• A pilot randomised controlled trial of a programme of psychosocial interventions (Resettle) for high risk personality disordered offenders

      Nathan, Rajan; Centifanti, Luna; Baker, Vikki; Hill, Jonathan (Elsevier, 2019-07-08)
      Abstract Background Offenders with personality disorder experience significant co-morbid mental health problems and present with an increased risk of offending. The evidence for the effectiveness of interventions for personality disordered offenders in the community is limited. This study was a pilot study to determine the feasibility of a randomised controlled trial (RCT) of an intervention known as Resettle for personality disordered offenders and to explore the possible effects of this intervention. Methods Potential participants were recruited from referrals of male prisoners to Resettle. Those consenting underwent baseline assessments before being randomised to Resettle or treatment as usual. Officially recorded and self-report offending was assessed over two years following release from custody. Of the 110 eligible participants, 72 (65%) participated in the study of whom 38 were randomised to Resettle and 34 to treatment as usual. The two groups had a similar psychiatric and offending profile. Results Analysis of officially recorded offences at two years found mixed results, but whether adopting an intent-to-treat approach or including only those who received the intervention there was no clear evidence of an effect of the intervention. A comparison of self-report offending found no effect of Resettle in an intent-to-treat analysis, but there was an effect when the analysis involved only those participating in the intervention. Conclusions This study demonstrated that with some adjustments it was possible to carry out an RCT of a complex intervention for personality disordered offenders in a criminal justice setting. Some, but not conclusive, evidence was found in favour of the intervention.
    • A preliminary cohort study assessing routine blood analyte levels and neurological outcome following spinal cord injury.

      Brown, Sharon J.; Bernardo Harrington,; Hulme, Charlotte; Morris, Rachel; Bennett, Anna; Tsang, Wai-Hung; Osman, Aheed; Chowdhury, Joy; Kumar, Naveen; Wright, Karina T. (2019-07-16)
      There is increasing interest in the identification of biomarkers that could predict neurological outcome following a spinal cord injury (SCI). Although initial American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade is a good indicator of neurological outcome, for the patient and clinicians, an element of uncertainty remains. This preliminary study aimed to assess the additive potential of routine blood analytes following Principal Component Analysis (PCA) to develop prognostic models for neurological outcome following spinal cord injury. Routine blood and clinical data were collected from SCI patients (n=82) and PCA used to reduce the number of blood analytes into related factors. Outcome neurology was obtained from AIS scores at 3- and 12-months post-injury, with Motor (AIS and Total including all myotomes) and Sensory (AIS, Touch and Pain) being assessed individually. Multiple regression models were created for all outcome measures. Blood analytes relating to 'liver function' and 'acute inflammation and liver function' factors were found to significantly increase prediction of neurological outcome at both 3 months (Touch, Pain and AIS Sensory) and at 1 year (Pain, R2 increased by 0.025 and Total Motor, R2 increased by 0.016). For some models 'liver function' and 'acute inflammation and liver function' factors were both significantly predictive with the greatest combined R2 improvement of 0.043 occurring for 3m Pain prediction. These preliminary findings support ongoing research into the use of routine blood analytes in the prediction of neurological outcome in SCI patients.
    • Accelerated and efficient neuronal differentiation of Sox1GFP mouse embryonic stem cells in vitro using nicotinamide

      Griffin, Sile; Pickard, Mark R.; Fricker, Rosemary; Keele University, United Kingdom (NECTAR (Network of European CNS Transplantation and Restoration) 24th Annual Meeting, 27/28th November 2014, Galway, Ireland, 2014)
      A major challenge for advancement of clinical neuronal replacement therapies is the production of high yields of purified neuronal populations of appropriate phenotype with control over proliferation to prevent tumorigenesis. We previously reported that treatment of mouse embryonic stem cell (mESC;46CSox1GFP reporter cell line) monolayer cultures with the vitamin B3 metabolite nicotinamide at the early onset of development not only increased the efficiency of neuronal generation by two-fold but also enriched the ratio of purified neurons to non-neuronal cells in culture. This study aimed to investigate if nicotinamide enhances neural induction in this model and whether it also promotes the production/differentiation of specific neuronal subtypes. To address these aims, monolayer mESC cultures were treated with nicotinamide (10 mM) for different durations and immunocytochemistry/fluorescence microscopy was performed to assess the expression of stem cell, neural progenitor (NP) and neuronal subtype markers. Morphometric analyses were also performed to assess the extent of differentiation. Nicotinamide treatment significantly decreased Oct4+ pluripotent cells and concomitantly increased GFP+ cells at day 4, suggesting enhanced neural lineage commitment. By day 14, nicotinamide treatment (from day 0-7) reduced both Oct4+ and GFP expression concomitant with enhanced expression of neuron-specific β-tubulin, indicative of accelerated neuronal differentiation. Nicotinamide selectively enhanced the production of catecholaminergic, serotonergic and GABAergic neurons and, moreover, enhanced various aspects of neuronal morphology and maturation. Collectively, these data demonstrate a direct effect of nicotinamide at the initial stages of embryonic stem cell differentiation which could be critical for rapidly andefficiently promoting neural commitment to highly enriched neuronal lineages. The strong clinical potential of nicotinamide could successfully be applied to future neural cell-based therapies including Parkinson’s and Huntington’s disease, both to eradicate proliferating cells and for a more enhanced and specific differentiation
    • Adherence to Pre-operative Exercise and the Response to Prehabilitation in Oesophageal Cancer Patients

      Halliday, Laura; Doganay, Emre; Winter-Blyth, Venetia; Osbourne, Hayley; Buckley, John P; Moorthy, Krishna; Imperial College London, University Centre Shrewsbury/Chester
      BACKGROUND: Prehabilitation is thought to reduce post-operative respiratory complications by optimising fitness before surgery. This prospective, single-centre study aimed to establish the effect of pre-operative exercise on cardiorespiratory fitness in oesophageal cancer patients and characterise the effect of adherence and weekly physical activity on response to prehabilitation. METHODS: Patients received a personalised, home-based pre-operative exercise programme and self-reported their adherence each week. Cardiorespiratory fitness (pVO2max and O2 pulse) was assessed at diagnosis, following completion of neoadjuvant chemotherapy (NAC) and immediately before surgery. Study outcomes included changes in fitness and post-operative pneumonia. RESULTS: Sixty-seven patients with oesophageal cancer underwent prehabilitation followed by surgery between January 2016 and December 2018. Fitness was preserved during NAC and then increased prior to surgery (pV02max Δ = +2.6 ml min-1, 95% CI 1.2-4.0 p = 0.001; O2 pulse Δ = +1.4 ml beat-1 95% CI 0.5-2.3 p = 0.001). Patients with higher baseline fitness completed more physical activity. Regression analyses found adherence was associated with improvement in fitness immediately before surgery (p = 0.048), and the amount of physical activity completed was associated with the risk of post-operative pneumonia (p = 0.035). CONCLUSION: Pre-operative exercise can maintain cardiorespiratory fitness during NAC and facilitate an increase in fitness before surgery. Greater exercise volumes were associated with a lower risk of post-operative pneumonia, highlighting the importance progressing exercise programmes throughout prehabilitation. Patients with high baseline fitness completed more physical activity and may require less supervision to reach their exercise goals. Further research is needed to explore stratified approaches to prehabilitation. KEYWORDS: Exercise therapy; Oesophageal cancer; Pre-operative care; Surgery
    • Alignment of multiple glial cell populations in 3D nanofiber scaffolds: toward the development of multicellular implantable scaffolds for repair of neural injury

      Weightman, Alan P.; Jenkins, Stuart I.; Pickard, Mark R.; Chari, Divya M.; Yang, Ying; Keele University, United Kingdom (Elsevier, 2014-02)
      Non-neuronal cells of the central nervous system (CNS), termed "neuroglia," play critical roles in neural regeneration; therefore, replacement of glial populations via implantable nanofabricated devices (providing a growth-permissive niche) is a promising strategy to enhance repair. Most constructs developed to date have lacked three-dimensionality, multiple glial populations and control over spatial orientations, limiting their ability to mimic in vivo neurocytoarchitecture. We describe a facile technique to incorporate multiple glial cell populations [astrocytes, oligodendrocyte precursor cells (OPCs) and oligodendrocytes] within a three-dimensional (3D) nanofabricated construct. Highly aligned nanofibers could induce elongation of astrocytes, while OPC survival, elongation and maturation required pre-aligned astrocytes. The potential to scale-up the numbers of constituent nanofiber layers is demonstrated with astrocytes. Such complex implantable constructs with multiple glial sub-populations in defined 3D orientations could represent an effective approach to reconstruct glial circuitry in neural injury sites.
    • Alternative methods of treating atelectasis in post-operative patients

      Fallows, Stephen; Mason-Whitehead, Elizabeth; Al Mutairi, Fouad (University of Chester, 2013)
      Cardiac surgery incisional pain can decrease inspiratory effort, alter normal respiratory mechanics, and increase the potential for post-operative pulmonary complications. Post-surgical atelectasis is the most frequent complication after coronary artery bypass grafting (CABG), ranging from 54% to 92%. All types of therapy such as an incentive spirometry (IS), deep breathing exercises (DBE) or continuous positive airway pressure (CPAP) have a valuable role to play in the prevention or the treatment of post-surgical atelectasis. However, the type of therapy that should be used is not completely clear yet. The present research aims to evaluate the benefit of early use of CPAP via mask therapy to treat or prevent post-surgical atelectasis after CABG, particularly in smokers and elderly patients, as compared to regular (IS) therapy. Also, it aims to evaluate the patients' and medical staff's experience about the use of the new method of CPAP via mask therapy. The present research was conducted at King Fahd Armed Forces Hospital in Saudi Arabia between March 2010 and December 2011. It used a mixed methods approach. The first two studies were intervention quantitative studies, which investigated the benefit of CPAP via mask therapy. The others were qualitative studies that evaluated the experience of patients and medical staff regarding CPAP therapy use.A total of 180 patients (male and female) (36 in each group) participated in the two quantitative studies. Ninety two participants (male and female) participated in the qualitative studies. The first quantitative study results showed an improvement in CPAP via mask therapy for half hours every two hours group measurements as compared to IS therapy groups. IC was increased significantly in the "CPAP every two hours group" as compared to control group (IS) (baseline mean for IS group 1.34L and "CPAP every two hours group" 1.42L, post- therapy mean 1.59L and 1.88L respectively, p= 0.037). In addition, when chest physiotherapy was added to the two regimens, the improvement of CPAP therapy measurements became more than IS therapy. Moreover, the patient’s acceptance rate for CPAP therapy every two hours was 93% and the medical staff acceptance rate was 86%. CPAP via mask therapy for half hour every two hours had better outcomes in treating or preventing post-surgical atelectasis after CABG, particularly in smokers and elderly patients. Adding chest physiotherapy led to even better outcomes. The use of the new method of CPAP therapy had high acceptance rate by the participants and medical staff.
    • Alzheimer’s Amyloidopathy: An Alternative Aspect

      Regland, Björn; McCaddon, Andrew (IOS Press, 2019-03-29)
    • Anti-epileptic drugs and bone loss: phenytoin reduces pro-collagen I and alters the electrophoretic mobility of osteonectin in cultured bone cells.

      Wilson, Emma L.; Garton, Mark; Fuller, Heidi R.; RJAH Orthopaedic Hospital; RJAH Orthopaedic NHS Foundation Trust; Keele University (Elsevier, 2016-05-31)
      Phenytoin is an antiepileptic drug used in the management of partial and tonic-clonic seizures. In previous studies we have shown that valproate, another antiepileptic drug, reduced the amount of two key bone proteins, pro-collagen I and osteonectin (SPARC, BM-40), in both skin fibroblasts and cultured osteoblast-like cells. Here we show that phenytoin also reduces pro-collagen I production in osteoblast-like cells, but does not appear to cause a decrease in osteonectin message or protein production. Instead, a 24h exposure to a clinically relevant concentration of phenytoin resulted in a dose-dependent change in electrophoretic mobility of osteonectin, which was suggestive of a change in post-translational modification status. The perturbation of these important bone proteins could be one of the mechanisms to explain the bone loss that has been reported following long-term treatment with phenytoin.
    • Assessing efficacy of cardiac rehabilitation exercise therapy in heart failure patients

      Leslie, Rosalind (University of Chester, 2015-10)
      Background: Exercise-based cardiac rehabilitation (CR) is considered routine practice for patients following an acute cardiac event or surgical intervention. Although there is a seemingly strong evidence base supporting it for patients with chronic heart failure (CHF), provision in the UK remains poor for this patient group. In addition, data for CHF patients reported in key CR reviews and meta-analyses are not a true representation of the UKs CHF population. The transferability of current evidence into actual practice settings in the UK therefore remains incongruous. Rationale and aims: Study outcomes have typically included an increase in VO2 peak/ VO2 max, a decrease in natriuretic peptides, improved left ventricular function and improved health related quality of life (QoL). Access to facilities and equipment, such as cardiopulmonary exercise testing equipment is limited in the UK for the majority of CR services thus an alternative means of assessment and exercise prescription is required. The recommended alternative for testing CHF patients is the six-minute walk test (6MWT); this requires a given space and a full practice test, the latter which adds to valuable clinical and staff time available. Methods: The first set of studies of this thesis therefore investigated two adapted assessment procedures for use with CHF patients: i. the use of a shorter practice walk test of two minutes vs six minutes prior to a 6MWT and ii. the use of the space saving Chester step test with an adapted lower step height protocol to accommodate the anticipated lower fitness in CHF (4-inch vs 6-inch). Having determined a more practical and efficient means of assessing exercise capacity in CHF patients, this thesis then used the 6MWT to evaluate the efficacy of a typically recommended 12-week programme (for the UK) of exercise-based rehabilitation. It was the aim of this PhD to also combine the use of the Chester step test with cardiopulmonary measures as a corresponding physiological outcome in a sub-sample of participants; however due to resource problems, only validation of the low-step protocol was possible. In the main intervention study, the efficacy of a 12-week course of supervised moderate intensity exercise in CHF patients (ejection fraction <44%, NYHA class II to III) was then evaluated. For purposes of evaluating safety and recovery of any acute myocardial stress induced by exercise in CHF, a sub-group study was performed to evaluate the influence of an acute exercise session on two-day post-exercise levels of circulating NT-proBNP. Results: In this current suite of studies, participants were more representative of the UK CHF population than typically reported in the current evidence. Their profile involved a median age of 76 ± 16 years (mean: 67 years and range: 30 to 84 years). 98% of whom were prescribed beta-blockers, 66% were diagnosed with atrial fibrillation and 98% had two or more co-morbidities. Study 1 (Chapter 3a) verified the efficacy of a two-minute practice walk in comparison to the recommended six-minute practice walk prior to performing a baseline 6MWT in patients with CHF. Study 2 (Chapter 3b) demonstrated that a 4-inch Chester step test is a reliable assessment when space is an issue, but the criterion validity of the actual oxygen costs at each stage compared with those estimated in healthy populations were significantly lower than recommended estimations from healthy populations. Study 3 (Chapter 4) revealed individual variability in the acute response of NT-proBNP release to exercise that is worthy of further study. However the NT-proBNP data overall did not suggest a need for ‘rest days’ between exercise training sessions. The main intervention study (Study 4, Chapter 5) demonstrated a significant improvement in 6MWT performance responses, compared with control, where an increased walking distance of 25 m (p < .0001) was coupled with a reduction in heart-rate-walking speed index (T1 16.3 ± 7.3 vs T2 15.3 ± 8.7 beats per 10 walked; p < .0001). Perceptually, patients were walking faster for the same rating of perceived exertion (RPE 12 to 13). This improved aerobic functioning coincided with an improved NYHA class (T1 2.3 ± .5 vs T2 1.8 ± .6; p < .0001); however there was no change in resting NT-proBNP levels after 12 weeks. Patients in the “control group” who then went on to be offered the same 12-week intervention achieved similar outcomes, but delaying their commencement of an exercise programme by 12 weeks negatively impacted on participation uptake. Key findings and conclusions: These results have demonstrated that exercise training in CHF can lead to an improvement in both physical and perceived functioning (NYHA class). In light of some previous studies showing decreases in BNP following an exercise programme and others like this one showing no change, further questions are raised about the effect of different types and doses of activity being offered to CHF patients and the responsiveness to training of different types of patients (disease severity and demographics). The nature of the cross-over design of this study revealed that delayed commencement of exercise negatively affects participation uptake by patients, which supports current UK standards in aiming for early referral to CR.
    • Attitudes of general hospital staff towards patients who self-harm in South India: A cross-sectional study

      Kumar, Narendra; Rajendra, Rajagopal; Majgi, Sumanth M.; Krishna, Murali; Keenan, Paul; Jones, Steven; University of Chester (Medknow, 2016-11-30)
      Background: There is growing global interest into the attitudes and clinical management of persons who deliberately self-harm. People who self-harm experience many problems and typically have many needs related to management of their psychological wellbeing. A positive attitude amongst general hospital staff should prevail with people who self-harm. The principal purpose was to determine student staff attitudes towards patients who self-harmed from a professional and cultural perspective, which might influence patient treatment following hospital admission. The focus concentrated upon staff knowledge, attitudes and beliefs regarding self-harm. Methods: A cross sectional survey of the hospital staff using a validated questionnaire was carried out. This paper reports on interdisciplinary staff from two large general hospitals in Mysuru, South India (n=773). Results: Findings suggest that within a general hospital setting there is wide variation in staff attitudes and knowledge levels related to self-harm. Whilst there is attitudinal evidence for staff attitudes, this study investigates interprofessional differences in an attempt to progress treatment approaches to a vulnerable societal group. Very few staff had any training in assessment of self harm survivors. Conclusion: There is an urgent need for training general hospital staff in self harm assessment and prevention in south India. The results allow a series of recommendations for educational and skills initiatives before progressing to patient assessment and treatment projects and opens potential for cross cultural comparison studies. In addition, interventions must focus on current resources and contexts to move the evidence base and approaches to patient care forward.
    • Autologous chondrocyte implantation-derived synovial fluids display distinct responder and non-responder proteomic profiles

      Hulme, Charlotte H.; Wilson, Emma L.; Peffers, Mandy J.; Roberts, Sally; Simpson, Deborah M.; Richardson, James B.; Gallacher, Pete; Wright, Karina T.; Keele University; Robert Jones and Agnes Hunt Orthopaedic Hospital; University of Chester; University of Liverpool (BioMed Central, 2017-06-30)
      Background Autologous chondrocyte implantation (ACI) can be used in the treatment of focal cartilage injuries to prevent the onset of osteoarthritis (OA). However, we are yet to understand fully why some individuals do not respond well to this intervention. Identification of a reliable and accurate biomarker panel that can predict which patients are likely to respond well to ACI is needed in order to assign the patient to the most appropriate therapy. This study aimed to compare the baseline and mid-treatment proteomic profiles of synovial fluids (SFs) obtained from responders and non-responders to ACI. Methods SFs were derived from 14 ACI responders (mean Lysholm improvement of 33 (17–54)) and 13 non-responders (mean Lysholm decrease of 14 (4–46)) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Label-free proteome profiling of dynamically compressed SFs was used to identify predictive markers of ACI success or failure and to investigate the biological pathways involved in the clinical response to ACI. Results Only 1 protein displayed a ≥2.0-fold differential abundance in the preclinical SF of ACI responders versus non-responders. However, there is a marked difference between these two groups with regard to their proteome shift in response to cartilage harvest, with 24 and 92 proteins showing ≥2.0-fold differential abundance between Stages I and II in responders and non-responders, respectively. Proteomic data has been uploaded to ProteomeXchange (identifier: PXD005220). We have validated two biologically relevant protein changes associated with this response, demonstrating that matrix metalloproteinase 1 was prominently elevated and S100 calcium binding protein A13 was reduced in response to cartilage harvest in non-responders. Conclusions The differential proteomic response to cartilage harvest noted in responders versus non-responders is completely novel. Our analyses suggest several pathways which appear to be altered in non-responders that are worthy of further investigation to elucidate the mechanisms of ACI failure. These protein changes highlight many putative biomarkers that may have potential for prediction of ACI treatment success.
    • Bone extracts can stimulate the secrtion of osteoprotegerin in the osteosarcoma cell lines MG-63 and SAOS-2

      Powell, Diane E.; Johnson, William Eustace Basil; Marshall, Michael J.; Williams, John H. H.; Davie, Michael W. J. (American Society for Bone and Mineral Research, 2005)
    • Bone Marrow-Derived Mesenchymal Stem Cells Become Antiangiogenic When Chondrogenically or Osteogenically Differentiated: Implications for Bone and Cartilage Tissue Engineering

      Bara, Jennifer; Johnson, William Eustace Basil; Roberts, Sally; McCarthy, Helen E.; Humphrey, Emma; AO Institute, Davos, Switzerland; Aston University; Keele University
      Osteochondral tissue repair requires formation of vascularized bone and avascular cartilage. Mesenchymal stem cells stimulate angiogenesis both in vitro and in vivo but it is not known if these proangiogenic properties change as a result of chondrogenic or osteogenic differentiation. We investigated the angiogenic/antiangiogenic properties of equine bone marrow-derived mesenchymal stem cells (eBMSCs) before and after differentiation in vitro. Conditioned media from chondrogenic and osteogenic cell pellets and undifferentiated cells was applied to endothelial tube formation assays using Matrigel. Additionally, the cell secretome was analysed using LC-MS/MS mass spectrometry and screened for angiogenesis and neurogenesis-related factors using protein arrays. Endothelial tube-like formation was supported by conditioned media from undifferentiated eBMSCs. Conversely, chondrogenic and osteogenic conditioned media was antiangiogenic as shown by significantly decreased length of endothelial tube-like structures and degree of branching compared to controls. Undifferentiated cells produced higher levels of angiogenesis-related proteins compared to chondrogenic and osteogenic pellets. In summary, eBMSCs produce an array of angiogenesis-related proteins and support angiogenesis in vitro via a paracrine mechanism. However, when these cells are differentiated chondrogenically or osteogenically, they produce a soluble factor(s) that inhibits angiogenesis. With respect to osteochondral tissue engineering, this may be beneficial for avascular articular cartilage formation but unfavourable for bone formation where a vascularized tissue is desired.
    • c-Myc inhibition decreases CIP2A and reduces BCR-ABL1 tyrosine kinase activity in chronic myeloid leukemia.

      Lucas, Claire; Harris, Robert; Giannoudis, Athina; Clark, Richard; University of Liverpool, Royal Liverpool University hospital (Ferrata Storti Foundation, 2015-05-01)
      NA
    • Ca

      Wong, Vincent K-W.; Qiu, Congling; Xu, Su-Wei; Law, Betty Yuen Kwan; Zeng, Wu; Wang, Hui; Michelangeli, Francesco; Dias, Ivo Ricardo De Seabra Rodrigues; Qu, Yuan Qing; Chan, Tsz Wai; et al. (2019-05-23)
      Celastrol exhibits anti-arthritic effect in rheumatoid arthritis (RA), but the role of celastrol-mediated Ca mobilization in treatment of RA remains unelucidated. Here, we illustrate the regulatory role of celastrol-induced Ca signalling in synovial fibroblasts of RA patients and adjuvant-induced arthritis (AIA) in rats. Molecular target of celastrol was determined by computational docking, Ca dynamic and functional assays on SERCA. Ca -mediated autophagy in RASFs/RAFLS and the underlying mechanism were verified by quantification of endogenous LC3-II puncta, immunoblotting, and flow cytometry with the Ca chelator (BAPTA/AM) or suitable inhibitors. The anti-arthritic effect of celastrol, autophagy induction and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes. The role of Ca in regulating the identified genes was investigated by knockdown of calmodulin, calpains, and calcineurin. Celastrol inhibited SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via CaMKKβ-AMPK-mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory- and autoimmunity-associated genes downregulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca in celastrol-regulated gene expression. Celastrol triggered Ca signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium-dependent/-binding proteins facilitating the exploitation of anti-arthritic drugs based on manipulation of Ca signalling. [Abstract copyright: This article is protected by copyright. All rights reserved.]
    • Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells

      Austin, James A.; orcid: 0000-0002-5384-5221; Jenkins, Rosalind E.; Austin, Gemma M.; Glenn, Mark A.; Dunn, Karen; Scott, Laura; Lucas, Claire M.; Clark, Richard E. (Portland Press Ltd., 2019-08-15)
      Abstract Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5′ AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.
    • Canine mesenchymal stem cells are neurotrophic and angiogenic: An in vitro assessment of their paracrine activity.

      Johnson, William Eustace Basil; Al Delfi, Ibtesam; Aston University, University of Chester, Veterinary Tissue Bank Ltd (Elsevier, 2016-09-19)
      Mesenchymal stem cells (MSCs) have been used in cell replacement therapies for connective tissue damage, but also can stimulate wound healing through paracrine activity. In order to further understand the potential use of MSCs to treat dogs with neurological disorders, this study examined the paracrine action of adipose-derived canine MSCs on neuronal and endothelial cell models. The culture-expanded MSCs exhibited a MSC phenotype according to plastic adherence, cell morphology, CD profiling and differentiation potential along mesenchymal lineages. Treating the SH-SY5Y neuronal cell line with serum-free MSC culture-conditioned medium (MSC CM) significantly increased SH-SY5Y cell proliferation (P <0.01), neurite outgrowth (P = 0.0055) and immunopositivity for the neuronal marker βIII-tubulin (P = 0.0002). Treatment of the EA.hy926 endothelial cell line with MSC CM significantly increased the rate of wound closure in endothelial cell scratch wound assays (P = 0.0409), which was associated with significantly increased endothelial cell proliferation (P <0.05) and migration (P = 0.0001). Furthermore, canine MSC CM induced endothelial tubule formation in EA.hy926 cells in a soluble basement membrane matrix. Hence, this study has demonstrated that adipose-derived canine MSC CM stimulated neuronal and endothelial cells probably through the paracrine activity of MSC-secreted factors. This supports the use of canine MSC transplants or their secreted products in the clinical treatment of dogs with neurological disorders and provides some insight into possible mechanisms of action.
    • Cardiac Rehabilitation Delivery Model for Low-Resource Settings: An International Council of Cardiovascular Prevention and Rehabilitation Consensus Statement

      Grace, Sherry L.; Turk-Adawi, Karam I.; Contractor, Aashish; Atrey, Alison; Campbell, Norman R. C.; Derman, Wayne; Ghisi, Gabriela L. M.; Sarkar, Bidyut K.; Yeo, Tee J.; Lopez-Jimenenez, Francisco; et al. (Elsevier, 2016-08-17)
      Cardiovascular disease (CVD) is a global epidemic, which is largely preventable. Cardiac rehabilitation (CR) is demonstrated to be efficacious and cost-effective for secondary prevention in high-income countries. Given its affordability, CR should be more broadly implemented in middle-income countries as well. Hence, the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR) convened a writing panel to recommend strategies to deliver all core CR components in low-resource settings, namely: (1) initial assessment, (2) lifestyle risk factor management (i.e., diet, tobacco, mental health), (3) medical risk factor management (lipids, blood pressure), (4) education for self-management; (5) return to work; and (6) outcome evaluation. Approaches to delivering these components in alternative, arguably lower-cost settings, such as the home, community and primary care, are provided. Recommendations on delivering each of these components where the most-responsible CR provider is a non-physician, such as an allied healthcare professional or community health care worker, are also provided.
    • CD271-selected mesenchymal stem cells from adipose tissue enhance cartilage repair and are less angiogenic than plastic adherent mesenchymal stem cells

      Kohli, Nupur; Johnson, William Eustace Basil; Uchida, Kenzo; Aston University, University of Chester, University of Fukui (Nature, 2019-02-28)
      CD271 is a marker of bone marrow MSCs with enhanced differentiation capacity for bone or cartilage repair. However, the nature of CD271+ MSCs from adipose tissue (AT) is less well understood. Here, we investigated the differentiation, wound healing and angiogenic capacity of plastic adherent MSCs (PA MSCs) versus CD271+ MSCs from AT. There was no difference in the extent to which PA MSCs and CD271+ MSCs formed osteoblasts, adipocytes or chondrocytes in vitro. In contrast, CD271+ MSCs transplanted into athymic rats significantly enhanced osteochondral wound healing with reduced vascularisation in the repair tissue compared to PA MSCs and control animals; there was little histological evidence of mature articular cartilage formation in all animals. Conditioned medium from CD271+ MSC cultures was less angiogenic than PA MSC conditioned medium, and had little effect on endothelial cell migration or endothelial tubule formation in vitro. The low angiogenic activity of CD271+ MSCs and improved early stage tissue repair of osteochondral lesions when transplanted, along with a comparable differentiation capacity along mesenchymal lineages when induced, suggests that these selected cells are a better candidate than PA MSCs for the repair of cartilaginous tissue.
    • CIP2A- and SETBP1-mediated PP2A inhibition reveals AKT S473 phosphorylation to be a new biomarker in AML

      Hills, Robert; Burnett, Alan; Lucas, Claire; Scott, Laura; Carmell, Natasha; Holcroft, Alison; Clark, Richard; University of Liverpool, Royal Liverpool University hospital, University of Cardiff (American Society for Hematology, 2018-04-27)
      Key Points PP2A inhibition occurs in AML by 2 different pathways: CIP2A in normal karyotype patients and SETBP1 in adverse karyotype patients. AKTS473 phosphorylation is a predictor of survival, and diagnostic levels of AKTS473 could be a novel biomarker in AML.