Cystatin D locates in the nucleus at sites of active transcription and modulates gene and protein expression

Cystatin D is an inhibitor of lysosomal and secreted cysteine proteases. Strikingly, cystatin D has been found to inhibit proliferation, migration, and invasion of colon carcinoma cells indicating tumor suppressor activity that is unrelated to protease inhibition. Here, we demonstrate that a proportion of cystatin D locates within the cell nucleus at specific transcriptionally active chromatin sites. Consistently, transcriptomic analysis show that cystatin D alters gene expression, including that of genes encoding transcription factors such as RUNX1, RUNX2, and MEF2C in HCT116 cells. In concordance with transcriptomic data, quantitative proteomic analysis identified 292 proteins differentially expressed in cystatin D-expressing cells involved in cell adhesion, cytoskeleton, and RNA synthesis and processing. Furthermore, using cytokine arrays we found that cystatin D reduces the secretion of several protumor cytokines such as fibroblast growth factor-4, CX3CL1/fractalkine, neurotrophin 4 oncostatin-M, pulmonary and activation-regulated chemokine/CCL18, and transforming growth factor B3. These results support an unanticipated role of cystatin D in the cell nucleus, controlling the transcription of specific genes involved in crucial cellular functions, which may mediate its protective action in colon cancer

Troponin elevation in acute ischemic stroke (TRELAS) - protocol of a prospective observational trial

<p>Abstract</p> <p>Background</p> <p>Levels of the cardiac muscle regulatory protein troponin T (cTnT) are frequently elevated in patients with acute ischemic stroke and elevated cTnT predicts poor outcome and mortality. The pathomechanism of troponin release may relate to co-morbid coronary artery disease and myocardial ischemia or, alternatively, to neurogenic cardiac damage due to autonomic activation after acute ischemic stroke. Therefore, there is uncertainty about how acute ischemic stroke patients with increased cTnT levels should be managed regarding diagnostic and therapeutic workup.</p> <p>Methods/Design</p> <p>The primary objective of the prospective observational trial TRELAS (TRoponin ELevation in Acute ischemic Stroke) is to investigate the frequency and underlying pathomechanism of cTnT elevation in acute ischemic stroke patients in order to give guidance for clinical practice. All consecutive patients with acute ischemic stroke admitted within 72 hours after symptom onset to the Department of Neurology at the Campus Benjamin Franklin of the University Hospital Charité will be screened for cTnT elevations (i.e. >= 0.05 μg/l) on admission and again on the following day. Patients with increased cTnT will undergo coronary angiography within 72 hours. Diagnostic findings of coronary angiograms will be compared with age- and gender-matched patients presenting with Non-ST-Elevation myocardial infarction to the Department of Cardiology. The primary endpoint of the study will be the occurrence of culprit lesions in the coronary angiogram indicating underlying co-morbid obstructive coronary artery disease. Secondary endpoints will be the localization of stroke in the cerebral imaging and left ventriculographic findings of wall motion abnormalities suggestive of stroke-induced global cardiac dysfunction.</p> <p>Discussion</p> <p>TRELAS will prospectively determine the frequency and possible etiology of troponin elevation in a large cohort of ischemic stroke patients. The findings are expected to contribute to clarify pathophysiologic concepts of co-morbid cardiac damage in ischemic stroke patients and also to provide a basis for clinical recommendations for cardiac workup of such patients.</p> <p>Trial registration</p> <p>clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01263964">NCT01263964</a></p

Intravenous Thrombolysis 4.5–9 Hours After Stroke Onset: A Cohort Study from the TRISP Collaboration

ObjectiveTo investigate the safety and effectiveness of intravenous thrombolysis (IVT) >4.5–9 hours after stroke onset, and the relevance of advanced neuroimaging for patient selection.MethodsProspective multicenter cohort study from the ThRombolysis in Ischemic Stroke Patients (TRISP) collaboration. Outcomes were symptomatic intracranial hemorrhage, poor 3‐month functional outcome (modified Rankin scale 3–6) and mortality. We compared: (i) IVT >4.5–9 hours versus 0–4.5 hours after stroke onset and (ii) within the >4.5–9 hours group baseline advanced neuroimaging (computed tomography perfusion, magnetic resonance perfusion or magnetic resonance diffusion‐weighted imaging fluid‐attenuated inversion recovery) versus non‐advanced neuroimaging.ResultsOf 15,827 patients, 663 (4.2%) received IVT >4.5–9 hours and 15,164 (95.8%) within 4.5 hours after stroke onset. The main baseline characteristics were evenly distributed between both groups. Time of stroke onset was known in 74.9% of patients treated between >4.5 and 9 hours. Using propensity score weighted binary logistic regression analysis (onset‐to‐treatment time >4.5–9 hours vs onset‐to‐treatment time 0–4.5 hours), the probability of symptomatic intracranial hemorrhage (OR$_{adjusted}$ 0.80, 95% CI 0.53–1.17), poor functional outcome (OR$_{adjusted}$ 1.01, 95% CI 0.83–1.22), and mortality (OR$_{adjusted}$ 0.80, 95% CI 0.61–1.04) did not differ significantly between both groups. In patients treated between >4.5 and 9 hours, the use of advanced neuroimaging was associated with a 50% lower mortality compared with non‐advanced imaging only (9.9% vs 19.7%; OR$_{adjusted}$ 0.51, 95% CI 0.33–0.79).InterpretationThis study showed no evidence in difference of symptomatic intracranial hemorrhage, poor outcome, and mortality in selected stroke patients treated with IVT between >4.5 and 9 hours after stroke onset compared with those treated within 4.5 hours. Advanced neuroimaging for patient selection was associated with lower mortality. ANN NEUROL 2023;94:309–32

Clinical Relevance of Cardiac Troponin Assessment in Patients Undergoing Carotid Endarterectomy

Objective: Myocardial infarction (MI) is a frequent complication of carotid endarterectomy (CEA), yet most events are silent. Routine post-operative monitoring of cardiac troponin was implemented to facilitate timely recognition of MI and stratify high risk patients. The aim was to evaluate the incidence of troponin elevation after CEA and its association with adverse cardiovascular events. Methods: This analysis included patients ≥60 years old who underwent CEA, whose troponin-I levels were routinely monitored post-operatively and were included in a cohort study that assessed clinical outcomes. A clinical troponin cutoff of 60 ng/L was used. The primary endpoint was the composite of MI, stroke, and cardiovascular death. Secondary endpoints were MI, stroke, coronary intervention, cardiovascular death, and all cause death. Results: 225 consecutive patients were included in the analysis. Troponin elevation occurred in 34 patients (15%) and a post-operative MI was diagnosed in eight patients. After a median follow up of 1.8 years (IQR 1.0-2.6), the primary endpoint occurred in 29% of patients with troponin elevation versus 6.3% without (HR 5.6, 95% CI 2.4-13), MI in 24% versus 1.6% (HR 18.0, 95% CI 4.7-68), stroke in 5.9% versus 4.2% (HR 1.4, 95% CI 0.3-6.7), coronary intervention in 5.9% versus 2.6% (HR 2.7, 95% CI 0.5-14), cardiovascular death in 5.9% versus 0.5% (HR 11.8, 95% CI 1.1-131), and all cause death in 15% versus 5.8% (HR 3.0, 95% CI 1.0-8.7), respectively. Incidences of the primary endpoint and all cause mortality in patients with a post-operative MI versus "troponin only" were 25% versus 7.7% and 25% versus 12%, respectively. Conclusion: Troponin elevation after CEA occurred in 15% of patients. The incidence of adverse cardiovascular events was significantly higher in patients with troponin elevation, which was mainly attributable to silent non-ST segment elevation MIs that occurred in the early post-operative phase