Mild clinical course of covid-19 in 3 patients receiving therapeutic monoclonal antibodies targeting c5 complement for hematologic disorders

© Am J Case Rep, 2020. Objective: Rare co-existance of disease or pathology Background: Patients receiving immunosuppressive therapies might be more susceptible to COVID-19. Conversely, an exaggerated inflammatory response to the SARS-CoV-2 infection might be blunted by certain forms of immunosuppression, which could be protective. Indeed, there are data from animal models demonstrating that complement may be a part of the pathophysiology of coronavirus infections. There is also evidence from an autopsy series demonstrating complement deposition in the lungs of patients with COVID-19. This raises the question of whether patients on anti-complement therapy could be protected from COVID-19. Case Reports: Case 1 is a 39-year-old woman with an approximately 20-year history of paroxysmal nocturnal hemoglobinuria (PNH), who had recently been switched from treatment with eculizumab to ravulizumab prior to SARS-CoV-2 infection. Case 2 is a 54-year-old woman with a cadaveric renal transplant for lupus nephritis, complicated by thrombotic microangiopathy, who was maintained on eculizumab, which she started several months before she developed the SARS-CoV-2 infection. Case 3 is a 60-year-old woman with a 14-year history of PNH, who had been treated with eculizumab since 2012, and was diagnosed with COVID-19 at the time of her scheduled infusion. All 3 patients had a relatively mild course of COVID-19. Conclusions: We see no evidence of increased susceptibility to SARS-CoV-2 in these patients on anti-complement therapy, which might actually have accounted for the mild course of infection. The effect of anti-complement therapy on COVID-19 disease needs to be determined in clinical trials

Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain

The role of cell location and spatial gradients in the evolutionary dynamics of colon and intestinal crypts

BACKGROUND: Colon and intestinal crypts serve as an important model system for adult stem cell proliferation and differentiation. We develop a spatial stochastic model to study the rate of somatic evolution in a normal crypt, focusing on the production of two-hit mutants that inactivate a tumor suppressor gene. We investigate the effect of cell division pattern along the crypt on mutant production, assuming that the division rate of each cell depends on its location. RESULTS: We find that higher probability of division at the bottom of the crypt, where the stem cells are located, leads to a higher rate of double-hit mutant production. The optimal case for delaying mutations occurs when most of the cell divisions happen at the top of the crypt. We further consider an optimization problem where the “evolutionary” penalty for double-hit mutant generation is complemented with a “functional” penalty that assures that fully differentiated cells at the top of the crypt cannot divide. CONCLUSION: The trade-off between the two types of objectives leads to the selection of an intermediate division pattern, where the cells in the middle of the crypt divide with the highest rate. This matches the pattern of cell divisions obtained experimentally in murine crypts. REVIEWERS: This article was reviewed by David Axelrod (nominated by an Editorial Board member, Marek Kimmel), Yang Kuang and Anna Marciniak-Czochra. For the full reviews, please go to the Reviewers’ comments section. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13062-016-0141-6) contains supplementary material, which is available to authorized users

Neutral evolution in paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic stem cell (HSC) disorder characterized by the partial or complete deficiency of glycosyl-phosphatidylinositol (GPI)-linked membrane proteins, which leads to intravascular hemolysis. A loss of function mutation in the PIG-A gene, required for GPI biosynthesis, explains how the deficiency of many membrane proteins can result from a single genetic event. However, to date the mechanism of expansion of the GPI− clone has not been fully understood. Two hypotheses have been proposed: A selective advantage of GPI− cells because of a second mutation or a conditional growth advantage of GPI− cells in the presence of an immune attack on normal (GPI+) HSCs. Here, we explore a third possibility, whereby the PNH clone does not have a selective advantage. Simulations in a large virtual population accurately reproduce the known incidence of the disease; and the fit is optimized when the number of stem cells is decreased, reflecting a component of bone marrow failure in PNH. The model also accounts for the occurrence of spontaneous cure in PNH, consequent on clonal extinction. Thus, a clonal advantage may not be always necessary to explain clonal expansion in PNH