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Introduction: Induced pluripotent stem cells (iPSC) represent an appealing cell source to develop disease-modeling assays, drug testing assays and cell-based replacement therapies especially for cardiac disorders., Areas Covered: The development of efficient protocols to generate pure populations of cardiac myocytes is a prerequisite to provide reproducible, robust and valid assays. Different techniques have been recently proposed that allow production of high-yield high-quality cardiomyocytes. In addition, the newly developed genome-editing techniques offer multiple opportunities to manipulate the genome of patient-specific iPSC thus generating syngeneic iPSC lines. Genome-editing techniques will also allow engineering of iPSC to make them suitable for replacement therapies., Expert Opinion: Since their discovery, iPSCs have shown promise to revolutionize the way human diseases are studied. During the last years, different protocols have been developed to achieve reproducible and efficient differentiation of iPSCs including in cardiac and vascular cells. The recent introduction of the genome-editing techniques now allow targeted manipulation of the genome of patient-specific and control iPSCs lines. This approach would help to address a couple of current limitations, including the generation of isogenic lines for disease modeling and of clinical-grade lines for replacement therapy.

Background: Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine, which contributes to cell migration, proliferation, and survival. It has been shown that SCF expression increases after myocardial infarction (MI) and may be involved in cardiac repair. The aim of this study was to determine whether gene transfer of membrane-bound human SCF improves cardiac function in a large animal model of MI., Methods and Results: A transmural MI was created by implanting an embolic coil in the left anterior descending artery in Yorkshire pigs. One week after the MI, the pigs received direct intramyocardial injections of either a recombinant adenovirus encoding for SCF (Ad.SCF, n=9) or β-gal (Ad.β-gal, n=6) into the infarct border area. At 3 months post-MI, ejection fraction increased by 12% relative to baseline after Ad.SCF therapy, whereas it decreased by 4.2% (P=0.004) in pigs treated with Ad.β-gal. Preload-recruitable stroke work was significantly higher in pigs after SCF treatment (Ad.SCF, 55.5±11.6 mm Hg versus Ad.β-gal, 31.6±12.6 mm Hg, P=0.005), indicating enhanced cardiac function. Histological analyses confirmed the recruitment of c-kit(+) cells as well as a reduced degree of apoptosis 1 week after Ad.SCF injection. In addition, increased capillary density compared with pigs treated with Ad.β-gal was found at 3 months and suggests an angiogenic role of SCF., Conclusions: Local overexpression of SCF post-MI induces the recruitment of c-kit(+) cells at the infarct border area acutely. In the chronic stages, SCF gene transfer was associated with improved cardiac function in a preclinical model of ischemic cardiomyopathy., (© 2014 American Heart Association, Inc.)

Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n = 15) or the proximal left circumflex artery (LCx; n = 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 ± 3.2% vs. 10.6 ± 1.9%, P = 0.03), depressed systolic function (LV ejection fraction; 39.8 ± 7.5% vs. 54.1 ± 4.6%, P < 0.001), and more LV remodeling (end-systolic volume index; 82 ± 25 ml/m(2) vs. 51 ± 18 ml/m(2), P = 0.02, LAD vs. LCx, respectively) compared with the LCx MI approach without compromising the survival rate. At the papillary muscle level, echocardiographic strain analysis revealed no differences in radial and circumferential strain between LAD and LCx MIs. However, in contrast with the LCx MI, the LAD MI resulted in significantly decreased longitudinal strain. The proximal LAD MI model induces more LV remodeling and depressed LV function relative to the LCx MI model. Location of MI significantly impacts the severity of HF, thus careful consideration is required when choosing an MI model for preclinical HF studies., (Copyright © 2014 the American Physiological Society.)

Purpose: Additional radiation following postmastectomy radiation (PMRT) has an undefined benefit. We investigate those likely to be selected for a chest wall boost (CWB) and its effect on breast cancer survival (BCS) and overall survival (OS)., Methods and Materials: A total of 4747 women diagnosed from 2005 to 2009 were treated with PMRT identified from the California Cancer Registry (CCR); 2686 (57%) received a CWB. Univariate and multivariate analyses compared those receiving and not receiving a CWB for BCS and OS., Results: With a median follow-up of 43.6 months, patients likely to receive a CWB were stage III (P ≤ .001), grade 3/4 (P = .03), positive nodes (P = .04), HER 2+ (P =.02). CWB was not related to BCS in the univariate (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.82-1.21), multivariate (HR, 1.04; 95% CI, 0.86 -1.26) analyses, and was not related OS for the univariate (HR, 0.92; 95% CI, 0.78-1.10), multivariate (HR, 0.95; 95% CI, 0.80-1.13) analyses. However, in multivariate analysis, patients not receiving chemotherapy who had a CWB had better BCS (HR, 1.77; 95% CI, 1.11-2.83)., Conclusions: The majority of patients were treated with a CWB. We found no difference in BCS or OS with the addition of a CWB.

In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca(2+)-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism., (Copyright © 2014 the American Physiological Society.)

During social interactions, listeners weigh the importance of linguistic and extra-linguistic speech cues (prosody) to infer the true intentions of the speaker in reference to what is actually said. In this study, we investigated what brain processes allow listeners to detect when a spoken compliment is meant to be sincere (true compliment) or not ("white lie"). Electroencephalograms of 29 participants were recorded while they listened to Question-Response pairs, where the response was expressed in either a sincere or insincere tone (e.g., "So, what did you think of my presentation?"/"I found it really interesting."). Participants judged whether the response was sincere or not. Behavioral results showed that prosody could be effectively used to discern the intended sincerity of compliments. Analysis of temporal and spatial characteristics of event-related potentials (P200, N400, P600) uncovered significant effects of prosody on P600 amplitudes, which were greater in response to sincere versus insincere compliments. Using low resolution brain electromagnetic tomography (LORETA), we determined that the anatomical sources of this activity were likely located in the (left) insula, consistent with previous reports of insular activity in the perception of lies and concealments. These data extend knowledge of the neurocognitive mechanisms that permit context-appropriate inferences about speaker feelings and intentions during interpersonal communication., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Elevated expression of MYC is a shared property of many human cancers. Epstein-Barr virus (EBV) has been associated with lymphoid malignancies, yet collaborative roles between MYC and EBV in lymphomagenesis are unclear. EBV latent membrane protein 2A (LMP2A) functions as a B-cell receptor (BCR) mimic known to provide survival signals to infected B cells. Co-expression of human MYC and LMP2A in mice (LMP2A/λ-MYC) accelerates B lymphoma onset compared with mice expressing human MYC alone (λ-MYC mice). Here we show a novel role of LMP2A in potentiating MYC to promote G1-S transition and hyperproliferation by downregulating cyclin-dependent kinase inhibitor p27(kip1) in a proteasome-dependent manner. Expressing a gain-of-function S10A mutant of p27(kip1) has minor effect on tumor latency. However, pretumor B cells from λ-MYC mice expressing homozygous S10A mutant show a significant decrease in the percentage of S-phase cells. Interestingly, LMP2A is able to counteract the antiproliferative effect of the S10A mutant to promote S-phase entry. Finally, we show that LMP2A expression correlates with higher levels of MYC expression and suppression of p27(kip1) before lymphoma onset. Our study demonstrates a novel function of EBV LMP2A in maximizing MYC expression, resulting in hyperproliferation and cellular transformation into cancer cells in vivo.

Background: Lack of annual population estimates for disaggregated Native Hawaiian and Other Pacific Islander (NHOPI) populations limits the ability to examine cancer incidence rates and trends to understand the cancer burdens among NHOPIs., Methods: Utilizing 1990 and 2000 population census data, we estimated the annual populations by age and sex for Native Hawaiians, Samoans, and Guamanians/Chamorros for 1990-2008 in regions covered by 13 of the National Cancer Institute's SEER registries. Cancer diagnoses during 1990-2008 from these registries were used to calculate the age-adjusted (2000 US Standard) incidence rates by sex, calendar year/period, and cancer type for each population. The annual percentage change (APC) in incidence rates was estimated with the 95% confidence intervals (95% CIs) calculated for both the rate and APC estimates., Results: Statistically significant declining trends were found in Native Hawaiians, in men for lung and stomach cancers (APC = -2.3%; 95% CI = -3.3 to -1.3; and APC = -3.8%; 95% CI = -6.0 to -1.6, respectively), and in women for breast cancer (APC = -4.1%; 95% CI = -5.7 to -2.5) since 1998 and lung cancer (APC = -6.4%; 95% CI = -10.7 to -1.8) since 2001. Rising incidence trends were experienced by Samoans, especially by Samoan women for breast (APC = 2.7%; 95% CI = 0.9 to 4.5) and uterus (APC = 7.3%; 95% CI = 6.2 to 8.4) cancers. With limited data, Guamanians/Chamorros demonstrated lower, but increasing, incidence rates than other NHOPIs., Conclusions: Population-based cancer incidence rates for disaggregated NHOPI populations help identify disparities in cancer burden and provide valuable information to improve cancer control efforts among NHOPIs.

Background: National cancer incidence trends are presented for eight Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans, Koreans, Laotians, and Vietnamese., Methods: Cancer incidence data from 1990 through 2008 were obtained from 13 Surveillance, Epidemiology, End Results (SEER) registries. Incidence rates from 1990 through 2008 and average percentage change were computed using SEER*Stat and Joinpoint software. The annual percentage change (APC) in incidence rates was estimated with 95% confidence intervals (95% CIs) calculated for both the rate and APC estimates. Rates for non-Hispanic whites are presented for comparison., Results: Prostate cancer was the most common malignancy among most groups, followed by lung, colorectal, liver, and stomach cancers. Breast cancer was generally the most common cancer in women, followed by colorectal and lung cancers; liver, cervix, thyroid, and stomach cancers also ranked highly. Among men, increasing trends were observed for prostate (Asian Indians and Pakistanis: APC 1990-2003 = 2.2, 95% CI = 0.3 to 4.1; Filipinos: APC 1990-1994 = 19.0, 95% CI = 4.5 to 35.4; Koreans: APC 1990-2008 = 2.9, 95% CI = 1.8 to 4.0), colorectal (Koreans: APC 1990-2008 = 2.2, 95% CI = 0.9 to 3.5), and liver cancers (Filipinos: APC 1990-2008 = 1.6, 95% CI = 0.4 to 2.7; Koreans: APC 1990-2006 = 2.1, 95% CI = 0.4 to 3.7; Vietnamese: APC 1990-2008 = 1.6, 95% CI = 0.3 to 2.8), whereas lung and stomach cancers generally remained stable or decreased. Among women, increases were observed for uterine cancer (Asian Indians: APC 1990-2008 = 3.0, 95% CI = 0.3 to 5.8; Chinese: APC 2004-2008 = 7.0, 95% CI = 1.4 to 12.9; Filipina: APC 1990-2008 = 3.0, 95% CI = 2.4 to 3.7; Japanese: APC 1990-2008 = 1.1, 95% CI = 0.1 to 2.0), colorectal cancer (Koreans: APC 1990-2008 = 2.8, 95% CI = 1.7 to 3.9; Laotians: APC: 1990-2008 = 5.9, 95% CI = 4.0 to 7.7), lung cancer (Filipinas: APC 1990-2008 = 2.1, 95% CI = 1.4 to 2.8; Koreans: APC 1990-2008 = 2.1, 95% CI = 0.6 to 3.6), thyroid cancer (Filipinas: APC 1990-2008 = 2.5, 95% CI = 1.7 to 3.3), and breast cancer in most groups (APC 1990-2008 from 1.2 among Vietnamese and Chinese to 4.7 among Koreans). Decreases were observed for stomach (Chinese and Japanese), colorectal (Chinese), and cervical cancers (Laotians and Vietnamese)., Conclusions: These data fill a critical knowledge gap concerning the cancer experience of Asian American groups and highlight where increased preventive, screening, and surveillance efforts are needed-in particular, lung cancer among Filipina and Korean women and Asian Indian/Pakistani men, breast cancer among all women, and liver cancer among Vietnamese, Laotian, and Kampuchean women and Filipino, Kampuchean, and Vietnamese men.

Gene therapy for heart failure treatment is currently being optimized and validated. The results to date are encouraging but challenges remain before it becomes a therapeutic approach in clinical cardiology. Much effort is dedicated to improve gene transduction efficiency by improving the vectors and the delivery methods. Successful translation from the benchtop to the bedside requires teams including biologists focusing on vector modification and cardiologists refining delivery methods. Two key components for translation to the clinic include safety and efficacy. Transduction efficiency is closely linked to invasiveness in most delivery methods. However, current candidates for cardiac gene therapy are patients without effective treatment option and are in advanced heart failure, thus a less invasive approach is preferred. This review focuses on injection methods of gene delivery with emphasis on percutaneous and endovascular approaches to summarize currently available percutaneous gene delivery methods and their features.

The aim of this study was to reveal the temporal and spatial changes of strain parameters during the progression of chronic coronary ischemia. Fourteen pigs received occluder implantation to create gradual ischemia (CI), while six pigs underwent a sham surgery (Control). Six pigs after myocardial infarction were also studied (MI). Strain analysis was performed using a speckle-tracking algorithm. Eleven of the 14 animals with occluder implantation had total occlusion of the left anterior descending artery with collaterals at 1 month (early occlusion group), whereas three pigs had occlusion at 3 months (late occlusion group). Both radial strain (RS) and circumferential strain (CS) of ischemic area deteriorated at 1 month in the early occlusion group and remained at the same level throughout the remaining 2 months of the experiment. In the late occlusion group, RS gradually declined, while CS took the same course as Control until the 2 month time point. Thereafter, both metrics reached the same level as the early occlusion group at the time of occlusion. Interestingly, RS in the remote area decreased moderately, whereas CS remained normal in CI pigs. The comparison between CI and MI revealed preserved CS at the ischemic area in CI pigs. Both RS and CS deteriorate by the time total coronary occlusion was established and remain at the same level thereafter. Altered RS in the remote area may be an indicator of remodeling in the non-ischemic area, whereas CS may be useful for distinguishing between transmural and non-transmural scar.

Background: Colorectal cancer (CRC) incidence and mortality rates vary across race/ethnicity. Socioeconomic status (SES) also influences CRC rates; however, these associations might be inconsistent across racial/ethnic groups and tumor subsite. We examined associations between area-level SES and CRC incidence and mortality in a population-based registry study of non-Hispanic Whites, African Americans, Hispanics, and Asians/Pacific Islanders from California., Methods: Data on 52,608 incident CRC cases (1998-2002) and 14,515 CRC deaths (1999-2001) aged ≥50 years were obtained from the California Cancer Registry. Based on 2000 U.S. Census data, each cancer case and death was assigned a multidimensional census tract-level SES index. SES-specific quintiles of CRC incidence and mortality rates, incidence rate ratios (IRR) and mortality rate ratios, and 95% confidence intervals (CI) were estimated. Analyses were stratified by anatomical site, including left- versus right-sided tumors, race/ethnicity, and stage of disease., Results: Overall CRC incidence and SES did not show a clear association, yet patterns of associations varied across tumor subsite and race/ethnicity. Positive associations between SES and CRC incidence were found in Hispanics [SES Q5 v. Q1: IRR = 1.54, CI = 1.39-1.69], irrespective of the subsite. For Whites [SES Q5 v. Q1: IRR = 0.80, CI = 0.77-0.83], and African Americans [SES Q5 v. Q1: IRR = 0.83, CI = 0.70-0.97] inverse associations were observed, predominantly for left-sided tumors. Mortality rates declined with increasing SES in Whites, whereas in Hispanics mortality rates significantly increased with SES., Conclusions: Our findings show that SES differences in CRC incidence and mortality vary considerably across anatomical subsite and race/ethnicity., Impact: Studies combining area- and individual-level SES information are warranted., (2012 AACR)

Epstein-Barr virus (EBV) infection and latency has been associated with malignant diseases including nasopharyngeal carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and immune deficiency associated lymphoproliferative diseases. EBV-encoded latent membrane protein 2A (LMP2A) recruits Lyn and Syk kinases via its SH2-domain binding motifs, and modifies their signaling pathways. LMP2A transgenic mice develop hyperproliferative bone marrow B cells and immature peripheral B cells through modulation of Lyn kinase signaling. LMP2A/λ-MYC double transgenic mice develop splenomegaly and cervical lymphomas starting at 8 weeks of age. We reasoned that targeting Lyn in LMP2A-expressing B cells with dasatinib would provide a therapeutic option for EBV-associated malignancies. Here, we show that dasatinib inhibits B cell colony formation by LMP2A transgenic bone marrow cells, and reverses splenomegaly and tumor growth in both a pre-tumor and a syngeneic tumor transfer model of EBV-associated Burkitt lymphoma. Our data support the idea that dasatinib may prove to be an effective therapeutic molecule for the treatment of EBV-associated malignancies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Several clinical trials are evaluating gene transfer as a therapeutic approach to treat cardiac diseases. Although it has just started on the path to clinical application, recent advances in gene delivery technologies with increasing knowledge of underlying mechanisms raise great expectations for the cardiac gene therapy. Although in vivo experiments using small animals provide the therapeutic potential of gene transfer, there exist many fundamental differences between the small animal and the human hearts. Before applying the therapy to clinical patients, large animal studies are a prerequisite to validate the efficacy in an animal model more relevant to the human heart. Several key factors including vector type, injected dose, delivery method and targeted cardiac disease are all important factors that determine the therapeutic efficacy. Selecting the most optimal combination of these factors is essential for successful gene therapy. In addition to the efficacy, safety profiles need to be addressed as well. In this regard, large animal studies are best suited for comprehensive evaluation at the preclinical stages of therapeutic development to ensure safe and effective gene transfer. As the cardiac gene therapy expands its potential, large animal studies will become more important to bridge the bench side knowledge to the clinical arena.

Objective: The aim of this study was to measure the effects of above-real-time-training (ARTT) speed and screen resolution on a simulated flight control task., Background: ARTT has been shown to improve transfer to the criterion task in some military simulation experiments. We tested training speed and screen resolution in a project, sponsored by Defence Research and Development Canada, to develop components for prototype air mission simulators., Method: For this study, 54 participants used a single-screen PC-based flight simulation program to learn to chase and catch an F-18A fighter jet with another F-18A while controlling the chase aircraft with a throttle and side-stick controller. Screen resolution was varied between participants, and training speed was varied factorially across two sessions within participants. Pretest and posttest trials were at high resolution and criterion (900 knots) speed., Results: Posttest performance was best with high screen resolution training and when one ARTT training session was followed by a session of criterion speed training., Conclusion: ARTT followed by criterion training improves performance on a visual-motor coordination task. We think that ARTT influences known facilitators of transfer, including similarity to the criterion task and contextual interference., Application: Use high-screen resolution, start with ARTT, and finish with criterion speed training when preparing a mission simulation.

Background: Better understanding about gastric cancer incidence patterns among Hispanics by birthplace, socioeconomic status (SES), and acculturation can improve preventive strategies and disease models., Methods: Incidence rates, rate ratios, and estimated annual percent change (EAPC) in rates of anatomic and histologic subtype-specific gastric cancer were calculated by age, sex, and nativity among Hispanics using California Cancer Registry data from 1988 through 2004. Incidence rates in 1998 to 2002 were compared by neighborhood SES and Hispanic enclave status according to 2000 US Census data., Results: Incidence rates of diffuse gastric cancer increased from 1988 through 2004 among foreign-born Hispanic men (EAPC: 3.5%, 95% CI: 1.5%-5.5%) and U.S.-born Hispanic women (EAPC: 3.0%, 95% CI: 0.7%-5.3%). During the same time period, incidence rates of intestinal gastric cancer declined significantly and both cardia and noncardia gastric cancer were steady or declined among foreign-born and U.S.-born Hispanic men and women. Noncardia and both intestinal and diffuse gastric cancer were more common in foreign-born than U.S.-born Hispanic men and women, and in those from lower SES, higher enclave neighborhoods. By contrast, among younger and middle-aged Hispanic men, cardia tumors were more common in the U.S.-born than the foreign-born, and in higher SES, lower enclave neighborhoods., Conclusions: Varying gastric cancer risk factors among Hispanic subgroups and increasing rates of diffuse gastric cancer in foreign-born Hispanic men and U.S.-born Hispanic women merit further investigation to identify separate disease etiologies., Impact: Age, sex, birthplace, SES, and acculturation modify gastric cancer incidence in Hispanics and should be considered when examining disease risk and prevention.

Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and maximum dP/dt (dP/dt(max)) are the simplest and most used. However, these parameters are often reported together, and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt(max) in assessing systolic dysfunction after myocardial infarction (MI) in swine. A total of 220 measurements were obtained. All measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of an MI revealed a good predictive value for EF [area under the curve (AUC): 0.998] but not by dP/dt(max) (AUC: 0.69, P < 0.001 vs. EF). Dividing dP/dt(max) by LV end-diastolic pressure and heart rate (HR) significantly increased the AUC to 0.87 (P < 0.001 vs. dP/dt(max) and P < 0.001 vs. EF). In naïve pigs, the coefficient of variation of dP/dt(max) was twice than that of EF (22.5% vs. 9.5%, respectively). Furthermore, in n = 19 pigs, dP/dt(max) increased after MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt(max) and strain parameters in the noninfarcted area (circumferential strain: r = 0.42, P = 0.05; radial strain: r = 0.71, P < 0.001). In conclusion, EF is a more accurate measure of systolic dysfunction than dP/dt(max) in a swine model of MI. Despite the variability of dP/dt(max) both in naïve pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.

In order to investigate whether the clinical behaviour of extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) varies by race within a geographic region, we identified a total of 213 non-Hispanic whites, Hispanics and Asians/Pacific islanders (APIs) diagnosed with ENKTL in the California Cancer Registry between 2001 and 2008. The incidence and outcomes of the disease in these racial groups were analysed. The incidence rates in non-Hispanic whites, Hispanics and APIs were 0.05, 0.18 and 0.23 per 100,000 person-years, respectively, among males; and 0.03, 0.07 and 0.10 per 100,000 person-years, respectively, among females. The overall survival (OS) at 5 years was 28.6% in non-Hispanic whites, 30.4% in Hispanic, and 24.0% in APIs. In multivariate analysis, distant versus local/regional disease (Hazard Ratio [HR]=2.01, 95% confidence interval [CI]: 1.36, 2.96), initial treatment with chemotherapy plus radiotherapy (HR=0.39, 95% CI: 0.22, 0.70) or radiotherapy alone (HR=0.48, 95% CI: 0.23, 0.99) versus no therapy were associated with OS. However, OS was not affected by age, sex, race, chemotherapy alone, socioeconomic status, or human immunodeficiency virus infection. In conclusion, ENKTL is more common and clinically more similar among Hispanics and APIs than non-Hispanic whites with poor outcome in all racial groups., (© 2011 Blackwell Publishing Ltd.)

Bcl-2 E1B 19-KDa interacting protein 3 (BNIP3) is a mitochondrial death and mitophagy marker, which is involved in inducing cardiac remodeling post myocardial infarction. In this study, we show that BNIP3 expression increases in stressed cardiomyocytes in vitro and in response to pressure overload in vivo, and that its transcription is directly related to JNK activity. BNIP3 expression gradually increased in the first weeks after pressure overload and peaked at the heart failure stage. Ultrastructurally, the mitochondrial area was inversely proportional to BNIP3 expression. Both JNK and AKT activities increased with pressure overload; however, JNK signaling dominated over AKT signaling for the activation of the transcription factor FOXO3a and for the transcription of its effector, BNIP3. 3-methyladenine attenuated JNK signaling and significantly decreased BNIP3 expression and reversed cardiac remodeling in heart failure. Ultrastructurally, the mitochondrial area was significantly increased in the 3-methyladenine group compared with placebo. Moreover, adenoviral gene delivery of dominant negative JNK in a rat model of pressure overload hypertrophy abolished the increase in BNIP3 expression in response to pressure overload. These results suggest that JNK signaling is a critical modulator of the transcription factor FOXO3a driving the expression of its effector, BNIP3, in heart failure and that JNK, through BNIP3, induces mitochondrial apoptosis and mitophagy.

Innate lymphoid cells (ILCs) expressing the nuclear receptor RORγt are essential for gut immunity presumably through production of interleukin-22 (IL-22). The molecular mechanism underlying the development of RORγt(+) ILCs is poorly understood. Here, we have shown that the aryl hydrocarbon receptor (Ahr) plays an essential role in RORγt(+) ILC maintenance and function. Expression of Ahr in the hematopoietic compartment was important for accumulation of adult but not fetal intestinal RORγt(+) ILCs. Without Ahr, RORγt(+) ILCs had increased apoptosis and less production of IL-22. RORγt interacted with Ahr and promoted Ahr binding at the Il22 locus. Upon IL-23 stimulation, Ahr-deficient RORγt(+) ILCs had reduced IL-22 expression, consistent with downregulation of IL-23R in those cells. Ahr-deficient mice succumbed to Citrobacter rodentium infection, whereas ectopic expression of IL-22 protected animals from early mortality. Our data uncover a previously unrecognized physiological role for Ahr in promoting innate gut immunity by regulating RORγt(+) ILCs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional profiles of tumor cells from LMP2A/λ-MYC and λ-MYC mice are strikingly similar, with fewer than 20 genes differentially expressed. We evaluated the functional significance of one of the most interesting differentially expressed genes, Egr1, and found that it was not required for acceleration of tumor onset by LMP2A. Our studies demonstrate the remarkable ability of LMP2A to affect the pretumor B-cell phenotype and tumorigenesis without substantially altering gene expression in tumor cells.

Gene therapy for the treatment of heart failure is emerging as a multidisciplinary field demonstrating advances with respect to identifying key signaling pathways, modernized vector creation and delivery technologies. Although these discoveries offer significant progress, selecting optimal methods for the vector delivery remains a key component for efficient cardiac gene therapy to validate the targets in rodent models and to test clinically relevant ones in pre-clinical models. Although the goals of higher transduction efficiency and cardiac specificity can be achieved with several delivery methods, the invasiveness and patient safety remain unclear for clinical application. In this review, we discuss various features of the currently available vector delivery methods for cardiac gene therapy., (Copyright © 2011 John Wiley & Sons, Ltd.)

Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine their efficacy and safety. Gene therapy using viral vectors is one of the most promising approaches for treating cardiac diseases. Viral delivery of various different genes by changing the carrier gene has immeasurable therapeutic potential. In this video, the full process of an animal model of heart failure creation followed by gene transfer is presented using a swine model. First, myocardial infarction is created by occluding the proximal left anterior descending coronary artery. Heart remodeling results in chronic heart failure. Unique to our model is a fairly large scar which truly reflects patients with severe heart failure who require aggressive therapy for positive outcomes. After myocardial infarct creation and development of scar tissue, an intracoronary injection of virus is demonstrated with simultaneous nitroglycerine infusion. Our injection method provides simple and efficient gene transfer with enhanced gene expression. This combination of a myocardial infarct swine model with intracoronary virus delivery has proven to be a consistent and reproducible methodology, which helps not only to test the effect of individual gene, but also compare the efficacy of many genes as therapeutic candidates.

Background: Lung cancer is the leading cause of cancer death among U.S. Asian/Pacific Islander (API) and Latina women despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS)., Methods: Women diagnosed with lung cancer from 1998 to 2003 and 2005 to 2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic (NH) white, 23 U.S.-born Latina, 32 foreign-born Latina, 30 U.S.-born API, and 190 foreign-born API never-smokers diagnosed with lung cancer and followed through 2008., Results: All-cause survival was poorer among APIs [HR=1.7 (95% CI: 1.0-2.8) among U.S.-born APIs and HR=1.2 (95% CI: 0.9-1.5) among foreign-born APIs] and Latinas [HR=2.1 (95% CI: 1.2-3.6) among U.S.-born Latinas; HR=1.4 (95% CI: 0.9-2.3) among foreign-born Latinas] relative to NH whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors., Conclusions: Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations as possible explanations for these striking racial/ethnic differences., Impact: Latina and API female never-smokers diagnosed with lung cancer were up to two times more likely to die than NH whites, highlighting the need for additional research to identify the underlying reasons for the disparities and heightened clinical awareness., (©2011 AACR.)

Introduction: Breast cancer comprises clinically distinct subtypes, but most risk statistics consider breast cancer only as a single entity. To estimate subtype-specific lifetime breast cancer risks, we took advantage of population-based data for which information regarding tumor expression of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu (HER2) was newly available., Methods: We included women whose breast cancer was diagnosed in the state of California from 2006 to 2007 and was reported to the National Cancer Institute's Surveillance, Epidemiology and End Results Program (N = 40,936). We calculated absolute lifetime and age-specific probabilities (percent, 95% confidence interval) of developing breast cancer subtypes defined by ER, PR, and HER2 status - luminal (ER and/or PR-positive, HER2-negative), HER2-positive (ER and PR-positive or negative, HER2-positive), and triple-negative (ER-negative, PR-negative, and HER2-negative) - separately for white, black, Hispanic, and Asian women., Results: The luminal breast cancer subtype predominates across racial/ethnic groups, with lifetime risk lowest in Hispanic women (4.60%, 4.41-4.80%) and highest in white women (8.10%, 7.94-8.20%). HER2-positive breast cancer varies less by race (1.56-1.91%). Lifetime risk of triple-negative breast cancer is highest in black women (1.98%, 1.80-2.17%), compared to 0.77% (0.67-0.88%) for Asians, 1.04% (0.96-1.13%) for Hispanics and 1.25% (1.20-1.30%) for whites. Across racial/ethnic groups, nearly half of all luminal breast cancers occur after age 70., Conclusions: These absolute risk estimates may inform health policy and resource planning across diverse populations, and can help patients and physicians weigh the probabilities of developing specific breast cancer subtypes against competing health risks.

The ability to accelerate the spatial encoding process during a chemical shift imaging (CSI) scan of hyperpolarized compounds is demonstrated through parallel imaging. A hardware setup designed to simultaneously acquire (13)C data from multiple receivers is presented here. A system consisting of four preamplifiers, four gain stages, a transmit coil, and a four receive channel rat coil was built for single channel excitation and simultaneous multi-channel detection of (13)C signals. The hardware setup was integrated with commercial scanner electronics, allowing the system to function similar to a conventional proton multi-channel setup, except at a different frequency. The ability to perform parallel imaging is demonstrated in vivo. CSI data from the accelerated scans are reconstructed using a self-calibrated multi-spectral parallel imaging algorithm, by using lower resolution coil sensitivity maps obtained from the central region of k-space. The advantages and disadvantages of parallel imaging in the context of imaging hyperpolarized compounds are discussed., ((c) 2009 John Wiley & Sons, Ltd.)

Complete physical examinations and biomedical sample collection were performed on 70 free-ranging ring-tailed lemurs (Lemur catta) from three different habitats in the Beza Mahfaly Special Reserve (BMSR), in southern Madagascar, to assess the impact of humans and habitat on lemur health. Lemurs were chemically immobilized with ketamine and diazepam administered via blow darts for concurrent biomedical, morphometric, and behavioral studies. Subsets of the animals had blood analyzed for hematology, serum chemistry, micronutrients, fat-soluble vitamins (vitamins A, D, and E), measures of iron metabolism, and polymerase chain reaction assays (PCR) for Toxoplasma gondii, Hemoplasma spp., Bartonella spp., Ehrlichia spp., Anaplasma phagocytophilum, and Neorickettsia risticii. Results were compared on the basis of gender and the habitats at the study site: reserve (intact gallery forest), degraded (human inhabited and altered), and marginal (dry didieracea forest with heavy grazing and tree cutting). Levels of vitamin D, triglycerides, and cholesterol, and measures of iron metabolism for BMSR lemurs were greater than those previously reported for a free-ranging lemur population (Tsimanampetsotsa Strict Nature Reserve, Madagascar) with less access to foods of anthropogenic origin. BMSR ring-tailed lemurs from a habitat with less water (marginal) had higher sodium (P = 0.051), chloride (P = 0.045), osmolality (P = 0.010), and amylase (P = 0.05) levels than lemurs from other BMSR habitats, suggesting that these lemurs were less hydrated. Vitamin D levels of male lemurs were higher (P = 0.011) than those of females at BMSR, possibly because of differences in sunning behavior or differential selection of food items. The biological significance is uncertain for other parameters with statistically significant differences. All samples tested (n = 20) were negative for the pathogens tested using PCR assays. Continued concurrent biomedical and ecological research is needed at BMSR to confirm these results and determine their association with population mortality and fecundity rates.

Routine assessment of impulsivity and accompanying coping skills is essential for planning care and appropriate management of patients identified as impulsive. Impulsivity can be defined in many ways, and many perspectives exist. Impulsivity is associated with several adult psychiatric disorders. In an inpatient psychiatric setting, nurses are more likely than members of other disciplines to encounter impulsive behavior due to the amount of time spent in direct patient care. As the primary caregivers in hospitals, nurses are responsible for the management of impulsive individuals. It is critical for treatment plans to incorporate interventions specifically targeting impulsivity.

Unlabelled: The primary goal of this study was to test the items in a rating system developed to evaluate anesthesiologists' performance in a simulated patient environment. A secondary goal was to determine whether the test scores could discriminate between resident and staff anesthesiologists. Two 5-item clinical scenarios included patient evaluation and induction and maintenance of anesthesia. Rating scales were no response to the problem (score = 0), compensating intervention (score = 1), and corrective treatment (score = 2). Internal consistency was estimated using Cronbach's coefficient alpha. Scores between groups were compared using the Cochran-Mantel-Haenszel test. Subjects consisted of 8 anesthesiology residents and 17 university clinical faculty. The Cronbach's coefficient alpha was 0.27 for Scenario A and 0.28 for Scenario B. Two items in each scenario markedly decreased internal consistency. When these four items were eliminated, Cronbach's coefficient alpha for the remaining six items was 0.66. Faculty anesthesiologists scored higher than residents on all six items (P < 0.001). A patient simulator-based evaluation process with acceptable reliability was developed., Implications: The reliability of anesthesia clinical performance in a patient simulation environment was assessed in this study. Of 10 items, 4 were poor in the evaluation process. When these items were removed, the reliability of the instrument improved to a level consistent with other studies. Because faculty scored higher than resident anesthesiologists, the instrument also showed discriminant validity.

Purpose: Assessment of physician performance has been a subjective process. An anaesthesia simulator could be used for a more structured and standardized evaluation but its reliability for this purpose is not known. We sought to determine if observers witnessing the same event in an anaesthesia simulator would agree on their rating of anaesthetist performance., Methods: The study had the approval of the research ethics board. Two one-hour clinical scenarios were developed, each containing five anaesthetic problems. For each problem, a rating scale defined the appropriate score (no response to the situation: score = 0; compensating intervention defined as physiological correction: score = 1; corrective treatment: defined as definitive therapy score = 2). Video tape recordings, for assessment of inter-rater reliability, were generated through role-playing with recording of the two scenarios three times each resulting in a total of 30 events to be evaluated. Two clinical anaesthetists, uninvolved in the development of the study and the clinical scenarios, reviewed and scored each of the 30 problems independently. The scores produced by the two observers were compared using the kappa statistic of agreement., Results: The raters were in complete agreement on 29 of the 30 items. There was excellent inter-rater reliability (= 0.96, P < 0.001)., Conclusions: The use of videotapes allowed the scenarios to be scored by reproducing the same event for each observer. There was excellent inter-rater agreement within the confines of the study. Rating of video recordings of anaesthetist performance in a simulation setting can be used for scoring of performance. The validity of the scenarios and the scoring system for assessing clinician performance have yet to be determined.

The major immediate-early (IE) gene region of human cytomegalovirus (HCMV) encodes several proteins as a result of differential RNA splicing events. By expression vector cloning of HCMV IE mRNA, we isolated and characterized a cDNA for a novel splice variant from the major IE gene region. The RNA product is a derivative of the IE55 mRNA and contains an additional splice from nucleotides 170,635 to 170,307 in the IE2 gene region (UL122), resulting in a 1.4-kb mRNA. The predicted open reading frame codes for a 164-amino-acid protein with a calculated molecular mass of 18 kDa (IE18). Mung bean nuclease analysis and PCR were used to characterize expression of IE18 mRNA in HCMV-infected cells. While the 1.4-kb mRNA was detected in infected human fibroblasts in the presence of a protein synthesis inhibitor, it was not detectable during a normal infection. However, the 1.4-kb mRNA was readily detected in infected human monocyte-derived macrophages at IE times. These results suggest that the novel IE18 mRNA exhibits cell type-specific expression indicating differential regulation of the major IE gene region in different permissive cell types.

The major immediate-early promoter (MIEP) of human cytomegalovirus directs the expression of several differentially spliced and polyadenylated mRNAs. These mRNAs encode nuclear phosphorproteins (IE55, IE72, and IE86), which consist of common and unique amino acid sequences. To date, very little is known of the functional role of the 55-kDa (IE55) protein. Here we present evidence that the IE55 protein is a positive activator of the MIEP. In human fibroblast cells IE55 protein activated the MIEP between 10- and 30-fold. Fusion of IE55 to the GAL4 DNA binding domain resulted in a chimeric protein capable of trans-activating a reporter with GAL4 recognition sequences. These results strongly suggest that IE55 is a bona fide transcriptional activator protein. In addition, the IE55 protein was found not to act synergistically with the IE72 activator protein. The IE55 protein shares the same amino acid sequence as IE86 except for a 154-amino-acid deletion at the C-terminal end of the protein. These proteins were functionally antagonistic; IE55 relieved repression by IE86 and, conversely, IE86 negated IE55 activation. Mutagenesis of the MIEP revealed that the target sequence for activation by IE55 is different from the IE86 autorepressive response element. These experiments suggest that the mechanism of action of the IE55 and IE86 isoforms is distinct. Moreover, from these results it is apparent that the interplay of these factors might be critical in determining the level of HCMV replication in the host.

Objective: To investigate a cluster of postoperative bleeding following open heart surgery., Design: A cohort and case/control study., Setting: Palo Alto Veterans Administration Medical Center, Palo Alto, California., Participants: Six (21.4%) of 28 patients undergoing open heart surgery who developed severe, nonsurgical, postoperative bleeding from July 1 through August 30, 1988 (outbreak period). All case-patients had chest tube drainage of greater than or equal to 1000 ml within 4 hours of surgery but did not have identifiable bleeding vessel(s) on exploration., Results: Upon comparison of the pre-outbreak (January 1986 through June 1988) and the outbreak period, a significant increase was found in the incidence of postoperative nonsurgical bleeding (5/440 versus 6/28, p = .0006), but not of postoperative surgical bleeding (8/440 versus 0/28, p = 1.0). Of all patients undergoing open heart surgery during the outbreak period, case patients were found to be older (67.8 versus 60.6, p = .02) and to have received a larger volume of hetastarch (HES), a synthetic colloidal plasma-volume expander (mean = 19.4 ml/kg versus 14.1 ml/kg, p = .02)., Conclusions: We conclude that the use of large volumes of HES during surgery in the elderly open heart surgery patient may increase the risk for severe, nonsurgical postoperative bleeding, probably caused by alterations of the coagulation system. As the incidence of open heart surgery increases among the elderly, surgeons and anesthesiologists should be alert to possible adverse reactions from exposures not associated with adverse reactions in younger patients.

To assess the potential for producing nephrotoxicity in rats with abnormal renal function, the renal effects of enflurane or halothane anesthesia, 1 MAC for two hours, were examined in six groups of six Fischer 344 rats each with surgically induced chronic renal impairment. As an additional predisposing factor, gentamicin, 5 mg/kg/day, was administered for one week before and for one week after anesthesia to three of the groups, one anesthetized with enflurane, one anesthetized with halothane, and one unanesthetized. No significant change in renal function could be attributed to either anesthetic agent. Serum inorganic fluoride levels four hours and 24 hours after enflurane anesthesia were similar in the gentamicin-treated and the non-gentamicin-treated groups. Clinically small but statistically significant increases in serum creatinine concentration and urinary flow occurred in all three gentamicin-treated groups during the period of treatment. Anesthesia with either enflurane or halothane in rats with chronic renal impairment treated with gentamicin did not result in additional renal damage.