Delay Differential Model for Tumour-Immune Response with Chemoimmunotherapy and Optimal Control

We present a delay differential model with optimal control that describes the interactions of the tumour cells and immune response cells with external therapy. The intracellular delay is incorporated into the model to justify the time required to stimulate the effector cells. The optimal control variables are incorporated to identify the best treatment strategy with minimum side effects by blocking the production of new tumour cells and keeping the number of normal cells above 75% of its carrying capacity. Existence of the optimal control pair and optimality system are established. Pontryagin’s maximum principle is applicable to characterize the optimal controls. The model displays a tumour-free steady state and up to three coexisting steady states. The numerical results show that the optimal treatment strategies reduce the tumour cells load and increase the effector cells after a few days of therapy. The performance of combination therapy protocol of immunochemotherapy is better than the standard protocol of chemotherapy alone

Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia

This is the final version of the article. Available from the publisher via the DOI in this record.Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases.This work was supported by the British Heart Foundation (a PhD studentship to KS and PG 13 89 30577), Medical Research Council, and an ERC Starting Investigator Grant (to TK), as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica and Pfizer). The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre

Population prevalence of asthma and its determinants based on European Community Respiratory Health Survey in the United Arab Emirates

<p>Abstract</p> <p>Background</p> <p>No population study has explored the population distribution of adult asthma in the United Arab Emirates (UAE). The objective is to estimate asthma prevalence in general population in UAE.</p> <p>Methods</p> <p>Using standard European Community Respiratory Health Survey (ECRHS) questionnaires and tools, this is a cross-sectional assessment of a random sample of the population in established quotas of the seven Emirates in the UAE. We surveyed 1,220 participants, of which 63.2% were male, and 20.1% were UAE Nationals, with a mean (SD) age of 32.9 (14.1) years.</p> <p>Results</p> <p>Prevalence of individual respiratory symptoms from the ECRHS screening questionnaire in all participants were generally ranging 8 - 10%, while participants 20-44 years presented lower prevalence in all symptoms (<it>p </it>< 0.05). The expected male:female ratio of reported wheezing and asthma attacks and its treatment by age was not observed. Participating women reported more individual symptoms than men. Overall, there were 15.4% (95% C.I. 13.5 - 17.5) participants who fulfilled our screening criteria for asthma, while for consistency with ECRHS, there were 12.1% (95% C.I. 10.4 - 14.1) participants who fulfilled the ECRHS asthma definition, being 9.8% (95% C.I. 7.8 - 12.2) of those 20-44 years, that is 8.6% of male and 11.8% of female young adults participating.</p> <p>Conclusion</p> <p>We conclude that asthma is common in the UAE, and gender differences are not observed in reported asthma symptoms in young adults. This being the first population based study exploring the prevalence of asthma and its determinants in the United Arab Emirates based on the ECRHS.</p

Conducting Environmental Health Research in the Arabian Middle East: Lessons Learned and Opportunities

Background: The Arabian Gulf nations are undergoing rapid economic development, leading to major shifts in both the traditional lifestyle and the environment. Although the pace of change is brisk, there is a dearth of environmental health research in this region