Publications by authors named "Oliver Pearce"

52 Publications

Targeting Versican as a Potential Immunotherapeutic Strategy in the Treatment of Cancer.

Front Oncol 2021 30;11:712807. Epub 2021 Aug 30.

Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

A growing body of literature links events associated with the progression and severity of immunity and inflammatory disease with the composition of the tissue extracellular matrix as defined by the matrisome. One protein in the matrisome that is common to many inflammatory diseases is the large proteoglycan versican, whose varied function is achieved through multiple isoforms and post-translational modifications of glycosaminoglycan structures. In cancer, increased levels of versican are associated with immune cell phenotype, disease prognosis and failure to respond to treatment. Whether these associations between versican expression and tumour immunity are the result of a direct role in the pathogenesis of tumours is not clear. In this review, we have focused on the role of versican in the immune response as it relates to tumour progression, with the aim of determining whether our current understanding of the immunobiology of versican warrants further study as a cancer immunotherapy target.
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http://dx.doi.org/10.3389/fonc.2021.712807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435723PMC
August 2021

Flexor tendon injuries: Repair & Rehabilitation.

Injury 2021 Aug;52(8):2053-2067

Consultant Hand & Plastic Surgeon, Lothian Hand Unit, St John's Hospital, Livingston, West Lothian EH54 6PP, UK.

Flexor tendon injuries are common and occur mostly by penetrating trauma. Suspected flexor tendon injuries require a thorough clinical assessment and often are not isolated injuries. A detailed understanding of flexor tendon anatomy and spatial relationships is essential, especially when repairing multi-tendon injuries. Principles of flexor tendon repair include a strong suture construct, minimising gap formation between tendon ends, preserving tendon blood supply and providing a smooth repair interface. Moreover, adequate exposure of the zone of injury using full-thickness skin flaps and preservation of neurovascular and pulley structures is essential. In this article an overview of contemporary management strategies is presented. Today's hand surgeons and therapists can choose from a variety of treatment options when managing these important and potentially life-changing injuries.
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http://dx.doi.org/10.1016/j.injury.2021.07.036DOI Listing
August 2021

Mechanical Stimulation Modulates Osteocyte Regulation of Cancer Cell Phenotype.

Cancers (Basel) 2021 Jun 10;13(12). Epub 2021 Jun 10.

Centre for Predictive in vitro Models, School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK.

Breast and prostate cancers preferentially metastasise to bone tissue, with metastatic lesions forming in the skeletons of most patients. On arriving in bone tissue, disseminated tumour cells enter a mechanical microenvironment that is substantially different to that of the primary tumour and is largely regulated by bone cells. Osteocytes, the most ubiquitous bone cell type, orchestrate healthy bone remodelling in response to physical exercise. However, the effects of mechanical loading of osteocytes on cancer cell behaviour is still poorly understood. The aim of this study was to characterise the effects of osteocyte mechanical stimulation on the behaviour of breast and prostate cancer cells. To replicate an osteocyte-controlled environment, this study treated breast (MDA-MB-231 and MCF-7) and prostate (PC-3 and LNCaP) cancer cell lines with conditioned media from MLO-Y4 osteocyte-like cells exposed to mechanical stimulation in the form of fluid shear stress. We found that osteocyte paracrine signalling acted to inhibit metastatic breast and prostate tumour growth, characterised by reduced proliferation and invasion and increased migration. In breast cancer cells, these effects were largely reversed by mechanical stimulation of osteocytes. In contrast, conditioned media from mechanically stimulated osteocytes had no effect on prostate cancer cells. To further investigate these interactions, we developed a microfluidic organ-chip model using the Emulate platform. This new organ-chip model enabled analysis of cancer cell migration, proliferation and invasion in the presence of mechanical stimulation of osteocytes by fluid shear stress, resulting in increased invasion of breast and prostate cancer cells. These findings demonstrate the importance of osteocytes and mechanical loading in regulating cancer cell behaviour and the need to incorporate these factors into predictive in vitro models of bone metastasis.
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http://dx.doi.org/10.3390/cancers13122906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230361PMC
June 2021

A human multi-cellular model shows how platelets drive production of diseased extracellular matrix and tissue invasion.

iScience 2021 Jun 29;24(6):102676. Epub 2021 May 29.

Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

Guided by a multi-level "deconstruction" of omental metastases, we developed a tetra (four cell)-culture model of primary human mesothelial cells, fibroblasts, adipocytes, and high-grade serous ovarian cancer (HGSOC) cell lines. This multi-cellular model replicated key elements of human metastases and allowed malignant cell invasion into the artificial omental structure. Prompted by findings in patient biopsies, we used the model to investigate the role of platelets in malignant cell invasion and extracellular matrix, ECM, production. RNA (sequencing and quantitative polymerase-chain reaction), protein (proteomics and immunohistochemistry) and image analysis revealed that platelets stimulated malignant cell invasion and production of ECM molecules associated with poor prognosis. Moreover, we found that platelet activation of mesothelial cells was critical in stimulating malignant cell invasion. Whilst platelets likely activate both malignant cells and mesothelial cells, the tetra-culture model allowed us to dissect the role of both cell types and model the early stages of HGSOC metastases.
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http://dx.doi.org/10.1016/j.isci.2021.102676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215303PMC
June 2021

Modelling TGFβR and Hh pathway regulation of prognostic matrisome molecules in ovarian cancer.

iScience 2021 Jun 29;24(6):102674. Epub 2021 May 29.

Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK.

In a multi-level "deconstruction" of omental metastases, we previously identified a prognostic matrisome gene expression signature in high-grade serous ovarian cancer (HGSOC) and twelve other malignancies. Here, our aim was to understand how six of these extracellular matrix (ECM) molecules, COL11A1, cartilage oligomeric matrix protein, FN1, versican, cathepsin B, and COL1A1, are upregulated in cancer. Using biopsies, we identified significant associations between TGFβR activity, Hedgehog (Hh) signaling, and these ECM molecules and studied the associations in mono-, co-, and tri-culture. Activated omental fibroblasts (OFs) produced more matrix than malignant cells, directed by TGFβR and Hh signaling cross talk. We "reconstructed" omental metastases in tri-cultures of HGSOC cells, OFs, and adipocytes. This combination was sufficient to generate all six ECM proteins and the matrisome expression signature. TGFβR and Hh inhibitor combinations attenuated fibroblast activation and gel and ECM remodeling in these models. The tri-culture model reproduces key features of omental metastases and allows study of diseased-associated ECM.
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http://dx.doi.org/10.1016/j.isci.2021.102674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215304PMC
June 2021

Telephone Fracture Clinic Consultations: A Satisfactory Solution in Lockdown.

Cureus 2021 Apr 8;13(4):e14371. Epub 2021 Apr 8.

Trauma and Orthopaedics, Southmead Hospital, Bristol, GBR.

Introduction The COVID-19 pandemic was a catalyst to many learning opportunities within clinical practice in the UK. Attempts were made to reduce footfall within all institutions and within the study unit; this led to alterations in fracture clinic provision. An alternative method was developed whereby most of the initial contacts were in person and much of the follow-up was done remotely. The aim of this study was to evaluate patient satisfaction and views on this alteration in service. Methods The first 299 patients who had fracture clinic appointments delivered by telephone consultation at this institution during the pandemic in early 2020 were retrospectively identified and sent a postal survey. Satisfaction levels were assessed through a degree of agreement with statements (nine items), yes/no answers (four questions), and space for comments. Results One hundred and thirty-one survey responses were included (44% response rate). The majority of patients (82%) were satisfied overall with the care they received. Although 78% of patients stated that they preferred a telephone consultation to attend a face-to-face hospital appointment during the pandemic, only 22% stated they would have preferred this in normal (pre-COVID-19) times. Interestingly 62% of patients stated they would be happy for further fracture clinic appointments to be carried out in the same way. Discussion Most of the remote consultations were in follow-up rather than new patients. Patients were adaptable to this alternative method of care delivery. There could be a role for its integration into the options for fracture clinic delivery in the future.
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http://dx.doi.org/10.7759/cureus.14371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106481PMC
April 2021

Acute Compartment Syndrome in Type IIIB Open Tibial Shaft Fractures Utilising a Two-Stage Orthoplastic Approach.

J Orthop Trauma 2021 Mar 22. Epub 2021 Mar 22.

Department of Trauma & Orthopaedics, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. Department of Trauma & Orthopaedics, Stanmore Hospital, London, United Kingdom. Department of Trauma & Orthopaedics, Southmead Hospital, Bristol, United Kingdom Department of Plastic Surgery, Southmead Hospital, Bristol, United Kingdom.

Objective: To determine the rate of acute compartment syndrome (ACS) in a series of patients with Gustilo-Anderson type IIIB open tibial shaft fractures that were treated using a specific two-stage orthoplastic protocol.

Design: Consecutive cohort study.Patients/Participants: Ninety-three (n =93) consecutive patients with a type IIIB open tibial shaft fracture (OTA/AO-42) treated utilizing a two-stage orthoplastic approach, between August 2015 and January 2018. Following exclusions, eighty-three (n=83) were eligible for analysis.

Intervention: Colloid resuscitation and two-stage orthoplastic reconstruction of type IIIB open tibial shaft fracture. Stage one consists of "three-vessel view" early debridement and temporary internal fixation, with stage two consisting of a single-stage fix and flap.

Main Outcome Measurements: Rate of ACS. Secondary outcomes included early/late sequelae of missed ACS, deep infection, arterial injury, nonunion and flap failure.

Results: Eighty-three (n = 83) patients were included for analysis. Median age was 45.4 years (Interquartile range (IQR) 35) with a median follow up of 1.6 years (IQR 0.8). Median number of operations was 2.0 (IQR 4). For the primary outcome, there were a total of zero (0/83) patients who required fasciotomy or developed early/late clinical sequelae of missed ACS. Six (6/83, 7.2%) patients developed deep infection, eighteen patients (18/83, 21.7%) experienced non-ischaemic arterial injury, five patients (5/83, 6.0%) experienced nonunion, with four patients (4/83, 4.8%) experiencing flap failure. Diabetes was the only variable associated with deep infection (p=0.025) and nonunion (p<0.001).

Conclusions: Patients with type IIIB open tibial shaft fractures treated with colloid resuscitation and a two-stage orthoplastic protocol, which includes early "three-vessel view" exposure and debridement, do not appear to develop ACS. Furthermore, no sequelae of missed compartment syndrome was observed at final follow up.

Level Of Evidence: Therapeutic level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000002129DOI Listing
March 2021

Measuring Daily Compliance With Physical Activity Tracking in Ambulatory Surgery Patients: Comparative Analysis of Five Compliance Criteria.

JMIR Mhealth Uhealth 2021 01 26;9(1):e22846. Epub 2021 Jan 26.

Trauma and Orthopaedics Department, Milton Keynes University Hospital, Milton Keynes, United Kingdom.

Background: Physical activity trackers such as the Fitbit can allow clinicians to monitor the recovery of their patients following surgery. An important issue when analyzing activity tracker data is to determine patients' daily compliance with wearing their assigned device, using an appropriate criterion to determine a valid day of wear. However, it is currently unclear as to how different criteria can affect the reported compliance of patients recovering from ambulatory surgery. Investigating this issue can help to inform the use of activity data by revealing factors that may impact compliance calculations.

Objective: This study aimed to understand how using different criteria can affect the reported compliance with activity tracking in ambulatory surgery patients. It also aimed to investigate factors that explain variation between the outcomes of different compliance criteria.

Methods: A total of 62 patients who were scheduled to undergo total knee arthroplasty (TKA, ie, knee replacement) volunteered to wear a commercial Fitbit Zip activity tracker over an 8-week perioperative period. Patients were asked to wear the Fitbit Zip daily, beginning 2 weeks prior to their surgery and ending 6 weeks after surgery. Of the 62 patients who enrolled in the study, 20 provided Fitbit data and underwent successful surgery. The Fitbit data were analyzed using 5 different daily compliance criteria, which consider patients as compliant with daily tracking if they either register >0 steps in a day, register >500 steps in a day, register at least one step in 10 different hours of the day, register >0 steps in 3 distinct time windows, or register >0 steps in 3 out of 4 six-hour time windows. The criteria were compared in terms of compliance outcomes produced for each patient. Data were explored using heatmaps and line graphs. Linear mixed models were used to identify factors that lead to variation between compliance outcomes across the sample.

Results: The 5 compliance criteria produce different outcomes when applied to the patients' data, with an average 24% difference in reported compliance between the most lenient and strictest criteria. However, the extent to which each patient's reported compliance was impacted by different criteria was not uniform. Some individuals were relatively unaffected, whereas others varied by up to 72%. Wearing the activity tracker as a clip-on device, rather than on the wrist, was associated with greater differences between compliance outcomes at the individual level (P=.004, r=.616). This effect was statistically significant (P<.001) in the first 2 weeks after surgery. There was also a small but significant main effect of age on compliance in the first 2 weeks after surgery (P=.040). Gender and BMI were not associated with differences in individual compliance outcomes. Finally, the analysis revealed that surgery has an impact on patients' compliance, with noticeable reductions in activity following surgery. These reductions affect compliance calculations by discarding greater amounts of data under strict criteria.

Conclusions: This study suggests that different compliance criteria cannot be used interchangeably to analyze activity data provided by TKA patients. Surgery leads to a temporary reduction in patients' mobility, which affects their reported compliance when strict thresholds are used. Reductions in mobility suggest that the use of lenient compliance criteria, such as >0 steps or windowed approaches, can avoid unnecessary data exclusion over the perioperative period. Encouraging patients to wear the device at their wrist may improve data quality by increasing the likelihood of patients wearing their tracker and ensuring that activity is registered in the 2 weeks after surgery.

Trial Registration: ClinicalTrials.gov NCT03518866; https://clinicaltrials.gov/ct2/show/NCT03518866.
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http://dx.doi.org/10.2196/22846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872832PMC
January 2021

Basement membrane stiffness determines metastases formation.

Nat Mater 2021 06 25;20(6):892-903. Epub 2021 Jan 25.

Center for Applied Tissue Engineering and Regenerative Medicine-CANTER, Munich University of Applied Sciences, Munich, Germany.

The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our biophysical and functional analyses in combination with mathematical simulations show that Net4 softens the mechanical properties of native BMs by opening laminin node complexes, decreasing cancer cell potential to transmigrate this barrier despite creating bigger pores. Our results therefore reveal that BM stiffness is dominant over pore size, and that the mechanical properties of 'normal' BMs determine metastases formation and patient survival independent of cancer-mediated alterations. Thus, identifying individual Net4 protein levels within native BMs in major metastatic organs may have the potential to define patient survival even before tumour formation. The ratio of Net4 to laminin molecules determines BM stiffness, such that the more Net4, the softer the BM, thereby decreasing cancer cell invasion activity.
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http://dx.doi.org/10.1038/s41563-020-00894-0DOI Listing
June 2021

Standards of open lower limb fracture care in the United Kingdom.

Injury 2021 Mar 13;52(3):378-383. Epub 2021 Jan 13.

Department of Orthopaedic Surgery, Southmead Hospital, Bristol, United Kingdom.

Open fractures of the lower limb remain a potentially devastating group of injuries that are challenging to manage. The primary aims of treatment are to optimise limb function and avoid serious complications such as infection and non-union, which are costly for both the patient and healthcare system. The management of these fractures has evolved significantly, and this is evident following the creation of national open fracture guidelines and a formal trauma system. These have served to standardise care for these injuries in the United Kingdom. The aim of this review is to update our colleagues on the current standard of lower limb open fracture care in the United Kingdom, and the impact this has had on patient outcomes.
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http://dx.doi.org/10.1016/j.injury.2021.01.021DOI Listing
March 2021

A Sweet Approach to Heat Up Cancer Response to Immunotherapy.

Cancer Discov 2020 12;10(12):1789-1790

Department of Biomedicine, University of Basel and Division of Oncology, University Hospital Basel, Basel, Switzerland.

Song and colleagues describe how N-glycans stabilize expression of checkpoint molecule B7-H4 that suppresses T-cell function. Inhibiting N-glycan stabilization of B7-H4 generates an immune hot cancer that is more responsive to combination therapies..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1355DOI Listing
December 2020

Predictive Factors for Revision and Survivorship Analysis of a Prevalent 36-mm Metal-on-Metal Total Hip Replacement System: A Large Single-Center Retrospective Cohort Study.

J Arthroplasty 2021 04 17;36(4):1380-1387. Epub 2020 Oct 17.

Department of Orthopaedic Surgery, Musgrove Park Hospital, Taunton, United Kingdom.

Background: To our knowledge, this is the largest single-center cohort of the 36-mm Corail-Pinnacle metal-on-metal total hip replacements system, aiming to determine 10-year survivorship and identify predictors of revision. We further assessed year of implantation given reports of manufacturing variations affecting shells made after 2006 predisposing these components to increasing wear.

Methods: All Corail-Pinnacle 36-mm metal-on-metal hips implanted in a single center (2005-2012). The effect of patient and implant-related variables, and year of implantation on revision risk was assessed using Kaplan-Meier, Cox regression, and interrupted time series analysis.

Results: In total, 1212 metal-on-metal total hip replacements were implanted with a 10-year survival rate of 83.4% (95% confidence interval [CI] = 81.3-85.5). Mean follow-up duration was 7.3 years with 61% of patients reaching a minimum of 7 years of follow-up. One hundred nineteen patients required revision surgery (9.8%). Univariate analysis identified female gender (hazard ratio [HR] = 1.608, CI = 1.093-2.364, P = .016), age at implantation (HR = 0.982, CI = 0.968-0.997, P = .019), smaller 50-mm to 54-mm cup diameter (HR = 1.527, CI = 1.026-2.274, P = .037), and high-offset stems (HR = 2.573, CI = 1.619-4.089, P < .001) as predictors of revision. Multivariate modeling confirmed female gender and high-offset stems as significant predictors of revision. For components implanted after 2007, the number of revisions showed no statistically significant step increase compared to pre-2007 implantation.

Conclusion: We observed a high 10-year failure rate (16.6%) with this implant, mostly due to adverse reaction to metal debris. Female gender and high femoral offset stems were significant predictors for all-cause revision. Year of implantation was not significantly associated with an increasing number of revisions from 2007 onwards, although further studies to validate the impact of manufacturing discrepancies are recommended.
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http://dx.doi.org/10.1016/j.arth.2020.10.028DOI Listing
April 2021

Ankle fractures in the elderly: Current concepts.

Injury 2020 Dec 24;51(12):2740-2747. Epub 2020 Oct 24.

Southmead Hospital, Department of Trauma and Orthopaedics, North Bristol NHS Trust, Southmead Road, BS10 5NB, Bristol, United Kingdom.

Ankle fractures remain the third most common musculoskeletal injury in the elderly population. The presence of osteoporosis, significant multiple comorbidities and limited functional independence makes treatment of such injuries challenging. Early studies highlighted high rates of post-operative complications and poor outcomes after surgical intervention. With advances in surgical techniques and a greater understanding of multi-disciplinary team (MDT)-driven peri-operative care and rehabilitation, evidence now appears to suggest improved outcomes for operative management. Approaches must be adapted according to co-morbidities, baseline function and patient wishes. This review article aims to discuss contemporary treatment strategies and the complex challenges associated with the management of the elderly ankle fracture.
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http://dx.doi.org/10.1016/j.injury.2020.10.093DOI Listing
December 2020

FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer.

EMBO Mol Med 2020 11 7;12(11):e12010. Epub 2020 Oct 7.

Cancer Research Center of Toulouse (CRCT), team 6 "Protein synthesis & secretion in carcinogenesis", Equipe labellisée Ligue Contre Le Cancer, Labex TOUCAN, INSERM UMR 1037- University Toulouse III Paul Sabatier, Toulouse, France.

Cancer-associated fibroblasts (CAFs) are considered the most abundant type of stromal cells in pancreatic ductal adenocarcinoma (PDAC), playing a critical role in tumour progression and chemoresistance; however, a druggable target on CAFs has not yet been identified. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease-free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK kinase-dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumours and dramatically decreases tumour spread. FAK pharmacologic or genetic inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion.
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http://dx.doi.org/10.15252/emmm.202012010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645544PMC
November 2020

Resilient and agile engineering solutions to address societal challenges such as coronavirus pandemic.

Mater Today Chem 2020 Sep 28;17:100300. Epub 2020 May 28.

School of Engineering, London South Bank University, 103 Borough Road, London, SE10AA, UK.

The world is witnessing tumultuous times as major economic powers including the US, UK, Russia, India, and most of Europe continue to be in a state of lockdown. The worst-hit sectors due to this lockdown are sales, production (manufacturing), transport (aerospace and automotive) and tourism. Lockdowns became necessary as a preventive measure to avoid the spread of the contagious and infectious "ronarus isease 20 (COVID-19). This newly identified disease is caused by a new strain of the virus being referred to as evere cute espiratory yndrome ronairus (SARS CoV-2; formerly called 2019-nCoV). We review the current medical and manufacturing response to COVID-19, including advances in instrumentation, sensing, use of lasers, fumigation chambers and development of novel tools such as lab-on-the-chip using combinatorial additive and subtractive manufacturing techniques and use of molecular modelling and molecular docking in drug and vaccine discovery. We also offer perspectives on future considerations on climate change, outsourced versus indigenous manufacturing, automation, and antimicrobial resistance. Overall, this paper attempts to identify key areas where manufacturing can be employed to address societal challenges such as COVID-19.
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http://dx.doi.org/10.1016/j.mtchem.2020.100300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254035PMC
September 2020

Managing polytrauma patients.

Injury 2020 Oct 25;51(10):2091-2096. Epub 2020 Jul 25.

Department of Trauma & Orthopaedic Surgery, Southmead Hospital, North Bristol Trust, Southmead Road, Bristol BS10 5NB, United Kingdom.

Embedding physiological markers into treatment algorithms has helped trauma teams rationalise interventions safely and signifies a departure from the dichotomy of damage control orthopaedics (DCO) and early total care (ETC) to early appropriate care (EAC). This has been shown to reduce length of stay and cost to treating centres. This article seeks to provide a clear summary of current concepts for managing orthopaedic injuries in the multiply injured patient.
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http://dx.doi.org/10.1016/j.injury.2020.07.051DOI Listing
October 2020

Proximal Humerus Fractures: Reliability of Neer Versus AO Classification on Plain Radiographs and Computed Tomography.

Cureus 2020 Jun 9;12(6):e8520. Epub 2020 Jun 9.

Orthopaedics, The Royal Infirmary of Edinburgh, Edinburgh, GBR.

Introduction: Several classifications for proximal humeral fractures exist, with excellent reliability and reproducibility of such classifications being a desirable feature. Despite their widespread use, these systems are variable in both reliability and accuracy. We aimed to, a) assess and compare the reliability of the Neer (complete and abbreviated versions) and Arbeitsgemeinschaft für Osteosynthesefragenbeing (AO) classifications, and b) identify if computed tomography (CT) made any difference to the reliability of Neer and AO classifications when compared to plain radiographs alone.  Materials and methods: This is a single-centre retrospective study identifying all proximal humeral fractures presenting between February 2016 and February 2017 as a result of trauma that subsequently proceeded to CT. Two specialty orthopaedic trainees analysed the plain radiographs as well as CT images over two rounds, spaced two weeks apart. The Neer 16-grade, abbreviated Neer 6-grade and AO classifications were used. Intra- and inter-observer reliability of each classification system was assessed using the Kappa coefficient.  Results: Twenty-two patients were included. The mean age was 62 years (SD 14.5). Management changed in 9/22 patients based on CT. Computed tomography changed Neer-16 type in 16% observations, Neer-6 in 10%, and AO in 23%. This was significant when comparing Neer-6 and AO classifications (p = 0.04). Neer-6 had the best inter-observer reliability (0.737) with the management of one patient changing after CT. On X-ray and CT, intra-observer agreement was substantial, >0.7, using Neer-16 and Neer-6 (p<0.005). Inter-observer agreement for Neer-16 and Neer-6 was substantial, >0.7 (p<0.005). In comparison, intra- and inter-observer agreements for AO were lower on X-ray and CT, 0.4-0.6, (p<0.005).

Conclusion: Our study shows that simplicity is key with a high degree of reliability in the abbreviated Neer classification. Computed tomography allowed greater reliability than radiographs in classifying fractures, affecting management decisions in 41% of patients. The comprehensive Neer classification showed similar intra- and inter-observer reliabilities to AO.
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http://dx.doi.org/10.7759/cureus.8520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346293PMC
June 2020

Versican-A Critical Extracellular Matrix Regulator of Immunity and Inflammation.

Front Immunol 2020 24;11:512. Epub 2020 Mar 24.

Division of Pulmonary/Critical Care Medicine, Center for Lung Biology, University of Washington School of Medicine, Seattle, WA, United States.

The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated gene-6 (TSG-6), and inter alpha trypsin inhibitor (IαI) during inflammation in a number of different diseases such as cardiovascular and lung disease, autoimmune diseases, and several different cancers. These interactions form stable scaffolds which can act as "landing strips" for inflammatory cells as they invade tissue from the circulation. The increase in versican is often coincident with the invasion of leukocytes early in the inflammatory process. Versican interacts with inflammatory cells either indirectly via hyaluronan or directly via receptors such as CD44, P-selectin glycoprotein ligand-1 (PSGL-1), and toll-like receptors (TLRs) present on the surface of immune and non-immune cells. These interactions activate signaling pathways that promote the synthesis and secretion of inflammatory cytokines such as TNFα, IL-6, and NFκB. Versican also influences inflammation by interacting with a variety of growth factors and cytokines involved in regulating inflammation thereby influencing their bioavailability and bioactivity. Versican is produced by multiple cell types involved in the inflammatory process. Conditional total knockout of versican in a mouse model of lung inflammation demonstrated significant reduction in leukocyte invasion into the lung and reduced inflammatory cytokine expression. While versican produced by stromal cells tends to be pro-inflammatory, versican expressed by myeloid cells can create anti-inflammatory and immunosuppressive microenvironments. Inflammation in the tumor microenvironment often contains elevated levels of versican. Perturbing the accumulation of versican in tumors can inhibit inflammation and tumor progression in some cancers. Thus versican, as a component of the ECM impacts immunity and inflammation through regulating immune cell trafficking and activation. Versican is emerging as a potential target in the control of inflammation in a number of different diseases.
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http://dx.doi.org/10.3389/fimmu.2020.00512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105702PMC
March 2021

Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment.

Cell Rep 2020 01;30(2):525-540.e7

Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address:

Although there are many prospective targets in the tumor microenvironment (TME) of high-grade serous ovarian cancer (HGSOC), pre-clinical testing is challenging, especially as there is limited information on the murine TME. Here, we characterize the TME of six orthotopic, transplantable syngeneic murine HGSOC lines established from genetic models and compare these to patient biopsies. We identify significant correlations between the transcriptome, host cell infiltrates, matrisome, vasculature, and tissue modulus of mouse and human TMEs, with several stromal and malignant targets in common. However, each model shows distinct differences and potential vulnerabilities that enabled us to test predictions about response to chemotherapy and an anti-IL-6 antibody. Using machine learning, the transcriptional profiles of the mouse tumors that differed in chemotherapy response are able to classify chemotherapy-sensitive and -refractory patient tumors. These models provide useful pre-clinical tools and may help identify subgroups of HGSOC patients who are most likely to respond to specific therapies.
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http://dx.doi.org/10.1016/j.celrep.2019.12.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963791PMC
January 2020

Is It Time We Changed How We Measure Length of Stay for Hip and Knee Arthroplasty?

J Am Acad Orthop Surg Glob Res Rev 2017 Sep 9;1(6):e032. Epub 2017 Oct 9.

Departments of Trauma and Orthopaedics, Oxford Rotation (Dr. McCulloch), and the Department of Trauma and Orthopaedics (Dr. Pearce), Milton Keynes University Hospital, Milton Keynes, UK; Services and Solutions Development, Zimmer Biomet, Warsaw, IN (Mr. Cottingham); and the Department of Exercise Physiology, Sport Science Program, College of Arts and Sciences, Qatar University, Doha, Qatar (Dr. Christmas).

Introduction: Patient length of stay (LOS) for lower limb arthroplasty is a frequently quoted outcome measure. However, the use of mean values in days is prone to being skewed by outliers.

Methods: Between January 2013 and December 2015, patient LOS for primary hip and knee replacement was collected in 1,168 patients. There were two groups: pre- and postinstitution of the Rapid Recovery Program. The hypothesis was that reducing LOS would highlight proportionate differences when using hours as the measuring unit.

Results: Statistical analysis confirmed a significant reduction in LOS between the Enhanced Recovery Program and Rapid Recovery Program ( < 0.001).

Discussion: Use of the median LOS reduces the impact of outliers. Use of hours as the unit of measure of LOS enabled analysis of the time of day of discharge. With decreasing LOS and day-case arthroplasty, a measurement in median hours should become the standard to allow for the detection of subtle changes.
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http://dx.doi.org/10.5435/JAAOSGlobal-D-17-00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132329PMC
September 2017

Cancer Immunotherapy.

Glycobiology 2018 09;28(9):638-639

Medical Oncology and Laboratory of Cancer Immunology, University Hospital Basel, Petersgraben 4, Basel, Switzerland.

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http://dx.doi.org/10.1093/glycob/cwy069DOI Listing
September 2018

Cancer glycan epitopes: biosynthesis, structure and function.

Glycobiology 2018 09;28(9):670-696

Centre for Cancer & Inflammation, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK.

Aberrant glycan epitopes are a classic hallmark of malignant transformation, yet their full clinical potential in cancer diagnostics and therapeutics is yet to be realized. This is partly because our understanding of how these epitopes are regulated remains poorly understood. In this review cancer glycan epitopes for the major glycan classes are summarized with a focus on their biosynthesis, structure and role in cancer progression. Their application as cancer biomarkers, in particular the more recent work on cancer glycoforms, and the advantages these offer over the glycan or protein alone are discussed. Finally, emerging concepts which expand on the current view of the cancer glycan epitope beyond the single structure, to patterns and the whole glycocalyx, are described. These new approaches that consider the cancer glycan epitope as a glycoform, or as a pattern of many epitope structures, are providing new targets both for cancer biomarkers and therapeutics currently in development at the bench and the clinic.
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http://dx.doi.org/10.1093/glycob/cwy023DOI Listing
September 2018

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers.

Cancer Discov 2018 03 1;8(3):304-319. Epub 2017 Dec 1.

Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK.

We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer. Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837004PMC
March 2018

-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils.

Proc Natl Acad Sci U S A 2017 09 11;114(39):E8155-E8164. Epub 2017 Sep 11.

Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093;

Biosynthesis of the common mammalian sialic acid -glycolylneuraminic acid (Neu5Gc) was lost during human evolution due to inactivation of the gene, possibly expediting divergence of the lineage, due to a partial fertility barrier. Neu5Gc catabolism generates -glycolylhexosamines, which are potential precursors for glycoconjugate biosynthesis. We carried out metabolic labeling experiments and studies of mice with human-like Neu5Gc deficiency to show that Neu5Gc degradation is the metabolic source of UDP-GlcNGc and UDP-GalNGc and the latter allows an unexpectedly selective incorporation of -glycolyl groups into chondroitin sulfate (CS) over other potential glycoconjugate products. Partially -glycolylated-CS was chemically synthesized as a standard for mass spectrometry to confirm its natural occurrence. Much lower amounts of GalNGc in human CS can apparently be derived from Neu5Gc-containing foods, a finding confirmed by feeding Neu5Gc-rich chow to human-like Neu5Gc-deficient mice. Unlike the case with Neu5Gc, -glycolyl-CS was also stable enough to be detectable in animal fossils as old as 4 My. This work opens the door for investigating the biological and immunological significance of this glycosaminoglycan modification and for an "ancient glycans" approach to dating of Neu5Gc loss during the evolution of .
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http://dx.doi.org/10.1073/pnas.1706306114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625913PMC
September 2017

Hypoxic Air Inhalation and Ischemia Interventions Both Elicit Preconditioning Which Attenuate Subsequent Cellular Stress Following Blood Flow Occlusion and Reperfusion.

Front Physiol 2017 2;8:560. Epub 2017 Aug 2.

ASPETAR, Athlete Health and Performance Research Centre, Qatar Orthopedic and Sports Medicine HospitalDoha, Qatar.

Ischemic preconditioning (IPC) is valid technique which elicits reductions in femoral blood flow occlusion mediated reperfusion stress (oxidative stress, Hsp gene transcripts) within the systemic blood circulation and/or skeletal muscle. It is unknown whether systemic hypoxia, evoked by hypoxic preconditioning (HPC) has efficacy in priming the heat shock protein (Hsp) system thus reducing reperfusion stress following blood flow occlusion, in the same manner as IPC. The comparison between IPC and HPC being relevant as a preconditioning strategy prior to orthopedic surgery. In an independent group design, 18 healthy men were exposed to 40 min of (1) passive whole-body HPC (FiO = 0.143; no ischemia. = 6), (2) IPC (FiO = 0.209; four bouts of 5 min ischemia and 5 min reperfusion. = 6), or (3) rest (FiO = 0.209; no ischemia. = 6). The interventions were administered 1 h prior to 30 min of tourniquet derived femoral blood flow occlusion and were followed by 2 h subsequent reperfusion. Systemic blood samples were taken pre- and post-intervention. Systemic blood and gastrocnemius skeletal muscle samples were obtained pre-, 15 min post- (15PoT) and 120 min (120PoT) post-tourniquet deflation. To determine the cellular stress response gastrocnemius and leukocyte Hsp72 mRNA and Hsp32 mRNA gene transcripts were determined by RT-qPCR. The plasma oxidative stress response (protein carbonyl, reduced glutathione/oxidized glutathione ratio) was measured utilizing commercially available kits. In comparison to control, at 15PoT a significant difference in gastrocnemius Hsp72 mRNA was seen in HPC (-1.93-fold; = 0.007) and IPC (-1.97-fold; = 0.006). No significant differences were observed in gastrocnemius Hsp32 and Hsp72 mRNA, leukocyte Hsp72 and Hsp32 mRNA, or oxidative stress markers ( > 0.05) between HPC and IPC. HPC provided near identical amelioration of blood flow occlusion mediated gastrocnemius stress response (Hsp72 mRNA), compared to an established IPC protocol. This was seen independent of changes in systemic oxidative stress, which likely explains the absence of change in Hsp32 mRNA transcripts within leukocytes and the gastrocnemius. Both the established IPC and novel HPC interventions facilitate a priming of the skeletal muscle, but not leukocyte, Hsp system prior to femoral blood flow occlusion. This response demonstrates a localized tissue specific adaptation which may ameliorate reperfusion stress.
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http://dx.doi.org/10.3389/fphys.2017.00560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539087PMC
August 2017

The Hsp72 and Hsp90α mRNA Responses to Hot Downhill Running Are Reduced Following a Prior Bout of Hot Downhill Running, and Occur Concurrently within Leukocytes and the Vastus Lateralis.

Front Physiol 2017 12;8:473. Epub 2017 Jul 12.

School of Sport, Exercise and Health Sciences, Loughborough UniversityLoughborough, United Kingdom.

The leukocyte heat shock response (HSR) is used to determine individual's thermotolerance. The HSR and thermotolerance are enhanced following interventions such as preconditioning and/or acclimation/acclimatization. However, it is unclear whether the leukocyte HSR is an appropriate surrogate for the HSR in other tissues implicated within the pathophysiology of exertional heat illnesses (e.g., skeletal muscle), and whether an acute preconditioning strategy (e.g., downhill running) can improve subsequent thermotolerance. Physically active, non-heat acclimated participants were split into two groups to investigate the benefits of hot downhill running as preconditioning strategy. A hot preconditioning group (HPC; = 6) completed two trials (HPC1 and HPC2) of 30 min running at lactate threshold (LT) on -10% gradient in 30°C and 50% relative humidity (RH) separated by 7 d. A temperate preconditioning group (TPC; = 5) completed 30 min running at LT on a -1% gradient in 20°C and 50% (TPC1) and 7 d later completed 30 min running at LT on -10% gradient in 30°C and 50% RH (TPC2). Venous blood samples and muscle biopsies (vastus lateralis; VL) were obtained before, immediately after, 3, 24, and 48 h after each trial. Leukocyte and VL Hsp72, Hsp90α, and Grp78 mRNA relative expression was determined via RT-QPCR. Attenuated leukocyte and VL Hsp72 (2.8 to 1.8 fold and 5.9 to 2.4 fold; < 0.05) and Hsp90α mRNA (2.9 to 2.4 fold and 5.2 to 2.4 fold; < 0.05) responses accompanied reductions ( < 0.05) in physiological strain [exercising rectal temperature (-0.3°C) and perceived muscle soreness (~ -14%)] during HPC2 compared to HPC1 (i.e., a preconditioning effect). Both VL and leukocyte Hsp72 and Hsp90α mRNA increased ( < 0.05) simultaneously following downhill runs and demonstrated a strong relationship ( < 0.01) of similar magnitudes with one another. Hot downhill running is an effective preconditioning strategy which ameliorates physiological strain, soreness and Hsp72 and Hsp90α mRNA responses to a subsequent bout. Leukocyte and VL analyses are appropriate tissues to infer the extent to which the HSR has been augmented.
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http://dx.doi.org/10.3389/fphys.2017.00473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506191PMC
July 2017

Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics.

J Proteome Res 2017 08 19;16(8):3083-3091. Epub 2017 Jul 19.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.

The extracellular matrix (ECM) is a complex meshwork of insoluble fibrillar proteins and signaling factors interacting together to provide architectural and instructional cues to the surrounding cells. Alterations in ECM organization or composition and excessive ECM deposition have been observed in diseases such as fibrosis, cardiovascular diseases, and cancer. We provide here optimized protocols to solubilize ECM proteins from normal or tumor tissues, digest the proteins into peptides, analyze ECM peptides by mass spectrometry, and interpret the mass spectrometric data. In addition, we present here two novel R-script-based web tools allowing rapid annotation and relative quantification of ECM proteins, peptides, and intensity/abundance in mass spectrometric data output files. We illustrate this protocol with ECMs obtained from two pairs of tissues, which differ in ECM content and cellularity: triple-negative breast cancer and adjacent mammary tissue, and omental metastasis from high-grade serous ovarian cancer and normal omentum. The complete proteomics data set generated in this study has been deposited to the public repository ProteomeXchange with the data set identifier: PXD005554.
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http://dx.doi.org/10.1021/acs.jproteome.7b00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078728PMC
August 2017

Predictors of Infective Outcomes Following Hip Fracture: A Cohort Study.

Gerontol Geriatr Med 2016 Jan-Dec;2:2333721416649488. Epub 2016 Jun 1.

Milton Keynes University Hospital, Milton Keynes, UK.

This study sought to assess the value of differing pre-operative measures in prediction of post-operative non-surgical site infection (NSSI) and length of hospital stay following hip fracture surgery. All patients admitted during a one year period with a hip fracture to our department were included in the study (n=207). Primary outcome measures were ten independent risk factors correlated to the development of non-surgical site infection following surgery for hip fracture. Secondary outcome measures were duration of hospital stay and inpatient mortality. The patients who had severe cognitive impairment had a 71.0% risk of developing non-surgical site infection. Patients who had multiple medical co-morbidities also had increased risk of developing non-surgical site infection at 59.1%. Patients who developed NSSI on average stayed in hospital 13.1 days longer than patients who did not (31.6 vs. 18.5, < .001). This study demonstrates the importance of reducing post-operative infection in hip fracture patients in view of reducing morbidity, mortality and cost. These patients can be stratified by risk factors and interventions can be employed in view of reducing inpatient post-operative infection rates in this cohort.
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http://dx.doi.org/10.1177/2333721416649488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119884PMC
June 2016
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