20 research outputs found
The dark Lμ − Lτ rises via kinetic mixing
No full textWe investigate the dark matter phenomenology of a Dirac fermion together with kinetic mixing in the context of an Lμ−Lτ model. We analyze which part of the parameter space can provide a viable dark matter candidate and explain the B-decay anomaly, while obeying current data. Although the allowed region of parameter space, satisfying these requirements, is still large at the moment, future direct detection experiments like XENONnT and DARWIN will, in case of null results, significantly strengthen the limits and push the model to a corner of the parameter space
Arsenic trioxide induces Noxa-dependent apoptosis in rhabdomyosarcoma cells and synergizes with antimicrotubule drugs
No full textThe prognosis of metastatic or relapsed rhabdomyosarcoma (RMS) is poor, highlighting the need of new treatment options. In the present study, we evaluated the in vitro efficacy of arsenic trioxide (ATO) in RMS, a FDA-approved drug used in pediatric leukemia. Here, we report that ATO exerts antitumor activity against RMS cells both as single agent and in combination with microtubule-targeting drugs. Monotherapy with ATO reduces cell viability, triggers apoptosis and suppresses clonogenic survival of RMS cells, at least in part, by transcriptional induction of the proapoptotic BH3-only protein Noxa. siRNA-mediated knockdown of Noxa significantly rescues ATO-mediated cell death, demonstrating that Noxa is required for cell death. Also, ATO suppresses endogenous Hedgehog (Hh) signaling, as it significantly reduces Gli1 transcriptional activity and expression levels of several Hh target genes. Furthermore, we identify synergistic induction of apoptosis by ATO together with several antimicrotubule agents including vincristine (VCR), vinblastine and eribulin. The addition of the broad-range caspase inhibitor zVAD.fmk or overexpression of the antiapoptotic protein Bcl-2 significantly reduce ATO/VCR-induced cell death, indicating that the ATO/VCR combination triggers caspase-dependent apoptosis via the mitochondrial pathway. In summary, ATO exerts antitumor activity against RMS, especially in combination with antimicrotubule drugs. These findings have important implications for the development of novel therapeutic strategies for RMS. (C) 2016 Elsevier Ireland Ltd. All rights reserved
Comparing 2HDM + Scalar and Pseudoscalar Simplified Models at LHC
No full textIn this work we compare the current experimental LHC limits of the 2HDM + scalar and pseudoscalar for the tt, mono-Z and mono-h signatures and forecast the reach of future LHC upgrades for the mono-Z channel. Furthermore, we comment on the possibility, in case of a signal detection, to discriminate between the two models. The 2HDM+S and 2HDM+PS are two notable examples of the so-called next generation of Dark Matter Simplified Models. They allow for a renormalizable coupling of fermionic, Standard Model singlet, Dark Matter with a two Higgs doublet sector, through the mixing of the latter with a scalar or pseudoscalar singlet
Low-scale new physics in dark sectors
No full textIn this thesis we investigate two particular examples of phenomena that require introducing new physics beyond the standard model, namely the baryon asymmetry of the universe and dark matter. As the corresponding newly introduced fields or particles have eluded detection so far, they are usually associated with so-called dark sectors. Our focus throughout this work is on low-scale realizations of mechanisms explaining these phenomena, with low scale either referring to a comparison to the standard scenarios of the mechanisms, or the mass scales of the fields or particles involved. One well-established mechanism to explain the baryon asymmetry of the universe is leptogenesis. We study the possibility to realize low-scale leptogenesis in both the scotogenic and the singlet scalar assisted model by employing analytical and semi-analytical methods, with a focus on understanding the important ingredients. Our parameter scans show that we are able to recreate the baryon asymmetry in the universe via leptogenesis for right-handed neutrino masses of as low as ~10TeV in the scotogenic model, while for singlet scalar assisted leptogenesis we can even reach scales below 1TeV. Importantly, both of these results are achieved without a strong degeneracy of right-handed neutrino masses. In our study of dark matter, we first analyze and compare the LHC signatures of two benchmark models given by the two Higgs doublet model with an additional scalar or pseudoscalar. To do so, we study their tt¯, mono-Z and mono-h signatures and derive limits from current experimental searches at the LHC. Furthermore, we also look at the reach of the mono-Z channel for future LHC upgrades and comment on the possibility to distinguish between the two models in case of a signal detection. Finally, we analyze a possibility to explain dark matter without using the standard particle dark matter picture via (pseudo)scalar and vector dark matter from non-minimal curvature couplings. With the misalignment and stochastic scenario, we investigate two different options how the dark matter could be created during the period of inflation. In the misalignment scenario we find that the parameter space substantially opens up due to the non-minimal coupling, whereas in the stochastic scenario any non-minimal coupling is tightly constrained for the mechanism to work while not violating isocurvature constraints. We conclude this thesis with a recapitulation of our main results and an outlook to further research
A fresh look at the gravitational-wave signal from cosmological phase transitions
No full textMany models of physics beyond the Standard Model predict a strong first-order phase transition (SFOPT) in the early Universe that leads to observable gravitational waves (GWs). In this paper, we propose a novel method for presenting and comparing the GW signals that are predicted by different models. Our approach is based on the observation that the GW signal has an approximately model-independent spectral shape. This allows us to represent it solely in terms of a finite number of observables, that is, a set of peak amplitudes and peak frequencies. As an example, we consider the GW signal in the real-scalar-singlet extension of the Standard Model (xSM). We construct the signal region of the xSM in the space of observables and show how it will be probed by future space-borne interferometers. Our analysis results in sensitivity plots that are reminiscent of similar plots that are typically shown for dark-matter direct-detection experiments, but which are novel in the context of GWs from a SFOPT. These plots set the stage for a systematic model comparison, the exploration of underlying model-parameter dependencies, and the construction of distribution functions in the space of observables. In our plots, the experimental sensitivities of future searches for a stochastic GW signal are indicated by peak-integrated sensitivity curves. A detailed discussion of these curves, including fit functions, is contained in a companion paper [1].Many models of physics beyond the Standard Model predict a strong first-order phase transition (SFOPT) in the early Universe that leads to observable gravitational waves (GWs). In this paper, we propose a novel method for presenting and comparing the GW signals that are predicted by different models. Our approach is based on the observation that the GW signal has an approximately model-independent spectral shape. This allows us to represent it solely in terms of a finite number of observables, that is, a set of peak amplitudes and peak frequencies. As an example, we consider the GW signal in the real-scalar-singlet extension of the Standard Model (xSM). We construct the signal region of the xSM in the space of observables and show how it will be probed by future space-borne interferometers. Our analysis results in sensitivity plots that are reminiscent of similar plots that are typically shown for dark-matter direct-detection experiments, but which are novel in the context of GWs from a SFOPT. These plots set the stage for a systematic model comparison, the exploration of underlying model-parameter dependencies, and the construction of distribution functions in the space of observables. In our plots, the experimental sensitivities of future searches for a stochastic GW signal are indicated by peak-integrated sensitivity curves. A detailed discussion of these curves, including fit functions, is contained in a companion paper [2002.04615]. The data and code that we used in our analysis can be downloaded from Zenodo [https://doi.org/10.5281/zenodo.3699415]
E-health as a sine qua non for modern healthcare
No full textIn each era we need to balance between being able to provide care with our “technical skill, scientific knowledge, and human understanding” (Harrison's Principles of Internal Medicine, 1950) to the individual patient and simultaneously ensure that our healthcare serves all. With the increasing demand of healthcare by an aging population and the lack of specialists, accessible healthcare within a reasonable time frame is not always guaranteed. E-health provides solutions for current situations where we do not meet our own aims of good healthcare, such as restrictions in access to care and a reduction in care availability by a reducing workforce. In addition, telemedicine offers opportunities to improve our healthcare beyond what is possible by in person visits. However, e-health is often viewed as an deficient version of healthcare of low quality. We disagree with this view. In this article we will discuss how to position e-health in the current situation of healthcare, given the continuing rapid development of digital technologies and the changing needs of healthcare professionals and patients. We will address the evolution of e-health towards connected and intelligent systems and the stakeholders perspective, aiming to open up the discussion on e-Health
Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group
No full textINTRODUCTION: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. METHOD: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively. RESULTS: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients. CONCLUSIONS: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed
Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer
No full textBackground: Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people.
Methods: This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485.
Results: We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules.
Conclusions: The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study
A new ex vivo human model of osteoarthritis cartilage calcification
No full textInternational audienceObjective Cartilage pathologic calcification is a hallmark of osteoarthritis (OA). Here, we aimed to describe a new ex vivo human model to study the progression of cartilage calcification. Method Cartilage explants (n = 11), as well as primary chondrocytes (n = 3), were obtained from OA patients undergoing knee replacement. Explants and chondrocytes were cultured in control (NT) or calcification (CM) medium (supplemented with ascorbic acid and β-glycerophosphate). Calcification was evaluated by micro-CT scan at day 0 and 21 in explants, and by Alizarin red staining in chondrocyte monolayers. Raman spectrometry allowed characterization of the crystal type. Interleukin-6 (IL-6) secretion in explant and cell supernatants was measured by ELISA. Finally, matrix degradation was evaluated by Safranin-O staining of explant sections and by glycosaminoglycans (GAG) released in supernatants. Results Micro-CT scan showed calcifications in all explants at baseline (day 0), which in the CM group increased significantly in number and size after 21 days compared with the NT group. Raman spectrometry revealed that crystals were exclusively basic calcium phosphate crystals (carbonated hydroxyapatite) both in NT and CM. IL-6 secretion was significantly increased in calcifying conditions. Finally, CM significantly increased cartilage catabolism as assessed by decreased Safranin-O staining of tissue explants and increased GAG release in supernatants. CM effects (enhanced calcification, IL-6 secretion and proteoglycans turn-over) were recapitulated in vitro in OA chondrocytes. Conclusions We have described a new ex vivo human model of cartilage calcification that can summarize the triad of events seen during osteoarthritis progression, i.e. calcification, inflammation and cartilage degradation. This model will allow the identification of new anti-calcification compounds
Aging and osteoarthritis: an inevitable encounter?
No full textOsteoarthritis (OA) is a major health burden of our time. Age is the most prominent risk factor for the development and progression of OA. The mechanistic influence of aging on OA has different facets. On a molecular level, matrix proteins such as collagen or proteoglycans are modified, which alters cartilage function. Collagen cross-linking within the bone results in impaired plasticity and increased stiffness. Synovial or fat tissue, menisci but also ligaments and muscles play an important role in the pathogenesis of OA. In the elderly, sarcopenia or other causes of muscle atrophy are frequently encountered, leading to a decreased stability of the joint. Inflammation in form of cellular infiltration of synovial tissue or subchondral bone and expression of inflammatory cytokines is more and more recognized as trigger of OA. It has been demonstrated that joint movement can exhibit anti-inflammatory mechanisms. Therefore physical activity or physiotherapy in the elderly should be encouraged, also in order to increase the muscle mass. A reduced stem cell capacity in the elderly is likely associated with a decrease of repair mechanisms of the musculoskeletal system. New treatment strategies, for example with mesenchymal stem cells (MSC) are investigated, despite clear evidence for their efficacy is lacking
