• Non-Alcoholic Fatty Liver Disease (NAFLD) and Potential Links to Depression, Anxiety, and Chronic Stress

      Shea, Sue; Lionis, Christos; Kite, Chris; Atkinson, Lou; Chaggar, Surinderjeet; Randeva, Harpal S; Kyrou, Ioannis; University of Warwick; University Hospitals Coventry and Warwickshire NHS Trust; University of Crete; University of Chester; Coventry University; Aston University; Forum Health Centre; Agricultural University of Athens (MDPI, 2021-11-16)
      Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease worldwide, and is frequently linked to the metabolic syndrome. The latter represents a clustering of related cardio-metabolic components, which are often observed in patients with NAFLD and increase the risk of cardiovascular disease. Furthermore, growing evidence suggests a positive association between metabolic syndrome and certain mental health problems (e.g., depression, anxiety, and chronic stress). Given the strong overlap between metabolic syndrome and NAFLD, and the common underlying mechanisms that link the two conditions, it is probable that potentially bidirectional associations are also present between NAFLD and mental health comorbidity. The identification of such links is worthy of further investigation, as this can inform more targeted interventions for patients with NAFLD. Therefore, the present review discusses published evidence in relation to associations of depression, anxiety, stress, and impaired health-related quality of life with NAFLD and metabolic syndrome. Attention is also drawn to the complex nature of affective disorders and potential overlapping symptoms between such conditions and NAFLD, while a focus is also placed on the postulated mechanisms mediating associations between mental health and both NAFLD and metabolic syndrome. Relevant gaps/weaknesses of the available literature are also highlighted, together with future research directions that need to be further explored.
    • Treatment-Free Remission in Chronic Myeloid Leukemia: Can We Identify Prognostic Factors?

      Lucas, Claire; Saifullah, Hilbeen H.; University of Chester; University of Liverpool (MDPI, 2021-08-19)
      Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40–60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.
    • A single dose of ChAdOx1 Chik vaccine induces neutralising antibodies against four chikungunya virus lineages in a phase 1 clinical trial

      Folegatti, Pedro M.; Harrison, Kate; Preciado-Llanes, Lorena; Ramos Lopez, Fernando; Bittaye, Mustapha; Kim, Young Chan; Flaxman, Amy; Bellamy, Duncan; Makinson, Rebecca; Sheridan, Jonathan; et al. (Nature Research, 2021-07-30)
      Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18–50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and Tcell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT50 seroconversion after a single dose.
    • A massively multi-scale approach to characterizing tissue architecture by synchrotron micro-CT applied to the human placenta

      Tun, W. M.; orcid: 0000-0003-0991-8785; Poologasundarampillai, G.; orcid: 0000-0002-8498-323X; Bischof, H.; Nye, Gareth; King, O. N. F.; orcid: 0000-0002-6152-7207; Basham, M.; orcid: 0000-0002-8438-1415; Tokudome, Y.; Lewis, R. M.; orcid: 0000-0003-4044-9104; Johnstone, E. D.; Brownbill, P.; orcid: 0000-0002-8328-7072; email: paul.brownbill@manchester.ac.uk; et al. (The Royal Society, 2021-06-02)
      Multi-scale structural assessment of biological soft tissue is challenging but essential to gain insight into structure–function relationships of tissue/organ. Using the human placenta as an example, this study brings together sophisticated sample preparation protocols, advanced imaging and robust, validated machine-learning segmentation techniques to provide the first massively multi-scale and multi-domain information that enables detailed morphological and functional analyses of both maternal and fetal placental domains. Finally, we quantify the scale-dependent error in morphological metrics of heterogeneous placental tissue, estimating the minimal tissue scale needed in extracting meaningful biological data. The developed protocol is beneficial for high-throughput investigation of structure–function relationships in both normal and diseased placentas, allowing us to optimize therapeutic approaches for pathological pregnancies. In addition, the methodology presented is applicable in the characterization of tissue architecture and physiological behaviours of other complex organs with similarity to the placenta, where an exchange barrier possesses circulating vascular and avascular fluid spaces.
    • Validation of CIP2A as a Biomarker of Subsequent Disease Progression and Treatment Failure in Chronic Myeloid Leukaemia

      Clark, Richard E.; email: clarkre@liverpool.ac.uk; Basabrain, Ammar A.; email: a.a.basabrain@liverpool.ac.uk; Austin, Gemma M.; email: gemmajon2003@yahoo.co.uk; Holcroft, Alison K.; email: alisonkholcroft@hotmail.co.uk; Loaiza, Sandra; email: sandra.loaiza@nhs.net; Apperley, Jane F.; email: j.apperley@imperial.ac.uk; Law, Christopher; email: K.C.Law@liverpool.ac.uk; Scott, Laura; email: l.scott1@liverpool.ac.uk; Parry, Alexandra D.; email: alexparry@virginmedia.com; Bonnett, Laura; orcid: 0000-0002-6981-9212; email: L.J.Bonnett@liverpool.ac.uk; et al. (MDPI, 2021-04-29)
      Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.
    • The Comparative Effects of Mesenchymal Stem Cell Transplantation Therapy for Spinal Cord Injury in Humans and Animal Models: A Systematic Review and Meta-Analysis

      Johnson, Louis D. V.; email: louisdvj@gmail.com; Pickard, Mark R.; email: m.pickard@chester.ac.uk; Johnson, William E. B.; email: eustace.johnson@chester.ac.uk (MDPI, 2021-03-16)
      Animal models have been used in preclinical research to examine potential new treatments for spinal cord injury (SCI), including mesenchymal stem cell (MSC) transplantation. MSC transplants have been studied in early human trials. Whether the animal models represent the human studies is unclear. This systematic review and meta-analysis has examined the effects of MSC transplants in human and animal studies. Following searches of PubMed, Clinical Trials and the Cochrane Library, published papers were screened, and data were extracted and analysed. MSC transplantation was associated with significantly improved motor and sensory function in humans, and significantly increased locomotor function in animals. However, there are discrepancies between the studies of human participants and animal models, including timing of MSC transplant post-injury and source of MSCs. Additionally, difficulty in the comparison of functional outcome measures across species limits the predictive nature of the animal research. These findings have been summarised, and recommendations for further research are discussed to better enable the translation of animal models to MSC-based human clinical therapy.
    • Acute glycaemic management before, during and after exercise for cardiac rehabilitation participants with diabetes mellitus; a joint statement of the British and Canadian Associations of Cardiovascular Prevention and Rehabilitation, the International Council for Cardiovascular Prevention and Rehabilitation and the British Association of Sport and Exercise Sciences

      Buckley, J.P.; Riddell, Michael; Mellor, Duane; Bracken, Richard; Ross, Marie-Kristelle; LaGerche, Andre; Poirier, Paul; University of Chester; University College London; York University, Toronto; LMC Healthcare; Aston University; Swansea University College of Engineering; Laval University; Baker Heart and Diabetes Institute; St Vincent's Hospital Melbourne; Institut universitaire de cardiologie et de pneumologie de Québec (BMJ, 2020-12-23)
      Type 1 (T1) and type 2 (T2) diabetes mellitus (DM) are significant precursors and comorbidities to cardiovascular disease and prevalence of both types is still rising globally. Currently,~25% of participants (and rising) attending cardiac rehabilitation in Europe, North America and Australia have been reported to have DM (>90% have T2DM). While there is some debate over whether improving glycaemic control in those with heart disease can independently improve future cardiovascular health-related outcomes, for the individual patient whose blood glucose is well controlled, it can aid the exercise programme in being more efficacious. Good glycaemic management not only helps to mitigate the risk of acute glycaemic events during exercising, it also aids in achieving the requisite physiological and psycho-social aims of the exercise component of cardiac rehabilitation (CR). These benefits are strongly associated with effective behaviour change, including increased enjoyment, adherence and self-efficacy. It is known that CR participants with DM have lower uptake and adherence rates compared with those without DM. This expert statement provides CR practitioners with nine recommendations aimed to aid in the participant’s improved blood glucose control before, during and after exercise so as to prevent the risk of glycaemic events that could mitigate their beneficial participation.
    • Occurrence of chemical pollutants in major e-waste sites in West Africa and usefulness of cytotoxicity and induction of ethoxyresorufin-O-deethylase (EROD) in determining the effects of some detected brominated flame retardants and e-waste soil-derived extracts.

      Eze, Chukwuebuka ThankGod; orcid: 0000-0001-8076-2926; email: thankgod.eze@fuoye.edu.ng; Michelangeli, Francesco; Otitoloju, Adebayo Akeem; Eze, Obianuju Oluchukwu; Ibraheem, Omodele; Ogbuene, Emeka Bright; Ogunwole, Germaine Akinola (2020-10-25)
      We investigated the occurrence of chemical pollutants in major e-waste sites in West Africa and usefulness of cytotoxicity and induction of ethoxyresorufin-O-deethylase (EROD) in determining the effects of some detected brominated flame retardants (BFRs) and e-waste soil-derived extracts. Analysis of the e-waste site samples using AAS and GC-MS techniques revealed the presence of a range of toxic metals as well as persistent and toxic organic pollutants, respectively, in the vicinity of the e-waste sites. As expected, the occurrence (%) of all the detected chemical pollutants in experimental soils significantly (P < 0.05) differs from occurrence (%) in control soil. The calculated LC values on RBL-2H3 cells of the detected tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) were 3.75 μM and 4.2 μM, respectively. Tribromophenol (TBP), dibromobiphenyl (DBB), and decabromodiphenyl ether (DBDE) were remarkably less toxic on RBL-2H3 cells compared with TBBPA and HBCD as they did not reduce RBL-2H3 cell viability below 50% in the tested concentration range (0-20 μM). The study revealed that TBBPA and HBCD could induce significant RBL-2H3 cell death through caspase-dependent apoptosis. The study further shows that the cytotoxicity of some of these BFRs could increase synergistically when in mixtures and potentially activate inflammation through the stimulation of mast cell degranulation. The e-waste soil-derived extracts induced a concentration-dependent increase in EROD activity in the exposed RTG-W1 cells. Ultimately, nonpolar extracts had higher EROD-inducing potency compared with polar extracts and hence suggesting the presence in higher amounts of AhR agonists in nonpolar e-waste soil-derived extracts than polar extracts. Overall, there is urgent need for actions in order to improve the environmental quality of the e-waste sites.
    • History of traction

      Flynn, Sandra (Elsevier, 2020-10-01)
    • Nicotinamide restricts neural precursor proliferation to enhance catecholaminergic neuronal subtype differentiation from mouse embryonic stem cells

      Borlongan, Cesar V.; Griffin, Síle M.; orcid: 0000-0002-6670-5084; email: silemgriffin@gmail.com; Pickard, Mark R.; Hawkins, Clive P.; Williams, Adrian C.; Fricker, Rosemary A.; orcid: 0000-0001-8768-510X (Public Library of Science, 2020-09-14)
      Emerging evidence indicates that a strong relationship exists between brain regenerative therapies and nutrition. Early life nutrition plays an important role during embryonic brain development, and there are clear consequences to an imbalance in nutritional factors on both the production and survival of mature neuronal populations and the infant’s risk of diseases in later life. Our research and that of others suggest that vitamins play a fundamental role in the formation of neurons and their survival. There is a growing body of evidence that nicotinamide, the water-soluble amide form of vitamin B3, is implicated in the conversion of pluripotent stem cells to clinically relevant cells for regenerative therapies. This study investigated the ability of nicotinamide to promote the development of mature catecholaminergic neuronal populations (associated with Parkinson’s disease) from mouse embryonic stem cells, as well as investigating the underlying mechanisms of nicotinamide’s action. Nicotinamide selectively enhanced the production of tyrosine hydroxylase-expressing neurons and serotonergic neurons from mouse embryonic stem cell cultures (Sox1GFP knock-in 46C cell line). A 5-Ethynyl-2´-deoxyuridine (EdU) assay ascertained that nicotinamide, when added in the initial phase, reduced cell proliferation. Nicotinamide drove tyrosine hydroxylase-expressing neuron differentiation as effectively as an established cocktail of signalling factors, reducing the proliferation of neural progenitors and accelerating neuronal maturation, neurite outgrowth and neurotransmitter expression. These novel findings show that nicotinamide enhanced and enriched catecholaminergic differentiation and inhibited cell proliferation by directing cell cycle arrest in mouse embryonic stem cell cultures, thus driving a critical neural proliferation-to-differentiation switch from neural progenitors to neurons. Further research into the role of vitamin metabolites in embryogenesis will significantly advance cell-based regenerative medicine, and help realize their role as crucial developmental signalling molecules in brain development.
    • Comparing physician associates and foundation year two doctors-in-training undertaking emergency medicine consultations in England: a mixed-methods study of processes and outcomes

      Halter, Mary; orcid: 0000-0001-6636-0621; Drennan, Vari; orcid: 0000-0002-8915-5185; Wang, Chao; Wheeler, Carly; Gage, Heather; Nice, Laura; de Lusignan, Simon; orcid: 0000-0001-5613-6810; Gabe, Jonathan; Brearley, Sally; Ennis, James; et al. (BMJ Publishing Group, 2020-09-01)
      Objectives: To compare the contribution of physician associates to the processes and outcomes of emergency medicine consultations with that of foundation year two doctors-in-training. Design: Mixed-methods study: retrospective chart review using 4 months’ anonymised clinical record data of all patients seen by physician associates or foundation year two doctors-in-training in 2016; review of a subsample of 40 records for clinical adequacy; semi-structured interviews with staff and patients; observations of physician associates. Setting: Three emergency departments in England. Participants: The records of 8816 patients attended by 6 physician associates and 40 foundation year two doctors-in-training; of these n=3197 had the primary outcome recorded (n=1129 physician associates, n=2068 doctor); 14 clinicians and managers and 6 patients or relatives for interview; 5 physician associates for observation. Primary and secondary outcome measures: The primary outcome was unplanned re-attendance at the same emergency department within 7 days. Secondary outcomes: consultation processes, clinical adequacy of care, and staff and patient experience. Results: Re-attendances within 7 days (n=194 (6.1%)) showed no difference between physician associates and foundation year two doctors-in-training (OR 0.87, 95% CI 0.61 to 1.24, p=0.437). If seen by a physician associate, patients were more likely receive an X-ray investigation (OR 2.10, 95% CI 1.72 to 4.24), p<0.001), after adjustment for patient characteristics, triage severity of condition and statistically significant clinician intraclass correlation. Clinical reviewers found almost all patients’ charts clinically adequate. Physician associates were evaluated as assessing patients in a similar way to foundation year two doctors-in-training and providing continuity in the team. Patients were positive about the care they had received from a physician associate, but had poor understanding of the role. Conclusions: Physician associates in emergency departments in England treated patients with a range of conditions safely, and at a similar level to foundation year two doctors-in-training, providing clinical operational efficiencies.
    • Attitudes of Female Warders towards inmate who self-harm: A pilot Exploratory Study from an Inner-city Prison in South India

      Jones, Steven; Kumar, Pradeep; Eost-Telling, Charlotte; Kirshna, Murali; University of Chester (The Indian Society of Criminology; National Law University Delhi, 2020-07-01)
      Self-harm is a global public health challenge. The management and treatment of those who self-harm is emotionally challenging, and can sometimes manifest in negative attitudes amongst staff who provide care. Health professional’s attitudes towards deliberate self-harm have been studied globally, however, evidence regarding prison staff attitudes is sparse, and particularly lacking in India. The primary aim of this study was to explore the attitudes of female prison warders towards prison inmates who self-harm in an Indian setting. A cross-sectional survey using a questionnaire to measure knowledge and attitudes was administered to prison warders from one city prison in South India. Out of the 210 approached to participate, 170 female warders completed the survey questionnaire. In general, sociodemographic factors of the prison warders were unrelated to their attitudes towards self-harm, and a negligible few had received any training specific to self-harm. A series of educational and skills recommendations have been developed from the study, which can be used to inform intervention initiatives and further, provide a basis for cross-cultural professional comparison studies. Current resources, cultures, practice and context must be considered in any future interventions aimed at progressing the evidence base further. In addition, training and education for staff should include information on knowledge and attitudes about causes, reasons, motivations, forms and purpose of self-harm. Records of staff responses to those who self-harm, irrespective of setting, should include assessment, management, interventions undertaken and incorporated daily practice. Importantly, this work may influence prisoner treatment outcomes and is worthy of further study.
    • Investigating the Prevalence of Anaemia in Rural Gambia, in Relation to Levels of Zinc Protoporphyrin, Haemoglobin and Haptoglobin (Phenotype and Genotype)

      Bah, Ebrima; Michelangeli, Frank (Oxford University Press (OUP), 2020-05-29)
      Abstract Objectives To find out the overlapping and correlating relationships between serum haptoglobin level, haptoglobin genotype and phenotype, blood haemoglobin level and zinc protoporphyrin (measured in washed RBCs) in association to prevalence of anaemia. It will focus on comparing all the mention components in contrast to each other. The study will also look for the frequency distribution of the major HP alleles. Methods 1278 participants were randomly selected. Blood samples collected by trained nurses. Data generation was done at the Medical research council (keneba field station) research site. Data Analysis was conducted at the university of Chester with the assistance of the computer department team. Results P = 0.000 indicating anaemia prevalence with HP 1 allele. P &amp;gt; 0.05 when ID, IDA and AI relates with HP genotype. Positive correlation between ZnPP and HP serum level, but negative between ZnPP and Hb. P = 0.000 between ZnPP and IDA. P = 0.024 between HP genotype and Hb level. P = 0.013 between HP genotype and HP serum. P = 0.100 between HP genotype and ZnPP. P = 0.000 between ZnPP and IDA. P = 0.024 between HP genotype and Hb. ZnPP shared a positive correlation with HP serum level, and a negative correlation with Hb level. The correlation significant = 0.01 level (2-tailed) P = 0.01. The correlation between HP genotype and HP serum level was significant with P = 0.013, but the correlation between HP genotype and ZnPP was not significant with P = 0.100. Conclusions HP genotype had association with anaemia prevalence and more occurrence was observed in carriers of the type ‘1’ allele. It had no association with ID, IDA and AI. HP genotype had association with HP serum level and Hb level but had no association with ZnPP level. ZnPP level was observed to have had association with HP serum level, Hb level and IDA; but had no association with ID and AI in the region. Funding Sources All the resources used in this study were from MRC Keneba (International Nutrition Group) which is supported by funds from the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (Hennig et al., 2015).
    • 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 (Springer, 2020-04-20)
      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
    • Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca

      Law, Betty Yuen Kwan; Michelangeli, Francesco; Qu, Yuan Qing; orcid: 0000-0003-3733-3661; Xu, Su-Wei; Han, Yu; Mok, Simon Wing Fai; Dias, Ivo Ricardo De Seabra Rodrigues; Javed, Masood-Ul-Hassan; Chan, Wai-Kit; Xue, Wei-Wei; et al. (2019-12-27)
      Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.
    • Stent Migration Following Endovascular Sealing of Abdominal Aortic Aneurysms

      Yafawi, Asma; McWilliams, Richard G.; Fisher, Robert K.; England, Andrew; Karouki, Maria; Torella, Francesco (Elsevier, 2019-12-09)
    • Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks

      Nye, Gareth; Erlich, Alexander; Brownbill, Paul; Chernyavsky, Igor; Jenson, Oliver; University of Manchester (Royal Society, 2019-08-16)
      The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regime
    • 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.
    • Comment on PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia

      Perrotti, D; Agarwal, A; Lucas, Claire; Narla, g; Nevanini, p; Odero, m; Ruvolo, p; Verrills, n; University of Maryland; Imperial College London; Oregon Health and Science University; University of Chester; University of Michigan; University of Southern California; University of Navarra; MD Anderson Cancer Center; University of Newcastle (AAAS, 2019-07-17)
      LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor–induced apoptosis.
    • Comment on "PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia".

      Perrotti, Danilo; Agarwal, Anupriya; Lucas, Claire; Narla, Goutham; Neviani, Paolo; Odero, Maria D.; Ruvolo, Peter P.; Verrills, Nicole M. (American Association for the Advancement of Science, 2019-07-17)
      LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor–induced apoptosis.