Immunomodulation in Patients Receiving Systemic Anti- Cancer Therapy

The use of immunotherapy to treat cancer is a rapidly expanding field. Over the last ten years, the number of clinical trials of immunotherapy, both alone and in combination with other agents, including cytotoxic chemotherapy, has grown exponentially. While the use of immunotherapy has revolutionised the management of cancers such as melanoma, renal cell carcinoma and lung cancer, other diseases, including colorectal cancer, have fared less well. In going forward, an increased understanding of the mechanism of immunotherapy in cancer patients is a vital step in being able to exploit these drugs in cancers where clinical efficacy has previously been limited. Better understanding of immune responses in these patients may identify potential responders to novel immunotherapy. To this end, we developed and validated a panel of immune functional assays, which can be used in clinical trials to assess the immune response in peripheral blood. This panel can therefore be used to gather translational data from clinical trials of anti-cancer therapy. We used these assays to analyse the peripheral blood immune response in patients with metastatic colorectal cancer undergoing first-line chemotherapy, with reference to the neutrophil lymphocyte ratio (NLR). Analysis of samples from 29 patients revealed that, in patients with a high NLR prior to treatment, there was evidence of an attenuated immune response, with increased levels of certain immunosuppressive cytokines and depressed NK cell function. Over the course of treatment, we demonstrated that chemotherapy could partially reverse this phenomenon, potentially enhancing anti-tumour immunity. Similarly, we interrogated blood samples of patients with metastatic melanoma receiving immune therapy with checkpoint inhibitors. Here, we observed evidence of a more active immune response, highlighting the differences between the two patient groups (those with colorectal cancer and those with melanoma). In conclusion, we confirmed that our functional immune assay panel can be used effectively in different groups of cancer patients undergoing a variety of treatments, with the aim of an improved understanding of the immune system in cancer, response to therapy and how this may be exploited in the development of novel treatment strategies

The Effects of Nitrogen Fertilisation on Plant Species Richness in European Permanent Grasslands: A Systematic Review and Meta-Analysis

Nitrogen fertilisation is a common form of agricultural intensification, aimed at increasing biomass, which can affect plant species diversity and ecosystem functioning. Using a systematic review and meta-analysis of nitrogen fertilisation studies in European permanent grasslands, we asked: (i) what relationship form exists between nitrogen application rate and change in plant diversity, compared to zero fertilisation controls; and (ii) how grassland, management and study characteristics affect this relationship. Meta-analysis of 34 control-treatment effects from 14 studies conducted across nine European countries revealed a negative linear relationship between nitrogen fertilisation rate and change in plant species richness, equivalent to approximately 1.5 species/m(2) lost for every 100 Kg ha(-1) yr(-1) of nitrogen added. Fertilisation induced reductions in plant species richness were greater when defoliation rates were lower. We found some evidence that grasslands with a higher baseline plant diversity lost more species when fertilised compared to more species poor grasslands, although uncertainty was high. Due to the diverse grassland types included in the analysis, the variability in fertilisation-driven changes in plant diversity was high. We identified several remaining limitations to our understanding, including uncertainty about non-linear effects, which could aid efforts to optimise the trade-off of plant diversity and increasing grassland yields

Evidence for oncolytic virotherapy: Where have we got to and where are we going?

The last few years have seen an increased interest in immunotherapy in the treatment of malignant disease. In particular, there has been significant enthusiasm for oncolytic virotherapy, with a large amount of pre-clinical data showing promise in animal models in a wide range of tumour types. How do we move forward into the clinical setting and translate something which has such potential into meaningful clinical outcomes? Here, we review how the field of oncolytic virotherapy has developed thus far and what the future may hold

An inflammation based score can optimize the selection of patients with advanced cancer considered for early phase clinical trials.

Background: Adequate organ function and good performance status (PS) are common eligibility criteria for phase I trials. As inflammation is pathogenic and prognostic in cancer we investigated the prognostic performance of inflammation-based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR). Methods: We studied inflammatory scores in 118 unselected referrals. NLR normalization was recalculated at disease reassessment. Each variable was assessed for progression-free (PFS) and overall survival (OS) on uni- and multivariate analyses and tested for 90 days survival (90DS) prediction using receiving operator curves (ROC). Results: We included 118 patients with median OS 4.4 months, 23% PS>1. LDH 65450 and NLR 655 were multivariate predictors of OS (p<0.001). NLR normalization predicted for longer OS (p<0.001) and PFS (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under ROC values of 0.66 and 0.64, and OS with c-score of 0.69 and 0.60. The combination of NLR+PS increased prognostic accuracy to 0.72. The NLR was externally validated in a cohort of 126 subjects. Conclusions: We identified the NLR as a validated and objective index to improve patient selection for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months. Prospective validation of the NLR is warranted. Copyright: \ua9 2014 Pinato et al

Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria

We hypothesise that antimicrobial resistance (AMR) cannot be overcome by simply ‘drugging’ single biological targets, therefore, our focus is developing broad-spectrum therapeutics. Herein we present the synthesis of two novel spacer-linked, anthraquinone-triphenylphosphonium (AQ-TPP) conjugates (4) and (5) as early lead compounds in a new class of agent designed to penetrate the lipophilic barriers of the membranes of a diverse family of species; and establish bacterial growth inhibitory properties against methicillin-resistant Staphylococcus aureus (NCTC 13616) and Mycobacterium smegmatis [mc2155] (as a surrogate for Mycobacterium tuberculosis). The MIC and MBC values of (4) and (5) were determined against MRSA and found to be equipotent [MIC for each: 1 µg/mL (1.2 µM)]. Whereas the amide-linked conjugate (5) was determined to have 2-fold greater bactericidal potency [MBC 1 µg/mL (1.2 µM] than ester-linked (4). The anthraquinone-TPP conjugates (4) and (5) were active in vitro against Mycobacterium smegmatis (graphical abstract) and were equipotent as determined by their MIC values; in contrast to MRSA, the less hydrophobic (4) had 2-fold greater bactericidal potency than (5) as measured by their MBC values. Notably, both conjugates showed potent intracellular growth inhibitory activity in infected THP-1 macrophages. The conjugates are promising leads for the development of new antibacterial drugs

Learning to generalise but not segment an artificial language at 17 months predicts children’s language skills 3 years later

We investigated whether learning an artificial language at 17 months was predictive of children’s natural language vocabulary and grammar skills at 54 months. Children at 17 months listened to an artificial language containing non-adjacent dependencies, and were then tested on their learning to segment and to generalise the structure of the language. At 54 months, children were then tested on a range of standardised natural language tasks that assessed receptive and expressive vocabulary and grammar. A structural equation model demonstrated that learning the artificial language generalisation at 17 months predicted language abilities – a composite of vocabulary and grammar skills – at 54 months, whereas artificial language segmentation at 17 months did not predict language abilities at this age. Artificial language learning tasks – especially those that probe grammar learning – provide a valuable tool for uncovering the mechanisms driving children’s early language development

Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity.

UNLABELLED: Two alleles of segment 8 (NS) circulate in nonchiropteran influenza A viruses. The A allele is found in avian and mammalian viruses, but the B allele is viewed as being almost exclusively found in avian viruses. This might reflect the fact that one or both of its encoded proteins (NS1 and NEP) are maladapted for replication in mammalian hosts. To test this, a number of clade A and B avian virus-derived NS segments were introduced into human H1N1 and H3N2 viruses. In no case was the peak virus titer substantially reduced following infection of various mammalian cell types. Exemplar reassortant viruses also replicated to similar titers in mice, although mice infected with viruses with the avian virus-derived segment 8s had reduced weight loss compared to that achieved in mice infected with the A/Puerto Rico/8/1934 (H1N1) parent. In vitro, the viruses coped similarly with type I interferons. Temporal proteomics analysis of cellular responses to infection showed that the avian virus-derived NS segments provoked lower levels of expression of interferon-stimulated genes in cells than wild type-derived NS segments. Thus, neither the A nor the B allele of avian virus-derived NS segments necessarily attenuates virus replication in a mammalian host, although the alleles can attenuate disease. Phylogenetic analyses identified 32 independent incursions of an avian virus-derived A allele into mammals, whereas 6 introductions of a B allele were identified. However, A-allele isolates from birds outnumbered B-allele isolates, and the relative rates of Aves-to-Mammalia transmission were not significantly different. We conclude that while the introduction of an avian virus segment 8 into mammals is a relatively rare event, the dogma of the B allele being especially restricted is misleading, with implications in the assessment of the pandemic potential of avian influenza viruses. IMPORTANCE: Influenza A virus (IAV) can adapt to poultry and mammalian species, inflicting a great socioeconomic burden on farming and health care sectors. Host adaptation likely involves multiple viral factors. Here, we investigated the role of IAV segment 8. Segment 8 has evolved into two distinct clades: the A and B alleles. The B-allele genes have previously been suggested to be restricted to avian virus species. We introduced a selection of avian virus A- and B-allele segment 8s into human H1N1 and H3N2 virus backgrounds and found that these reassortant viruses were fully competent in mammalian host systems. We also analyzed the currently available public data on the segment 8 gene distribution and found surprisingly little evidence for specific avian host restriction of the B-clade segment. We conclude that B-allele segment 8 genes are, in fact, capable of supporting infection in mammals and that they should be considered during the assessment of the pandemic risk of zoonotic influenza A viruses.Wellcome Trust (Grant ID: 108070/Z/15/Z), Medical Research Council (Grant ID: MR/K000276/1), Biotechnology and Biological Sciences Research Council (Grant IDs: BB/J004324/1, BB/J01446X/1), Division of Intramural Research National Institute of Allergy and Infectious Diseases, University Of Edinburgh (Chancellor’s Fellowship)This is the final version of the article. It first appeared from the American Society for Microbiology via http://dx.doi.org/10.1128/JVI.01205-1

2-Acetyl­pyridinium bromanilate

In the crystal of the title mol­ecular salt (systematic name: 2-acetyl­pyridinium 2,5-dibromo-4-hydr­oxy-3,6-dioxocyclo­hexa-1,4-dienolate), C7H8NO+·C6HBr2O4 −, centrosymmetric rings consisting of two cations and two anions are formed, with the components linked by alternating O—H⋯O and N—H⋯O hydrogen bonds. Short O⋯Br contacts [3.243 (2) and 3.359 (2) Å] may help to consolidate the packing