Molecular alterations and potential actionable mutations in peritoneal mesothelioma:a scoping review of high-throughput sequencing studies

Background: Peritoneal mesothelioma (PeM) is a rare malignancy with a poor prognosis. Currently there is a lack of effective systemic therapies. Due to the rarity of PeM, it is challenging to study new treatment options. Off-label use of targeted drugs could be an effective approach. This scoping review aims to explore the genomic landscape of PeM to identify potential therapeutic targets. Materials and methods: A systematic literature search of Embase, Medline, Web of Science, the Cochrane Library, and Google Scholar was carried out up to 1 November 2022. Studies that reported on molecular alterations in PeM detected by high-throughput sequencing techniques were included. Genes that were altered in ≥1% of PeMs were selected for the identification of potential targeted therapies. Results: Thirteen articles were included, comprising 824 PeM patients. In total, 142 genes were altered in ≥1% of patients, of which 7 genes were altered in ≥10%. BAP1 was the most commonly altered gene (50%). Other commonly altered genes were NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%), and SETD2 (13%). In total, 17% of PeM patients were carriers of a germline mutation, mainly in BAP1 (7%). Conclusions: This scoping review provides an overview of the mutational landscape of PeM. Germline mutations might be a larger contributor to the incidence of PeM than previously thought. Currently available targeted therapy options are limited, but several targeted agents [such as poly (ADP-ribose) polymerase (PARP), enhancer of zeste homolog 2 (EZH2), and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors] were identified that might provide new targeted therapy options in the future.</p

Different bottom trawl fisheries have a differential impact on the status of the North Sea seafloor habitats

Fisheries using bottom trawls are the most widespread source of anthropogenic physical disturbance to seafloor habitats. To mitigate such disturbances, the development of fisheries-, conservation-, and ecosystem-based management strategies requires the assessment of the impact of bottom trawling on the state of benthic biota. We explore a quantitative and mechanistic framework to assess trawling impact. Pressure and impact indicators that provide a continuous pressure–response curve are estimated at a spatial resolution of 1 χ 1 min latitude and longitude (~2 km2) using three methods: L1 estimates the proportion of the community with a life span exceeding the time interval between trawling events; L2 estimates the decrease in median longevity in response to trawling; and population dynamic (PD) estimates the decrease in biomass in response to trawling and the recovery time. Although impact scores are correlated, PD has the best performance over a broad range of trawling intensities. Using the framework in a trawling impact assessment of ten métiers in the North Sea shows that muddy habitats are impacted the most and coarse habitats are impacted the least. Otter trawling for crustaceans has the highest impact, followed by otter trawling for demersal fish and beam trawling for flatfish and flyshooting. Beam trawling for brown shrimps, otter trawling for industrial fish, and dredging for molluscs have the lowest impact. Trawling is highly aggregated in core fishing grounds where the status of the seafloor is low but the catch per unit of effort (CPUE) per unit of impact is high, in contrast to peripheral grounds, where CPUE per unit of impact is low.</p

Weakly-Coupled Higgs Bosons and Precision Electroweak Physics

We examine the prospects for discovering and elucidating the weakly-coupled Higgs sector at future collider experiments. The Higgs search consists of three phases: (i) discovery of a Higgs candidate, (ii) verification of the Higgs interpretation of the signal, and (iii) precision measurements of Higgs sector properties. The discovery of one Higgs boson with Standard Model properties is not sufficient to expose the underlying structure of the electroweak symmetry breaking dynamics. It is critical to search for evidence for a non-minimal Higgs sector and/or new physics associated with electroweak symmetry breaking dynamics. An improvement in precision electroweak data at future colliders can play a useful role in confirming the theoretical interpretation of the Higgs search results

Averages of b-hadron Properties at the End of 2005

This article reports world averages for measurements on b-hadron properties obtained by the Heavy Flavor Averaging Group (HFAG) using the available results as of at the end of 2005. In the averaging, the input parameters used in the various analyses are adjusted (rescaled) to common values, and all known correlations are taken into account. The averages include lifetimes, neutral meson mixing parameters, parameters of semileptonic decays, branching fractions of B meson decays to final states with open charm, charmonium and no charm, and measurements related to CP asymmetries

Cosmic ray tests of the D0 preshower detector

The D0 preshower detector consists of scintillator strips with embedded wavelength-shifting fibers, and a readout using Visible Light Photon Counters. The response to minimum ionizing particles has been tested with cosmic ray muons. We report results on the gain calibration and light-yield distributions. The spatial resolution is investigated taking into account the light sharing between strips, the effects of multiple scattering and various systematic uncertainties. The detection efficiency and noise contamination are also investigated.Comment: 27 pages, 24 figures, submitted to NIM

Insights Into Enhanced Complement Activation by Structures of Properdin and Its Complex With the C-Terminal Domain of C3b

Properdin enhances complement-mediated opsonization of targeted cells and particles for immune clearance. Properdin occurs as dimers, trimers and tetramers in human plasma, which recognize C3b-deposited surfaces, promote formation, and prolong the lifetime of C3bBb-enzyme complexes that convert C3 into C3b, thereby enhancing the complement-amplification loop. Here, we report crystal structures of monomerized properdin, which was produced by co-expression of separate N- and C-terminal constructs that yielded monomer-sized properdin complexes that stabilized C3bBb. Consistent with previous low-resolution X-ray and EM data, the crystal structures revealed ring-shaped arrangements that are formed by interactions between thrombospondin type-I repeat (TSR) domains 4 and 6 of one protomer interacting with the N-terminal domain (which adopts a short transforming-growth factor B binding protein-like fold) and domain TSR1 of a second protomer, respectively. Next, a structure of monomerized properdin in complex with the C-terminal domain of C3b showed that properdin-domain TSR5 binds along the C-terminal a-helix of C3b, while two loops, one from domain TSR5 and one from TSR6, extend and fold around the C3b C-terminus like stirrups. This suggests a mechanistic model in which these TSR5 and TSR6 "stirrups" bridge interactions between C3b and factor B or its fragment Bb, and thereby enhance formation of C3bB pro-convertases and stabilize C3bBb convertases. In addition, properdin TSR6 would sterically block binding of the protease factor I to C3b, thus limiting C3b proteolytic degradation. The presence of a valine instead of a third tryptophan in the canonical Trp-ladder of TSR domains in TSR4 allows a remarkable ca. 60 degrees-domain bending motion of TSR4. Together with variable positioning of TSR2 and, putatively, TSR3, this explains the conformational flexibility required for properdin to form dimers, trimers, and tetramers. In conclusion, the results indicate that binding avidity of oligomeric properdin is needed to distinguish surface-deposited C3b molecules from soluble C3b or C3 and suggest that properdin-mediated interactions bridging C3b-B and C3b-Bb enhance affinity, thus promoting convertase formation and stabilization. These mechanisms explain the enhancement of complement-mediated opsonization of targeted cells and particle for immune clearance

Complement Is Activated During Normothermic Machine Perfusion of Porcine and Human Discarded Kidneys

Background: The gap between demand and supply of kidneys for transplantation necessitates the use of kidneys from extended criteria donors. Transplantation of these donor kidneys is associated with inferior results, reflected by an increased risk of delayed graft function. Inferior results might be explained by the higher immunogenicity of extended criteria donor kidneys. Normothermic machine perfusion (NMP) could be used as a platform to assess the quality and function of donor kidneys. In addition, it could be useful to evaluate and possibly alter the immunological response of donor kidneys. In this study, we first evaluated whether complement was activated during NMP of porcine and human discarded kidneys. Second, we examined the relationship between complement activation and pro-inflammatory cytokines during NMP. Third, we assessed the effect of complement activation on renal function and injury during NMP of porcine kidneys. Lastly, we examined local complement C3d deposition in human renal biopsies after NMP. Methods: NMP with a blood-based perfusion was performed with both porcine and discarded human kidneys for 4 and 6 h, respectively. Perfusate samples were taken every hour to assess complement activation, pro-inflammatory cytokines and renal function. Biopsies were taken to assess histological injury and complement deposition. Results: Complement activation products C3a, C3d, and soluble C5b-9 (sC5b-9) were found in perfusate samples taken during NMP of both porcine and human kidneys. In addition, complement perfusate levels positively correlated with the cytokine perfusate levels of IL-6, IL-8, and TNF during NMP of porcine kidneys. Porcine kidneys with high sC5b-9 perfusate levels had significantly lower creatinine clearance after 4 h of NMP. In line with these findings, high complement perfusate levels were seen during NMP of human discarded kidneys. In addition, kidneys retrieved from brain-dead donors had significantly higher complement perfusate levels during NMP than kidneys retrieved from donors after circulatory death. Conclusion: Normothermic kidney machine perfusion induces complement activation in porcine and human kidneys, which is associated with the release of pro-inflammatory cytokines and in porcine kidneys with lower creatinine clearance. Complement inhibition during NMP might be a promising strategy to reduce renal graft injury and improve graft function prior to transplantation

Can we distinguish between h^{SM} and h^0 in split supersymmetry?

We investigate the possibility to distinguish between the Standard Model Higgs boson and the lightest Higgs boson in Split Supersymmetry. We point out that the best way to distinguish between these two Higgs bosons is through the decay into two photons. It is shown that there are large differences of several percent between the predictions for \Gamma(h\to\gamma\gamma) in the two models, making possible the discrimination at future photon-photon colliders. Once the charginos are discovered at the next generation of collider experiments, the well defined predictions for the Higgs decay into two photons will become a cross check to identify the light Higgs boson in Split Supersymmetry.Comment: 8 pages, 3 Figures, typos fixed, version published in J.Phys. G31 (2005) 563-56

Averages of b-hadron properties at the end of 2006

This article reports the world averages for measurements on b-hadron properties obtained by the Heavy Flavor Averaging Group (HFAG) using the available results at the end of 2006. In the averaging, the input parameters used in the various analyses are adjusted (rescaled) to common values, and all known correlations are taken into account. The averages include lifetimes, neutral meson mixing parameters, parameters of semileptonic decays, branching fractions of B decays to final states with open charm, charmonium and no charm, and measurements related to CP asymmetries.This article reports the world averages for measurements on b-hadron properties obtained by the Heavy Flavor Averaging Group (HFAG) using the available results at the end of 2006. In the averaging, the input parameters used in the various analyses are adjusted (rescaled) to common values, and all known correlations are taken into account. The averages include lifetimes, neutral meson mixing parameters, parameters of semileptonic decays, branching fractions of B decays to final states with open charm, charmonium and no charm, and measurements related to CP asymmetries