• Endothelial dysfunction on cerebral small vessel disease

      Medina, M; Sander, L; Moncada, Salvador; National Autonomous University of Honduras, Faculty of Medical Sciences, Tegucigalpa, Honduras (2019)
    • Regional nodal metastasis and 5-year survival in patients with thin melanoma in Queensland: a population-based study

      Theile, H; Moore, J; Dunn, N; Cossio, D; Forristal, CE; Green, Ad�le C; Smithers, BM; Discipline of Surgery, The University of Queensland, Brisbane, Queensland, Australia. (2020)
    • The relationship between tumour associated macrophage markers and tumour, demographic & behavioural factors in breast cancer

      Singh, U; Castle, J; Greenhalgh, S; Hussain, U; Descamps, Tine; Nash, S; Wilson, M; Hunt, R; Kirwan, CC; University of Manchester, Manchester (2020)
    • Current models, challenges and best practices for work conducted between European academic cooperative groups and industry

      Stahel, RA; Lacombe, D; Cardoso, F; Casali, PG; Negrouk, A; Marais, Richard; Hiltbrunner, A; Vyas, M; Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland (2020)
    • Survival in patients with multiple primary melanomas: systematic review and meta-analysis

      Peek, G; Olsen, CM; Baade, P; Youlden, DR; Aitken, JF; Green, Ad�le C; Khosrotehrani, K; Queensland Skin and Cancer Foundation, Queensland Institute of Dermatology, South-Brisbane, Queensland, Australia. (2020)
    • The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

      Kelly James R; Martini, S; Brownlow, N; Joshi, D; Federico, S; Jamshidi, S; Kjaer, S; Lockwood, N; Rahmen, KM; Fraternali, F; et al. (2020)
    • Early detection of melanoma: a consensus report from the Australian Skin and Skin Cancer Research Centre Melanoma Screening Summit

      Janda, M; Cust, AE; Neale, RE; Aitken, JF; Baade, PD; Green, Ad�le C; Khosrotehrani, K; Mar, V; Soyer, HP; Whiteman, DC; et al. (2020)
    • Specific requirements for translation of biological research into clinical radiation oncology

      Krause, M; Alsner, J; Linge, A; Butof, R; Lock, S; Bristow, Robert G; German Cancer Consortium (DKTK), Partner Site Dresden, Germany. (2020)
    • D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition

      de Chiara C; Homsak M; Prosser GA, Douglas HL; Garza-Garcia A, Kelly G; Purkiss AG; Tate EW; de Carvalho LPS; Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, UK. (2020)
    • Hypoxic activation of glucose-6-phosphate dehydrogenase controls the expression of genes involved in the pathogenesis of pulmonary hypertension through the regulation of DNA methylation

      Joshi SR; Kitagawa A, Jacob C; Hashimoto R; Dhagia V; Ramesh A; Zheng C; Zhang H; Jordan Allan M; Waddell Ian D; Leopold J; et al. (2020)
    • EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7

      O'Regan, L; Barone, G; Adib, R; Woo, CG; Jeong, HG; Richardson, EL; Richards, MW; Muller, Patricia; Collis, SJ; Fennell, DA; et al. (2020)
    • 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.
    • 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.
    • TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

      Moukengue, B; Brown, HK; Charrier, C; Battaglia, S; Baud'huin, M; Quillard, T; Pham, TM; Pateras, IS; Gorgoulis, Vassilis G; Helleday, T; et al. (2020)
      BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
    • Diffusion model comparison identifies distinct tumor sub-regions and tracks treatment response

      McHugh, Damien J; Lipowska-Bhalla, Grazyna; Babur, M; Watson, Y; Peset, Isabel; Mistry, Hitesh; Hubbard, Cristinacce PL; Naish, JH; Honeychurch, Jamie; Williams, KJ; et al. (2020)
      PURPOSE: MRI biomarkers of tumor response to treatment are typically obtained from parameters derived from a model applied to pre-treatment and post-treatment data. However, as tumors are spatially and temporally heterogeneous, different models may be necessary in different tumor regions, and model suitability may change over time. This work evaluates how the suitability of two diffusion-weighted (DW) MRI models varies spatially within tumors at the voxel level and in response to radiotherapy, potentially allowing inference of qualitatively different tumor microenvironments. METHODS: DW-MRI data were acquired in CT26 subcutaneous allografts before and after radiotherapy. Restricted and time-independent diffusion models were compared, with regions well-described by the former hypothesized to reflect cellular tissue, and those well-described by the latter expected to reflect necrosis or oedema. Technical and biological validation of the percentage of tissue described by the restricted diffusion microstructural model (termed %MM) was performed through simulations and histological comparison. RESULTS: Spatial and radiotherapy-related variation in model suitability was observed. %MM decreased from a mean of 64% at baseline to 44% 6 days post-radiotherapy in the treated group. %MM correlated negatively with the percentage of necrosis from histology, but overestimated it due to noise. Within MM regions, microstructural parameters were sensitive to radiotherapy-induced changes. CONCLUSIONS: There is spatial and radiotherapy-related variation in different models' suitability for describing diffusion in tumor tissue, suggesting the presence of different and changing tumor sub-regions. The biological and technical validation of the proposed %MM cancer imaging biomarker suggests it correlates with, but overestimates, the percentage of necrosis.
    • Cooperative behaviour and phenotype plasticity evolve during melanoma progression

      Rowling, E; Miskolczi, Z; Nagaraju, R; Wilcock, DJ; Wang, P; Telfer, B; Li, Y; Lasheras-Otero, I; Redondo-Munoz, M; Sharrocks, AD; et al. (2020)
      A major challenge for managing melanoma is its tumour heterogeneity based on individual co-existing melanoma cell phenotypes. These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative. Melanoma phenotypes are defined by distinct transcriptional states, which relate to different melanocyte lineage development phases, ranging from a mesenchymal, neural crest-like to a proliferative, melanocytic phenotype. It is thought that adaptive phenotype plasticity based on transcriptional reprogramming drives melanoma progression, but at which stage individual phenotypes dominate and moreover, how they interact is poorly understood. We monitored melanocytic and mesenchymal phenotypes throughout melanoma progression and detected transcriptional reprogramming at different stages, with a gain in mesenchymal traits in circulating melanoma cells (CTCs) and proliferative features in metastatic tumours. Intriguingly, we found that distinct phenotype populations interact in a cooperative manner, which generates tumours of greater "fitness," supports CTCs and expands organotropic cues in metastases. Fibronectin, expressed in mesenchymal cells, acts as key player in cooperativity and promotes survival of melanocytic cells. Our data reveal an important role for inter-phenotype communications at various stages of disease progression, suggesting these communications could act as therapeutic target.
    • 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.
    • Statins may reduce disease recurrence in patients with ulcerated primary melanoma

      von Schuckmann, LA; Khosrotehrani, K; Ghiasvand, R; Hughes, MCB; van der Pols, JC; Malt, M; Smithers, BM; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Australia (2020)
    • Androgen receptor and poly(ADP-ribose) glycohydrolase inhibition increases efficiency of androgen ablation in prostate cancer cells

      Zhang, M; Lai, Y; Vasquez, JL; James, Dominic I; Smith, Kate M; Waddell, Ian D; Ogilvie, Donald J; Liu, Y; Agoulnik, IU; Biochemistry Ph.D. Program, Florida International University, Miami, FL, (2020)
      There is mounting evidence of androgen receptor signaling inducing genome instability and changing DNA repair capacity in prostate cancer cells. Expression of genes associated with base excision repair (BER) is increased with prostate cancer progression and correlates with poor prognosis. Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are key enzymes in BER that elongate and degrade PAR polymers on target proteins. While PARP inhibitors have been tested in clinical trials and are a promising therapy for prostate cancer patients with TMPRSS2-ERG fusions and mutations in DNA repair genes, PARG inhibitors have not been evaluated. We show that PARG is a direct androgen receptor (AR) target gene. AR is recruited to the PARG locus and induces PARG expression. Androgen ablation combined with PARG inhibition synergistically reduces BER capacity in independently derived LNCaP and LAPC4 prostate cancer cell lines. A combination of PARG inhibition with androgen ablation or with the DNA damaging drug, temozolomide, significantly reduces cellular proliferation and increases DNA damage. PARG inhibition alters AR transcriptional output without changing AR protein levels. Thus, AR and PARG are engaged in reciprocal regulation suggesting that the success of androgen ablation therapy can be enhanced by PARG inhibition in prostate cancer patients.