Platelet glycoprotein VI (GPVI) for early identification of acute coronary syndrome in patients with chest pain.

BACKGROUND: Platelet glycoprotein VI (GPVI) is elevated in patients with acute coronary syndrome (ACS), stroke and associated with acute coronary events. GPVI may be helpful to distinguish an imminent ACS from non-coronary (NC) causes in patients with chest pain who were transferred to chest pain unit, before the myocardial necrosis is evident with classical biomarkers. METHODS: Based on the findings of our previous studies, we consecutively examined 1004 patients with chest pain in a prospective study design. ACS was found in 416 (41.4%), stable angina pectoris (SAP) in 233 (23.2%), and NC causes of chest pain (hypertension, musculoskeletal disease, pulmonary embolism, myocarditis, cardiophobia) in 355 patients (35.4%). Platelet surface expression of GPVI was measured by flow cytometry. RESULTS: Patients with ACS showed significantly enhanced GPVI expression levels compared to patients with SAP or NC causes of chest pain (ACSvs.SAP(mean fluorescence intensity (MFI)+/-SD):18.9+/-7.4vs.17.9+/-9.5;P=0.028;ACSvs.NC:15.4+/-6.9;P=0.002). Elevated GPVI expression was associated with ACS independent of markers of myocardial necrosis like troponin and creatine kinase-MB. Patients with an elevated GPVI expression (MFI>or=18.6) had a poorer clinical outcome than patients with baseline GPVI expression in regard to composite cumulative survival that included myocardial infarction, stroke, and cardiovascular death at three months (Log rank;P=0.025). DISCUSSION: Platelet GPVI surface expression is enhanced in patients at risk for an ACS and is an early marker for imminent acute coronary events in patients with chest pain

Life-threatening pneumonitis after first-line treatment with osimertinib for primary T790M mutated non-small cell lung cancer

Epithelial growth factor receptor (EGFR) directed tyrosine kinase inhibitor (TKI) treatment is the standard approach in patients with advanced, EGFR-mutated non-small cell lung cancer (NSCLC). Although benefit/risk ratio is favorable for these TKI and side effects are manageable in the vast majority of patients, severe and even life-threatening side effects have been reported. TKI-induced interstitial lung disease (ILD) has been reported for single cases in modest severity, predominantly in EGFR-TKI pretreated patients. Here, we report a case of successful stabilization of a life-threatening ILD in a de novo T790M mutated NSCLC during first-line treatment with osimertinib. As osimertinib will be used more often in many EGFR-positive NSCLC patients in the future, this potentially life-threatening side effect should receive special attention, especially in first-line treatmen

Evidence against a direct role of klotho in insulin resistance.

The klotho gene may be involved in the aging process. Klotho is a coactivator of FGF23, a regulator of phosphate and vitamin D metabolism. It has also been reported to be downregulated in insulin resistance syndromes and paradoxically to directly inhibit IGF-1 and insulin signaling. Our aim was to study klotho's regulation and effects on insulin and IGF-1 signaling to unravel this paradox. We studied klotho tissue distribution and expression by quantitative real-time polymerase chain reaction and Western blotting in obese Zucker rats and high-fat fed Wistar rats, two models of insulin resistance. Klotho was expressed in kidneys but at much lower levels (<1.5%) in liver, muscle, brain, and adipose tissue. There were no significant differences between insulin resistant and control animals. We next produced human recombinant soluble klotho protein (KLEC) and studied its effects on insulin and IGF-1 signaling in cultured cells. In HEK293 cells, FGF23 signaling (judged by FRS2-alpha and ERK1/2 phosphorylation) was activated by conditioned media from KLEC-producing cells (CM-KLEC); however, IGF-1 signaling was unaffected. CM-KLEC did not inhibit IGF-1 and insulin signaling in L6 and Hep G2 cells, as judged by Akt and ERK1/2 phosphorylation. We conclude that decreased klotho expression is not a general feature of rodent models of insulin resistance. Further, the soluble klotho protein does not inhibit IGF-1 and/or insulin signaling in HEK293, L6, and HepG2 cells, arguing against a direct role of klotho in insulin signaling. However, the hypothesis that klotho indirectly regulates insulin sensitivity via FGF23 activation remains to be investigated

On two problems related to cancellativity

SIGLETIB: RN 7281 (138) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases

Resin bead micro-UV - visible absorption spectroscopy

The construction and design of a microscope coupled with a miniature UV-vis spectrometer is described. This was applied to the study of dyes linked to solid supports and displayed good correlation in spectral shape and λmax values when compared to the dyes in solution, as well as showing a linear relationship between dye loading and UV-vis absorbance. The spectral profiles of these dyes at various pH's were measured and used to determine the pK(a) of the dyes on the beads, which were compared with the pK(a) values of the dyes in solution, thus enabling the dye-loaded beads to act as pH sensors