Gene-specific detection rate of adenomas and advanced adenomas in Lynch syndrome

Colonoscopy is expected to reduce colorectal cancer (CRC) incidence in Lynch syndrome (LS) by detecting and removing adenomas. The existence of gene-specific differences in adenoma detection has been proposed yet remains insufficiently explored. This study aims to elucidate gene-specific adenoma detection rates and their association with post-colonoscopy CRC (PCCRC), which stands as an important issue in LS surveillance.

Read More

Splenic CD169+Tim4+ Marginal Metallophilic Macrophages Are Essential for Wound Healing After Myocardial Infarction

Circulation, Ahead of Print. BACKGROUND:Fidelity of wound healing after myocardial infarction (MI) is an important determinant of subsequent adverse cardiac remodeling and failure. Macrophages derived from infiltrating Ly6Chi(lymphocyte antigen 6 complex, locus C) blood monocytes are a key component of this healing response; however, the importance of other macrophage populations is unclear.METHODS:We used a variety of in vivo murine models and orthogonal approaches, including surgical MI, flow cytometry and single-cell RNA sequencing, lineage tracing and cell tracking, splenectomy, parabiosis, cell adoptive transfer, and functional characterization, to establish an essential role for splenic CD169+Tim4+(cluster of differentiation 169+; T cell immunoglobulin– and mucin-domain–containing molecule 4) marginal metallophilic macrophages (MMMs) in post-MI wound healing in mice. Flow cytometry was used to measure circulating CD169+Tim4+monocytes in humans with ST-segment–elevation MI and control participants with stable coronary artery disease undergoing elective percutaneous coronary intervention.RESULTS:Splenic CD169+Tim4+MMMs circulate in blood as Ly6Clowmonocytes expressing macrophage markers and help populate CD169+Tim4+CCR2−LYVE1lowmacrophages in the naive heart. After acute MI, splenic MMMs augment phagocytosis and CCR (C-C motif chemokine receptor) 3 and CCR4 expression, and robustly mobilize to the heart, resulting in marked expansion of cardiac CD169+Tim4+LYVE1lowmacrophages with an immunomodulatory and proresolving gene signature. These macrophages are obligatory for apoptotic neutrophil clearance, suppression of inflammation, and induction of a reparative macrophage phenotype in the infarcted heart. Splenic MMMs are both necessary and sufficient for post-MI wound healing, and limit late pathological remodeling. Liver X receptor-α agonist–induced expansion of the splenic marginal zone and MMMs during acute MI alleviates inflammation and improves short- and long-term cardiac remodeling. Humans with acute ST-segment–elevation MI also exhibit expansion of circulating CD169+Tim4+cells, primarily within the intermediate (CD14+CD16+) monocyte population.CONCLUSIONS:Splenic CD169+Tim4+MMMs are required for proresolving and reparative responses after MI and can be manipulated for therapeutic benefit to limit long-term heart failure.

Read More

Artemisinin Partial Resistance in Ugandan Children

To the Editor The article by Dr Henrici and colleagues notes an urgent problem of artemisinin combination therapies that induced artemisinin partial resistance in 110 Ugandan children. Resistance was promoted by Pfkelch13 gene variations in Plasmodium falciparum. Even before the 2015 Nobel Prize for artemisinin’s discovery and isolation from the plant Artemisia annua, reports of resistance arose in Cambodia and Thailand. It was inevitable that resistance to a single compound would develop in a highly mutable parasite. Centuries before artemisinin’s discovery, the A annua plant itself was used as a therapy and may constitute a natural combination therapy more robust than monotherapy or artemisinin combination therapies against the inexorable evolutionary pressure toward drug resistance.

Read More

Diagnosis and Treatment of Polycythemia Vera

To the Editor I appreciated the recent comprehensive Review of the diagnostic approach, risk stratification, and treatment options for PV. The authors highlighted the use of exogenous androgens and erythropoietin as causes of secondary erythrocytosis. However, there was no mention of the use of SGLT2 inhibitors (canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, and sotagliflozin) as a cause of drug-induced secondary polycythemia. Current guidelines strongly recommend an SGLT2 inhibitor in patients with type 2 diabetes and cardiovascular disease or for those at high risk of cardiovascular disease. Due to their multiple health benefits, SGLT2 inhibitors are increasingly used not only for patients with diabetes but also for those with heart failure and chronic kidney disease. However, SGLT2 inhibitors are associated with erythrocytosis and increased hematocrit. The potential mechanisms behind erythrocytosis involve increased erythropoietin production through activation of hypoxia-inducible factor 2α and regulation of iron metabolism via hepcidin. A 2021 meta-analysis of 40 randomized clinical trials with 21 050 participants demonstrated that SGLT2 inhibitors significantly increased hematocrit levels, especially at higher doses. In a Mayo Clinic analysis of 100 consecutive patients without JAK2 gene variants characteristic of PV who were treated with an SGLT2 inhibitor, the median increase of baseline hemoglobin and hematocrit was 2.5 g/dL (range, 0.4-7.3 g/dL) and 7.5% (range, 1.8%-21.1%), respectively. Understanding that these increases are a known pharmacological response to SGLT2 inhibitors, rather than an indication of a pathological condition, is important to avoid unnecessary and expensive diagnostic tests. By informing clinicians and patients about this effect, we can prevent unnecessary stress for patients and their families and avoid unnecessary testing, allowing for more efficient use of health care resources and improving patient care and outcomes.

Read More

Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2–Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation, Ahead of Print. BACKGROUND:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by irregular rhythms and right ventricular dysplasia. Sequence variations in desmosomal protein-encoding genes are linked to ARVC development. Effective treatments for ARVC are lacking. Whereas mRNA-based therapies have shown efficacy in humans, their therapeutic potential for inherited cardiomyopathies remains unclear.METHODS:Whole-exome sequencing identified a novelDSC2sequence variation causing autosomal recessive ARVC in a Chinese family with consanguineous marriage. Mouse models withDsc2sequence variation knock-in and constitutive knock-out were generated and analyzed using echocardiography and histology. Transcriptomic and biochemical analyses were conducted to explore ARVC mechanisms.Dsc2mRNA delivered by intracardiac or transcoronary injection was assessed as a treatment for ARVC inDsc2knock-out mice. In addition, effects ofDsc2mRNA were examined in a transverse aortic constriction mouse model with noninherited right ventricular systolic dysfunction.RESULTS:Dsc2-deficient mice exhibited right ventricular dilation and dysfunction, mimicking human disease. Transcriptomic analysis identifiedMyl7as the most downregulated gene in the right ventricles ofDsc2-deficient mice, and its restoration by adeno-associated virus 9 rescued heart function.Dsc2mRNA delivery, with or without lipid nanoparticle encapsulation, normalized heart size and function inDsc2-deficient mice. ReducedDSC2andMLC2aexpression was also noted in patients with noninherited dilated cardiomyopathy and in mice with transverse aortic constriction. A single dose of mRNA provided therapeutic effects lasting 2 to 3 months before declining.CONCLUSIONS:Our study reveals novel mechanisms of ARVC caused byDSC2loss of function, supported by human and mouse data. Loss ofMyl7contributes to reduced cardiac contractility in ARVC and dilated cardiomyopathy with right ventricular systolic dysfunction.Dsc2mRNA treatment demonstrated significant therapeutic potential in ARVC and transverse aortic constriction models, providing a basis for future clinical applications.

Read More

Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator POU2AF2

Background
Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk.

Objective
Undertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.

Design
We employ analysis of RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation sequencing and single-cell ATAC sequencing data to identify, prioritise and characterise the genes that contribute to CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.

Results
We establish rs3087967 as a prime eQTL variant at 11q23.1, colocalising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell-specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the ApcMin/+ mouse phenotype on abrogation of Pou2af2 expression specifically.

Conclusion
We demonstrate that genotype at rs3087967 controls a portfolio of genes through misregulation of POU2AF2. POU2AF2 is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.

Read More

Olmesartan Restores LMNA Function in Haploinsufficient Cardiomyocytes

Circulation, Ahead of Print. BACKGROUND:Gene mutations are responsible for a sizeable proportion of cases of heart failure. However, the number of patients with any specific mutation is small. Repositioning of existing US Food and Drug Administration–approved compounds to target specific mutations is a promising approach to efficient identification of new therapies for these patients.METHODS:The National Institutes of Health Library of Integrated Network-Based Cellular Signatures database was interrogated to identify US Food and Drug Administration–approved compounds that demonstrated the ability to reverse the transcriptional effects ofLMNAknockdown. Top hits from this screening were validated in vitro with patient-specific induced pluripotent stem cell–derived cardiomyocytes combined with force measurement, gene expression profiling, electrophysiology, and protein expression analysis.RESULTS:Several angiotensin receptor blockers were identified from our in silico screen. Of these, olmesartan significantly elevated the expression of sarcomeric genes and rate and force of contraction and ameliorated arrhythmogenic potential. In addition, olmesartan exhibited the ability to reduce phosphorylation of extracellular signal–regulated kinase 1 inLMNA-mutant induced pluripotent stem cell–derived cardiomyocytes.CONCLUSIONS:In silico screening followed by in vitro validation with induced pluripotent stem cell–derived models can be an efficient approach to identifying repositionable therapies for monogenic cardiomyopathies.

Read More