Alexander Herner

Glutamate has been implicated in tumorigenesis through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR). However, the function of a glutamate-to-AMPAR signal in pancreatic ductal adenocarcinoma (PDAC) has remained elusive. We now show that glutamate-mediated AMPA receptor activation increases invasion and migration of pancreatic cancer cells via activation of the classical MAPK pathway. Glutamate levels were increased in pancreatic cancer accompanied by downregulation of GluR subunits 1, 2, and 4. In pancreatic cancer precursor lesions, pancreatic intraepithelial neoplasia (PanIN), GluR1 subunit levels were strikingly and step-wise increased but its expression was rare in PDAC. Pharmacological inhibition or RNAi-mediated suppression of GluR1 or GluR2 did not affect cancer cell growth but significantly decreased invasion. In a K-ras wildtype cell line, AMPA receptor activation enhanced K-ras activity and--further downstream--phosphorylation of p38 and of p44/42. Preemptive blockade of AMPA receptors in a mouse model of pancreatic cancer inhibited tumor cell settling. AMPA receptor activation thus not only activates MAPK signalling but also directly increases activity of K-ras. Glutamate might serve as a molecular switch that decreases the threshold of K-ras-induced oncogenic signalling and increases the chance of malignant transformation of pancreatic cancer precursor lesions.

BACKGROUND: Superinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of critically ill patients with severe viral pneumonia. Aim of this study was to evaluate the incidence, risk factors and outcome of IPA in critically ill patients with severe COVID-19 pneumonia. METHODS: We prospectively screened 32 critically ill patients with severe COVID-19 pneumonia for a time period of 28 days using a standardized study protocol for oberservation of developement of COVID-19 associated invasive pulmonary aspergillosis (CAPA). We collected laboratory, microbiological, virological and clinical parameters at defined timepoints in combination with galactomannan-antigen-detection from nondirected bronchial lavage (NBL). We used logistic regression analyses to assess if COVID-19 was independently associated with IPA and compared it with matched controls. FINDINGS: CAPA was diagnosed at a median of 4 days after ICU admission in 11/32 (34%) of critically ill patients with severe COVID-19 pneumonia as compared to 8% in the control cohort. In the COVID-19 cohort, mean age, APACHE II score and ICU mortality were higher in patients with CAPA than in patients without CAPA (36% versus 9.5%; p<0.001). ICU stay (21 versus 17 days; p = 0.340) and days of mechanical ventilation (20 versus 15 days; p = 0.570) were not different between both groups. In regression analysis COVID-19 and APACHE II score were independently associated with IPA. INTERPRETATION: CAPA is highly prevalent and associated with a high mortality rate. COVID-19 is independently associated with invasive pulmonary aspergillosis. A standardized screening and diagnostic approach as presented in our study can help to identify affected patients at an early stage.

INTRODUCTION: Visualization of B-lines via lung ultrasound provides a non-invasive estimation of pulmonary hydration. Extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) assessed by transpulmonary thermodilution (TPTD) represent the most validated parameters of lung water and alveolocapillary permeability, but measurement is invasive and expensive. This study aimed to compare the correlations of B-lines scores from extensive 28-sector and simplified 4-sector chest scan with EVLWI and PVPI derived from TPTD in the setting of intensive care unit (primary endpoint). METHODS: We performed scoring of 28-sector and 4-sector B-Lines in 50 critically ill patients. TPTD was carried out with the PiCCO-2-device (Pulsion Medical Systems SE, Maquet Getinge Group). Median time exposure for ultrasound procedure was 12 minutes for 28-sector and 4 minutes for 4-sector scan. RESULTS: = 0.742). Both B-lines scores showed high accuracy to identify patients with specific levels of EVLWI and PVPI. The extensive 28-sector B-lines score revealed a moderate advantage compared to simplified 4-sector scan in detecting a normal EVLWI ≤ 7 (28-sector scan: sensitivity = 81.8%, specificity = 94.9%, AUC = 0.939 versus 4-sector scan: sensitivity = 81.8%, specificity = 82.1%, AUC = 0.902). Both protocols were approximately equivalent in prediction of lung edema with EVLWI ≥ 10 (28-sector scan: sensitivity = 88.9%, specificity = 95.7%, AUC = 0.977 versus 4-sector scan: sensitivity = 81.5%, specificity = 91.3%, AUC = 0.958) or severe pulmonary edema with EVLWI ≥ 15 (28-sector scan: sensitivity = 91.7%, specificity = 97.4%, AUC = 0.995 versus 4-sector scan: sensitivity = 91.7%, specificity = 92.1%, AUC = 0.978). As secondary endpoints, our evaluations resulted in significant associations of 28-sector as well as simplified 4-sector B-Lines score with parameters of respiratory function. CONCLUSION: Both B-line protocols provide accurate non-invasive evaluation of lung water in critically ill patients. The 28-sector scan offers a marginal advantage in prediction of pulmonary edema, but needs substantially more time than 4-sector scan.