Effects of the Strong Hearts program at two years post program completion.

Context: This is a follow-up to the original published article, Effects of the Strong Hearts Program after a Major Cardiovascular Event in Patients with Cardiovascular Disease.

Objectives: This study evaluated the long-term efficacy of the Strong Hearts program up to 2 years after program completion.

Methods: All study participants who initially completed the Strong Hearts program between 2020 and 2021 (n=128) were contacted at 12 months and 24 months following the date of program completion.

Effects of the Strong Hearts program after a major cardiovascular event in patients with cardiovascular disease.

Context: Cardiac rehabilitation (CR) and intensive cardiac rehabilitation (ICR) are secondary prevention interventions for cardiovascular disease (CVD) with a class 1a indication yet suboptimal utilization. To date, there are only three approved ICR programs. Alternative programing should be explored to increase enrollment and adherence in these interventions.

A Potential Role of Keratinocyte-Derived Bilirubin in Human Skin Yellowness and Its Amelioration by Sucrose Laurate/Dilaurate.

Sallow and/or dull skin appearance is greatly attributable to the yellow components of skin tone. Bilirubin is a yellow chromophore known to be made in the liver and/or spleen and is transported throughout the body via the blood stream. Recent publications suggest bilirubin may be synthesized in other cells/organs, including the skin.

Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines.

Background: Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available.

Methods: We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms 'breast cancer' AND 'HER2' AND 'advanced' AND ('phase II' OR 'phase III').

The rapidly evolving landscape of novel targeted therapies in advanced non-small cell lung cancer.

Lung cancer is a highly heterogeneous disease often driven by well-characterized driver mutations. Although the best studied are common alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) oncogenes, rapid advances in molecular characterization has led to the development of novel therapeutics that inhibit additional oncogenic alterations in advanced NSCLC. The literature search identified 62 eligible phase I/II clinical trials or integrated analyses of assessing novel targeted agents against the following molecular alterations: ROS1-rearranged, BRAF V600E-mutant, NTRK-rearranged, MET-altered, uncommon EGFR-mutant, RET-rearranged, HER2-positive, KRAS G12C-mutant and NRG1-rearranged.

Optimizing Survival and the Changing Landscape of Targeted Therapy for Intermediate and Advanced Hepatocellular Carcinoma: A Systematic Review.

Background: Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice.

Methods: Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA).

An evolutionary path to altered cofactor specificity in a metalloenzyme.

Almost half of all enzymes utilize a metal cofactor. However, the features that dictate the metal utilized by metalloenzymes are poorly understood, limiting our ability to manipulate these enzymes for industrial and health-associated applications. The ubiquitous iron/manganese superoxide dismutase (SOD) family exemplifies this deficit, as the specific metal used by any family member cannot be predicted.

Supraventricular tachycardia of the sick, a unique entity.

Objective: This study explored a unique form of atrioventricular nodal reentrant tachycardia (AVNRT) in which certain acutely ill patients have a first episode of supraventricular tachycardia (SVT) with a short RP interval.

Methods: A retrospective chart review was conducted of patients at a single institution who developed SVT with short RP and yielded 19 patients.

Results: None of the 19 patients had a prior history of AVNRT or any other arrhythmia.

Immune checkpoint-inhibitors and chemoradiation in stage III unresectable non-small cell lung cancer.

Lung cancer resulted in an estimated 1.8 million deaths worldwide in 2018 and approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with stage III unresectable disease. Phase III data from the PACIFIC trial show significantly improved progression-free survival for the checkpoint-inhibitor durvalumab given as consolidation following definitive chemoradiotherapy (cCRT).

Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer.

Purpose: Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics.

Canadian perspectives: update on inhibition of -positive tumours in advanced non-small-cell lung cancer.

Background: Inhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update.

Stapling for wound dehiscence after cardiac implantable electronic device implantation.

Objective: Wound dehiscence (WD) has been reported as a complication in 0.3% of cardiac implantable electronic device (CIED) procedures. Stapling has not previously been reported as a treatment modality for WD.

Evolving Strategies in the Treatment of Tuberous Sclerosis Complex-associated Angiomyolipomas (TSC-AML).

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder characterized by the development of numerous benign tumors that occur in multiple organ systems throughout the lifetime of the affected individuals. Renal angiomyolipomas occur in up to 80% of TSC patients, and chronic kidney disease from increasing tumor burden is the primary cause of TSC-related mortality. Our review evaluates evidence for localized and systemic therapy in the management of TSC-angiomyolipomas.

Regulating the ARNT/TACC3 axis: multiple approaches to manipulating protein/protein interactions with small molecules.

For several well-documented reasons, it has been challenging to develop artificial small molecule inhibitors of protein/protein complexes. Such reagents are of particular interest for transcription factor complexes given links between their misregulation and disease. Here we report parallel approaches to identify regulators of a hypoxia signaling transcription factor complex, involving the ARNT subunit of the HIF (Hypoxia Inducible Factor) activator and the TACC3 (Transforming Acidic Coiled Coil Containing Protein 3) coactivator.

MicroRNA silencing improves the tumor specificity of adenoviral transgene expression.

Adenoviral technology has been thoroughly evaluated for delivering genetic material to tumor tissue and the surrounding microenvironment. Almost any gene can be cloned into an adenovirus (Ad) vector, which when combined with strong, constitutively active promoters permit up to a million-fold amplification of the transgene in a single adenoviral particle, thus facilitating their use in cancer therapy and imaging. However, widespread infection of the liver and other non-targeted tissues by Ad vectors is a substantial problem that often results in significant liver inflammation and hepatotoxicity at doses required to achieve efficient tumor transduction.

Molecular basis of coiled coil coactivator recruitment by the aryl hydrocarbon receptor nuclear translocator (ARNT).

The aryl hydrocarbon receptor nuclear translocator (ARNT) serves as the obligate heterodimeric partner for bHLH-PAS proteins involved in sensing and coordinating transcriptional responses to xenobiotics, hypoxia, and developmental pathways. Although its C-terminal transactivation domain is dispensable for transcriptional activation in vivo, ARNT has recently been shown to use its N-terminal bHLH and/or PAS domains to interact with several transcriptional coactivators that are required for transcriptional initiation after xenobiotic or hypoxic cues. Here we show that ARNT uses a single PAS domain to interact with two coiled coil coactivators, TRIP230 and CoCoA.

ARNT PAS-B has a fragile native state structure with an alternative beta-sheet register nearby in sequence space.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix Period/ARNT/Single-minded (bHLH-PAS) protein that controls various biological pathways as part of dimeric transcriptional regulator complexes with other bHLH-PAS proteins. The two PAS domains within ARNT, PAS-A and PAS-B, are essential for the formation of these complexes because they mediate protein-protein interactions via residues located on their beta-sheet surfaces. While investigating the importance of residues in ARNT PAS-B involved in these interactions, we uncovered a point mutation (Y456T) on the solvent-exposed beta-sheet surface that allowed this domain to interconvert with a second, stable conformation.

Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a promiscuous bHLH-PAS (Per-ARNT-Sim) protein that forms heterodimeric transcriptional regulator complexes with several other bHLH-PAS subunits to control a variety of biological pathways, some of which are centrally involved in disease initiation and/or progression. One of these is the hypoxia response pathway, which allows eukaryotic cells to respond to low oxygen tension via the formation of a heterodimeric complex between ARNT and another bHLH-PAS protein, the hypoxia-inducible factor alpha (HIF-alpha). We have previously shown that the C-terminal PAS domains of an HIF-alpha isoform (HIF-2alpha) and ARNT interact in vitro, and that mutations in the solvent-exposed beta-sheet surface of the HIF-2alpha domain not only disrupt this interaction, but also greatly attenuate the hypoxia response in living cells.

Identification and optimization of protein domains for NMR studies.

The success of genomic sequencing projects in recent years has presented protein scientists with a formidable challenge in characterizing the vast number of gene products that have subsequently been identified. NMR has proven to be a valuable tool in the elucidation of various properties for many of these proteins, allowing versatile studies of structure, dynamics, and interactions in the solution state. But the characteristics needed for proteins amenable to this kind of study, such as folding capability, long-term stability, and high solubility, require robust and expeditious methods for the identification and optimization of target protein domains.

Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor.

Biological responses to oxygen availability play important roles in development, physiological homeostasis, and many disease processes. In mammalian cells, this adaptation is mediated in part by a conserved pathway centered on the hypoxia-inducible factor (HIF). HIF is a heterodimeric protein complex composed of two members of the basic helix-loop-helix Per-ARNT-Sim (PAS) (ARNT, aryl hydrocarbon receptor nuclear translocator) domain family of transcriptional activators, HIFalpha and ARNT.

Fluorine-19 NMR imaging of glucose metabolism.

Metabolic imaging reflecting glucose metabolism in the glycolytic and aldose reductase sorbitol (ARS) pathways was performed noninvasively in rat using fluorinated glucose analogs, 2-fluoro-2-deoxy-D-glucose (2-FDG) or 3-fluoro-3-deoxy-D-glucose (3-FDG), and fluorine-19 (19F) nuclear magnetic resonance (NMR) imaging. 19F images of 2-FDG-6-phosphate, a main metabolite of 2-FDG in the glycolytic pathway, showed high glucose utilization in the brain, spinal cord, and heart. Images of 3-fluoro-3-deoxy-D-sorbitol (3-FDSL), a main metabolite of 3-FDG in the ARS pathway, demonstrated the heterogeneous nature of the spatial distribution of aldose reductase activities, being highest in the brain and lens.

Noninvasive demonstration of in vivo 3-fluoro-3-deoxy-D-glucose metabolism in rat brain by 19F nuclear magnetic resonance spectroscopy: suitable probe for monitoring cerebral aldose reductase activities.

The metabolism of 3-fluoro-3-deoxy-D-glucose (3-FDG) in rat brain in vivo was investigated noninvasively using 19F nuclear magnetic resonance (NMR) spectroscopy. Following an intravenous infusion of 3-FDG, 400 mg/kg, four resonances assigned to the alpha and beta anomers of 3-FDG, 3-fluoro-3-deoxy-D-sorbitol, and 3-fluoro-3-deoxy-D-fructose were clearly resolved in brain, a result indicating that 3-FDG is metabolized primarily into the aldose reductase sorbitol (ARS) pathway. An orally administered aldose reductase inhibitor, sorbinil, caused reduction of the flux of 3-FDG into the ARS, an observation suggesting that the method can be applied in quantitative studies of ARS pathway activities.

Substrate recognition by a sucrose transporting protein.

Protoplasts derived from developing soybean cotyledons were used to study substrate recognition by a sucrose transporting protein in plant membranes. When used as alternate substrate inhibitors of [14C] sucrose influx, five different fructosyl-substituted sucrose derivatives, phenyl-alpha-D-glucopyranoside, and phenyl-alpha-D-thioglucopyranoside proved to bind effectively to the sucrose carrier-active site. These results are interpreted to indicate that a large portion of substrate recognition by this carrier may arise from the interaction of a relatively hydrophobic portion of the sucrose molecule and a hydrophobic region of the carrier protein binding site.