Controlling cancer through the autotaxin-lysophosphatidic acid receptor axis

LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX-LPA signalling axis an emerging target for cancer therapy.     

Conditional deletion of Dicer in vascular smooth muscle cells leads to the developmental delay and embryonic mortality

Dicer is a RNAase III enzyme that cleaves double stranded RNA and generates small interfering RNA (siRNA) and microRNA (miRNA). The goal of this study is to examine the role of Dicer and miRNAs in vascular smooth muscle cells (VSMCs). We deleted Dicer in VSMCs of mice, which caused a developmental delay that manifested as early as embryonic day E12.5, leading to embryonic death between E14.5 and E15.5 due to extensive hemorrhage in the liver, brain, and skin. Dicer KO embryos showed dilated blood vessels and a disarray of vascular architecture between E14.5 and E15.5. VSMC proliferation was significantly inhibited in Dicer KOs. The expression of VSMC marker genes were significantly downregulated in Dicer cKO embryos. The vascular structure of the yolk sac and embryo in Dicer KOs was lost to an extent that no blood vessels could be identified after E15.5. Expression of most miRNAs examined was compromised in VSMCs of Dicer KO. Our results indicate that Dicer is required for vascular development and regulates vascular remodeling by modulating VSMC proliferation and differentiation.     

Frequent simian foamy virus infection in persons occupationally exposed to nonhuman primates

The recognition that AIDS originated as a zoonosis heightens public health concerns associated with human infection by simian retroviruses endemic in nonhuman primates (NHPs). These retroviruses include simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus (STLV), simian type D retrovirus (SRV), and simian foamy virus (SFV). Although occasional infection with SIV, SRV, or SFV in persons occupationally exposed to NHPs has been reported, the characteristics and significance of these zoonotic infections are not fully defined. Surveillance for simian retroviruses at three research centers and two zoos identified no SIV, SRV, or STLV infection in 187 participants. However, 10 of 187 persons (5.3%) tested positive for SFV antibodies by Western blot (WB) analysis. Eight of the 10 were males, and 3 of the 10 worked at zoos. SFV integrase gene (int) and gag sequences were PCR amplified from the peripheral blood lymphocytes available from 9 of the 10 persons. Phylogenetic analysis showed SFV infection originating from chimpanzees (n = 8) and baboons (n = 1). SFV seropositivity for periods of 8 to 26 years (median, 22 years) was documented for six workers for whom archived serum samples were available, demonstrating long-standing SFV infection. All 10 persons reported general good health, and secondary transmission of SFV was not observed in three wives available for WB and PCR testing. Additional phylogenetic analysis of int and gag sequences provided the first direct evidence identifying the source chimpanzees of the SFV infection in two workers. This study documents more frequent infection with SFV than with other simian retroviruses in persons working with NHPs and provides important information on the natural history and species origin of these infections. Our data highlight the importance of studies to better define the public health implications of zoonotic SFV infections.     

Structural and Psycho-Social Limits to Climate Change Adaptation in the Great Barrier Reef Region

Adaptation, as a strategy to respond to climate change, has limits: there are conditions under which adaptation strategies fail to alleviate impacts from climate change. Research has primarily focused on identifying absolute bio-physical limits. This paper contributes empirical insight to an emerging literature on the social limits to adaptation. Such limits arise from the ways in which societies perceive, experience and respond to climate change. Using qualitative data from multi-stakeholder workshops and key-informant interviews with representatives of the fisheries and tourism sectors of the Great Barrier Reef region, we identify psycho-social and structural limits associated with key adaptation strategies, and examine how these are perceived as more or less absolute across levels of organisation. We find that actors experience social limits to adaptation when: i) the effort of pursuing a strategy exceeds the benefits of desired adaptation outcomes; ii) the particular strategy does not address the actual source of vulnerability, and; iii) the benefits derived from adaptation are undermined by external factors. We also find that social limits are not necessarily more absolute at higher levels of organisation: respondents perceived considerable opportunities to address some psycho-social limits at the national-international interface, while they considered some social limits at the local and regional levels to be effectively absolute.     

Truncated human LMP-1 triggers differentiation of C2C12 cells to an osteoblastic phenotype in vitro

LIM mineralization protein-1 （LMP-1） is a novel intracellular osteoinductive protein that has been shown to induce bone formation both in vitro and in viva. LMP-1 contains an N-terminal PDZ domain and three C-terminal LIM domains. In this study, we investigated whether a truncated form of human LMP-1 （hLMP-1 [t]）, lacking the three C-terminal LIM domains, triggers the differentiation of pluripotent myoblastic C2C12 cells to the osteoblast lineage. C2C12 cells were transiently transduced with AdS-hLMP-1 （t）-green fluorescent protein or viral vector control. The expression of hLMP-1 （t） RNA and the truncated protein were examined. The results showed that hLMP-1 （t） blocked myotube formation in C2C12 cultures and significantly enhanced the alkaline phosphatase （ALP） activity. In addition, the expressions of ALP, osteocalcin, and bone morphogenetic protein （BMP）-2 and BMP-7 genes were also increased. The induction of these key osteogenic markers suggests that hLMP- 1 （t） can trigger the pluripotent myoblastic C2C12 cells to differentiate into osteoblastic lineage, thus extending our previous observation that LMP-1 and LMP-1 （t） enhances the osteoblastic phenotype in cultures of cells already committed to the osteoblastic lineage. Therefore, C2C12 cells are an appropriate model system for the examination of LMP-1 induction of the osteoblastic phenotype and the study of mechanisms of LMP-1 action.     

ird1 is a Vps15 homologue important for antibacterial immune responses in Drosophila

The immune response-deficient 1 (ird1) gene was identified in a forward genetic screen as a novel regulator for the activation of Imd NFkappaB immune signalling pathway in Drosophila. ird1 animals are also more susceptible to Escherichia coli and Micrococcus luteus bacterial infection. ird1 encodes the Drosophila homologue of the Vps15/p150 serine/threonine kinase that regulates a class III phosphoinositide 3-kinase and is necessary for phagosome maturation and starvation-induced autophagy in yeast and mammalian cells. To gain insight into the role of ird1 in the immune response, we examine how amino acid starvation affects the immune signalling pathways in Drosophila. Starvation, in the absence of infection, leads to expression of antimicrobial peptide (AMP) genes and this response is dependent on ird1 and the Imd immune signalling pathway. Starvation, in addition to bacterial infection, suppresses the AMP response in wild-type animals and reduces the ability to survive M. luteus infection. Our results suggest that starvation and innate immune signalling may be intimately linked processes.     

Haplotypes in the urotensin II gene and urotensin II receptor gene are associated with insulin resistance and impaired glucose tolerance

We studied single nucleotide polymorphisms (SNPs) and haplotypes in the urotensin-II (UTS2) and urotensin-II receptor gene (UTS2R) in Hong Kong Chinese (224 hypertensive and 306 normotensive unrelated subjects) and their relation to hypertension and the metabolic syndrome. For UTS2, the GGT haplotype (-605G, 143G and 3836T) was associated with higher plasma level of U-II and insulin, and higher homeostasis model assessment of insulin resistance index and beta-cell function. For UTS2R, the AC haplotype (-11640A and -8515C) was associated with higher 2 h plasma glucose after a 75 g oral glucose load. Therefore, U-II and its receptor may play a role in insulin resistance.     

Management of strawberry grey mould using mixtures of biocontrol agents with different mechanisms of action

Experiments were conducted using combinations of commercially available biological control agents (BCAs) to control infection of detached strawberry leaves by Botrytis cinerea Pers.;Fr. Combinations were tested either as mixtures, or as sequential treatments before and after disease loading. Five BCAs were initially tested, giving a range of mechanisms of antagonism. Only three (Sentinel?, Serenade? and Trianum?) were effective in single agent experiments and were taken forward for combinatorial tests. Biocontrol efficacies, relative to the control, varied considerably among replicate trials, but all treatments involving Sentinel (BCA: Trichoderma atroviride P. Karsten LC52) and Trianum (BCA: Trichoderma harzianum Rifai T22) were very effective, either in sequential combination with other BCA or alone. Serenade (BCA: Bacillus subtilis (Ehrenberg) Cohn) was least effective, and sometimes did not result in any significant reduction in disease. Combinations of BCAs as mixtures resulted in less control (i.e., higher disease) than when the most effective BCA within the combination was applied alone, indicating possible antagonism between the BCAs. However, when two BCAs were applied sequentially about 48 h apart, there was no strong evidence for antagonism between the BCAs; this was also confirmed in an experiment using whole plants in controlled environment cabinets. We conclude that there was usually no benefit in applying two BCAs either together or sequentially, so in general we would not advise combinations as the method of choice. Thus, research is necessary to investigate possible interference among specific BCAs, since several BCAs may be applied simultaneously under field conditions to control several diseases.     

A Population-Based Epidemiologic Study of Helicobacter Pylori Infection and its Association with Systemic Inflammation

Background:  Infection with Helicobacter pylori is associated with a variety of non-gastrointestinal sequelae. These may be mediated by an increase in systemic inflammation. We assessed if serologic evidence of infection with H. pylori is associated with increased serum C-reactive protein (CRP) levels.
Methods:  The study design consisted of a randomly selected, cross-sectional population-based study of 2633 individuals phenotyped in 1991, of whom 2361 participants provided serum samples to permit measurement of H. pylori 's serologic status and CRP levels.
Results:  Male gender (odds ratio (OR): 1.65; 95% confidence interval (CI): 1.23–2.21), age (OR per year: 1.05; 95% CI: 1.04–1.06), height (OR per meter: 0.05; 95% CI: 0.01–0.24), current smoking habit (compared with never smokers, OR: 1.46; 95% CI: 1.13–1.88), and less affluent socioeconomic status were associated with increased odds of being seropositive for H. pylori . Helicobacter pylori infection was associated with increased risk of having an elevated serum CRP (above 3 mg/L) after adjustment for gender, age, height, smoking status, and socioeconomic status (OR: 1.32; 95% CI: 1.05–1.67). Similar associations were seen using a threshold for elevated serum CRP of greater than 1 mg/L.
Conclusions:  Our data suggest that infection with H. pylori is associated with increased systemic inflammation. This suggests one potential mechanism to explain the extra-gastrointestinal conditions associated with H. pylori infection.