Explore the vast range of titles available.

Background ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. Methods In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). Results ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. Conclusion FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

Background Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett’s multiple comparison test. Results We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration ( n  ≥ 3, p  < 0.05) and invasion ( n  ≥ 3, p  < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model ( p  < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content ( n  ≥ 3, p  < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 ( p  < 0.05) or 21 days ( p  < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

ObjectiveTo investigate the levels and correlates of physical activity during COVID-19 social distancing in a sample of the UK public.MethodsThis paper presents analyses of data from a cross-sectional study. Levels of physical activity during COVID-19 social distancing were self-reported. Participants also reported on sociodemographic and clinical data. The association between several factors and physical activity was studied using regression models.ResultsNine hundred and eleven adults were included (64.0% were women and 50.4% of the participants were aged 35–64 years). 75.0% of the participants met the physical activity guidelines during social distancing. Meeting these guidelines during social distancing was significantly associated with sex (reference: male; female: OR=1.60, 95% CI 1.10 to 2.33), age (reference: 18–34 years; ≥65 years: OR=4.11, 95% CI 2.01 to 8.92), annual household income (reference: <£15 000; £15 000–<£25 000: OR=2.03, 95% CI 1.11 to 3.76; £25 000–<£40 000: OR=3.16, 95% CI 1.68 to 6.04; £40 000–<£60 000: OR=2.27, 95% CI 1.19 to 4.34; ≥£60 000: OR=2.11, 95% CI 1.09 to 4.09), level of physical activity per day when not observing social distancing (OR=1.00 (per 1 min increase), 95% CI 1.00 to 1.01), and any physical symptom experienced during social distancing (reference: no; yes: OR=0.31, 95% CI 0.21 to 0.46).ConclusionDuring COVID-19, social distancing interventions should focus on increasing physical activity levels among younger adults, men and those with low annual household income. It should be noted in the present sample that women and younger adults are over-represented.

FK506 binding protein-like (FKBPL) and its peptide derivatives exert potent anti-angiogenic activity in vitro and in vivo and control tumour growth in xenograft models, when administered exogenously. However, the role of endogenous FKBPL in angiogenesis is not well characterised. Here we investigated the molecular effects of the endogenous protein and its peptide derivative, AD-01, leading to their anti-migratory activity. Inhibition of secreted FKBPL using a blocking antibody or siRNA-mediated knockdown of FKBPL accelerated the migration of human microvascular endothelial cells (HMEC-1). Furthermore, MDA-MB-231 tumour cells stably overexpressing FKBPL inhibited tumour vascular development in vivo suggesting that FKBPL secreted from tumour cells could inhibit angiogenesis. Whilst FKBPL and AD-01 target CD44, the nature of this interaction is not known and here we have further interrogated this aspect. We have demonstrated that FKBPL and AD-01 bind to the CD44 receptor and inhibit tumour cell migration in a CD44 dependant manner; CD44 knockdown abrogated AD-01 binding as well as its anti-migratory activity. Interestingly, FKBPL overexpression and knockdown or treatment with AD-01, regulated CD44 expression, suggesting a co-regulatory pathway for these two proteins. Downstream of CD44, alterations in the actin cytoskeleton, indicated by intense cortical actin staining and a lack of cell spreading and communication were observed following treatment with AD-01, explaining the anti-migratory phenotype. Concomitantly, AD-01 inhibited Rac-1 activity, up-regulated RhoA and the actin binding proteins, profilin and vinculin. Thus the anti-angiogenic protein, FKBPL, and AD-01, offer a promising and alternative approach for targeting both CD44 positive tumours and vasculature networks.

RALA is a novel 30 mer bioinspired amphipathic peptide that is showing promise for gene delivery. Here, we used RALA to deliver the FK506-binding protein like - gene (pFKBPL) - a novel member of the immunophilin protein family. FKBPL is a secreted protein, with overexpression shown to inhibit angiogenesis, tumor growth and stemness, through a variety of intra- and extracellular signaling mechanisms. We also elucidated proangiogenic activity and stemness after utilizing RALA to deliver siRNA (siFKBPL). The RALA/pFKBPL and RALA/siFKBPL nanoparticles were characterized in terms of size, charge, stability and toxicity. Overexpression and knockdown of FKBPL was assessed and . RALA delivered both pFKBPL and siFKBPL with less cytotoxicity than commercially available counterparts. , RALA/pFKBPL delivery retarded tumor growth, and prolonged survival with an associated decrease in angiogenesis, while RALA/siFKBPL had no effect on tumor growth rate or survival, but resulted in an increase in angiogenesis and stemness. RALA is an effective delivery system for both FKBPL DNA and RNAi and highlights an alternative therapeutic approach to harnessing FKBPL's antiangiogenic and antistemness activity.

Public health restrictions, in response to the COVID-19 pandemic, have had potentially wide-ranging, unintended effects on health-related behaviours such as diet and physical activity and also affected mental health due to reduced social interactions. This study explored how health-related behaviours and mental health were impacted in a sample of the UK public during the first set of COVID-19 public health restrictions. Two online surveys were administered in the UK, one within the first three months of the restrictions (Timepoints 1 (T1—involving pre-pandemic recall) and 2/T2) and another ten weeks later (Timepoint 3/T3). Moderate–vigorous physical activity (MVPA), outdoor time, sitting time, screen time and sexual activity were self-reported. Diet was assessed using the Dietary Instrument for Nutrition Education questionnaire. Mental health was measured using the short-form Warwick–Edinburgh Mental Wellbeing Scale and Becks’ Anxiety and Depression Inventories. Differences between timepoints were explored using the Friedman, Wilcoxon signed-rank, McNemar and McNemar–Bowker tests. Two hundred and ninety-six adults (74% under 65 years old; 65% female) provided data across all timepoints. Between T1 and T2, MVPA, time outdoors and sexual activity decreased while sitting, and screen time increased (p < 0.05). Between T2 and T3, saturated fat intake, MVPA, time outdoors, and mental wellbeing increased while sitting, screen time and anxiety symptoms decreased (p < 0.05). This study found that depending on the level of COVID-19 public health restrictions in place, there appeared to be a varying impact on different health-related behaviours and mental health. As countries emerge from restrictions, it is prudent to direct necessary resources to address these important public health issues.

Background AQ4N is metabolised in hypoxic cells by cytochrome P450s (CYPs) to the cytotoxin AQ4. Most solid tumours are known to contain regions of hypoxia whereas levels of CYPs have been found to vary considerably. Enhancement of CYP levels may be obtained using gene‐directed enzyme prodrug therapy (GDEPT). We have therefore examined the potential of a CYP2B6‐mediated GDEPT strategy to enhance the anti‐tumour effect of the combination of AQ4N with radiation or cyclophosphamide (CPA). Methods In vitro and in vivo transient transfection of human CYP2B6 ± CYP reductase (CYPRED) was investigated in RIF‐1 mouse tumours. Efficacy in vitro was assessed using the alkaline comet assay (ACA). In vivo, the time to reach 4× the treatment volume (quadrupling time; VQT) was used as the end point. Results When CYP2B6 was transfected into RIF‐1 cells and treated with AQ4N under hypoxic conditions there was a significant increase in DNA damage (measured by the ACA) compared with non‐transfected cells. In vivo, a single intra‐tumoural injection of a CYP2B6 vector construct significantly enhanced tumour growth delay in combination with AQ4N (100 mg/kg) and 10 Gy X‐rays. AQ4N (100 mg/kg) and CPA (100 mg/kg) with CYP2B6 and CYPRED also enhanced tumour growth delay; this effect became significant when the schedule was repeated 14 days later (p = 0.0197). Conclusions The results show the efficacy of a CYP2B6‐mediated GDEPT strategy for bioreduction of AQ4N; this may offer an additional approach to target radiation‐ and chemo‐resistant hypoxic tumours that should enhance overall tumour control. Copyright © 2005 John Wiley & Sons, Ltd.

Thebgl operon ofEscherichia coli, which encodes the genes necessary for transport and catabolism of β-glucosides, is silent in wild-type cells and is activated by the transposition of IS elements. The silent form of the operon appears to be the stable state. We isolated Bgl^sup -^ revertants of an activated strain after growth under nonselective conditions to understand whether activation of the cryptic operon by IS elements is reversible. Genetic and molecular analyses revealed that a majority of revertants carry deletions of thebgl structural genes, indicating that an irreversible alteration has occurred in the operon. Implications of these results for the evolution and maintenance of cryptic genes are discussed. [Yakkundi A., Moorthy S. and Mahadevan S. 1998 Reversion of anE. coli strain carrying an IS1-activatedbgl operon under nonselective conditions is predominantly due to deletions within the structural genes.J. Genet. 77, 21-26][PUBLICATION ABSTRACT]