Immunomodulatory and clinical effects of receptor-interacting protein kinase 1 (RIPK1) inhibitor eclitasertib (SAR443122) in patients with severe COVID-19: a phase 1b, randomized, double-blinded, placebo-controlled study.

Background: Targeting receptor-interacting serine/threonine protein kinase 1 could mitigate the devastating sequelae of the hyperinflammatory state observed in severe cases of COVID-19. This study explored the immunomodulatory and clinical effects of the receptor-interacting serine/threonine protein kinase 1 inhibitor SAR443122 (eclitasertib) in patients with severe COVID-19.

Methods: In this Phase 1b, double-blinded, placebo-controlled study (NCT04469621) a total of 82 patients were screened, of whom 68 patients were eligible and randomized (2:1) to receive eclitasertib 600 mg (300 mg twice daily) or placebo up to 14 days.

Dupilumab pharmacokinetics in Chinese healthy subjects and patients with atopic dermatitis: Results of two randomized, double-blind, placebo-controlled studies.

Background: Dupilumab, a fully human monoclonal antibody targeting IL-4Rα, has demonstrated rapid and sustained improvements in clinical outcomes in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps.

Methods: In a phase 1, double-blind, ascending-dose study, 30 healthy Chinese adults were randomized to single subcutaneous doses of dupilumab 200, 300, 600 mg, or placebo. In a phase 3, double-blind study, 165 Chinese adults with AD were randomized to dupilumab 300 mg or placebo every 2 weeks.

Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study.

Purpose: Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI.

Methods: Patients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m, respectively.

A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function.

Purpose: Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function.

Methods: Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.

Prognostic significance of a combined clinicopathologic score for response to primary systemic therapy in locally advanced breast cancer.

The response to chemotherapy is one of the best indicators of prognosis in locally advanced breast cancer (LABC). The pathologic response (pR) of 108 LABC patients was analysed and compared with their clinical response (cR). Our aim was to define a new combined clinicopathologic response score (cpR) and to explore its correlation with survival data.

Placental transfer of SR49059 in the human dually perfused cotyledon in vitro.

SR49059 is an antagonist of vasopressin V(1a)receptors currently developed as a tocolytic drug. We investigated the transplacental transfer of SR49059 in vitro using the single pass dually perfused human cotyledon model. Thirteen placentae were collected from normal term pregnancies immediately after delivery.

[Carcinoma arising within mammary fibroadenomas. A study of six patients].

We report six cases of carcinomas arising within fibroadenomas. Fibroadenoma is a benign neoplasm occurring in young women. Its association with carcinomas is unfrequent and particularly reported in older women.

Cytochrome P4502E1 inducibility and hydroxyethyl radical formation among alcoholics.

Background/aims: Animal studies have shown that the induction of cytochrome P4502E1 (CYP2E1) modulates oxidative damage induced by ethanol. Since CYP2E1 activity varies substantially in humans, we have investigated whether differences in CYP2E1 activity might influence the formation of hydroxyethyl free radicals and the stimulation of lipid peroxidation among alcohol abusers.

Methods: Chlorzoxazone oxidation, an index of CYP2E1 activity, and the levels of antibodies reacting with hydroxyethyl radical and malonyldialdehyde protein adducts were investigated in 51 alcoholic patients.

Plasma membrane hydroxyethyl radical adducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol.

Background & Aims: We reported previously that patients with alcoholic liver disease (ALD) have circulating immunoglobulins reacting with cytochrome P4502E1 (CYP2E1) complexed with hydroxyethyl free radicals. The aim of this study was to investigate whether hydroxyethyl radical adducts are present on the plasma membranes of ethanol-treated hepatocytes and their role in antibody-dependent cytotoxicity.

Methods: Immunofluorescence confocal laser microscopy, Western blotting, and antibody-dependent cell-mediated cytotoxicity assay were used.

Lipid peroxidation, CYP2E1 and arachidonic acid metabolism in alcoholic liver disease in rats.

The role of cytochrome P450 metabolism of fatty acids and lipid peroxidation in the alterations of the fatty acid composition of the liver and liver pathology was investigated. The CYP2E1 inhibitors partially prevented CYP2E1 induction by ethanol and completely blocked lipid peroxidation. However, the liver pathology induced by ethanol was only partially prevented as was the decrease in arachidonic acid in total liver lipid, triglycerides and cholesterol esters.

Free radicals and not acetaldehyde influence the circulating levels of glutathione after acute or chronic alcohol abuse: in vivo and in vitro studies.

Background: The oxidation of ethanol and acetaldehyde enhances the production of various free radicals involved in membrane lipoperoxidation, and decreases glutathione levels.

Aims: We evaluated the effects of acute and chronic ethanol use in vivo, with or without the administration of S-adenosyl-methionine (SAME, 2 g I.v.

Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics.

Background & Aims: We have previously reported that alcoholics have increased titers of immunoglobulins reacting with protein adducts of hydroxyethyl free radicals. Because hydroxyethyl radicals are produced during ethanol metabolism by liver microsomes, the aim of this study was to determine whether such antibodies recognize microsomal proteins complexed with hydroxyethyl radicals.

Methods: Liver microsomal proteins reacting with the anti-hydroxyethyl radical antibodies were characterized by an enzyme-linked immunosorbent assay and Western blotting.

Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol.

We have previously shown that the treatment with diallyl sulfide (DAS) and phenylethyl isothiocyanate (PIC) of rats receiving ethanol in the alcohol tube-feeding model effectively suppressed the induction of cytochrome P4502E1 (CYP2E1) by ethanol. Here we report that rat treatment with DAS and PIC significantly decreased the trapping of hydroxyethyl free radicals in liver microsomes incubated in vitro with ethanol. Furthermore, these inhibitors also greatly reduced the production of hydroxyethyl radical-derived epitopes detectable in vivo in the liver of ethanol-fed rats.

Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors.

This study was done to determine if a relationship exists between CYP2E1 induction by ethanol, lipid peroxidation, and liver pathology in experimental alcohol-induced liver disease in the rat. Rats were fed ethanol with or without diallyl sulfide (DAS) or phenethyl isothiocyanate (PIC) intragastrically for 1 month. CYP2E1 induction by ethanol was correlated with lipid peroxidation, liver microsomal CYP2E1 hydroxylation of paranitrophenol, and the liver pathology score using the data from the PIC-fed rats.

Activation of alkylhydrazines to free radical intermediates by ethanol-inducible cytochrome P-4502E1 (CYP2E1).

Electron spin resonance (EPR) spectroscopy analysis using the spin trapping agent 4-pyridyl-1-oxide-t-butyl nitrone (4-POBN) was used to measure the formation of free radical intermediates during NADPH-dependent oxidation of 1-methyl-, 1-ethyl-, and 1-isopropylhydrazine in rat liver microsomes and in reconstituted enzyme systems. The experiments in microsomes revealed that the specific activation of the hydrazines, as measured by the EPR signal intensities, was about two-fold higher, when expressed per nmol of P-450, in microsomes from rats treated with ethanol (EtOH) as compared to membranes isolated from either phenobarbital (PB)-, beta-naphthoflavone (beta-NF)-treated or control rats. Furthermore, kinetic experiments revealed that EtOH-microsomes had an apparent affinity for 1-ethylhydrazine about one order of magnitude higher than PB-microsomes.

Detection of antibodies against proteins modified by hydroxyethyl free radicals in patients with alcoholic cirrhosis.

Background/aims: We have previously shown that hydroxyethyl free radicals produced during cytochrome P4502E1-mediated oxidation of ethanol covalently bind to microsomal proteins. The present study examined whether alkylation of proteins by hydroxyethyl radicals induces an immunologic response in alcoholic patients.

Methods: A microplate enzyme-linked immunosorbent assay was developed using as antigen human serum albumin or bovine fibrinogen reacted with chemically produced hydroxyethyl radicals.

Monitoring oxidative damage in patients with liver cirrhosis and different daily alcohol intake.

This study looked at the possible association between alcohol abuse and free radical mediated oxidative injury by examining the presence of oxidative damage, as monitored by erythrocyte malonildialdehyde and plasma lipid hydroperoxides, in patients with liver cirrhosis and different lifetime daily alcohol intake. All patients with an alcohol intake above 100 g/day (ALC) showed concentrations of malonildialdehyde and lipid hydroperoxide on average four to fivefold higher than cirrhotic patients with alcohol intake below 100 g/day (NAC) or healthy controls. Further subgrouping of ALC patients showed that those with alcohol intake ranging between 100 and 200 g/day (ALC1) had malonildialdehyde and lipid hydroperoxide concentrations significantly lower than those with an intake higher than 200 g/day (ALC2).

Risks and benefits of splenectomy in myelofibrosis: an analysis of 39 cases.

From 1980 to 1993, 39 splenectomies were performed in the Department of Visceral Surgery of Saint-Louis Hospital, in patients referred for myelofibrosis associated with myeloid splenomegaly. The short term morbidity was considerable: 33 serious haemorrhagic, infectious or thrombotic complications including 5 fatal accidents were observed in 18 patients. Severe thrombotic or infectious complications leading to 6 further deaths occurred in 8 patients over the two years following splenectomy, while six cases of acute leukaemia appeared between 6 months and 3 years after splenectomy.

Free radical activation of acetaldehyde and its role in protein alkylation.

The formation of carbon centered free radicals, identified as methylcarbonyl species, was observed using ESR spectroscopy and the spin trapping agent 4-pyridyl-1-oxide-N-t-butyl nitrone (4-POBN) during the oxidation of acetaldehyde by xanthine oxidase. The reaction was dependent upon the presence of OH. radicals and was inhibited by the addition of superoxide dismutase, catalase or OH.

Specificity of autoantibodies against oxidized LDL as an additional marker for atherosclerotic risk.

Background: LDL oxidation is a crucial step in the development and progression of atherosclerotic lesions. The detection of an increase in the anti-oxidized LDL antibody titre may thus represent a biological marker of enhanced LDL oxidation in vivo.

Methods: The occurrence of anti-oxidized LDL autoantibodies was investigated in control patients, in patients with atherosclerotic coronary artery disease, in those without clinically relevant signs of atherosclerosis, but considered at risk, and in patients with chronic alcohol-related liver disease.

Ethanol-inducible cytochrome P4502E1: genetic polymorphism, regulation, and possible role in the etiology of alcohol-induced liver disease.

In the Tsukamoto-French model, ethanol causes an important 10-20-fold induction of ethanol-inducible cytochrome P4502E1 (CYP2E1), mediated through enzyme stabilization and increased rate of gene transcription. The CYP2E1 induction results in a pronounced increase in the rate of NADPH-dependent microsomal lipid peroxidation, an elevation which is not seen after simultaneous administration of the CYP2E1 inhibitor diallylsulfide. Increased amounts of lipid peroxides are seen in plasma and red blood cells of both rats and humans during high ethanol intake.

Possible role of free radical intermediates in hepatotoxicity of hydrazine derivatives.

Hydrazine derivatives constitute a wide group of compounds and have found application in industry, agriculture, and (as therapeutical agents) medicine. In spite of their widely spread use, several hydrazine derivatives are known to exert hepatotoxic effects and are carcinogenic. Free radical species are produced during the hepatic biotransformation of alkylhydrazines by both rat and humans liver microsomes.

Splenectomy in human immunodeficiency virus-related thrombocytopenia.

To evaluate the efficacy and safety of splenectomy in patients with human immunodeficiency virus (HIV)-related thrombocytopenia, 30 HIV-infected patients with thrombocytopenia (platelet count < 50 x 10(9)/l) who underwent splenectomy were followed prospectively for a mean period of 42 months. There were no perioperative deaths and morbidity was minimal. Twenty-one patients had a persistent complete response, six had a partial response and were asymptomatic after splenectomy, and only three showed no response.