Background: DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences in tumours. RFWD3, a key component of multiple DNA repair and maintenance pathways, was investigated to characterise its impact in HGSOC.
Methods: RFWD3 expression and association with clinical features was assessed using analysis in the TCGA HGSOC dataset, and in a further cohort of HGSOC tumours stained for RFWD3 using immunohistochemistry.
CISD-1/mitoNEET is an evolutionarily conserved outer mitochondrial membrane [2Fe-2S] protein that regulates mitochondrial function and morphology. The [2Fe-2S] clusters are redox reactive and shown to mediate oxidative stress and . However, there is limited research studying CISD-1/mitoNEET mediation of oxidative stress in response to environmental stressors.
View Article and Find Full Text PDFExplor Target Antitumor Ther
February 2020
The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways.
View Article and Find Full Text PDFAcclimatization to altitude has been shown to improve elements of performance. Use of simulated altitude is popular among athletes across the sports spectrum. This work was on a handheld, re-breathing device touted to enhance performance.
View Article and Find Full Text PDFMore than 700,000 people in the UK are living with an eating disorder. They can experience physical complications, poor quality of life, disrupted relationships, emotional distress, social isolation and economic disadvantage. The risk of early death is one of the highest among patients with psychiatric disorders.
View Article and Find Full Text PDFCombination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade.
View Article and Find Full Text PDFAs the lifetime risk, societal cost, and overall functional impact of osteoarthritis (OA) is imposing, it is imperative that clinicians provide an individualized care model for patients. Patients must be offered a multiplicity of care strategies and encouraged to embrace lifestyle approaches for self-managing the effects and symptoms of OA. Certainly, the attitude of the clinician and patient will directly influence receptivity and implementation of lifestyle approaches.
View Article and Find Full Text PDFDepression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models.
View Article and Find Full Text PDFMultiple small-molecule inhibitors of the β-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid β (Aβ) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models.
View Article and Find Full Text PDFA series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
View Article and Find Full Text PDF