bluuebunny/crossref_metadata_2025 huggingface dataset:
Analgesic and Anti-Inflammatory Activities of the Ethanolic Extract ofArtemisia morrisonensisHayata in Mice
Authors: Chou Shen-Chieh , Chiu Yung-Jia , Chen Chao-Jung , Lin Ying-Chih , Wu Chung-Hao , Chao Chien-Ti , Chang Ching-Wen , Peng Wen-Huang
Published: December 2012

The aim of this study was to investigate the possible analgesic and anti-inflammatory mechanisms of the ethanolic extract ofA. morrisonensisHayata (AMEtOH). Two models were employed for evaluation of the analgesic effects: acetic acid-induced writhing response and formalin-induced paw licking. The results demonstrated thatAMEtOHdecreased writhing response for both the acetic acid assay and the licking time in the formalin test. The anti-inflammatory effect was evaluated by paw edema of mice induced byλ-carrageenan.AMEtOHsignificantly decreased induced paw edema three to four hours afterλ-carrageenan injection. Additionally, the results indicated that the anti-inflammatory mechanism ofAMEtOHmay be due to the declined levels of nitric oxide (NO) and malondialdehyde (MDA) in the edematous paw. Furthermore,AMEtOHdecreased the tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels, leading to the reduction of prostaglandins and subsequently alleviated edema. Isolation and purification of theAMEtOHextract determinedp-hydroxyacetophenone to be a major component at 130 mg/g of extract. No mortality was observed in the acute toxicity test given at the dose of 10 g/kg. This study demonstrated the possible mechanisms for the analgesic and anti-inflammatory effects ofAMEtOHfor mice and provided evidence for the ethnobotanical uses ofA. morrisonensisin treating inflammatory diseases.
The Inhibition of Spinal Astrocytic JAK2-STAT3 Pathway Activation Correlates with the Analgesic Effects of Triptolide in the Rat Neuropathic Pain Model
Authors: Tang Jun , Li Zhi-Hong , Ge Shun-Nan , Wang Wei , Mei Xiao-Peng , Wang Wen , Zhang Ting , Xu Li-Xian , Li Jin-Lian
Published: December 2012

Neuropathic pain (NP) is an intractable clinical problem without satisfactory treatments. However, certain natural products have been revealed as effective therapeutic agents for the management of pain states. In this study, we used the spinal nerve ligation (SNL) pain model to investigate the antinociceptive effect of triptolide (T10), a major active component of the traditional Chinese herbTripterygium wilfordiiHook F. Intrathecal T10 inhibited the mechanical nociceptive response induced by SNL without interfering with motor performance. Additionally, the anti-nociceptive effect of T10 was associated with the inhibition of the activation of spinal astrocytes. Furthermore, intrathecal administration of T10 attenuated SNL-induced janus kinase (JAK) signal transducers and activators of transcription 3 (STAT3) signalling pathway activation and inhibited the upregulation of proinflammatory cytokines, such as interleukin-6, interleukin-1 beta, and tumour necrosis factor-α, in dorsal horn astrocytes. Moreover, NR2B-containing spinal N-methyl D-aspartate receptor (NMDAR) was subsequently inhibited. Above all, T10 can alleviate SNL-induced NP via inhibiting the neuroinflammation in the spinal dorsal horn. The anti-inflammation effect of T10 may be related with the suppression of spinal astrocytic JAK-STAT3 activation. Our results suggest that T10 may be a promising drug for the treatment of NP.
Production of Biomass-Degrading Multienzyme Complexes under Solid-State Fermentation of Soybean Meal Using a Bioreactor
Authors: Vitcosque Gabriela L. , Fonseca Rafael F. , Rodríguez-Zúñiga Ursula Fabiola , Bertucci Neto Victor , Couri Sonia , Farinas Cristiane S.
Published: December 2012

Biomass-degrading enzymes are one of the most costly inputs affecting the economic viability of the biochemical route for biomass conversion into biofuels. This work evaluates the effects of operational conditions on biomass-degrading multienzyme production by a selected strain of Aspergillus niger. The fungus was cultivated under solid-state fermentation (SSF) of soybean meal, using an instrumented lab-scale bioreactor equipped with an on-line automated monitoring and control system. The effects of air flow rate, inlet air relative humidity, and initial substrate moisture content on multienzyme (FPase, endoglucanase, and xylanase) production were evaluated using a statistical design methodology. Highest production of FPase (0.55 IU/g), endoglucanase (35.1 IU/g), and xylanase (47.7 IU/g) was achieved using an initial substrate moisture content of 84%, an inlet air humidity of 70%, and a flow rate of 24 mL/min. The enzymatic complex was then used to hydrolyze a lignocellulosic biomass, releasing 4.4 g/L of glucose after 36 hours of saccharification of 50 g/L pretreated sugar cane bagasse. These results demonstrate the potential application of enzymes produced under SSF, thus contributing to generate the necessary technological advances to increase the efficiency of the use of biomass as a renewable energy source.
Syringic Acid Extracted fromHerba dendrobiiPrevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity
Authors: Wei Xiaoyong , Chen Dan , Yi Yanchun , Qi Hui , Gao Xinxin , Fang Hua , Gu Qiong , Wang Ling , Gu Lianquan
Published: December 2012

Objective. Effects of Syringic acid (SA) extracted from dendrobii on diabetic cataract (DC) pathogenesis were explored.Methods. Bothin vitroandin vivoDC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using qRT-PCR. Interaction sites and binding characteristics were determined by molecule-docking techniques and dynamic models.Results. Targeting AR, SA provided protection from D-gal-induced damage by consistently maintaining lens transparency and delaying lens turbidity development. Inhibition of AR gene expression by SA was confirmed by qRT-PCR. IC50of SA for inhibition of AR activity was 213.17 μg/mL. AR-SA binding sites were Trp111, His110, Tyr48, Trp20, Trp79, Leu300, and Phe122. The main binding modes involved hydrophobic interactions and hydrogen bonding. The stoichiometric ratio of non-covalent bonding between SA and AR was 1.0 to 13.3.Conclusion. SA acts to prevent DC in rat lenses by inhibiting AR activity and gene expression, which has potential to be developed into a novel drug for therapeutic management of DC.
A Smoothing Interval Neural Network
Authors: Yang Dakun , Wu Wei
Published: December 2012

In many applications, it is natural to use interval data to describe various kinds of uncertainties. This paper is concerned with an interval neural network with a hidden layer. For the original interval neural network, it might cause oscillation in the learning procedure as indicated in our numerical experiments. In this paper, a smoothing interval neural network is proposed to prevent the weights oscillation during the learning procedure. Here, by smoothing we mean that, in a neighborhood of the origin, we replace the absolute values of the weights by a smooth function of the weights in the hidden layer and output layer. The convergence of a gradient algorithm for training the smoothing interval neural network is proved. Supporting numerical experiments are provided.
Properties of Surfactin C‐15 Nanopeptide and Its Cytotoxic Effect on Human Cervix Cancer (HeLa) Cell Line
Authors: Nozhat Zahra , Asadi Asadollah , Zahri Saber
Published: December 2012

Surfactin is one of the most powerful biosurfactants that has been known so far. It is an acidic cyclic nonribosomal lipoheptapeptide that is produced by Bacillus subtilis. In this presentation we investigated different properties of surfactin C‐15. The nanomicelle forming ability of surfactin C‐15 in different aqueous environments with various ionic strengths was studied by scanning electron microscope. Surfactin second structure was investigated by Far‐UV CD spectrum. Its hemolytic activity and cytotoxicity were measured by hemolysis and MTT assays, respectively. Surfactin formed spherical nanomicelles in distilled water (pH = 7.4) and amorphous nanomicelles in PBS buffer (pH = 7.4). The hemolysis assay results indicated that HC50 of surfactin was 47 μM. Surfactin C‐15 arrested growth of human cervix cancer HeLa cell line in a time‐ and dosage‐dependent method, so that its IC50 at 16, 24, and 48h were 86.9, 73.1, and 50.2 μM, respectively.
Network Architecture, Security Issues, and Hardware Implementation of a Home Area Network for Smart Grid
Authors: Saponara Sergio , Bacchillone Tony
Published: December 2012

This paper discusses aims, architecture, and security issues of Smart Grid, taking care of the lesson learned at University of Pisa in research projects on smart energy and grid. A key element of Smart Grid is the energy home area network (HAN), for which an implementation is proposed, dealing with its security aspects and showing some solutions for realizing a wireless network based on ZigBee. Possible hardware-software architectures and implementations using COTS (Commercial Off The Shelf) components are presented for key building blocks of the energy HAN such as smart power meters and plugs and a home smart information box providing energy management policy and supporting user's energy awareness.
Missed Appendicitis: Mimicking Urologic Symptoms
Authors: Akhavizadegan Hamed
Published: December 2012

Appendicitis, a common disease, has different presentations. This has made its diagnosis difficult. This paper aims to present two cases of missed appendicitis with completely urologic presentation and the way that helped us to reach the correct diagnosis. The first case with symptoms fully related to kidney and the second mimicking epididymorchitis hindered prompt diagnosis. Right site of the pain, relapsing fever, frequent physical examination, and resistance to medical treatment were main clues which help us to make correct diagnosis.
ℓp-Norm Multikernel Learning Approach for Stock Market Price Forecasting
Authors: Shao Xigao , Wu Kun , Liao Bifeng
Published: December 2012

Linear multiple kernel learning model has been used for predicting financial time series. However,ℓ1-norm multiple support vector regression is rarely observed to outperform trivial baselines in practical applications. To allow for robust kernel mixtures that generalize well, we adoptℓp-norm multiple kernel support vector regression (1≤p<∞) as a stock price prediction model. The optimization problem is decomposed into smaller subproblems, and the interleaved optimization strategy is employed to solve the regression model. The model is evaluated on forecasting the daily stock closing prices of Shanghai Stock Index in China. Experimental results show that our proposed model performs better thanℓ1-norm multiple support vector regression model.
Transcutaneous Auricular Vagus Nerve Stimulation Protects Endotoxemic Rat from Lipopolysaccharide-Induced Inflammation
Authors: Zhao Yu Xue , He Wei , Jing Xiang Hong , Liu Jun Ling , Rong Pei Jing , Ben Hui , Liu Kun , Zhu Bing
Published: December 2012

Background. Transcutaneous auricular vagus nerve stimulation (ta-VNS) could evoke parasympathetic activities via activating the brainstem autonomic nuclei, similar to the effects that are produced after vagus nerve stimulation (VNS). VNS modulates immune function through activating the cholinergic anti-inflammatory pathway.Methods. VNS, ta-VNS, or transcutaneous electrical acupoint stimulation (TEAS) on ST36 was performed to modulate the inflammatory response. The concentration of serum proinflammatory cytokines and tissue NF-kappa B p65 (NF-κB p65) were detected in endotoxaemia affected anesthetized rats.Results. Similar to the effect of VNS, ta-VNS suppressed the serum proinflammatory cytokines levels, such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) as well as NF-kappa B p65 expressions of lung tissues. ST36 stimulation also decreases LPS-induced high TNF-αlevel and NF-κB signal, but it did not restrain proinflammatory cytokine IL-1βand IL-6. Neither ta-VNS nor ST36 stimulation could suppress LPS-induced TNF-αand NF-κB after vagotomy or withα7nAChR antagonist injection.Conclusions. The present paper demonstrated that ta-VNS could be utilized to suppress LPS-induced inflammatory responses viaα7nAChR-mediated cholinergic anti-inflammatory pathway.
The Effects of Instructions on Dual-Task Walking and Cognitive Task Performance in People with Parkinson's Disease
Authors: Kelly Valerie E. , Eusterbrock Alexis J. , Shumway-Cook Anne
Published: December 2012

Gait impairments are prevalent among people with Parkinson’s disease (PD). Instructions to focus on walking can improve walking in PD, but the use of such a cognitive strategy may be limited under dual-task walking conditions, when walking is performed simultaneously with concurrent cognitive or motor tasks. This study examined how dual-task performance of walking and a concurrent cognitive task was affected by instructions in people with PD compared to healthy young and older individuals. Dual-task walking and cognitive task performance was characterized under two sets of instructions as follows: (1) focus on walking and (2) focus on the cognitive task. People with PD and healthy adults walked faster when instructed to focus on walking. However, when focused on walking, people with PD and young adults demonstrated declines in the cognitive task. This suggests that dual-task performance is flexible and can be modified by instructions in people with PD, but walking improvements may come at a cost to cognitive task performance. The ability to modify dual-task performance in response to instructions or other task and environmental factors is critical to mobility in daily life. Future research should continue to examine factors that influence dual-task performance among people with PD.
On the Zeroes and the Critical Points of a Solution of a Second Order Half‐Linear Differential Equation
Authors: Almenar Pedro , Jódar Lucas
Published: December 2012

This paper presents two methods to obtain upper bounds for the distance between a zero and an adjacent critical point of a solution of the second‐order half‐linear differential equation (p(x)Φ(y′))′ + q(x)Φ(y) = 0, with p(x) and q(x) piecewise continuous and p(x) > 0, Φ(t) = |t|r−2t and r being real such that r > 1. It also compares between them in several examples. Lower bounds (i.e., Lyapunov inequalities) for such a distance are also provided and compared with other methods.
Dynamic Proportional Reinsurance and Approximations for Ruin Probabilities in the Two‐Dimensional Compound Poisson Risk Model
Authors: Li Yan , Liu Guoxin
Published: December 2012

We consider the dynamic proportional reinsurance in a two‐dimensional compound Poisson risk model. The optimization in the sense of minimizing the ruin probability which is defined by the sum of subportfolio is being ruined. Via the Hamilton‐Jacobi‐Bellman approach we find a candidate for the optimal value function and prove the verification theorem. In addition, we obtain the Lundberg bounds and the Cramér‐Lundberg approximation for the ruin probability and show that as the capital tends to infinity, the optimal strategies converge to the asymptotically optimal constant strategies. The asymptotic value can be found by maximizing the adjustment coefficient.
Hand Robotics Rehabilitation: Feasibility and Preliminary Results of a Robotic Treatment in Patients with Hemiparesis
Authors: Sale Patrizio , Lombardi Valentina , Franceschini Marco
Published: December 2012

Background. No strongly clinical evidence about the use of hand robot-assisted therapy in stroke patients was demonstrated. This preliminary observer study was aimed at evaluating the efficacy of intensive robot-assisted therapy in hand function recovery, in the early phase after a stroke onset.Methods. Seven acute ischemic stroke patients at their first-ever stroke were enrolled. Treatment was performed using Amadeo robotic system (Tyromotion GmbH Graz, Austria). Each participant received, in addition to inpatients standard rehabilitative treatment, 20 sessions of robotic treatment for 4 consecutive weeks (5 days/week). Each session lasted for 40 minutes. The exercises were carried out as follows: passive modality (5 minutes), passive/plus modality (5 minutes), assisted therapy (10 minutes), and balloon (10 minutes). The following impairment and functional evaluations, Fugl-Meyer Scale (FM), Medical Research Council Scale for Muscle Strength (hand flexor and extensor muscles) (MRC), Motricity Index (MI), and modified Ashworth Scale for wrist and hand muscles (AS), were performed at the beginning (T0), after 10 sessions (T1), and at the end of the treatment (T2). The strength hand flexion and extension performed by Robot were assessed at T0 and T2. The Barthel Index and COMP (performance and satisfaction subscale) were assessed at T0 and T2.Results. Clinical improvements were found in all patients. No dropouts were recorded during the treatment and all subjects fulfilled the protocol. Evidence of a significant improvement was demonstrated by the Friedman test for the MRC (P<0.0123). Evidence of an improvement was demonstrated for AS, FM, and MI.Conclusions. This original rehabilitation treatment could contribute to increase the hand motor recovery in acute stroke patients. The simplicity of the treatment, the lack of side effects, and the first positive results in acute stroke patients support the recommendations to extend the clinical trial of this treatment, in association with physiotherapy and/or occupational therapy.
Discrete-State Stochastic Models of Calcium-Regulated Calcium Influx and Subspace Dynamics Are Not Well-Approximated by ODEs That Neglect Concentration Fluctuations
Authors: Weinberg Seth H. , Smith Gregory D.
Published: December 2012

Cardiac myocyte calcium signaling is often modeled using deterministic ordinary differential equations (ODEs) and mass-action kinetics. However, spatially restricted “domains” associated with calcium influx are small enough (e.g., 10−17liters) that local signaling may involve 1–100 calcium ions. Is it appropriate to model the dynamics of subspace calcium using deterministic ODEs or, alternatively, do we require stochastic descriptions that account for the fundamentally discrete nature of these local calcium signals? To address this question, we constructed a minimal Markov model of a calcium-regulated calcium channel and associated subspace. We compared the expected value of fluctuating subspace calcium concentration (a result that accounts for the small subspace volume) with the corresponding deterministic model (an approximation that assumes large system size). When subspace calcium did not regulate calcium influx, the deterministic and stochastic descriptions agreed. However, when calcium binding altered channel activity in the model, the continuous deterministic description often deviated significantly from the discrete stochastic model, unless the subspace volume is unrealistically large and/or the kinetics of the calcium binding are sufficiently fast. This principle was also demonstrated using a physiologically realistic model of calmodulin regulation of L-type calcium channels introduced by Yue and coworkers.
Two-Dimensional Matrix Algorithm Using Detrended Fluctuation Analysis to Distinguish Burkitt and Diffuse Large B-Cell Lymphoma
Authors: Yeh Rong-Guan , Lin Chung-Wu , Abbod Maysam F. , Shieh Jiann-Shing
Published: December 2012

A detrended fluctuation analysis (DFA) method is applied to image analysis. The 2-dimensional (2D) DFA algorithms is proposed for recharacterizing images of lymph sections. Due to Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), there is a significant different 5-year survival rates after multiagent chemotherapy. Therefore, distinguishing the difference between BL and DLBCL is very important. In this study, eighteen BL images were classified as group A, which have one to five cytogenetic changes. Ten BL images were classified as group B, which have more than five cytogenetic changes. Both groups A and B BLs are aggressive lymphomas, which grow very fast and require more intensive chemotherapy. Finally, ten DLBCL images were classified as group C. The short-term correlation exponentα1 values of DFA of groups A, B, and C were0.370±0.033,0.382±0.022,and0.435±0.053, respectively. It was found thatα1 value of BL image was significantly lower (P<0.05) than DLBCL. However, there is no difference between the groups A and B BLs. Hence, it can be concluded thatα1 value based on DFA statistics concept can clearly distinguish BL and DLBCL image.
A Case of Early-Stage Ovarian Carcinoid Tumor Metastasized to the Liver
Authors: Kanayama Seiji , Yamada Yoshihiko , Tanase Yasuhito , Haruta Shoji , Nagai Akira , Kawaguchi Ryuji , Yoshida Shozo , Furukawa Naoto , Oi Hidekazu , Kobayashi Hiroshi
Published: December 2012

We report a case of ovarian carcinoid tumor that recurred with multiple liver metastases and was successfully treated with chemoembolization. A 76-year-old woman was admitted to our hospital presented with abdominal distension and abnormal uterine bleeding for about 6 months. She presented with hyperestrogenic and androgenic manifestations such as vaginal bleeding with endometrial hyperplasia and hirsutism. Magnetic resonance (MR) imaging revealed a large solid and cystic ovarian tumor of 17 cm at maximum diameter. On the basis of the clinical diagnosis of sex cord stromal tumor containing a mature cystic teratoma, she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The pathology report revealed that the mass in the left ovary was a carcinoid tumor, insular type, with mature cystic teratoma. Two years after surgical treatment, multiple liver metastases were revealed by abdominal CT. Hepatic arterial infusion of cisplatin was performed for 2 courses, and multiple metastatic nodules have remarkably reduced. No established chemotherapy or radiation therapy treatments are currently available for recurrent or advanced carcinoid tumors. Our paper suggests that chemoembolization with cisplatin may be effective in treatment of patients with multiple liver metastases of ovarian carcinoid tumor.
Positive Effect of Severe Nakagami-mFading on the Performance of Multiuser TAS/MRC Systems with High Selection Gain
Authors: Hung Chia-Chun , Chiang Ching-Tai , Wu Rong-Ching , Lee C.
Published: December 2012

This paper investigates the positive effect of severe Nakagami-mfading on the performance of multiuser transmit antenna selection/maximal-ratio combining (TAS/MRC) systems with high selection gain. Both amount of fading (AF) and symbol error rate (SER) ofM-QAM are derived as closed-form expressions for integerm. For arbitrarym, the AF and the SER are expressible as a single infinite series of Gamma function and Gauss hypergeometric function, respectively. The analytical results lead to the following observations. First, the SER performance can demonstrate the positive effect of severe Nakagami-mfading on multiuser TAS/MRC systems with high selection gain. Second, the AF performance only exhibits the negative impact of severe fading regardless of high selection gain. Last, the benefit of severe fading to the system performance diminishes at high signal-to-noise ratio (SNR).
Pregnancy Outcome of Multiparous Women Aged over 40 Years
Authors: Ates Seda , Batmaz Gonca , Sevket Osman , Molla Taner , Dane Cem , Dane Banu
Published: December 2012

Objective. The aim of this study was to evaluate the effect of maternal age on prenatal and obstetric outcome in multiparaous women.Materials and Methods. A retrospective case control study was conducted, including women aged 40 years and over (study group,n=97) who delivered at 20 week’s gestation or beyond and women aged 20–29 years (control group,n=97).Results. The mean age of women in the study group was41.2±1.7years versus25.4±2.3years in the control group. Advanced maternal age was associated with a significantly higher rate of hypertension, diabetes mellitus, fetal complication, and 5-minute Apgar scores <7 (P<0.05). Caeserean section rate, incidence of placental abruption, preterm delivery, and neonatal intensive care unit admission were more common in the older group, but the differences were not statistically significant.Conclusions. Advanced maternal age is related to maternal and neonatal complications.
Direct Effect of Chenodeoxycholic Acid on Differentiation of Mouse Embryonic Stem Cells Cultured under Feeder-Free Culture Conditions
Authors: Park Soon-Jung , Lee Seul-Bi , Lee Dong-Sup , Ryu Young-Joon , Lee Gene , Cho Jaejin
Published: December 2012

Chenodeoxycholic acid (CDCA), a farnesoid X receptor (FXR) ligand, is a member of the nuclear receptor family and is probably involved in regulating the cellular activities of embryonic stem (ES) cells. Recently, although it was reported that the FXR ligand can mediate differentiation, apoptosis, and/or growth arrest in several cell types, it is still not well known how CDCA mediates effects in ES cells. Therefore, we investigated the direct effect of CDCA on mES cells. Feeder-free mES cells were treated in a dose-dependent manner with CDCA (50, 100, and 200 μM) for 72 h, and then a 100 μM CDCA treatment was performed for an additional 72 h. We analyzed the morphology, cell growth, cell characteristics, immunocytochemistry, and RT-PCR. In CDCA-treated cells, we observed the disappearance of pluripotent stem cell markers including alkaline phosphatase, Oct4, and Nanog and a time- and dose-dependent increase in expression of nestin, PAX6, andα-smooth muscle actin, but notα-fetoprotein. The 100 μM CDCA-treated cells in their second passage continued this differentiation pattern similar to those in the controls. In conclusion, these results suggest that CDCA can guide mES cells by an FXR-independent pathway to differentiate into ectoderm and/or mesoderm, but not endoderm.
Regulation of Tight Junctions in Upper Airway Epithelium
Authors: Kojima Takashi , Go Mitsuru , Takano Ken-ichi , Kurose Makoto , Ohkuni Tsuyoshi , Koizumi Jun-ichi , Kamekura Ryuta , Ogasawara Noriko , Masaki Tomoyuki , Fuchimoto Jun , Obata Kazufumi , Hirakawa Satoshi , Nomura Kazuaki , Keira Takashi , Miyata Ryou , Fujii Nobuhiro , Tsutsumi Hiroyuki , Himi Tetsuo , Sawada Norimasa
Published: December 2012

The mucosal barrier of the upper respiratory tract including the nasal cavity, which is the first site of exposure to inhaled antigens, plays an important role in host defense in terms of innate immunity and is regulated in large part by tight junctions of epithelial cells. Tight junction molecules are expressed in both M cells and dendritic cells as well as epithelial cells of upper airway. Various antigens are sampled, transported, and released to lymphocytes through the cells in nasal mucosa while they maintain the integrity of the barrier. Expression of tight junction molecules and the barrier function in normal human nasal epithelial cells (HNECs) are affected by various stimuli including growth factor, TLR ligand, and cytokine. In addition, epithelial-derived thymic stromal lymphopoietin (TSLP), which is a master switch for allergic inflammatory diseases including allergic rhinitis, enhances the barrier function together with an increase of tight junction molecules in HNECs. Furthermore, respiratory syncytial virus infection in HNECsin vitroinduces expression of tight junction molecules and the barrier function together with proinflammatory cytokine release. This paper summarizes the recent progress in our understanding of the regulation of tight junctions in the upper airway epithelium under normal, allergic, and RSV-infected conditions.
Racial/Ethnic Differences in Use and Duration of Adjuvant Hormonal Therapy for Breast Cancer in the Women's Health Initiative
Authors: Livaudais Jennifer C. , LaCroix Andrea , Chlebowski Rowan T. , Li Christopher I. , Habel Laurel A. , Simon Michael S. , Thompson Beti , Erwin Deborah O. , Hubbell F. Allan , Coronado Gloria D.
Published: December 2012

Background: Five-year breast cancer survival rates are lower among Hispanic and African-American women than among Non-Hispanic White women. Differences in breast cancer treatment likely play a role. Adjuvant hormonal therapies increase overall survival among women with hormone receptor-positive breast cancer.

Methods: We examined racial/ethnic differences in use and duration of adjuvant hormonal therapy among 3,588 postmenopausal women enrolled in the Women's Health Initiative (WHI) Extension Study. Women diagnosed with hormone receptor-positive localized or regional stage breast cancer after study enrollment were surveyed between September 2009 and August 2010 and asked to recall prior use and duration of adjuvant hormonal breast cancer therapy. ORs comparing self-reported use and duration with race/ethnicity (Hispanic, African-American, Asian/Pacific Islander vs. Non-Hispanic White) were estimated using multivariable-adjusted logistic regression.

Results: Of the 3,588 women diagnosed from 1994 to 2009; 3,039 (85%) reported any use of adjuvant hormonal therapy, and 67% of women reporting ever-use who were diagnosed before 2005 reported using adjuvant hormonal therapy for the optimal duration of 5 years or more. In adjusted analysis, no statistically significant differences in use or duration by race/ethnicity were observed.

Conclusions: This study did not find significant differences in use or duration of use of adjuvant hormonal therapy by race/ethnicity.

Impact: Findings should be confirmed in other population-based samples, and potential reasons for discontinuation of therapy across all racial/ethnic groups should be explored. Cancer Epidemiol Biomarkers Prev; 22(3); 365–73. ©2012 AACR.
Suppression of Prostate Epithelial Proliferation and Intraprostatic Progrowth Signaling in Transgenic Mice by a New Energy Restriction-Mimetic Agent
Authors: Berman-Booty Lisa D. , Chu Po-Chen , Thomas-Ahner Jennifer M. , Bolon Brad , Wang Dasheng , Yang Tiffany , Clinton Steven K. , Kulp Samuel K. , Chen Ching-Shih
Published: December 2012

Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent. Cancer Prev Res; 6(3); 232–41. ©2012 AACR.
β-Cryptoxanthin Restores Nicotine-Reduced Lung SIRT1 to Normal Levels and Inhibits Nicotine-Promoted Lung Tumorigenesis and Emphysema in A/J Mice
Authors: Iskandar Anita R. , Liu Chun , Smith Donald E. , Hu Kang-Quan , Choi Sang-Woon , Ausman Lynne M. , Wang Xiang-Dong
Published: December 2012

Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-β mRNA levels in the lungs. Using this mouse model, we then determined whether β-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-β to that of the control group, increased survival probability, and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments. Cancer Prev Res; 6(4); 309–20. ©2012 AACR.
Combined Lifestyle Factors and Risk of Incident Colorectal Cancer in a Chinese Population
Authors: Odegaard Andrew O. , Koh Woon-Puay , Yuan Jian-Min
Published: December 2012

A body of research links dietary intake, alcohol consumption, smoking, physical activity, body mass index (BMI), and possibly sleep patterns with colorectal cancer risk. However, little research has examined the association of the combination of these lifestyle factors with incidence of colorectal cancer, especially in non-Western populations. A protective lifestyle factor index of these six aforementioned factors was created and examined in relation to risk of developing colorectal cancer. This study is a prospective observational study of 50,466 Chinese men and women in Singapore ages 45 to 74 years during enrollment in the Singapore Chinese Health Study in 1993–1998 and followed up through 2007. The main outcome measures were standardized rates and HRs of incident colorectal cancer. The protective levels of each lifestyle factor were independently associated with reduced age- and sex-standardized incidence rates of colon cancer. When all the factors were combined into a single protective lifestyle factor index, there was a strong, monotonic decrease in incidence rate of colon cancer with an increasing score. Relative to participants with an index score of 0 to 3, the HRs (95% confidence intervals) of colon cancer for an index score of 4, 5, 6, 7, 8, and 9/10 were 0.58 (0.35–0.95), 0.56 (0.36–0.86), 0.50 (0.33–0.76), 0.43 (0.28–0.66), 0.39 (0.25–0.63), and 0.25 (0.12–0.54; Ptrend < 0.0001). The results were consistent by sex. Conversely, there was no association with rectal cancer risk. An increasing protective lifestyle factor index score is associated with a marked decreased risk of developing colon cancer in Chinese men and women. Cancer Prev Res; 6(4); 360–7. ©2012 AACR.
Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression
Authors: Wang Yufang , Velho Sérgia , Vakiani Efsevia , Peng Shouyong , Bass Adam J. , Chu Gerald C. , Gierut Jessica , Bugni James M. , Der Channing J. , Philips Mark , Solit David B. , Haigis Kevin M.
Published: December 2012

N-RAS is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in NRAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to the onset and progression of the disease. Using genetically engineered mice, we find that mutant N-RAS strongly promotes tumorigenesis in the context of inflammation. The protumorigenic nature of mutant N-RAS is related to its antiapoptotic function, which is mediated by activation of a noncanonical mitogen-activated protein kinase pathway that signals through STAT3. As a result, inhibition of MAP–ERK kinase selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-RAS. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for patients with colorectal cancer. These data show for the first time the important role that N-RAS plays in colorectal cancer.

Significance: Little is known about N-RAS function in normal biology or in cancer. Our study links the antiapoptotic function of mutant N-RAS to its ability to promote colorectal cancer in an inflammatory context. In addition, our study pinpoints a therapeutic strategy for this distinct colorectal cancer subtype. Cancer Discov; 3(3); 294–307. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 239
Mcl-1 and FBW7 Control a Dominant Survival Pathway Underlying HDAC and Bcl-2 Inhibitor Synergy in Squamous Cell Carcinoma
Authors: He Lei , Torres-Lockhart Kristine , Forster Nicole , Ramakrishnan Saranya , Greninger Patricia , Garnett Mathew J. , McDermott Ultan , Rothenberg Stephen M. , Benes Cyril H. , Ellisen Leif W.
Published: December 2012

Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here, we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the histone deacetylase (HDAC) inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3-mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression in vivo. Moreover, somatic FBW7 mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with the combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.

Significance: This study reveals the tissue-specific landscape and biochemistry of the Bcl-2 family in SCC, which underlie moderate sensitivity of these tumors to HDAC inhibitor therapy but dramatic synergy in combination with BH3-mimetic therapy. By establishing predictive biomarkers, we provide evidence that tumors most likely to respond to this therapeutic combination, including those harboring somatic FBW7 mutations, are those most resistant to standard chemotherapy. Cancer Discov; 3(3); 324–37. ©2012 AACR.

See related commentary by Pickering and Myers, p. 258

This article is highlighted in the In This Issue feature, p. 239
Microembolism and Catheter Ablation II
Authors: Haines David E. , Stewart Mark T. , Barka Noah D. , Kirchhof Nicole , Lentz Linnea R. , Reinking Nicki M. , Urban Jon F. , Halimi Franck , Deneke Thomas , Kanal Emanuel
Published: December 2012

Background—

Asymptomatic cerebral lesions have been observed on diffusion weighted MRI (DWI) scans shortly after catheter ablation of atrial fibrillation, but the pathogenesis of these lesions is incompletely understood.

Methods and Results—

Twelve dogs underwent selective catheterization of the internal carotid or vertebral arteries. Either a microbubbled mixture of air (1.0–4.0 mL), blood, contrast, and saline (n=5), or heat-dried pulverized blood (particle size <600 μm) mixed with saline and contrast (n=6) was injected. One sham control experiment was performed. MRI scans were performed preinjection, and at 1, 2, and 4 days postinjection. Neurological tests were performed daily. Gross pathology and histopathology were performed on the brains after being euthanized on day 4. Three animals died <24 hours after injection. Hyperintense lesions were observed on DWI (median maximum diameter 3.1 mm) in 2 of 4 animals after air embolism and in 3 of 5 animals after particulate embolism. No DWI lesions were detected in the remaining 5 animals (including the sham control). Lesions seen on DWI and confirmed on the fluid attenuating inversion recovery sequence correlated well with anatomic lesions on histopathology.

Conclusions—

Cerebral embolization of air microbubbles or microparticulate debris that approximate the embolic sources from catheter ablation can create hyperintense DWI punctate lesions in a canine model. The location and size of the DWI/fluid attenuating inversion recovery lesions correlate with pathological findings.
Early Risk of Mortality After Coronary Artery Revascularization in Patients With Left Ventricular Dysfunction and Potential Role of the Wearable Cardioverter Defibrillator
Authors: Zishiri Edwin T. , Williams Sarah , Cronin Edmond M. , Blackstone Eugene H. , Ellis Stephen G. , Roselli Eric E. , Smedira Nicholas G. , Gillinov A. Marc , Glad Jo Ann , Tchou Patrick J. , Szymkiewicz Steven J. , Chung Mina K.
Published: December 2012

Background—

Implantation of implantable cardioverter defibrillator for prevention of sudden cardiac death is deferred for 90 days after coronary revascularization, but mortality may be highest early after cardiac procedures in patients with ventricular dysfunction. We determined mortality risk in postrevascularization patients with left ventricular ejection fraction ≤35% and compared survival with those discharged with a wearable cardioverter defibrillator (WCD).

Methods and Results—

Hospital survivors after surgical (coronary artery bypass graft surgery) or percutaneous (percutaneous coronary intervention [PCI]) revascularization with left ventricular ejection fraction ≤35% were included from Cleveland Clinic and national WCD registries. Kaplan–Meier, Cox proportional hazards, propensity score-matched survival, and hazard function analyses were performed. Early mortality hazard was higher among 4149 patients discharged without a defibrillator compared with 809 with WCDs (90-day mortality post–coronary artery bypass graft surgery 7% versus 3%,
P
=0.03; post-PCI 10% versus 2%,
P
<0.0001). WCD use was associated with adjusted lower risks of long-term mortality in the total cohort (39%,
P
<0.0001) and both post–coronary artery bypass graft surgery (38%,
P
=0.048) and post-PCI (57%,
P
<0.0001) cohorts (mean follow-up, 3.2 years). In propensity-matched analyses, WCD use remained associated with lower mortality (58% post–coronary artery bypass graft surgery,
P
=0.002; 67% post-PCI,
P
<0.0001). Mortality differences were not attributable solely to therapies for ventricular arrhythmia. Only 1.3% of the WCD group had a documented appropriate therapy.

Conclusions—

Patients with left ventricular ejection fraction ≤35% have higher early compared to late mortality after coronary revascularization, particularly after PCI. As early hazard seemed less marked in WCD users, prospective studies in this high-risk population are indicated to confirm whether WCD use as a bridge to left ventricular ejection fraction improvement or implantable cardioverter defibrillator implantation can improve outcomes after coronary revascularization.
Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans
Authors: Fox Ervin R. , Musani Solomon K. , Barbalic Maja , Lin Honghuang , Yu Bing , Ogunyankin Kofo O. , Smith Nicholas L. , Kutlar Abdullah , Glazer Nicole L. , Post Wendy S. , Paltoo Dina N. , Dries Daniel L. , Farlow Deborah N. , Duarte Christine W. , Kardia Sharon L. , Meyers Kristin J. , Sun Yan V. , Arnett Donna K. , Patki Amit A. , Sha Jin , Cui Xiangqui , Samdarshi Tandaw E. , Penman Alan D. , Bibbins-Domingo Kirsten , Bůžková Petra , Benjamin Emelia J. , Bluemke David A. , Morrison Alanna C. , Heiss Gerardo , Carr J. Jeffrey , Tracy Russell P. , Mosley Thomas H. , Taylor Herman A. , Psaty Bruce M. , Heckbert Susan R. , Cappola Thomas P. , Vasan Ramachandran S.
Published: December 2012

Background—

Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

Methods and Results—

Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10
−7
). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in
UBE2V2
(
P
=1.43×10
−7
) for left ventricular mass, rs7213314 in
WIPI1
(
P
=1.68×10
−7
) for left ventricular internal diastolic diameter, rs1571099 in
PPAPDC1A
(
P
=2.57×10
−8
) for interventricular septal wall thickness, and rs9530176 in
KLF5
(
P
=4.02×10
−7
) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

Conclusions—

In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.