213 research outputs found
Co-treatment With BGP-15 Exacerbates 5-Fluorouracil-Induced Gastrointestinal Dysfunction
Gastrointestinal (GI) side-effects of chemotherapy present a constant impediment to efficient and tolerable treatment of cancer. GI symptoms often lead to dose reduction, delays and cessation of treatment. Chemotherapy-induced nausea, bloating, vomiting, constipation, and/or diarrhea can persist up to 10 years post-treatment. We have previously reported that long-term 5-fluorouracil (5-FU) administration results in enteric neuronal loss, acute inflammation and intestinal dysfunction. In this study, we investigated whether the cytoprotectant, BGP-15, has a neuroprotective effect during 5-FU treatment. Balb/c mice received tri-weekly intraperitoneal 5-FU (23 mg/kg/d) administration with and without BGP-15 (15 mg/kg/d) for up to 14 days. GI transit was analyzed via in vivo serial X-ray imaging prior to and following 3, 7, and 14 days of treatment. On day 14, colons were collected for assessment of ex vivo colonic motility, neuronal mitochondrial superoxide, and cytochrome c levels as well as immunohistochemical analysis of myenteric neurons. BGP-15 did not inhibit 5-FU-induced neuronal loss, but significantly increased the number and proportion of choline acetyltransferase (ChAT)-immunoreactive (IR) and neuronal nitric oxide synthase (nNOS)-IR neurons in the myenteric plexus. BGP-15 co-administration significantly increased mitochondrial superoxide production, mitochondrial depolarization and cytochrome c release in myenteric plexus and exacerbated 5-FU-induced colonic inflammation. BGP-15 exacerbated 5-FU-induced colonic dysmotility by reducing the number and proportion of colonic migrating motor complexes and increasing the number and proportion of fragmented contractions and increased fecal water content indicative of diarrhea. Taken together, BGP-15 co-treatment aggravates 5-FU-induced GI side-effects, in contrast with our previous findings that BGP-15 alleviates GI side-effects of oxaliplatin
Moderate and heavy metabolic stress interval training improve arterial stiffness and heart rate dynamics in humans
Traditional continuous aerobic exercise training attenuates age-related increases of arterial stiffness, however, training studies have not determined whether metabolic stress impacts these favourable effects. Twenty untrained healthy participants (n = 11 heavy metabolic stress interval training, n = 9 moderate metabolic stress interval training) completed 6 weeks of moderate or heavy intensity interval training matched for total work and exercise duration. Carotid artery stiffness, blood pressure contour analysis, and linear and non-linear heart rate variability were assessed before and following training. Overall, carotid arterial stiffness was reduced (p 0.05). This study demonstrates the effectiveness of interval training at improving arterial stiffness and autonomic function, however, the metabolic stress was not a mediator of this effect. In addition, these changes were also independent of improvements in aerobic capacity, which were only induced by training that involved a high metabolic stress
The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the Prostaglandin E2 human model of headache
Using a human Prostaglandin E2 (PGE2) model of headache, we examined whether a novel potent and selective EP4 receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healthy volunteers were randomly allocated to receive 200 and 400 mg BGC20-1531 and placebo, followed by a 25-min infusion of PGE2. We recorded headache intensity on a verbal rating scale, MCA blood flow velocity and STA diameter. There was no difference in headache response or prevention of the dilation of the MCA or the STA (P > 0.05) with either dose of BGC20-1531 relative to placebo, although putative therapeutic exposures were not reached in all volunteers. In conclusion, these data suggest that the other EP receptors may be involved in PGE2 induced headache and dilatation in normal subjects
Ras GTPase-like protein MglA, a controller of bacterial social-motility in Myxobacteria, has evolved to control bacterial predation by Bdellovibrio
Bdellovibrio bacteriovorus invade Gram-negative bacteria in a predatory process requiring Type IV pili (T4P) at a single invasive pole, and also glide on surfaces to locate prey. Ras-like G-protein MglA, working with MglB and RomR in the deltaproteobacterium Myxococcus xanthus, regulates adventurous gliding and T4P-mediated social motility at both M. xanthus cell poles. Our bioinformatic analyses suggested that the GTPase activating protein (GAP)-encoding gene mglB was lost in Bdellovibrio, but critical residues for MglABd GTP-binding are conserved. Deletion of mglABd abolished prey-invasion, but not gliding, and reduced T4P formation. MglABd interacted with a previously uncharacterised tetratricopeptide repeat (TPR) domain protein Bd2492, which we show localises at the single invasive pole and is required for predation. Bd2492 and RomR also interacted with cyclic-di-GMP-binding receptor CdgA, required for rapid prey-invasion. Bd2492, RomRBd and CdgA localize to the invasive pole and may facilitate MglA-docking. Bd2492 was encoded from an operon encoding a TamAB-like secretion system. The TamA protein and RomR were found, by gene deletion tests, to be essential for viability in both predatory and non-predatory modes. Control proteins, which regulate bipolar T4P-mediated social motility in swarming groups of deltaproteobacteria, have adapted in evolution to regulate the anti-social process of unipolar prey-invasion in the “lone-hunter” Bdellovibrio. Thus GTP-binding proteins and cyclic-di-GMP inputs combine at a regulatory hub, turning on prey-invasion and allowing invasion and killing of bacterial pathogens and consequent predatory growth of Bdellovibrio
Potency of human cardiosphere-derived cells from patients with ischemic heart disease is associated with robust vascular supportive ability
Cardiosphere-derived cell (CDC) infusion into damaged myocardium has shown some reparative
effect; this could be improved by better selection of patients and cell subtype. CDCs isolated from
patients with ischemic heart disease are able to support vessel formation in vitro but this ability
varies between patients. The primary aim of our study was to investigate whether the vascular
supportive function of CDCs impacts on their therapeutic potential, with the goal of improving
patient stratification. A subgroup of patients produced CDCs which did not efficiently support vessel
formation (poor supporter CDCs), had reduced levels of proliferation and increased senescence,
despite them being isolated in the same manner and having a similar immunophenotype to CDCs
able to support vessel formation. In a rodent model of myocardial infarction, poor supporter CDCs
had a limited reparative effect when compared to CDCs which had efficiently supported vessel formation
in vitro. This work suggests that not all patients provide cells which are suitable for cell
therapy. Assessing the vascular supportive function of cells could be used to stratify which patients
will truly benefit from cell therapy and those who would be better suited to an allogeneic transplant
or regenerative preconditioning of their cells in a precision medicine fashion. This could
reduce costs, culture times and improve clinical outcomes and patient prognosis
HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC
A case study in serendipity: Environmental researchers use of traditional and social media for dissemination
In the face of demands for researchers to engage more actively with a wider range of publics and to capture different kinds of research impacts and engagements, we explored the ways a small number of environmental researchers use traditional and social media to disseminate research. A questionnaire was developed to investigate the impact of different media as a tool to broker contact between researchers and a variety of different stakeholders (for example, publics, other researchers, policymakers, journalists) as well as how researchers perceive that their use of these media has changed over the past five years. The questionnaire was sent to 504 researchers whose work had featured in a policy-oriented e-news service. 149 valid responses were received (29%). Coverage in traditional media (newspapers, broadcast) not only brokers contact with other journalists, but is a good source of contact from other researchers (n=47, 62%) and members of the public (n=36, 26%). Although the use of social media was limited amongst our sample, it did broker contact with other researchers (n=17, 47%) and the public (n=10, 28%). Nevertheless, few environmental researchers were actively using social media to disseminate their research findings, with many continuing to rely on academic journals and face-to-face communication to reach both academic and public audiences. © 2013 Wilkinson, Weitkamp
Optimised Anaesthesia to Reduce Post Operative Cognitive Decline (POCD) in Older Patients Undergoing Elective Surgery, a Randomised Controlled Trial
Background
The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery.
Methods and Trial Design
The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery.
Results
In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (?2 = 17.9 p<0.0001), moderate (?2 = 7.8 p = 0.005) and severe (?2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, ?2 = 5.1 p = 0.02 and ?2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (?2 = 4.4 p = 0·037 and ?2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z = ?2.1 p = 0.03, MWU Z = ?2.7 p = 0.004, MWU Z = ?3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = ?2.9 p = 0.003, MWU Z = ?3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = ?2.4 p = .0.018, MWU Z = ?2.4 p = 0.019).
Conclusion
POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment
Booster vaccination against SARS-CoV-2 induces potent immune responses in people with human immunodeficiency virus
Background
People with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) with good CD4 T-cell counts make effective immune responses following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are few data on longer term responses and the impact of a booster dose.
Methods
Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed 12 months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µL. Immune responses to the ancestral strain and variants of concern were measured by anti-spike immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, activation induced marker (AIM) assay, and T-cell proliferation.
Findings
In total, 54 participants received 2 doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) 1 year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titers (MSD), ACE-2 inhibition, and IgG ELISA results were significantly higher compared to Day 182 titers (P < .0001 for all 3). SARS-CoV-2 specific CD4+ T-cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4+ and CD8+ T-cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron.
Conclusions
In PWH receiving a third vaccine dose, there were significant increases in B- and T-cell immunity, including to known variants of concern (VOCs)
The Opportunistic Pathogen Propionibacterium acnes: Insights into Typing, Human Disease, Clonal Diversification and CAMP Factor Evolution
We previously described a Multilocus Sequence Typing (MLST) scheme based on eight genes that facilitates population
genetic and evolutionary analysis of P. acnes. While MLST is a portable method for unambiguous typing of bacteria, it is
expensive and labour intensive. Against this background, we now describe a refined version of this scheme based on two
housekeeping (aroE; guaA) and two putative virulence (tly; camp2) genes (MLST4) that correctly predicted the phylogroup
(IA1, IA2, IB, IC, II, III), clonal complex (CC) and sequence type (ST) (novel or described) status for 91% isolates (n = 372) via
cross-referencing of the four gene allelic profiles to the full eight gene versions available in the MLST database (http://
pubmlst.org/pacnes/). Even in the small number of cases where specific STs were not completely resolved, the MLST4
method still correctly determined phylogroup and CC membership. Examination of nucleotide changes within all the MLST
loci provides evidence that point mutations generate new alleles approximately 1.5 times as frequently as recombination;
although the latter still plays an important role in the bacterium’s evolution. The secreted/cell-associated ‘virulence’ factors
tly and camp2 show no clear evidence of episodic or pervasive positive selection and have diversified at a rate similar to
housekeeping loci. The co-evolution of these genes with the core genome might also indicate a role in commensal/normal
existence constraining their diversity and preventing their loss from the P. acnes population. The possibility that members of
the expanded CAMP factor protein family, including camp2, may have been lost from other propionibacteria, but not P.
acnes, would further argue for a possible role in niche/host adaption leading to their retention within the genome. These
evolutionary insights may prove important for discussions surrounding camp2 as an immunotherapy target for acne, and
the effect such treatments may have on commensal lineages
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