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In recent years, studies have suggested that promoter methylation in human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) has a mechanistic role and has the potential to improve patient survival. The present study aimed to replicate key molecular findings from previous analyses of the methylomes of HPV positive and HPV negative HNSCC in an independent cohort, to assess the reliability of differentially methylated markers in HPV-associated tumors. HPV was measured using real-time quantitative PCR and the biological significance of methylation differences was assessed by Ingenuity Pathway Analysis (IPA). Using an identical experimental design of a 450K methylation platform, 7 of the 11 genes were detected to be significantly differentially methylated and all 11 genes were either hypo- or hypermethylated, which was in agreement with the results of a previous study. IPA's enriched networks analysis identified one network with msh homeobox 2 (MSX2) as a central node. Locally dense interactions between genes in networks tend to reflect significant biology; therefore MSX2 was selected as an important gene. Sequestration in the top four canonical pathways was noted for 5-hydroxytryptamine receptor 1E (serotonin signaling), collapsin response mediator protein 1 (semaphorin signaling) and paired like homeodomain 2 (bone morphogenic protein and transforming growth factor-β signaling). Placement of 9 of the 11 genes in highly ranked pathways and bionetworks identified key biological processes to further emphasize differences between HNSCC HPV positive and negative pathogenesis.

Sudden cardiac death (SCD) is defined as sudden unexplained death due to cardiac causes with an acute change in cardiovascular status within 1 hour of onset of symptoms. Alternatively, in unwitnessed cases, SCD can also be defined as a person last seen functionally normal 24 hours before being found dead. Despite significant advances in understanding the pathophysiology of cardiovascular diseases and the resultant improvement in resuscitation science, SCD remains a major healthcare challenge worldwide. Although the most pronounced risk factor for SCD is the presence of coronary artery disease in the setting of a depressed left ventricular function, most deaths occur in the larger, lower-risk subgroups where genetic variations and other conditions may be the precipitating factors in triggering SCD. Recently, a common genetic variation in a neuronal nitric oxide synthase regulator, nitric oxide synthase 1 adaptor protein (NOS1AP) also known as carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (CAPON) gene, has been identified as a new genetic marker in modulating QT interval prolongation and SCD in general populations. Animal study revealed that NOS1AP is expressed in the heart and interacts with NOS1-NO pathways to modulate cardiac repolarization via suppressing the sarcolemmal L-type calcium current and enhancing the IKr current. This important genetic implication was soon replicated in other racial/ethnic populations and extended to a variety of clinical settings including diabetes mellitus, coronary artery disease, myocardial infarction, and congenital or drug-induced long QT syndrome. The purpose of this review aims to provide up-to-date information about the emerging new genetic marker, NOS1AP, in relation to QT prolongation and SCD.NOS1AP; QT interval; Sudden cardiac death.

BACKGROUND A policy for new pictorial health warning labels on tobacco packaging was introduced by Health Canada in 2012. The labels included, for the first time, a prominently displayed toll-free number for a quit-smoking line. We used data from the Ontario provincial quitline to investigate the call volume and number of new callers receiving treatment in the months before and after the new policy was introduced. METHODS We used an interrupted time-series analysis to examine trends in the overall call volume and number of new callers receiving treatment (≥ 1 telephone counselling session) through Ontario's quitline (Smokers' Helpline) between January 2010 and December 2013. We analyzed data using Box-Jenkins autoregressive integrated moving-average models; we adjusted the models for a major campaign promoting the quitline, a seasonality (January) effect and tobacco pricing. RESULTS We found a relative increase of 160% in the average monthly call volume during the 7 months after the introduction of the new labels (870 calls per month at baseline and 1391 additional calls per month on average after the policy change; standard error [SE] 108.94, p < 0.001), and a sustained increase of 43% in subsequent months. We observed a relative increase of 174% in the number of new callers receiving treatment (153 new callers per month at baseline and 267 additional new callers per month after the policy change; SE 40.03, p < 0.001) and a sustained increase of 80% in subsequent months. The effect was significant even after controlling for a major promotion campaign and the January effect. INTERPRETATION We found a significant increase in the monthly overall call volume and number of new callers receiving treatment per month after the introduction of the new tobacco health warning labels, with a sustained increase in overall calls and new callers beyond the first 7 months. Our findings add to the body of evidence on the benefit of including a toll-free quitline number on tobacco packaging.

// Arati A. Inamdar 1 , Andre Goy 2 , Nehad M. Ayoub 3 , Christen Attia 1 , Lucia Oton 1 , Varun Taruvai 1 , Mark Costales 1 , Yu-Ting Lin 1 , Andrew Pecora 2 and K. Stephen Suh 1 1 The Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA 2 Clinical Divisions, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA 3 Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Correspondence to: K. Stephen Suh, email: // Keywords : biomarker, clinical trial, mantle cell lymphoma, personalized therapy, prognosis Received : December 24, 2015 Accepted : April 10, 2016 Published : April 23, 2016 Abstract Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.

PurposeThe purpose of this paper is to investigate short‐selling around private investment in public equity (PIPE) issuances, for evidence of manipulative short‐selling by hedge funds.Design/methodology/approachThe authors use the Regulation SHO short‐selling data in combination with information about hedge fund participation in traditional stock PIPE offerings from Sagient Research, and share price and trading volume data from the Center for Research in Security Prices (CRSP) to examine the relations among hedge fund participation, short‐selling levels and stock returns surrounding such offerings.FindingsIt is found that significantly less pre‐deal short‐selling occurs when hedge funds are included in the PIPE investor group, and adjusted returns for firms with hedge funds as investors are positive in the pre‐deal period and negative in the post‐deal period. Both of these findings are opposite of the patterns expected given manipulative short‐selling by hedge funds. Pre‐deal and post‐deal adjusted returns and PIPE discount are unrelated to pre‐deal short‐selling by hedge funds, findings inconsistent with manipulative short‐selling by these investors. The evidence suggests that most hedge funds that invest in traditional stock PIPEs do not engage in manipulative short‐selling around these deals.Originality/valueThis paper is the first, to the authors' knowledge, to examine hedge fund participation and daily short‐selling around traditional stock PIPE issuances. Previous studies focus on structured PIPE deals, which do not represent the majority of the PIPE market at present. The daily short selling data used in this study allow for detailed investigation of market behavior not afforded by monthly short interest data used in previous studies.

PurposeThe purpose of this paper is to suggest a superior method for assessing mean stationarity of asset pricing effects.Design/methodology/approachThe authors suggest the use of an F‐test to examine mean stationarity of asset pricing effects across subperiods. The superiority of this test is demonstrated through examination of the Halloween Effect using simulated data and the Morgan Stanley Capital International (MSCI) data for 18 developed economies.FindingsIt is found that the suggested F‐test provides results superior to a simple examination of the magnitude and statistical significance of estimated regression coefficients across subperiods when attempting to determine mean stationarity.Originality/valueThis paper sheds light on an analytical oversight in the asset pricing anomalies literature and suggests an appropriate test to address this oversight.

ObjectiveThere is a lack of consensus regarding the causes of the differences in the higher incidence of and the mortality from head and neck squamous cell carcinoma (HNSCC) in African Americans (AA) versus Caucasian Americans (CA). We examined a comprehensive array of risk factors influencing health and disease in an access-to-care, racially diverse, primary HNSCC cohort.Study DesignCross-sectional study.SettingPrimary care academic health care system.Subjects and MethodsThe cohort of 673 patients comprised 391 CA and 282 AA (42%). Risk variables included demographic, histopathology, and clinical/epidemiologic factors. Tumor DNA was interrogated for loss and gain of 113 genes with known involvement in HNSCC/cancer. Logistic regression for univariate analysis was followed by multivariate modeling with determination of model predictability (c-index).ResultsOf the 39 univariate differences between AA and CA, multivariate modeling (c-index = 0.81) retained 7 differences (P < .05). AA were less likely to be m...

IntroductionMicroRNAs (miRNAs) are endogenous, small, noncoding RNAs of 17 to 25 nucleotides that regulate approximately 30% of human genes. They are differentially expressed in various types of cancers compared with noncancerous tissues, suggesting that they may have crucial roles in tumorigenesis. The objective of this study was to identify laryngeal squamous cell cancer (LSCC)-specific miRNAs.Materials and methodsA retrospective cohort of 10 LSCC and five normal laryngeal squamous epithelium samples were examined using a global miRNA profiling approach (HTG, Tucson, AZ, USA, 800 human miRNAs plus 10 endogenous control miRNAs). The expression status of selected dysregulated miRNAs that were significantly different from normal were verified by real-time quantitative PCR (qPCR).ResultsTwenty-three of the 800 human miRNAs had significantly different expression levels (p < 0.05) between LSCC and normal tissues. Fifteen of the 23 have not been previously reported in HNSCC and include: miR-663b, miR-663, miR-193b, miR-1291, miR-720, miR-191, miR-1224-3p, miR-214, miR- 1285, miR-1207-5p, miR-483-5p, miR-1225-3p, miR-1228, miR-1280 and miR-638. Consistently upregulated miR-31 and miR- 193b and differentially expressed miR-663b in LSCC were verified by qPCR.ConclusionThe 15 novel miRNAs identified in this exploratory study, pending further confirmation and validation, may have clinical utility as LSCC-specific markers.How to cite this articleChen KM, Stephen JK, Havard S Shah V, Gardner G, Schweitzer VG, Worsham MJ. Novel Dysregulated MicroRNAs in Primary Laryngeal Squamous Cell Cancer. Int J Head Neck Surg 2012;3(2):76-81.

Genetic events specific to the pathogenesis of malignancy can offer clues to the tumorigenesis process. The objective of this study was to identify gene alterations that differentiate tumor and nontumor lesions in squamous head and neck cancer (HNSCC). DNA from 220 primary HNSCC with concurrently present tumor and nontumor lesions from the same patient was interrogated for genomic alterations of loss or gain of copy. Conditional logistic regression dealt with tumor and non-tumor records within a patient. Of 113 genes, 53 had univariate effects (P<0.01), of which 16 genes remained in the multivariable model withP<0.01. The model had a C-index (ROC) of 0.93. Loss ofCDKN2Band gain ofBCL6, FGF3, andPTP4A3predicted tumor. Loss ofBAK1andCCND1and gain ofSTCHpredicted nontumor. This highly powered model assigned alterations in 16 genes specific for malignant versus nonmalignant lesions, supporting their contribution to the pathogenesis of HNSCC as well as their potential utility as relevant targets for further evaluation as markers of early detection and progression.

The mediating role of cessation medications in the association between health professional advice and quitting behaviors is unclear.Data were from the Ontario Tobacco Survey longitudinal study, collected between July 2005 and June 2011 in Ontario, Canada. The analytic sample included 3437 baseline smokers who were seen by health professionals during follow-up. Logistic regression with generalized estimating equations and mediation analysis techniques were used to examine the impact of advice and medications on quitting outcomes (making a quit attempt, short-term quitting 1-6months and long-term quitting6months).Those who received advice to quit smoking were more likely to use cessation medications than those who did not receive advice (21% vs. 13%, P0.001). Receiving advice was associated with making a quit attempt (adjusted odds ratio (OR) 1.25, 95% confidence interval (CI) 1.10-1.41) and long-term quitting (adjusted OR 1.49, 95% CI 1.10-2.02), but not with short-term quitting. Use of cessation medications was associated with making a quit attempt (adjusted OR 11.83, 95% CI 9.93-14.08), short-term quitting (adjusted OR 3.69, 95% CI 2.90-4.68), and long-term quitting (adjusted OR 2.73, 95% CI 1.95-3.82). Using prescription medications was associated with a higher likelihood of quitting short-term (adjusted OR 2.43, 95% CI 2.59-3.74) and long-term (adjusted OR 2.27, 95% CI 1.23-4.17) than using NRT. Use of cessation medications was a significant mediator in the pathway from receiving advice to quitting.Health professionals should advise smokers to quit and encourage them to use cessation medications, especially prescription medications when trying to quit.

Methadone and QT Prolongation. Background: Methadone is associated with QTc prolongation and sudden death in susceptible patients. We sought to investigate whether there is a gender-based difference in susceptibility to methadone-associated QTc prolongation in heroin-dependent patients receiving a low-dose treatment regimen. Methods: A cross-sectional assessment of dose and gender effects was performed in 283 patients (229 males, 54 females) who received a 12-lead ECG for QTc measurement 59 days (interquartile range: 36–288 days) after methadone treatment. To determine the effects of methadone over time, a subset of 150 participants (126 men, 24 women) who underwent a 12-lead ECG before and 37 days (interquartile range: 32–44 days) after methadone treatment were selected. Results: In the cross-sectional study, a significant dose-dependent interaction between methadone and QTc (r = 0.201, P = 0.0007) was observed in individuals receiving a median methadone dose of 40 mg/day (interquartile range: 30–60 mg/day). The methadone-QTc correlation was significant in males (r = 0.210, P = 0.0014) but not in females (r = 0.164, P = 0.2363). The longitudinal assessment of methadone's effects over a 6-month period showed that 60.7% of individuals experienced an increase in QTc compared to baseline data. The adjusted QTc significantly increased from 418.5 to 426.9 milliseconds in males (P < 0.0001), compared to an insignificant change in females (437.7 milliseconds vs 441.1 milliseconds, P = 0.468). Conclusions: Low-dose methadone therapy shows dose-dependent QTc prolongation and is associated with significant QTc lengthening within 6 months of treatment initiation. Men are more susceptible than women to low-dose methadone-associated QTc prolongation. (J Cardiovasc Electrophysiol, Vol. 23, pp. 527-533, May 2012)

Aims To examine the use and role of planned quit attempts by smokers and their impact on abstinence.Design Ret- rospective, using longitudinal data from the Ontario Tobacco Survey. Setting Ontario, Canada. Participants A total of 551 adult smokers who reported having made a quit attempt during 2007-08.Measurements Reported planning of the most recent quit attempt (i.e. unplanned or planned some time in advance), engaging in preparatory behaviours believed to be related to planning (i.e. use of quit aids such as pharmacotherapy, formal support or health professionals) and abstinence at 1 week and 1 month following the attempt. Findings Of the smokers, 73.6% planned their quit attempt in advance. Reported planning was more likely among those who thought they were very addicted, compared with those who were less addicted (odds ratio (OR) = 2.22, 95% confidence interval (CI): 1.15-4.28). Smokers who planned a quit attempt were much more likely to use a quit aid (OR = 3.50, 95% CI: 1.80-6.79), particularly phar- macotherapy (OR = 6.13, 95% CI: 3.05-12.34). The odds of abstaining for 1 week were lower among those who planned (OR = 0.45, 95% CI: 0.22-0.89), independent of perceived addiction. No significant difference was observed for abstinence lasting 1 month. Other factors associated with abstinence were smoking fewer cigarettes per day and having personal support. Conclusions Although most quit attempts were planned and planners had higher odds of using quit aids, planning did not increase the likelihood of success.

Around the world, teams of researchers continue to develop a wide range of systems to capture, store, and analyze data including treatment, patient outcomes, tumor registries, next-generation sequencing, single-nucleotide polymorphism, copy number, gene expression, drug chemistry, drug safety, and toxicity. Scientists mine, curate, and manually annotate growing mountains of data to produce high-quality databases, while clinical information is aggregated in distant systems. Databases are currently scattered, and relationships between variables coded in disparate datasets are frequently invisible. The challenge is to evolve oncology informatics from a "systems" orientation of standalone platforms and silos into an "integrated knowledge environments" that will connect "knowable" research data with patient clinical information. The aim of this article is to review progress toward an integrated knowledge environment to support modern oncology with a focus on supporting scientific discovery and improving cancer care.

Background: Implantable cardioverter-defibrillators (ICDs) reduce the rate of sudden cardiac death (SCD) in patients with cardiomyopathy and reduced left ventricular systolic function. It is unclear if this benefit extends to the very elderly patient population. Methods: Patients who underwent initial ICD implantation at age 80 or older between January 1995 and April 2010 for primary SCD prevention were identified. Clinical data were collected from the medical record, including periprocedural complications, device type, and therapies delivered. Results: Three-hundred eighty patients were identified; 84 patients met eligibility criteria. The mean age was 82.68 years; mean follow-up was 34 months. Mean left ventricular ejection fraction was 28.1%. Mortality during follow-up was 17.9%. One- and 5-year survival estimates were 100% and 60%, respectively. Periprocedural complications occurred in 9.4% of patients; serious complications occurred in 4.8% with no periprocedural deaths. Device therapies occurred in 11.9% (n = 10) of patients (9.5% appropriate, n = 8; 2.4% inappropriate, n = 2). Cardiac resynchronization therapy-defibrillator (CRT-D) implantation was associated with prolonged median survival and decreased risk of death (hazard ratio 0.212; 95% confidence interval 0.048−.942, P = 0.042) compared to ICD alone. Conclusions: Implantation of primary prevention ICDs in patients 80 years of age or older was associated with a low risk of serious complications and a 5-year survival estimate of 60%. Inappropriate therapies after implantation were uncommon. CRT-D implantation was associated with a decreased risk of death compared to ICD alone. These data suggest that, in selected patients in this age group, ICD implantation is safe and effective. (PACE 2011; 34:900–906)

Thyroid cancer is the most common endocrine cancer with 1,690 deaths each year. There are four main types of which the papillary and follicular types together account for >90% followed by medullary cancers with 3% to 5% and anaplastic carcinomas making up < 3%. Epigenetic events of DNA hypermethylation are emerging as promising molecular targets for cancer detection. Our immediate and long term goal is to identify DNA methylation markers for early detection of thyroid cancer. This pilot study comprised of 21 patients to include 11 papillary thyroid cancers (PTC), 2 follicular thyroid cancers (FTC), 5 normal thyroid cases, and 3 hyperthyroid cases. Aberrant promoter methylation was examined in 24 tumor suppressor genes using the methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) assay and in the NIS gene using methylation-specific PCR (MSP). The frequently methylated genes were CASP8 (17/21), RASSF1 (16/21) and NIS (9/21). In the normal samples, CASP8, RASSF1 and NIS were methylated in 5/5, 4/5 and 1/5 respectively. In the hyperthyroid samples, CASP8, RASSF1 and NIS were methylated in 3/3, 2/3 and 1/3 respectively. In the thyroid cancers, CASP8, RASSF1, and NIS were methylated in 9/13, 10/13, and 7/13 respectively. CASP8, RASSF1 and NIS were also methylated in concurrently present normal thyroid tissue in 3/11, 4/11 and 3/11 matched thyroid cancer cases (matched for presence of both normal thyroid tissue and thyroid cancer), respectively. Our data suggests that aberrant methylation of CASP8, RASSF1, and NIS maybe an early change in thyroid tumorigenesis regardless of cell type.

This study provides insight into the proportion of the variation across countries in the desirable outcomes of freedom and peace that can be accounted for using a set of national characteristics which are difficult, if not impossible, to change. The majority of prior studies in this area have utilized bivariate (correlational) analysis. While these studies have made important contributions to the field, they have not been able to disentangle the effects of other important national characteristics from the effect of culture on freedom and peace. Through our multivariate framework, we are able to shed light on the relative importance of these national characteristics in explaining the variation in freedom and peace across countries.

Research documents higher stock returns in November through April than for the rest of the year. This anomaly is known as the “Halloween effect” and results in the following trading rule: sell stocks in early May, invest in T-bills, and re-invest in stocks on Halloween. In contrast to recent studies, we show that the Halloween effect is robust to consideration of outliers and the “January effect.” Additionally, we show that investing in a “Halloween portfolio” provides risk-adjusted returns in excess of buy and hold equity returns even after consideration of transaction costs.

Background A substantial challenge in addressing adolescent tobacco use is that smoking behaviors occur in complex environments that involve the school setting and larger community context. Purpose This study provides an integrated description of factors from the school and community environment that affect youth smoking and explains variation in individual smoking behaviors both within and across schools/communities. Methods Data were collected from 82 randomly sampled secondary schools in five Canadian provinces (British Columbia, Manitoba, Ontario, Quebec, Newfoundland, and Labrador) during the 2003–2004 school year. Cross-sectional data were obtained from students; school administrators (school-based tobacco control policies and programs); and from observations in the community. In 2009, hierarchic logistic regression was used to model the role of individual, school, and community variables in predicting student smoking outcomes. Results Students who attended a school with a focus on tobacco prevention (OR=0.87, 95% CI=0.81, 0.94) and stronger policies prohibiting tobacco use (OR=0.92, 95% CI=0.88, 0.97) were less likely to smoke than students who attended a school without these characteristics. A student was more likely to smoke if a greater number of students smoked on the school periphery (OR=1.25, 95% CI=1.07, 1.47). Within the community, price per cigarette (OR=0.91, 95% CI=0.84, 0.99) and immigrants (OR=0.99, 95% CI=0.98, 0.99) were inversely related to students' smoking status. Conclusions The results suggest that school and community characteristics account for variation in smoking levels across schools. Based on the current findings, the ideal school setting that supports low student smoking levels is located in a neighborhood where the cost of cigarettes is high, provides tobacco prevention education, and has a policy prohibiting smoking.

Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation–mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.

We document that the use of private investment in public equity (PIPE) by foreign firms listed on U.S. exchanges is growing even faster than its use by U.S. firms. On average, foreign firm PIPE stock deals represent a similar proportion of the firm's market capitalization to U.S. firm PIPEs, but suffer less of a share price discount than U.S. firm PIPE issuances, a relation that is robust to consideration of exchange, deal size, share turnover and return volatility. We document that hedge funds are only small investors in foreign firm PIPEs issued in the U.S., which tend to be purchased by pensions, government funds and corporations. PIPE, in combination with the reverse merger method of going public, provides a cost-effective means for foreign firms to raise capital in the U.S. capital market.

Research on firm internationalization has focused primarily on the antecedents, rather than outcomes, of the strategic decision to enter foreign markets. In addition, factors moderating the outcomes of internationalization have not received systematic analysis. Aiming to fill these gaps in the literature, the current study examines the moderating effects of firm age on postinternationalization survival and growth. Consistent with the liabilities of newness perspective, we suggest that firm age will have a positive moderating effect on postinternationalization survival. Building from the liabilities of aging perspective, we propose that firm age will have a negative moderating effect on postinternationalization short-term growth. We test these arguments using a longitudinal sample of 787 firms. Results showed that, postinternationalization, younger firms experienced significantly higher rates of short-term growth than older firms. Findings regarding firm age and survival, postinternationalization, were, however, not conclusive. Overall, our findings indicate that the timing of internationalization has important implications with regard to the short-term growth of firms. Copyright © 2010 Strategic Management Society.

Aman P. Mann 1,6 , Rohan C. Bhavane 2 , Anoma Somasunderam 3 , Brenda Liz Montalvo-Ortiz 4 , Ketan B. Ghaghada 2 , David Volk 3 , Rene Nieves-Alicea 5 , K. Stephen Suh 5 , Mauro Ferrari 6 , Ananth Annapragada 2 , David G. Gorenstein 3 , Takemi Tanaka 4 1 Department of Nanomedicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, Texas, 77030 2 School of Biomedical Informatics, University of Texas Health Science Center at Houston, 7000 Fannin, Houston, Texas, 77030 3 Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, Texas, 77030 4 Department of Pharmaceutical Sciences, Thomas Jefferson University,130 South 9th Street, Philadelphia, PA, 19107 5 The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, 07601 6 The Methodist Hospital Research Institute, Houston, Texas, 77030 Keywords: drug delivery; aptamer; E-selectin Received: April 11, 2011; Accepted: May 6, 2011; Published: May 7, 2011; Correspondence: Takemi Tanaka, e-mail: // // Abstract Recent developments in multi-functional nanoparticles offer a great potential for targeted delivery of therapeutic compounds and imaging contrast agents to specific cell types, in turn, enhancing therapeutic effect and minimizing side effects. Despite the promise, site specific delivery carriers have not been translated into clinical reality. In this study, we have developed long circulating liposomes with the outer surface decorated with thioated oligonucleotide aptamer (thioaptamer) against E-selectin (ESTA) and evaluated the targeting efficacy and PK parameters. In vitro targeting studies using Human Umbilical Cord Vein Endothelial Cell (HUVEC) demonstrated efficient and rapid uptake of the ESTA conjugated liposomes (ESTA-lip). In vivo , the intravenous administration of ESTA-lip resulted in their accumulation at the tumor vasculature of breast tumor xenografts without shortening the circulation half-life. The study presented here represents an exemplary use of thioaptamer for targeting and opens the door to testing various combinations of thioaptamer and nanocarriers that can be constructed to target multiple cancer types and tumor components for delivery of both therapeutics and imaging agents.

We proposed a model in which culture plays a dominant role, along with religion and legal origin, in determining the quality of governance in a country. We examined four dimensions of culture and four measurements of governance quality across 71 countries. Our empirical results demonstrated the dominant role played by culture, over and above religion and legal origin, in explaining governance quality. As culture is persistent and unlikely to be easily changed, efforts to improve governance quality might be doomed to failure in nations with cultural values that are hostile to good governance.

Public investment in private equity (PIPE) is a financing form growing in popularity in the U.S., recently surpassing seasoned equity offerings in number and value. Research to date is highly focused on the U.S., with little attention paid to international markets. We use newly available data to examine PIPE deals in Hong Kong, Australia, Canada, and the U.K. We document similarities and differences relative to the U.S. market. PIPE firms tend to be small, high-growth firms with poor accounting and stock performance prior to PIPE issuance. However, these stylized facts do not hold uniformly across the exchanges we study. We also document a lack of significant market reaction to the announcement of PIPE deals on these exchanges.

Acyclovir is effective in the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The aim of this study was to characterize the population pharmacokinetics of acyclovir observed following treatment with intravenous acyclovir and oral valacyclovir (valaciclovir) in young people with malignancy. Plasma acyclovir concentration-time data were collected from 43 patients (age range, 9 months to 20 years) who had been given multiple doses of acyclovir (5 mg/kg of body weight) and/or valacyclovir (10 mg/kg). Nonlinear mixed-effect modeling was employed to analyze acyclovir population pharmacokinetics and identify influential covariates. Simulations ( n = 1,000) were conducted to explore the ability of the current doses to maintain acyclovir concentrations above the recommended 50% inhibitory concentration for HSV or VZV (0.56 mg/liter or 1.125 mg/liter, respectively) for more than 12 h. A one-compartment pharmacokinetic model with first-order elimination best described the acyclovir concentration-time data. The population mean estimates for clearance (CL), volume of distribution ( V ), absorption rate ( k a ), and bioavailability ( F ) were 3.55 liters/h, 7.36 liters, 0.63 h −1 , and 0.60, respectively. Inclusion of body weight and estimated creatinine CL (CL CR ) in the final model reduced the interindividual variabilities in CL and V from 61% to 24% and from 75% to 36%, respectively. Simulations revealed that with the use of the current doses, maximal efficacy can be achieved in over 45% of patients weighing 25 to 50 kg and with CL CR levels of 2.0 to 4.0 liters/h/m 2 , but only in a much smaller proportion of patients, with low weights (10 kg) and high CL CR s (5.5 liters/h/m 2 ), suggesting that higher doses are required for this subgroup. This validated population pharmacokinetic model for acyclovir may be used to develop dosing guidelines for safe and effective antiviral therapy in young people with malignancy.

The purpose of this study was to explore individual- and school-level policy characteristics on student smoking behavior using an ecological perspective. Participants were 24,213 (51% female) Grade 10–11 students from 81 schools in five Canadian provinces. Data were collected using student self-report surveys, written policies collected from schools, interviews with school administrators, and school property observations to assess multiple dimensions of the school tobacco policy. The multi-level modeling results revealed that the school a student attended was associated with his/her smoking behavior. Individual-level variables that were associated with student smoking included lower school connectedness, a greater number of family and friends who smoked, higher perceptions of student smoking prevalence, lower perceptions of student smoking frequency, and stronger perceptions of the school tobacco context. School-level variables associated with student smoking included weaker policy intention indicating prohibition and assistance to overcome tobacco addiction, weaker policy implementation involving strategies for enforcement, and a higher number of students smoking on school property. These findings suggest that the school environment is important to tobacco control strategies, and that various policy dimensions have unique relationships to student smoking. School tobacco policies should be part of a comprehensive approach to adolescent tobacco use.

OBJECTIVE Differentiation of the tachycardia originating from the superior vena cava (SVC) or the right superior pulmonary vein (RSPV) is limited by the similar surface P-wave morphology and intraatrial activation pattern during tachycardia. We sought to find a simple method to distinguish between the two tachycardias by analyzing the interatrial conduction time. METHODS Sixteen consecutive patients consisting of 8 with SVC tachycardia and the other 8 with RSPV tachycardia were studied. The interatrial conduction time from the high right atrium (HRA) to the distal coronary sinus (DCS) and the intraatrial conduction time from the HRA to the atrial electrogram at the His bundle region (HIS) were measured during the sinus beat (SR) and during the tachycardia-triggering ectopic atrial premature beat (APB). The differences of interatrial (Delta[HRA-DCS](SR-APB)) and intraatrial (Delta[HRA-HIS](SR-APB)) conduction time between SR and APB were then obtained. RESULTS The mean Delta[HRA-DCS](SR-APB) was 1.0 +/- 5.2 ms (95% confident interval [CI]-3.3-5.3 ms) in SVC tachycardia and 38.5 +/- 8.8 ms (95% CI 31.1-45.9 ms) in RSPV tachycardia. The mean Delta[HRA-HIS](SR-APB) was 1.5 +/- 5.3 ms (95% CI -2.9-5.9 ms) in SVC tachycardia and 19.9 +/- 12.0 ms (95% CI 9.9-29.9 ms) in RSPV tachycardia. The difference of Delta[HRA-DCS](SR-APB) between SVC and RSPV tachycardias was wider than that of Delta[HRA-HIS](SR-APB) (37.5 +/- 9.3 ms vs. 18.4 +/- 15.4 ms, P < 0.01). CONCLUSIONS The wide difference of the interatrial conduction time Delta[HRA-DCS](SR-APB) between SVC and RSPV tachycardias is a useful parameter to distinguish the two tachycardias and may avoid unnecessary atrial transseptal puncture.

According to theory, comovement in stock prices reflects comovement in the fundamental factors underlying the values of stocks. Recent theory contends that stock price comovement can be driven by information markets or the informational opacity of the firm. To the extent that voluntary disclosure reduces information acquisition cost and enhances firm transparency, we predict that enhanced voluntary disclosure reduces stock price comovement. We provide evidence in support of this prediction using analyst evaluation of firm disclosure policy. Overall, our evidence supports the effectiveness of firm disclosure policy in increasing the amount of firm-specific information contained in stock returns.

Prior studies of the role of risk in executive compensation focus on market risk and firm risk, neglecting the role of industry risk in explaining executive compensation. We include industry risk and find that the portion of CEO compensation for bearing industry risk is greater than the portion of CEO compensation for bearing market risk. Consistent with the human capital of a CEO being non-diversifiable, CEOs also receive compensation for bearing firm-specific risk, in contrast to investors, who can diversify their risk over many assets. CEOs are compensated for bearing firm-specific risks through all the compensation tools we examine; salary, bonus, option grants and option exercises. CEOs are compensated for bearing market and industry risk primarily through stock option grants.