Oncogenic Mutations of MYD88 and CD79B in Diffuse Large B-Cell Lymphoma and Implications for Clinical Practice

Simple SummaryA diagnosis of diffuse large B-cell lymphoma in our therapeutic era should be implemented by the definition of the cell of origin, additional immunohistochemistry (i.e., BCL2 and MYC), and by fluorescent in-situ hybridization. The next step, suggested by the seminary works we will discuss in this review, will be to implement the definition of sub-categories by the recognition of single gene mutations and pathways that may be targetable by newer drugs. We here describe the impact that MYD88 and CD79B activating mutations, two of the most frequent mutations in several DLBCL subtypes, may achieve in the next future in the diagnosis and therapeutics of such a relevant lymphoma subtype.Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma in adults. Despite the recognition of transcriptional subtypes with distinct functional characteristics, patient outcomes have not been substantially altered since the advent of chemoimmunotherapy (CIT) twenty years ago. Recently, a few pivotal studies added to the disease heterogeneity by describing several activating mutations, which have been associated with disease presentation, B-cell function and behavior, and final outcome. DLBCL arises from antigen exposed B-cells, with the B-cell receptor (BCR) playing a central role. BCR-activity related mutations, such as CD79B and MYD88, are responsible for chronic activation of the BCR in a substantial subset of patients. These mutations, often coexisting in the same patient, have been found in a substantial subset of patients with immune-privileged (IP) sites DLBCLs, and are drivers of lymphoma development conferring tissue-specific homing properties. Both mutations have been associated with disease behavior, including tumor response either to CIT or to BCR-targeted therapy. The recognition of CD79B and MYD88 mutations will contribute to the heterogeneity of the disease, both in recognizing the BCR as a potential therapeutic target and in providing genetic tools for personalized treatment

Homocysteine, MTHFR C677T gene polymorphism, folic acid and vitamin B 12 in patients with retinal vein occlusion

BACKGROUND: Many available data have suggested that hyperhomocysteinaemia, an established independent risk factor for thrombosis (arterial and venous), may be associated with an increased risk of retinal vein occlusion (RVO). AIM OF THE STUDY: To evaluate homocysteine metabolism in consecutive caucasian patients affected by RVO from Northern Italy. PATIENTS AND METHODS: 69 consecutive patients from Northern Italy (mean age 64.1 ± 14.6 yy) with recent RVO, were tested for plasma levels of homocysteine (tHcy: fasting and after loading with methionine), cyanocobalamine and folic acid levels (CMIA-Abbot) and looking for MTHFR C677T mutation (Light Cycler-Roche) and compared to 50 volunteers, enrolled as a control group. RESULTS: Fasting levels of tHcy were significantly higher in patients than in controls: mean value 14.7 ± 7.7 vs 10.2 ± 8 nmol/ml. Post load levels were also significantly higher: mean value 42.7 ± 23.7 vs 30.4 ± 13.3 nmol/ml; Total homocysteine increase was also evaluated (i.e. Δ-tHcy) after methionine load and was also significantly higher in patients compared to control subjects: mean Δ-tHcy 27.8 ± 21.5 vs 21.0 ± 16 nmol/ml (normal value < 25 nmol/ml). Furthermore, patients affected by RVO show low folic acid and/or vitamin B12 levels, although differences with control group did not reach statistical significance. Heterozygous and homozygous MTHFR mutation were respectively in study group 46% and 29% vs control group 56% and 4%. CONCLUSION: our data confirm that hyperhomocysteinaemia is a risk factor for RVO, and also that TT genotype of MTHFR C677T is more frequently associated with RVO: if the mutation per se is a risk factor for RVO remains an open question to be confirmed because another study from US did not reveal this aspect. Hyperomocysteinemia is modifiable risk factor for thrombotic diseases. Therefore, a screening for tHcy plasma levels in patients with recent retinal vein occlusion could allow to identify patients who might benefit from supplementation with vitamins and normalization of homocysteine levels, in fasting and after methionine load

Interactive stratospheric aerosol models' response to different amounts and altitudes of SO2 injection during the 1991 Pinatubo eruption

A previous model intercomparison of the Tambora aerosol cloud has highlighted substantial differences among simulated volcanic aerosol properties in the pre-industrial stratosphere and has led to questions about the applicability of global aerosol models for large-magnitude explosive eruptions prior to the observational period. Here, we compare the evolution of the stratospheric aerosol cloud following the well-observed June 1991 Mt. Pinatubo eruption simulated with six interactive stratospheric aerosol microphysics models to a range of observational data sets. Our primary focus is on the uncertainties regarding initial SO2 emission following the Pinatubo eruption, as prescribed in the Historical Eruptions SO2 Emission Assessment experiments (HErSEA), in the framework of the Interactive Stratospheric Aerosol Model Intercomparison Project (ISA-MIP). Six global models with interactive aerosol microphysics took part in this study: ECHAM6-SALSA, EMAC, ECHAM5-HAM, SOCOL-AERv2, ULAQ-CCM, and UM-UKCA. Model simulations are performed by varying the SO2 injection amount (ranging between 5 and 10 Tg S) and the altitude of injection (between 18–25 km). The comparisons show that all models consistently demonstrate faster reduction from the peak in sulfate mass burden in the tropical stratosphere. Most models also show a stronger transport towards the extratropics in the Northern Hemisphere, at the expense of the observed tropical confinement, suggesting a much weaker subtropical barrier in all the models, which results in a shorter e-folding time compared to the observations. Furthermore, simulations in which more than 5 Tg S in the form of SO2 is injected show an initial overestimation of the sulfate burden in the tropics and, in some models, in the Northern Hemisphere and a large surface area density a few months after the eruption compared to the values measured in the tropics and the in situ measurements over Laramie. This draws attention to the importance of including processes such as the ash injection for the removal of the initial SO2 and aerosol lofting through local heating.</p

The rs1001179 SNP and CpG methylation regulate catalase expression in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by an extremely variable clinical course. We have recently shown that high catalase (CAT) expression identifies patients with an aggressive clinical course. Elucidating mechanisms regulating CAT expression in CLL is preeminent to understand disease mechanisms and develop strategies for improving its clinical management. In this study, we investigated the role of the CAT promoter rs1001179 single nucleotide polymorphism (SNP) and of the CpG Island II methylation encompassing this SNP in the regulation of CAT expression in CLL. Leukemic cells harboring the rs1001179 SNP T allele exhibited a significantly higher CAT expression compared with cells bearing the CC genotype. CAT promoter harboring the T -but not C- allele was accessible to ETS-1 and GR-β transcription factors. Moreover, CLL cells exhibited lower methylation levels than normal B cells, in line with the higher CAT mRNA and protein expressed by CLL in comparison with normal B cells. Methylation levels at specific CpG sites negatively correlated with CAT levels in CLL cells. Inhibition of methyltransferase activity induced a significant increase in CAT levels, thus functionally validating the role of CpG methylation in regulating CAT expression in CLL. Finally, the CT/TT genotypes were associated with lower methylation and higher CAT levels, suggesting that the rs1001179 T allele and CpG methylation may interact in regulating CAT expression in CLL. This study identifies genetic and epigenetic mechanisms underlying differential expression of CAT, which could be of crucial relevance for the development of therapies targeting redox regulatory pathways in CLL

Analysis of the global atmospheric background sulfur budget in a multi-model framework

Sulfate aerosol in the stratosphere is an important climate driver, causing solar dimming in the years after major volcanic eruptions. Hence, a growing number of general circulation models are adapting interactive sulfur and aerosol schemes to improve the representation of relevant chemical processes and associated feedbacks. However, uncertainties of these schemes are not well constrained. Stratospheric sulfate is modulated by natural emissions of sulfur-containing species, including volcanic eruptive, and anthropogenic emissions. Model intercomparisons have examined the effects of volcanic eruptions, whereas the background conditions of the sulfur cycle have not been addressed in a global model intercomparison project. Assessing background conditions in global models allows us to identify model discrepancies as they are masked by large perturbations such as volcanic eruptions, yet may still matter in the aftermath of such a disturbance. Here, we analyze the atmospheric burden, seasonal cycle, and vertical and meridional distribution of the main sulfur species among nine global atmospheric aerosol models that are widely used in the stratospheric aerosol research community. We use observational and reanalysis data to evaluate model results. Overall, models agree that the three dominant sulfur species in terms of burdens (sulfate aerosol, OCS, and SO2) make up about 98 % of stratospheric sulfur and 95 % of tropospheric sulfur. However, models vary considerably in the partitioning between these species. Models agree that anthropogenic emission of SO2 strongly affects the sulfate aerosol burden in the Northern Hemispheric troposphere, while its importance is very uncertain in other regions. The total deposition of sulfur varies among models, deviating by a factor of two, but models agree that sulfate aerosol is the main form in which sulfur is deposited. Additionally, the partitioning between wet and dry deposition fluxes is highly model dependent. We investigate the areas of greatest variability in the sulfur species burdens and find that inter-model variability is low in the tropics and increases towards the poles. Seasonality in the southern hemisphere is depicted very similar among models. Differences are largest in the dynamically active northern hemispheric extratropical region, hence some of the differences could be attributed to the differences in the representation of the stratospheric circulation among underlying general circulation models. This study highlights that the differences in the atmospheric sulfur budget among the models arise from the representation of both chemical and dynamical processes, whose interplay complicates the bias attribution. Several problematic points identified for individual models are related to the specifics of the chemistry schemes, model resolution, and representation of cross-tropopause transport in the extratropics. Further model intercomparison research is needed focusing on the clarification of the reasons for biases, given also the importance of this topic for the stratospheric aerosol injection studies.</p

SV-IV Peptide1–16 reduces coagulant power in normal Factor V and Factor V Leiden

Native Factor V is an anticoagulant, but when activated by thrombin, Factor X or platelet proteases, it becomes a procoagulant. Due to these double properties, Factor V plays a crucial role in the regulation of coagulation/anticoagulation balance

Hunga Tonga-Hunga Ha&rsquo;apai Volcano Impact Model Observation Comparison (HTHH-MOC) Project: Experiment Protocol and Model Descriptions

The 2022 Hunga volcanic eruption injected a significant amount of water vapor and a moderate amount of sulfur dioxide into the stratosphere causing observable responses in the climate system. We have developed a model-observation comparison project to investigate the evolution of volcanic water and aerosols, and their impacts on atmospheric dynamics, chemistry, and climate, using several state-of-the-art chemistry climate models. The project goals are: 1. Evaluate the current chemistry-climate models to quantify their performance in comparison to observations; and 2. Understand atmospheric responses in the Earth system after this exceptional event and investigate the potential impacts in the projected future. To achieve these goals, we designed specific experiments for direct comparisons to observations, for example from balloons and the Microwave Limb Sounder satellite instrument. Experiment 1 is a free-running ensemble experiment from 2022 to 2031. Experiment 2 is a nudged-run experiment from 2022 to 2023 using observed meteorology. To allow participation of more climate models with varying complexities of aerosol simulation, we include two sets of simulations in Experiment 2: Experiment 2a is designed for models with internally-generated aerosol while Experiment 2b is designed for models using prescribed aerosol surface area density. We take model results from the previously developed Tonga-MIP to fulfill Experiment 3, which focuses on the initial dispersion and microphysical evolution of aerosol and water plumes. Experiment 4 is designed to understand the climate impact on the mesosphere from 2022&ndash;2027, for which the experiment design is the same as Experiment 1 but for models that resolve the upper stratosphere and mesosphere

Potential for a Circular Autopoietic Economy on Canavese Territory

The aim of this gigamap is to describe and summarize a student work carried out during the semester course Open Systems Design at Politecnico Torino. The map is one of the outputs from an analysis of the Canavese, Piedmont region and subsequently an in-depth study of the relationships and “flows” with certain “currencies” between some selected economic and public actors. Canavese is a historical-geographical area located in the province of Turin, Italy; it’s full of great natural and geological spots, with a strong enogastronomic identity, historical re-enactments, a well-known manufacture sector like the ceramic of Castellamonte, as well as the leading high-tech branch like Arduino. Through the approach deriving from systemic design, it was possible to identify some strategies for the creation of new networks aimed at transforming the economy and production processes from linear to circular approach. Five types of “circular flows” were assessed and “designed into” the current linear system, thus proposing an improved economy based on circularity: flows of matter (energy/CO2, water, materials), economic flows, and social flows. The Gigamap will be presented to stakeholders in a public hearing and supposedly be used to illustrate and incubate a circular economy that is more resilient and more regenerative. Reading the map The reading should start at the top left, where the abstract is located, next, there is an outline that shows the connections between the five topics investigated. Subsequently, there is a timeline with some fundamental events in the history of the Canavese. In the center there is the circularity map with the main cities, focusing on new opportunities of circular flows between the 15 analysed economic actors. At the bottom, some general data and on the right a brief description of the role and territorial qualities of the companies. Lastly, there is a summary of the emerging properties