Reis door de wereld van het oog

Oratie uitgesproken door Prof.dr. Martine J. Jager bij de aanvaarding van het ambt van hoogleraar in de Oogheelkunde, in het bijzonder het ogmelanoom, aan de Universiteit Leiden, op maandag 25 april 2016Oratie uitgesproken door Prof.dr. Martine J. Jager bij de aanvaarding van het ambt van hoogleraar in de Oogheelkunde, in het bijzonder het ogmelanoom, aan de Universiteit Leiden, op maandag 25 april 201

Travels in the world of the eye

Inaugural lecture by Prof.dr. Martine J. Jager on the acceptance of her position as professor of Ophthalmology, especially Eye Melanoma at Leiden University on Monday April 25, 2016Inaugural lecture by Prof.dr. Martine J. Jager on the acceptance of her position as professor of Ophthalmology, especially Eye Melanoma at Leiden University on Monday April 25, 201

Eye diseases direct interest to complement pathway and macrophages as regulators of inflammation in COVID-19

Many of the risk factors for developing severe coronavirus disease 2019 (COVID-19) are also risk factors for eye diseases such as age-related macular degeneration (AMD). During the past decades, macro-phages and the complement pathway (as a part of the innate immune system) have been identified as important contributors to the development of AMD, and we suggest that these mechanisms are of similar importance for the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Based on the experience with AMD, we discuss how behavioral factors such as diet, smoking and higher body mass index, as well as genetic determinants such as the complement and immune pathway genes may lead to the overactive inflammatory phenotypes seen in some patients with COVID-19, and may in part explain the heterogeneity of disease manifestations and outcomes. Based on this experience, we discuss potential genetic research projects and elaborate on preventive and treatment approaches related to COVID-19.Ophthalmic researc

Winkelkeuze van biologische kopers : onderzoek onder consumenten en ondernemers

This study describes how health food stores can reinforce their market position and reveal further growth potential within this retail channel. Through a qualitative and quantitative study among consumers, we looked at purches pattern and motives of heavy users and light users of organic products who are both customers and non customers of the health food store. Associations with the health food store and supermarket were compared and the main areas distinguishing health food stores are described. Retailers were also interviewed in order to discover whether consumer perception corresponded with that of the retaile

The impact of menstruation persistence or recovery after chemotherapy on survival in young patients with hormone receptor negative breast cancer

Introduction: Hormone replacement therapy can diminish hormone depletion-related complaints in postmenopausal women, but is contraindicated for postmenopausal breast cancer (BC) patients. Recovery of menstruation after chemotherapy-induced amenorrhea in young hormone receptor-negative BC patients however, is accepted. To determine the safety of this strategy, we investigated the effect of recovery of menstruation on disease-free survival (DFS) and overall survival (OS) in young hormone receptor-negative BC patients treated with (neo)adjuvant chemotherapy. Methods: We selected 636 patients from a single-center cohort with early stage hormone receptornegative BC and under the age of 50 years when treated with chemotherapy. Sufficient data on course of menstruation in medical records was retrospectively found for 397 patients, of whom 299 patients (75%) had a recovery of menstruation after chemotherapy. We used Cox proportional hazards models to estimate hazard ratios (HR) for the effect of recovery of menstruation on DFS and OS. Results: Patients with recovery of menstruation after chemotherapy less frequ

Multidimensional relativistic MHD simulations of Pulsar Wind Nebulae: dynamics and emission

Pulsar Wind Nebulae, and the Crab nebula in particular, are the best cosmic laboratories to investigate the dynamics of magnetized relativistic outflows and particle acceleration up to PeV energies. Multidimensional MHD modeling by means of numerical simulations has been very successful at reproducing, to the very finest details, the innermost structure of these synchrotron emitting nebulae, as observed in the X-rays. Therefore, the comparison between the simulated source and observations can be used as a powerful diagnostic tool to probe the physical conditions in pulsar winds, like their composition, magnetization, and degree of anisotropy. However, in spite of the wealth of observations and of the accuracy of current MHD models, the precise mechanisms for magnetic field dissipation and for the acceleration of the non-thermal emitting particles are mysteries still puzzling theorists to date. Here we review the methodologies of the computational approach to the modeling of Pulsar Wind Nebulae, discussing the most relevant results and the recent progresses achieved in this fascinating field of high-energy astrophysics.Comment: 29 pages review, preliminary version. To appear in the book "Modelling Nebulae" edited by D. Torres for Springer, based on the invited contributions to the workshop held in Sant Cugat (Barcelona), June 14-17, 201

Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy

Purpose: Conjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro. Methods: 131 conjunctival lesions obtained from 129 patients were collected. The presence of BRAF V600E mutation and expression of phosphorylated (p)-ERK and p-AKT were assessed by immunohistochemistry. We studied cell proliferation, phosphorylation, cell cycling and apoptosis in three CM cell lines using two BRAF inhibitors (Vemurafenib and Dabrafenib), a MEK inhibitor (MEK162) and an AKT inhibitor (MK2206). Results: The BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM). Nuclear and cytoplasmic p-ERK and p-AKT were expressed in all conjunctival lesions. Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death. MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines. Conclusion: ERK and AKT are constitutively activated in conjunctival nevi, PAM and melanoma. While BRAF inhibitors prohibited cell growth, they were not always cytotoxic. Combining MEK and AKT inhibitors led to more growth inhibition and cell death in CM cells. The combination may benefit patients suffering from metastatic conjunctival melanoma

Combining photodynamic therapy with immunostimulatory nanoparticles elicits effective anti-tumor immune responses in preclinical murine models

Photodynamic therapy (PDT) has shown encouraging but limited clinical efficacy when used as a standalone treatment against solid tumors. Conversely, a limitation for immunotherapeutic efficacy is related to the immunosuppressive state observed in large, advanced tumors. In the present study, we employ a strategy, in which we use a combination of PDT and immunostimulatory nanoparticles (NPs), consisting of poly(lactic-co-glycolic) acid (PLGA)-polyethylene glycol (PEG) particles, loaded with the Toll-like receptor 3 (TLR3) agonist poly(I:C), the TLR7/8 agonist R848, the lymphocyte-attracting chemokine, and macrophage inflammatory protein 3 alpha (MIP3 alpha). The combination provoked strong anti-tumor responses, including an abscopal effects, in three clinically relevant murine models of cancer: MC38 (colorectal), CT26 (colorectal), and TC-1 (human papillomavirus 16-induced). We show that the local and distal anti-tumor effects depended on the presence of CD8(+) T cells. The combination elicited tumor-specific oncoviral- or neoepitope-directed CD8(+) T cells immune responses against the respective tumors, providing evidence that PDT can be used as an in situ vaccination strategy against cancer (neo)epitopes. Finally, we show that the treatment alters the tumor microenvironment in tumor-bearing mice, from cold (immunosuppressed) to hot (pro-inflammatory), based on greater neutrophil infiltration and higher levels of inflammatory myeloid and CD8(+) T cells, compared to untreated mice. Together, our results provide a rationale for combining PDT with immunostimulatory NPs for the treatment of solid tumors.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Uveal melanoma: Towards a molecular understanding

Uveal melanoma is an aggressive malignancy that originates from melanocytes in the eye. Even if the primary tumor has been successfully treated with radiation or surgery, up to half of all UM patients will eventually develop metastatic disease. Despite the common origin from neural crest-derived cells, uveal and cutaneous melanoma have few overlapping genetic signatures and uveal melanoma has been shown to have a lower mutational burden. As a consequence, many therapies that have proven effective in cutaneous melanoma -such as immunotherapy- have little or no success in uveal melanoma. Several independent studies have recently identified the underlying genetic aberrancies in uveal melanoma, which allow improved tumor classification and prognostication of metastatic disease. In most cases, activating mutations in the Gα11/Q pathway drive uveal melanoma oncogenesis, whereas mutations in the BAP1, SF3B1 or EIF1AX genes predict progression towards metastasis. Intriguingly, the composition of chromosomal anomalies of chromosome 3, 6 and 8, shown to correlate with an adverse outcome, are distinctive in the BAP1mut, SF3B1mut and EIF1AXmut uveal melanoma subtypes. Expression profiling and epigenetic studies underline this subdivision in high-, intermediate-, or low-metastatic risk subgroups and suggest a different approach in the future towards prevention and/or treatment based on the specific mutation present in the tumor of the patients. In this review we discuss the current knowledge of the underlying genetic events that lead to uveal melanoma, their implication for the disease course and prognosis, as well as the therapeutic possibilities that arise from targeting these different aberrant pathways