Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism. The resultant TDs in TDP augment global oncogene expression and disrupt tumor suppressor genes. Importantly, the TDP strongly correlates with cisplatin sensitivity in both TNBC cell lines and primary patient-derived xenografts. We conclude that the TDP is a common cancer chromotype that coordinately alters oncogene/tumor suppressor expression with potential as a marker for chemotherapeutic response.
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Objective To study mechanisms of formation of fractionated electrograms on the posterior left atrial wall (PLAW) in human paroxysmal atrial fibrillation (AF). Background The mechanisms responsible for complex fractionated atrial electrograms formation during AF are poorly understood. Methods In 24 pts we induced sustained AF by pacing from a pulmonary vein (PV). We analyzed transitions between organized patterns and changes in electrogram morphology leading to fractionation in relation to interbeat interval duration (systolic interval) and dominant frequency (DF). Computer simulations of rotors helped in the interpretation of the results. Results Organized patterns were recorded 31±18% of the time. In 47% of organized patterns, the electrograms and PLAW activation sequence were similar to those of incoming waves during PV stimulation that induced AF. Transitions to fractionation were preceded by significant increases in electrogram duration, spikes number, and systolic interval shortening (R2=0.94). Similarly, adenosine infusion during organized patterns caused significant systolic interval shortening leading to fractionated electrogram formation. Activation maps during organization showed incoming wave patterns, with earliest activation located closest to the highest DF site. Activation maps during transitions to fragmentation showed areas of slowed conduction and unidirectional block. Simulations predicted that systolic interval abbreviation that heralds fractionated electrograms formation may result from a Doppler effect on wavefronts preceding an approaching rotor, or by acceleration of a stationary or meandering, remotely located source. Conclusions During induced AF, systolic interval shortening following either drift or acceleration of a source results in intermittent fibrillatory conduction and formation of fractionated electrograms at the PLAW.
Atrial and ventricular tachyarrhythmias can be perpetuated by up-regulation of inward rectifier potassium channels. Thus, it may be beneficial to block inward rectifier channels under conditions in which their function becomes arrhythmogenic (e.g., inherited gain-of-function mutation channelopathies, ischemia, and chronic and vagally mediated atrial fibrillation). We hypothesize that the antimalarial quinoline chloroquine exerts potent antiarrhythmic effects by interacting with the cytoplasmic domains of Kir2.1 (I(K1)), Kir3.1 (I(KACh)), or Kir6.2 (I(KATP)) and reducing inward rectifier potassium currents. In isolated hearts of three different mammalian species, intracoronary chloroquine perfusion reduced fibrillatory frequency (atrial or ventricular), and effectively terminated the arrhythmia with resumption of sinus rhythm. In patch-clamp experiments chloroquine blocked I(K1), I(KACh), and I(KATP). Comparative molecular modeling and ligand docking of chloroquine in the intracellular domains of Kir2.1, Kir3.1, and Kir6.2 suggested that chloroquine blocks or reduces potassium flow by interacting with negatively charged amino acids facing the ion permeation vestibule of the channel in question. These results open a novel path toward discovering antiarrhythmic pharmacophores that target specific residues of the cytoplasmic domain of inward rectifier potassium channels.
Abstract-Previous studies have shown that the gating kinetics of the slow component of the delayed rectifier K ϩ current (I Ks ) contribute to postrepolarization refractoriness in isolated cardiomyocytes. However, the impact of such kinetics on arrhythmogenesis remains unknown. We surmised that expression of I Ks in rat cardiomyocyte monolayers contributes to wavebreak formation and facilitates fibrillatory conduction by promoting postrepolarization refractoriness. Optical mapping was performed in 44 rat ventricular myocyte monolayers infected with an adenovirus carrying the genomic sequences of KvLQT1 and minK (molecular correlates of I Ks ) and 41 littermate controls infected with a GFP adenovirus. Repetitive bipolar stimulation was applied at increasing frequencies, starting at 1 Hz until loss of 1:1 capture or initiation of reentry. Action potential duration (APD) was significantly shorter in I Ks -infected monolayers than in controls at 1 to 3 Hz (PϽ0.05), whereas differences at higher pacing frequencies did not reach statistical significance. Stable rotors occurred in both groups, with significantly higher rotation frequencies, lower conduction velocities, and shorter action potentials in the I Ks group. Wavelengths in the latter were significantly shorter than in controls at all rotation frequencies. Wavebreaks leading to fibrillatory conduction occurred in 45% of the I Ks reentry episodes but in none of the controls. Moreover, the density of wavebreaks increased with time as long as a stable source sustained the fibrillatory activity. These results provide the first demonstration that I Ks -mediated postrepolarization refractoriness can promote wavebreak formation and fibrillatory conduction during pacing and sustained reentry and may have important implications in tachyarrhythmias. Key Words: I Ks , postrepolarization refractoriness Ⅲ wavebreak Ⅲ gene expression D uring ventricular and atrial fibrillation, conduction of the electrical wavefront is characterized by complex patterns of propagation, including reentry, wavefront fragmentation (wavebreak), and wavelet formation. 1 A wavebreak occurs if the stimulatory efficacy of a wavefront does not suffice to excite all the tissue downstream. The free shoulder of a broken wave is then prone to curl and give rise to a rotor. 2 To date, the molecular mechanisms of wavebreaks leading to fibrillatory conduction remain poorly understood.Studies in single guinea pig myocytes showed that slow recovery of excitability during diastole was, in part, a consequence of the slow gating kinetics of the delayed rectifier potassium outward current I K . 3,4 Shortly after these studies were published, I K was found to be the result of the activation of 2 outward currents: I Kr and the I Ks . 5 Given the large amounts of I Ks present in guinea pig myocytes 6,7 and the slow deactivation kinetics of this current, 8 we surmise that I Ks is a likely candidate to have an important role in regulating excitability during the diastolic interval, ie, postrepolarization refractorin...
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