• Association between preadmission frailty and care level at discharge in older adults undergoing emergency laparotomy

      Carter, B; Law, J; Hewitt, J; Parmar, Kat; Boyle, JM; Casey, P; Maitra, I; Pearce, L; Moug, SJ; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK (2020)
      BACKGROUND: Older adults undergoing emergency abdominal surgery have significantly poorer outcomes than younger adults. For those who survive, the level of care required on discharge from hospital is unknown and such information could guide decision-making. The ELF (Emergency Laparotomy and Frailty) study aimed to determine whether preoperative frailty in older adults was associated with increased dependence at the time of discharge. METHODS: The ELF study was a UK-wide multicentre prospective cohort study of older patients (65?years or more) undergoing emergency laparotomy during March and June 2017. The objective was to establish whether preoperative frailty was associated with increased care level at discharge compared with preoperative care level. The analysis used a multilevel logistic regression adjusted for preadmission frailty, patient age, sex and care level. RESULTS: A total of 934 patients were included from 49 hospitals. Mean(s.d.) age was 76á2(6á8) years, with 57á6 per cent women; 20á2 per cent were frail. Some 37á4 per cent of older adults had an increased care level at discharge. Increasing frailty was associated with increased discharge care level, with greater predictive power than age. The adjusted odds ratio for an increase in care level was 4á48 (95 per cent c.i. 2á03 to 9á91) for apparently vulnerable patients (Clinical Frailty Score (CFS) 4), 5á94 (2á54 to 13á90) for those mildly frail (CFS 5) and 7á88 (2á97 to 20á79) for those moderately or severely frail (CFS 6 or 7), compared with patients who were fit. CONCLUSION: Over 37 per cent of older adults undergoing emergency laparotomy required increased care at discharge. Frailty scoring was a significant predictor, and should be integrated into all acute surgical units to aid shared decision-making and discharge planning.
    • Circulating tumour cells in lung cancer

      Chemi, Francesca; Mohan, Sumitra; Brady, Ged; Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, UK (2020)
    • Prevalence of perineural invasion in keratinocyte cancer in the general population and among organ transplant recipients

      Adams, A; Pandeya, N; De'Ambrosis, B; Plasmeijer, E; Panizza, B; Green, Adèle C; Olsen, CM; Whiteman, DC; Faculty of Medicine, The University of Queensland, St Lucia, Queensland, Australia (2020)
      BACKGROUND/OBJECTIVES: Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most commonly encountered cancers in fair-skinned populations worldwide. Perineural invasion is associated with worse outcomes for patients with BCC or SCC. Estimates of perineural invasion prevalence range widely, likely reflecting non-representative patient samples. We sought to determine the prevalence of perineural invasion in BCC and SCC in the general population, as well as among cancers arising in solid organ transplant recipients. METHODS: We retrospectively analysed histopathology reports of BCC and SCC from patients enrolled in the QSkin Study (a population-based cohort of 43 794 Queensland residents recruited 2010-2011) and the Skin Tumours in Allograft Recipients (STAR) study (a cohort of 509 high-risk kidney or liver transplant recipients at the Princess Alexandra Hospital, Brisbane, recruited 2012-2014.) We estimated the prevalence of perineural invasion (and 95% confidence interval) in BCC and SCC, respectively, and identified clinical factors associated with perineural invasion. RESULTS: In QSkin, we observed 35 instances of perineural invasion in 9850 histopathologically confirmed BCCs (0.36%) and 9 instances of perineural invasion in 3982 confirmed SCC (0.23%) lesions. In the STAR cohort, we identified 4 lesions with perineural invasion in 692 BCCs (0.58%) and 16 reports of perineural invasion in 875 SCC lesions (1.9%). CONCLUSIONS: These data suggest that the overall prevalence of perineural invasion in keratinocyte cancer is low, although perineural invasion prevalence may be slightly higher among organ transplant recipients when compared to the general population.
    • Key steps in vaccine development

      Stern, Peter L; University of Manchester, UK (2020)
      OBJECTIVE: The goal of a vaccine is to prime the immune response so the immune memory can facilitate a rapid response to adequately control the pathogen on natural infection and prevent disease manifestation. This article reviews the main elements that provide for the development of safe and effective vaccines Data Sources: Literature covering target pathogen epidemiology, the key aspects of the functioning immune response underwriting target antigen selection, optimal vaccine formulation, preclinical and clinical trial studies necessary to deliver safe and efficacious immunization. STUDY SELECTIONS: Whole live, inactivated, attenuated or partial fractionated organism based vaccines are discussed in respect of the balance of reactogenicity and immunogenicity. The use of adjuvants to compensate for reduced immunogenicity is described. The requirements from preclinical studies, including establishing a proof of principle in animal models, the design of clinical trials with healthy volunteers that that lead to licensure and beyond are reviewed. RESULTS: The three vaccine development phases, preclinical, clinical and post licensure integrate the requirements to ensure safety, immunogenicity and efficacy in the final licensed product. Continuing monitoring of efficacy and safety in the immunized populations is essential to sustain confidence in vaccination programs. CONCLUSION: In an era of increasing vaccine hesitancy the need for a better and widespread understanding of how immunization acts to counteract the continuing and changing risks from the pathogenic world is required. This demands a societal responsibility for obligate education on the benefits of vaccination, which as a medical intervention has saved more lives than any other procedure.
    • RUNX1 dosage in development and cancer

      Lie-a-ling, Michael; Mevel, Renaud; Patel, Rahima; Blyth, K; Baena, Esther; Kouskoff, V; Lacaud, Georges; Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield, SK10 4TG, UK (2020)
      The transcription factor RUNX1 first came to prominence due to its involvement in the t(8;21) translocation in acute myeloid leukemia (AML). Since this discovery, RUNX1 has been shown to play important roles not only in leukemia but also in the ontogeny of the normal hematopoietic system. Although it is currently still challenging to fully assess the different parameters regulating RUNX1 dosage, it has become clear that the dose of RUNX1 can greatly affect both leukemia and normal hematopoietic development. It is also becoming evident that varying levels of RUNX1 expression can be used as markers of tumor progression not only in the hematopoietic system, but also in non-hematopoietic cancers. Here, we provide an overview of the current knowledge of the effects of RUNX1 dosage in normal development of both hematopoietic and epithelial tissues and their associated cancers.
    • Why young women gain weight: A narrative review of influencing factors and possible solutions

      Pegington, Mary; French, DP; Harvie, Michelle N; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK (2020)
      Significant weight gain occurs in women during young adulthood, which increases risk of diseases such as diabetes, cardiovascular disease, and many cancers. This review aims to inform future individually targeted weight gain prevention programmes and summarizes possible targets: key life events, mediators that influence energy intake and physical activity levels, and moderators that could identify groups of women at greatest risk. Life events affecting weight include pregnancy and motherhood, smoking cessation, marriage and cohabiting, attending university, and possibly bereavement. Research has identified successful methods for preventing weight gain associated with pregnancy and motherhood, which could now be used in practice, but evidence is inconclusive for preventing weight gain around other life events. Weight gain is mediated by lack of knowledge and skills around food and nutrition, depression, anxiety, stress, satiety, neural responses, and possibly sleep patterns and premenstrual cravings. A paucity of research exists into altering these to limit weight gain. Moderators include socioeconomic status, genetics, personality traits, and eating styles. More research is required to identify at-risk females and engage them in weight gain prevention. There is a need to address evidence gaps highlighted and implement what is currently known to develop effective strategies to limit weight gain in young women.
    • New biomarkers improve stratification of patients with melanoma

      Craig, Sarah; Viros, Amaya; Skin Cancer and Ageing, Cancer Research UK Manchester Institute, University of Manchester, U.K (2020)
    • Prognostic implications of biopsy with tumour transection for high-risk primary melanoma patients

      von Schuckmann, LA; Khosrotehrani, K; Celia, BH; Van der Pols, JC; Malt, M; Smithers, BM; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Australia (2020)
    • A framework for advancing our understanding of cancer-associated fibroblasts

      Sahai, E; Astsaturov, I; Cukierman, E; DeNardo, DG; Egeblad, M; Evans, RM; Fearon, D; Greten, FR; Hingorani, SR; Hunter, T; et al. (2020)
      Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
    • Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

      Zhou, S; Hawley, JR; Soares, F; Grillo, G; Teng, M; Madani, Tonekaboni SA; Hua, JT; Kron, KJ; Mazrooei, P; Ahmed, M; et al. (2020)
      Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.
    • Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion

      Shaker, Hudhaifah; Bundred, Nigel J; Landberg, G; Pritchard, SA; Albadry, H; Nicholson, SL; Harries, LJ; Heah, JYE; Castle, John; Kirwan, Cliona C; et al. (2020)
      BACKGROUND: Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS). METHODS: In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival. RESULTS: Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ? .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (?3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT. CONCLUSION: This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.
    • Cdc6 as a novel target in cancer: oncogenic potential, senescence and subcellular localisation

      Lim, N; Townsend, Paul A; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Manchester Cancer Research Centre, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, UK (2020)
      Cdc6 is a key replication licencing factor with a pivotal role in regulating the process of DNA replication, rendering it an important investigatory focus in tumourigenesis. Indeed, Cdc6 overexpression has been found to be a feature in certain tumours and has been associated as an early event in malignancies. With a focus on pancreatic cancer, there are evidence of its convergence in downstream pathways implicated in major genetic alterations found in pancreatic cancer, primarily KRAS. There is also data of its direct influence on protumourigenic processes as a transcriptional regulator, repressing the key tumour suppressor loci CDH1 (E-Cadherin) and influencing epithelial to mesenchymal transition (EMT). Moreover, gene amplification of Cdc6 as well as of E2F (an upstream regulator of Cdc6) have also been found to be a key feature in tumours overexpressing Cdc6, further highlighting this event as a potential driver of tumourigenesis. In this review, we summarise the evidence for the role of Cdc6 overexpression in cancer, specifically that of pancreatic cancer. More importantly, we recapitulate the role of Cdc6 as part of the DNA damage response and on senescence-an important antitumour barrier-in the context of pancreatic cancer. Finally, recent emerging observations suggest that the potential of the subcellular localisation of Cdc6 in inducing senescence. In this regard, we speculate and hypothesise potentially exploitable mechanisms in the context of inducing senescence via a novel pathway involving cytoplasmic retention of Cdc6 and Cyclin E.
    • Dynamic induction of drug resistance through a stress-responsive enhancer in acute myeloid leukemia

      Williams, Mark S; Somervaille, Tim CP; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Oglesby Cancer Research Building Manchester (2020)
    • The MEK5-ERK5 kinase axis controls lipid metabolism in small cell lung cancer

      Cristea, S; Coles, GL; Hornburg, D; Gershkovitz, M; Arand, J; Cao, S; Sen, T; Williamson, Stuart; Kim, JW; Drainas, AP; et al. (2020)
      Small cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here we investigated the contribution of the MAP kinase module MEK5/ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacological inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC.
    • Divergent mutational processes distinguish hypoxic and normoxic tumours

      Bhandari, V; Li, CH; Bristow, Robert G; Boutros, PC; Department of Medical Biophysics, University of Toronto, Toronto, Canada (2020)
      Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
    • Myosin II reactivation and cytoskeletal remodeling as a hallmark and a vulnerability in melanoma therapy resistance

      Orgaz, JL; Crosas-Molist, E; Sadok, A; Perdrix-Rosell, A; Maiques, O; Rodriguez-Hernandez, I; Monger, J; Mele, S; Georgouli, M; Bridgeman, V; et al. (2020)
      BACKGROUND & AIMS: Activation factor-1 transcription factor family members activating transcription factors 2 and 7 (ATF2 and ATF7) have highly redundant functions owing to highly homologous DNA binding sites. Their role in intestinal epithelial homeostasis and repair is unknown. Here, we assessed the role of these proteins in these conditions in an intestine-specific mouse model. METHODS: We performed in vivo and ex vivo experiments using Villin-CreERT2Atf2fl/flAtf7ko/ko mice. We investigated the effects of intestinal epithelium-specific deletion of the Atf2 DNA binding region in Atf7-/- mice on cellular proliferation, differentiation, apoptosis, and epithelial barrier function under homeostatic conditions. Subsequently, we exposed mice to 2% dextran sulfate sodium (DSS) for 7 days and 12 Gy whole-body irradiation and assessed the response to epithelial damage. RESULTS: Activating phosphorylation of ATF2 and ATF7 was detected mainly in the crypts of the small intestine and the lower crypt region of the colonic epithelium. Under homeostatic conditions, no major phenotypic changes were detectable in the intestine of ATF mutant mice. However, on DSS exposure or whole-body irradiation, the intestinal epithelium showed a clearly impaired regenerative response. Mutant mice developed severe ulceration and inflammation associated with increased epithelial apoptosis on DSS exposure and were less able to regenerate colonic crypts on irradiation. In vitro, organoids derived from double-mutant epithelium had a growth disadvantage compared with wild-type organoids, impaired wound healing capacity in scratch assay, and increased sensitivity to tumor necrosis factor-?-induced damage. CONCLUSIONS: ATF2 and ATF7 are dispensable for epithelial homeostasis, but are required to maintain epithelial regenerative capacity and protect against cell death during intestinal epithelial damage and repair.
    • Pluripotent hematopoietic stem cells augment alpha-adrenergic receptor-mediated contraction of pulmonary artery and contribute to the pathogenesis of pulmonary hypertension

      Hashimoto, R; Lanier, GM; Dhagia, V; Joshi, SR; Jordan, Allan M; Waddell, Ian D; Tuder, R; Stenmark, KR; Wolin, MS; McMurtry, IF; et al. (2020)
      Pulmonary hypertension (PH) is a multicellular and progressive disease with a high mortality rate. Among many cell types, hematopoietic stem cells (HSCs) are incriminated in the pathogenesis of PH. However, our understanding of the mechanisms that increase HSCs in blood and lungs of hypertensive animals or patients and the role played by HSCs in the pathogenesis of PH remains elusive. Studies suggest that glycolysis is critical for the survival and growth of HSCs. In various cell types from hypertensive lungs of animals and patients, glycolysis and the glucose-6-phosphate dehydrogenase (G6PD) activity are increased. Herein, we demonstrated in mice that chronic hypoxia increased HSCs (CD34+, CD117+, CD133+, CD34+/CD117+, and CD34+/CD133+) in bone marrow and blood and around hypertensive pulmonary arteries in a time-dependent manner. Intriguingly, we found fewer CD133+ cells in the bone marrow of C57BL/6 mice compared with Sv129J mice, and C57BL mice developed less severe chronic hypoxia-elicited PH and heart failure than Sv129J mice. Similarly, the numbers of CD34+ and CD117+ cells in blood of patients with pulmonary arterial hypertension (PAH) were higher (>3-fold) compared with healthy individuals. By allogeneic bone marrow transplantation, we found that GFP+ bone marrow cells infiltrated the lungs and accumulated around the pulmonary arteries in lungs of hypoxic mice, and these cells contributed to increased α-adrenergic receptor-mediated contraction of the pulmonary artery cultured in hypoxia. Inhibition of G6PD activity with (3β,5α)-3,21-dihydroxypregnan-20-one, a novel and potent G6PD inhibitor, decreased HSCs in bone marrow, blood, and lungs of hypoxic mice and reduced α-agonist-induced contraction of the pulmonary artery and established hypoxia-induced PH. We did not observe CD133+ cells around the pulmonary arteries in the lungs of chronically hypoxic G6PD-deficient mice. Furthermore, knockdown of G6PD and inhibition of G6PD activity: 1) downregulated canonical and noncanonical Wnt and Fzd receptors genes; 2) upregulated Bmpr1a; 3) decreased Cxcl12, and 4) reduced HSC (CD117+ and CD133+) numbers. In all, our findings demonstrate unexpected function for bone marrow-derived HSCs in augmenting α-adrenergic receptor-mediated contraction of pulmonary arteries and remodeling of pulmonary arteries that contribute to increase pulmonary vascular resistance in PAH patients and hypoxic mice and suggest that G6PD, by regulating expression of genes in the WNT and BMPR signaling, contributed to increase and release of HSCs from the bone marrow in response to hypoxic stimuli.
    • Association of indoor tanning regulations with health and economic outcomes in North America and Europe

      Gordon, LG; Rodriguez-Acevedo, AJ; Koster, B; Guy, GP; Sinclair, C; Van, DE; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (2020)
      IMPORTANCE: UV radiation emissions from indoor tanning devices are carcinogenic. Regulatory actions may be associated with reduced exposure of UV radiation at a population level. OBJECTIVE: To estimate the long-term health and economic consequences of banning indoor tanning devices or prohibiting their use by minors only in North America and Europe compared with ongoing current levels of use. DESIGN, SETTING, AND PARTICIPANTS: This economic analysis modeled data for individuals 12 to 35 years old in North America and Europe, who commonly engage in indoor tanning. A Markov cohort model was used with outcomes projected during the cohort's remaining life-years. Models were populated by extracting data from high-quality systematic reviews and meta-analyses, epidemiologic reports, and cancer registrations. MAIN OUTCOMES AND MEASURES: Main outcomes were numbers of melanomas and deaths from melanoma, numbers of keratinocyte carcinomas, life-years, and health care and productivity costs. Extensive sensitivity analyses were performed to assess the stability of results. RESULTS: In an estimated population of 110 932 523 in the United States and Canada and 141 970 492 in Europe, for the next generation of youths and young adults during their remaining lifespans, regulatory actions that ban indoor tanning devices could be expected to gain 423 000 life-years, avert 240 000 melanomas (-8.2%), and avert 7.3 million keratinocyte carcinomas (-7.8%) in North America and gain 460 000 life-years, avert 204 000 melanomas (-4.9%), and avert 2.4 million keratinocyte carcinomas (-4.4%) in Europe compared with ongoing current levels of use. Economic cost savings of US $31.1 billion in North America and €21.1 billion (US $15.9 billion) in Europe could occur. Skin cancers averted and cost savings after prohibiting indoor tanning by minors may be associated with one-third of the corresponding benefits of a total ban. CONCLUSIONS AND RELEVANCE: Banning indoor tanning may be associated with reduced skin cancer burden and health care costs. Corresponding gains from prohibiting indoor tanning by minors only may be smaller.
    • The Shb scaffold binds the Nck adaptor protein, p120 RasGAP and Chimaerins and thereby facilitates heterotypic cell segregation by the receptor EphB2

      Wagner, MJ; Hsiung, MS; Gish, GD; Bagshaw, RD; Doodnauth, SA; Soliman, MA; Jorgensen, Claus; Tucholska, M; Rottapel, R; Princess Margaret Cancer Centre, CanadaLunenfeld-Tanenbaum Research Institute, Canada (2020)
      Eph receptors are a family of receptor tyrosine kinases that control directional cell movement during various biological processes, including embryogenesis, neuronal pathfinding, and tumor formation. The biochemical pathways of Eph receptors are context-dependent in part because of the varied composition of a heterotypic, oligomeric, active Eph receptor complex. Downstream of the Eph receptors, little is known about the essential phosphorylation events that define the context and instruct cell movement. Here, we define a pathway that is required for Eph receptor B2 (EphB2)-mediated cell sorting and is conserved among multiple Eph receptors. Utilizing a HEK293 model of EphB2+/ephrinB1+ cell segregation, we found that the scaffold adaptor protein SH2 domain-containing adaptor protein B (Shb) is essential for EphB2 functionality. Further characterization revealed that Shb interacts with known modulators of cytoskeletal rearrangement and cell mobility, including Nck adaptor protein (Nck), p120-Ras GTPase-activating protein (RasGAP), and the α- and β-Chimaerin Rac GAPs. We noted that phosphorylation of Tyr297, Tyr246, and Tyr336 of Shb is required for EphB2-ephrinB1 boundary formation, as well as binding of Nck, RasGAP, and the chimaerins, respectively. Similar complexes were formed in the context of EphA4, EphA8, EphB2, and EphB4 receptor activation. These results indicate that phosphotyrosine-mediated signaling through Shb is essential in EphB2-mediated heterotypic cell segregation and suggest a conserved function for Shb downstream of multiple Eph receptors.
    • Ixekizumab for the treatment of psoriasis: up-to-date

      Craig, Sarah; Warren, RB; Skin cancer and Ageing group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK (2020)
      Introduction: Ixekizumab (an IL-17A antagonist) is a biologic therapeutic licensed for use in moderate-to-severe plaque psoriasis and psoriatic arthritis. IL-17 antagonists (also including Secukinumab and Brodalumab) represent a new generation of biologic therapy with rapid and high response rates, quickly becoming a crucial part of the psoriasis treatment armamentarium.Areas covered: In this review, we describe how IL-17A antagonists disrupt inflammatory cascades in psoriasis and summarize results from clinical trials examining the safety and efficacy of ixekizumab against placebo and comparators.Expert opinion: Ixekizumab induces a 75% reduction in psoriasis area severity index (PASI 75) in 89% of patients after 12 weeks and after 1 year, PASI 75 is maintained in 80% of patients. Ixekizumab is superior to both etanercept and ustekinumab, however, further comparator trials are needed to determine superiority between newer agents. Network meta-analysis suggests that ixekizumab is one of the most rapid and efficacious agents for treating psoriasis, but ideally more long-term real-world data are needed to determine the persistence of response. Candida may be commonly encountered during treatment and IL-17 agents should be avoided in patients with inflammatory bowel disease. Overall, ixekizumab represents an efficacious and well-studied therapeutic that can offer biologic-naïve and bio-failure patients durable disease control.