Superconducting booster cyclotron studies at GANIL

International audienc

Les Modeling of a Diurnal Cycle

LES modeling of a diurnal cycl

Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer

Thyroid cancer is the most prevalent endocrine malignancy in the United States with greater than 53,000 new cases in 2020. There is a significant gender disparity in disease incidence as well, with women developing thyroid cancer three times more often than men; however, the underlying cause of this disparity is poorly understood. Using RNA-sequencing, we profiled the immune landscape of papillary thyroid cancer (PTC) and identified a significant inverse correlation between androgen receptor (AR) levels and the immune checkpoint molecule PD-L1. The expression of PD-L1 was then measured in an androgen responsive-thyroid cancer cell line. Dihydrotestosterone (DHT) treatment resulted in significant reduction in surface PD-L1 expression in a time and dose-dependent manner. To determine if androgen-mediated PD-L1 downregulation was AR-dependent, we treated cells with flutamide, a selective AR antagonist, and prior to DHT treatment to pharmacologically inhibit AR-induced signaling. This resulted in a \u3e 90% restoration of cell surface PD-L1 expression, suggesting a potential role for AR activity in PD-L1 regulation. Investigation into the AR binding sites showed AR activation impacts NF-kB signaling by increasing IkBalpha and by possibly preventing NF-kB translocation into the nucleus, reducing PD-L1 promoter activation. This study provides evidence of sex-hormone mediated regulation of immune checkpoint molecules in vitro with potential ramification for immunotherapies

Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer

Earlier studies have demonstrated an unexplained depletion of the epidermal growth factor receptor (EGFR) protein expression in prostatic cancer. We now attribute this phenomenon to the presence of a variant EGFR (EGFRvIII) that is highly expressed in malignant prostatic neoplasms. In a retrospective study, normal, benign hyperplastic and malignant prostatic tissues were examined at the mRNA and protein levels for the presence of this mutant receptor. The results demonstrated that whilst EGFRvIII was not present in normal prostatic glands, the level of expression of this variant protein increased progressively with the gradual transformation of the tissues to the malignant phenotype. The selective association of high EGFRvIII levels with the cancer phenotype underlines the role that this mutant receptor may maintain in the initiation and progression of malignant prostatic growth, and opens the way for new approaches in the management of this disease including gene therapy. © 2000 Cancer Research Campaig

Cystic hygroma and potential airway obstruction in a newborn: a case report and review of the literature

BACKGROUND: Cervical cystic hygroma is a benign congenital malformation of the lymphatic system. Incidence of cystic hygroma is 1/6000 live births. We present a case of right neck mass with potential respiratory compromise in a newborn. CASE PRESENTATION: The patient was a full term baby girl with an incidental finding of right neck mass which was described on ultrasound and magnetic resonance imaging as a cystic lesion in the nasopharynx and right neck which inferiorly followed the course of the right carotid artery, consistent with cystic hygroma. She started with respiratory compromise, and a follow-up magnetic resonance imaging showed increased size of the cystic hygroma. Dexamethasone was started to reduce fluid build up in the mass. When the cystic hygroma was found to be inseparable from the right half of the thyroid gland, the otolaryngologist performed hemithyroidectomy. CONCLUSION: The patient had neuropraxia involving the marginal mandibular branch of the facial nerve, which was expected to correct with time. Large cervical cystic hygromas may surround or displace neurovascular structures making their identification quite challenging intraoperatively. A team of experienced surgeons will help to ensure a successful surgical outcome

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Avant projet d'un post-accélérateur de 500 MeV/A à GANIL : CSS3

La communauté des physiciens utilisateurs du GANIL a commencé en 1989 à réfléchir aux domaines de recherche que pourraient ouvrir l'existence à GANIL de faisceau d'ions à 500 MeV/nucléon dont les qualités optiques et les intensités seraient équivalentes à celles attendues après l’achèvement de l'Opération d'Augmentation d'Intensité (phases 1 et 2)

Mass Measurements near N=Z

Abstract After an outline of the physics motivations, that illustrate why we think it is important to measure masses in the region N≈Z, we report on on experiments performed at Ganil. An experiment aimed at measuring the masses of proton-rich nuclei in the mass region A ≈ 60–80 has been performed, using a direct time-of-flight technique in conjunction with SISSI and the SPEG spectrometer at GANIL. The nuclei were produced via the fragmentation of a 78 Kr beam (73 meV/nucleon). A novel technique for the purification of the secondary beams, based on the stripping of the ions and using the α and the SPEG spectrometers, was succesfully checked. It allows for good selectivity without altering the beam quality. Secondary ions of 100 Ag, 100 Cd, 100 In and 100 Sn were produced via the fusion-evaporation reaction 50 Cr + 58 Ni at an energy of 5.1 MeV/nucleon, and were accelerated simultaneously in the second cyclotron of GANIL (CSS2). About 10 counts were observed from the production and acceleration of 100 Sn 22+ . The masses of 100 Cd, 100 In and 100 Sn were measured with respect to 100 Ag using the CSS2 cyclotron, with precisions of 2 × 10 −6 , 3 × 10 −6 and 10 −5 respectively

New targets for therapy in breast cancer: Small molecule tyrosine kinase inhibitors

Over the past several years many advances have been made in our understanding of critical pathways involved in carcinogenesis and tumor growth. These advances have led to the investigation of small molecule inhibitors of the ErbB family of receptor tyrosine kinases across a broad spectrum of malignancies. In this article we summarize the rationale for targeting members of the ErbB family in breast cancer, and review the preclinical and clinical data for the agents that are furthest in development. In addition, we highlight directions for future research, such as exploration of the potential crosstalk between the ErbB and hormone receptor signal transduction pathways, identification of predictive markers for tumor sensitivity, and development of rational combination regimens that include the tyrosine kinase inhibitors

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco?supplementation in Orthobiologics

The aim of this study is to review developments in glycosaminoglycan and proteoglycan research relevant to cartilage repair biology and in particular the treatment of osteoarthritis (OA). Glycosaminoglycans decorate a diverse range of extracellular matrix and cell associated proteoglycans conveying structural organization and physico‐chemical properties to tissues. They play key roles mediating cellular interactions with bioactive growth factors, cytokines, and morphogenetic proteins, and structural fibrillar collagens, cell interactive and extracellular matrix proteoglycans, and glycoproteins which define tissue function. Proteoglycan degradation detrimentally affects tissue functional properties. Therapeutic strategies have been developed to counter these degenerative changes. Neo‐proteoglycans prepared from chondroitin sulfate or hyaluronan and hyaluronan or collagen‐binding peptides emulate the interactive, water imbibing, weight bearing, and surface lubricative properties of native proteoglycans. Many neo‐proteoglycans outperform native proteoglycans in terms of water imbibition, matrix stabilization, and resistance to proteolytic degradation. The biospecificity of recombinant proteoglycans however, provides precise attachment to native target molecules. Visco‐supplements augmented with growth factors/therapeutic cells, hyaluronan, and lubricin (orthobiologicals) have the capacity to lubricate and protect cartilage, control inflammation, and promote cartilage repair and regeneration of early cartilage lesions and may represent a more effective therapeutic approach to the treatment of mild to moderate OA and deserve further study