Publications by authors named "Andrew Robinson"

425 Publications

Superior Frontal Gyrus Locus DNA Methylation in Alzheimer's Disease.

J Alzheimers Dis Rep 2021 Apr 6;5(1):275-282. Epub 2021 Apr 6.

Department of Life Sciences, Manchester Metropolitan University, Manchester, UK.

Background: The ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). The neighboring gene has also been implicated in AD due to its close proximity to .

Objective: Here we tested whether methylation of the locus may influence ApoE protein levels and AD pathology.

Methods: DNA methylation levels across the locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for and scored for AD neuropathology.

Results: Methylation levels within the CpG island in the promoter or CpG island in Exon 4 did not differ between ɛ4 carriers versus non-carriers. However, ɛ4 carriers had significantly higher methylation the promoter compared with non-carriers. Although DNA methylation at , promoter region, or did not differ between AD pathological groups, there was a negative association between methylation and CERAD scores. ApoE protein concentrations did not significantly different between ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels.

Conclusion: gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the locus in the brain in controlling ApoE protein levels and AD neuropathology.
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http://dx.doi.org/10.3233/ADR-201000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150259PMC
April 2021

A new model of care and in-house general practitioners for residential aged care facilities.

Med J Aust 2021 Jun 3. Epub 2021 Jun 3.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS.

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http://dx.doi.org/10.5694/mja2.51116DOI Listing
June 2021

Early changes in visuospatial episodic memory can help distinguish primary age-related tauopathy from Alzheimer's disease.

Neuropathol Appl Neurobiol 2021 May 9. Epub 2021 May 9.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

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http://dx.doi.org/10.1111/nan.12726DOI Listing
May 2021

Health Resource and Cost Savings Achieved in a Multidisciplinary Lung Cancer Clinic.

Curr Oncol 2021 Apr 29;28(3):1681-1695. Epub 2021 Apr 29.

Department of Medicine, Queen's University, Kingston, ON K7L 5P9, Canada.

: Lung cancer (LC) care is resource and cost intensive. We launched a Multidisciplinary LC Clinic (MDC), where patients with a new LC diagnosis received concurrent oncology consultation, resulting in improved time to LC assessment and treatment. Here, we evaluate the impact of MDC on health resource utilization, patient and caregiver costs, and secondary patient benefits. : We retrospectively analyzed patients in a rapid assessment clinic with a new LC diagnosis pre-MDC (September 2016-February 2017) and post-MDC implementation (February 2017-December 2018). Data are reported as means; unpaired t-tests and ANOVA were used to assess for significance. We also conducted a cost analysis. Resource utilization, out-of-pocket costs, procedure-related costs, and indirect costs were evaluated from the societal perspective and presented in 2019 Canadian dollars (CAD); multi-way worst/best case and threshold sensitivity analyses were conducted. : We reviewed 428 patients (78 traditional model, 350 MDC). Patients in the MDC model required significantly fewer oncology visits from LC diagnosis to first LC treatment (1.62 vs. 2.68, < 0.001), which was significant for patients with stage 1, 3, and 4 disease. Compared with the traditional model, there was no change in mean biopsies/patient (1.32 traditional vs. 1.17 MDC, = 0.18) or staging investigations/patient (2.24 traditional vs. 2.02 MDC, = 0.20). Post-MDC, there was an increase in invasive mediastinal staging for patients with stage 2/3 LC (15.0% vs. 60.0%, < 0.001). Over 22 months, MDC resulted in savings of CAD 48,389 including CAD 24,167 CAD in direct patient out-of-pocket expenses. For the threshold analyses, MDC was estimated to cost CAD 25,708 per quality-adjusted life year (QALY), considered to be below current willingness to pay thresholds (at CAD 80,000 per QALY). MDC also facilitated oncology assessment for 29 non-LC patients. : An MDC led to a reduction in patient visits and direct patient and caregiver costs.
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http://dx.doi.org/10.3390/curroncol28030157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161784PMC
April 2021

Low-Risk Essential Thrombocythemia: A Comprehensive Review.

Hemasphere 2021 Feb 27;5(2):e521. Epub 2021 Jan 27.

Haematopathology and Oncology Diagnostics Service/Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by a persistently elevated platelet count in the absence of a secondary cause. The clinical consequences of uncontrolled thrombocytosis can include both thrombosis and hemorrhage. Patients with features conferring a "high risk" of vascular events benefit from reduction of the platelet count through cytoreductive therapy. The management of patients who lack such high-risk features has until recently been less well defined, but it is now apparent that many require minimal or even no intervention. In this review, we discuss the diagnostic pathway for younger patients with unexplained thrombocytosis, including screening molecular investigations, the role of bone marrow biopsy, and investigations in those patients negative for the classic myeloproliferative neoplasm driver mutations (, , ). We discuss conventional and novel risk stratification methods in essential thrombocythemia and how these can be best applied in clinical practice, particularly in the era of more comprehensive genomic testing. The treatment approach for "low risk" patients is discussed including antiplatelets and the options for cytoreductive therapy, if indicated, together with areas of clinical need for future study.
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http://dx.doi.org/10.1097/HS9.0000000000000521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051994PMC
February 2021

Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50.

J Clin Oncol 2021 Apr 19:JCO2100174. Epub 2021 Apr 19.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing or alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS).

Methods: Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point.

Results: Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3-40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48-0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure.

Conclusion: Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.
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http://dx.doi.org/10.1200/JCO.21.00174DOI Listing
April 2021

Characterization of a Glyphosate-Tolerant Enzyme from : A Distinct Class of 5-Enolpyruvylshikimate-3-phosphate Synthases.

J Agric Food Chem 2021 May 7;69(17):5096-5104. Epub 2021 Apr 7.

Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States.

Natural and modified versions of the 5-enolpyruvylshikimate-3-phosphate synthase () gene have been used to confer tolerance to the broad-spectrum herbicide glyphosate in a variety of commercial crops. The most widely utilized trait was obtained from the strain CP4 and has been commercialized in several glyphosate-tolerant crops. The EPSPS gene products are enzymes that have been divided into three classes based on sequence similarity, sensitivity to glyphosate, and steady-state catalytic parameters. Herein, we describe the informatics-guided identification and biochemical and structural characterization of a novel EPSPS from (DGT-28 EPSPS). The data suggest DGT-28 EPSPS and other closely related homologues exemplify a distinct new class (Class IV) of EPSPS enzymes that display intrinsic tolerance to high concentrations of glyphosate ( ≥ 5000 μM). We further demonstrate that , when transformed into stable plants, provides robust (≥4× field rates) vegetative/reproductive herbicide tolerance and has utility in weed-control systems comparable to that of commercialized events.
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http://dx.doi.org/10.1021/acs.jafc.1c00439DOI Listing
May 2021

Animal Models and Alternatives in Vaginal Research: a Comparative Review.

Reprod Sci 2021 Jun 6;28(6):1759-1773. Epub 2021 Apr 6.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, 77030, USA.

While developments in gynecologic health research continue advancing, relatively few groups specifically focus on vaginal tissue research for areas like wound healing, device development, and/or drug toxicity. Currently, there is no standardized animal or tissue model that mimics the full complexity of the human vagina. Certain practical factors such as appropriate size and anatomy, costs, and tissue environment vary across species and moreover fail to emulate all aspects of the human vagina. Thus, investigators are tasked with compromising specific properties of the vaginal environment as it relates to human physiology to suit their particular scientific question. Our review aims to facilitate the appropriate selection of a model aptly addressing a particular study by discussing pertinent vaginal characteristics of conventional animal and tissue models. In this review, we first cover common laboratory animals studied in vaginal research-mouse, rat, rabbit, minipig, and sheep-as well as human, with respect to the estrus cycle and related hormones, basic reproductive anatomy, the composition of vaginal layers, developmental epithelial origin, and microflora. In light of these relevant comparative metrics, we discuss potential selection criteria for choosing an appropriate animal vaginal model. Finally, we allude to the exciting prospects of increasing biomimicry for in vitro applications to provide a framework for investigators to model, interpret, and predict human vaginal health.
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http://dx.doi.org/10.1007/s43032-021-00529-yDOI Listing
June 2021

Reactive Oxygen Species Rewires Metabolic Activity in Acute Myeloid Leukemia.

Front Oncol 2021 11;11:632623. Epub 2021 Mar 11.

Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Acute myeloid leukemia (AML) is a heterogeneous disease with poor clinical outcomes. We have previously shown that constitutive activation of NADPH oxidase 2 (NOX2), resulting in over-production of reactive oxygen species (ROS), occurs in over 60% of AML patients. We have also shown that increased ROS production promotes increased glucose uptake and proliferation in AML cells, mediated by changes in carbohydrate metabolism. Given that carbohydrate, lipid, and protein metabolisms are all intricately interconnected, we aimed to examine the effect of cellular ROS levels on these pathways and establish further evidence that ROS rewires metabolism in AML. We carried out metabolomic profiling of AML cell lines in which NOX2-derived ROS production was inhibited and conversely in cells treated with exogenous HO. We report significant ROS-specific metabolic alterations in sphingolipid metabolism, fatty acid oxidation, purine metabolism, amino acid homeostasis and glycolysis. These data provide further evidence of ROS directed metabolic changes in AML and the potential for metabolic targeting as novel therapeutic arm to combat this disease.
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http://dx.doi.org/10.3389/fonc.2021.632623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993200PMC
March 2021

Treatment and Patient Selection for Patients with Metastatic Castration-resistant Prostate After Progression on Docetaxel and Abiraterone/Enzalutamide: When to Play Your CARD and When to Do Your PARP.

Eur Urol 2021 Mar 25. Epub 2021 Mar 25.

Division of Medical Oncology, Department of Oncology, Queen's University, Kingston, ON, Canada. Electronic address:

For patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after an androgen receptor axis-targeted therapy and docetaxel, poly (ADP-ribose) polymerase (PARP) inhibitors and chemotherapy with cabazitaxel have shown promise. We address the trials for the two approaches and consider possible sequencing of these drugs. We suggest that only patients with a BRCA2 mutation should receive a PARP inhibitor, and docetaxel or cabazitaxel should be favored in the absence of BRCA2 alterations, provided the patient is naïve to these drugs.
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http://dx.doi.org/10.1016/j.eururo.2021.03.001DOI Listing
March 2021

Ankle Arthritis Networking: Getting the right treatment to the right patient first time.

Foot Ankle Surg 2021 Mar 18. Epub 2021 Mar 18.

Cambridge University Hospitals, NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom. Electronic address:

End stage ankle joint arthritis is a debilitating condition. Surgical treatment, most commonly ankle arthrodesis or fusion, can be highly effective. The authors outline the nature and prevalence of ankle arthritis and show that the frequency of each type of procedure varies geographically. They present data supporting the hypothesis that units performing ankle replacement more frequently tend to have better outcomes, both clinically and financially. Adoption of country-wide Ankle Arthritis Networks is proposed, ensuring that every patient seeing a foot and ankle orthopaedic surgeon has potential access to all treatment options whether their surgeon chooses to perform replacement or not. The case is made that establishment of Ankle Arthritis Networks will avoid the need for units to perform a low number of replacements per year, homogenise treatment availability across the country and enables the right patient to receive the right treatment first time. LEVEL OF EVIDENCE: IV.
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http://dx.doi.org/10.1016/j.fas.2021.03.006DOI Listing
March 2021

Human tauopathy-derived tau strains determine the substrates recruited for templated amplification.

Brain 2021 Mar 9. Epub 2021 Mar 9.

Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.

Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer's disease (AD), three-repeat tau in Pick's disease (PiD) and four-repeat in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryo-electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and AD-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrates. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity.
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http://dx.doi.org/10.1093/brain/awab091DOI Listing
March 2021

Approaches for estimating benefits and costs of interventions in plant biosecurity across invasion phases.

Ecol Appl 2021 Mar 4:e02319. Epub 2021 Mar 4.

Scion (NZ Forest Research Institute), P.O. Box 29237, Christchurch, 8540, New Zealand.

Nonnative plant pests cause billions of dollars in damages. It is critical to prevent or reduce these losses by intervening at various stages of the invasion process, including pathway risk management (to prevent pest arrival), surveillance and eradication (to counter establishment), and management of established pests (to limit damages). Quantifying benefits and costs of these interventions is important to justify and prioritize investments and to inform biosecurity policy. However, approaches for these estimations differ in (1) the assumed relationship between supply, demand, and prices, and (2) the ability to assess different types of direct and indirect costs at invasion stages, for a given arrival or establishment probability. Here we review economic approaches available to estimate benefits and costs of biosecurity interventions to inform the appropriate selection of approaches. In doing so, we complement previous studies and reviews on estimates of damages from invasive species by considering the influence of economic and methodological assumptions. Cost accounting is suitable for rapid decisions, specific impacts, and simple methodological assumptions but fails to account for feedbacks, such as market adjustments, and may overestimate long-term economic impacts. Partial equilibrium models consider changes in consumer and producer surplus due to pest impacts or interventions and can account for feedbacks in affected sectors but require specialized economic models, comprehensive data sets, and estimates of commodity supply and demand curves. More intensive computable general equilibrium models can account for feedbacks across entire economies, including capital and labor, and linkages among these. The two major considerations in choosing an approach are (1) the goals of the analysis (e.g., consideration of a single pest or intervention with a limited range of impacts vs. multiple interventions, pests or sectors), and (2) the resources available for analysis such as knowledge, budget and time.
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http://dx.doi.org/10.1002/eap.2319DOI Listing
March 2021

The feasibility and acceptability of mobile health monitoring for real-time assessment of traumatic injury outcomes.

Mhealth 2021 20;7. Epub 2021 Jan 20.

University of Pennsylvania Injury Science Center, University of Pennsylvania, Philadelphia, PA, USA.

Background: Traumatic injuries are a health event that can begin a trajectory towards chronic health and social challenges. Mobile technology-based prevention and treatment interventions have been used to monitor and transform outcomes across a myriad of health conditions, but their potential in long-term injury recovery is unexplored. The goal of this pilot study was to assess the acceptability and feasibility of mobile health monitoring for long-term outcomes in a population of trauma patients with known barriers to health and social care after injury.

Methods: We re-recruited 25 individuals, 12-36 months after acute hospitalization, from a recently concluded study of psychological outcomes in seriously injured Black men in Philadelphia, Pennsylvania. This mixed- methods pilot study was conducted in three phases: (I) qualitative interviews and development of a pilot monitoring platform; (II) a 3-month feasibility trial of mobile monitoring of patient-reported outcomes and biometric data using a wrist-worn commercial fitness monitor (n=18); (III) post-implementation qualitative interviews.

Results: Analysis of data from pre-implementation interviews indicated that the majority of participants used smartphones as a primary means of communicating with their social network and to access the internet. The 90-day pilot trial of mobile monitoring indicated participants' preference text-delivered communication and survey elicitation. Response rates for 12 automated surveys ranged from 84-92%. Twenty-four hours a day adherence to optional biometric monitoring was generally lower than 50% but ranged widely indicating both very low adherence and very high adherence. Four of 25 participants, 2 who had opted for Fitbit monitoring, were lost to follow-up at the end of the 90-day pilot trial. In post-implementation assessments, participants endorsed the acceptability of mobile monitoring highlighting the benefit of its convenience and flexibility over in-person outcome monitoring. Participants also perceived its potential benefit in long-term engagement with health and social services to assist with the challenges they faced when attempting to achieve physical, psychological, social, and financial recovery after hospitalization. These findings were reinforced through qualitative interviews which highlighted, in addition to acceptability, the perceived value of self-monitoring through the use of wearable devices to track health data like physical activity and sleep.

Conclusions: This study indicates the feasibility and acceptability of mobile health monitoring used to examine long-term injury sequalae. Future research may leverage this novel strategy, refining its application to address current limitations in the reliability and accuracy of commercially available wearable technology, relative costs and benefits of different mobile data collection strategies, integration within current clinical paradigms and generalizability across injured populations and socio-ecological environments.
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http://dx.doi.org/10.21037/mhealth-19-200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882274PMC
January 2021

Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom real-world analysis of outcomes in 211 patients.

Br J Haematol 2021 Apr 23;193(2):290-298. Epub 2021 Feb 23.

Peninsula Medical School, University of Plymouth, Plymouth, United Kingdom.

Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.
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http://dx.doi.org/10.1111/bjh.17363DOI Listing
April 2021

Ex vivo modelling of PD-1/PD-L1 immune checkpoint blockade under acute, chronic, and exhaustion-like conditions of T-cell stimulation.

Sci Rep 2021 Feb 17;11(1):4030. Epub 2021 Feb 17.

Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK.

Blockade of PD-1/PD-L1 interactions is proving an exciting, durable therapeutic modality in a range of cancers whereby T cells are released from checkpoint inhibition to revive their inherent anti-tumour activity. Here we have studied various ways to model ex vivo T cell function in order to compare the impact of the clinically utilised anti-PD-1 antibody, pembrolizumab (Keytruda) on the activation of human T cells: focussing on the release of pro-inflammatory IFNγ and anti-inflammatory IL-10 to assess functionality. Firstly, we investigated the actions of pembrolizumab in an acute model of T-cell activation with either immature or mature allogeneic dendritic cells (DCs); pembrolizumab enhanced IFNγ and IL-10 release from purified CD4+ T-cells in the majority of donors with a bias towards pro-inflammatory cytokine release. Next, we modelled the impact of pembrolizumab in settings of more chronic T-cell activation. In a 7-day antigen-specific response to EBV peptides, the presence of pembrolizumab resulted in a relatively modest increase in both IFNγ and IL-10 release. Where pembrolizumab was assessed against long-term stimulated CD4+ cells that had up-regulated the exhaustion markers TIM-3 and PD-1, there was a highly effective enhancement of the otherwise exhausted response to allogeneic DCs with respect to IFNγ production. By contrast, the restoration of IL-10 production was considerably more limited. Finally, to assess a direct clinical relevance we investigated the consequence of PD-1/PD-L1 blockade in the disease setting of dissociated cells from lung and colon carcinomas responding to allogeneic DCs: here, pembrolizumab once more enhanced IFNγ production from the majority of tumour preparations whereas, again, the increase in IL-10 release was modest at best. In conclusion, we have shown that the contribution of PD-1-revealed by using a canonical blocking antibody to interrupt its interaction with PD-L1-to the production of an exemplar pro- and anti-inflammatory cytokine, respectively, depends in magnitude and ratio on the particular stimulation setting and activation status of the target T cell. We have identified a number of in vitro assays with response profiles that mimic features of dissociated cell populations from primary tumours thereby indicating these represent disease-relevant functional assays for the screening of immune checkpoint inhibitors in current and future development. Such in vitro assays may also support patient stratification of those likely to respond to immuno-oncology therapies in the wider population.
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http://dx.doi.org/10.1038/s41598-021-83612-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889918PMC
February 2021

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update.

J Clin Oncol 2021 Mar 16;39(9):1040-1091. Epub 2021 Feb 16.

Helen F. Graham Cancer Center and Research Institute, Newark, DE.

Purpose: To provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) with driver alterations. A guideline update for systemic therapy for patients with stage IV NSCLC without driver alterations was published separately.

Methods: The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic review of randomized controlled trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020.

Results: This guideline update reflects changes in evidence since the previous update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis provide the evidence base (total 54). Outcomes of interest included efficacy and safety. Additional literature suggested by the Expert Panel is discussed.

Recommendations: All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status recommendations, when possible, following other existing high-quality testing guidelines. Most patients should receive targeted therapy for these alterations: Targeted therapies against -1 fusions, V600e mutations, fusions, exon 14 skipping mutations, and fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting. New or revised recommendations include the following: Osimertinib is the optimal first-line treatment for patients with activating epidermal growth factor receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M); alectinib or brigatinib is the optimal first-line treatment for patients with anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the guideline includes recommendations regarding alterations. Chemotherapy is still an option at most stages.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.03570DOI Listing
March 2021

A single institution study evaluating outcomes of PD-L1 high KRAS-mutant advanced non-small cell lung cancer (NSCLC) patients treated with first line immune checkpoint inhibitors.

Cancer Treat Res Commun 2021 6;27:100330. Epub 2021 Feb 6.

Cancer Centre of Southeastern Ontario, Canada; Kingston Health Sciences Centre, Canada; Department of Medical Oncology, Queen's University, Canada. Electronic address:

Aim: This study aimed to evaluate the impact of KRAS status on the efficacy of first-line immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC).

Patients And Methods: Patients with advanced incurable or metastatic NSCLC with PD-L1 ≥50% treated with palliative-intent, single-agent PD-1/PD-L1 inhibitors at the Cancer Centre of Southeastern Ontario were included. KRAS mutation status was determined via massively parallel sequencing. Primary study outcome was median overall survival (mOS).

Results: Seventy-eight patients (59 non-squamous, 19 squamous) were identified; only non-squamous patients were included in KRAS mutation analyses. Thirty patients (51%) were KRAS-MT (mutant), with G12C (19%), G12V (15%), and G12D (13%) accounting for the most common KRAS mutation subtypes. There was no difference in mOS between KRAS-MT and KRAS-WT (wild-type) patients (12.9 vs. 19.3 months, p = 0.879). There was a non-significant trend towards worse mOS in KRAS G12C patients compared to non-G12C and KRAS-WT patients (11.4 vs. 44.9 vs. 19.3 months, p = 0.772). On multivariable analysis, KRAS-MT status was not associated with mOS (HR 0.901, 95%CI 0.417-1.946, p = 0.791). ECOG≥2 was an independent prognostic factor for worse mOS (HR 2.853, 95%CI 1.237-6.583, p = 0.014). Immune-related adverse events did not differ between KRAS-MT and KRAS-WT groups (48% vs. 52%, p = 1.000).

Conclusions: KRAS mutation status did not have a significant impact on ICI efficacy or safety. However, a non-significant trend towards worse survival was noted in patients treated with ICI whose tumours harboured the KRAS G12C variant. This study provides valuable information for comparative analysis in the future.
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http://dx.doi.org/10.1016/j.ctarc.2021.100330DOI Listing
February 2021

Automating the assessment of biofouling in images using expert agreement as a gold standard.

Sci Rep 2021 Feb 2;11(1):2739. Epub 2021 Feb 2.

Centre of Excellence for Biosecurity Risk Analysis, The University of Melbourne, Melbourne, Australia.

Biofouling is the accumulation of organisms on surfaces immersed in water. It is of particular concern to the international shipping industry because it increases fuel costs and presents a biosecurity risk by providing a pathway for non-indigenous marine species to establish in new areas. There is growing interest within jurisdictions to strengthen biofouling risk-management regulations, but it is expensive to conduct in-water inspections and assess the collected data to determine the biofouling state of vessel hulls. Machine learning is well suited to tackle the latter challenge, and here we apply deep learning to automate the classification of images from in-water inspections to identify the presence and severity of fouling. We combined several datasets to obtain over 10,000 images collected from in-water surveys which were annotated by a group biofouling experts. We compared the annotations from three experts on a 120-sample subset of these images, and found that they showed 89% agreement (95% CI: 87-92%). Subsequent labelling of the whole dataset by one of these experts achieved similar levels of agreement with this group of experts, which we defined as performing at most 5% worse (p [Formula: see text] 0.009-0.054). Using these expert labels, we were able to train a deep learning model that also agreed similarly with the group of experts (p [Formula: see text] 0.001-0.014), demonstrating that automated analysis of biofouling in images is feasible and effective using this method.
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http://dx.doi.org/10.1038/s41598-021-81011-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854599PMC
February 2021

Long-Term Mental Health Service Utilization Among Survivors of Testicular Cancer: A Population-Based Cohort Study.

J Clin Oncol 2021 Mar 28;39(7):779-786. Epub 2021 Jan 28.

Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Eastern Ontario, Canada.

Purpose: Testicular cancer survivors may experience mental illness as a consequence of their cancer diagnosis and treatment.

Methods: All incident cases of testicular cancer treated with orchiectomy in Ontario, Canada (2000-2010), were identified using the Ontario Cancer Registry. Cases were matched to controls in a 1:5 ratio on age and geography. Population-level databases were used to identify mental health service use episodes; outpatient use included visits to a general practitioner for a mental health concern or any visit to a psychiatrist. Negative binomial regression modeling was used to estimate the rate of mental health service use in the pretreatment (2 years prior until 1 month before orchiectomy), peritreatment (1 month before until 1 month after orchiectomy), and post-treatment periods (1 month after orchiectomy until end of follow-up). Rate ratios (RR) comparing cases with controls in the peri- and post-treatment periods were adjusted for baseline mental health service use.

Results: Two thousand six hundred nineteen cases of testicular cancer were matched to 13,095 controls. There was no baseline difference in the rate of mental health service use. Cases were significantly more likely than controls to have an outpatient visit for a mental health concern in the peritreatment (adjusted RR [aRR], 2.45; 95% CI, 2.06 to 2.92) and post-treatment periods (aRR, 1.30; 95% CI, 1.12 to 1.52). The difference in mental health service use persisted over a median follow-up of 12 years. In the postorchiectomy period, cases with baseline mental health service use were those most likely to use mental health services (aRR, 5.64; 95% CI, 4.64 to 6.85).

Conclusion: Testicular cancer survivors use mental health services more often than healthy controls. Survivorship care plans that address the long-term mental healthcare needs of this population are needed.
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http://dx.doi.org/10.1200/JCO.20.02298DOI Listing
March 2021

Single-molecule fluorescence microscopy reveals modulation of DNA polymerase IV-binding lifetimes by UmuD (K97A) and UmuD'.

Curr Genet 2021 Apr 1;67(2):295-303. Epub 2021 Jan 1.

Molecular Horizons Institute and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia.

DNA polymerase IV (pol IV) is expressed at increased levels in Escherichia coli cells that suffer DNA damage. In a recent live-cell single-molecule fluorescence microscopy study, we demonstrated that the formation of pol IV foci is strongly recB-dependent in cells treated with the DNA break-inducing antibiotic ciprofloxacin. The results of that study support a model in which pol IV acts to extend D-loop structures during recombinational repair of DNA double-strand breaks. In the present study, we extend upon this work, investigating the UmuD and UmuD' proteins as potential modulators of pol IV activity in ciprofloxacin-treated cells. We found that the non-cleavable mutant UmuD(K97A) promotes long-lived association of pol IV with the nucleoid, whereas its cleaved form, UmuD', which accumulates in DNA-damaged cells, reduces binding. The results provide additional support for a model in which UmuD and UmuD' directly modulate pol IV-binding to the nucleoid.
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http://dx.doi.org/10.1007/s00294-020-01134-3DOI Listing
April 2021

Influence of APOE genotype in primary age-related tauopathy.

Acta Neuropathol Commun 2020 12 7;8(1):215. Epub 2020 Dec 7.

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, The University of Manchester, Salford, M6 8HD, UK.

The term "Primary age-related tauopathy" (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer's disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.
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http://dx.doi.org/10.1186/s40478-020-01095-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720601PMC
December 2020

Comparison of Common and Disease-Specific Post-translational Modifications of Pathological Tau Associated With a Wide Range of Tauopathies.

Front Neurosci 2020 4;14:581936. Epub 2020 Nov 4.

Department of Brain and Neuroscience, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Tauopathies are the most common type of neurodegenerative proteinopathy, being characterized by cytoplasmic aggregates of hyperphosphorylated tau protein. The formation and morphologies of these tau inclusions, the distribution of the lesions and related metabolic changes in cytoplasm differ among different tauopathies. The aim of this study was to examine whether there are differences in the post-translational modifications (PTMs) in the pathological tau proteins. We analyzed sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy, and frontotemporal dementia and parkinsonisms linked to chromosome 17 with tau inclusions using liquid chromatography mass spectrometry. In pathological tau proteins associated with a wide range of tauopathies, 170 PTMs in total were identified including new PTMs. Among them, common PTMs were localized in the N- and C-terminal flanking regions of the microtubule binding repeats and PTMs, which were considered to be disease-specific, were found in microtubule binding repeats forming filament core. These suggested that the differences in PTMs reflected the differences in tau filament core structures in each disease.
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http://dx.doi.org/10.3389/fnins.2020.581936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672045PMC
November 2020