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Discovery of Potent Multikinase Type-II Inhibitors Targeting CDK5 in the DFG-out Inactive State with Promising Potential against Glioblastoma
Get PDFKinases have proven valuable targets in successful cancer drug discovery projects, but not yet for malignant brain tumors where type-II inhibition of cyclin-dependent kinase 5 (CDK5) stabilizing the DFG-out inactive state has potential for design of selective and clinically efficient drug candidates. In the absence of crystallographic evidence for a CDK5 DFG-out inactive state protein–ligand complex, for the first time, a model was designed using metadynamics/molecular dynamics simulations. Glide docking of the ZINC15 biogenic database identified [pyrimidin-2-yl]amino-furo[3,2-b]-furyl-urea/amide hit chemical scaffolds. For four selected analogues (4, 27, 36, and 42), potent effects on glioblastoma cell viability in U87-MG, T98G, and U251-MG cell lines and patient-derived cultures were generally observed (IC50s ∼ 10–40 μM at 72 h). Selectivity profiling against 11 homologous kinases revealed multikinase inhibition (CDK2, CDK5, CDK9, and GSK-3α/β), most potent for GSK-3α in the nanomolar range (IC50s ∼ 0.23–0.98 μM). These compounds may therefore have diverse anticancer mechanisms of action and are of considerable interest for lead optimization
Culpeper's herbal The English Physitian and its debt to apothecary John Parkinson
Get PDFIn this textual comparison of seventeenth-century herbals, I show in detail that most of the descriptions and medicinal uses of English herbs included in Culpeper’s small folio The English Physitian (1652) and its enlargement of the following year were lifted straight out of the works of John Parkinson, apothecary. This was a deliberate act by Culpeper, to make available to the people of England the best information on native plant medicines for use in treating their illnesses. He attacked the College of Physicians of London, whom the great majority of the population could not afford to engage, for trying to keep this knowledge secret. Among later historians of the herbal tradition, Culpeper’s work was not accorded the same status as the great English herbals of William Turner, John Gerard, and John Parkinson, not because this borrowing was recognised but because its astrological content worked to divert attention from the quality and source of much of its guidance on treatment. Even contemporaries of Culpeper did not recognise the extent of the borrowing. Comparisons also reveal the limitations of Culpeper’s powers of plant description and his lack of interest in the developing science of botany. The editorial decisions Culpeper made to reduce a great folio herbal to a much smaller book to be sold for 3d touch on domestic and other non-medical uses, while points of discussion common to both authors such as the doctrine of signatures and superstitious beliefs about plants are explored
Swallowed topical steroid therapy for eosinophilic oesophagitis in children: Practical, evidence-based guidance by the BSPGHAN eosinophilic oesophagitis working group
Get PDFObjective To develop evidence-based guidance for topical steroid use in paediatric eosinophilic oesophagitis (pEoE) in the UK for both induction and maintenance treatment.
Methods A systematic literature review using Cochrane guidance was carried out by the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) Eosinophilic Oesophagitis (EoE) Working Group (WG) and research leads to determine the evidence base for preparation, dosing and duration of use of swallowed topical steroid (STS) formulations in EoE. Seven themes relating to pEoE were reviewed by the WG, alongside the Cochrane review this formed the evidence base for consensus recommendations for pEoE in the UK. We provide an overview of practical considerations including treatment regimen and dosing. Oral viscous budesonide (OVB) and, if agreed by local regulatory committees, orodispersible budesonide (budesonide 1 mg tablets) were selected for ease of use and with most improvement in histology. A practical ‘how to prepare and use’ OVB appendix is included. Side effects identified included candidiasis and adrenal gland suppression. The use of oral systemic steroids in strictures is discussed briefly.
Results 2638 citations were identified and 18 randomised controlled trials were included. Evidence exists for the use of STS for induction and maintenance therapy in EoE, especially regarding histological improvement. Using the Appraisal of Guidelines, Research and Evaluation criteria, dosing of steroids by age (0.5 mg two times per day <10 years and 1 mg two times per day ≥10 years) for induction of at least 3 months was suggested based on evidence and practical consideration. Once histological remission is achieved, maintenance dosing of steroids appears to reduce the frequency and severity of relapse, as such a maintenance weaning regimen is proposed.
Conclusion A practical, evidence-based flow chart and guidance recommendations with consensus from the EoE WG and education and research representatives of BSPGHAN were developed with detailed practical considerations for use in the UK
Understanding the impact on children’s citizenship of participating in community-based action research
Get PDFThis paper explores the lived experience of citizenship of working-class girls from a marginalised ex-mining town in northern England engaged as community researchers in participatory action research. The research aimed to better understand the relationships within their local community. Qualitative methods were used to examine the girls’ experience of the research and its impact on their sense of community, which is discussed using the lens of ‘lived citizenship’ (Kallio et al. 2020). We conclude that children’s experience of participatory research approaches can be understood as subjective or lived citizenship. This contributes to understanding how they perceived their acts of citizenship, particularly in relation to others in their community. Supporting the international literature on subjectivity in citizenship studies and the critical appreciation of intersectionality in in participatory research, this paper demonstrates how such involvement can lead to positive subjective outcomes in groups experiencing marginalisation, such as working-class girls
BECN1 mRNA expression in breast cancer tissue; significant correlation to tumor grade
Get PDFBreast cancer (BC) is a heterogenous disease with multiple pathways implicated in its development, progression, and drug resistance. Autophagy, a cellular process responsible for self-digestion of damaged organelles, had been recognized as eminent player in cancer progression and chemotherapeutic resistance. The haploinsufficiency of Beclin 1 (BECN1), autophagy protein, is believed to contribute to cancer pathogenesis and progression. In our study, we investigated the expression of BECN1 in a BC female Egyptian patient cohort, as well as its prognostic role through evaluating its association with disease free survival (DFS) after 2 years follow up and association of tumor clinicopathological features. Twenty frozen female BC tissue samples and 17 adjacent normal tissue were included and examined for the expression levels of BECN1. Although the tumor tissues showed lower expression 0.73 (0–8.95) than their corresponding normal tissues 1.02 (0.04–19.59), it was not statistically significant, p: 0.463. BECN1 expression was not associated with stage, nodal metastasis or tumor size, p:0.435, 0.541, 0.296, respectively. However, statistically significant negative correlation was found between grade and BECN1 mRNA expression in the studied cases, p:0.028. BECN1 expression had no statistically significant association with DFS, P = 0.944. However, we observed that triple negative (TNBC) cases had significantly lower DFS rate than luminal BC patients, p: 0.022, with mean DFS 19.0 months, while luminal BC patients had mean DFS of 23.41 months. Our study highlights the potential role of BECN1 in BC pathogenesis, showing that BECN1 expression correlates with poorer differentiation of BC, indicating its probable link with disease aggressiveness. DFS two years follow up showed that TNBC subtype remains associated with less favorable prognosis
Why are organisational approvals needed for low-risk staff studies in the UK? Procedures, barriers, and burdens
Get PDFBackground
Health care staff should be given the opportunity to participate in research, but recruiting clinicians via their employing organisation is not always straightforward or quick in the UK. Unlike many countries outside the UK, very low-risk survey, interview or focus group studies can be subject to some of the same governance approval procedures as interventional studies. An exemplar study carried out by the NIHR funded Palliative Care Research Partnership North West Coast is used to highlight the challenges still faced by researchers and health care organisations when setting up a low-risk staff study across multiple NHS and non-NHS sites.
Methods
A study database was created and information was collected on the first point of contact with the clinical site, Health Research Authority (HRA) and local organisational approval times, time from trust or hospice agreement to the first survey participant recruited and overall site survey recruitment numbers. Descriptive statistics (median, range) were used to analyse these data.
Results
Across participating NHS trusts, it took a median of 147.5 days (range 99–195) from initial contact with the local collaborator to recruitment of the first survey participant and hospice sites mirrored these lengthy timescales (median 142 days, range 110–202). The lengthiest delays in the HRA approval process were the period between asking NHS trusts to assess whether they had capacity and capability to support the research and them granting local agreement. Local approval times varied between trusts and settings which may indicate organisations are applying national complex guidance differently.
Conclusions
There is the potential for HRA processes to use more NHS resources than the research study itself when recruiting to a low-risk staff study across multiple organisations. There is a need to reduce unnecessary administrative burden and bureaucracy to give clinicians and research staff more opportunities to participate in research, and to free up NHS R&D departments, research nurses and clinicians to focus on more demanding and patient focused research studies. Hospices need standardised guidance on how to assess the risk of being involved in low-risk research without adopting the unnecessarily complex systems that are currently used within the NHS
The impact of oil rents and institutional governance on human development index: evidence from oil exporting Sub-Saharan African countries.
Get PDFThis study aims to empirically verify the impact of oil rents, their transmission mechanisms, and institutional governance on the human development index for 11 oil exporting Sub – Saharan Africa countries from 2000 to 2020. The explanatory variables are oil rents as % to GDP, Foreign direct investment inflow as % to GDP, trade openness as % to GDP, government effectiveness index, income inequality index and the corruption perception index.
Primary investigation was applied, such as central tendency and also bivariate plots between oil rents and human development index. Further investigation was performed employing balanced panel data techniques. Instrumental variable estimation which is a valuable strategy to address endogeneity and strengthen the credibility of the research finding was applied.
The initial analysis reveals that the characteristics of the data set for those countries in the sample are asymmetrical; they are skewed to the right, except for the human development index variable, which has an almost equal distribution. Moreover, the 11 SSA oil-exporting countries remain at low levels of human development index.
The two-way fixed effects model was estimated. However, it is necessary to consider the endogeneity issue. Thus, instrumental variables were employed, supported by diagnostic analysis. The model was improved by correcting for endogeneity; the magnitudes of some estimation coefficients of the explanatory variables changed considerably; and all the coefficients were significant, except foreign direct investment. The results reveal that, the oil rents had no negative impact on the human development index in those countries in the sample, and this is evidence that oil rents are not a curse per se.
Interestingly, the findings show a positive association between government effectiveness and the human development index. This could be because this index is aggregate index consisting of different indicators. As for trade openness, it has a detrimental impact on such nations' human development indices. This is because skilled labour is more likely to benefit from trade openness than unskilled labour.
The findings add to a new line of investigation that addresses a critical gap in our understanding of the resource curse, human development and has policy implications
TCT-260 Lipoprotein(a) and Endoluminal Disease Phenotype
No full textBackground
Elevated lipoprotein(a) [Lp(a)] is associated with accelerated progression of coronary plaques, a high prevalence of thin-cap fibroatheroma, and an increased risk of spontaneous myocardial infarction; however, its impact on coronary artery disease (CAD) patterns is not fully defined. In this study, we sought to evaluate how elevated Lp(a) affects epicardial coronary flow and the endoluminal disease pattern (focal or diffuse).
Methods
This substudy of the ongoing PIONEER IV randomized controlled trial (NCT04923191) propensity-matched a cohort of patients with elevated Lp(a) (>0 mg/dL or 125 nmol/L) to control subjects based on traditional CAD risk factors. Epicardial flow velocity was quantified using quantitative flow ratio (QFR), with virtual QFR–pressure pullback gradient index (PPGi) characterizing the endoluminal phenotype. A QFR <0.80 indicated significant epicardial flow restriction.
Results
Lp(a) was elevated in 19% (n = 123/645) of patients. In 123 matched pairs, 77% (566/738) of vessels were suitable for QFR analysis. Significant flow limitation was more frequent in elevated Lp(a) vessels compared with matched controls (35% vs 21%; absolute risk difference: 14%; 95% CI: 6.9%-22.0%; P < 0.001) of a significantly more diffuse endoluminal disease phenotype (absolute difference, QFR-PPGi: −0.05; 95% CI: −0.08 to −0.03). Figure 1 shows the cumulative frequency distributions of QFR and QFR-PPGi values.
Conclusions
Elevated plasma levels of Lp(a) were associated with increased epicardial flow limitation and a diffuse endoluminal disease pattern
Unravelling the speed-going relationship: A proof of concept study from British turf flat and jump race meetings
Get PDFThe maximum galloping speeds of racehorses during a race are influenced by the functional performance of the ground (‘going’) amongst other factors. For turf racecourses in Britain, the ground is descriptively classified and numerically quantified on the morning of a race meeting by the clerk of the course and subsequently published to assist decision making. Importantly, this includes deciding whether a horse should or should not run. The going is also assessed and classified during the meeting by racing analysts using the normalized winning times from each race result. Differences between going assessments are regularly reported, therefore this study aimed to evaluate whether an alternative method of measuring going could better predict going measured from performances. Measurement and performance data from 25 flat and 25 jump meetings were compared using linear and nonlinear regression models. A continuous two-phase polynomial model for cushioning was found to be the best predictor of performance going for all 50 meetings (adjusted r2=0.819, P<0.001). As cushioning can provide a going related indicator of the forces that the horse will experience at gallop, this measurement may be useful when evaluating racecourse going. This initial model suggests that there is little performance advantage at maximal galloping speeds above a cushioning value of approximately10 kN, possibly due to changes in limb contact timings to manage limb forces limits as the ground becomes firmer. An expansion of objective measurements of going that relate to performance across a wider geographic region, if not internationally are needed to confirm this limit