👤 Heike Lüders

Lipoprotein(a) [Lp(a)] is a known independent risk factor for cardiovascular disease, yet awareness and management remain limited. The psychosocial implications of elevated Lp(a)-levels have been poorly characterized. To compare cardiovascular outcomes and cardiovascular risk factor (CVRF) modification in individuals with normal vs. elevated Lp(a) levels, and to assess the impact of individualized prevention recommendations. For the first time, the individual psychological stress caused by Lp(a) is being surveyed. The ELITE study is a prospective, interventional cohort study conducted in north-western Germany. Participants were regularly assessed for CVRFs, including Lp(a), hypertension, dyslipidemia, diabetes mellitus, weight, nicotine - as well as lipoprotein (a), physical activity, dietary habits, depression and stress. They received written, personalized prevention recommendations. Follow-up averaged 4.4 years. Two groups were analyzed: Group 1 (Gr1, n=3,241) with normal Lp(a), and Group 2 (Gr2, n=841) with elevated Lp(a ≥75 nmol/l). Gr2 (mean Lp(a) 154.8 nmol/l) and Gr1 (mean Lp(a) 16.4 nmol/l) were comparable in age (~53 years) and sex distribution (~49% female). Most participants with elevated Lp(a) were previously unaware of their levels; 30% were referred to specialists, and ~40% reported concern or anxiety. Combined cardiovascular endpoints (CHD, stroke, heart failure, PAD, carotid stenosis, AF) occurred significantly more often in Gr2 (p<0.001), despite similar CVRF profiles, except for higher baseline LDL-C in Gr2 (p<0.001). Hypertension (61%) and physical inactivity (57%) were the most prevalent CVRFs. Personalized prevention measures led to significant improvements in blood pressure, LDL-C, smoking, physical activity, and weight in both groups. Lipid-lowering therapy improved markedly in Gr2 (12% to 23%). Elevated Lp(a) is associated with a significantly higher rate of cardiovascular events, independent of traditional CVRFs. This confirms a causal role of Lp(a) in CV morbidity. Personalized written prevention recommendations improved CVRFs across both groups, though further optimization is needed. Notably, elevated Lp(a) also imposes a psychosocial burden, underlining the need for enhanced education, counseling, and clinical pathways. Show less

Checkpoint-inhibitor pneumonitis (CIP) represents a major immune-related adverse event (irAE) in patients with lung cancer. We aimed for the clinical characterization, diagnostics, risk factors, treatment and outcome in a large cohort of patients from everyday clinical practice. For this retrospective analysis, 1,376 patients having received checkpoint inhibitors (CPI) in any line of therapy from June 2015 until February 2020 from three large-volume lung cancer centers in Berlin, Germany were included and analyzed. With a median follow-up of 35 months, all-grade, high-grade (CTCAE ≥ 3) and fatal CIP were observed in 83 (6.0%), 37 (2.7%) and 12 (0.9%) patients, respectively, with a median onset 4 months after initiation of CPI therapy. The most common radiologic patterns were organizing pneumonia (OP) and non-specific interstitial pneumonia (NSIP) (37% and 31%). All except 7 patients with G1-2 CIP interrupted treatment. Corticosteroids were administered to 74 patients with a median starting dose of 0.75 mg/kg. After complete restitution (n = 67), re-exposure to CPI (n = 14) led to additional irAE in 43% of the cases. Thoracic radiotherapy targeting the lung was the only independent risk factor for CIP (odds ratio 2.8, p < 0.001) and pretherapeutic diffusing capacity for carbon monoxide inversely correlated with CIP severity. Compared with patients without CIP and non-CIP irAE, CIP was associated with impaired overall survival (hazard ratios 1.23, p = 0.24 and 2.01, p = 0.005). High-grade CIP accounts for almost half of all CIP cases in an allcomer lung cancer population. A continuous vigilance, rapid diagnostics and adequate treatment are key to prevent disease progression associated with impaired survival. Show less

Centriole biogenesis and maintenance are crucial for cells to generate cilia and assemble centrosomes that function as microtubule organizing centers (MTOCs). Centriole biogenesis and MTOC function both require the microtubule nucleator γ-tubulin ring complex (γTuRC). It is widely accepted that γTuRC nucleates microtubules from the pericentriolar material that is associated with the proximal part of centrioles. However, γTuRC also localizes more distally and in the centriole lumen, but the significance of these findings is unclear. Here we identify spatially and functionally distinct subpopulations of centrosomal γTuRC. Luminal localization is mediated by augmin, which is linked to the centriole inner scaffold through POC5. Disruption of luminal localization impairs centriole integrity and interferes with cilium assembly. Defective ciliogenesis is also observed in γTuRC mutant fibroblasts from a patient suffering from microcephaly with chorioretinopathy. These results identify a non-canonical role of augmin-γTuRC in the centriole lumen that is linked to human disease. Show less

Centrosomes organize microtubule (MT) arrays and are comprised of centrioles surrounded by ordered pericentriolar proteins. Centrioles are barrel-shaped structures composed of MTs, and as basal bodies they template the formation of cilia/flagella. Defects in centriole assembly can lead to ciliopathies and genome instability. The assembly of procentrioles requires a set of conserved proteins. It is initiated at the G1-to-S transition by PLK4 and CEP152, which help recruit SASS6 and STIL to the vicinity of the mother centriole to organize the cartwheel. Subsequently, CPAP promotes centriolar MT assembly and elongation in G2. While centriole integrity is maintained by CEP135 and POC1 through MT stabilization, centriole elongation requires POC5 and is restricted by CP110 and CEP97. How strict control of centriole length is achieved remains unclear. Here, we show that CEP120 and SPICE1 are required to localize CEP135 (but not SASS6, STIL, or CPAP) to procentrioles. CEP120 associates with SPICE1 and CPAP, and depletion of any of these proteins results in short procentrioles. Furthermore, CEP120 or CPAP overexpression results in excessive centriole elongation, a process dependent on CEP120, SPICE1, and CPAP. Our findings identify a shared function for these proteins in centriole length control. Show less