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The KASCADE-Grande experiment has significantly contributed to the current knowledge about the energy spectrum and composition of cosmic rays for energies between the knee and the ankle. Meanwhile, post-LHC versions of the hadronic interaction models are available and used to interpret the entire data set of KASCADE-Grande. In addition, a new, combined analysis of both arrays, KASCADE and Grande, was developed significantly increasing the accuracy of the shower observables. First results of the new analysis with the entire data set of the KASCADE-Grande experiment will be the focus of this contribution.
Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor
(2019)
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
Background: Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce.
Methods: In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire—Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials.
Results: Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n = 152; sulfasalazine n = 123; azathioprine n = 59; and leflunomide n = 397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were –0.54 vs –0.44 (ATTAIN), –0.43 vs –0.43 (ASSURE), and –0.39 vs –0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE).
Conclusions: Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX.
The purpose of this study was to investigate whether a six-week, twice weekly resistance training (4 sets at 30% 1-RM until failure) with practical blood flow restriction (BFR) using 7cm wide cuffs with a twist lock placed below the patella is superior to training without BFR (NoBFR) concerning muscle mass and strength gains in calf muscles.
A two-group (BFR n = 12, mean age 27.33 (7.0) years, training experience 7.3 (7.0) years; NoBFR n = 9, mean age 28.9 (7.4) years, training experience 7.1 (6.6) years) randomized matched pair design based on initial 1-RM was used to assess the effects on structural and functional adaptations in healthy males (Perometer calf volume [CV], gastrocnemius muscle thickness using ultrasound [MT], 7-maximal hopping test for leg stiffness [LS], 1-RM smith machine calf raise [1-RM], and visual analogue scale as a measure of pain intensity [VAS]).
The mean number of repetitions completed per training session across the intervention period was higher in the NoBFR group compared to the BFR group (70 (16) vs. 52 (9), p = 0.002). VAS measured during the first session increased similarly in both groups from first to fourth set (p<0.001). No group effects or time×group interactions were found for CV, MT, LS, and 1-RM. However, there were significant time effects for MT (BFR +0.07 cm; NoBFR +0.04; p = 0.008), and 1-RM (BFR +40 kg; NoBFR +34 kg; p<0.001).
LS and CV remained unchanged through training. VAS in both groups were similar, and BFR and NoBFR were equally effective for increasing 1-RM and MT in trained males. However, BFR was more time efficient, due to lesser repetition per training session.
The National Institutes of Health Stroke Scale (NIHSS) score is the most frequently used score worldwide for assessing the clinical severity of a stroke. Prior research suggested an association between acute symptomatic seizures after stroke and poorer outcome. We determined the frequency of acute seizures after ischemic stroke in a large population-based registry in a central European region between 2004 and 2016 and identified risk factors for acute seizures in univariate and multivariate analyses. Additionally, we determined the influence of seizures on morbidity and mortality in a matched case–control design. Our analysis of 135,117 cases demonstrated a seizure frequency of 1.3%. Seizure risk was 0.6% with an NIHSS score at admission <3 points and increased up to 7.0% with >31 score points. Seizure risk was significantly higher in the presence of acute non-neurological infections (odds ratio: 3.4; 95% confidence interval: 2.8–4.1). A lower premorbid functional level also significantly increased seizure risk (OR: 1.7; 95%CI: 1.4–2.0). Mortality in patients with acute symptomatic seizures was almost doubled when compared to controls matched for age, gender, and stroke severity. Acute symptomatic seizures increase morbidity and mortality in ischemic stroke. Their odds increase with a higher NIHSS score at admission.