathway is associated with mortality and in vitro cell invasion in squamous cell carcinoma of the oral cavity
Authors: Weaver Alice N. , Cooper Tiffiny S. , Manna Deborah Della , Wei Shi , Rosenthal Eben L. , Yang Eddy S.
Published: January 2017

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with low survival rates, which have not significantly improved despite advances in surgery and radiotherapy. Although human papillomavirus is a strong predictor of outcomes in oropharyngeal tumors, other HNSCC subtypes lack reliable prognostic and therapeutic biomarkers. The purpose of this study was to identify molecular targets to improve the management of oral cavity SCC (OSCC). We isolated RNA from 19 OSCCs treated surgically at UAB and evaluated gene expression using the NanoString nCounter system and PanCancer Pathways analysis module. Results were confirmed using data from the oral cavity anatomic subdivision of the Head and Neck Squamous Cell Carcinoma cancer study generated by the TCGA Research Network. Associated in vitro phenotype was assessed in HNSCC cell lines UM-SCC1, UM-SCC6 and FaDu treated with the activating Notch ligand DLL4 and included evaluation of gene expression, proliferation, cell cycle, migration, invasion, and radiosensitivity. We identified a significant association between upregulation of the Notch pathway and mortality in both the UAB and TCGA OSCC sample sets. In vitro activation of Notch signaling altered transcription in a pattern similar to that found in patient samples from the mortality cohorts. HNSCC cells with Notch activation had increased expression of pro-invasive genes FGF1, IL1B, SIX1, and CCNA1. In addition, Notch activated cells displayed increased cell migration and invasion. Proliferation, cell cycle distribution, and radiosensitivity were unchanged in ligand-treated cells. Our results identify a subset of OSCC patients who have increased Notch pathway activity and worsened outcomes. These clinical findings may reflect a more invasive cell phenotype driven by Notch-mediated changes in transcription. Additional studies are needed to fully elucidate the mechanism underlying this association and to investigate the efficacy of therapies targeting Notch signaling in OSCC.

Citation Format: Alice N. Weaver, Tiffiny S. Cooper, Deborah Della Manna, Shi Wei, Eben L. Rosenthal, Eddy S. Yang. Upregulation of the Notch signaling pathway is associated with mortality and in vitro cell invasion in squamous cell carcinoma of the oral cavity. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A32.
Abstract A38: MTH1 Inhibition as an effective tumor-suppressive strategy in RAS-driven cancer
Authors: Samaranayake Govindi Jayanika , Troccoli Clara Issabella , Cunningham Tyler Andrew , Rai Priyamvada
Published: January 2017

Oncogenic RAS mutations confer multiple malignant traits to cancer cells, many of which are mediated by oncogene-induced reactive oxygen species (ROS). However, oncogenic ROS also create vulnerabilities in the cancer cells, sensitizing them to oxidative DNA damage and strand breaks which can trigger cellular senescence or cell death. Thus RAS-driven tumor cells require adaptive redox protective mechanisms to inhibit ROS-associated tumor suppression. We previously reported that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase, comprises one such critical adaptation. We have shown MTH1 is important for facilitating the full gamut of RAS-driven malignancy by promoting evasion of the first barrier to transformation, viz. oncogene-induced senescence (OIS), enhancing RAS-mediated transformation and related pro-malignant traits, and maintaining proliferation and tumorigenicity in established RAS-driven tumor cells. Recently chemical inhibitors against MTH1 have been developed, although there is some controversy surrounding their efficacy and mode of action. Our work here discusses RAS regulation of MTH1 expression, and the molecular contexts under which MTH1 inhibition can synergize with oncogenic oxidative stress in RAS-driven tumor cells for optimal tumor suppressive response.

Citation Format: Govindi Jayanika Samaranayake, Clara Issabella Troccoli, Tyler Andrew Cunningham, Priyamvada Rai. MTH1 Inhibition as an effective tumor-suppressive strategy in RAS-driven cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A38.