Evaluation, prevention and management of cancer therapy-induced cardiotoxicity: a contemporary approach for clinicians.

PURPOSE OF REVIEW: While targeted therapies have improved cancer outcomes, unique cardiovascular toxicities are increasingly recognized, particularly when administered sequentially after anthracyclines or radiation. Patients with cancer therapy-induced cardiotoxicity benefit from collaborative care involving cardiology and oncology, leading to a new interdisciplinary field called cardio-oncology. The present review will highlight contemporary clinical issues in cardio-oncology. RECENT FINDINGS: Recently, risk factors for cancer therapy-induced cardiotoxicity have been evaluated in real-world rather than in clinical trial patients. Biomarkers and advanced echocardiography are emerging as sensitive tools for preclinical identification of cancer therapy-induced cardiotoxicity. Single-center studies suggest that cancer therapy-induced cardiotoxicity responds to prompt heart failure medical treatment, and such therapy may even prevent cardiotoxicity. SUMMARY: Modern cancer therapy has short-term cardiac risk that may require collaborative management by clinicians with expertise in cardiology and oncology. The increased effectiveness of modern cancer therapy is resulting in a growing population of cancer survivors who are at long-term risk for cardiovascular disease. The present review of contemporary clinical issues in cardio-oncology will be of interest to healthcare providers who manage cardiotoxicity during cancer therapy, and who follow patients who survive cancer but face increased long-term cardiovascular risk.

Providing Hepatitis C Treatment Locally for Substance-Using Patients.

This quality improvement (QI) project provided Hepatitis C virus (HCV) treatment at a Federally Qualified Health Clinic (FQHC) for persons who use illicit drugs. Many of these individuals sought treatment at the local Infectious Disease (ID) clinic but were denied care as they require a patient be drug-free for 6 months prior to HCV treatment. These individuals expressed a desire to be cured of HCV, which can lead to liver failure or cirrhosis if left untreated. This project bridged the existing gap in HCV treatment that currently exists for substance-users in this city. Pre-treatment HCV levels were obtained from 20 participants who completed an 8-week daily regimen of Mavyret, a direct-acting antiviral (DAA) agent, prescribed by a primary care Nurse Practitioner (NP), trained to treat HCV. Pre-treatment HCV loads were compared to the sustained viral load, obtained 12 weeks post-treatment (SVR-12), which is considered the "test of cure." The results indicate that 100% of returning patients were considered cured of HCV. This program successfully integrated HCV treatment at a community health center, in a population affected by substance use. Adoption of similar programs in primary care clinics can help meet the clinical needs of this often stigmatized and vulnerable population as well as cure them of HCV.

Improving yeast strains using recyclable integration cassettes, for the production of plant terpenoids.

BACKGROUND: Terpenoids constitute a large family of natural products, attracting commercial interest for a variety of uses as flavours, fragrances, drugs and alternative fuels. Saccharomyces cerevisiae offers a versatile cell factory, as the precursors of terpenoid biosynthesis are naturally synthesized by the sterol biosynthetic pathway. RESULTS: S. cerevisiae wild type yeast cells, selected for their capacity to produce high sterol levels were targeted for improvement aiming to increase production. Recyclable integration cassettes were developed which enable the unlimited sequential integration of desirable genetic elements (promoters, genes, termination sequence) at any desired locus in the yeast genome. The approach was applied on the yeast sterol biosynthetic pathway genes HMG2, ERG20 and IDI1 resulting in several-fold increase in plant monoterpene and sesquiterpene production. The improved strains were robust and could sustain high terpenoid production levels for an extended period. Simultaneous plasmid-driven co-expression of IDI1 and the HMG2 (K6R) variant, in the improved strain background, maximized monoterpene production levels. Expression of two terpene synthase enzymes from the sage species Salvia fruticosa and S. pomifera (SfCinS1, SpP330) in the modified yeast cells identified a range of terpenoids which are also present in the plant essential oils. Co-expression of the putative interacting protein HSP90 with cineole synthase 1 (SfCinS1) also improved production levels, pointing to an additional means to improve production. CONCLUSIONS: Using the developed molecular tools, new yeast strains were generated with increased capacity to produce plant terpenoids. The approach taken and the durability of the strains allow successive rounds of improvement to maximize yields.

Metabolomic investigations of American oysters using H-NMR spectroscopy.

The Eastern oyster (Crassostrea virginica) is a useful, robust model marine organism for tissue metabolism studies. Its relatively few organs are easily delineated and there is sufficient understanding of their functions based on classical assays to support interpretation of advanced spectroscopic approaches. Here we apply high-resolution proton nuclear magnetic resonance ((1)H NMR)-based metabolomic analysis to C. virginica to investigate the differences in the metabolic profile of different organ groups, and magnetic resonance imaging (MRI) to non-invasively identify the well separated organs. Metabolites were identified in perchloric acid extracts of three portions of the oyster containing: (1) adductor muscle, (2) stomach and digestive gland, and (3) mantle and gills. Osmolytes dominated the metabolome in all three organ blocks with decreasing concentration as follows: betaine > taurine > proline > glycine > ß-alanine > hypotaurine. Mitochondrial metabolism appeared most pronounced in the adductor muscle with elevated levels of carnitine facilitating ß-oxidation, and ATP, and phosphoarginine synthesis, while glycogen was elevated in the mantle/gills and stomach/digestive gland. A biochemical schematic is presented that relates metabolites to biochemical pathways correlated with physiological organ functions. This study identifies metabolites and corresponding (1)H NMR peak assignments for future NMR-based metabolomic studies in oysters.

The Clinical Utility of Continuous QT Interval Monitoring in Patients Admitted With COVID-19 Compared With Standard of Care: A Prospective Cohort Study.

BACKGROUND: QT interval monitoring has gained much interest during the COVID-19 pandemic because of the use of QT-prolonging medications and the concern about viral transmission with serial electrocardiograms (ECGs). We hypothesized that continuous telemetry-based QT monitoring is associated with better detection of prolonged QT episodes. METHODS: We introduced continuous cardiac telemetry (CCT) with an algorithm for automated QT interval monitoring to our designated COVID-19 units. The daily maximum automated heart rate-corrected QT (Auto-QTc) measurements were recorded. We compared the proportion of marked QTc prolongation (Long-QTc) episodes, defined as QTc ≥ 500 ms, in patients with suspected or confirmed COVID-19 who were admitted before and after CCT was implemented (control group vs CCT group, respectively). Manual QTc measurement by electrophysiologists was used to verify Auto-QTc. Charts were reviewed to describe the clinical response to Long-QTc episodes. RESULTS: We included 33 consecutive patients (total of 451 monitoring days). Long-QTc episodes were detected more frequently in the CCT group (69/206 [34%] vs 26/245 [11%]; P < 0.0001) and ECGs were performed less frequently (32/206 [16%] vs 78/245 [32%]; P < 0.0001). Auto-QTc correlated well with QTc measurement by electrophysiologists with an excellent agreement in detecting Long-QTc (κ = 0.8; P < 0.008). Only 28% of patients with Long-QTc episodes were treated with recommended therapies. There was 1 episode of torsade de pointes in the control group and none in the CCT group. CONCLUSIONS: Continuous QT interval monitoring is superior to standard of care in detecting episodes of Long-QTc with minimal need for ECGs. The clinical response to Long-QTc episodes is suboptimal.

INTRODUCTION: La surveillance de l'intervalle QT a suscité beaucoup d'intérêt durant la pandémie de la COVID-19 en raison de l'utilisation de médicaments prolongeant l'intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l'hypothèse que la surveillance en continu de l'intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l'intervalle QT. MÉTHODES: Nous avons introduit la télémétrie cardiaque en continu (TCC) à l'aide d'un algorithme de surveillance automatisée de l'intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l'intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l'intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin vs groupe de TCC, respectivement). La mesure manuelle de l'intervalle QTc par les électrophysiologistes a été utilisée pour vérifier les mesures auto-QTc. Nous avons passé en revue les dossiers pour décrire la réponse clinique aux épisodes de QTc long. RÉSULTATS: Nous avons sélectionné 33 patients consécutifs (total de 451 journées de surveillance). Les épisodes de QTc long étaient détectés plus fréquemment dans le groupe de TCC (69/206 [34 %] vs 26/245 [11 %]; p < 0,0001) et les ECG étaient moins fréquemment effectués (32/206 [16 %] vs 78/245 [32 %]; p < 0,0001). Les mesures auto-QTc corrélaient bien avec les mesures manuelles du QTc par les électrophysiologistes et montraient une excellente concordance dans la détection de QTc long (κ = 0,8; p < 0,008). Seuls 28 % des patients ayant des épisodes de QTc long ont reçu les thérapies recommandées. Il y a eu une épisode de torsade de pointes dans le groupe témoin et aucun dans le groupe de TCC. CONCLUSIONS: La surveillance en continu de l'intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d'ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.

Paging the eCardiologist: insights into referral behaviour of primary care physicians from qualitative analysis of a cardiology eConsult service.

OBJECTIVE: The purpose of this study is to investigate determinants of primary care physician cardiology referrals by performing qualitative analysis of questions asked by primary care physicians in cardiology electronic consultation services (eConsults). SETTING: A health region in eastern Ontario, Canada, where primary care providers have had access to an eConsult service since 2010. PARTICIPANTS: We included all consecutive cardiology eConsults initiated by registered primary care provider users of our eConsult service and who initiated one or more eConsult between July 2014 and January 2015. We excluded eConsults in which the primary care provider attached a document without asking a question. A convenience sample of 100 consecutive eConsults initiated by 61 primary care providers was analysed after excluding 14 eConsults.Primary and secondary outcome measures: Primary care provider eConsult questions are categorised into thematic categories based on the constant comparison method of qualitative analysis with external validation by content experts. Secondary outcomes include sample primary care provider eConsult questions to illustrate each theme and any emergent subthemes. RESULTS: Thematic saturation occurred after analysis of 30 eConsults. An additional 70 eConsults were coded with no new emergent themes. Themes include exceptions to clinical guidelines (n=13), non-cardiac treatment in a cardiac patient (n=13), specific investigation/management (n=18), interpretation of diagnostic testing (n=46), clinical concerns despite normal testing (n=4) and screening for positive family history (n=6). Subthemes include multiple comorbidities and mild abnormalities on cardiac tests. CONCLUSIONS: We report categories of clinical questions that drive primary care provider cardiology eConsults. Multimorbidity leads to cardiology eConsults as primary care providers try to apply treatment guidelines in medically complex patients. Mild test abnormalities unrelated to clinical problems commonly lead to cardiology eConsult requests. Further research is needed to determine how guidelines can better account for multimorbidity, and how cardiologists can better communicate with primary care providers to put cardiac test results in clinical context.

Shared Risk Factors for Cardiovascular Disease and Cancer: Implications for Preventive Health and Clinical Care in Oncology Patients.

The cardiovascular toxicity of cancer therapy has raised awareness of the importance of heart disease in cancer care among oncologists and cardiologists, leading to the new interdisciplinary field of cardio-oncology. Evidence is accumulating to suggest that risk factors associated with cardiovascular disease are also related to an increased incidence of cancer and excess cancer mortality. We review the epidemiologic evidence that smoking, obesity, poor diet, and inactivity can cause both heart disease and cancer. The importance of cardiovascular disease and cardiovascular risk factors in adversely affecting oncological outcomes and leading to increased cancer mortality is discussed. Cardiotoxicity prediction tools that incorporate cardiac disease and risk factors are described. Raising awareness about shared risk factors for cancer and heart disease may result in more effective advocacy to promote healthy lifestyle changes through the combined efforts of the historically separate specialties of cardiology and oncology.

Impending paradoxical embolus: a case report and review of the literature.

A case of a 43-year-old man with impending paradoxical embolism (IPE) is described. The patient initially presented with pulmonary embolism and was diagnosed with an IPE on transthoracic and transesophageal echocardiography. He was subsequently treated with heparin and thrombolysis. A comprehensive review of the English literature over the past 20 years identified 60 previously reported cases of IPE. This report discusses the main clinical features, the diagnostic role of echocardiography and the outcome of medical and surgical treatment strategies in patients with IPE. Based on the literature to date, we recommend that patients with impending paradoxical embolism be treated with initial systemic heparinization followed by emergent surgical embolectomy if the surgical risks are acceptable.

Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma.

ALT-803, a complex of an interleukin (IL)-15 superagonist mutant and a dimeric IL-15 receptor αSu/Fc fusion protein, was found to exhibit significantly stronger in vivo biologic activity on NK and T cells than IL-15. In this study, we show that a single dose of ALT-803, but not IL-15 alone, eliminated well-established 5T33P and MOPC-315P myeloma cells in the bone marrow of tumor-bearing mice. ALT-803 treatment also significantly prolonged survival of myeloma-bearing mice and provided resistance to rechallenge with the same tumor cells through a CD8(+) T-cell-dependent mechanism. ALT-803 treatment stimulated CD8(+) T cells to secrete large amounts of IFN-γ and promoted rapid expansion of CD8(+)CD44(high) memory T cells in vivo. These memory CD8(+) T cells exhibited ALT-803-mediated upregulation of NKG2D (KLRK1) but not PD-1 (PDCD1) or CD25 (IL2RA) on their cell surfaces. ALT-803-activated CD8(+) memory T cells also exhibited nonspecific cytotoxicity against myeloma and other tumor cells in vitro, whereas IFN-γ had no direct effect on myeloma cell growth. ALT-803 lost its antimyeloma activity in tumor-bearing IFN-γ knockout mice but retained the ability to promote CD8(+)CD44(high) memory T-cell proliferation, indicating that ALT-803-mediated stimulation of CD8(+)CD44(high) memory T cells is IFN-γ-independent. Thus, besides well-known IL-15 biologic functions in host immunity, this study shows that IL-15-based ALT-803 could activate CD8(+)CD44(high) memory T cells to acquire a unique innate-like phenotype and secrete IFN-γ for nonspecific tumor cell killing. This unique immunomodulatory property of ALT-803 strongly supports its clinical development as a novel immunotherapeutic agent against cancer and viral infections.

Rational conversion of substrate and product specificity in a Salvia monoterpene synthase: structural insights into the evolution of terpene synthase function.

Terpene synthases are responsible for the biosynthesis of the complex chemical defense arsenal of plants and microorganisms. How do these enzymes, which all appear to share a common terpene synthase fold, specify the many different products made almost entirely from one of only three substrates? Elucidation of the structure of 1,8-cineole synthase from Salvia fruticosa (Sf-CinS1) combined with analysis of functional and phylogenetic relationships of enzymes within Salvia species identified active-site residues responsible for product specificity. Thus, Sf-CinS1 was successfully converted to a sabinene synthase with a minimum number of rationally predicted substitutions, while identification of the Asn side chain essential for water activation introduced 1,8-cineole and alpha-terpineol activity to Salvia pomifera sabinene synthase. A major contribution to product specificity in Sf-CinS1 appears to come from a local deformation within one of the helices forming the active site. This deformation is observed in all other mono- or sesquiterpene structures available, pointing to a conserved mechanism. Moreover, a single amino acid substitution enlarged the active-site cavity enough to accommodate the larger farnesyl pyrophosphate substrate and led to the efficient synthesis of sesquiterpenes, while alternate single substitutions of this critical amino acid yielded five additional terpene synthases.

UV-B is required for normal development of oil glands in Ocimum basilicum L. (sweet basil).

Plants of Ocimum basilicum L. grown under glass were exposed to short treatments with supplementary UV-B. The effect of UV-B on volatile essential oil content was analysed and compared with morphological effects on the peltate and capitate glandular trichomes. In the absence of UV-B, both peltate and capitate glands were incompletely developed in both mature and developing leaves, the oil sacs being wrinkled and only partially filled. UV-B was found to have two main effects on the glandular trichomes. During the first 4 d of treatment, both peltate and capitate glands filled and their morphology reflected their 'normal' mature development as reported in the literature. During the following days there was a large increase in the number of broken oil sacs among the peltate glands as the mature glands broke open, releasing volatiles. Neither the number of glands nor the qualitative or quantitative composition of the volatiles was affected by UV-B. There seems to be a requirement for UV-B for the filling of the glandular trichomes of basil.

Seasonal, populational and ontogenic variation in the volatile oil content and composition of individuals of Origanum vulgare subsp. Hirtum, assessed by GC headspace analysis and by SPME sampling of individual oil glands.

Small-scale GC headspace analyses combined with SPME sampling of individual oil glands have been used to measure the variation in volatile content and composition in and within different oregano plants as affected by age, season and developmental state. The main monoterpenes found were p-cymene, carvacrol and their precursor gamma-terpinene. The early season preponderance of p-cymene over carvacrol was reversed as the season progressed and this pattern could also be seen at any time within the plant, from the latest leaves to be produced (low in cymene) to the earliest (high in cymene). Seedlings from the same mother plant developed this pattern at different rates. Within individual leaves the pattern was not observed, even within the youngest developing leaves. However it was found that the oil composition of individual glands within a single leaf varied considerably, most notably in respect of the production of carvacrol and its isomer thymol.