Publications by authors named "Hannah Maple"

23 Publications

  • Page 1 of 1

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma.

Oncogenesis 2021 Oct 12;10(10):68. Epub 2021 Oct 12.

Lillehei Heart Institute, Minneapolis, USA.

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.
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http://dx.doi.org/10.1038/s41389-021-00357-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511258PMC
October 2021

Building a bridge between patients and transplant healthcare professionals - a descriptive study.

Transpl Int 2021 Nov 7;34(11):2098-2105. Epub 2021 Oct 7.

Donation and Transplant Coordination Unit, Associate Professor Surgical Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.

This article describes a pathway for collaboration between transplant healthcare professionals and organ recipients. Under the umbrella of the European Society for Organ Transplantation (ESOT) a joint initiative started from three Sections and Committees of ESOT: EDTCO (European Donation and Transplant Coordination Organisation), ETHAP (European Transplant Allied Healthcare Professionals) and ELPAT (Ethical, Legal and Psycho-social Aspects of Transplantation). The formal 'kick-off' of the Advisory Board Meeting of the European Transplant Patient Organisation (ETPO) was during the ESOT congress in 2019. The aim was to produce a series of statements to serve as a path to dialogue between patients and transplant professionals and to define the next steps towards giving a voice to the patient network. To include the patients' perspectives, two surveys have been performed. The results identified the unmet needs and lead to a proposal for future plans. Educational activities have since started leading to a patient learning workstream. All initiatives taken have one purpose: to include patients, give them a voice and build a foundation for collaboration between patients and transplant professionals. ESOT has created a platform for mutual understanding, learning and a collaborative partnership between ETPO and European donation and transplant professionals.
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http://dx.doi.org/10.1111/tri.14111DOI Listing
November 2021

Reviewing the toolbox for degrader development in oncology.

Curr Opin Pharmacol 2021 08 28;59:43-51. Epub 2021 May 28.

Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Avonmouth, Bristol, UK. Electronic address:

The field of targeted protein degradation encompasses a growing number of modalities that achieve potent and selective knockdown of target proteins at the post-translational level. Among the most clinically advanced are bifunctional small-molecule degraders, also referred to as PROteolysis Targeting Chimeras, Degronimids, SNIPERs, or uSMITEs. Although applicable to many disease indications, oncology stands to be the first to benefit from this promising therapeutic approach, with the first investigational new drugs (INDs) filed in 2019 and a proliferation of research specifically focused on harnessing degraders for cancer treatment. In this review, we consider the toolbox of guidelines, reagents, and technologies that has evolved alongside the field to support degrader research and development.
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http://dx.doi.org/10.1016/j.coph.2021.04.009DOI Listing
August 2021

Experiences of completed and withdrawn unspecified kidney donor candidates in the United Kingdom: An inductive thematic analysis from the BOUnD study.

Br J Health Psychol 2021 09 18;26(3):958-976. Epub 2021 Feb 18.

Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Objectives This study sheds light on some controversial aspects of unspecified kidney donation (UKD) as well as the ways in which potential donors are screened and prepared for the donation experience and its aftermath. The aim of this study was to qualitatively investigate the experiences of individuals involved in the United Kingdom (UK) UKD scheme, including those who complete the donation, are eventually medically withdrawn, or self-withdraw. Better insight into the different experiences of these groups will provide useful guidance to clinical teams on how to better address the differing psychological needs of completed donors as well as those who do not proceed to donation. Methods A purposive sample was recruited through the Barriers and Outcomes in Unspecified Donation (BOUnD) study covering 23 transplant centres in the United Kingdom. Semi-structured interviews were audio-recorded and transcribed verbatim and subjected to inductive thematic analysis. Results Participants consisted of 15 individuals who had donated, 11 who had been withdrawn by the transplant team and nine who had self-withdrawn. The analysis resulted in six themes and 14 subthemes. The major themes were maximizing and sharing benefits; risk-to-motivation analysis; support; self-actualization/finding meaning; the donor as patient; and relationship with the transplant team. Conclusions The data demonstrate that, although all donors enter the process with a similar level of commitment, those who did not proceed to donation expressed dissatisfaction and lingering emotional consequences linked to lack of follow-up from transplant teams. The implication for the UKD programme is that from the beginning there needs to be a strategic and consistent approach to managing expectations in order to prepare those who embark on the donation process for all possible outcomes and their associated emotional consequences.
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http://dx.doi.org/10.1111/bjhp.12514DOI Listing
September 2021

Solution Structure and Conformational Dynamics of a Doublet Acyl Carrier Protein from Prodigiosin Biosynthesis.

Biochemistry 2021 01 8;60(3):219-230. Epub 2021 Jan 8.

Department of Chemistry, Special Research Unit for Advanced Magnetic Resonance and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.

The acyl carrier protein (ACP) is an indispensable component of both fatty acid and polyketide synthases and is primarily responsible for delivering acyl intermediates to enzymatic partners. At present, increasing numbers of multidomain ACPs have been discovered with roles in molecular recognition of trans-acting enzymatic partners as well as increasing metabolic flux. Further structural information is required to provide insight into their function, yet to date, the only high-resolution structure of this class to be determined is that of the doublet ACP (two continuous ACP domains) from mupirocin synthase. Here we report the solution nuclear magnetic resonance (NMR) structure of the doublet ACP domains from PigH (PigH ACP-ACP), which is an enzyme that catalyzes the formation of the bipyrrolic intermediate of prodigiosin, a potent anticancer compound with a variety of biological activities. The PigH ACP-ACP structure shows each ACP domain consists of three conserved helices connected by a linker that is partially restricted by interactions with the ACP domain. Analysis of the holo (4'-phosphopantetheine, 4'-PP) form of PigH ACP-ACP by NMR revealed conformational exchange found predominantly in the ACP domain reflecting the inherent plasticity of this ACP. Furthermore, ensemble models obtained from SAXS data reveal two distinct conformers, bent and extended, of both apo (unmodified) and holo PigH ACP-ACP mediated by the central linker. The bent conformer appears to be a result of linker-ACP interactions detected by NMR and might be important for intradomain communication during the biosynthesis. These results provide new insights into the behavior of the interdomain linker of multiple ACP domains that may modulate protein-protein interactions. This is likely to become an increasingly important consideration for metabolic engineering in prodigiosin and other related biosynthetic pathways.
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http://dx.doi.org/10.1021/acs.biochem.0c00830DOI Listing
January 2021

Donating a Kidney to a Stranger: A Review of the Benefits and Controversies of Unspecified Kidney Donation.

Ann Surg 2020 07;272(1):45-47

Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Of Background Data: Unspecified kidney donation (UKD) describes living donation of a kidney to a stranger. The practice is playing an increasingly important role within the transplant programme in the United Kingdom, where these donors are commonly used to trigger a chain of transplants; thereby amplifying the benefit derived from their donation. The initial reluctance to accept UKD was in part due to uncertainty about donor motivations and whether the practice was morally and ethically acceptable.

Objectives: This article provides an overview of UKD and answers common questions regarding the ethical considerations, clinical assessment, and how UKD kidneys are used to maximize utility. Existing literature on outcomes after UKD is also discussed, along with current controversies.

Conclusions: We believe UKD is an ethically acceptable practice which should continue to grow, despite its controversies. In our experience, these donors are primarily motivated by a desire to help others and utilization of their kidney as part of a sharing scheme means that many more people seek to benefit from their very generous donation.
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http://dx.doi.org/10.1097/SLA.0000000000003855DOI Listing
July 2020

Developing degraders: principles and perspectives on design and chemical space.

Medchemcomm 2019 Oct 12;10(10):1755-1764. Epub 2019 Aug 12.

Bio-Techne (Tocris) , The Watkins Building , Atlantic Road, Avonmouth , Bristol , BS11 9QD , UK . Email:

Degraders ( PROTACs, SNIPERs, degronimers ) are a new modality offering increasing potential both as tools for basic research and therapeutic development. They occupy chemical space that lies outside the classical Lipinski 'Rule of 5', which poses fresh challenges for achieving cell permeability and oral bioavailability. This study presents a comprehensive database of degrader structures from the peer reviewed literature, including both optimized degraders and first generation compounds, in order to provide a thorough assessment of the chemical space associated with this modality and identify common trends used during the 'hit to lead' process. The results provide insights into this new area of chemical space as well as pointers for degrader design, which we anticipate will be useful for researchers entering this field.
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http://dx.doi.org/10.1039/c9md00272cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894040PMC
October 2019

The Effect of Pre-Analytical Conditions on Blood Metabolomics in Epidemiological Studies.

Metabolites 2019 Apr 3;9(4). Epub 2019 Apr 3.

Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK.

Serum and plasma are commonly used in metabolomic-epidemiology studies. Their metabolome is susceptible to differences in pre-analytical conditions and the impact of this is unclear. Participant-matched EDTA-plasma and serum samples were collected from 37 non-fasting volunteers and profiled using a targeted nuclear magnetic resonance (NMR) metabolomics platform ( = 151 traits). Correlations and differences in mean of metabolite concentrations were compared between reference (pre-storage: 4 °C, 1.5 h; post-storage: no buffer addition delay or NMR analysis delay) and four pre-storage blood processing conditions, where samples were incubated at (i) 4 °C, 24 h; (ii) 4 °C, 48 h; (iii) 21 °C, 24 h; and (iv) 21 °C, 48 h, before centrifugation; and two post-storage sample processing conditions in which samples thawed overnight (i) then left for 24 h before addition of sodium buffer followed by immediate NMR analysis; and (ii) addition of sodium buffer, then left for 24 h before NMR profiling. We used multilevel linear regression models and Spearman's rank correlation coefficients to analyse the data. Most metabolic traits had high rank correlation and minimal differences in mean concentrations between samples subjected to reference and the different conditions tested, that may commonly occur in studies. However, glycolysis metabolites, histidine, acetate and diacylglycerol concentrations may be compromised and this could bias results in association/causal analyses.
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http://dx.doi.org/10.3390/metabo9040064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523923PMC
April 2019

Good long-term patency: 10-year follow-up using the mid-thigh adductor loop arteriovenous graft.

J Vasc Access 2019 May 22;20(3):313-320. Epub 2018 Oct 22.

2 Wessex Kidney Centre, Queen Alexandra Hospital, Portsmouth, UK.

Introduction: Definitive access in patients requiring renal replacement therapy is an ever-increasing challenge. For those where autogenous venous access is no longer a viable option, arteriovenous grafts can be considered. This article describes long-term follow-up, complications and patency rates of the mid-thigh 'adductor loop' arteriovenous graft.

Methods: 50 mid-thigh loop arteriovenous grafts have been inserted into 48 patients in our unit over the past 11 years. A prospective database was collected on patients receiving an arteriovenous graft at our unit by the senior author. All remained under the care of our unit ensuring accurate follow-up data collection and database was updated at regular intervals.

Results: Death-only censored primary patency at 1, 3 and 5 years was 76%, 44% and 23%, respectively. Patients receiving transplants were not censored as follow-up of the arteriovenous grafts was possible. Secondary patency at 1, 3 and 5 years was 95%, 63% and 45%. These rates are higher than previous studies looking at lower limb arteriovenous grafts. Graft thrombosis occurred in 14 patients (28%). Six patients were treated for an infection (12%) but only four grafts were excised; much lower than documented in previous studies.

Conclusion: Autogenous venous access remains the perceived gold standard for patients requiring dialysis for end stage renal failure, despite some published data reporting poor outcomes. We have shown that adductor loop arteriovenous grafts can be a reliable, safe and long-term alternative in those whom fistula formation is not possible and may have a role earlier in the patient journey than previously thought, as a result of good patency and lower complications.
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http://dx.doi.org/10.1177/1129729818805955DOI Listing
May 2019

Donor and Recipient Perspectives on Anonymity in Kidney Donation From Live Donors: A Multicenter Survey Study.

Am J Kidney Dis 2018 01 20;71(1):52-64. Epub 2017 Nov 20.

Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands. Electronic address:

Background: Maintaining anonymity is a requirement in the Netherlands and Sweden for kidney donation from live donors in the context of nondirected (or unspecified) and paired exchange (or specified indirect) donation. Despite this policy, some donors and recipients express the desire to know one another. Little empirical evidence informs the debate on anonymity. This study explored the experiences, preferences, and attitudes of donors and recipients toward anonymity.

Study Design: Retrospective observational multicenter study using both qualitative and quantitative methods.

Setting & Participants: 414 participants from Dutch and Swedish transplantation centers who received or donated a kidney anonymously (nondirected or paired exchange) completed a questionnaire about anonymity. Participation was a median of 31 months after surgery.

Factors: Country of residence, donor/recipient status, transplant type, time since surgery.

Outcomes: Experiences, preferences, and attitudes toward anonymity.

Results: Most participants were satisfied with their experience of anonymity before and after surgery. A minority would have liked to have met the other party before (donors, 7%; recipients, 15%) or after (donors, 22%; recipients, 31%) surgery. Significantly more recipients than donors wanted to meet the other party. Most study participants were open to meeting the other party if the desire was mutual (donors, 58%; recipients, 60%). Donors agree significantly more with the principle of anonymity before and after surgery than recipients. Donors and recipients thought that if both parties agreed, it should be permissible to meet before or after surgery. There were few associations between country or time since surgery and experiences or attitudes. The pros and cons of anonymity reported by participants were clustered into relational and emotional, ethical, and practical and logistical domains.

Limitations: The relatively low response rate of recipients may have reduced generalizability. Recall bias was possible given the time lag between transplantation and data collection.

Conclusions: This exploratory study illustrated that although donors and recipients were usually satisfied with anonymity, the majority viewed a strict policy on anonymity as unnecessary. These results may inform policy and education on anonymity.
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http://dx.doi.org/10.1053/j.ajkd.2017.07.014DOI Listing
January 2018

Understanding barriers and outcomes of unspecified (non-directed altruistic) kidney donation from both professional's and patient's perspectives: research protocol for a national multicentre mixed-methods prospective cohort study.

BMJ Open 2017 Sep 21;7(9):e015971. Epub 2017 Sep 21.

Department of Renal Transplantation, Guy's and St. Thomas' NHS Foundation Trust/King's College London, London, UK.

Introduction: Living donation accounts for over one-third of all kidney transplants taking place in the UK. The concept of anonymously donating a kidney to a stranger (non-directed altruistic or unspecified kidney donation (UKD)) remains uncomfortable for some clinicians, principally due to concerns about the motivations and long-term physical and psychological outcomes in this donor group.

Aims: The research programme aims to provide a comprehensive assessment of the unspecified donor programme in the UK. It aims to identify reasons for variations in practice across centres, explore outcomes for donors and ascertain barriers and facilitators to UKD, as well as assess the economic implications of unspecified donation.

Methods: The research programme will adopt a mixed-methods approach to assessing UKD nationally using focus groups, interviews and questionnaires. Two study populations will be investigated. The first will include transplant professionals involved in unspecified kidney donation. The second will include a 5-year prospective cohort of individuals who present to any of the 23 UK transplant centres as a potential unspecified living kidney donor. Physical and psychological outcomes will be followed up to 1 year following donation or withdrawal from the donation process. A matched sample of specified donors (those donating to someone they know) will be recruited as a control group. Further qualitative work consisting of interviews will be performed on a purposive sample of unspecified donors from both groups (those who do and do not donate).

Dissemination: The findings will be reported to NHS Blood and Transplant and the British Transplant Society with a view to developing national guidelines and a protocol for the management of those presenting for unspecified donation.

Trial Registration Number: ISRCTN23895878, Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-015971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623565PMC
September 2017

The ELPAT living organ donor Psychosocial Assessment Tool (EPAT): from 'what' to 'how' of psychosocial screening - a pilot study.

Transpl Int 2018 01 21;31(1):56-70. Epub 2017 Sep 21.

Department of Public Health and Primary Care, Academic Centre for Nursing and Midwifery, KU Leuven - University of Leuven, Leuven, Belgium.

Thorough psychosocial screening of donor candidates is required in order to minimize potential negative consequences and to strive for optimal safety within living donation programmes. We aimed to develop an evidence-based tool to standardize the psychosocial screening process. Key concepts of psychosocial screening were used to structure our tool: motivation and decision-making, personal resources, psychopathology, social resources, ethical and legal factors and information and risk processing. We (i) discussed how each item per concept could be measured, (ii) reviewed and rated available validated tools, (iii) where necessary developed new items, (iv) assessed content validity and (v) pilot-tested the new items. The resulting ELPAT living organ donor Psychosocial Assessment Tool (EPAT) consists of a selection of validated questionnaires (28 items in total), a semi-structured interview (43 questions) and a Red Flag Checklist. We outline optimal procedures and conditions for implementing this tool. The EPAT and user manual are available from the authors. Use of this tool will standardize the psychosocial screening procedure ensuring that no psychosocial issues are overlooked and ensure that comparable selection criteria are used and facilitate generation of comparable psychosocial data on living donor candidates.
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http://dx.doi.org/10.1111/tri.13041DOI Listing
January 2018

Psychosocial wellbeing after living kidney donation - a longitudinal, prospective study.

Transpl Int 2017 Oct 2;30(10):987-1001. Epub 2017 Jun 2.

Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Living kidney donation (LKD) has become routine practice across the world as the gold standard treatment of end-stage renal failure. Whilst the physical risks and harms of LKD surgery are well documented, relatively little is known about psychosocial outcomes. The aim of this study was to determine whether it was possible to quantify the psychosocial impact of LKD. A prospective longitudinal study of 93 living kidney donors was performed. Data were collected preoperatively, and 3 and 12 months after donation. Questionnaires included 11 validated psychosocial outcome measures and questions specific to LKD. Over time, there was no significant change in wellbeing, life satisfaction, self-esteem, social comparison, distress, depression, stress, anxiety or social support at 3 or 12 months. Despite this, questions specific to LKD indicated that donors felt positively about donation, with low levels of regret. This study provides a thorough assessment of psychosocial outcomes after LKD over the first year. Donors felt positive about LKD although there was no evidence of any significant change in psychosocial outcomes. Despite no measurable psychosocial benefit after living kidney donation, there was also no evidence of harm.
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http://dx.doi.org/10.1111/tri.12974DOI Listing
October 2017

Motivations, outcomes, and characteristics of unspecified (nondirected altruistic) kidney donors in the United Kingdom.

Transplantation 2014 Dec;98(11):1182-9

1 Department of Transplantation, Guy's Hospital, London, United Kingdom. 2 Health Psychology Section, Institute of Psychiatry, King's College London, Guy's Hospital, London, United Kingdom. 3 NHS Blood and Transplant, Organ Donation and Transplantation Directorate, Stoke Gifford, Bristol, United Kingdom. 4 Queen Alexandra Hospital, Hampshire, United Kingdom. 5 South London and Maudsley NHS Foundation Trust, York Clinic, Guy's Hospital, London, United Kingdom. 6 Address correspondence to: Nizam Mamode, F.R.C.S., Department of Transplantation, 6th Floor Renal Offices, Borough Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.

Background: Unspecified (nondirected altruistic) kidney donation is becoming increasingly common in the United Kingdom. Questions regarding motivation and characteristics of these donors persist, alongside concerns about regret and long-term psychosocial outcomes. The aims of this study were to compare psychosocial and physical outcomes in unspecified kidney donors (UKDs) versus specified kidney donors (SKDs).

Methods: We performed a cross-sectional study, in which a detailed assessment of psychosocial outcomes was made using validated questionnaires. Additional questions specific to donation were also asked, including questions regarding motivation, regret, and anonymity.

Results: One hundred ninety responses were received from 296 participants studied (110 UKDs [74.3%] vs. 80 SKDs [54.1%], P<0.001). Unspecified kidney donors were older (54 years vs. 44 years; P<0.001), predominantly white (99.1% vs. 78.5%; P<0.001), and donated more recently (1.3 years vs. 2.6 years; P<0.001). There was no difference in psychiatric history or personality type, or current depression, anxiety, stress, self-esteem, or well-being between the groups (P>0.05). Unspecified kidney donors were more engaged in other altruistic behaviours (P<0.001). There was no difference in physical outcomes, although UKDs recovered quicker (P<0.001). Regret was low (3.7% UKDs vs. 7.5% SKDs; P=0.078).

Conclusion: This study has demonstrated that UKDs have comparable physical and psychosocial outcomes to SKDs. These favorable outcomes may be, in part, because of the rigorous evaluation process which currently includes a mental health assessment. We conclude that the program can continue to expand safely across the United Kingdom.
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http://dx.doi.org/10.1097/TP.0000000000000340DOI Listing
December 2014

Stress predicts the trajectory of wound healing in living kidney donors as measured by high-resolution ultrasound.

Brain Behav Immun 2015 Jan 25;43:19-26. Epub 2014 Jun 25.

Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, Department of Transplantation, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom. Electronic address:

Background: Psychological stress has been shown to be an influential factor on the rate of wound healing; however these findings have been demonstrated predominantly on artificially created wounds. Due to the absence of major co-morbidities, living kidney donors are a unique group in which to study this relationship. This study investigated the effect of preoperative stress and personality on surgical wound healing through the use of high-resolution ultrasound.

Methods: Living kidney donors due to undergo a hand-assisted laparoscopic donor nephrectomy were asked to complete the Perceived Stress Scale, the Life Orientation Test-Revised and the Ten Item Personality Inventory prior to surgery. High-resolution ultrasound scans of surgical wounds were performed on the first three post-operative days and once following discharge (mean=15.3 days; s.d. 2.8). Two measurements from each image were obtained: wound width (size of wound) and median intensity (a marker of tissue fluid). Latent Growth Curve Models (LGCMs) were used to evaluate wound healing.

Results: 52 living kidney donors participated. Higher pre-operative life stress, lower optimism and lower conscientiousness were associated with delayed wound healing in living kidney donors for both outcomes. Increased emotional stability was associated with faster wound healing as demonstrated by a change in median intensity. Possible confounding factors, such as age, BMI, smoking status, local anaesthetic use and wound drain placement were not influential.

Conclusions: This study, which measured wound healing in a novel patient sample using a novel technique, has demonstrated a negative association between stress and wound healing and the positive influence of optimism, conscientiousness and emotional stability.
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http://dx.doi.org/10.1016/j.bbi.2014.06.012DOI Listing
January 2015

Application of the Exactive Plus EMR for automated protein-ligand screening by non-covalent mass spectrometry.

Rapid Commun Mass Spectrom 2014 Jul;28(13):1561-8

UCB Celltech, 216 Bath Road, Slough, SL1 4EN, UK.

Rationale: Non-covalent mass spectrometry (MS) offers considerable potential for protein-ligand screening in drug discovery programmes. However, there are some limitations with the time-of-flight (TOF) instrumentation typically employed that restrict the application of non-covalent MS in industrial laboratories.

Methods: An Exactive Plus EMR mass spectrometer was investigated for its ability to characterise non-covalent protein-small molecule interactions. Nano-electrospray ionisation (nanoESI) infusion was achieved with a TriVersa NanoMate. The transport multipole and ion lens voltages, dissociation energies and pressure in the Orbitrap™ were optimised. Native MS was performed, with ligand titrations to judge retention of protein-ligand interactions, serial dilutions of native proteins as an indication of sensitivity, and a heterogeneous protein analysed for spectral resolution.

Results: Interactions between native proteins and ligands are preserved during analysis on the Exactive Plus EMR, with the binding affinities determined in good agreement with expected values. High spectral resolution allows baseline separation of adduct ions, which should improve the accuracy and limit of detection for measuring ligand interactions. Data are also presented showing baseline resolution of glycoforms of a highly glycosylated protein, allowing binding of a fragment molecule to be detected.

Conclusions: The high sensitivity and spectral resolution achievable with the Orbitrap technology confer significant advantages over TOF mass spectrometers, and offer a solution to current limitations regarding throughput, data analysis and sample requirements. A further benefit of improved spectral resolution is the possibility of using heterogeneous protein samples such as glycoproteins for fragment screening. This would significantly expand the scope of applicability of non-covalent MS in the pharmaceutical and other industries.
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http://dx.doi.org/10.1002/rcm.6925DOI Listing
July 2014

Depression and kidney transplantation.

Transplantation 2014 Apr;97(7):717-21

1 Health Psychology Section, Psychology Department, Institute of Psychiatry, King's College London, UK. 2 Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK. 3 Department of Transplantation, Guy's Hospital, London, UK. 4 Address correspondence to: Joseph Chilcot, Ph.D., Health Psychology Section, Psychology Department, Institute of Psychiatry, King's College London, 5th floor Bermondsey Wing, Guy's Hospital Campus, London Bridge, London, SE1 9RT, UK.

While kidney transplantation offers several advantages in terms of improved clinical outcomes and quality of life compared to dialysis modalities, depressive symptoms are still present in approximately 25% of patients, rates comparable to that of the hemodialysis population. Correlates of depressive symptoms include marital status, income, kidney function, history of affective illness, malnutrition, and inflammation. Depressive symptoms are also associated with poor outcomes following kidney transplantation including nonadherence to immunosuppressant medication, graft failure, and all-cause mortality. Efforts to detect and treat depression should be a priority if one is to improve treatment adherence, quality of life, and outcomes in transplant recipients.
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http://dx.doi.org/10.1097/01.TP.0000438212.72960.aeDOI Listing
April 2014

Identification of differential protein binding affinities in an atropisomeric pharmaceutical compound by noncovalent mass spectrometry, equilibrium dialysis, and nuclear magnetic resonance.

Anal Chem 2013 Jun 3;85(12):5958-64. Epub 2013 Jun 3.

School of Chemistry, University of Bristol, Cantock's Close, Clifton, Bristol BS8 1TS, United Kingdom.

Atropisomerism of pharmaceutical compounds is a challenging area for drug discovery programs (Angew. Chem., Int. Ed. 2009, 48, 6398-6401). Strategies for dealing with these compounds include raising the energy barrier to atropisomerization in order to develop the drug as a single isomer (Tetrahedron 2004, 60, 4337-4347) or reducing the barrier to rotation and developing a mixture of rapidly interconverting isomers (Chirality 1996, 8, 364-371). Commonly, however, the atropisomers will be differentiated in terms of their affinity for a given protein target, and it is therefore important to rapidly identify the most active component prior to further compound development. We present equilibrium dialysis and saturation transfer difference NMR (STD-NMR) as techniques for assessing relative affinities of an atropisomeric mixture against antiapoptotic protein targets Bcl-2 and Bcl-xL. These techniques require no prior separation of the mixture of compounds and are therefore rapid and simple approaches. We also explore the use of noncovalent mass spectrometry for determining KD values of individual atropisomers separated from the equilibrium mixture and compare the results to solution-phase measurements. Results from equilibrium dialysis, STD-NMR, and noncovalent mass spectrometry are all in excellent agreement and provide complementary information on differential binding, amplification of the strongest binders, and KD values.
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http://dx.doi.org/10.1021/ac400760pDOI Listing
June 2013

Horseshoe polycystic kidney.

Clin Kidney J 2013 Feb;6(1):102

Department of Transplantation , Guys and St Thomas' NHS Foundation Trust , London , UK.

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http://dx.doi.org/10.1093/ckj/sfs142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094387PMC
February 2013

Automated protein-ligand interaction screening by mass spectrometry.

J Med Chem 2012 Jan 12;55(2):837-51. Epub 2012 Jan 12.

School of Chemistry, University of Bristol, Cantock's Close, Clifton, Bristol BS8 1TS, United Kingdom.

Identifying protein-ligand binding interactions is a key step during early-stage drug discovery. Existing screening techniques are often associated with drawbacks such as low throughput, high sample consumption, and dynamic range limitations. The increasing use of fragment-based drug discovery (FBDD) demands that these techniques also detect very weak interactions (mM K(D) values). This paper presents the development and validation of a fully automated screen by mass spectrometry, capable of detecting fragment binding into the millimolar K(D) range. Low sample consumption, high throughput, and wide dynamic range make this a highly attractive, orthogonal approach. The method was applied to screen 157 compounds in 6 h against the anti-apoptotic protein target Bcl-x(L). Mass spectrometry results were validated using STD-NMR, HSQC-NMR, and ITC experiments. Agreement between techniques suggests that mass spectrometry offers a powerful, complementary approach for screening.
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http://dx.doi.org/10.1021/jm201347kDOI Listing
January 2012

Analysis of Streptomyces coelicolor phosphopantetheinyl transferase, AcpS, reveals the basis for relaxed substrate specificity.

Biochemistry 2011 Jun 6;50(25):5704-17. Epub 2011 Jun 6.

Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Clifton, Bristol BS8 1TD, U.K.

The transfer of the phosphopantetheine chain from coenzyme A (CoA) to the acyl carrier protein (ACP), a key protein in both fatty acid and polyketide synthesis, is catalyzed by ACP synthase (AcpS). Streptomyces coelicolor AcpS is a doubly promiscuous enzyme capable of activation of ACPs from both fatty acid and polyketide synthesis and catalyzes the transfer of modified CoA substrates. Five crystal structures have been determined, including those of ligand-free AcpS, complexes with CoA and acetyl-CoA, and two of the active site mutants, His110Ala and Asp111Ala. All five structures are trimeric and provide further insight into the mechanism of catalysis, revealing the first detailed structure of a group I active site with the essential magnesium in place. Modeling of ACP binding supported by mutational analysis suggests an explanation for the promiscuity in terms of both ACP partner and modified CoA substrates.
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http://dx.doi.org/10.1021/bi2003668DOI Listing
June 2011

Robotic telemanipulating surgical systems for laparoscopy: the story so far in the UK.

Expert Rev Med Devices 2010 Nov;7(6):745-52

Department of Surgery, King's College Hospital, London, UK.

Surgical robotics is, at present, one of the most dynamically developing areas of biomedical engineering that has been proven to increase the stability and robustness of surgery. Robotics can integrate, assist, control and extend the human capabilities, correcting for manual errors, or record the spatial points-of-interest and motions. This is of importance as an adjunct to many laparoscopic subspecialty procedures, from cardiac to pelvic surgery. Evidence-based medicine is now demonstrating that robotized equipment can greatly add to the preoperative simulation, the ergonomics of the procedure, the preoperative simulation and the risk-free training of the surgeon with precision surgery and less trauma to the patient. This article discusses the robots that are clinically available at present and their importance to the surgeon and patient.
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http://dx.doi.org/10.1586/erd.10.65DOI Listing
November 2010

The role of 'notch' in urological cancers.

BJU Int 2009 Jul 21;104(1):1-2. Epub 2009 Apr 21.

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http://dx.doi.org/10.1111/j.1464-410X.2009.08479.xDOI Listing
July 2009
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