Now showing items 1-20 of 4489

    • Statins reduce disease recurrence in patients with ulcerated primary melanoma

      von Schuckmann, L. A.; Khosrotehrani, K.; Ghiasvand, R.; Hughes, M. C. B.; van der Pols, J. C.; Malt, M.; Smithers, M.; Green, Adèle C; Department of Population Health, University of Queensland, Herston, Queensland, Australia (2021)
      Background: Statins may restrict cellular functions required for melanoma growth and metastasis. We examined whether long‐term statin use commenced before diagnosis of the primary is associated with reduced risk of melanoma recurrence. Patients and methods: We prospectively followed a cohort of patients newly diagnosed between 2010 and 2014 with localised tumour‐stage T1b to T4b melanoma in Queensland, Australia. We used Cox‐regression analyses to examine associations between long‐term statin use and melanoma recurrence for the entire cohort, and then separately by sex and by presence of ulceration due to evidence of effect modification. Results: Amongst 700 patients diagnosed with stage T1b to T4b primary melanoma (mean age 62, 59% male, 28% with ulcerated tumors), 94 patients (13%) developed melanoma recurrence within 2 years. Long‐term statin users (n = 204, 29%) had a significantly lower risk of disease recurrence compared to non‐users (Adjusted hazard ratio (HRadj) 0.55, 95% Confidence Interval (CI) 0.32–0.97) regardless of statin subtype or potency. Compared to non‐statin users, risk of recurrence was significantly decreased in male statin‐users (HRadj 0.39, 95% CI: 0.19–0.79) but not female statin users (HRadj 0.82, 95% CI: 0.29–2.27) and in statin‐users with ulcerated (HRadj 0.17, 95% CI: 0.05–0.52) but not non‐ulcerated (HRadj 0.91, 95% CI: 0.46–1.81) primary melanoma. Conclusion: Statins commenced before melanoma diagnosis, may reduce the risk of melanoma recurrence, especially in males and those with ulcerated tumors. Clinical trial evaluation of the potential role of statins in improving the prognosis of high‐risk melanoma is warranted.
    • Assessing drug development risk using big data and machine learning

      Vergetis, V.; Skaltsas, D.; Gorgoulis, Vassilis G; Tsirigos, A.; Intelligencia Inc., New York, New York. (2021)
      Identifying new drug targets and developing safe and effective drugs is both challenging and risky. Furthermore, characterizing drug development risk, the probability that a drug will eventually receive regulatory approval, has been notoriously hard given the complexities of drug biology and clinical trials. This inherent risk is often misunderstood and mischaracterized, leading to inefficient allocation of resources and, as a result, an overall reduction in R&D productivity. Here we argue that the recent resurgence of Machine Learning in combination with the availability of data can provide a more accurate and unbiased estimate of drug development risk.
    • Genetic and non-genetic mechanisms underlying cancer evolution

      Shlyakhtina, Yelyzaveta; Moran, Katherine L; Portal, Maximiliano M; Cell Plasticity and Epigenetics Lab. Cancer Research UK-Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG, UK (2021)
      Cancer development can be defined as a process of cellular and tissular microevolution ultimately leading to malignancy. Strikingly, though this concept has prevailed in the field for more than a century, the precise mechanisms underlying evolutionary processes occurring within tumours remain largely uncharacterized and rather cryptic. Nevertheless, although our current knowledge is fragmentary, data collected to date suggest that most tumours display features compatible with a diverse array of evolutionary paths, suggesting that most of the existing macro-evolutionary models find their avatar in cancer biology. Herein, we discuss an up-to-date view of the fundamental genetic and non-genetic mechanisms underlying tumour evolution with the aim of concurring into an integrated view of the evolutionary forces at play throughout the emergence and progression of the disease and into the acquisition of resistance to diverse therapeutic paradigms. Our ultimate goal is to delve into the intricacies of genetic and non-genetic networks underlying tumour evolution to build a framework where both core concepts are considered non-negligible and equally fundamental.
    • A KRAS-responsive long non-coding RNA controls microRNA processing

      Shi, Lei; Magee, Peter; Fassan, M.; Sahoo, Sudhakar; Leong, Hui Sun; Lee, Dave; Sellers, Robert; Brullé-Soumaré, L.; Cairo, S.; Monteverde, Tiziana; et al. (2021)
      Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.
    • The RAC1 activator Tiam1 regulates centriole duplication through controlling PLK4 levels

      Porter, Andrew P; Reed, Hannah; White, Gavin R M; Ogg, Erinn-Lee; Whalley, Helen J; Malliri, Angeliki; Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK (2021)
      Centriole duplication is tightly controlled to maintain correct centriole number through the cell cycle. Key to this is the regulated degradation of PLK4, the master regulator of centriole duplication. Here we show that the Rac1 guanine nucleotide exchange factor (GEF) Tiam1 localises to centrosomes during S-phase, where it is required for maintenance of normal centriole number. Depletion of Tiam1 leads to an increase in centrosomal PLK4 and centriole overduplication, whereas overexpression of Tiam1 can restrict centriole overduplication. Ultimately Tiam1 depletion leads to lagging chromosomes at anaphase and aneuploidy, potential drivers of malignant progression. The effects of Tiam1 depletion on centrosomal PLK4 levels and centriole overduplication can be rescued by re-expression of both wild-type Tiam1 and catalytically inactive (GEF*) Tiam1, but not by Tiam1 mutants unable to bind to the F-box protein βTRCP, implying that Tiam1 regulates PLK4 levels through promoting βTRCP-mediated degradation independently of Rac1 activation.
    • E2 enzymes in genome stability: pulling the strings behind the scenes

      Osborne, Hugh C; Irving, E.; Forment, J. V.; Schmidt, Christine K; Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, 555 Wilmslow Road, Manchester M20 4GJ (2021)
      Ubiquitin and ubiquitin-like proteins (UBLs) function as critical post-translational modifiers in the maintenance of genome stability. Ubiquitin/UBL-conjugating enzymes (E2s) are responsible, as part of a wider enzymatic cascade, for transferring single moieties or polychains of ubiquitin/UBLs to one or multiple residues on substrate proteins. Recent advances in structural and mechanistic understanding of how ubiquitin/UBL substrate attachment is orchestrated indicate that E2s can exert control over chain topology, substrate-site specificity, and downstream physiological effects to help maintain genome stability. Drug discovery efforts have typically focussed on modulating other members of the ubiquitin/UBL cascades or the ubiquitin-proteasome system. Here, we review the current standing of E2s in genome stability and revisit their potential as pharmacological targets for developing novel anti-cancer therapies.
    • Using depth of response to stratify patients to front line Autologous Stem Cell Transplant: results of the phase II PADIMAC Myeloma Trial

      Popat, R.; Counsell, N.; de Tute, R.; De-Silva, D.; Phillips, Elizabeth H; Cavenagh, J. D.; Adedayo, T.; Braganca, N.; Roddie, C.; Streetly, M.; et al. (2021)
      None
    • Promises and challenges of adoptive T-cell therapies for solid tumours

      Morotti, M.; Albukhari, A.; Alsaadi, A.; Artibani, M.; Brenton, J. D.; Curbishley, S. M.; Dong, T.; Dustin, M. L.; Hu, Z.; McGranahan, N.; et al. (2021)
      Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.
    • Hepatic senescence accompanies the development of NAFLD in non-aged mice independently of obesity

      Moustakas, II; Katsarou, A.; Legaki, A. I.; Pyrina, I.; Ntostoglou, K.; Papatheodoridi, A. M.; Gercken, B.; Pateras, I. S.; Gorgoulis, Vassilis G; Koutsilieris, M.; et al. (2021)
      Senescence is considered to be a cardinal player in several chronic inflammatory and metabolic pathologies. The two dominant mechanisms of senescence include replicative senescence, predominantly depending on age-induced telomere shortening, and stress-induced senescence, triggered by external or intracellular harmful stimuli. Recent data indicate that hepatocyte senescence is involved in the development of nonalcoholic fatty liver disease (NAFLD). However, previous studies have mainly focused on age-related senescence during NAFLD, in the presence or absence of obesity, while information about whether the phenomenon is characterized by replicative or stress-induced senescence, especially in non-aged organisms, is scarce. Herein, we subjected young mice to two different diet-induced NAFLD models which differed in the presence of obesity. In both models, liver fat accumulation and increased hepatic mRNA expression of steatosis-related genes were accompanied by hepatic senescence, indicated by the increased expression of senescence-associated genes and the presence of a robust hybrid histo-/immunochemical senescence-specific staining in the liver. Surprisingly, telomere length and global DNA methylation did not differ between the steatotic and the control livers, while malondialdehyde, a marker of oxidative stress, was upregulated in the mouse NAFLD livers. These findings suggest that senescence accompanies NAFLD emergence, even in non-aged organisms, and highlight the role of stress-induced senescence during steatosis development independently of obesity.
    • Characteristics and skin cancer risk of psoriasis patients with a history of skin cancer in BADBIR

      Mason, K. J.; Burden, A. D.; Barker, J.; Lunt, M.; Ali, H.; Kleyn, C. E.; McElhone, K.; Soliman, M. M.; Green, Adele C; Griffiths, C. E. M.; et al. (2021)
      None
    • Inhibition of G6PD activity attenuates right ventricle pressure and hypertrophy elicited by VEGFR inhibitor + hypoxia

      Kitagawa, A.; Jacob, C.; Jordan, Allan M; Waddell, Ian D; McMurtry, I. F.; Gupte, S. A.; Pharmacology, New York Medical College, United States (2021)
      Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP) - a fundamental glucose metabolism pathway - is vital for cell growth. Because treatment for PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH. PH was induced in mice by exposure to 10% oxygen (Hx) or weekly injection of vascular endothelial growth factor receptor blocker (Sugen5416 (SU); 20 mg.kg-1) during exposure to hypoxia (Hx+SU). A novel G6PD inhibitor (PDD4091;1.5 mg kg-1) was injected daily during exposure to Hx. We measured right ventricle (RV) pressure and left ventricle (LV) pressure-volume relationships, and gene expression in lungs of normoxic, Hx, and Hx+SU, and G6PD inhibitor-treated, mice. RV systolic and end-diastolic pressures were higher in Hx and Hx+SU than normoxic-control mice. Hx and Hx+SU decreased expression of epigenetic modifiers (writers and erasers), increased hypomethylation of the DNA, and induced aberrant gene expression in lungs. G6PD inhibition decreased maladaptive expression of genes and SMC growth, reduced pulmonary vascular remodeling, decreased RV pressures, and increased cardiac index, compared to untreated PH groups. Pharmacologic inhibition of G6PD activity, by normalizing activity of epigenetic modifiers and DNA methylation, efficaciously reduces RV pressure overload in Hx and Hx+SU mice, pre-clinical models of PH, appears to be a safe pharmacotherapeutic strategy. Significance Statement The results of this study demonstrated inhibition of a metabolic enzyme efficaciously reduces pulmonary hypertension. For first time, we show that a novel inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the fundamental pentose phosphate pathway, modulates DNA methylation and alleviates pulmonary artery remodeling and dilates pulmonary artery to reduce pulmonary hypertension.
    • Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia

      Jakobczyk, H.; Debaize, L.; Soubise, B.; Avner, S.; Rouger-Gaudichon, J.; Commet, S.; Jiang, Y.; Sérandour, A. A.; Rio, A. G.; Carroll, J. S.; et al. (2021)
      Background: B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) is the most common pediatric cancer. Identifying key players involved in proliferation of BCP-ALL cells is crucial to propose new therapeutic targets. Runt Related Transcription Factor 1 (RUNX1) and Core-Binding Factor Runt Domain Alpha Subunit 2 Translocated To 3 (CBFA2T3, ETO2, MTG16) are master regulators of hematopoiesis and are implicated in leukemia. Methods: We worked with BCP-ALL mononuclear bone marrow patients' cells and BCP-ALL cell lines, and performed Chromatin Immunoprecipitations followed by Sequencing (ChIP-Seq), co-immunoprecipitations (co-IP), proximity ligation assays (PLA), luciferase reporter assays and mouse xenograft models. Results: We demonstrated that CBFA2T3 transcript levels correlate with RUNX1 expression in the pediatric t(12;21) ETV6-RUNX1 BCP-ALL. By ChIP-Seq in BCP-ALL patients' cells and cell lines, we found that RUNX1 is recruited on its promoter and on an enhancer of CBFA2T3 located - 2 kb upstream CBFA2T3 promoter and that, subsequently, the transcription factor RUNX1 drives both RUNX1 and CBFA2T3 expression. We demonstrated that, mechanistically, RUNX1 and CBFA2T3 can be part of the same complex allowing CBFA2T3 to strongly potentiate the activity of the transcription factor RUNX1. Finally, we characterized a CBFA2T3-mimicking peptide that inhibits the interaction between RUNX1 and CBFA2T3, abrogating the activity of this transcription complex and reducing BCP-ALL lymphoblast proliferation. Conclusions: Altogether, our findings reveal a novel and important activation loop between the transcription regulator CBFA2T3 and the transcription factor RUNX1 that promotes BCP-ALL proliferation, supporting the development of an innovative therapeutic approach based on the NHR2 subdomain of CBFA2T3 protein.
    • Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium

      Gillessen, Silke; Sauvé, N.; Collette, L.; Daugaard, G.; de Wit, R.; Albany, C.; Tryakin, A.; Fizazi, K.; Stahl, O.; Gietema, J. A.; et al. (2021)
      Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. Materials and methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set. Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update). Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
    • Re-evaluating experimental validation in the Big Data Era: a conceptual argument

      Jafari, M.; Guan, Y. F.; Wedge, David C; Ansari-Pour, N.; Faculty of Medicine, University of Helsinki, Helsinki, Finland (2021)
      None
    • Correction to: Incorporating radiomics into clinical trials: expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers

      Fournier, L.; Costaridou, L.; Bidaut, L.; Michoux, N.; Lecouvet, F. E.; de Geus-Oei, L. F.; Boellaard, R.; Oprea-Lager, D. E.; Obuchowski, N. A.; Caroli, A.; et al. (2021)
      None
    • A unified haplotype-based method for accurate and comprehensive variant calling

      Cooke, D. P.; Wedge, David C; Lunter, G.; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK (2021)
      Almost all haplotype-based variant callers were designed specifically for detecting common germline variation in diploid populations, and give suboptimal results in other scenarios. Here we present Octopus, a variant caller that uses a polymorphic Bayesian genotyping model capable of modeling sequencing data from a range of experimental designs within a unified haplotype-aware framework. Octopus combines sequencing reads and prior information to phase-called genotypes of arbitrary ploidy, including those with somatic mutations. We show that Octopus accurately calls germline variants in individuals, including single nucleotide variants, indels and small complex replacements such as microinversions. Using a synthetic tumor data set derived from clean sequencing data from a sample with known germline haplotypes and observed mutations in a large cohort of tumor samples, we show that Octopus is more sensitive to low-frequency somatic variation, yet calls considerably fewer false positives than other methods. Octopus also outputs realigned evidence BAM files to aid validation and interpretation.
    • Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study

      Dave, R. V.; Kim, B.; Courtney, A.; O'Connell, R.; Rattay, T.; Taxiarchi, V. P.; Kirkham, J. J.; Camacho, E. M.; Fairbrother, P.; Sharma, N.; et al. (2021)
      Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated 'standard' or 'COVID-altered', in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had 'COVID-altered' management. 'Bridging' endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2-9%) using 'NHS Predict'. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of 'COVID-altered' management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.
    • Research evaluation alongside clinical treatment in COVID-19 (REACT COVID-19): an observational and biobanking study

      Burke, H.; Freeman, A.; Dushianthan, A.; Celinski, M.; Batchelor, J.; Phan, H.; Borca, F.; Kipps, C.; Thomas, G. J.; Faust, S. N.; et al. (2021)
      Introduction: The COVID-19 pandemic caused by SARS-CoV-2 places immense worldwide demand on healthcare services. Earlier identification of patients at risk of severe disease may allow intervention with experimental targeted treatments, mitigating the course of their disease and reducing critical care service demand. Methods and analysis: This prospective observational study of patients tested or treated for SARS-CoV-2, who are under the care of the tertiary University Hospital Southampton NHS Foundation Trust (UHSFT), captured data from admission to discharge; data collection commenced on 7 March 2020. Core demographic and clinical information, as well as results of disease-defining characteristics, was captured and recorded electronically from hospital clinical record systems at the point of testing. Manual data were collected and recorded by the clinical research team for assessments which are not part of the structured electronic healthcare record, for example, symptom onset date. Thereafter, participant records were continuously updated during hospital stay and their follow-up period. Participants aged >16 years were given the opportunity to provide consent for excess clinical sample storage with optional further biological sampling. These anonymised samples were linked to the clinical data in the Real-time Analytics for Clinical Trials platform and were stored within a biorepository at UHSFT. Ethics and dissemination: Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent for the database-only cohort; the procedures conform with the Declaration of Helsinki. The study design, protocol and patient-facing documentation for the biobanking arm of the study have been approved by North West Research Ethics Committee (REC 17/NW/0632) as an amendment to the National Institute for Health Research Southampton Clinical Research Facility-managed Southampton Research Biorepository. This study will be published as peer-reviewed articles and presented at conferences, presentations and workshops.
    • Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-update consortium

      Beyer, J.; Collette, L.; Sauvé, N.; Daugaard, G.; Feldman, D. R.; Tandstad, T.; Tryakin, A.; Stahl, O.; Gonzalez-Billalabeitia, E.; De Giorgi, U.; et al. (2021)
      Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. Materials and methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
    • Implication of dietary iron-chelating bioactive compounds in molecular mechanisms of oxidative stress-induced cell ageing

      Barbouti, A.; Lagopati, N.; Veroutis, D.; Goulas, V.; Evangelou, K.; Kanavaros, P.; Gorgoulis, Vassilis G; Galaris, D.; Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece (2021)
      One of the prevailing perceptions regarding the ageing of cells and organisms is the intracellular gradual accumulation of oxidatively damaged macromolecules, leading to the decline of cell and organ function (free radical theory of ageing). This chemically undefined material known as "lipofuscin," "ceroid," or "age pigment" is mainly formed through unregulated and nonspecific oxidative modifications of cellular macromolecules that are induced by highly reactive free radicals. A necessary precondition for reactive free radical generation and lipofuscin formation is the intracellular availability of ferrous iron (Fe2+) ("labile iron"), catalyzing the conversion of weak oxidants such as peroxides, to extremely reactive ones like hydroxyl (HO•) or alcoxyl (RO•) radicals. If the oxidized materials remain unrepaired for extended periods of time, they can be further oxidized to generate ultimate over-oxidized products that are unable to be repaired, degraded, or exocytosed by the relevant cellular systems. Additionally, over-oxidized materials might inactivate cellular protection and repair mechanisms, thus allowing for futile cycles of increasingly rapid lipofuscin accumulation. In this review paper, we present evidence that the modulation of the labile iron pool distribution by nutritional or pharmacological means represents a hitherto unappreciated target for hampering lipofuscin accumulation and cellular ageing.