• Regucalcin ameliorates doxorubicin-induced cytotoxicity in Cos-7 kidney cells and translocates from the nucleus to the mitochondria

      Mohammed, Noor A.; Hakeem, Israa J.; Hodges, Nikolas; Michelangeli, Francesco; orcid: 0000-0002-4878-046X (Portland Press Ltd., 2022-01-06)
      Abstract Doxorubicin (DOX) is a potent anticancer drug, which can have unwanted side-effects such as cardiac and kidney toxicity. A detailed investigation was undertaken of the acute cytotoxic mechanisms of DOX on kidney cells, using Cos-7 cells as kidney cell model. Cos-7 cells were exposed to DOX for a period of 24 h over a range of concentrations, and the LC50 was determined to be 7 µM. Further investigations showed that cell death was mainly via apoptosis involving Ca2+ and caspase 9, in addition to autophagy. Regucalcin (RGN), a cytoprotective protein found mainly in liver and kidney tissues, was overexpressed in Cos-7 cells and shown to protect against DOX-induced cell death. Subcellular localization studies in Cos-7 cells showed RGN to be strongly correlated with the nucleus. However, upon treatment with DOX for 4 h, which induced membrane blebbing in some cells, the localization appeared to be correlated more with the mitochondria in these cells. It is yet to be determined whether this translocation is part of the cytoprotective mechanism or a consequence of chemically induced cell stress.
    • Regucalcin ameliorates Doxorubicin-induced cytotoxicity in Cos-7 kidney cells and translocates from the nucleus to the mitochondria.

      Mohammed, Noor A; Hakeem, Israa; Hodges, Nikolas J; Michelangeli, Francesco (2021-12-14)
      Doxorubicin (DOX) is a potent anti-cancer drug, which can have unwanted side-effects such as cardiac and kidney toxicity. A detailed investigation was undertaken of the acute cytotoxic mechanisms of DOX on kidney cells, using Cos-7 cells as kidney cell model. Cos-7 cells were exposed to DOX for a period of 24 hours over a range of concentrations and the LC50 was determined to be 7µM. Further investigations showed that cell death was mainly via apoptosis involving Ca2+ and caspase 9, in addition to autophagy. Regucalcin (RGN), a cytoprotective protein found mainly in liver and kidney tissues, was overexpressed in Cos-7 cells and shown to protect against DOX-induced cell death. Subcellular localization studies in Cos-7 cells showed RGN to be strongly correlated with the nucleus. However, upon treatment with DOX for 4 hours, which induced membrane blebbing in some cells, the localization appeared to be correlated more with the mitochondria in these cells. It is yet to be determined whether this translocation is part of the cytoprotective mechanism or a consequence of chemically-induced cell stress. [Abstract copyright: Copyright 2021 The Author(s).]
    • Regulating patient safety during hospital discharges: Casting the Patient Safety Commissioner as the Representative of Order

      Moore, Victoria L.; orcid: 0000-0002-1349-3612; email: victoria.moore@manchester.ac.uk (SAGE Publications, 2021-06-11)
      This article examines the challenges in regulating patient safety during hospital discharges in England through the lens of liminality. Hospital discharges are internationally recognised as being a dangerous time for patients, and yet the role that regulators should play in addressing this has received little attention in any jurisdiction. Liminality’s spotlight on the in-between highlights how the discharge process can give rise to patient safety incidents that fall between regulator’s boundaries. Falling between boundaries results in a dearth of effective regulatory responses to address these incidents. By positioning the new role of Patient Safety Commissioner (PSC) as that of a ‘Representative of Order’, this article proposes a means by which this poorly regulated space could be navigated more successfully. This analysis suggests that the remit of the PSC role be expanded to include improving patient safety with regard to processes – not just medicines and medical devices. The full implications of this are also addressed.
    • Reid Bryson: The crisis climatologist

      Naylor, Robert Luke; orcid: 0000-0002-9585-9939; email: robert.naylor-4@postgrad.manchester.ac.uk (John Wiley & Sons, Inc., 2021-10-25)
      Abstract: Reid Allen Bryson (1920–2008) was a forceful orator who consistently fought against institutional pressures to get his messages out to the public. In the 1960s, Bryson was a leader in the wider academic turn toward politically charged interdisciplinarianism. To the dismay of many of his colleagues, he publicly made climatological prognoses in the 1970s, becoming a significant figure in the media landscape. He was not swayed by the arguments for global warming, even as the framing became the recognized face of climate change in the late 1980s. By examining the controversies that Bryson instigated and the currents that he swam against, we can see the wider community crystallizing and promoting positions that may have previously gone unstated. In addition, Bryson's personal contribution to the rise of climate discourse has been underexplored in the historical literature. Bryson was instrumental in bringing climate onto the political radar during the World Food Crisis of 1973, shocking both the US and Canadian political establishments into paying more attention to the issue. Bryson's narrative linking climate change to both food supply and a series of climate anomalies in the 1970s remained predominant in the first World Climate Conference of 1979. Bryson also helped break a seal on climatologists speaking directly to the media, leading to unprecedented climate discourse in the 1970s and giving climate change a springboard to become one of the defining issues of the 21st century. This article is categorized under: Climate, History, Society, Culture > Thought Leaders
    • Reimagining climate‐informed development: From “matters of fact” to “matters of care”

      Tozzi, Arianna; orcid: 0000-0002-7639-0178; email: arianna.tozzi@postgrad.manchester.ac.uk (2021-06-03)
      This paper is concerned with the impasse climate‐informed development practices currently find themselves in. This is represented by the fact that while “solutions” to reduce vulnerabilities and enhance capacities for adaptation and resilience are increasingly adopted around the world, we have enough evidence to suggest that strategies adopted “from above” have been unable to engender transformations towards more just and liveable futures. Situating the paper within recent calls for a “post‐adaptation” turn in the field, I propose a generative critique of climate‐informed development through the lens of care as a place from where to begin thinking and practicing development differently. The aim of this critique is not to discard or discredit development practices as necessarily tainted or flawed but to make them accountable to a whole set of concerns and cares going into their stories of success or failures. Throughout the paper, I therefore speculatively ask the reader to think though the possibilities that may be opened when we stop treating climate‐informed development projects as neutral and undisputable “matters of fact,” engaging with them instead as necessary and non‐innocent “matters of care.” Thinking through a tryptic notion of “matters of care,” as at the same time a neglected doing necessary for the sustenance of life, an affective state, and an ethico‐politics, I look at examples from semi‐arid areas of India to give visibility to those practices, relations, and emotions of care that have been marginalised by mainstream development circles. Through this shift in perception, a deeper understanding of vulnerability as a state of shared fragility emerges, one that grounds an ethico‐politics of climate‐informed development to concrete circumstances and becomes the foundation upon which more inclusive practices can be built upon.
    • The relationship between target joints and direct resource use in severe haemophilia

      O’Hara, Jamie; Walsh, Shaun; Camp, Charlotte; Mazza, Giuseppe; Carroll, Liz; Hoxer, Christina; Wilkinson, Lars; University of Chester; HCD Economics, The Innovation Centre, Daresbury; University College London; The Haemophilia Society; Novo Nordisk A/S (SpringerOpen, 2018-01-16)
      Objectives Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related direct costs (NDDCs) has not been studied. Methods Data on haemophilia patients without inhibitors was drawn from the ‘Cost of Haemophilia across Europe – a Socioeconomic Survey’ (CHESS) study, a cost assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) in which 139 haemophilia specialists provided demographic and clinical information for 1285 adult patients. NDDCs were calculated using publicly available cost data, including 12-month ambulatory and secondary care activity: haematologist and other specialist consultant consultations, medical tests and examinations, bleed-related hospital admissions, and payments to professional care providers. A generalized linear model was developed to investigate the relationship between NDDCs and target joints (areas of chronic synovitis), adjusted for patient covariates. Results Five hundred and thirteen patients (42% of the sample) had no diagnosed target joints; a total of 1376 target joints (range 1–10) were recorded in the remaining 714 patients. Mean adjusted NDDCs for persons with no target joints were EUR 3134 (standard error (SE) EUR 158); for persons with one or more target joints, mean adjusted NDDCs were EUR 3913 (SE EUR 157; average mean effect EUR 779; p < 0.001). Conclusions Our analysis suggests that the presence of one or more target joints has a significant impact on NDDCs for patients with severe haemophilia, ceteris paribus. Prevention and management of target joints should be an important consideration of managing haemophilia patients.
    • Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

      Fachim; email: helene.fachim@manchester.ac.uk; Iqbal; email: zohaib@doctors.org.uk; Gibson; email: martin.gibson@manchester.ac.uk; Baricevic-Jones; email: ivona.baricevic-jones@manchester.ac.uk; Campbell; email: amy.campbell@manchester.ac.uk; Geary; orcid: 0000-0002-5592-5532; email: bethany.geary@manchester.ac.uk; Syed; orcid: 0000-0001-8696-7121; email: akheel.syed@manchester.ac.uk; Whetton; orcid: 0000-0002-1098-3878; email: tony.whetton@manchester.ac.uk; Soran; email: handrean.soran@mft.nhs.uk; Donn; orcid: 0000-0001-6976-9828; email: Rachelle.donn@manchester.ac.uk; et al. (MDPI, 2021-10-19)
      Severe obesity is a disease associated with multiple adverse effects on health. Metabolic bariatric surgery (MBS) can have significant effects on multiple body systems and was shown to improve inflammatory markers in previous short-term follow-up studies. We evaluated associations between changes in inflammatory markers (CRP, IL6 and TNFα) and circulating proteins after MBS. Methods: Sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics was performed on plasma samples taken at baseline (pre-surgery) and 6 and 12 months after MBS, and concurrent analyses of inflammatory/metabolic parameters were carried out. The change in absolute abundances of those proteins, showing significant change at both 6 and 12 months, was tested for correlation with the absolute and percentage (%) change in inflammatory markers. Results: We found the following results: at 6 months, there was a correlation between %change in IL-6 and fold change in HSPA4 (rho = −0.659; p = 0.038) and in SERPINF1 (rho = 0.714, p = 0.020); at 12 months, there was a positive correlation between %change in IL-6 and fold change in the following proteins—LGALS3BP (rho = 0.700, p = 0.036), HSP90B1 (rho = 0.667; p = 0.05) and ACE (rho = 0.667, p = 0.05). We found significant inverse correlations at 12 months between %change in TNFα and the following proteins: EPHX2 and ACE (for both rho = −0.783, p = 0.013). We also found significant inverse correlations between %change in CRP at 12 months and SHBG (rho = −0.759, p = 0.029), L1CAM (rho = −0.904, p = 0.002) and AMBP (rho = −0.684, p = 0.042). Conclusion: Using SWATH-MS, we identified several proteins that are involved in the inflammatory response whose levels change in patients who achieve remission of T2DM after bariatric surgery in tandem with changes in IL6, TNFα and/or CRP. Future studies are needed to clarify the underlying mechanisms in how MBS decreases low-grade inflammation.
    • Relationships among unmet needs, depression, and anxiety in non–advanced cancer patients

      Ferrari, Martina; Ripamonti, Carla I.; Hulbert-Williams, Nicholas J.; Miccinesi, Guido (SAGE Publications, 2018-04-16)
      Introduction: In oncology settings, less attention is given to patients’ unmet needs and to existential and emotional distress compared to physical symptoms. We aimed to evaluate correlations between unmet needs and emotional distress (self-reported anxiety and depression) in a consecutive cohort of cancer patients. The influence of sociodemographic and clinical factors was also considered. Methods: A total of 300 patients with cancer recruited from an outpatient Supportive Care Unit of a Comprehensive Cancer Centre completed the Need Evaluation Questionnaire and the Edmonton Symptom Assessment System (ESAS). Unmet needs covered 5 distinct domains (informational, care/assistance, relational, psychoemotional, and material). Results: After removal of missing data, we analyzed data from 258 patients. Need for better information on future health concerns (43%), for better services from the hospital (42%), and to speak with individuals in the same condition (32%) were the most frequently reported as unmet. Based on the ESAS, 27.2% and 17.5% of patients, respectively, had a score of anxiety or depression &gt;3 and needed further examination for psychological distress. Female patients had significantly higher scores for anxiety ( p &lt; 0.001) and depression ( p = 0.008) compared to male patients. Unmet needs were significantly correlated with both anxiety ( rs = 0.283) and depression ( rs = 0.284). Previous referral to a psychologist was significantly associated with depression scores ( p = 0.015). Results were confirmed by multiple regression analysis. Conclusions: Screening for unmet needs while also considering sociodemographic and clinical factors allows early identification of cancer patients with emotional distress. Doing so will enable optimal management of psychological patient-reported outcomes in oncology settings.
    • Reliability and prognostic value of radiomic features are highly dependent on choice of feature extraction platform

      Fornacon-Wood, Isabella; orcid: 0000-0002-3736-2967; email: Isabella.fornacon-wood@postgrad.manchester.ac.uk; Mistry, Hitesh; Ackermann, Christoph J.; Blackhall, Fiona; McPartlin, Andrew; Faivre-Finn, Corinne; Price, Gareth J.; O’Connor, James P. B. (Springer Berlin Heidelberg, 2020-06-01)
      Abstract: Objective: To investigate the effects of Image Biomarker Standardisation Initiative (IBSI) compliance, harmonisation of calculation settings and platform version on the statistical reliability of radiomic features and their corresponding ability to predict clinical outcome. Methods: The statistical reliability of radiomic features was assessed retrospectively in three clinical datasets (patient numbers: 108 head and neck cancer, 37 small-cell lung cancer, 47 non-small-cell lung cancer). Features were calculated using four platforms (PyRadiomics, LIFEx, CERR and IBEX). PyRadiomics, LIFEx and CERR are IBSI-compliant, whereas IBEX is not. The effects of IBSI compliance, user-defined calculation settings and platform version were assessed by calculating intraclass correlation coefficients and confidence intervals. The influence of platform choice on the relationship between radiomic biomarkers and survival was evaluated using univariable cox regression in the largest dataset. Results: The reliability of radiomic features calculated by the different software platforms was only excellent (ICC > 0.9) for 4/17 radiomic features when comparing all four platforms. Reliability improved to ICC > 0.9 for 15/17 radiomic features when analysis was restricted to the three IBSI-compliant platforms. Failure to harmonise calculation settings resulted in poor reliability, even across the IBSI-compliant platforms. Software platform version also had a marked effect on feature reliability in CERR and LIFEx. Features identified as having significant relationship to survival varied between platforms, as did the direction of hazard ratios. Conclusion: IBSI compliance, user-defined calculation settings and choice of platform version all influence the statistical reliability and corresponding performance of prognostic models in radiomics. Key Points: • Reliability of radiomic features varies between feature calculation platforms and with choice of software version. • Image Biomarker Standardisation Initiative (IBSI) compliance improves reliability of radiomic features across platforms, but only when calculation settings are harmonised. • IBSI compliance, user-defined calculation settings and choice of platform version collectively affect the prognostic value of features.
    • 'Relieved to be seen'-patient and carer experiences of psychosocial assessment in the emergency department following self-harm: qualitative analysis of 102 free-text survey responses.

      Quinlivan, Leah M; orcid: 0000-0002-3944-3613; email: leah.quinlivan@manchester.ac.uk; Gorman, Louise; Littlewood, Donna L; Monaghan, Elizabeth; Barlow, Steven J; Campbell, Stephen M; Webb, Roger T; Kapur, Navneet (2021-05-23)
      We sought to explore patient and carer experiences of psychosocial assessments following presentations to hospital after self-harm. Thematic analysis of free-text responses to an open-ended online survey. Between March and November 2019, we recruited 88 patients (82% women) and 14 carers aged ≥18 years from 16 English mental health trusts, community organisations, and via social media. Psychosocial assessments were experienced as helpful on some occasions but harmful on others. Participants felt better, less suicidal and less likely to repeat self-harm after good-quality compassionate and supportive assessments. However, negative experiences during the assessment pathway were common and, in some cases, contributed to greater distress, less engagement and further self-harm. Participants reported receiving negative and stigmatising comments about their injuries. Others reported that they were refused medical care or an anaesthetic. Stigmatising attitudes among some mental health staff centred on preconceived ideas over self-harm as a 'behavioural issue', inappropriate use of services and psychiatric diagnosis. Our findings highlight important patient experiences that can inform service provision and they demonstrate the value of involving patients/carers throughout the research process. Psychosocial assessments can be beneficial when empathetic and collaborative but less helpful when overly standardised, lacking in compassion and waiting times are unduly long. Patient views are essential to inform practice, particularly given the rapidly changing service context during and after the COVID-19 emergency. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.]
    • 'Relieved to be seen'-patient and carer experiences of psychosocial assessment in the emergency department following self-harm: qualitative analysis of 102 free-text survey responses.

      Quinlivan, Leah M; orcid: 0000-0002-3944-3613; email: leah.quinlivan@manchester.ac.uk; Gorman, Louise; Littlewood, Donna L; Monaghan, Elizabeth; Barlow, Steven J; Campbell, Stephen M; Webb, Roger T; Kapur, Navneet (2021-05-23)
      <h4>Objectives</h4>We sought to explore patient and carer experiences of psychosocial assessments following presentations to hospital after self-harm.<h4>Design</h4>Thematic analysis of free-text responses to an open-ended online survey.<h4>Setting</h4>Between March and November 2019, we recruited 88 patients (82% women) and 14 carers aged ≥18 years from 16 English mental health trusts, community organisations, and via social media.<h4>Results</h4>Psychosocial assessments were experienced as helpful on some occasions but harmful on others. Participants felt better, less suicidal and less likely to repeat self-harm after good-quality compassionate and supportive assessments. However, negative experiences during the assessment pathway were common and, in some cases, contributed to greater distress, less engagement and further self-harm. Participants reported receiving negative and stigmatising comments about their injuries. Others reported that they were refused medical care or an anaesthetic. Stigmatising attitudes among some mental health staff centred on preconceived ideas over self-harm as a 'behavioural issue', inappropriate use of services and psychiatric diagnosis.<h4>Conclusion</h4>Our findings highlight important patient experiences that can inform service provision and they demonstrate the value of involving patients/carers throughout the research process. Psychosocial assessments can be beneficial when empathetic and collaborative but less helpful when overly standardised, lacking in compassion and waiting times are unduly long. Patient views are essential to inform practice, particularly given the rapidly changing service context during and after the COVID-19 emergency.
    • Renewable and tuneable bio-LPG blends derived from amino acids

      Amer, Mohamed; Hoeven, Robin; Kelly, Paul; Faulkner, Matthew; Smith, Michael H.; Toogood, Helen S.; Scrutton, Nigel S.; orcid: 0000-0002-4182-3500; email: nigel.scrutton@manchester.ac.uk (BioMed Central, 2020-07-14)
      Abstract: Background: Microbial biorefinery approaches are beginning to define renewable and sustainable routes to clean-burning and non-fossil fuel-derived gaseous alkanes (known as ‘bio-LPG’). The most promising strategies have used a terminal fatty acid photodecarboxylase, enabling light-driven propane production from externally fed waste butyric acid. Use of Halomonas (a robust extremophile microbial chassis) with these pathways has enabled bio-LPG production under non-sterile conditions and using waste biomass as the carbon source. Here, we describe new engineering approaches to produce next-generation pathways that use amino acids as fuel precursors for bio-LPG production (propane, butane and isobutane blends). Results: Multiple pathways from the amino acids valine, leucine and isoleucine were designed in E. coli for the production of propane, isobutane and butane, respectively. A branched-chain keto acid decarboxylase-dependent pathway utilising fatty acid photodecarboxylase was the most effective route, generating higher alkane gas titres over alternative routes requiring coenzyme A and/or aldehyde deformylating oxygenase. Isobutane was the major gas produced in standard (mixed amino acid) medium, however valine supplementation led to primarily propane production. Transitioning pathways into Halomonas strain TQ10 enabled fermentative production of mixed alkane gases under non-sterile conditions on simple carbon sources. Chromosomal integration of inducible (~ 180 mg/g cells/day) and constitutive (~ 30 mg/g cells/day) pathways into Halomonas generated production strains shown to be stable for up to 7 days. Conclusions: This study highlights new microbial pathways for the production of clean-burning bio-LPG fuels from amino acids. The use of stable Halomonas production strains could lead to gas production in the field under non-sterile conditions following process optimisation.
    • Replication catastrophe is responsible for intrinsic PAR glycohydrolase inhibitor-sensitivity in patient-derived ovarian cancer models

      Coulson-Gilmer, Camilla; Morgan, Robert D.; Nelson, Louisa; Barnes, Bethany M.; Tighe, Anthony; Wardenaar, René; Spierings, Diana C. J.; Schlecht, Helene; Burghel, George J.; Foijer, Floris; et al. (BioMed Central, 2021-10-16)
      Abstract: Background: Patients with ovarian cancer often present at advanced stage and, following initial treatment success, develop recurrent drug-resistant disease. PARP inhibitors (PARPi) are yielding unprecedented survival benefits for women with BRCA-deficient disease. However, options remain limited for disease that is platinum-resistant and/or has inherent or acquired PARPi-resistance. PARG, the PAR glycohydrolase that counterbalances PARP activity, is an emerging target with potential to selectively kill tumour cells harbouring oncogene-induced DNA replication and metabolic vulnerabilities. Clinical development of PARG inhibitors (PARGi) will however require predictive biomarkers, in turn requiring an understanding of their mode of action. Furthermore, differential sensitivity to PARPi is key for expanding treatment options available for patients. Methods: A panel of 10 ovarian cancer cell lines and a living biobank of patient-derived ovarian cancer models (OCMs) were screened for PARGi-sensitivity using short- and long-term growth assays. PARGi-sensitivity was characterized using established markers for DNA replication stress, namely replication fibre asymmetry, RPA foci, KAP1 and Chk1 phosphorylation, and pan-nuclear γH2AX, indicating DNA replication catastrophe. Finally, gene expression in sensitive and resistant cells was also examined using NanoString or RNAseq. Results: PARGi sensitivity was identified in both ovarian cancer cell lines and patient-derived OCMs, with sensitivity accompanied by markers of persistent replication stress, and a pre-mitotic cell cycle block. Moreover, DNA replication genes are down-regulated in PARGi-sensitive cell lines consistent with an inherent DNA replication vulnerability. However, DNA replication gene expression did not predict PARGi-sensitivity in OCMs. The subset of patient-derived OCMs that are sensitive to single-agent PARG inhibition, includes models that are PARPi- and/or platinum-resistant, indicating that PARG inhibitors may represent an alternative treatment strategy for women with otherwise limited therapeutic options. Conclusions: We discover that a subset of ovarian cancers are intrinsically sensitive to pharmacological PARG blockade, including drug-resistant disease, underpinned by a common mechanism of replication catastrophe. We explore the use of a transcript-based biomarker, and provide insight into the design of future clinical trials of PARGi in patients with ovarian cancer. However, our results highlight the complexity of developing a predictive biomarker for PARGi sensitivity.
    • Replication catastrophe is responsible for intrinsic PAR glycohydrolase inhibitor-sensitivity in patient-derived ovarian cancer models.

      Coulson-Gilmer, Camilla; Morgan, Robert D; Nelson, Louisa; Barnes, Bethany M; Tighe, Anthony; Wardenaar, René; Spierings, Diana C J; Schlecht, Helene; Burghel, George J; Foijer, Floris; orcid: 0000-0003-0989-3127; et al. (2021-10-16)
      <h4>Background</h4>Patients with ovarian cancer often present at advanced stage and, following initial treatment success, develop recurrent drug-resistant disease. PARP inhibitors (PARPi) are yielding unprecedented survival benefits for women with BRCA-deficient disease. However, options remain limited for disease that is platinum-resistant and/or has inherent or acquired PARPi-resistance. PARG, the PAR glycohydrolase that counterbalances PARP activity, is an emerging target with potential to selectively kill tumour cells harbouring oncogene-induced DNA replication and metabolic vulnerabilities. Clinical development of PARG inhibitors (PARGi) will however require predictive biomarkers, in turn requiring an understanding of their mode of action. Furthermore, differential sensitivity to PARPi is key for expanding treatment options available for patients.<h4>Methods</h4>A panel of 10 ovarian cancer cell lines and a living biobank of patient-derived ovarian cancer models (OCMs) were screened for PARGi-sensitivity using short- and long-term growth assays. PARGi-sensitivity was characterized using established markers for DNA replication stress, namely replication fibre asymmetry, RPA foci, KAP1 and Chk1 phosphorylation, and pan-nuclear γH2AX, indicating DNA replication catastrophe. Finally, gene expression in sensitive and resistant cells was also examined using NanoString or RNAseq.<h4>Results</h4>PARGi sensitivity was identified in both ovarian cancer cell lines and patient-derived OCMs, with sensitivity accompanied by markers of persistent replication stress, and a pre-mitotic cell cycle block. Moreover, DNA replication genes are down-regulated in PARGi-sensitive cell lines consistent with an inherent DNA replication vulnerability. However, DNA replication gene expression did not predict PARGi-sensitivity in OCMs. The subset of patient-derived OCMs that are sensitive to single-agent PARG inhibition, includes models that are PARPi- and/or platinum-resistant, indicating that PARG inhibitors may represent an alternative treatment strategy for women with otherwise limited therapeutic options.<h4>Conclusions</h4>We discover that a subset of ovarian cancers are intrinsically sensitive to pharmacological PARG blockade, including drug-resistant disease, underpinned by a common mechanism of replication catastrophe. We explore the use of a transcript-based biomarker, and provide insight into the design of future clinical trials of PARGi in patients with ovarian cancer. However, our results highlight the complexity of developing a predictive biomarker for PARGi sensitivity.
    • Reporting Microaggressions: Kinship Carers’ Complaints about Identity Slights

      Wilkes, Julie; orcid: 0000-0003-4768-3825; email: julie.wilkes@postgrad.manchester.ac.uk; Speer, Susan A. (SAGE Publications, 2020-10-28)
      The psychological concept of “microaggression” has refocused interest on what counts as prejudicial action. It redirects attention from standard socio-cognitive explanations of overt prejudice among social groups toward recipients’ perspectives of largely unwitting and subtle everyday racism. Microaggression studies define common implicit identity challenges faced by minority groups, including kinship carers. However, criticisms of the “microaggressions program” raise difficulties inherent in establishing prejudicial action from accounts of necessarily ambiguous actions, and contend that reliance on self-reporting inevitably lacks validity. This conversation analytic (CA) study offers a complementary approach: from videos of ten kinship carer support groups it shows how participants construct accountabilities for prejudicial actions in their retrospective reports of questions, challenges and suspicions in ways that build these actions as microaggressive. It addresses methodological shortcomings in microaggression studies, and extends CA research on accountability in offense construction, and on prejudicial social actions that are contested and difficult to analyze.
    • Researching online counselling and psychotherapy: The past, the present and the future

      Hanley, Terry; orcid: 0000-0001-5861-9170; email: terry.hanley@manchester.ac.uk (2020-12-29)
      Abstract: This paper reflects upon the history of online counselling and psychotherapy research. It provides a reflection upon the growing body of research in this field and discusses the impact of the recent global COVID‐19 pandemic upon it. It specifically argues that the pandemic has been an evolutionary catalyst for developments in online therapy. Therapeutic practices, and attitudes towards them, have changed in ways that will alter the shape and form of therapies in the future. As a consequence, research into online therapeutic work needs to be responsive and adapt to this changing world. Counselling and psychotherapy researchers therefore have to situate themselves in a way that allows them to keep one foot in the present and one foot in the future to stay abreast of technological developments. There may be a reluctance to do so from some areas in the therapeutic profession, but their presence might prove vital in ensuring that ethical sensitivity, which acknowledges and values the complexity of the human experience, remains at the foreground of psychological support.
    • Resilience and mindfulness in nurse training on an undergraduate curriculum

      Mitchell, Andrew E. P.; orcid: 0000-0001-6244-5249 (Wiley, 2020-12-23)
    • The ReSiT study (reducing sitting time): rationale and protocol for an exploratory pilot study of an intervention to reduce sitting time among office workers

      Gardner, Benjamin; Dewitt, Stephen; Smith, Lee; Buckley, John P.; Biddle, Stuart J. H.; Mansfield, Louise; King's College London; Anglia Ruskin University; University of Chester; University of Southern Queensland; Brunel University (BioMed Central, 2017-11-28)
      Background Desk-based workers engage in long periods of uninterrupted sitting time, which has been associated with morbidity and premature mortality. Previous workplace intervention trials have demonstrated the potential of providing sit-stand workstations, and of administering motivational behaviour change techniques, for reducing sitting time. Yet, few studies have combined these approaches or explored the acceptability of discrete sitting-reduction behaviour change strategies. This paper describes the rationale for a sitting-reduction intervention that combines sit-stand workstations with motivational techniques, and procedures for a pilot study to explore the acceptability of core intervention components among university office workers. Methods The intervention is based on a theory and evidence-based analysis of why office workers sit, and how best to reduce sitting time. It seeks to enhance motivation and capability, as well as identify opportunities, required to reduce sitting time. Thirty office workers will participate in the pilot study. They will complete an initial awareness-raising monitoring and feedback task and subsequently receive a sit-stand workstation for a 12-week period. They will also select from a ‘menu’ of behaviour change techniques tailored to self-declared barriers to sitting reduction, effectively co-producing and personally tailoring their intervention. Interviews at 1, 6, and 12 weeks post-intervention will explore intervention acceptability. Discussion To our knowledge, this will be the first study to explore direct feedback from office workers on the acceptability of discrete tailored sitting-reduction intervention components that they have received. Participants’ choice of and reflections on intervention techniques will aid identification of strategies suitable for inclusion in the next iteration of the intervention, which will be delivered in a self-administered format to minimise resource burden. Trial registration ISRCTN29395780 (registered 21 November 2016)
    • Resolution of Lithium Deposition versus Intercalation of Graphite Anodes in Lithium Ion Batteries: An In Situ Electron Paramagnetic Resonance Study

      Wang, Bin; Le Fevre, Lewis W.; Brookfield, Adam; McInnes, Eric J. L.; email: eric.mcinnes@manchester.ac.uk; Dryfe, Robert A. W.; orcid: 0000-0002-9335-4451; email: robert.dryfe@manchester.ac.uk (2021-08-13)
      Abstract: In situ electrochemical electron paramagnetic resonance (EPR) spectroscopy is used to understand the mixed lithiation/deposition behavior on graphite anodes during the charging process. The conductivity, degree of lithiation, and the deposition process of the graphite are reflected by the EPR spectroscopic quality factor, the spin density, and the EPR spectral change, respectively. Classical over‐charging (normally associated with potentials ≤0 V vs. Li+/Li) are not required for Li metal deposition onto the graphite anode: Li deposition initiates at ca. +0.04 V (vs. Li+/Li) when the scan rate is lowered to 0.04 mV s−1. The inhibition of Li deposition by vinylene carbonate (VC) additive is highlighted by the EPR results during cycling, attributed to a more mechanically flexible and polymeric SEI layer with higher ionic conductivity. A safe cut‐off potential limit of +0.05 V for the anode is suggested for high rate cycling, confirmed by the EPR response over prolonged cycling.