Search

BACKGROUND AND OBJECTIVES: The incidence of melanoma is increasing. This places significant burden on societies to provide efficient cancer care. The European Cancer Organisation recently published the essential requirements for quality melanoma care. The present study is aimed for the first time to roughly estimate the extent to which these requirements have been met in Europe. MATERIALS AND METHODS: A web-based survey of experts from melanoma centers in 27 European countries was conducted from 1 February to 1 August, 2019. Data on diagnostic techniques, surgical and medical treatment, organisation of cancer care and education were collected and correlated with national health and economic indicators and mortality-to-incidence ratio (MIR) as a surrogate for survival. Univariate linear regression analysis was performed to evaluate the correlations. SPSS software was used. Statistical significance was set at p < 0.05. RESULTS: The MIR was lower in countries with a high health expenditure per capita and with a higher numbers of general practitioners (GPs) and surgeons per million inhabitants. In these countries, GPs and dermatologists were involved in melanoma detection; high percentage of dermatologists used dermatoscopy and were involved in the follow-up of all melanoma stages; both medical oncologists and dermato-oncologists administered systemic treatments and patients had better access to sentinel lymph node biopsy and were treated within multidisciplinary tumour boards CONCLUSION: Based on these first estimates, the greater involvement of GPs in melanoma detection; the greater involvement of highly trained dermatologists in dermatoscopy, dermatosurgery, follow-up and the systemic treatment of melanoma; and the provision of ongoing dermato-oncology training for pathologists, surgeons, dermatologists and medical oncologists are necessary to provide an optimal melanoma care pathway. A comprehensive analysis of the melanoma care pathway based on clinical melanoma registries, will be needed to more accurately evaluate these first insights.

Tenascin-C (TnC) is an extracellular matrix glycoprotein implicated in a variety of processes ranging from brain development to synaptic plasticity in the adult vertebrates. Although the role of the TnC gene in regulation of behavior has been investigated, it remained elusive how TnC deficiency interacts with the environment in shaping the behavioral phenotype. To address this, 3-week-old TnC+/+ and TnC-/- male mice were housed over an 8-week period in standard conditions (SC), or enriched environment (EE). A comprehensive battery of tests was used in behavioral phenotyping. When housed in SC, TnC-/- mice showed spontaneous nocturnal hyperactivity, as well as poor sensorimotor coordination and low swimming velocity. However, housing of TnC-/- mice in EE abolished hyperlocomotion, led to faster habituation to novel environment, strengthened the grasp of fore limbs and partially improved movement coordination, while the swimming ability remained deficient. Conversely, TnC deficiency attenuated both the beneficial effects of EE on learning/memory capacity and the anxiolytic effect of EE in reducing the level of acrophobia. This study expands the existing knowledge about the phenotype associated with TnC deficiency, and reveals that the effect of genetic background on the behavioral response could be altered by post-weaning housing in a highly stimulating environment.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi+MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p=0.02), median market price (p=0.001), HEPC and Mackenbach scores (p&nbsp

Background. Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europeand estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). Materials and methods Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. Results The recommended BRAF inhibitor (BRAFi)+MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r=0.662; p Previous article in issue

Acquired pure red-cell aplasia (PRCA) is an uncommon disorder of erythrocytopoiesis that can develop in association with thymic tumors. We present the very rare case of a severely anemic 62-year-old man with PRCA and a concurrent neuroendocrine carcinoid tumor of the thymus. The anterior mediastinal thymus tumor was completely excised, and following histological and immunohistochemical analyses (showing positive staining for cytokeratin, chromogranin A, synaptophysin, and neuron-specific enolase) the diagnosis of a (grade I; T(1)N(0)M(0)) typical carcinoid tumor of the thymus was made. Postoperatively the anemia persisted despite no signs of residual tumor on CT chest. A hematological work up found: normocellularity with

The morphology of the epithelioid malignant mesothelioma (MM) of the pleura is similar to lung adenocarcinoma involving pleura. The aim of this study was to evaluate the value of immunohistochemistry in the accurate diagnosis of MM, especially of the epithelioid type with needle biopsy of the pleura.The diagnosis of MM was established with pleural needle biopsy and tumor immunophenotyping in 30 patients. A broad spectrum of monoclonal antibodies was applied: HBME-1, E-cadherin, calretinin, cytokeratin 5/6, vimentin, thyroid transcription factor (TTF-1) and surfactant apoprotein A (SP-A).We diagnosed 24 epithelioid, 2 biphasic and 4 sarcomatoid MM. HMBE-1 was the most sensitive tumor marker of the epithelioid type, being positive in 100% of the cases. Calretinin, E-cadherin and cytokeratin 5/6 were positive in 70%, 73%, and 50% of all tumors, respectively. TTF-1 and SP-A were negative in all MM. Vimentin was positive in spindle cells of all sarcomatoid and biphasic MM (20%).The accurate diagnosis of MM is mandatory for appropriate treatment decision (surgical or nonsurgical). Our results demonstrate that HMBE-1 is a most useful diagnostic antibody for epithelioid MM, and TTF-1 for lung adenocarcinoma (its thyroid origin excluded) involving pleura.

Three Drosophila embryonic deoxyribonucleases, designated den1, den2 and den3, are identified in nuclear extracts separated by glycerol density gradient centrifugation. Den1, removes short products from the 5'-ends of single-stranded DNA or double-stranded DNA with either blunt or 5'-recessed termini. Den2 is inactive with single-stranded DNA and acts as 3'-exonuclease with double-stranded DNA possessing either blunt or 3'-recessed termini. Den3 preferentially uses partial duplex DNA containing single-stranded gap and it catalyzes hydrolysis, in 3'-5' direction, of one of the shorter strands that flank the gap. Nucleolytic activities of den1, den2 and den3 are inhibited with ATP.

The effect of experimental protein malnutrition on gastrin producing cells in the antral part of the stomach was studied in male Wistar rats. Isoenergetic diets containing 25% (C-25) or 6% (PD-6) were given in isocaloric amounts during a 4-month experiment. All rats were offered drinking water ad libitum. The results showed that the long-term protein diet did not produce changes in the gastrin cell number. At the ultrastructural level G cells exhibited a decreased size of the nucleus. They were found to have an increased total granule volume density but the volume density of dense-cored granules was lower. The serum gastrin levels were significantly lowered by feeding the low protein diet. These changes are compatible with decreased functional activity of G cells under long-term protein deprivation.

In this investigation the following phenomena were observed: 1. Rat interscapular brown adipocytes were found to be capable of erythrophagocytosis; 2. Before leaving the capillary lumen, erythrocytes took some material from the blood plasma by endocytosis and passed the endothelial junction carrying endocytotic vacuole. Some erythrocytes were in transit: the so-called "head" was in the process of engulfment by brown adipocytes while the rest of the cell had not left the capillary lumen. Fragmentation of erythrocytes was observed during passage through the endothelial junction as well as in the cytoplasm of adipocytes. 3. In some brown adipocytes erythrocytes retained the same shape as in the capillary, but in many cases they exhibited unusual form. Intracytoplasmic erythrocytes were seen in a semithin sections stained with toluidine blue. 4. Erythrocytes either became cells which phagocytized mitochondria and lipid droplets before their transformation into lipofuscin bodies or they were degraded into ferritin-like particles observed (on unstained sections) in the mitochondrial matrix, intercristal space, on the periphery of lipid droplets and in brown adipocyte cytoplasm.

In this study, we present radioimmunoassay data describing the concentration of Vasoactive Intestinal Polypeptide (VIP) in both plasma and colonic biopsies, as well as immunostaining of VIPergic innervation in mucosal biopsies of normal subjects and patients with ulcerative colitis (UC).Thirty three patients with UC and 17 healthy subjects were investigated. All UC patients suffered from active disease. Fasting circulating levels of VIP in plasma as well as tissue concentrations were measured by radioimmunoassay. For the immunohistochemistry, polyclonal antibody against VIP and the streptavidin-biotin peroxidase complex technique were carried out.Overall plasma VIP concentrations in the UC patients were similar to those in the controls. Significantly decreased concentrations of VIP were found in UC of rectum compared to the normal tissue. However, both plasma VIP values and tissue concentrations were found to be significantly lower in patients expressing minimal or mild active disease according to clinical activity index (AI) and histological activity index (HAI), but marked increase of plasma VIP was clear in UC patients with moderate or severe AI and HAI. There was a trend towards increased tissue concentrations of VIP in the group of patients with moderate or severe AI and HAI. Our immunohistochemical analysis of VIP fibers and nerve cell bodies revealed consistently weaker VIP-immunoreactivity in the rectum in UC patients with minimal or mild HAI. Simultaneously, in the rectal biopsies from UC patients with moderate and severe disease, the fibers in the lamina propria and ganglion cells in the submucous plexus were markedly increased in density and in degree of immunostaining. Very strong immunoreactivity was also found in inflammatory cells of the lamina propria as well as in the epithelial layer of the biopsies from UC patients with obvious disease.Our study shows clearly the heterogeneity in the response of VIP plasma level as well as rectum concentration and distribution in UC patients at different stages of the active disease. The possible role of VIP in the colon suggests that further studies of the alterations of this gut peptide may be useful in the understanding of UC pathophysiology.

Immunomorphological characteristics of 27 renal cell carcinoma (RCC): 18 clear cell, 6 granular (chromophilic), 2 chromophobe, 1 spindle cell (sarcomatoid) as well as of 1 oncocytoma, were analyzed. The investigation was performed on cryostat sections by immunoperoxidase technique applying a panel of monoclonal antibodies which defined: proximal (TNE3, TN5, 5D9) and distal (TN8, TN9, 7C2) tubular antigens; intercellular adhesion molecule 1 (ICAM1); HLA class II (-DQ, -DR and -DP) antigens, intermediary filaments (cytokeratin and vimentin); and antigens on tumour infiltrating mononuclear leucocytes (TT1, TT2 and LeuM3 for CD4, CD8 and CD14 antigens, respectively). All RCC with exception of chromophobe co-expressed cytokeratin and vimentin. In addition, they were usually positive for all proximal and two distal tubular markers (TN8, TN9) indicating primitive cells which could differentiate into the epithelium of both parts of tubule system as the most probable originators of in RCC. Almost all RCC but the chromophobe aberrantly expressed HLA class II antigens which great variability from case to case. The presence of HLA-DR antigens was more intensive and widespread than of HLA-DQ and -DP antigens. Expression of ICAM1 mostly correlated with presence of HLA class II antigens, particularly with -DR on tumour cells of RCC. HLA-DR antigen expression was always more prominent than mononuclear cell infiltrate (among which macrophages prevailed over T cells) which could suggest that increased histocompatibility antigen expression precedes mononuclear cell influx. In contrast to all other RCC, chromophobe tumours had quite distinct features revealing the most intense reaction with 7C2 (MAb that produced the weakest reaction with other tumour types), absence of vimentin and very weak reaction with antibodies for HLA class II Ag and ICAM1.(ABSTRACT TRUNCATED AT 250 WORDS)

Torture is considered as physical or mental harassment, torment, causing pain, injuries and humiliation of an innocent person occurring during the shorter or longer period of time.Is human emotional behavior based on primary biological mechanism that human inherited not only from close animal predecessors, but also significantly more distant kinds on evolutionary ladder?Results of researches indicate that aggressiveness is stable pattern of behavior in children and young people. Aggressive behavior of humans decreases over the years, although certain types of personalities preserve stability of aggressive behavior.Psychological profile of torturer includes diagnostical category of antisocial personality disorder.Mental consequences resulting from torture are depression, psychosomatic reactions, aggression, state of anxiety. The contribution of victimology is significant, particularly from aspect of “selecting” psychopathological reaction. It is also important whether the torturer is known to be victims or it is a stranger. It is understandable that consequences are much more severe with people who had unfortunate to be tortured by known person.The most common psychopathological reactions are:1.Fear lived during the torture.2.Depressive reaction.3.Aggression - which may not be demonstrated in adequate manner, may be shifted to other people, which may create interpersonal disputes, before all for the victim and represents one of physical consequences resulting from torture.Torture prevention is problem of individuals, community and society as whole.Degradation of authorities in one society leads to moral erosion, and on its part, to torture on all functioning levels.

Microfluidic technology is a valuable tool for realizing more in vitro models capturing cellular and organ level responses for rapid and animal-free risk assessment of new chemicals and drugs. Microfluidic cell-based devices allow high-throughput screening and flexible automation while lowering costs and reagent consumption due to their miniaturization. There is a growing need for faster and animal-free approaches for drug development and safety assessment of chemicals (Registration, Evaluation, Authorisation and Restriction of Chemical Substances, REACH). The work presented describes a microfluidic platform for in vivo-like in vitro cell cultivation. It is equipped with a wafer-based silicon chip including integrated electrodes and a microcavity. A proof-of-concept using different relevant cell models shows its suitability for label-free assessment of cytotoxic effects. A miniaturized microscope within each module monitors cell morphology and proliferation. Electrodes integrated in the microfluidic channels allow the noninvasive monitoring of barrier integrity followed by a label-free assessment of cytotoxic effects. Each microfluidic cell cultivation module can be operated individually or be interconnected in a flexible way. The interconnection of the different modules aims at simulation of the whole-body exposure and response and can contribute to the replacement of animal testing in risk assessment studies in compliance with the 3Rs to replace, reduce, and refine animal experiments., T.K. and Y.K. contributed equally to this work. The authors thank Frank Bauerfeld for system assembly and electrical testing, Werner Haberer for assembly of the microfluidic cartridges, Axel Brenner for the fabrication of the silicon micro cavity chips, Hoffman La Roche for providing the Ro 19-8022, NorGenoTech for providing the Fpg enzyme, and Karen Steenson for proofreading. This research was funded by the European Commission under the Horizon2020 programme (HISENTS, Grant Agreement No. 685817 and VISION, Grant Agreement No. 857381); and by the Norwegian Research Council Norway (RCN) via the European Research Area Network (ERA-NET) EuroNanoMed II project INNOCENT (RCN 271075) and the ERA-NET EuroNanoMed III project Graphene-encapsulated magnetic nanoparticles (RCN 246672/O70). K.K. received Short Term Scientific Mission Grant (ID 42926) under COST Action CA 17140 “Cancer Nanomedicine from the Bench to the Bedside” supported by COST (European Cooperation in Science and Technology). E.E. received funding from the Norwegian Research Council (272412/F40). O.H.M. received funding from the Spanish Ministry of Economy and Competitiveness (SEV-2013-0295-17-3).

Replication of eukaryotic cell genomes is a tightly controlled process occurring once and only once per cell cycle. Replication initiates at several thousand origins, whose cis-acting sequences and trans-acting proteins have been partially characterized in the yeast S. cerevisiae in the last few years. In contrast, identification of origins of DNA replication in mammalian cells have proven much more difficult. Currently, less then 20 bona fide mammalian origins have been identified, of which only few characterized in detail. Here we discuss the available methods for origin identification in mammalian DNA and the main results, sometimes controversial, so far generated by their application. In particular, we review the currently available information concerning the three best characterized origins, namely those in the lamin B2 and b-globin gene domains in human cells and the one located downstream of the dihydrofolate reductase gene in hamster cells.