Protective immunity to H7N9 influenza viruses elicited by synthetic DNA vaccine

Despite an intensive vaccine program influenza infections remain a major health problem, due to the viruses’ ability to change its envelope glycoprotein hemagglutinin (HA), through shift and drift, permitting influenza to escape protection induced by current vaccines or natural immunity. Recently a new variant, H7N9, has emerged in China causing global concern. First, there have been more than 130 laboratory-confirmed human infections resulting in an alarmingly high death rate (32.3%). Second, genetic changes found in H7N9 appear to be associated with enabling avian influenza viruses to spread more effectively in mammals, thus transmitting infections on a larger scale. Currently, no vaccines or drugs are effectively able to target H7N9. Here, we report the rapid development of a synthetic consensus DNA vaccine (pH7HA) to elicit potent protective immunity against the H7N9 viruses. We show that pH7HA induces broad antibody responses that bind to divergent HAs from multiple new members of the H7N9 family. These antibody responses result in high-titer HAI against H7N9. Simultaneously, this vaccine induces potent polyfunctional effector CD4 and CD8T cell memory responses. Animals vaccinated with pH7HA are completely protected from H7N9 virus infection and any morbidity associated with lethal challenge. This study establishes that this synthetic consensus DNA vaccine represents a new tool for targeting emerging infection, and more importantly, its design, testing and development into seed stock for vaccine production in a few days in the pandemic setting has significant implications for the rapid deployment of vaccines protecting against emerging infectious diseases.     

Pre-treatment of mice with tumor-conditioned media accelerates metastasis to lymph nodes and lungs: a new spontaneous breast cancer metastasis model

Current spontaneous metastasis models require a long period of observation after establishment of primary tumors to see significant metastatic progression. The degree of metastasis is not consistent among animals: this is problematic since it requires the use of a large number of animals to obtain reliable statistics. Here we report that pre-treatment of animals with tumor-conditioned media (TCM) consistently accelerates spontaneous metastasis in breast cancer. An inguinal breast tumor model facilitated by TCM showed robust anterior metastasis to the axillary and brachial lymph nodes (LN), and the lungs compared to the serum-free media treated group. The LN in TCM-treated animals showed enhanced angiogenesis and lymphangiogenesis. Primary tumors and lungs in TCM-treated animals showed enhanced lymphangiogenesis with no significant change in angiogenesis. TCM-treated animals also showed metastatic dissemination to abdomen from the primary injection site: this would generally enhance metastasis to other organs. In sum, the addition of TCM pre-treatment to current metastasis models results in accelerated and robust metastasis which would enable more efficient evaluation of anti-metastatic agents.     

AN INVESTIGATION OF THE DOSE PROPORTIONALITY OF DEFLAZACORT PHARMACOKINETICS

The dose proportionality of deflazacort was assessed following single-dose oral administration at doses of 3, 6, and 36 mg to 24 healthy young adult volunteers. The active metabolite of deflazacort (21-desacetyl deflazacort) was monitored in plasma using a sensitive, semi-microbore liquid chromatographic method. C_max averaged 10·4±5·0, 19·8±7·5, and 132·6±52·5 ng mL⁻¹ for the 3, 6, and 36 mg doses, respectively. AUC(0–∞) averaged 38·5±37·1, 64·9±20·8, and 411·7±148·5 ng h mL⁻¹ for the same three doses, respectively. Elimination half-life ranged from 1·9±0·5 h at the 6 mg dose to 2·4±1·5 h at the 36 mg dose. Regression analyses of dose versus C_max and AUC(0–∞) yielded intercepts which were not significantly different from zero (p>0·05) and slopes which were significant (p<0·05). Regression analysis of dose versus apparent oral clearance yielded a slope which was not significantly different from zero (p>0·05). These data indicate that deflazacort exhibits dose-proportional pharmacokinetics.     

Imaging biomarkers of cardiovascular disease

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Current clinical techniques that rely on stenosis measurement alone appear to be insufficient for risk prediction in atherosclerosis patients. Many novel imaging methods have been developed to study atherosclerosis progression and to identify new features that can predict future clinical risk. MRI of atherosclerotic vessel walls is one such method. It has the ability to noninvasively evaluate multiple biomarkers of the disease such as luminal stenosis, plaque burden, tissue composition and plaque activity. In addition, the accuracy of in vivo MRI has been validated against histology with high reproducibility, thus paving the way for application to epidemiological studies of disease pathogenesis and, by serial MRI, in monitoring the efficacy of therapeutic intervention. In this review, we describe the various MR techniques used to evaluate aspects of plaque progression, discuss imaging‐based measurements (imaging biomarkers), and also detail their validation. The application of plaque MRI in clinical trials as well as emerging imaging techniques used to evaluate plaque compositional features and biological activities are also discussed. J. Magn. Reson. Imaging 2010;32:502–515. © 2010 Wiley‐Liss, Inc.     

Pre-operative embolization of auricular arteriovenous fistula

Treatment of auricular arteriovenous fistula (AVF) is a challenge with surgery being the preferred option until now. We present three cases of auricular AVFs who underwent pre-operative embolization and its outcome on surgery. Three patients were diagnosed to have auricular AVF by angiography. All three patients underwent pre-operative embolization with n-butyl 2-cyanoacrylate after which they underwent surgical resection of the AVF. Pre-operative embolization resulted in significant devascularization of the AVF thus leading to near bloodless and clean surgery. Pre-operative embolization of auricular AVFs is a good treatment option, leading to significantly reduced blood loss during surgical excision.