Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases

The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies.     

Effect of detection heterogeneity in occupancy‐detection models: an experimental test of time‐to‐first‐detection methods

Imperfect detection can bias estimates of site occupancy in ecological surveys but can be corrected by estimating detection probability. Time‐to‐first‐detection (TTD) occupancy models have been proposed as a cost–effective survey method that allows detection probability to be estimated from single site visits. Nevertheless, few studies have validated the performance of occupancy‐detection models by creating a situation where occupancy is known, and model outputs can be compared with the truth. We tested the performance of TTD occupancy models in the face of detection heterogeneity using an experiment based on standard survey methods to monitor koala Phascolarctos cinereus populations in Australia. Known numbers of koala faecal pellets were placed under trees, and observers, uninformed as to which trees had pellets under them, carried out a TTD survey. We fitted five TTD occupancy models to the survey data, each making different assumptions about detectability, to evaluate how well each estimated the true occupancy status. Relative to the truth, all five models produced strongly biased estimates, overestimating detection probability and underestimating the number of occupied trees. Despite this, goodness‐of‐fit tests indicated that some models fitted the data well, with no evidence of model misfit. Hence, TTD occupancy models that appear to perform well with respect to the available data may be performing poorly. The reason for poor model performance was unaccounted for heterogeneity in detection probability, which is known to bias occupancy‐detection models. This poses a problem because unaccounted for heterogeneity could not be detected using goodness‐of‐fit tests and was only revealed because we knew the experimentally determined outcome. A challenge for occupancy‐detection models is to find ways to identify and mitigate the impacts of unobserved heterogeneity, which could unknowingly bias many models.     

Invertebrate Sampling in the Substratum of an Experimental Recirculating Stream

In order to determine the efficacy of sampling benthic invertebrates to a depth of 100 mm as compared with 200 mm, the gravel substratum of an experimental recirculating stream was sampled to both depths. Except for 6 taxa which were significantly more numerous in the shallower samplers, there was no significant difference between the densities determined from the two depths.     

Completeness of NOEs in protein structures: A statistical analysis of NMR data

The completeness of experimentally observed NOE restraints of a set of 97 NMR protein structures deposited in the PDB has been assessed. Completeness is defined as the ratio of the number of experimentally observed NOEs and the number of 'expected NOEs'. A practical definition of 'expected NOEs' based on inter-proton distances in the structures up to a given cut-off distance is proposed. The average completeness for the set of 97 structures is 68, 48, and 26% up to 3, 4, and 5 Å cut-off distances, respectively. For recent state-of-the-art structures these numbers are approximately 90, 75, and 45%. Almost 20% of the observed NOEs are between atoms that are further than 5 Å apart in the final structures. The completeness is independent of the relative surface accessibility and does not depend strongly on residue type, secondary structure or local precision, although the number of observed NOEs in these classes varies considerably. The completeness of NOE restraints is a useful quality criterion in the course of structure refinement. The completeness per residue is more informative than the number of NOEs per residue, which makes it a useful tool to assess the quality of the NMR data set in relation to the resulting structures.     

Oligodendroglial Response to the Immune Cytokine Interferon Gamma

In the human demyelinating disorder multiple sclerosis, and its animal model experimental allergic encephalomyelitis, there is a breakdown of the blood-brain barrier and an infiltration of immune cells into the CNS. Infiltrating T lymphocytes and macrophages are believed to be key mediators of the disease process. Considerable circumstantial and experimental evidence has suggested that the pleiotropic cytokine interferon gamma (IFN-), which is exclusively expressed by T cells and natural killer cells, is a deleterious component of the immune response in these disorders. When experimentally introduced into the CNS IFN- promotes many of the pathological changes that occur in immune-mediated demyelinating disorders. In vitro, this cytokine elicits a number of effects on oligodendrocytes, including cell death. The harmful actions of IFN- on CNS myelin are likely mediated through direct effects on the myelinating cells, as well as through the activation of macrophages and microglia. In this review we summarize relevant studies concerning the action of IFN- in demyelinating disorders and discuss possible mechanisms for the observed effects.     

Millimeter wave-induced suppression of B16 F10 melanoma growth in mice: involvement of endogenous opioids

Millimeter wave treatment (MMWT) is widely used in Eastern European countries, but is virtually unknown in Western medicine. Among reported MMWT effects is suppression of tumor growth. The main aim of the present "blind" and dosimetrically controlled experiments was to evaluate quantitatively the ability of MMWT to influence tumor growth and to assess whether endogenous opioids are involved. The murine experimental model of B16 F10 melanoma subcutaneous growth was used. MMWT characteristics were: frequency, 61.22 GHz; average incident power density, 13.3 x 10(-3) W/cm2; single exposure duration, 15 min; and exposure area, nose. Naloxone (1 mg/kg, intraperitoneally, 30 min prior to MMWT) was used as a nonspecific blocker of opioid receptors. Five daily MMW exposures, if applied starting at the fifth day following B16 melanoma cell injection, suppressed subcutaneous tumor growth. Pretreatment with naloxone completely abolished the MMWT-induced suppression of melanoma growth. The same course of 5 MMW treatments, if started on day 1 or day 10 following tumor inoculations, was ineffective. We concluded that MMWT has an anticancer therapeutic potential and that endogenous opioids are involved in MMWT-induced suppression of melanoma growth in mice. However, appropriate indications and contraindications have to be developed experimentally before recommending MMWT for clinical usage.     

Optimization of bovine serum albumin sorption and recovery by hydrogels

Aqueous two-phase systems are composed of aqueous solutions of either two water-soluble polymers, usually polyethylene glycol (PEG) and dextran (Dx), or a polymer and a salt, usually PEG and phosphate or sulfate. Partitioning of proteins in such systems provides a powerful method for separating and purifying mixtures of biomolecules by extraction. If one of the phase forming polymers is a crosslinked gel, then the solution-controlled gel sorption may be considered as a modification of aqueous two-phase extraction. Since PEG/dextran systems are widely used in aqueous two-phase extraction and dextran gels (Sephadex) are common chromatographic media, we choose a PEG/dextran gel system as a model system in this study. The partitioning behavior of pure bovine serum albumin (BSA) in PEG/dextran gel systems is investigated to see the effects of variations in PEG and NaCl concentrations on the partition coefficient K. By making use of the Box-Wilson experimental design, K is shown to be maximized at 9.8 (%, w/w) PEG and 0.2 M NaCl concentrations, respectively, as 182.     

Local co-adaptation leading to a geographical mosaic of coevolution in a social parasite system

The geographical mosaic theory of coevolution predicts differences in the advance or trajectory of the coevolutionary process between local communities due to their composition and the strength of ecological selection pressures through competition and resource availability. In this study, we investigate local co-adaptation in different populations of a social parasite. We conducted cross-fostering experiments to test for interpopulational differences in raiding efficiency between various populations of a slave-making ant and the defence abilities of local hosts. Here, we demonstrate that the success of raids strongly depends on the combination of populations of the parasite Harpagoxenus sublaevis and its host Leptothorax acervorum, indicating very localized coevolution. We found no absolute differences between slave-maker populations; the outcome of an encounter depended more on whether the two opponents occur in sympatry or allopatry. Furthermore, this study supports the results of our earlier work, that the unparasitized English L. acervorum population is most aggressive against the parasite.     

The devil in the details of life-history evolution: Instability and reversal of genetic correlations during selection on<Emphasis Type="Italic">Drosophila</Emphasis> development

The evolutionary relationships between three major components of Darwinian fitness, development rate, growth rate and preadult survival, were estimated using a comparison of 55 distinct populations ofDrosophila melanogaster variously selected for age-specific fertility, environmental-stress tolerance and accelerated development. Development rate displayed a strong net negative evolutionary correlation with weight at eclosion across all selection treatments, consistent with the existence of a size-versus-time tradeoff between these characters. However, within the data set, the magnitude of the evolutionary correlation depended upon the particular selection treatments contrasted. A previously proposed tradeoff between preadult viability and growth rate was apparent only under weak selection for juvenile fitness components. Direct selection for rapid development led to sharp reductions in both growth rates and viability. These data add to the mounting results from experimental evolution that illustrate the sensitivity of evolutionary correlations to (i) genotype-by-environment (G X E) interaction, (ii) complex functional-trait interactions, and (iii) character definition. Instability, disappearance and reversal of patterns of genetic covariation often occur over short evolutionary time frames and as the direct product of selection, rather than some stochastic process. We suggest that the functional architecture of fitness is a rapidly evolving matrix with reticulate properties, a matrix that we understand only poorly.     

High-throughput optimization by statistical designs: example with rat liver slices cryopreservation

The purpose of this study was to optimize cryopreservation conditions of rat liver slices in a high-throughput format, with focus on reproducibility. A statistical design of 32 experiments was performed and intracellular lactate dehydrogenase (LDHi) activity and antipyrine (AP) metabolism were evaluated as biomarkers. At freezing, modified University of Wisconsin solution was better than Williams'E medium, and pure dimethyl sulfoxide was better than a cryoprotectant mixture. The best cryoprotectant concentrations were 10% for LDHi and 20% for AP metabolism. Fetal calf serum could be used at 50 or 80%, and incubation of slices with the cryoprotectant could last 10 or 20 min. At thawing, 42 degrees C was better than 22 degrees C. After thawing, 1h was better than 3h of preculture. Cryopreservation increased the interslice variability of the biomarkers. After cryopreservation, LDHi and AP metabolism levels were up to 84 and 80% of fresh values. However, these high levels were not reproducibly achieved. Two factors involved in the day-to-day variability of LDHi were identified: the incubation time with the cryoprotectant and the preculture time. In conclusion, the statistical design was very efficient to quickly determine optimized conditions by simultaneously measuring the role of numerous factors. The cryopreservation procedure developed appears suitable for qualitative metabolic profiling studies.