The tumour-promoting receptor tyrosine kinase, EphB4, regulates expression of integrin-ß8 in prostate cancer cells.

BACKGROUND: The EphB4 receptor tyrosine kinase is overexpressed in many cancers including prostate cancer. The molecular mechanisms by which this ephrin receptor influences cancer progression are complex as there are tumor-promoting ligand-independent mechanisms in place as well as ligand-dependent tumor suppressive pathways. METHODS: We employed transient knockdown of EPHB4 in prostate cancer cells, coupled with gene microarray analysis, to identify genes that were regulated by EPHB4 and may represent linked tumor-promoting factors. We validated target genes using qRT-PCR and employed functional assays to determine their role in prostate cancer migration and invasion. RESULTS: We discovered that over 500 genes were deregulated upon EPHB4 siRNA knockdown, with integrin ß8 (ITGB8) being the top hit (29-fold down-regulated compared to negative non-silencing siRNA). Gene ontology analysis found that the process of cell adhesion was highly deregulated and two other integrin genes, ITGA3 and ITGA10, were also differentially expressed. In parallel, we also discovered that over-expression of EPHB4 led to a concomitant increase in ITGB8 expression. In silico analysis of a prostate cancer progression microarray publically available in the Oncomine database showed that both EPHB4 and ITGB8 are highly expressed in prostatic intraepithelial neoplasia, the precursor to prostate cancer. Knockdown of ITGB8 in PC-3 and 22Rv1 prostate cancer cells in vitro resulted in significant reduction of cell migration and invasion. CONCLUSIONS: These results reveal that EphB4 regulates integrin ß8 expression and that integrin ß8 plays a hitherto unrecognized role in the motility of prostate cancer cells and thus targeting integrin ß8 may be a new treatment strategy for prostate cancer.

Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4.

EphB4 is a membrane-bound receptor tyrosine kinase (RTK) commonly over-produced by many epithelial cancers but with low to no expression in most normal adult tissues. EphB4 over-production promotes ligand-independent signaling pathways that increase cancer cell viability and stimulate migration and invasion. Several studies have shown that normal ligand-dependent signaling is tumour suppressive and therefore novel therapeutics which block the tumour promoting ligand-independent signaling and/or stimulate tumour suppressive ligand-dependent signaling will find application in the treatment of cancer. An EphB4-specific polyclonal antibody, targeting a region of 200 amino acids in the extracellular portion of EphB4, showed potent in vitro anti-cancer effects measured by an increase in apoptosis and a decrease in anchorage independent growth. Peptide exclusion was used to identify the epitope targeted by this antibody within the cysteine-rich region of the EphB4 protein, a sequence defined as a potential ligand interacting interface. Addition of antibody to cancer cells resulted in phosphorylation and subsequent degradation of the EphB4 protein, suggesting a mechanism that is ligand mimetic and tumour suppressive. A monoclonal antibody which specifically targets this identified extracellular epitope of EphB4 significantly reduced breast cancer xenograft growth in vivo confirming that EphB4 is a useful target for ligand-mimicking antibody-based anti-cancer therapies.

Epidermolysis bullosa pruriginosa showing good response to low-dose thalidomide - a report of two cases.

Epidermolysis bullosa pruriginosa is a rare distinctive variant of dystrophic epidermolysis bullosa characterized by intense pruritus, lichenified plaques in linear distribution, and anonychia. It is a difficult condition to treat and causes a great deal of distress. The present authors report two cases showing good response to low-dose thalidomide, with clinical and symptomatic improvement. The exact mechanism of action is not yet clear.

Intestinal infection with Trichinella spiralis induces distinct, regional immune responses.

The aim of this study was to evaluate differences between the small and large intestines (SI and LI) with regard to colonization and immunity during infection with Trichinella spiralis. In orally infected C57BL/6 mice, the gender ratios of worms differed among the SI, cecum, and LI. Mucosal mastocytosis developed in the SI but not in the LI, consistent with reduced IL-9 and IL-13 production by explants from the LI. Despite these differences, worms were cleared at the same rate from both sites. Furthermore, IL-10 production was reduced in the LI, yet it was instrumental in limiting local inflammation. Finally, passive immunization of rat pups with tyvelose-specific antibodies effectively cleared fist-stage larvae from all intestinal regions. We conclude that despite regional differences in immune responsiveness and colonization, immune mechanisms that clear T. spiralis operate effectively throughout the intestinal tract.

Comparative analysis of peptidylarginine deiminase-2 expression in canine, feline and human mammary tumours.

The peptidylarginine deiminase (PAD) enzyme family converts arginine residues in proteins to citrulline. In the canine mammary gland, PAD2 expression is first detected in epithelial cells in oestrus and becomes more widely expressed during dioestrus. PAD2 appears to modify nuclear histones, suggesting a role for the enzyme in chromatin remodelling and gene regulation. Recent evidence suggests that PAD2 plays a role in gene regulation in primary human breast epithelial cells. PAD2 may therefore be involved in gene regulation as it relates to mammary development, the oestrus cycle and potentially to neoplasia. The aim of the present study was to determine whether PAD2 expression was increased or decreased in mammary carcinoma compared with normal mammary tissue. A human mammary tissue microarray and archival surgical biopsy tissues from canine and feline mammary tumours were used to demonstrate differential expression of PAD2 in mammary carcinoma that appeared to be consistent across species. Normal human and canine mammary epithelium showed strong cytoplasmic and nuclear expression of PAD2, but there was reduced PAD2 expression in mammary carcinomas from both species. Feline mammary carcinomas had complete loss of nuclear PAD2 expression. Loss of nuclear PAD2 expression may therefore represent a marker of progression towards more aggressive neoplasia.

Clinicopathologic characterization of naturally occurring diabetes mellitus in vervet monkeys.

Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasting hyperglycemia, and it can be of either polygenic or monogenic origin. Animal models have played an important role in elucidating the pathophysiology of the polygenic Type 1 and type 2 DM forms; however, useful animal models of the monogenic forms do not exist. The authors describe 4 cases of naturally occurring DM in vervet monkeys (Chlorocebus aethiops sabaeus), 1 of which has clinicopathologic findings consistent with type 2 DM, including persistent hyperglycemia, hypertriglyceridemia, islet amyloidosis, and reduced islet insulin immunostaining. In contrast, the 3 remaining animals have clinicopathologic similarities to a monogenic form of the disease, including a lack of islet amyloidosis and hypertriglyceridemia, as well as normal islet insulin immunostaining. In addition, pedigree analysis conducted on one of these animals is consistent with either an autosomal dominant or mitochondrial inheritance pattern, which supports a monogenic form of DM. The authors thus hypothesize that a naturally occurring monogenic form of diabetes may occur in vervet monkeys, making them a potential animal model for future studies.

Response of the potential of a gold electrode to elastic strain.

We describe the measurement of the response, sigma, of the potential of a metal electrode to elastic strain under open circuit conditions. The experimental response exhibits a frequency dependence due to Faraday loss currents, which become negligible beyond 30 Hz. For a (111)-textured gold film the experimental value at higher frequency, sigma = -1.83 V, compares well with the intrinsic value of Au(111) predicted by recent ab initio computation.

Influence of an oil soluble inhibitor on microbiologically influenced corrosion in a diesel transporting pipeline.

Microbial degradation of the oil soluble corrosion inhibitor (OSCI) Baker NC 351 contributed to a decrease in inhibitor efficiency. Corrosion inhibition efficiency was studied by the rotating cage and flow loop methods. The nature of the biodegradation of the corrosion inhibitor was also analysed using Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry. The influence of bacterial activity on the degradation of the corrosion inhibitor and its influence on corrosion of API 5LX were evaluated using a weight loss technique and impedance studies. Serratia marcescens ACE2 and Bacillus cereus ACE4 can degrade aromatic and aliphatic hydrocarbons present in the corrosion inhibitor. The present study also discusses the demerits of the oil soluble corrosion inhibitors used in petroleum product pipeline.

Biocidal effects of photocatalytic semiconductor TiO2.

Photocatalytic action of the commercial TiO(2) was the subject of study on the destruction of the microbes within the biofilms. The TiO(2) powder was characterized by X-ray diffraction (XRD) for identifying its type and the particle size was determined. The biofilm was allowed to form over TiO(2) coatings over glass slides irradiated with polychromatic light for different time durations and distances. It indicates that a five-fold decrease in bacterial count due to the formation of H(2)O(2) at TiO(2)/biofilm interface. The formation of H(2)O(2) at the TiO(2)/biofilm interface is estimated and it does not destroy the entire bacterial population within the biofilm. Bacterial killing effect is supported by FT-IR analysis.

Control of metallic corrosion through microbiological route.

Involvement of biofilm or microorganisms in corrosion processes is widely acknowledged. Although majority of the studies on microbiologically induced corrosion (MIC) have concentrated on aerobic/anaerobic bacteria. There are numerous aerobic bacteria, which could hinder the corrosion process. The microbiologically produced exopolymers provide the structural frame work for the biofilm. These polymers combine with dissolved metal ions and form organometallic complexes. Generally heterotrophic bacteria contribute to three major processes: (i) synthesis of polymers (ii) accumulation of reserve materials like poly-beta-hydroxy butrate (iii) production of high molecular weight extracellular polysaccharides. Poly-beta-hydroxy butyrate is a polymer of D(-)beta-hydroxy butrate and has a molecular weight between 60,000 and 2,50,000. Some extracellular polymers also have higher molecular weights. It seems that higher molecular weight polymer acts as biocoating. In the present review, role of biochemistry on corrosion inhibition and possibilities of corrosion inhibition by various microbes are discussed. The role of bacteria on current demand during cathodic protection is also debated. In addition, some of the significant contributions made by CECRI in this promising area are highlighted.

Microbiologically influenced corrosion in petroleum product pipelines--a review.

Microbiologically influenced corrosion is responsible for most of the internal corrosion problems in oil transportation pipelines and storage tanks. One problematic area in treating gas lines is the occurrence of the stratification of water in the line. Under these conditions, corrosion inhibitors do not come into contact properly and oil and inhibitors undergo degradation. The role of bacteria on oil degradation, the consequences of oil degradation in fuel systems and its influence on corrosion have been explained in detail. Besides, factors influencing on degradation of oil and corrosion inhibitors have also been discussed. Mechanism of microbiologically influenced corrosion in oil pipeline has been explained. Many of the misapplication of biocides/inhibitors occur mainly because the characteristics of biocides/inhibitors are not considered before use in pipeline industry. List of biocides and monitoring programme have been collected from literature and presented.