bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards Driver's State Recognition on Real Driving Conditions
Authors: Rigas George , Goletsis Yorgos , Bougia Panagiota , Fotiadis Dimitrios I.
Published: July 2011

In this work a methodology for detecting drivers' stress and fatigue and predicting driving performance is presented. The proposed methodology exploits a set of features obtained from three different sources: (i) physiological signals from the driver (ECG, EDA, and respiration), (ii) video recordings from the driver's face, and (iii) environmental information. The extracted features are examined in terms of their contribution to the classification of the states under investigation. The most significant indicators are selected and used for classification using various classifiers. The approach has been validated on an annotated dataset collected during real-world driving. The results obtained from the combination of physiological signals, video features, and driving environment parameters indicate high classification accuracy (88% using three fatigue scales and 86% using two stress scales). A series of experiments on a simulation environment confirms the association of fatigue states with driving performance.
Optimal Routing for Multiclass Networks
Authors: Kameda Hisao , Li Jie , Altman Eitan
Published: July 2011

Overall optimal routing is considered along with individually optimal routing for networks with nodes interconnected in a generally configured manner and with multiple classes of users. The two problems are formulated, and we discuss the mutual equivalence between the problems, the existence and uniqueness of solutions, and the relation between the formulations with path and link flow patterns. We show that a link-traffic loop-free property holds within each class for both individually and overall optimal routing for a wide range of networks, and we show the condition that characterizes the category of networks for which the property holds.
Quasi-Model-Based Control of Type 1 Diabetes Mellitus
Authors: György András , Kovács Levente , Szalay Péter , Drexler Dániel A. , Benyó Balázs , Benyó Zoltán
Published: July 2011

Glucose-insulin models appeared in the literature are varying in complexity. Hence, their use in control theory is not trivial. The paper presents an optimal controller design framework to investigate the type 1 diabetes from control theory point of view. Starting from a recently published glucose-insulin model a Quasi Model with favorable control properties is developed minimizing the physiological states to be taken into account. The purpose of the Quasi Model is not to model the glucose-glucagon-insulin interaction precisely, but only to grasp the characteristic behavior such that the designed controller can successfully regulate the unbalanced system. Different optimal control strategies (pole-placement, LQ, Minimax control) are designed on the Quasi Model, and the obtained controllers' applicability is investigated on two more sophisticated type 1 diabetic models using two absorption scenarios. The developed framework could help researchers engaging the control problem of diabetes.
Demographic Analysis of Emergency Department Patients at the Ruijin Hospital, Shanghai
Authors: Lammers Wim , Folmer Willem , Van Lieshout Esther M. M. , Mulligan Terry , Christiaanse Jan C. , Den Hartog Dennis , Tong Jianjing , Lu Yiming , Patka Peter
Published: July 2011

Emergency medicine is an upcoming discipline that is still under development in many countries. Therefore, it is important to gain insight into the organization and patients presenting to the Emergency Department (ED). The aim of this cross-sectional study was to provide an epidemiological description of complaints and referrals of the patients visiting the ED of the Ruijin Hospital in Shanghai, China. A questionnaire was developed and completed for a convenience sample of all patients presenting to the Triage Desk of the ED. The study was performed in June 2008. A total of 2183 questionnaires were completed. The most common complaints were fever (15%), stomach/abdominal pain (15%), vertigo/dizziness (11%), and cough (10%). Following triage, patients were predominantly referred to an internist (41%), neurologist (14%), pulmonologist (11%), or general surgeon (9%). This study provides a better understanding of the reason for the ED visit and the triage system at the ED of the Ruijin Hospital. The results can be used in order to improve facilities appropriate for the specific population in the ED.
Clinical Therapeutics in Pregnancy
Authors: Feghali Maisa N. , Mattison Donald R.
Published: July 2011

Most drugs are not tested for use during pregnancy, consequently, labeling, which may include information about fetal safety, includes nothing about dosing, efficacy, or maternal safety. Yet these are concerns of health care providers considering treatment of disease during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treatment? This paper, which summarizes metabolic and physiologic changes induced by pregnancy, illustrates that standard adult dosing is likely to be incorrect during pregnancy.
Predictors of Weight Change in Male HIV-Positive Injection Drug Users Initiating Antiretroviral Therapy in Hanoi, Vietnam
Authors: Tang Alice M. , Sheehan Heidi B. , Jordan Michael R. , Duong Dang Van , Terrin Norma , Dong Kimberly , Lien Trinh Thi Minh , Trung Nguyen Vu , Wanke Christine A. , Hien Nguyen Duc
Published: July 2011

We examined clinical and nutritional predictors of weight change over two consecutive 6-month intervals among 99 HIV-positive male injection drug users initiating antiretroviral therapy (ART) in Hanoi, Vietnam. The average weight gain was 3.1 ± 4.8 kg in the first six months after ART and 0.8 ± 3.0 kg in the following six months. Predictors of weight change differed by interval. In the first interval, CD4 < 200 cells/μL, excellent/very good adherence to ART, bothersome nausea, and liquid supplement use were all associated with positive weight changes. Moderate to heavy alcohol use and tobacco smoking were associated with negative weight changes. In the second interval, having a CD4 count <200 cells/μL at the beginning of the interval and tobacco smoking were the only significant predictors and both were associated with negative weight changes. We identified several potential areas for interventions to promote weight gain immediately after starting ART in this population. Studies are needed to determine whether improving weight prior to, or at, ART initiation will result in improved outcomes on ART.
Effective Control of Postprandial Glucose Level through Inhibition of Intestinal Alpha Glucosidase byCymbopogon martinii(Roxb.)
Authors: Ghadyale Varsha , Takalikar Shrihari , Haldavnekar Vivek , Arvindekar Akalpita
Published: July 2011

Inhibition of intestinal alpha glucosidase plays a major role in preventing rise in postprandial glucose level in diabetics.Cymbopogon martinii(CM) (family Poaceae) is used in traditional Indian medicine in treatment of diabetes mellitus. The alpha glucosidase inhibitory action of the plant is studied. The active component was separated using hot water extraction of the whole plant powder, differential solvent extraction, and silica gel column chromatography. The 30 : 70 toluene : ethyl acetate fraction showed optimum activity. The silica gel chromatography fraction demonstrated 98, 98, and 68% inhibition for starch, maltose, and sucrose, respectively, at 5 mg/kg body weight of rats. Intestinal absorption studies using noneverted intestinal sacs, as well as in vivo studies in streptozotocin-induced diabetic rats using oral glucose tolerance with maltose and sucrose load, revealed better inhibition of alpha glucosidase as compared to acarbose. Kinetic studies using Lineweaver Burk plot showed mixed to noncompetitive type of inhibition by CM. In vivo studies with maltose load of 2 mg and 3 mg/gm body weight showed a noncompetitive pattern of inhibition at 5 mg/kg body weight of CM as against 60 mg/kg body weight of acarbose. Thus CM is more effective alpha glucosidase inhibitor and at lower concentration than acarbose.
The Physical Properties of Erbium‐Doped Yttrium Iron Garnet Films Prepared by Sol‐Gel Method
Authors: Shaiboub Ramadan , Ibrahim Noor Baa′yah , Abdullah Mustafa , Abdulhade Ftema
Published: July 2011

ErxY3−xFe5O12 nanoparticle films (x = 0.0, 0.6, 1.2, 2.0, and 2.5) have been synthesized by a sol‐gel technique. All of the samples were annealed at 1000°C. The nanostructures were characterized by an X‐ray diffractometer (XRD), the magnetic properties and the grain size were studied using a vibrating sample magnetometer (VSM), and a field emission scanning electron microscope (FE‐SEM), respectively. The XRD patterns of the films show single phase structure. The sizes of the particles are in the range of 78 to 89 nm. The VSM result shows that the saturation magnetization of ErxY3−xFe5O12 films decreased with the increment of Er concentration (x).
An Ecological Comparison of Floristic Composition in Seasonal Semideciduous Forest in Southeast Brazil: Implications for Conservation
Authors: Lopes Sérgio de Faria , Schiavini Ivan , Oliveira Ana Paula , Vale Vagner Santiago
Published: July 2011

We examined floristic patterns of ten seasonal semideciduous forest sites in southeastern Brazil and conducted a central sampling of one hectare for each site, where we took samples and identified all individual living trees with DBH (diameter at breast height, 1.30 m) ≥4.8 cm. Arboreal flora totaled 242 species, 163 genera, and 58 families. Fabaceae (38 species) and Myrtaceae (20 species) were families with the largest number of species. OnlyCopaifera langsdorffiiandHymenaea courbariloccurred at all sites. Multivariate analysis (detrended correspondence analysis and cluster analysis) using two-way indicator species analysis (TWINSPAN) indicated the formation of a group containing seven fragments in whichSiparuna guianensiswas the indicator species. This analysis revealed that similarities between studied fragments were due mainly to the successional stage of the community.
Optimized Operator-Splitting Methods in Numerical Integration of Maxwell's Equations
Authors: Huang Z. X. , Wu X. L. , Sha W. E. I. , Wu B.
Published: July 2011

Optimized operator splitting methods for numerical integration of the time domain Maxwell's equations in computational electromagnetics (CEM) are proposed for the first time. The methods are based on splitting the time domain evolution operator of Maxwell's equations into suboperators, and corresponding time coefficients are obtained by reducing the norm of truncation terms to a minimum. The general high-order staggered finite difference is introduced for discretizing the three-dimensional curl operator in the spatial domain. The detail of the schemes and explicit iterated formulas are also included. Furthermore, new high-order Padé approximations are adopted to improve the efficiency of the proposed methods. Theoretical proof of the stability is also included. Numerical results are presented to demonstrate the effectiveness and efficiency of the schemes. It is found that the optimized schemes with coarse discretized grid and large Courant-Friedrichs-Lewy (CFL) number can obtain satisfactory numerical results, which in turn proves to be a promising method, with advantages of high accuracy, low computational resources and facility of large domain and long-time simulation. In addition, due to the generality, our optimized schemes can be extended to other science and engineering areas directly.
YB-1 Bridges Neural Stem Cells and Brain Tumor–Initiating Cells via Its Roles in Differentiation and Cell Growth
Authors: Fotovati Abbas , Abu-Ali Samah , Wang Pei-Shan , Deleyrolle Loic P. , Lee Cathy , Triscott Joanna , Chen James Y. , Franciosi Sonia , Nakamura Yasuhiro , Sugita Yasuo , Uchiumi Takeshi , Kuwano Michihiko , Leavitt Blair R. , Singh Sheila K. , Jury Alexa , Jones Chris , Wakimoto Hiroaki , Reynolds Brent A. , Pallen Catherine J. , Dunn Sandra E.
Published: July 2011

The Y-box binding protein 1 (YB-1) is upregulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here, we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knockout mice had reduced Sox-2, nestin, and musashi-1 expression in the SVZ. Although primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Glial tumors often express NSC markers and tend to loose the cellular control that governs differentiation; therefore, we addressed whether YB-1 served a similar role in cancer cells. YB-1, Sox-2, musashi-1, Bmi-1, and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary brain tumor–initiating cells (BTIC). Silencing YB-1 with siRNA attenuated the expression of these NSC markers, reduced neurosphere growth, and triggered differentiation via coordinate loss of GSK3-β. Furthermore, differentiation of BTIC with 1% serum or bone morphogenetic protein-4 suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 expression increased with tumor grade (n = 49 cases). YB-1 was also coexpressed with Bmi-1 (Spearmans 0.80, P > 0.001) and Sox-2 (Spearmans 0.66, P > 0.001) based on the analysis of 282 cases of high-grade gliomas. These proteins were highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 correlatively expresses with NSC markers where it functions to promote cell growth and inhibit differentiation. Cancer Res; 71(16); 5569–78. ©2011 AACR.
TLR4 Engagement during TLR3-Induced Proinflammatory Signaling in Dendritic Cells Promotes IL-10–Mediated Suppression of Antitumor Immunity
Authors: Bogunovic Dusan , Manches Olivier , Godefroy Emmanuelle , Yewdall Alice , Gallois Anne , Salazar Andres M. , Marie Isabelle , Levy David E. , Bhardwaj Nina
Published: July 2011

Toll-like receptor (TLR) agonists are promising adjuvants for immune therapy of cancer, but their potential efficacy as single or combinatorial agents has yet to be fully evaluated. Here, we report that among all TLR agonists tested, dendritic cells (DC) stimulated with the TLR3 agonist polyI:C displayed the strongest activity in stimulating proinflammatory responses and the production of melanoma antigen-specific CD8+ T cells. Simultaneous treatment with TLR7/8 agonists further improved these responses, but the inclusion of bacterial lipopolysaccharide (LPS), a TLR4 agonist, suppressed proinflammatory cytokine production. This inhibition was contingent upon rapid induction of the suppressive cytokine interleukin (IL)-10 by LPS, leading to dysregulated immune responses and it could be reversed by signal transducers and activators of transcription 3 knockdown, p38 blockade or antibodies to IL-10 and its receptor. Our findings show how certain TLR agonist combinations can enhance or limit DC responses associated with antitumor immunity, through their relative ability to induce IL-10 pathways that are immune suppressive. Cancer Res; 71(16); 5467–76. ©2011 AACR.
Dual Function of ERRα in Breast Cancer and Bone Metastasis Formation: Implication of VEGF and Osteoprotegerin
Authors: Fradet Anaïs , Sorel Helène , Bouazza Lamia , Goehrig Delphine , Dépalle Baptiste , Bellahcène Akeila , Castronovo Vincent , Follet Hélène , Descotes Françoise , Aubin Jane E. , Clézardin Philippe , Bonnelye Edith
Published: July 2011

Bone metastasis is a complication occurring in up to 70% of advanced breast cancer patients. The estrogen receptor-related receptor alpha (ERRα) has been implicated in breast cancer and bone development, prompting us to examine whether ERRα may function in promoting the osteolytic growth of breast cancer cells in bone. In a mouse xenograft model of metastatic human breast cancer, overexpression of wild-type ERRα reduced metastasis, whereas overexpression of a dominant negative mutant promoted metastasis. Osteoclasts were directly affected and ERRα upregulated the osteoclastogenesis inhibitor, osteoprotegerin (OPG), providing a direct mechanistic basis for understanding how ERRα reduced breast cancer cell growth in bone. In contrast, ERRα overexpression increased breast cancer cell growth in the mammary gland. ERRα-overexpressing primary tumors were highly vascularized, consistent with an observed upregulation of angiogenic growth factor, the VEGF. In support of these findings, we documented that elevated expression of ERRα mRNA in breast carcinomas was associated with high expression of OPG and VEGF and with disease progression. In conclusion, our results show that ERRα plays a dual role in breast cancer progression in promoting the local growth of tumor cells, but decreasing metastatic growth of osteolytic lesions in bone. Cancer Res; 71(17); 5728–38. ©2011 AACR.
Advanced Glycation End Products, Soluble Receptor for Advanced Glycation End Products, and Risk of Colorectal Cancer
Authors: Jiao Li , Taylor Philip R. , Weinstein Stephanie J. , Graubard Barry I. , Virtamo Jarmo , Albanes Demetrius , Stolzenberg-Solomon Rachael Z.
Published: July 2011

Background: Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE–ligand engagement.

Methods: We examined the association between Nϵ-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case–cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985–1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI.

Results: Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39–1.07; Ptrend = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30–0.89; Ptrend = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64–2.26).

Conclusions: Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers.

Impact: This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development. Cancer Epidemiol Biomarkers Prev; 20(7); 1430–8. ©2011 AACR.
A Large Cohort Study of Long-term Acetaminophen Use and Prostate Cancer Incidence
Authors: Jacobs Eric J. , Newton Christina C. , Stevens Victoria L. , Gapstur Susan M.
Published: July 2011

Background: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAID), particularly long-term use, has been associated with modestly reduced risk of prostate cancer in previous epidemiologic studies. Acetaminophen, a commonly used pain reliever, is not traditionally considered an NSAID but can have anti-inflammatory effects. Few studies have examined the association between long-term acetaminophen use and prostate cancer incidence.

Methods: We examined the association between acetaminophen use and prostate cancer incidence among 78,485 men in the Cancer Prevention Study II Nutrition Cohort. Information on acetaminophen use was obtained from a questionnaire completed at study enrollment in 1992 and updated by using follow-up questionnaires in 1997 and every two years thereafter. Relative risks (RR) were estimated by using proportional hazards regression models. All models were adjusted for age, race, education, body mass index, diabetes, NSAID use, and history of prostate-specific antigen testing.

Results: During follow-up from 1992 through 2007, 8,092 incident prostate cancer cases were identified. Current regular use of acetaminophen (30 or more pills per month) for 5 or more years was associated with lower risk of overall prostate cancer (RR = 0.62, 95% CI: 0.44–0.87) and aggressive prostate cancer (RR = 0.49, 95% CI: 0.27–0.88). Current regular use of less than 5 years duration was not associated with prostate cancer risk.

Conclusion: These results suggest that long-term regular acetaminophen use may be associated with lower prostate cancer risk.

Impact: If the association between acetaminophen use and lower risk of prostate cancer is confirmed, it could provide clues about biological mechanisms that are important in prostate carcinogenesis. Cancer Epidemiol Biomarkers Prev; 20(7); 1322–8. ©2011 AACR.
Understanding Suboptimal Human Papillomavirus Vaccine Uptake Among Ethnic Minority Girls
Authors: Bastani Roshan , Glenn Beth A. , Tsui Jennifer , Chang L. Cindy , Marchand Erica J. , Taylor Victoria M. , Singhal Rita
Published: July 2011

Background: The introduction of human papillomavirus (HPV) vaccines represents a breakthrough in the primary prevention of cervical cancer. However, little is known about vaccination uptake and correlates among low-income, ethnic minority, and immigrant populations in the U.S. who may benefit most from the vaccine.

Methods: Telephone interviews (N = 490) were conducted in six languages between January and November 2009 among mothers of vaccine-eligible girls (ages 9–18) using the Los Angeles County Department of Public Health, Office of Women's Health service referral hotline. HPV and vaccine awareness, knowledge, beliefs, barriers, and daughter's vaccine receipt were assessed.

Results: The sample consisted of low-income, uninsured, ethnic minority, and immigrant women. Only 29% of daughters initiated the vaccine and 11% received all three doses. No ethnic differences were observed in initiation or completion rates. Ethnic differences were observed in HPV awareness, perceived risk, and other vaccine-related beliefs. The strongest predictor of initiation was vaccine awareness (OR = 12.00). Daughter's age and reporting a younger acceptable age for vaccination were positively associated with initiation. Mothers of unvaccinated girls reported lacking information about the vaccine to make a decision (66%) and not knowing where they could obtain the vaccine (74%).

Conclusion: Vaccination rates in this sample were lower than state and national estimates, and were associated with low levels of vaccine awareness. Interventions, including culturally targeted messaging, may be helpful for enhancing HPV–vaccine knowledge, modifying vaccine-related beliefs and increasing uptake.

Impact: Our findings provide valuable guidance for developing interventions to address suboptimal HPV vaccination in high-risk groups. Cancer Epidemiol Biomarkers Prev; 20(7); 1463–72. ©2011 AACR.
Rapamycin Is a Potent Inhibitor of Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate
Authors: Checkley L. Allyson , Rho Okkyung , Moore Tricia , Hursting Steve , DiGiovanni John
Published: July 2011

Aberrant activation of phosphoinositide-3-kinase (PI3K)/Akt signaling has been implicated in the development and progression of multiple human cancers. During the process of skin tumor promotion induced by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), activation of epidermal Akt occurs as well as several downstream effectors of Akt, including the activation of mTORC1. Rapamycin, an established mTORC1 inhibitor, was used to further explore the role of mTORC1 signaling in epithelial carcinogenesis, specifically during the tumor promotion stage. Rapamycin blocked TPA-induced activation of mTORC1 as well as several downstream targets. In addition, TPA-induced epidermal hyperproliferation and hyperplasia were inhibited in a dose-dependent manner with topical rapamycin treatments. Immunohistochemical analyses of the skin from mice in this multiple treatment experiment revealed that rapamycin also significantly decreased the number of infiltrating macrophages, T cells, neutrophils, and mast cells seen in the dermis following TPA treatment. Using a two-stage skin carcinogenesis protocol with 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and TPA as the promoter, rapamycin (5–200 nmol per mouse given topically 30 minutes prior to TPA) exerted a powerful antipromoting effect, reducing both tumor incidence and tumor multiplicity. Moreover, topical application of rapamycin to existing papillomas induced regression and/or inhibited further growth. Overall, the data indicate that rapamycin is a potent inhibitor of skin tumor promotion and suggest that signaling through mTORC1 contributes significantly to the process of skin tumor promotion. The data also suggest that blocking this pathway either alone or in combination with other agents targeting additional pathways may be an effective strategy for prevention of epithelial carcinogenesis. Cancer Prev Res; 4(7); 1011–20. ©2011 AACR.
Role of Autophagy in Cancer Prevention
Authors: Chen Hsin-Yi , White Eileen
Published: July 2011

Macroautophagy (autophagy hereafter) is a catabolic process by which cells degrade intracellular components in lysosomes. This cellular garbage disposal and intracellular recycling system maintains cellular homeostasis by eliminating superfluous or damaged proteins and organelles and invading microbes and by providing substrates for energy generation and biosynthesis in stress. Autophagy thus promotes the health of cells and animals and is critical for the development, differentiation, and maintenance of cell function and for the host defense against pathogens. Deregulation of autophagy is linked to susceptibility to various disorders including degenerative diseases, metabolic syndrome, aging, infectious diseases, and cancer. Autophagic activity emerges as a critical factor in the development and progression of diseases that are associated with increased cancer risk as well as in different stages of cancer. Given that cancer is a complex process and autophagy exerts its effects in multiple ways, the role of autophagy in tumorigenesis is context-dependent. As a cytoprotective survival pathway, autophagy prevents chronic tissue damage that can lead to cancer initiation and progression. In this setting, stimulation or restoration of autophagy may prevent cancer. In contrast, once cancer occurs, many cancer cells upregulate basal autophagy and utilize autophagy to enhance fitness and survive in the hostile tumor microenvironment. These findings revealed the concept that aggressive cancers can be addicted to autophagy for survival. In this setting, autophagy inhibition is a therapeutic strategy for established cancers. Cancer Prev Res; 4(7); 973–83. ©2011 AACR.
Lung Cancer Chemoprevention with Celecoxib in Former Smokers
Authors: Mao Jenny T. , Roth Michael D. , Fishbein Michael C. , Aberle Denise R. , Zhang Zuo-Feng , Rao Jian Yu , Tashkin Donald P. , Goodglick Lee , Holmes E. Carmack , Cameron Robert B. , Dubinett Steven M. , Elashoff Robert , Szabo Eva , Elashoff David
Published: July 2011

Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2–selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥ 45, ≥ 30 pack-years of smoking, ≥ 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI) after 6 months of treatment. Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t test). In participants who crossed over to the other study arm at 6 months (all of whom had received 6 months of celecoxib at the end of a 12 months treatment period), the decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in bronchoalveolar lavage (BAL) samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in BAL cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease. Cancer Prev Res; 4(7); 984–93. ©2011 AACR.
Rapamycin and mTORC1 Inhibition in the Mouse: Skin Cancer Prevention
Authors: Athar Mohammad , Kopelovich Levy
Published: July 2011

Therapeutic and preventive effects of rapamycin include reduced risk of nonmelanoma skin cancer (NMSC). In this issue of the journal (beginning on page 1011), Checkley and colleagues report that rapamycin inhibits mTOR complex 1 in murine epidermis, thereby inhibiting tumor promotion mediated by tetradecanoyl phorbol-13 acetate in association with a strong anti-inflammatory effect. Rapamycin is an immunosuppressive drug for preventing graft rejection in organ transplant recipients and reduces the risk of NMSC and Kaposi's sarcoma in this population, albeit by mechanisms distinct from immunosuppression. Important future directions include identifying molecular predictors of rapamycin/rapalog sensitivity or resistance (potentially, for example, PI3K pathway alterations and KRAS mutations) and combined non-rapalog, mTOR-targeting approaches, all of which should increase efficacy and minimize toxicity. Cancer Prev Res; 4(7); 957–61. ©2011 AACR.
The Structure of Genetic Linkage Data: From LIPED to 1M SNPs
Authors: Thompson Elizabeth
Published: July 2011

There are three assumptions of independence or conditional independence that underlie linkage likelihood computations on sets of related individuals. The first is the independence of meioses, which gives rise to the conditional independence of haplotypes carried by offspring, given those of their parents. The second derives from the assumption of absence of genetic interference, which gives rise to the conditional independence of inheritance vectors, given the inheritance vector at an intermediate location. The third is the assumption of independence of allelic types, at the population level, both among haplotypes of unrelated individuals and also over the loci along a given haplotype. These three assumptions have been integral to likelihood computations since the first lod scores were computed, and remain key components in analysis of modern genetic data. In this paper we trace the role of these assumptions through the history of linkage likelihood computation, through to a new framework of genetic linkage analysis in the era of dense genomic marker data.
Von Willebrand Factor, and Soluble Intercellular and Vascular Cell Adhesion Molecules as Indices of Endothelial Activation in Patients with Congenital Hypothyroidism
Authors: Hashemipour Mahin , Dehkordi Elham Hashemi , Javanmard Shaghayegh Haghjooy , Hovsepian Silva , Moaddab Mohammad Hassan , Kelishadi Roya , Aghanouri Zahra , Tavalaian Hosein , Salekardestani Mehdi , Amini Massoud
Published: July 2011

Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan, the possible involvement of endothelial dysfunction in the pathogenesis of CH and the lack of studies in this field, the aim of this study was to determine the endothelial function in CH patients. Methods: During this case-control study, the endothelial function in CH neonates and in those with normal screening results was evaluated during a CH screening program in Isfahan. Peripheral blood samples were obtained for measurement of the von Willebrand factor (vWf), and intercellular and vascular cell adhesion molecule (ICAM and VCAM). In CH patients these biomarkers were measured twice: before and 4 weeks after treatment. Results: In this study, 56 neonates were evaluated: 30 of them were neonates with normal screening results and 26 were diagnosed with CH and classified into two groups according to their TSH levels. The mean ICAM and VCAM were higher in CH patients than in the control group (p < 0.05). The mean ICAM and VCAM decreased significantly after treatment in CH patients (p < 0.05). There is no significant relationship between TSH, ICAM, VCAM and vWf (p > 0.05). Conclusion: The findings of this study demonstrate the possible involvement of the endothelial system in the pathogenesis of CH and its cardiovascular complications. Further studies with a larger sample size and with the measurement of other endothelial function markers are needed.
Diffuse Large B Cell Lymphoma Complicating Total Knee Arthroplasty: Case Report and Literature Review of the Association of Diffuse Large B Cell Lymphoma with Joint Replacement
Authors: Chaudhry Mohammed Suhail , Mather Harriet , Marks Alexandra , Naresh Kikkeri
Published: July 2011

Primary lymphoma of bone is extremely rare. There are increasing reports of lymphoma arising in bone adjacent to metallic prostheses. Herein, we describe the case of a 76-year-old man who developed diffuse large B cell lymphoma in the tibia 3 years after total knee arthroplasty for osteoarthritis. A review of the literature has identified 11 other cases of lymphoma arising in the context of orthopaedic metallic implants. To our knowledge this is the first reported case of a primary lymphoma arising in bone adjacent to a knee prosthesis. Possible pathogenetic mechanisms may include chronic antigenic stimulation of lymphocytes, proliferation of EBV-infected B lymphocytes, and direct mutagenic effects of metallic ions. Further research is required to investigate this intriguing link between metallic orthopaedic prostheses and localized lymphoma.
The French Version of Speech Handicap Index: Validation and Comparison with the Voice Handicap Index
Authors: Degroote Gaëlle , Simon Jézabelle , Borel Stéphanie , Crevier-Buchman Lise
Published: July 2011

Objective: This study aimed to adapt the Speech Handicap Index (SHI) in French, to compare it with the Voice Handicap Index (VHI) and to study its relevance in dysarthric patients. Patients and Methods: Two hundred and twenty-nine subjects filled out the French versions of the SHI and VHI. SHI test-retest reliability was performed on 82 subjects. Psychometric properties were analyzed in 112 healthy controls and 89 patients with speech disorders. Mean scores of 89 speech-disordered and 28 dysphonic patients were obtained. Results: For SHI, internal consistency (Cronbach’s alpha >0.9) and test-retest reliability (Spearman’s r > 0.75) were high. Mean scores were significantly different between healthy subjects (8/120) and patients (52/120) (p < 0.0001). Scores were statistically different between dysphonic (40/120) and speech-disordered patients (52/120) (p < 0.05), and also between patients with oropharyngeal surgery (44/120) and dysarthric patients (57/120) (p < 0.05). Patients with speech difficulties had higher scores on the SHI than dysphonic patients (p < 0.05). Conclusion: The French SHI is a reliable and sensitive tool. It can be proposed to all patients with speech disorders. The contrasting results between the SHI and the VHI highlight the importance in giving the appropriate questionnaire tailored to the patient’s pathology.
Gene Expression and Biochemical Characterization of Azotobacter vinelandii Cyclophilins and Protein Interaction Studies of the Cytoplasmic Isoform with dnaK and lpxH
Authors: Dimou Maria , Venieraki Anastasia , Liakopoulos Georgios , Kouri Evangelia D. , Tampakaki Anastasia , Katinakis Panagiotis
Published: July 2011

The soil nitrogen-fixing bacterium Azotobacter vinelandii possesses two cyclophilins, comprising putative cytoplasmic and periplasmic isoforms, designated as AvPPIB and AvPPIA, respectively. Both recombinant cyclophilins have been purified and their peptidyl-prolyl cis/trans isomerase activity against Suc-Ala-Xaa-Pro-Phe-pNA synthetic peptides has been characterized. The substrate specificity of both cyclophilins is typical for bacterial cyclophilins, with Suc-Ala-Ala-Pro-Phe-pNA being the most rapidly catalyzed substrate. The cytoplasmic cyclophilin also displays a chaperone function in the citrate synthase thermal aggregation assay. Using real-time quantitative RT-PCR, we demonstrate that AvppiB is expressed under various physiological and growth conditions, mainly upregulated by acetate and downregulated by the stationary growth state, while AvppiA shows a tendency for downregulation under the tested conditions. Further, we identified chaperone protein dnaK and UDP-2, 3-diacylglucosamine hydrolase lpxH as probable interacting partners of AvPPIB and we demonstrate their physical interaction by coexpression studies. An increase in AvPPIB PPIase activity in the presence of AvdnaK and a decrease in the presence of AvlpxH further confirms each interaction. However, the PPIase activity does not seem to be essential for those interactions since AvPPIB active site mutants still interact with dnaK and lpxH, while their minor PPIase activity cannot be modulated by the interaction.
Incremental Prognostic Value of Cardiac Computed Tomography in Coronary Artery Disease Using CONFIRM
Authors: Chow Benjamin J.W. , Small Gary , Yam Yeung , Chen Li , Achenbach Stephan , Al-Mallah Mouaz , Berman Daniel S. , Budoff Matthew J. , Cademartiri Filippo , Callister Tracy Q. , Chang Hyuk-Jae , Cheng Victor , Chinnaiyan Kavitha M. , Delago Augustin , Dunning Allison , Hadamitzky Martin , Hausleiter Jörg , Kaufmann Philipp , Lin Fay , Maffei Erica , Raff Gilbert L. , Shaw Leslee J. , Villines Todd C. , Min James K.
Published: July 2011

Background—

Large multicenter studies validating the prognostic value of coronary computed tomographic angiography (CCTA) and left ventricular ejection fraction (LVEF) are lacking. We sought to confirm the independent and incremental prognostic value of coronary artery disease (CAD) severity measured using 64-slice CCTA over LVEF and clinical variables.

Methods and Results—

A large international multicenter registry (CONFIRM Registry) was queried, and CCTA patients with LVEF data on CCTA were screened. Patients with a history of myocardial infarction, coronary revascularization, or cardiac transplantation were excluded. The National Cholesterol Education Program-Adult Treatment Panel III risk was calculated for each patient, and CCTA was evaluated for CAD severity (normal, nonobstructive, non–high-risk, or high-risk CAD) and LVEF <50%. Patients were followed for an end point of all-cause mortality; 27 125 patients underwent CCTA at 12 participating centers, with a total of 14 064 patients meeting the analysis criteria. Follow-up was available for 13 966 (99.3%) patients (mean follow-up of 22.5 months; 95% confidence interval, 22.3 to 22.7 months). All-cause mortality (271 deaths) occurred in 0.65% of patients without coronary atherosclerosis, 1.99% of patients with nonobstructive CAD, 2.90% of patients with non–high-risk CAD, and 4.95% for patients with high-risk CAD. Multivariable analysis confirmed that LVEF <50% (hazard ratio, 2.74; 95% confidence interval, 2.12 to 3.51) and CAD severity (hazard ratio,1.58; 95% confidence interval, 1.42 to 1.76) were predictors of all-cause mortality, and CAD severity had incremental value over LVEF and clinical variables.

Conclusions—

Our results demonstrate that CCTA measures of CAD severity and LVEF have independent prognostic value. Incorporation of CAD severity provides incremental value for predicting all-cause death over routine clinical predictors and LVEF in patients with suspected obstructive CAD.
Global Variation in the Relative Burden of Stroke and Ischemic Heart Disease
Authors: Kim Anthony S. , Johnston S. Claiborne
Published: July 2011

Background—

Although stroke and ischemic heart disease (IHD) have several well-established risk factors in common, the extent of global variation in the relative burdens of these forms of vascular disease and reasons for any observed variation are poorly understood.

Methods and Results—

We analyzed mortality and disability-adjusted life-year loss rates from stroke and IHD, as well as national estimates of vascular risk factors that have been developed by the World Health Organization Burden of Disease Program. National income data were derived from World Bank estimates. We used linear regression for univariable analysis and the Cuzick test for trends. Among 192 World Health Organization member countries, stroke mortality rates exceeded IHD rates in 74 countries (39%), and stroke disability-adjusted life-year loss rates exceeded IHD rates in 62 countries (32%). Stroke mortality ranged from 12.7% higher to 27.2% lower than IHD, and stroke disability-adjusted life-year loss rates ranged from 6.2% higher to 10.2% lower than IHD. Stroke burden was disproportionately higher in China, Africa, and South America, whereas IHD burden was higher in the Middle East, North America, Australia, and much of Europe. Lower national income was associated with higher relative mortality (
P
<0.001) and burden of disease (
P
=0.001) from stroke. Diabetes mellitus prevalence and mean serum cholesterol were each associated with greater relative burdens from IHD even after adjustment for national income.

Conclusions—

There is substantial global variation in the relative burden of stroke compared with IHD. The disproportionate burden from stroke for many lower-income countries suggests that distinct interventions may be required.
Tryptase/Protease-Activated Receptor 2 Interactions Induce Selective Mitogen-Activated Protein Kinase Signaling and Collagen Synthesis by Cardiac Fibroblasts
Authors: McLarty Jennifer L. , Meléndez Giselle C. , Brower Gregory L. , Janicki Joseph S. , Levick Scott P.
Published: July 2011

The mast cell product, tryptase, has recently been implicated to mediate fibrosis in the hypertensive heart. Tryptase has been shown to mediate noncardiac fibroblast function via activation of protease-activated receptor 2 and subsequent activation of the mitogen-activated protein kinase pathway, including extracellular signal–regulated kinase 1/2. Therefore, we hypothesized that this pathway may be a mechanism leading to fibrosis in the hypertensive heart. Isolated adult cardiac fibroblasts were treated with tryptase, which induced activation of extracellular signal–regulated kinase 1/2 via protease-activated receptor 2. Blockade of protease activated receptor 2 with FSLLRY (10 μmol/L) and inhibition of the extracellular signal–regulated kinase pathway with PD98059 (10 μmol/L) prevented collagen synthesis in isolated cardiac fibroblasts stimulated with tryptase. In contrast, p38 mitogen-activated protein kinase and stress-activated protein/c-Jun N-terminal kinase were not activated by tryptase. Cardiac fibroblasts isolated from spontaneously hypertensive rats showed this same pattern of activation. Treatment of spontaneously hypertensive rats with FSLLRY prevented fibrosis in these animals, indicating the in vivo applicability of the cultured fibroblast findings. Also, tryptase induced a myofibroblastic phenotype indicated by elevations in α-smooth muscle actin and extra type III domain A (ED-A) fibronectin. Thus, the results from this study demonstrate the importance of tryptase for inducing a cardiac myofibroblastic phenotype, ultimately leading to the development of cardiac fibrosis. Specifically, tryptase causes cardiac fibroblasts to increase collagen synthesis via a mechanism involving activation of protease-activated receptor 2 and subsequent induction of extracellular signal–regulated kinase signaling.
Neural Dissociation of Number from Letter Recognition and Its Relationship to Parietal Numerical Processing
Authors: Park Joonkoo , Hebrank Andrew , Polk Thad A. , Park Denise C.
Published: July 2011

The visual recognition of letters dissociates from the recognition of numbers at both the behavioral and neural level. In this article, using fMRI, we investigate whether the visual recognition of numbers dissociates from letters, thereby establishing a double dissociation. In Experiment 1, participants viewed strings of consonants and Arabic numerals. We found that letters activated the left midfusiform and inferior temporal gyri more than numbers, replicating previous studies, whereas numbers activated a right lateral occipital area more than letters at the group level. Because the distinction between letters and numbers is culturally defined and relatively arbitrary, this double dissociation provides some of the strongest evidence to date that a neural dissociation can emerge as a result of experience. We then investigated a potential source of the observed neural dissociation. Specifically, we tested the hypothesis that lateralization of visual number recognition depends on lateralization of higher-order numerical processing. In Experiment 2, the same participants performed addition, subtraction, and counting on arrays of nonsymbolic stimuli varying in numerosity, which produced neural activity in and around the intraparietal sulcus, a region associated with higher-order numerical processing. We found that individual differences in the lateralization of number activity in visual cortex could be explained by individual differences in the lateralization of numerical processing in parietal cortex, suggesting a functional relationship between the two regions. Together, these results demonstrate a neural double dissociation between letter and number recognition and suggest that higher-level numerical processing in parietal cortex may influence the neural organization of number processing in visual cortex.
Clause Structure Folding and the “Wh-in-Situ Effect”
Authors: Moro Andrea
Published: July 2011

Why must a coordinative head show up before an adverbial wh-phrase in situ in Italian? In this article, I explore this rather neglected fact, showing that it reveals an otherwise hidden structure. More specifically, I propose that the coordinative head does not directly merge with the wh-phrase it precedes; rather, it takes a full clausal complement, inducing remnant movement and stranding of the highest wh-phrase. This configuration yields the observed word order and explains many properties of these constructions by means of independent locality conditions. I argue that it is a rescue strategy languages may adopt to meet a structural property of the left periphery, and I address some questions that the comparative perspective raises.
Voice Mismatch and Syntactic Identity
Authors: Tanaka Hidekazu
Published: July 2011

On the basis of an asymmetry between VP-deletion and pseudogapping, Merchant (2008a) concludes that ellipsis is conditioned by syntax. This article demonstrates that both pseudogapping and VP-deletion potentially allow voice mismatch. The unacceptable cases of voice mismatch in these constructions are attributed to a discourse factor (Kehler 2000, 2002). Nevertheless, since sluicing does not allow voice mismatch (Merchant 2001, 2007) even in the same context that allows voice mismatch in VP-ellipsis, Merchant's (2007, 2008a) conclusion is still valid. A syntactic condition on ellipsis is proposed, based on a semantic condition from Takahashi and Fox 2005. Kehler's discourse explanation is phrased in a revised format.