Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached.

Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic to non-transformed cells but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, is frequently up-regulated in melanoma, allowing melanoma cells to tolerate excess FA. DGAT1 over-expression alone transforms p53-mutant zebrafish melanocytes and co-operates with oncogenic BRAF or NRAS for more rapid melanoma formation. Antagonism of DGAT1 induces oxidative stress in melanoma cells, which adapt by up-regulating cellular reactive oxygen species defenses. We show that inhibiting both DGAT1 and superoxide dismutase 1 profoundly suppress tumor growth through eliciting intolerable oxidative stress.

Infective endocarditis is associated with worse outcomes in stroke: A Thailand National Database Study.

BACKGROUND: There is lack of data on the association between infective endocarditis (IE) and outcomes of mortality and complications in stroke. We aimed to compare characteristics and outcomes of stroke patients with and without IE. METHODS: We retrospectively examined the above association using data obtained from an insurance database which covers ~75% of the Thai population. All hospitalised strokes between 8 January 2003 and 31 December 2013 were included in the current study. Characteristics and outcomes were compared between stroke patients with or without IE, and then between two main stroke types. Multiple logistic regression models including propensity score-matched analyses were constructed to assess study outcomes controlling for age, sex, stroke type and comorbidities. RESULTS: A total of 590 115 stroke patients (mean (SD) age = 64.2 ± 13.7 years; ischaemic = 51.7%; haemorrhagic = 32.6%; undetermined = 15.7%) were included, of whom 2129 (0.36%) had stroke associated with IE. After adjustment, we found that IE was significantly associated with the following complications: arrhythmias (adjusted odds ratio (95% CI) 6.94 (6.29-7.66)), sepsis (1.24 (1.01-1.52)), pneumonia (1.34 (1.17-1.53)), respiratory failure (1.43 (1.24-1.66)) and in-hospital mortality (1.29 (1.13-1.47)) (P for all <.001). Patients with haemorrhagic stroke with IE had poorer outcomes for in-hospital mortality and respiratory failure compared with their counterparts with ischaemic stroke. Propensity score-matched analysis showed similar results. CONCLUSIONS: Our results suggest that stroke patients with IE differ from that of the general stroke population and these patients have worse outcomes. Future studies are needed to determine the best treatment strategies for stroke patients with IE.

Analysis of H5N1 avian influenza infections from wild bird surveillance in Hong Kong from January 2006 to October 2007.

Intensive surveillance of dead wild birds for H5N1 avian influenza infection is conducted in Hong Kong. Between January 2006 and October 2007 pooled cloacal and tracheal swabs from 17692 dead wild birds (from 16 different orders including 82 genera) were tested and 33 H5N1 highly pathogenic avian influenza viruses were isolated. No H5N1 infection has occurred in poultry farms since January 2003, or in live poultry markets in Hong Kong since November 2003 until a recent detection of H5N1 virus by surveillance of live poultry markets in June 2008. The gross and histopathology in the various H5N1-infected avian species is described, along with the performance of the virus isolation and polymerase chain reaction (PCR) tests used. This evaluation also included determination of virus titres and detection limits for the H5 haemagglutinin gene (H5)and matrix gene real-time reverse-transcription PCR tests in cloacal and tracheal swabs from 12 wild birds. The viruses isolated belonged to Clades 2.3.2 and 2.3.4, and within Clade 2.3.4 some clustering was evident based on H5 haemagglutinin gene haemagglutinating sequencing. There were no differences in the pathology findings between these subgroupings and the various diagnostic tests gave similar results for these viruses, except for a loss in sensitivity of the H5 real-time reverse-transcription PCR for several viruses in one cluster from birds submitted in February 2007. The use of multiple test methods was important in maintaining the diagnostic sensitivity for detecting avian influenza viruses with high genetic variability.

Characterization of avian influenza viruses A (H5N1) from wild birds, Hong Kong, 2004-2008.

From January 2004 through June 2008, surveillance of dead wild birds in Hong Kong, People's Republic of China, periodically detected highly pathogenic avian influenza (HPAI) viruses (H5N1) in individual birds from different species. During this period, no viruses of subtype H5N1 were detected in poultry on farms and in markets in Hong Kong despite intensive surveillance. Thus, these findings in wild birds demonstrate the potential for wild birds to disseminate HPAI viruses (H5N1) to areas otherwise free from the viruses. Genetic and antigenic characterization of 47 HPAI (H5N1) viruses isolated from dead wild birds in Hong Kong showed that these isolates belonged to 2 antigenically distinct virus groups: clades 2.3.4 and 2.3.2. Although research has shown that clade 2.3.4 viruses are established in poultry in Asia, the emergence of clade 2.3.2 viruses in nonpasserine birds from Hong Kong, Japan, and Russia raises the possibility that this virus lineage may have become established in wild birds.

Performance evaluation of five detection tests for avian influenza antigen with various avian samples.

In this paper, we report on the evaluation of five influenza antigen detection tests by avian influenza H5N 1 virus-positive swab samples to estimate their diagnostic sensitivity. The tests included two chromatographic immunoassays, an H5 avian influenza-specific antigen detection enzyme-linked immunosorbent assay (ELISA), an influenza A antigen detection ELISA, and an H5 rapid immunoblot assay. The results showed that the overall sensitivities of these tests ranged from 36.3% to 51.4% (95% confidence interval ranging from 31.0% to 57.0%), which were comparable to Directigen Flu A antigen detection tests but substantially lower than genome detection methods. Diagnostic sensitivity performance is a function of the concentration of antigens in samples and the analytical sensitivity of the individual test. The test sensitivities were significantly higher for sick and dead birds by cloacal, tracheal, or tissue swabs than for fecal swabs from apparently healthy birds, and these tests would not be suitable for surveillance testing of clinically healthy birds. Furthermore, the sensitivity for testing tracheal and cloacal swabs from waterfowl and wild birds was not as good as for chickens. This was most likely to be associated with variation in virus titers between specimens from different bird species. However, the tests showed good sensitivities for testing brain swabs from clinically affected waterfowl species. The results indicate that these antigen detection tests could be used for preliminary investigations of H5N 1 outbreaks as a low-cost, simple flock test in sick and dead birds for the rapid detection of H5N1 infection. However, the relatively low sensitivity of the tests as individual bird tests means that they should be used on optimal clinical specimens from diseased birds, testing birds on a flock basis, or testing samples as close to the onset of disease as possible before viral titers diminish. They should be followed up by confirmatory tests, such as reverse transcription polymerase chain reaction or viral culture, wherever possible but could assist in facilitating rapid investigations and control interventions.

Characterization of class I Newcastle disease virus isolates from Hong Kong live bird markets and detection using real-time reverse transcription-PCR.

Newcastle disease viruses isolated from Hong Kong live bird markets (LBMs) were not detected by a USDA-validated matrix gene real-time reverse transcription-PCR (RT-PCR) assay. Based upon phylogenetic analysis of the fusion gene, these viruses were related to lentogenic class I viruses found in U.S. LBMs and wild waterfowl. An alternative real-time RT-PCR assay which complements the matrix gene assay was developed to efficiently detect class I viruses.