Adjuvant hemoadsorption therapy in patients with severe COVID-19 and related organ failure requiring CRRT or ECMO therapy: A case series.

INTRODUCTION: Severe cases of the COVID-19 are often associated with the development of a fulminant sepsis-like state with a concomitant cytokine release syndrome. Recently, immunomodulating approaches to treat such a hyperinflammation have come into focus, including the use of new extracorporeal organ support therapies such as CytoSorb hemoadsorption designed to remove cytokines and other circulating mediators from blood. PATIENTS AND METHODS: Thirteen critically ill COVID-19 patients with ARDS who received either ECMO therapy and/or CRRT with concomitant multiple organ failure were included. Hemoadsorption therapy was initiated once the patient had established-or was at high risk of developing-a hyperinflammatory state with marked hemodynamic instability or progressive lung failure. Levels of inflammatory markers, vasopressor requirements, oxygenation, and ventilation parameters were measured, as well as clinically relevant outcome measures. RESULTS: Combined therapy was associated with a significant reduction in inflammatory mediators, hemodynamic stabilization with a concomitant decrease in requirements for vasoactive substances, and a pronounced improvement in lung function and the need for ventilatory support. Treatment appeared safe and well-tolerated. CONCLUSIONS: In this case series of SARS-CoV-2 infected patients admitted to the intensive care unit with ARDS, we report effective interleukin (IL)-6 removal, reduced norepinephrine requirement, and improved lung function while receiving adjuvant, extracorporeal hemoadsorption therapy in the context of a multimodal treatment approach. The presented protocol for CytoSorb initiation may be a good foundation for the development of further prospective studies in the field and may eventually also be applied to other forms of hyperinflammatory ARDS.

Roscovitine up-regulates p53 protein and induces apoptosis in human HeLaS(3) cervix carcinoma cells.

Exposure of human HeLaS(3) cervix carcinoma cells to high doses of conventional cytostatic drugs, e.g. cisplatin (CP) strongly inhibits their proliferation. However, most cytostatic agents are genotoxic and may generate a secondary malignancy. Therefore, therapeutic strategy using alternative, not cytotoxic drugs would be beneficial. Inhibition of cyclin-dependent kinases (CDKs) by pharmacological inhibitors became recently a promising therapeutic option. Roscovitine (ROSC), a selective CDK inhibitor, efficiently targets human malignant cells. ROSC induces cell cycle arrest and apoptosis in human MCF-7 breast cancer cells. ROSC also activates p53 protein. Activation of p53 tumor suppressor protein is essential for induction of apoptosis in MCF-7 cells. Considering the fact that in HeLaS(3) cells wt p53 is inactivated by the action of HPV-encoded E6 oncoprotein, we addressed the question whether ROSC would be able to reactivate p53 protein in them. Their exposure to ROSC for 24 h induced cell cycle arrest at G(2)/M and reduced the number of viable cells. Unlike CP, ROSC in the used doses did not induce DNA damage and was not directly cytotoxic. Despite lack of detectable DNA lesions, ROSC activated wt p53 protein. The increase of p53 levels was attributable to the ROSC-mediated protein stabilization. Further analyses revealed that ROSC induced site-specific phosphorylation of p53 protein at Ser46. After longer exposure, ROSC induced apoptosis in HeLaS(3) cells. These results indicate that therapy of HeLaS(3) cells by ROSC could offer an advantage over that by CP due to its increased selectivity and markedly reduced risk of generation of a secondary cancer.