Preprocedural Anxiety in Adults With Congenital Heart Disease: The PANIC Study.

Background: Preprocedural anxiety may have detrimental effects both cognitively and physiologically.

Objectives: The objective of this study was to determine the association between state (situational) and trait (persistent in everyday life) anxiety and differences between the adult congenital heart disease (ACHD) and acquired heart disease populations.

Methods: The State-Trait Anxiety Inventory and financial stress scale were administered to adults with acquired and CHD at 4 tertiary referral centers in the United States prior to cardiac catheterization.

TCAB1 prevents nucleolar accumulation of the telomerase RNA to facilitate telomerase assembly.

Localization of a variety of RNAs to non-membrane-bound cellular compartments such as nucleoli and Cajal bodies is critical for their stability and function. The molecular mechanisms that underly the recruitment and exclusion of RNAs from these phase-separated organelles is incompletely understood. Telomerase is a ribonucleoprotein composed of the reverse transcriptase protein telomerase reverse transcriptase (TERT), the telomerase RNA (TR), and several auxiliary proteins, including TCAB1.

Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization.

Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies.

Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder.

Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in the genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, because TBD mutations show highly variable penetrance and genetic anticipation related to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential.

ACC/AHA/ASE/HRS/ISACHD/SCAI/SCCT/SCMR/SOPE 2020 Appropriate Use Criteria for Multimodality Imaging During the Follow-Up Care of Patients With Congenital Heart Disease: A Report of the American College of Cardiology Solution Set Oversight Committee and Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Pediatric Echocardiography.

The American College of Cardiology (ACC) collaborated with the American Heart Association, American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and the Society of Pediatric Echocardiography to develop Appropriate Use Criteria (AUC) for multimodality imaging during the follow-up care of patients with congenital heart disease (CHD). This is the first AUC to address cardiac imaging in adult and pediatric patients with established CHD. A number of common patient scenarios (also termed "indications") and associated assumptions and definitions were developed using guidelines, clinical trial data, and expert opinion in the field of CHD.

Critical Role for Cold Shock Protein YB-1 in Cytokinesis.

High levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cancer cell lines and in immortalized fibroblasts resulted in cytokinesis failure and consequent multinucleation.

A mechanism for the extension and unfolding of parallel telomeric G-quadruplexes by human telomerase at single-molecule resolution.

Telomeric G-quadruplexes (G4) were long believed to form a protective structure at telomeres, preventing their extension by the ribonucleoprotein telomerase. Contrary to this belief, we have previously demonstrated that parallel-stranded conformations of telomeric G4 can be extended by human and ciliate telomerase. However, a mechanistic understanding of the interaction of telomerase with structured DNA remained elusive.

Targeted Covalent Inhibition of Telomerase.

Telomerase is a ribonuceloprotein complex responsible for maintaining telomeres and protecting chromosomal integrity. The human telomerase reverse transcriptase (hTERT) is expressed in ∼90% of cancer cells where it confers the capacity for limitless proliferation. Along with its established role in telomere lengthening, telomerase also serves noncanonical extra-telomeric roles in oncogenic signaling, resistance to apoptosis, and enhanced DNA damage response.

Dephosphorylation of YB-1 is Required for Nuclear Localisation During G Phase of the Cell Cycle.

Elevated levels of nuclear Y-box binding protein 1 (YB-1) are linked to poor prognosis in cancer. It has been proposed that entry into the nucleus requires specific proteasomal cleavage. However, evidence for cleavage is contradictory and high YB-1 levels are prognostic regardless of cellular location.

Modular ssDNA binding and inhibition of telomerase activity by designer PPR proteins.

DNA is typically found as a double helix, however it must be separated into single strands during all phases of DNA metabolism; including transcription, replication, recombination and repair. Although recent breakthroughs have enabled the design of modular RNA- and double-stranded DNA-binding proteins, there are currently no tools available to manipulate single-stranded DNA (ssDNA). Here we show that artificial pentatricopeptide repeat (PPR) proteins can be programmed for sequence-specific ssDNA binding.

Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension.

Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS).

Forced vital capacity predicts morbidity and mortality in adults with repaired tetralogy of Fallot.

Objective: Abnormal lung function characterized by a reduced forced vital capacity (FVC) is common in adults with repaired tetralogy of Fallot (TOF) and is associated with previous thoracotomies and sternotomies. The impact of abnormal lung function on clinical outcomes in adult patients with repaired TOF is unclear. The aim of this study was to determine the impact of abnormal lung function on the outcome of hospitalization and death in adults with repaired TOF when analyzed with other traditional cardiac risk factors.

Quantitative assays for measuring human telomerase activity and DNA binding properties.

Telomerase is the ribonucleoprotein enzyme that catalyzes the processive addition of the telomeric DNA repeat 5'-TTAGGG-3' onto chromosome ends. In addition to its fascinating biochemical and enzymatic properties, clinical interest in telomerase stems from its dysregulated expression in ∼90% of human cancers, representing a broad spectrum of diseases. Exploiting telomerase as a therapeutic target and hence identifying and/or evaluating potential inhibitors requires quantitative measurement of its activity.

Telomeric G-quadruplexes are a substrate and site of localization for human telomerase.

It has been hypothesized that G-quadruplexes can sequester the 3' end of the telomere and prevent it from being extended by telomerase. Here we purify and characterize stable, conformationally homogenous human telomeric G-quadruplexes, and demonstrate that human telomerase is able to extend parallel, intermolecular conformations in vitro. These G-quadruplexes align correctly with the RNA template of telomerase, demonstrating that at least partial G-quadruplex resolution is required.

The Impact of Obesity on Postoperative Outcomes in Adults with Congenital Heart Disease Undergoing Pulmonary Valve Replacement.

Objective: The impact of obesity on surgical morbidity in adults with congenital heart disease is currently unknown. The aim of our study was to investigate the impact of obesity on postoperative outcomes in adults with congenital heart disease undergoing reoperation for pulmonary valve replacement.

Methods: A retrospective analysis was performed assessing the influence of obesity on surgical outcomes.

Takeuchi repair of anomalous left coronary artery from the pulmonary artery.

Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare form of congenital heart disease that has been successfully palliated for decades. Prior to coronary reimplantation, the Takeuchi repair was the most common operative palliation. The Takeuchi repair is still seen today at less experienced congenital centers or when reimplantation is not possible.

Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer.

Reactivation of telomerase, the chromosome end-replicating enzyme, drives human cell immortality and cancer. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter occur at high frequency in multiple cancers, including urothelial cancer (UC), but their effect on telomerase function has been unclear. In a study of 23 human UC cell lines, we show that these promoter mutations correlate with higher levels of TERT messenger RNA (mRNA), TERT protein, telomerase enzymatic activity, and telomere length.

Tricuspid repair at pulmonary valve replacement does not alter outcomes in tetralogy of Fallot.

Background: Chronic pulmonary regurgitation after tetralogy of Fallot repair often leads to progressive right ventricle dilation, dysfunction, and frequently, pulmonary valve replacement. For those with significant tricuspid regurgitation at the time of pulmonary valve replacement, it is unknown whether concomitant tricuspid valve repair improves postoperative outcomes.

Methods: This is a retrospective review of patients after tetralogy of Fallot repair who underwent pulmonary valve replacement between 1999 and 2012.

Two-step mechanism involving active-site conformational changes regulates human telomerase DNA binding.

The ribonucleoprotein enzyme telomerase maintains telomeres and is essential for cellular immortality in most cancers. Insight into the telomerase mechanism can be gained from syndromes such as dyskeratosis congenita, in which mutation of telomerase components manifests in telomere dysfunction. We carried out detailed kinetic and thermodynamic analyses of wild-type telomerase and two disease-associated mutations in the reverse transcriptase domain.

Quantitative Assessment of Right Ventricular Volumes and Ejection Fraction in Patients with Left Ventricular Systolic Dysfunction by Real Time Three-Dimensional Echocardiography versus Cardiac Magnetic Resonance Imaging.

Aims: The aim of this study was to assess the accuracy and reproducibility of real time three-dimensional echocardiographic (RT3DE) for the determination of right ventricular (RV) volumes and function in patients with left ventricular (LV) systolic dysfunction.

Methods And Results: Dedicated RT3DE was prospectively performed to assess RV volumes and EF in patients with LV systolic function identified on routine clinical cardiac magnetic resonance (CMR) imaging. RV end-diastolic volume (RV EDV), RV end-systolic volume (RV ESV), and RV EF were obtained using an offline analysis software (TomTec) by two observers blinded to CMR results.

Extracardiac complications in adults with congenital heart disease.

With the increasing number of adults living with repaired, or unrepaired, congenital heart disease, there is a growing incidence of extracardiac comorbidities. These comorbidities can affect various organ systems in complex ways, and may have a significant impact on a patient's quality of life and survival. Many of these potential complications may go undiagnosed until there is already a significant bearing on the patient's life.

Myocardial infarction due to a retained epicardial pacing wire.

A 20-year-old man with a temporary epicardial pacing wire retained after infant repair of an atrioventricular septal defect presented with cardiopulmonary arrest. After resuscitation with extracorporeal membranous oxygenation, a coronary angiogram demonstrated a retained epicardial pacing wire compressing the left anterior descending artery and obtuse marginals. Owing to poor prognostic findings on a computed tomography scan of his head, he was terminally withdrawn from mechanical support.

Telomerase recruitment requires both TCAB1 and Cajal bodies independently.

The ability of most cancer cells to grow indefinitely relies on the enzyme telomerase and its recruitment to telomeres. In human cells, recruitment depends on the Cajal body RNA chaperone TCAB1 binding to the RNA subunit of telomerase (hTR) and is also thought to rely on an N-terminal domain of the catalytic subunit, hTERT. We demonstrate that coilin, an essential structural component of Cajal bodies, is required for endogenous telomerase recruitment to telomeres but that overexpression of telomerase can compensate for Cajal body absence.

Prognostic association of YB-1 expression in breast cancers: a matter of antibody.

The literature concerning the subcellular location of Y-box binding protein 1 (YB-1), its abundance in normal and cancer tissues, and its prognostic significance is replete with inconsistencies. An explanation for this could be due in part to the use of different antibodies in immunohistochemical and immunofluorescent labeling of cells and tissues. The inconsistencies could also be due to poor resolution of immunohistochemical data.