Synthesis and application of cyclodextrin conjugates.

Cyclodextrins, a family of compounds formed from a cyclic array of glucose monomers, contain a hydrophobic cavity which displays selective complexation of size specific guests. This selective molecular recognition is critical to the development of successful chemosensors. A selection of cyclodextrin-conjugates have been designed to report complexation of guests into the cyclodextrin cavity by optical and electrochemical means. Alkylated cyclodextrins containing a single linker group have been synthesised allowing the development of two cyclen-appended cyclodextrin conjugates and their lanthanide complexes. The tetraamide ligand (25) displayed a high rigidity, assessed by (^1)H NMR and luminescence methods. The Tb complex of the monoamide ligand [Tb.26] displayed long lived luminescence arising from energy transfer from cyclodextrin-complexed napthalene to the lanthanide. The association constant, K(_11), between naphthalene and the cyclodextrin [Tb.26], was calculated as 10,200 M(^-1). K(_11) between the Gd complex [Gd.26] and GdDOTAPh (40) was determined to be 1740M(^-1) by NMRD. These association constants are ca 14 and 7 times greater respectively than for the corresponding complexes with β-cyclodextrin (1). Bromonaphthalenes exhibit long lived phosphorescence when complexed within cyclodextrins. Four bromonaphthalene-appended cyclodextrins (57-60) were designed to form inframolecular self-complexes. Competitive complexation of optically transparent guests was expected to reduce the lifetime of phosphorescent emission. The four conjugates were successfully synthesised, although luminescence studies revealed no evidence for complex formation and no response upon competitive guest complexation was observed. The rotaxane (95) and corresponding thread (92) of a hydrophilic ferrocene- cyclodextrin conjugate were made and structurally assessed by CD, (^-1)H NMR and MALDI-TOF MS. The hydrophilic per-O-ethyl conjugates (93 & 100) were also synthesised. A lipophilic quinoline-cyclodextrin conjugate (94) was made, which, when incorporated into an optode membrane, allowed the detection of acetylcholine at micromolar concentrations

Metabolic targeting, immunotherapy and radiation in locally advanced non-small cell lung cancer: Where do we go from here?

In the US, there are ~250,000 new lung cancer diagnoses and ~130,000 deaths per year, and worldwide there are an estimated 1.6 million deaths per year from this deadly disease. Lung cancer is the most common cause of cancer death worldwide, and it accounts for roughly a quarter of all cancer deaths in the US. Non-small cell lung cancer (NSCLC) represents 80-85% of these cases. Due to an enormous tobacco cessation effort, NSCLC rates in the US are decreasing, and the implementation of lung cancer screening guidelines and other programs have resulted in a higher percentage of patients presenting with potentially curable locoregional disease, instead of distant disease. Exciting developments in molecular targeted therapy and immunotherapy have resulted in dramatic improvement in patients’ survival, in combination with new surgical, pathological, radiographical, and radiation techniques. Concurrent platinum-based doublet chemoradiation therapy followed by immunotherapy has set the benchmark for survival in these patients. However, despite these advances, ~50% of patients diagnosed with locally advanced NSCLC (LA-NSCLC) survive long-term. In patients with local and/or locoregional disease, chemoradiation is a critical component of curative therapy. However, there remains a significant clinical gap in improving the efficacy of this combined therapy, and the development of non-overlapping treatment approaches to improve treatment outcomes is needed. One potential promising avenue of research is targeting cancer metabolism. In this review, we will initially provide a brief general overview of tumor metabolism as it relates to therapeutic targeting. We will then focus on the intersection of metabolism on both oxidative stress and anti-tumor immunity. This will be followed by discussion of both tumor- and patient-specific opportunities for metabolic targeting in NSCLC. We will then conclude with a discussion of additional agents currently in development that may be advantageous to combine with chemo-immuno-radiation in NSCLC

Gene content evolution in the arthropods

Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma

INTRODUCTION: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4:1 (fat:carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas. METHODS: We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging. RESULTS: Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days. CONCLUSIONS: KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas

Social work and food security: Case study on the nutritional capabilities of the landfill waste pickers in South Africa

Food security (or the lack of it) has a direct impact on people’s well-being and is of great concern to many disciplines. The study on which the article is based used Drèze and Sen’s ‘nutritional capability’ concept as a theoretical framework to explain the food (in)security of landfill waste pickers. A cross-sectional research approach was followed, coupled with a triangulation mixed method research design. Viewing the waste pickers against the nutritional capability framework highlighted the important role that social work should play in focusing on people’s capabilities within their particular context

Ecological effects of alternative fuel-reduction treatments: highlights of the National Fire and Fire Surrogate study (FFS)

The 12-site National Fire and Fire Surrogate study (FFS) was a multivariate experiment that evaluated ecological consequences of alternative fuel-reduction treatments in seasonally dry forests of the US. Each site was a replicated experiment with a common design that compared an un-manipulated control, prescribed fire, mechanical and mechanical + fire treatments. Variables within the vegetation, fuelbed, forest floor and soil, bark beetles, tree diseases and wildlife were measured in 10-ha stands, and ecological response was compared among treatments at the site level, and across sites, to better understand the influence of differential site conditions. For most sites, treated stands were predicted to be more resilient to wildfire if it occurred shortly after treatment, but for most ecological variables, short-term response to treatments was subtle and transient. Strong site-specificity was observed in the response of most ecosystem variables, suggesting that practitioners employ adaptive management at the local scale. Because ecosystem components were tightly linked, adaptive management would need to include monitoring of a carefully chosen set of key variables. Mechanical treatments did not serve as surrogates for fire for most variables, suggesting that fire be maintained whenever possible. Restoration to pre-settlement conditions will require repeated treatments over time, with eastern forests requiring more frequent applications.Keywords: Oak, Prescribed fire, Frequent fire regimes, Pine, Mechanical treatment, Forest thinning, Dry forest management, Seasonally dry forest

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements