Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at ...least 2 major subtypes (germinal center B cell GCB-like and activated B cell ABC-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2–specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.
•As a result of low glutathione and glutathione peroxidase 4 levels and high 5-lipoxygenase expression, DMF induces ferroptosis in GCB DLBCL.•In ABC DLBCL, DMF induces succination of kinases IKK2 and JAK1, thus inhibiting NF-κB and JAK/STAT survival signaling.
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Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials ...are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects.
We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis.
This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease.
ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Heart failure was identified in 2% of patients with type 1 diabetes.•Heart failure was identified in 16% of patients with type 2 diabetes.•Of the identified cases of heart failure, ...60% were previously undiagnosed.•Of the newly identified cases, 61 % had undergone echocardiography within 2 years.•There is a need to raise awareness of heart failure among healthcare professionals.
To evaluate the prevalence of heart failure (HF) in patients with diabetes in tertiary care, and the implementation of sodium-glucose co-transporter 2 inhibitor (SGLT2i).
Between 28.09.2020 and 31.03.2022, patients enrolled in the Swiss Diabetes Registry at one study centre were screened for HF based on the recommendations by the European Society of Cardiology. Indicated patients were referred for echocardiography and a clinical evaluation of HF, further stratified by preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) left ventricular ejection fraction.
In total, 534 patients were screened (31.5%, type 1 diabetes (T1D); 59.7%, type 2 diabetes (T2D); 8.8%, other forms). Overall, HF was present in 11.2% (HFpEF, 56.7%; HFmrEF, 11.7%; HFrEF, 31.7%). Prevalence by diabetes type was 2.4%, T1D; 16.0%, T2D; and 10.6%, other forms. Of the identified cases, 40.0% were previously diagnosed and 60.0% were diagnosed as a result of the screening. Of the 24 patients with previously known HF, 50.0% were prescribed SGLT2i (including 2 out of 3 patients with HFrEF).
The fact that most cases of HF were previously undiagnosed and treatment with SGLT2i could be improved highlights the need to increase awareness of HF among healthcare professionals treating patients with diabetes.
Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials ...are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after greater than or equal to28 treatment days with greater than or equal to420 mg cumulative and greater than or equal to7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after greater than or equal to28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Les estimateurs du RDS Le but de la présente annexe est d’expliciter les formules utilisées pour les estimations présentées dans notre article. Aussi, il ne s’agit pas ici de présenter la totalité ...des outils statistiques qui ont été proposés dans le sillage des travaux sur le RDS, mais d’aider le lecteur à comprendre, à partir d’une analyse relativement détaillée des trois techniques les plus utilisées dans les travaux disponibles pour produire des estimations (les « estimateurs » RDS I, RDS ...
L’échantillonnage de populations dont il est impossible de connaître a priori les contours avec précision constitue un défit majeur en sciences sociales. Certaines solutions ont néanmoins été ...proposées pour tenter de produire des données fiables dans ce type de cas. Parmi les procédures d’échantillonnage alternatives, c’est indubitablement la méthode du Respondant Driven Sampling (RDS) – « échantillonnage guidé par les répondants » –, apparue à la fin des années 1990 qui a connu la plus forte audience. L’ambition de cet article sera de présenter les points forts et les faiblesses de cette procédure, à travers un retour sur expérience dans le cadre d’une recherche sur des « musicien‑ne‑s ordinaires » suisses romand‑e‑s. Il s’agira premièrement de présenter l’outillage théorique, méthodologique et statistique qui structure cette procédure d’échantillonnage. Dans un deuxième temps, on montrera comment le RDS permet de construire des données originales et de qualité par rapport à d’autres procédures plus souvent utilisées – notamment l’enquête « en ligne » – pour des recherches sur des populations « rares ». Enfin, on reviendra sur les limites de l’échantillon recruté, du point de vue de la structuration du réseau complet des collaborations musicales sur une année de référence.
L'échantillonnage de populations dont il est impossible de connaître a priori les contours avec précision constitue un défit majeur en sciences sociales. Certaines solutions ont néanmoins été ...proposées pour tenter de produire des données fiables dans ce type de cas. Parmi les procédures d'échantillonnage alternatives, c'est indubitablement la méthode du Respondant Driven Sampling (RDS) - « échantillonnage guidé par les répondants » -, apparue à la fin des années 1990 qui a connu la plus forte audience. L'ambition de cet article sera de présenter les points forts et les faiblesses de cette procédure, à travers un retour sur expérience dans le cadre d'une recherche sur des « musicien-ne-s ordinaires » suisses romand-e-s. Il s'agira premièrement de présenter l'outillage théorique, méthodologique et statistique qui structure cette procédure d'échantillonnage. Dans un deuxième temps, on montrera comment le RDS permet de construire des données originales et de qualité par rapport à d'autres procédures plus souvent utilisées - notamment l'enquête « en ligne » - pour des recherches sur des populations « rares ». Enfin, on reviendra sur les limites de l'échantillon recruté, du point de vue de la structuration du réseau complet des collaborations musicales sur une année de référence.
In this paper, we propose a collision avoidance safety filter for autonomous electric scooters to enable safe operation of such vehicles in pedestrian areas. In particular, we employ multiple ...low-cost ultrasonic sensors to detect a wide range of possible obstacles in front of the e-scooter. Based on possibly faulty distance measurements, we design a filter to mitigate measurement noise and missing values as well as a gain-scheduled controller to limit the velocity commanded to the e-scooter when required due to imminent collisions. The proposed controller structure is able to prevent collisions with unknown obstacles by deploying a reduced safe velocity ensuring a suficiently large safety distance. The collision avoidance approach is designed such that it may be easily deployed in similar applications of general micromobility vehicles. The effectiveness of our proposed safety filter is demonstrated in real-world experiments.
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