Considering the role of Murine double minute 2 in the cardiovascular system

The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.York University Librarie

Investigating MDM2 Regulation of Endothelial Cell Angiomir Biosynthesis in Response to High Glucose Treatment

MiRNAs are a class of short, non-coding RNAs that regulate gene expression at the post-transcriptional level. Dysregulation of miRNA production contributes to the pathogenesis of hyperglycemia-related complications. Although many studies have examined the effect of hyperglycemia on the expression of miRNAs, the effect of hyperglycemia specifically on the endothelial cell miRNA biogenesis machinery is poorly understood. The aim of my project is to better characterize the effect of high glucose treatment on the miRNA biogenesis machinery and miRNA expression in endothelial cells. HDMECs were incubated with low (5mM) and high (30mM) glucose concentrations for 6 and 24 hours and subsequent miRNA expression was measured. My results indicate that exposure to high glucose concentrations enhances MDM2:DROSHA binding and represses DROSHA expression both in vitro and in diabetic mice (db/db) muscles. Treatment with MDM2 inhibitors repealed glucose-induced DROSHA downregulation. This suggests that high glucose concentrations downregulates DROSHA expression through an MDM2-mediated mechanism

Trading Safety Versus Performance: Rapid Deployment of Robotic Swarms with Robust Performance Constraints

In this paper we consider a stochastic deployment problem, where a robotic swarm is tasked with the objective of positioning at least one robot at each of a set of pre-assigned targets while meeting a temporal deadline. Travel times and failure rates are stochastic but related, inasmuch as failure rates increase with speed. To maximize chances of success while meeting the deadline, a control strategy has therefore to balance safety and performance. Our approach is to cast the problem within the theory of constrained Markov Decision Processes, whereby we seek to compute policies that maximize the probability of successful deployment while ensuring that the expected duration of the task is bounded by a given deadline. To account for uncertainties in the problem parameters, we consider a robust formulation and we propose efficient solution algorithms, which are of independent interest. Numerical experiments confirming our theoretical results are presented and discussed

Collison-Induced Dissociation of 4-imidazolone Ions; Isomers of [bn]+ Derived from Peptides After Water Loss

Collision-induced dissociation spectra of protonated peptides [(aminoacid)n + H]+ form, after the loss of water, nominal [bn]+ ions which are dependent on both peptide length and amino acid sequence. Protonated tetraglycine loses water predominantly from the first amide; loss from the second amide is a minor channel. The resultant [b4]+ ions have identical CID spectra, indicating interconversion prior to dissociation. Protonated pentaglycine loses water from the first and second amides in high abundances, and the resulting CID spectra of the [b5]+ ions are different, suggesting that interconversion is no longer the dominant pathway. The [b6]+ ions of hexaglycine, formed from the first three amides are in high abundance and their CID spectra are not identical. The substitution of an alanine or proline for a glycine of tetraglycine generally showed reduced water loss and the [b4]+ ions had different fragmentation pathways than those of the [b4]+ ions of tetraglycine

Clinical significance of tumour-infiltrating B lymphocytes (TIL-Bs) in breast cancer: a systematic literature review

Although T lymphocytes have been considered the major players in the tumour microenvironment to induce tumour regression and contribute to anti-tumour immunity, much less is known about the role of tumour-infiltrating B lymphocytes (TIL-Bs) in solid malignancies, particularly in breast cancer, which has been regarded as heterogeneous and much less immunogenic compared to other common tumours like melanoma, colorectal cancer and non-small cell lung cancer. Such paucity of research could translate to limited opportunities for this most common type of cancer in the UK to join the immunotherapy efforts in this era of precision medicine. Here, we provide a systematic literature review assessing the clinical significance of TIL-Bs in breast cancer. Articles published between January 2000 and April 2022 were retrieved via an electronic search of two databases (PubMed and Embase) and screened against pre-specified eligibility criteria. The majority of studies reported favourable prognostic and predictive roles of TIL-Bs, indicating that they could have a profound impact on the clinical outcome of breast cancer. Further studies are, however, needed to better define the functional role of B cell subpopulations and to discover ways to harness this intrinsic mechanism in the fight against breast cancer

A Review of the Pathogenesis and Management of Multinodular Goiter

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