Search

The efficacy of convalescent plasma for COVID-19 is unclear. While most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content may influence patient outcomes.We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 days of respiratory symptom onset. Patients were allocated 2:1 to 500 mL of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 days. The effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression.The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. 940 patients were randomized and 921 patients were included in the intent-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) in the convalescent plasma arm and 86/307 (28.0%) in the standard of care arm; relative risk (RR) 1.16 (95% confidence interval (CI) 0.94-1.43; p=0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% vs. 26.4%; RR=1.27, 95% CI 1.02-1.57, p=0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standard log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (OR=0.74; 0.57-0.95 and OR=0.66; 0.50-0.87, respectively), while IgG against the full transmembrane Spike protein increased it (OR=1.53, 95% CI 1.14-2.05).Convalescent plasma did not reduce the risk of intubation or death at 30 days among hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavourable antibody profiles may be associated with worse clinical outcomes compared to standard care.Trial registrationCONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1); NCT04348656; https://www.clinicaltrials.gov/ct2/show/NCT04348656

A series of PF-8380 analogs, a recently developed autotaxin inhibitor, was explored. Inhibition of autotaxin by these analogs, as well as by all PF-8380 synthetic intermediates, shows the importance of meta-dichlorobenzyl and benzo[d]oxazol-2(3H)-one fragments. However, analogs 8 and 9, bearing only the benzo[d]oxazol-2(3H)-one moiety, are more cytotoxic on the LN229 glioblastoma cell line than PF-8380 and temozolomide (TMZ).

Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by unpredictable clinical behaviors that suggest distinct molecular subtypes. With the tumor metabolic phenotype being one of the hallmarks of cancer, we have set upon to investigate whether GBMs show differences in their metabolic profiles. 1H NMR analysis was performed on metabolite extracts from a selection of nine glioblastoma cell lines. Analysis was performed directly on spectral data and on relative concentrations of metabolites obtained from spectra using a multivariate regression method developed in this work. Both qualitative and quantitative sample clustering have shown that cell lines can be divided into four groups for which the most significantly different metabolites have been determined. Analysis shows that some of the major cancer metabolic markers (such as choline, lactate, and glutamine) have significantly dissimilar concentrations in different GBM groups. The obtained lists of metabolic markers for subgroups were correlated with gene expression data for the same cell lines. Metabolic analysis generally agrees with gene expression measurements, and in several cases, we have shown in detail how the metabolic results can be correlated with the analysis of gene expression. Combined gene expression and metabolomics analysis have shown differential expression of transporters of metabolic markers in these cells as well as some of the major metabolic pathways leading to accumulation of metabolites. Obtained lists of marker metabolites can be leveraged for subtype determination in glioblastomas.

Changes across metabolic networks are emerging as an integral part of cancer development and progression. Increasing comprehension of the importance of metabolic processes as well as metabolites in cancer is stimulating exploration of novel, targeted treatment options. Arachidonic acid (AA) is a major component of phospholipids. Through the cascade catalyzed by cyclooxygenases and lipoxygenases, AA is also a precursor to cellular signaling molecules as well as molecules associated with a variety of diseases including cancer. 5-Lipoxygenase catalyzes the transformation of AA into leukotrienes (LT), important mediators of inflammation. High-throughput analysis of metabolic profiles was used to investigate the response of glioblastoma cell lines to treatment with 5-lipoxygenase inhibitors. Metabolic profiling of cells following drug treatment provides valuable information about the response and metabolic alterations induced by the drug action and give an indication of both on-target and off-target effects of drugs. Four different 5-lipoxygenase inhibitors and antioxidants were tested including zileuton, caffeic acid, and its analogues caffeic acid phenethyl ester and caffeic acid cyclohexethyl ester. A NMR approach identified metabolic signatures resulting from application of these compounds to glioblastoma cell lines, and metabolic data were used to develop a better understanding of the mode of action of these inhibitors.

Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in clinical practice. The safety and efficacy of these agents in peritoneal dialysis (PD) patients are unclear. Objectives We conducted a systematic review to study the safety and efficacy of ACEI and ARB use in PD patients. Primary outcome measures were mortality and cardiovascular (CV) events; secondary outcome measures were renal function, proteinuria, hyperkalemia, and erythropoietin requirement at 3 months. Methods We searched Medline, EMBASE, Cochrane Central Register of Controlled Trials, trial registry Web sites, reference lists of eligible and review articles, as well as abstracts from the American Society of Nephrology and Canadian Society of Nephrology meetings. To be eligible, studies had to be randomized controlled trials that allocated PD patients to ACEI and ARB use or to placebo or other antihypertensive medications, included adult patients, and reported on at least one of the outcome measures. Results 418 citations were identified. Four met the eligibility criteria. Three examined CV events and mortality, of which two studies did not have any events. The third showed no statistically significant difference between control and treatment groups in either CV events or mortality: odds ratio 1.56 [95% confidence interval (CI) 0.24 – 10.05] for mortality and odds ratio 1.00 (95% CI 0.19 – 5.40) for CV events. Two studies reported renal function at 12 months and the weighted mean difference was 0.91 mL/minute/1.73 m2 (95% CI 0.14 – 1.68), favoring ACEI and ARB use. Conclusions In PD patients, evidence for the use of ACEIs and ARBs for reduction of mortality and CV events is lacking. Limited data suggest that they slow the loss of residual renal function.