Identification of homozygous deletion in ACAN and other candidate variants in familial classical Hodgkin lymphoma by exome sequencing

Tutkimuksessamme tarkastelimme Lähi-idästä lähtöisin olevaa perhettä, jossa kolmella viidestä lapsesta on todettu nuorellä iällä klassinen Hodgkinin lymfooma (cHL). Perinnöllinen alttius cHL:lle tunnetaan huonosti, eikä taudille mahdollisesti altistavia geenimuutoksia ole aiemmin raportoitui kuin yksi kappale. Geenimuutosten selvittämiseksi eksomisekvensoimme kolmen sairastuneen lapsen verinäytteestä eristetyn DNA:n ja poimimme joukosta kaikkien kolmen jakamat muutokset. Suodatimme lasten jakamien DNA-muutosten joukosta pois omissa vertailujoukoissamme ja useissa julkisissa tietokannoissa esiintyvät geneettiset muutokset ja arvioimme jäljellejääneiden muutosten haitallisuutta kahdella laskennallisella priorisaatioalgoritmilla. Näin saimme järjestettyä jäljelle jääneet 35 jaettua muutosta laskennalliseen haitallisuusjärjestykseen. Jaetuista muutoksista merkittävimmäksi nousi ACAN-geenissä oleva homotsygoottinen 57 emäksen pituinen deleetio c.2836_2892del, jota ei ole aiemmin liitytty cHL-fenotyyppiin

Maps of solar wind plasma precipitation onto Mercury's surface: a geographical perspective

Mercury is the closest planet to the Sun, possesses a weak intrinsic magnetic field and has only a very tenuous atmosphere (exosphere). These three conditions result in a direct coupling between the plasma emitted from the Sun (namely the solar wind) and Mercury’s surface. The planet’s magnetic field leads to a non-trivial pattern of plasma precipitation onto the surface, that is expected to contribute to the alteration of the regolith over geological time scales. The goal of this work is to study the solar wind plasma precipitation onto the surface of Mercury from a geographical perspective, as opposed to the local-time-of-day approach of previous precipitation modeling studies. We employ solar wind precipitation maps for protons and electrons from two fully-kinetic numerical simulations of Mercury’s plasma environment. These maps are then integrated over two full Mercury orbits (176 Earth days). We found that the plasma precipitation pattern at the surface is most strongly affected by the upstream solar wind conditions, particularly by the interplanetary magnetic field direction, and less by Mercury’s 3:2 spin-orbit resonance. We also found that Mercury’s magnetic field is able to shield the surface from roughly 90% of the incoming solar wind flux. At the surface, protons have a broad energy distribution from below 500 eV to more than 1.5 keV; while electrons are mostly found in the range 0.1-10 keV. These results will help to better constrain space weathering and exosphere source processes at Mercury, as well as to interpret observations by the ongoing ESA/JAXA BepiColombo mission

Surgical treatment of primitive gastro-intestinal lymphomas: a systematic review

Primitive Gastrointestinal Lymphomas (PGIL) are uncommon tumours, although time-trend analyses have demonstrated an increase. The role of surgery in the management of lymphoproliferative diseases has changed over the past 40 years. Nowadays their management is centred on systemic treatments as chemo-/radio- therapy. Surgery is restricted to very selected indications, always discussed in a multidisciplinary setting. The aim of this systematic review is to evaluate the actual role of surgery in the treatment of PGIL

Infliximab Induces Clonal Expansion of γδ-T Cells in Crohn's Disease: A Predictor of Lymphoma Risk?

BACKGROUND: Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion. METHODOLOGY/PRINCIPAL FINDINGS: We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n=20) or adalimumab (Humira®; n=26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5-15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells. CONCLUSION/SIGNIFICANCE: CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy

The HIV Matrix Protein p17 Subverts Nuclear Receptors Expression and Induces a STAT1-Dependent Proinflammatory Phenotype in Monocytes

BACKGROUND: Long-term remission of HIV-1 disease can be readily achieved by combinations of highly effective antiretroviral therapy (HAART). However, a residual persistent immune activation caused by circulating non infectious particles or viral proteins is observed under HAART and might contribute to an higher risk of non-AIDS pathologies and death in HIV infected persons. A sustained immune activation supports lipid dysmetabolism and increased risk for development of accelerated atehrosclerosis and ischemic complication in virologically suppressed HIV-infected persons receiving HAART. AIM: While several HIV proteins have been identified and characterized for their ability to maintain immune activation, the role of HIV-p17, a matrix protein involved in the viral replication, is still undefined. RESULTS: Here, we report that exposure of macrophages to recombinant human p17 induces the expression of proinflammatory and proatherogenic genes (MCP-1, ICAM-1, CD40, CD86 and CD36) while downregulating the expression of nuclear receptors (FXR and PPARγ) that counter-regulate the proinflammatory response and modulate lipid metabolism in these cells. Exposure of macrophage cell lines to p17 activates a signaling pathway mediated by Rack-1/Jak-1/STAT-1 and causes a promoter-dependent regulation of STAT-1 target genes. These effects are abrogated by sera obtained from HIV-infected persons vaccinated with a p17 peptide. Ligands for FXR and PPARγ counteract the effects of p17. CONCLUSIONS: The results of this study show that HIV p17 highjacks a Rack-1/Jak-1/STAT-1 pathway in macrophages, and that the activation of this pathway leads to a simultaneous dysregulation of immune and metabolic functions. The binding of STAT-1 to specific responsive elements in the promoter of PPARγ and FXR and MCP-1 shifts macrophages toward a pro-atherogenetic phenotype characterized by high levels of expression of the scavenger receptor CD36. The present work identifies p17 as a novel target in HIV therapy and grounds the development of anti-p17 small molecules or vaccines

Rationale for BepiColombo Studies of Mercury's Surface and Composition

BepiColombo has a larger and in many ways more capable suite of instruments relevant for determination of the topographic, physical, chemical and mineralogical properties of Mercury's surface than the suite carried by NASA's MESSENGER spacecraft. Moreover, BepiColombo's data rate is substantially higher. This equips it to confirm, elaborate upon, and go beyond many of MESSENGER's remarkable achievements. Furthermore, the geometry of BepiColombo's orbital science campaign, beginning in 2026, will enable it to make uniformly resolved observations of both northern and southern hemispheres. This will offer more detailed and complete imaging and topographic mapping, element mapping with better sensitivity and improved spatial resolution, and totally new mineralogical mapping. We discuss MESSENGER data in the context of preparing for BepiColombo, and describe the contributions that we expect BepiColombo to make towards increased knowledge and understanding of Mercury's surface and its composition. Much current work, including analysis of analogue materials, is directed towards better preparing ourselves to understand what BepiColombo might reveal. Some of MESSENGER's more remarkable observations were obtained under unique or extreme conditions. BepiColombo should be able to confirm the validity of these observations and reveal the extent to which they are representative of the planet as a whole. It will also make new observations to clarify geological processes governing and reflecting crustal origin and evolution. We anticipate that the insights gained into Mercury's geological history and its current space weathering environment will enable us to better understand the relationships of surface chemistry, morphologies and structures with the composition of crustal types, including the nature and mobility of volatile species. This will enable estimation of the composition of the mantle from which the crust was derived, and lead to tighter constraints on models for Mercury's origin including the nature and original heliocentric distance of the material from which it formed.Peer reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries