Severe arterial thromboembolism in patients with Covid-19.

INTRODUCTION: The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has emerged early December 2019 and was recently confirmed by the World Health Organization (WHO) to be a public health emergency of international concern. Earlier reports have shown coagulopathy in patients with severe coronavirus disease 2019 (Covid-19). MAIN SYMPTOMS AND IMPORTANT CLINICAL FINDINGS: We present four critically ill Covid-19 patients, who were admitted to our hospital. They were treated with supportive care, oral chloroquine, and standard 2500 or 5000 International Units (IU) of dalteparine subcutaneously once daily. Two patients died during the course of their stay as a consequence of severe large vessel arterial thromboembolism. The other two patients survived but symptoms of paralysis and aphasia persisted after cerebral ischemia due to large vessel arterial thromboembolism. Patients showed no signs of overt disseminated intravascular coagulation (DIC) in their laboratory analysis. CONCLUSION: This case series suggest that even in absence of overt DIC, arterial thromboembolic complications occur in critically ill patients with Covid-19. Further studies are needed to determine which parameters are useful in monitoring coagulopathy and which dose of anti-thrombotic therapy in Covid-19 patients is adequate, even when overt DIC is not present.

High steady-state levels of p53 are not a prerequisite for tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.

CTLs specific to p53 were previously shown to efficiently eradicate p53-overexpressing tumor cells in vitro as well as in vivo. In this report, we demonstrate that these CTLs can also eliminate tumors that display moderate or even low levels of p53. Neither high steady-state levels of p53 nor elevated p53 synthesis is a prerequisite for recognition of tumors by p53-specific CTLs. Instead, our data show that a high p53 turnover rate is an important factor in determining the sensitivity of tumor cells to p53-specific CTLs. Our data suggest that p53 turnover is related to the MHC class I-restricted presentation of p53-derived epitopes at the tumor cell surface and indicate that CTL-mediated immunotherapy that targets p53 can be applied to a wider range of tumors than has thus far been anticipated.

Cross-priming of CTL responses in vivo does not require antigenic peptides in the endoplasmic reticulum of immunizing cells.

It has been proposed that the cross-priming of CTL responses in vivo involves the transfer to host APCs of heat shock protein glycoprotein 96-chaperoned antigenic peptides released from the endoplasmic reticulum (ER) of dying or infected cells. We have tested this possibility directly using TAP-deficient cell lines lacking antigenic ER peptides derived from two model Ags, the human adenovirus type 5 early regions E1A and E1B. Although both proteins were well expressed, the cells were not recognized by E1A- or E1B-specific CTLs unless the relevant epitope was either provided exogenously as a synthetic peptide or targeted to the ER in a TAP-independent fashion. Despite the absence of these ER peptides, the TAP1-/- cells were able to efficiently cross-prime E1A- and E1B-specific CTLs following immunization of syngeneic mice. These results indicate that, although purified peptide/glycoprotein 96 complexes are potent immunogens, the mechanism of CTL cross-priming in vivo does not depend upon antigenic peptides in the ER of immunizing cells.