Regulation of inflammation in uveal melanoma

As HLA Class I expression is an important target for cytotoxic T cells but an in inhibitor of NKcells, we were interested in the regulation of its expression.We review HLA expression in UM, how it is involved in the inflammatory phenotype, how it is regulated and how putative treatments might be effective in its expression.We investigate the potential role of the NFkB pathway in the regulation of inflammation in UM and its potential association with HLA Class I expression.In order to increase our understanding for the reason behind the elevated HLA Class I expression in UM tumours, we investigate the involvement of epigenetics. We focus on a set of epigenetic enzymes called histone deacetylases and report that these regulators are highly expressed in Monosomy 3 UM.We wonder whether HDAC expression is influenced by the presence of infiltrating lymphocytes and macrophages.We focus on miRNA’s as another set of epigenetic regulators of inflammation. We investigate the potential relation of a set of 125 miRNA’s with HLA Class I expression and the presence of an infiltrate in UM and report two patterns of miRNA expression.We study the LAG3 immune checkpoint in UM tumours. As immune checkpoints might be responsible for the T cell exhaustion which is observed in UM, we investigate the involvement of LAG in prognostication and study how LAG3 and its ligands are distributed among different UM tumours.This thesis was made possible by the contribution of the Iranian Ministry of Science Research and Technology; Grant UL 2011-4991 from the Dutch Cancer Society (KW F); Stichting Leids Oogheelkundig Ondersteunings Fonds LOOF; a Horizon 2020 grant from the European Community; CURE UM, nr. 667787; Nelly Reef Fund and Ms I. BrouwerLUMC / Geneeskund

Expression of HDACs 1, 3 and 8 Is upregulated in the presence of Infiltrating lymphocytes in uveal melanoma

Simple Summary Uveal melanoma (UM) is an ocular malignancy which is derived from melanocytes in the uveal tract. Epigenetic regulators such as Histone Deacetylase (HDACs) inhibitors are being tested as treatment of UM metastases. Expression of different HDACs is variable, and some are increased in high-risk tumors with loss of one chromosome 3. As this genetic abnormality is also associated with an inflammatory phenotype, we analyzed whether HDAC expression was influenced by inflammation. In two cohorts of UM cases, expression of several HDACs showed a positive correlation with tumor-infiltrating T cells, while HDACs 2 and 11 showed a negative association with macrophages. Interferon-gamma stimulated expression of some HDACs on UM cell lines. These data suggest that cytokines produced by T cells may be responsible for the increased expression of some HDACs in UM with monosomy 3. In Uveal Melanoma (UM), an inflammatory phenotype is strongly associated with the development of metastases and with chromosome 3/BAP1 expression loss. As an increased expression of several Histone Deacetylases (HDACs) was associated with loss of chromosome 3, this suggested that HDAC expression might also be related to inflammation. We analyzed HDAC expression and the presence of leukocytes by mRNA expression in two sets of UM (Leiden and TCGA) and determined the T lymphocyte fraction through ddPCR. Four UM cell lines were treated with IFN gamma (50IU, 200IU). Quantitative PCR (qPCR) was used for mRNA measurement of HDACs in cultured cells. In both cohorts (Leiden and TCGA), a positive correlation occurred between expression of HDACs 1, 3 and 8 and the presence of a T-cell infiltrate, while expression of HDACs 2 and 11 was negatively correlated with the presence of tumor-infiltrating macrophages. Stimulation of UM cell lines with IFN gamma induced an increase in HDACs 1, 4, 5, 7 and 8 in two out of four UM cell lines. We conclude that the observed positive correlations between HDAC expression and chromosome 3/BAP1 loss may be related to the presence of infiltrating T cells.Cancer Signaling networks and Molecular Therapeutic

Enhancing long-term trend simulation of the global tropospheric hydroxyl (TOH) and its drivers from 2005 to 2019: a synergistic integration of model simulations and satellite observations

The tropospheric hydroxyl (TOH) radical is a key player in regulating oxidation of various compounds in Earth's atmosphere. Despite its pivotal role, the spatiotemporal distributions of OH are poorly constrained. Past modeling studies suggest that the main drivers of OH, including NO2, tropospheric ozone (TO3), and H2O(v), have increased TOH globally. However, these findings often offer a global average and may not include more recent changes in diverse compounds emitted on various spatiotemporal scales. Here, we aim to deepen our understanding of global TOH trends for more recent years (2005–2019) at 1×1°. To achieve this, we use satellite observations of HCHO and NO2 to constrain simulated TOH using a technique based on a Bayesian data fusion method, alongside a machine learning module named the Efficient CH4-CO-OH (ECCOH) configuration, which is integrated into NASA's Goddard Earth Observing System (GEOS) global model. This innovative module helps efficiently predict the convoluted response of TOH to its drivers and proxies in a statistical way. Aura Ozone Monitoring Instrument (OMI) NO2 observations suggest that the simulation has high biases for biomass burning activities in Africa and eastern Europe, resulting in a regional overestimation of up to 20 % in TOH. OMI HCHO primarily impacts the oceans, where TOH linearly correlates with this proxy. Five key parameters, i.e., TO3, H2O(v), NO2, HCHO, and stratospheric ozone, can collectively explain 65 % of the variance in TOH trends. The overall trend of TOH influenced by NO2 remains positive, but it varies greatly because of the differences in the signs of anthropogenic emissions. Over the oceans, TOH trends are primarily positive in the Northern Hemisphere, resulting from the upward trends in HCHO, TO3, and H2O(v). Using the present framework, we can tap the power of satellites to quickly gain a deeper understanding of simulated TOH trends and biases.</p

MiRNAs correlate with HLA expression in uveal melanoma: both up- and downregulation are related to monosomy 3

Simple Summary Uveal melanoma (UM) is a rare ocular malignancy that often gives rise to metastases. Tumours with an inflammatory phenotype have an especially bad prognosis. As an increased HLA expression and the presence of tumour-infiltrating lymphocytes and macrophages may be regulated by miRNAs, we set out to investigate whether any miRNAs are associated with inflammatory parameters in this malignancy. Some miRNAs were increased in UM with a high HLA expression and high T cell numbers, while others were decreased, showing two opposing patterns; however, both patterns were related to the tumour's chromosome 3/BAP1 status. We conclude that specific miRNAs are related to the inflammatory phenotype and that these are differentially expressed between disomy 3/BAP1-positive versus monosomy 3/BAP1-negative UM. MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM's genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs.Development and application of statistical models for medical scientific researc

Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective

The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA 2 B 2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis

Global retrieval of stratospheric and tropospheric BrO columns from the Ozone Mapping and Profiler Suite Nadir Mapper (OMPS-NM) on board the Suomi-NPP satellite

Quantifying the global bromine monoxide (BrO) budget is essential to understand ozone chemistry better. In particular, the tropospheric BrO budget has not been well characterized. Here, we retrieve nearly a decade (February 2012–July 2021) of stratospheric and tropospheric BrO vertical columns from the Ozone Mapping and Profiling Suite Nadir Mapper (OMPS-NM) on board the Suomi National Polar-orbiting Partnership (Suomi-NPP) satellite. In quantifying tropospheric BrO enhancements from total slant columns, the key aspects involve segregating them from stratospheric enhancements and applying appropriate air mass factors. To address this concern and improve upon the existing methods, our study proposes an approach that applies distinct BrO vertical profiles based on the presence or absence of tropospheric BrO enhancement at each pixel, identifying it dynamically using a satellite-derived stratospheric-ozone–BrO relationship. We demonstrate good agreement for both stratosphere (r = 0.81–0.83) and troposphere (r = 0.50–0.70) by comparing monthly mean BrO vertical columns from OMPS-NM with ground-based observations from three stations (Lauder, Utqiaġvik, and Harestua). Although algorithm performance is primarily assessed at high latitudes, the OMPS-NM BrO retrievals successfully capture tropospheric enhancements not only in polar regions but also in extrapolar areas, such as the Rann of Kutch and the Great Salt Lake. We also estimate random uncertainties in the retrievals pixel by pixel, which can assist in quantitative applications of the OMPS-NM BrO dataset. Our BrO retrieval algorithm is designed for cross-sensor applications and can be adapted to other space-borne ultraviolet spectrometers, contributing to the creation of continuous long-term satellite BrO observation records.</p

HDAC inhibition increases HLA class I expression in uveal melanoma

The treatment of uveal melanoma (UM) metastases or adjuvant treatment may imply immunological approaches or chemotherapy. It is to date unknown how epigenetic modifiers affect the expression of immunologically relevant targets, such as the HLA Class I antigens, in UM. We investigated the expression of HDACs and the histone methyl transferase EZH2 in a set of 64 UMs, using an Illumina HT12V4 array, and determined whether a histone deacetylase (HDAC) inhibitor and EZH2 inhibitor modified the expression of HLA Class I on three UM cell lines. Several HDACs (HDAC1, HDAC3, HDAC4, and HDAC8) showed an increased expression in high-risk UM, and were correlated with an increased HLA expression. HDAC11 had the opposite expression pattern. While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell sur

Association of waterpipe smoking and road traffic crashes

<p>Abstract</p> <p>Background</p> <p>The purpose of this research was to examine whether waterpipe smokers experience increased risk of motor vehicle crashes.</p> <p>Methods</p> <p>In a telephone survey, a random sample of Iranian drivers were asked to report their age, gender, vehicle age, whether their vehicles were equipped with anti-lock braking system (ABS), average daily drive time (DDT), whether they smoked cigarette or waterpipe, whether they had diabetes mellitus (DM), number of traffic crashes during the last calendar year and whether the crash involved a pedestrian or another vehicle.</p> <p>Results</p> <p>A total of 2070 motor vehicle owners with the mean age of 41.6 ± 11.45 were interviewed. The annual incidence of Road Traffic Crashes (RTC) was 14.9%; 14.0% involved a collision/s with other vehicles and 0.9% with pedestrians. There was an association between the RTC and male gender, DDT, being a cigarette smoker, being a waterpipe smoker and DM in univariable analysis. The association between RTC and being a waterpipe smoker and also cigarette smoker was significant in multivariable analysis after adjustment for DDT.</p> <p>Conclusions</p> <p>Being waterpipe and/or cigarette smoker and DDT were the independent predictors of the number of traffic crashes in Poisson regression model. If the increased risk of RTC among waterpipe or cigarette smokers is seen in other studies, it would be beneficial to promote tobacco cessation and control strategies through injury prevention initiatives.</p

Climate-smart agriculture practices for mitigating greenhouse gas emissions

Agricultural lands make up approximately 37% of the global land surface, and agriculture is a significant source of greenhouse gas (GHG) emissions, including carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O). Those GHGs are responsible for the majority of the anthropogenic globalwarming effect.Agricultural GHG emissions are associated with agricultural soil management (e.g. tillage), use of both synthetic and organic fertilisers, livestock management, burning of fossil fuel for agricultural operations, and burning of agricultural residues and land use change. When natural ecosystems such as grasslands are converted to agricultural production, 20-40% of the soil organic carbon (SOC) is lost over time, following cultivation.We thus need to develop management practices that can maintain or even increase SOC storage in and reduce GHG emissions from agricultural ecosystems. We need to design systematic approaches and agricultural strategies that can ensure sustainable food production under predicted climate change scenarios, approaches that are being called climate-smart agriculture (CSA). Climate-smart agricultural management practices, including conservation tillage, use of cover crops and biochar application to agricultural fields, and strategic application of synthetic and organic fertilisers have been considered a way to reduce GHG emission from agriculture. Agricultural management practices can be improved to decreasing disturbance to the soil by decreasing the frequency and extent of cultivation as a way to minimise soil C loss and/or to increase soil C storage. Fertiliser nitrogen (N) use efficiency can be improved to reduce fertilizer N application and N loss. Management measures can also be taken to minimise agricultural biomass burning. This chapter reviews the current literature on CSA practices that are available to reduce GHG emissions and increase soil C sequestration and develops a guideline on best management practices to reduce GHG emissions, increase C sequestration, and enhance crop productivity in agricultural production systems

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700