Single-cell spatial mapping reveals alteration of cell type composition and tissue microenvironment during early colorectal cancer formation.

Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Familial adenomatous polyposis (FAP) is a hereditary syndrome that raises the risk of developing CRC, with total colectomy as the only effective prevention. Even though FAP is rare (0.

Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation.

Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.

Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects.

Optogenetic Stimulation Using Anion Channelrhodopsin (GtACR1) Facilitates Termination of Reentrant Arrhythmias With Low Light Energy Requirements: A Computational Study.

Optogenetic defibrillation of hearts expressing light-sensitive cation channels (e.g., ChR2) has been proposed as an alternative to conventional electrotherapy.

Cardiac Optogenetics: 2018.

Cardiac optogenetics is an emergent research area involving the delivery of light-sensitive proteins (opsins) to excitable heart tissue to enable optical modulation of cardiac electrical function. Optogenetic stimulation has many noteworthy advantages over conventional electrical methods, including selective electrophysiological modulation in specifically targeted cell subpopulations, high-resolution spatiotemporal control via patterned illumination, and use of different opsins to elicit inward or outward transmembrane current. This review summarizes developments achieved since the inception of cardiac optogenetics research, which has spanned nearly a decade.

Termination of re-entrant atrial tachycardia via optogenetic stimulation with optimized spatial targeting: insights from computational models.

Key Points: Optogenetics has emerged as a potential alternative to electrotherapy for treating heart rhythm disorders, but its applicability for terminating atrial arrhythmias remains largely unexplored. We used computational models reconstructed from clinical MRI scans of fibrotic patient atria to explore the feasibility of optogenetic termination of atrial tachycardia (AT), comparing two different illumination strategies: distributed vs. targeted.

Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm.

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling.

Light-based Approaches to Cardiac Arrhythmia Research: From Basic Science to Translational Applications.

Light has long been used to image the heart, but now it can be used to modulate its electrophysiological function. Imaging modalities and techniques have long constituted an indispensable part of arrhythmia research and treatment. Recently, advances in the fields of optogenetics and photodynamic therapy have provided scientists with more effective approaches for probing, studying and potentially devising new treatments for cardiac arrhythmias.

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations.

Ventricular arrhythmias are among the most severe complications of heart disease and can result in sudden cardiac death. Patients at risk currently receive implantable defibrillators that deliver electrical shocks to terminate arrhythmias on demand. However, strong electrical shocks can damage the heart and cause severe pain.

Opsin spectral sensitivity determines the effectiveness of optogenetic termination of ventricular fibrillation in the human heart: a simulation study.

Key Points: Optogenetics-based defibrillation, a theoretical alternative to electrotherapy, involves expression of light-sensitive ion channels in the heart (via gene or cell therapy) and illumination of the cardiac surfaces (via implanted LED arrays) to elicit light-induced activations. We used a biophysically detailed human ventricular model to determine whether such a therapy could terminate fibrillation (VF) and identify which combinations of light-sensitive ion channel properties and illumination configurations would be effective. Defibrillation was successful when a large proportion (> 16.

Computational modeling of cardiac optogenetics: Methodology overview & review of findings from simulations.

Cardiac optogenetics is emerging as an exciting new potential avenue to enable spatiotemporally precise control of excitable cells and tissue in the heart with low-energy optical stimuli. This approach involves the expression of exogenous light-sensitive proteins (opsins) in target heart tissue via viral gene or cell delivery. Preliminary experiments in optogenetically-modified cells, tissue, and organisms have made great strides towards demonstrating the feasibility of basic applications, including the use of light stimuli to pace or disrupt reentrant activity.

"Beauty is a light in the heart": the transformative potential of optogenetics for clinical applications in cardiovascular medicine.

Optogenetics is an exciting new technology in which viral gene or cell delivery is used to inscribe light sensitivity in excitable tissue to enable optical control of bioelectric behavior. Initial progress in the fledgling domain of cardiac optogenetics has included in vitro expression of various light-sensitive proteins in cell monolayers and transgenic animals to demonstrate an array of potentially useful applications, including light-based pacing, silencing of spontaneous activity, and spiral wave termination. In parallel to these developments, the cardiac modeling community has developed a versatile computational framework capable of realistically simulating optogenetics in biophysically detailed, patient-specific representations of the human heart, enabling the exploration of potential clinical applications in a predictive virtual platform.

Optogenetics-enabled dynamic modulation of action potential duration in atrial tissue: feasibility of a novel therapeutic approach.

Aims: Diseases that abbreviate the cardiac action potential (AP) by increasing the strength of repolarizing transmembrane currents are highly arrhythmogenic. It has been proposed that optogenetic tools could be used to restore normal AP duration (APD) in the heart under such disease conditions. This study aims to evaluate the efficacy of an optogenetic treatment modality for prolonging pathologically shortened APs in a detailed computational model of short QT syndrome (SQTS) in the human atria, and compare it to drug treatment.