Evaluation of Cardiotoxic Effects of Non-Small Cell Lung Cancer (NSCLC) Treatments: Insights from Multiple Databases in the United Kingdom

Cancer and heart diseases are two of the major causes of death in the world. In the last few decades, there is a rapid development in cancer therapies and early detection strategies, hence the death rates caused by cancer have decreased. Although survival rates have improved, it is observed that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Thus, the risk of cardiotoxicity is one of the major limitations of oncology drug development. Cardiotoxicity can occur during any stage of the cancer, and it includes, but is not limited to, subclinical myocardial toxicity, ischemia, hypertension, supraventricular and ventricular arrhythmias, systolic and diastolic cardiac dysfunction, coronary artery disease and heart failure. Therefore, the aim of this study was to investigate the association between non-small cell lung cancer (NSCLC) drugs and cardiotoxicity by using real-world data and clinical trials data available from public domains, reports and published literatures. A systematic review using several electronic databases was completed to evaluate randomised controlled trials data, in which cardiotoxicity was developed in non-small cell lung cancer patients after the administration of anticancer drugs. A full version protocol of this systematic review (CRD42020191760) is published on PROSPERO. A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that reported to be associated with cardiovascular events included bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities included arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. A feasibility assessment was conducted to identify the most suitable database for investigating the association between non-small cell lung cancer and cardiotoxicity. A total of 103 data sources were identified from the Health Data Research Innovation Gateway and public domain using the search term ‘cancer’. Data sources which healthcare settings are primary care only were not suitable for this research question. Primary care only data is a major limitation for oncology studies as oncology treatment and follow-ups are mostly followed in secondary care settings. Consequently, only 2 eligible data sources (#34 and #54) were included for data extraction. An observational study based on a retrospective design using real-world data from the DEFINE database in England was performed. Monthly secondary data of 40 shortlisted drugs (20 anticancer drugs and 20 cardiology drugs) from April 2017 to July 2022 were extracted. From the correlation matrix, it can be concluded that hypertension was the most associated cardiovascular disease with the 20 shortlisted oncology drugs. A pharmacovigilance study was conducted utilising the UK Yellow Card System. All NSCLC drugs available within the UK Yellow Card System were shortlisted. Proportional reporting ratio (PRR) and reporting odds ratio (ROR) were calculated to detect signals. The total number of adverse events reported was 128,214 with 6133 reports being cardiovascular adverse reactions. Alectinib had the highest signal for potential cardiovascular adverse events among the drugs analysed, as indicated by both the highest ROR and PRR values. Due to drug-induced cardiotoxic complications, it is important to understand the suspected associations in order to maintain a benefit-risk balance between therapeutic gain and risk of cardiotoxicity. The combined findings of the systematic review, the pharmacoepidemiology study and the pharmacovigilance report have elucidated the types of cardiotoxicities associated with certain NSCLC therapeutics. To enhance the therapeutic management of NSCLC, continued research on identifying patients at elevated risk of cardiovascular adverse events as well as implementation of early detection and screening strategies are imperative

Dry Powder Formulation of Azithromycin for COVID-19 Therapeutics

Aim: The aim of this study is to develop dry powder formulations of azithromycin-loaded poly(lactic-co-glycolic acid) (PLGA) nanocomposite microparticles for pulmonary delivery to improve the low bioavailability of azithromycin. Methods: Double emulsion method was used to produce nanoparticles, which were then spray dried to form nanocomposite microparticles. Encapsulation efficiency and drug loading were analysed, and formulations were characterised by particle size, zeta potential, morphology, crystallinity and in-vitro aerosol dispersion performance. Results: The addition of chitosan changed the neutrally-charged azithromycin only formulation to positively-charged nanoparticles. However, the addition of chitosan also increased the particle size of the formulations. It was observed in the NGI® data that there is an improvement in dispersibility of the chitosan-related formulations. Conclusion: It was demonstrated in this study that all dry powder formulations were able to deliver azithromycin to the deep lung regions, which suggests the potential of using azithromycin via pulmonary drug delivery as an effective method to treat COVID-19

Dry powder formulation of azithromycin for COVID-19 therapeutics

Aim: The aim of this study is to develop dry powder formulations of azithromycin-loaded poly(lactic-co-glycolic acid) (PLGA) nanocomposite microparticles for pulmonary delivery to improve the low bioavailability of azithromycin. Methods: Double emulsion method was used to produce nanoparticles, which were then spray dried to form nanocomposite microparticles. Encapsulation efficiency and drug loading were analysed, and formulations were characterised by particle size, zeta potential, morphology, crystallinity and in-vitro aerosol dispersion performance. Results: The addition of chitosan changed the neutrally-charged azithromycin only formulation to positively-charged nanoparticles. However, the addition of chitosan also increased the particle size of the formulations. It was observed in the NGI® data that there is an improvement in dispersibility of the chitosan-related formulations. Conclusion: It was demonstrated in this study that all dry powder formulations were able to deliver azithromycin to the deep lung regions, which suggests the potential of using azithromycin via pulmonary drug delivery as an effective method to treat COVID-19

Identification of cardiotoxicity related to non-small cell lung cancer (NSCLC) treatments: A systematic review

© 2023 Chan, Khatib, Webley, Layton and Salek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/Introduction: In the last few decades, there has been a rapid development in cancer therapies and improved detection strategies, hence the death rates caused by cancer have decreased. However, it has been reported that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Cardiotoxicity from anticancer drugs affects the heart’s function and structure and can occur during any stage of the cancer treatments, which leads to the development of cardiovascular disease. Objectives: To investigate the association between anticancer drugs for non-small cell lung cancer (NSCLC) and cardiotoxicity as to whether: different classes of anticancer drugs demonstrate different cardiotoxicity potentials; different dosages of the same drug in initial treatment affect the degree of cardiotoxicity; and accumulated dosage and/or duration of treatments affect the degree of cardiotoxicity. Methods: This systematic review included studies involving patients over 18 years old with NSCLC and excluded studies in which patients’ treatments involve radiotherapy only. Electronic databases and registers including Cochrane Library, National Cancer Institute (NCI) Database, PubMed, Scopus, Web of Science, ClinicalTrials.gov and the European Union Clinical Trials Register were systematically searched from the earliest available date up until November 2020. A full version protocol of this systematic review (CRD42020191760) had been published on PROSPERO. Results: A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that are associated with cardiovascular events include bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities include arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. Conclusion: The findings of this systematic review have provided a better understanding of the possible association between cardiotoxicities and anticancer drugs for NSCLC. Whilst variation is observed across different drug classes, the lack of information available on cardiac monitoring can result in underestimation of this association. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191760, identifier PROSPERO CRD42020191760.Peer reviewe

Identification of cardiotoxicity related to non-small cell lung cancer (NSCLC) treatments: A systematic review

Introduction: In the last few decades, there has been a rapid development in cancer therapies and improved detection strategies, hence the death rates caused by cancer have decreased. However, it has been reported that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Cardiotoxicity from anticancer drugs affects the heart’s function and structure and can occur during any stage of the cancer treatments, which leads to the development of cardiovascular disease.Objectives: To investigate the association between anticancer drugs for non-small cell lung cancer (NSCLC) and cardiotoxicity as to whether: different classes of anticancer drugs demonstrate different cardiotoxicity potentials; different dosages of the same drug in initial treatment affect the degree of cardiotoxicity; and accumulated dosage and/or duration of treatments affect the degree of cardiotoxicity.Methods: This systematic review included studies involving patients over 18 years old with NSCLC and excluded studies in which patients’ treatments involve radiotherapy only. Electronic databases and registers including Cochrane Library, National Cancer Institute (NCI) Database, PubMed, Scopus, Web of Science, ClinicalTrials.gov and the European Union Clinical Trials Register were systematically searched from the earliest available date up until November 2020. A full version protocol of this systematic review (CRD42020191760) had been published on PROSPERO.Results: A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that are associated with cardiovascular events include bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities include arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia.Conclusion: The findings of this systematic review have provided a better understanding of the possible association between cardiotoxicities and anticancer drugs for NSCLC. Whilst variation is observed across different drug classes, the lack of information available on cardiac monitoring can result in underestimation of this association.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191760, identifier PROSPERO CRD42020191760

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe