Platinum binding preferences dominate the binding of novel polyamide amidine anthraquinone platinum(II) complexes to DNA

Complexes incorporating a threading anthraquinone intercalator with pyrrole lexitropsin and platinum(II) moieties attached were developed with the goal of generating novel DNA binding modes, including the targeting of AT-rich regions in order to have high cytotoxicities. The binding of the complexes to DNA has been investigated and profiles surprisingly similar to that for cisplatin were observed; the profiles were different to those for a complex lacking the pyrrole lexitropsin component. The lack of selective binding to AT-rich regions suggests the platinum binding was dominating the sequence selectivity, and is consistent with the pyrrole lexitropsin slowing intercalation. The DNA unwinding profiles following platinum binding were evaluated by gel electrophoresis and suggested that intercalation and platinum binding were both occurring

Genetic overlap between bipolar illness and event-related potentials

Background. Electrophysiological endophenotypes are far less explored in bipolar disorder as compared to schizophrenia. No previous twin study of event-related potentials (ERPs) in bipolar illness has been reported. This study uses a twin design and advanced genetic model fitting analyses aiming to (1) assess and quantify the relationship of a range of ERP components with bipolar disorder with psychotic features, and (2) examine the source of the relationship (due to genetic or environmental factors). Method. P300, P50 suppression and mismatch negativity (MMN) were recorded in 10 discordant monozygotic (MZ) bipolar twin pairs, six concordant MZ bipolar twin pairs and 78 control twin pairs. Statistical analyses were based on structural equation modelling. Results. Bipolar disorder was significantly associated with smaller P300 amplitude and decreased P50 suppression. Genetic correlations were the main source of the associations, estimated to be -0.33 for P300 amplitude and 0·46 for P50 ratio. Individual-specific environmental influences were not significant. MMN and P300 latency were not associated with the illness. Conclusions. The results provide supporting evidence that P300 amplitude and P50 suppression ratio are ERP endophenotypes for bipolar disorder. © 2007 Cambridge University Press.published_or_final_versio

Radiocarbon dating of methane and carbon dioxide evaded from a temperate peatland stream

Streams draining peatlands export large quantities of carbon in different chemical forms and are an important part of the carbon cycle. Radiocarbon (14C) analysis/dating provides unique information on the source and rate that carbon is cycled through ecosystems, as has recently been demonstrated at the air-water interface through analysis of carbon dioxide (CO2) lost from peatland streams by evasion (degassing). Peatland streams also have the potential to release large amounts of methane (CH4) and, though 14C analysis of CH4 emitted by ebullition (bubbling) has been previously reported, diffusive emissions have not. We describe methods that enable the 14C analysis of CH4 evaded from peatland streams. Using these methods, we investigated the 14C age and stable carbon isotope composition of both CH4 and CO2 evaded from a small peatland stream draining a temperate raised mire. Methane was aged between 1617-1987 years BP, and was much older than CO2 which had an age range of 303-521 years BP. Isotope mass balance modelling of the results indicated that the CO2 and CH4 evaded from the stream were derived from different source areas, with most evaded CO2 originating from younger layers located nearer the peat surface compared to CH4. The study demonstrates the insight that can be gained into peatland carbon cycling from a methodological development which enables dual isotope (14C and 13C) analysis of both CH4 and CO2 collected at the same time and in the same way

Variations in the slope of the resolved star-forming main sequence: A tool for constraining the mass of star-forming regions

The correlation between galaxies' integrated stellar masses and star formation rates (the 'star formation main sequence', SFMS) is a well-established scaling relation. Recently, surveys have found a relationship between the star formation rate (SFR) and stellar mass surface densities on kpc and sub-kpc scales (the 'resolved SFMS', rSFMS). In this work, we demonstrate that the rSFMS emerges naturally in Feedback In Realistic Environments 2 (FIRE-2) zoom-in simulations of Milky Way-mass galaxies. We make SFR and stellar mass maps of the simulated galaxies at a variety of spatial resolutions and star formation averaging time-scales and fit the rSFMS using multiple methods from the literature. While the absolute value of the SFMS slope (αMS) depends on the fitting method, the slope is steeper for longer star formation time-scales and lower spatial resolutions regardless of the fitting method employed. We present a toy model that quantitatively captures the dependence of the simulated galaxies' αMS on spatial resolution and use it to illustrate how this dependence can be used to constrain the characteristic mass of star-forming clumps

Pneumothorax, pneumomediastinum and subcutaneous emphysema following closed percutaneous pleural biopsy: a case report

Minimally invasive investigations, such as pleural fluid cytological assessment and closed percutaneous pleural biopsy, are often performed first in the investigation of suspected malignant pleural effusions. Malignant pleural effusions can be diagnosed with pleural fluid cytology alone in most cases; however, closed pleural biopsy is performed to increase the diagnostic yield when pleural fluid cytology is negative. This additional yield is at the expense of increased complication rates. We report a 64-year old man with a negative pleural fluid cytology but suspected malignant pleural effusion who underwent a closed pleural biopsy, which was complicated by pneumothorax, pneumomediastinum and severe subcutaneous emphysema. Pulmonary laceration by the pleural biopsy needle is the most likely aetiology of these complications. Our case report highlights an infrequent but significant complication of closed percutaneous pleural biopsy

Preferred reporting items for animal studies in endodontology (PRIASE): a development protocol

The regulated use of animals in endodontic research is often necessary to investigate the biological mechanisms of endodontic diseases and to measure the preclinical efficacy, biocompatibility, toxicology and safety of new treatments, biomaterials, sealers, drugs, disinfectants, irrigants, devices and instruments. Animal testing is most crucial in situations when research on humans is not ethical, practical or has unknown health risks. Currently, there is a wide variability in the quality of manuscripts that report the results of animal studies. Towards the goal of improving the quality of publications, guidelines for preventing disability, pain, and suffering to animals, and enhanced reporting requirements for animal research have been developed. These guidelines are referred to as Animals in Research: Reporting In Vivo Experiments (ARRIVE). Henceforth, causing any form of animal suffering for research purposes is not acceptable and cannot be justified under any circumstances. The present report describes a protocol for the development of welfare and reporting guidelines for animal studies conducted in the specialty of Endodontology: the Preferred Reporting Items for Animal Studies in Endodontology (PRIASE) guidelines. The PRIASE guidelines will be developed by adapting and modifying the ARRIVE guidelines and the Clinical and Laboratory Images in Publication (CLIP) principles. The development of the new PRIASE guidelines will include a five‐step consensus process. An initial draft of the PRIASE guidelines will be developed by a steering committee. Each item in the draft guidelines will then be evaluated by members of a PRIASE Delphi Group (PDG) for its clarity using a dichotomous scale (yes or no) and suitability for its inclusion using a 9‐point Likert scale. The online surveys will continue until each item achieves this standard, and a set of items are agreed for further analysis by a PRIASE Face‐to‐face Consensus Meeting Group (PFCMG). Following the consensus meeting, the steering committee will finalize and confirm the PRIASE guidelines taking into account the responses and comments of the PFCMG. The PRIASE guidelines will be published and disseminated internationally and updated periodically based on feedback from stakeholders

The role of multidisciplinary meetings for benign pancreatobiliary diseases: a tertiary centre experience

Multidisciplinary meetings are central to the management of chronic and complex diseases and they have become widely established across the modern healthcare. Patients with pancreatobiliary diseases can often present with complex clinical dilemmas, which fall out with the scope of current guidelines. Therefore, these patients require a personalised management approach discussed in a multidisciplinary meeting

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an 'Immune Cold' Phenotype Associated with Poor Survival.

New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an 'immune cold' tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC

Investigating the biological properties of carbohydrate derived fulvic acid (CHD-FA) as a potential novel therapy for the management of oral biofilm infections.

Background: A number of oral diseases, including periodontitis, derive from microbial biofilms and are associated with increased antimicrobial resistance. Despite the widespread use of mouthwashes being used as adjunctive measures to control these biofilms, their prolonged use is not recommended due to various side effects. Therefore, alternative broad-spectrum antimicrobials that minimise these effects are highly sought after. Carbohydrate derived fulvic acid (CHD-FA) is an organic acid which has previously demonstrated to be microbiocidal against Candida albicans biofilms, therefore, the aims of this study were to evaluate the antibacterial activity of CHD-FA against orally derived biofilms and to investigate adjunctive biological effects.&lt;p&gt;&lt;/p&gt; Methods: Minimum inhibitory concentrations were evaluated for CHD-FA and chlorhexidine (CHX) against a range of oral bacteria using standardised microdilution testing for planktonic and sessile. Scanning electron microscopy was also employed to visualise changes in oral biofilms after antimicrobial treatment. Cytotoxicity of these compounds was assessed against oral epithelial cells, and the effect of CHD-FA on host inflammatory markers was assessed by measuring mRNA and protein expression.&lt;p&gt;&lt;/p&gt; Results: CHD-FA was highly active against all of the oral bacteria tested, including Porphyromonas gingivalis, with a sessile minimum inhibitory concentration of 0.5%. This concentration was shown to kill multi-species biofilms by approximately 90%, levels comparable to that of chlorhexidine (CHX). In a mammalian cell culture model, pretreatment of epithelial cells with buffered CHD-FA was shown to significantly down-regulate key inflammatory mediators, including interleukin-8 (IL-8), after stimulation with a multi-species biofilm.&lt;p&gt;&lt;/p&gt; Conclusions: Overall, CHD-FA was shown to possess broad-spectrum antibacterial activity, with a supplementary function of being able to down-regulate inflammation. These properties offer an attractive spectrum of function from a naturally derived compound, which could be used as an alternative topical treatment strategy for oral biofilm diseases. Further studies in vitro and in vivo are required to determine the precise mechanism by which CHD-FA modulates the host immune response.&lt;p&gt;&lt;/p&gt