Histone-deacetylase inhibitors for the treatment of cancer

Histone deacetylase inhibitors (HDACi) are a promising new class of chemotherapeutic drug currently in early phase clinical trials. A large number of structurally diverse HDACi have been purified or synthesised that mostly inhibit the activity of all eleven class I and II HDACs. While these agents demonstrate many features required for anti-cancer activity such as low toxicity against normal cells and an ability to inhibit tumor cell growth and survival at nanomolar concentrations, their mechanisms of action are largely unknown. Initially, a model was proposed whereby HDACi-mediated transactivation of a specific gene or set of genes was responsible for the inhibition of cell cycle progression or induction of apoptosis. Given that HDACs can regulate the activity of a number of nonhistone proteins and that histone acetylation is important for events such as DNA replication and mitosis that do not directly involve gene transcription, it appears that the initial mechanistic model for HDACi may have been too simple. Herein, we provide an update on the transcription-dependent and - independent events that may be important for the anti-tumor activities of HDACi and discuss the use of these compounds in combination with other chemotherapeutic drugs.

Wrapping things up about virus RNA replication

All single-stranded 'positive-sense' RNA viruses that infect mammalian, insect or plant cells rearrange internal cellular membranes to provide an environment facilitating virus replication. A striking feature of these unique membrane structures is the induction of 70-100 nm vesicles (either free within the cytoplasm, associated with other induced vesicles or bound within a surrounding membrane) harbouring the viral replication complex (RC). Although similar in appearance, the cellular composition of these vesicles appears to vary for different viruses, implying different organelle origins for the intracellular sites of viral RNA replication. Genetic analysis has revealed that induction of these membrane structures can be attributed to a particular viral gene product, usually a non-structural protein. This review will highlight our current knowledge of the formation and composition of virus RCs and describe some of the similarities and differences in RNA-membrane interactions observed between the virus families Flaviviridae and Picornaviridae.

Functional dissection of the Suppressor of UnderReplication protein of Drosophila melanogaster: identification of domains influencing chromosome binding and DNA replication

The Suppressor of UnderReplication (SuUR) gene controls the DNA underreplication in intercalary and pericentric heterochromatin of Drosophila melanogaster salivary gland polytene chromosomes. In the present work, we investigate the functional importance of different regions of the SUUR protein by expressing truncations of the protein in an UAS-GAL4 system. We find that SUUR has at least two separate chromosome-binding regions that are able to recognize intercalary and pericentric heterochromatin specifically. The C-terminal part controls DNA underreplication in intercalary heterochromatin and partially in pericentric heterochromatin regions. The C-terminal half of SUUR suppresses endoreplication when ectopically expressed in the salivary gland. Ectopic expression of the N-terminal fragments of SUUR depletes endogenous SUUR from polytene chromosomes, causes the SuUR(-) stopphenotype and induces specific swellings in heterochromatin.

Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis

The mechanisms for progressive fibrosis and exacerbation by steatosis in patients with chronic hepatitis C (HCV) are still unknown. We hypothesized that proliferative blockade in HCV-infected and steatotic hepatocytes results in the default activation of hepatic progenitor cells (HPC), capable of differentiating into both biliary and hepatocyte lineages, and that the resultant ductular reaction promotes portal fibrosis. To study this concept, 115 liver biopsy specimens from subjects with HCV were scored for steatosis, inflammation, and fibrosis. Biliary epithelium and HPC were decorated by cytokeratin 7 immunoperoxidase, and the replicative state of hepatocytes was assessed by p21 and Ki-67 immunohistochemistry. A ductular reaction at the portal interface was common. There was a highly significant correlation between the area of ductular reaction and fibrosis stage (r = 0.453, P < .0001), which remained independently associated after multivariate analysis. HPC numbers also correlated with fibrosis (r = 0.544, P < .0001) and the ductular area (r = 0.624, P < .0001). Moreover, steatosis correlated with greater HPC proliferation (r = 0.372, P = .0004) and ductular reaction (r = 0.374, P < .0001) but was not an obligate feature. Impaired hepatocyte replication by p21 expression was independently associated with HPC expansion (P = .002) and increased with the body mass index (P < .001) and lobular inflammation (P = .005). In conclusion, the strong correlation between portal fibrosis and a periportal ductular reaction with HPC expansion, the exacerbation by steatosis, and the associations with impaired hepatocyte replication suggest that an altered regeneration pathway drives the ductular reaction. We believe this triggers fibrosis at the portal tract interface. This may be a stereotyped response of importance in other chronic liver diseases.

Diverse members of the Ralstonia solanacearum species complex cause bacterial wilts of banana

The bacterial wilts of banana known as Moko disease, Bugtok disease and blood disease are caused by members of the R. solanacearum species complex. R. solanacearum is a heterogeneous species which has been divided into 4 genetic groups known as phylotypes. Within the R. solanacearum species complex, strains that cause Moko and Bugtok diseases belong to phylotype II. The blood disease bacterium, the cause of blood disease, belongs to phylotype IV. This study employs phylogenetic analysis of partial endoglucanase gene sequences to further assess the evolutionary relationships between strains of R. solanacearum causing Moko disease and Bugtok disease and the relationship of the blood disease bacterium to other R. solanacearum strains within phylotype IV of the R. solanacearum species complex. These analyses showed that R. solanacearum Moko disease-causing strains are polyphyletic, forming four related, but distinct, clusters of strains. One of these clusters is a previously unrecognised group of R. solanacearum Moko disease-causing strains. It was also found that R. solanacearum strains that cause Bugtok disease are indistinguishable from strains causing Moko disease in the Philippines. Phylogenetic analysis of partial endoglucanase gene sequences of the strains of the blood disease confirms a close relationship of these strains to R. solanacearum strains within phylotype IV of the R. solanacearum species complex.

Replication of Heliothis virescens ascovirus in insect cell lines

Ascoviruses (AVs) infect larvae of various insect pests belonging to the family Noctuidae. The result of AV infection in the hosts is cleavage of infected cells into vesicles, a unique feature of AV infection. Since insect cell lines facilitate the study of virus life cycles, attempts were made to analyze Heliothis virescens AV (HvAV3e) infection in several cell lines and compare cell pathology to larval infection. In this study, replication and cytopathological effects of HvAV3e on four different cell lines were investigated. HvAV3e replication was confirmed in three noctuid cell lines from Spodoptera frugiperda (Sf9) and Helicoverpa zea (BCIRL-Hz-AM1 and FB33). However, the virus did not replicate in the non-noctuid insect cell line from Pieris rapae (Pieridae). Despite replication of the virus in the three permissive cell lines, the cytopathological effects of the virus were significantly different from that of larval infection.

Short-term hyperthermic treatment of Penaeus monodon increases expression of heat shock protein 70 (HSP70) and reduces replication of gill associated virus (GAV)

Disease is the result of interactions amongst pathogens, the environment and host organisms. To investigate the effect of stress on Penaeus monodon, juvenile shrimp were given short term exposure to hypoxic, hyperthermic and osmotic stress twice over a 1-week period and estimates of total haemocyte count (THC), heat shock protein (HSP) 70 expression and load of gill associated virus (GAV) were determined at different time points. While no significant differences were observed in survival and THC between stressed and control shrimp (P>0.05), HSP 70 expression and GAV load changed significantly (P

A DHA14 drug efflux gene from Xanthomonas albilineans confers high-level albicidin antibiotic resistance in Escherichia coli

Aims: Identification of a gene for self-protection from the antibiotic-producing plant pathogen Xanthomonas albilineans, and functional testing by heterologous expression. Methods and Results: Albicidin antibiotics and phytotoxins are potent inhibitors of prokaryote DNA replication. A resistance gene (albF) isolated by shotgun cloning from the X. albilineans albicidin-biosynthesis region encodes a protein with typical features of DHA14 drug efflux pumps. Low-level expression of albF in Escherichia coli increased the MIC of albicidin 3000-fold, without affecting tsx-mediated albicidin uptake into the periplasm or resistance to other tested antibiotics. Bioinformatic analysis indicates more similarity to proteins involved in self-protection in polyketide-antibiotic-producing actinomycetes than to multi-drug resistance pumps in other Gram-negative bacteria. A complex promoter region may co-regulate albF with genes for hydrolases likely to be involved in albicidin activation or self-protection. Conclusions: AlbF is the first apparent single-component antibiotic-specific efflux pump from a Gram-negative antibiotic producer. It shows extraordinary efficiency as measured by resistance level conferred upon heterologous expression. Significance and Impact of the Study: Development of the clinical potential of albicidins as potent bactericidial antibiotics against diverse bacteria has been limited because of low yields in culture. Expression of albF with recently described albicidin-biosynthesis genes may enable large-scale production. Because albicidins are X. albilineans pathogenicity factors, interference with AlbF function is also an opportunity for control of the associated plant disease.

A diverse suite of spiroacetals, including a novel branched representative, is released by female Bactrocera tryoni (Queensland fruit fly)

A remarkably diverse suite of spiroacetals including a novel member of the rare, branched chain class has been identified in the glandular secretions of Bactrocera tryoni, the most destructive horticultural pest in Australia.

Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese

Objective: To test the association of interleukin 1 ( IL1) gene family members with ankylosing spondylitis ( AS), previously reported in Europid subjects, in an ethnically remote population. Methods: 200 Taiwanese Chinese AS patients and 200 ethnically matched healthy controls were genotyped for five single nucleotide polymorphisms ( SNPs) and the IL1RN. VNTR, markers previously associated with AS. Allele, genotype, and haplotype frequencies were compared between cases and controls. Results: Association of alleles and genotypes of the markers IL1F10.3, IL1RN. 4, and IL1RN. VNTR was observed with AS ( p < 0.05). Haplotypes of pairs of these markers and of the markers IL1RN.6/1 and IL1RN.6/2 were also significantly associated with AS. The strongest associations observed were with the marker IL1RN. 4, and with the two-marker haplotype IL1RN.4-IL1RN.VNTR ( both p = 0.004). Strong linkage disequilibrium was observed between all marker pairs except those involving IL1B-511 ( D' 0.4 to 0.9, p < 0.01). Conclusions: The IL1 gene cluster is associated with AS in Taiwanese Chinese. This finding provides strong statistical support that the previously observed association of this gene cluster with AS is a true positive finding.

Climatic regulation of seed dormancy and emergence of diverse Malva parviflora populations from a Mediterranean-type environment

Malva parviflora L. (Malvaceae) is rapidly becoming a serious weed of Australian farming systems. An understanding of the variability of its seed behaviour is required to enable the development of integrated weed management strategies. Mature M. parviflora seeds were collected from four diverse locations in the Mediterranean-type climatic agricultural region of Western Australia. All of the seeds exhibited physical dormancy at collection; manual scarification or a period of fluctuating summer temperatures (50/20 degrees C or natural) were required to release dormancy. When scarified and germinated soon (1 month) after collection, the majority of seeds were able to germinate over a wide range of temperatures (5-37 degrees C) and had no light requirement. Germination was slower for seeds stored for 2 months than seeds stored for 2 years, suggesting the presence of shallow physiological dormancy. Seed populations from regions with similar annual rainfall exhibited similar dormancy release patterns; seeds from areas of low rainfall (337-344mm) were more responsive to fluctuating temperatures, releasing physical dormancy earlier than those from areas of high rainfall (436-444mm). After 36 months, maximum seedling emergence from soil in the field was 60%, with buried seeds producing 13-34% greater emergence than seeds on the surface. Scanning electron microscopy of the seed coat revealed structural differences in the chalazal region of permeable and impermeable seeds, suggesting the importance of this region in physical dormancy breakdown of M. parviflora seeds. The influence of rainfall during plant growth in determining dormancy release, and hence, germination and emergence timing, must be considered when developing management strategies for M. parviflora.

Neogenin: A multi-functional receptor regulating diverse developmental processes

Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-l-Neogenin interactions result in a chernoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. Evidence is now accumulating that Neogenin is a multi-functional receptor regulating many diverse developmental processes, including neural tube and mammary gland formation, myogenesis and angiogenesis. Little is known of the function of Neogenin in the adult, however, a novel role in the regulation of iron homeostasis is now emerging. While the signal transduction pathways activated by Neogenin are poorly understood, it is clear that the functional outcome of Neogenin activation, at least in the embryo, depends on both the developmental context as well as the nature of the ligand. (c) 2006 Elsevier Ltd. All rights reserved.