Common data models to streamline metabolomics processing and annotation, and implementation in a Python pipeline.

To standardize metabolomics data analysis and facilitate future computational developments, it is essential to have a set of well-defined templates for common data structures. Here we describe a collection of data structures involved in metabolomics data processing and illustrate how they are utilized in a full-featured Python-centric pipeline. We demonstrate the performance of the pipeline, and the details in annotation and quality control using large-scale LC-MS metabolomics and lipidomics data and LC-MS/MS data. Multiple previously published datasets are also reanalyzed to showcase its utility in biological data analysis. This pipeline allows users to streamline data processing, quality control, annotation, and standardization in an efficient and transparent manner. This work fills a major gap in the Python ecosystem for computational metabolomics.

Aziridination via Nitrogen-Atom Transfer to Olefins from Photoexcited Azoxy-Triazenes.

Herein, we report that readily accessible azoxy-triazenes can serve as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination of alkenes. This approach eliminates the need for external oxidants, precious transition metals, and photocatalysts, marking a departure from conventional methods. The versatility of this transformation extends to the selective aziridination of both activated and unactivated multisubstituted alkenes of varying electronic profiles. Notably, this process avoids the formation of competing C-H insertion products. The described protocol is operationally simple, scalable, and adaptable to photoflow conditions. Mechanistic studies support the idea that the photofragmentation of azoxy-triazenes results in the generation of a free singlet nitrene. Furthermore, a mild photoredox-catalyzed N-N cleavage of the protecting group to furnish the free aziridines is reported. Our findings contribute to the advancement of sustainable and practical methodologies for the synthesis of nitrogen-containing compounds, showcasing the potential for broader applications in synthetic chemistry.

Identification Drug Targets for Oxaliplatin-Induced Cardiotoxicity without Affecting Cancer Treatment through Inter Variability Cross-Correlation Analysis (IVCCA).

The successful treatment of side effects of chemotherapy faces two major limitations: the need to avoid interfering with pathways essential for the cancer-destroying effects of the chemotherapy drug, and the need to avoid helping tumor progression through cancer promoting cellular pathways. To address these questions and identify new pathways and targets that satisfy these limitations, we have developed the bioinformatics tool Inter Variability Cross-Correlation Analysis (IVCCA). This tool calculates the cross-correlation of differentially expressed genes, analyzes their clusters, and compares them across a vast number of known pathways to identify the most relevant target(s). To demonstrate the utility of IVCCA, we applied this platform to RNA-seq data obtained from the hearts of the animal models with oxaliplatin-induced CTX. RNA-seq of the heart tissue from oxaliplatin treated mice identified 1744 differentially expressed genes with False Discovery Rate (FDR) less than 0.05 and fold change above 1.5 across nine samples. We compared the results against traditional gene enrichment analysis methods, revealing that IVCCA identified additional pathways potentially involved in CTX beyond those detected by conventional approaches. The newly identified pathways such as energy metabolism and several others represent promising target for therapeutic intervention against CTX, while preserving the efficacy of the chemotherapy treatment and avoiding tumor proliferation. Targeting these pathways is expected to mitigate the damaging effects of chemotherapy on cardiac tissues and improve patient outcomes by reducing the incidence of heart failure and other cardiovascular complications, ultimately enabling patients to complete their full course of chemotherapy with improved quality of life and survival rates.

Common data models to streamline metabolomics processing and annotation, and implementation in a Python pipeline.

To standardize metabolomics data analysis and facilitate future computational developments, it is essential is have a set of well-defined templates for common data structures. Here we describe a collection of data structures involved in metabolomics data processing and illustrate how they are utilized in a full-featured Python-centric pipeline. We demonstrate the performance of the pipeline, and the details in annotation and quality control using large-scale LC-MS metabolomics and lipidomics data and LC-MS/MS data. Multiple previously published datasets are also reanalyzed to showcase its utility in biological data analysis. This pipeline allows users to streamline data processing, quality control, annotation, and standardization in an efficient and transparent manner. This work fills a major gap in the Python ecosystem for computational metabolomics.

Moving towards establishing centres of excellence in cardiac amyloidosis: an International Cardio-Oncology Society statement.

The prevalence of amyloidosis has been increasing, driven by a combination of improved awareness, evolution of diagnostic pathways, and effective treatment options for both transthyretin and light chain amyloidosis. Due to the complexity of amyloidosis, centralised expert providers with experience in delineating the nuances of confirmatory diagnosis and management may be beneficial. There are many potential benefits of a centre of excellence designation for the treatment of amyloidosis including recognition of institutions that have been leading the way for the optimal treatment of this condition, establishing the expectations for any centre who is engaging in the treatment of amyloidosis and developing cooperative groups to allow more effective research in this disease space. Standardising the expectations and criteria for these centres is essential for ensuring the highest quality of clinical care and community education. In order to define what components are necessary for an effective centre of excellence for the treatment of amyloidosis, we prepared a survey in cooperation with a multidisciplinary panel of amyloidosis experts representing an international consortium. The purpose of this position statement is to identify the essential elements necessary for highly effective clinical care and to develop a general standard with which practices or institutions could be recognised as a centre of excellence.

OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials.

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features in simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations with only a modest increase in cost.

OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials.

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features on simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein (GFP) chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations at only a modest increase in cost.

Advances in Screening for Radiation-Associated Cardiotoxicity in Cancer Patients.

PURPOSE OF REVIEW: Radiation is foundational to the treatment of cancer and improves overall survival. Yet, it is important to recognize the potential cardiovascular effects of radiation therapy and how to best minimize or manage them. Screening-both through imaging and with biomarkers-can potentially identify cardiovascular effects early, allowing for prompt initiation of treatment to mitigate late effects. RECENT FINDINGS: Cardiac echocardiography, magnetic resonance imaging (MRI), computed tomography, and measurements of troponin and natriuretic peptides serve as the initial screening tests of choice for RICD. Novel imaging applications, including positron emission tomography and specific MRI parameters, and biomarker testing, including myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and metabolomics, hold promise for earlier detection and more specific characterization of RICD. Advances in imaging and novel applications of biomarkers have potential to identify subclinical RICD and may reveal opportunities for early intervention. Further research is needed to elucidate optimal imaging screening modalities, biomarkers, and surveillance strategies.

The Cardiac Amyloidosis Registry Study (CARS): Rationale, Design and Methodology.

BACKGROUND: CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA) evaluated at major amyloidosis centers between 1997 and 2025. CARS aims to describe the natural history of CA with attention to clinical and diagnostic variables at the time of diagnosis, real-world treatment patterns, and associated outcomes of patients in a diverse cohort that is more representative of the at-risk population than that described in CA clinical trials. METHODS AND RESULTS: This article describes the design and methodology of CARS, including procedures for data collection and preliminary results. As of February 2023, 20 centers in the United States enrolled 1415 patients, including 1155 (82%) with ATTR and 260 (18%) with AL CA. Among those with ATTR, wild-type is the most common ATTR (71%), and most of the 305 patients with variant ATTR have the p.V142I mutation (68%). A quarter of the total population identifies as Black. More individuals with AL are female (39%) compared to those with ATTR (13%). CONCLUSIONS: CARS will answer crucial clinical questions about CA natural history and permit comparison of different therapeutics not possible through current clinical trials. Future international collaboration will further strengthen the validity of observations of this increasingly recognized condition.

Early Increases in Blood Pressure and Major Adverse Cardiovascular Events in Patients With Renal Cell Carcinoma and Thyroid Cancer Treated With VEGFR TKIs.

BACKGROUND: Although VEGFR tyrosine kinase inhibitors (TKIs) are a preferred systemic treatment approach for patients with advanced renal cell carcinoma (RCC) and thyroid carcinoma (TC), treatment-related cardiovascular (CV) toxicity is an important contributor to morbidity. However, the clinical risk assessment and impact of CV toxicities, including early significant hypertension, among real-world advanced cancer populations receiving VEGFR TKI therapies remain understudied. METHODS: In a multicenter, retrospective cohort study across 3 large and diverse US health systems, we characterized baseline hypertension and CV comorbidity in patients with RCC and those with TC who are newly initiating VEGFR TKI therapy. We also evaluated baseline patient-, treatment-, and disease-related factors associated with the risk for treatment-related early hypertension (within 6 weeks of TKI initiation) and major adverse CV events (MACE), accounting for the competing risk of death in an advanced cancer population, after VEGFR TKI initiation. RESULTS: Between 2008 and 2020, 987 patients (80.3% with RCC, 19.7% with TC) initiated VEGFR TKI therapy. The baseline prevalence of hypertension was high (61.5% and 53.6% in patients with RCC and TC, respectively). Adverse CV events, including heart failure and cerebrovascular accident, were common (occurring in 14.9% of patients) and frequently occurred early (46.3% occurred within 1 year of VEGFR TKI initiation). Baseline hypertension and Black race were the primary clinical factors associated with increased acute hypertensive risk within 6 weeks of VEGFR TKI initiation. However, early significant "on-treatment" hypertension was not associated with MACE. CONCLUSIONS: These multicenter, real-world findings indicate that hypertensive and CV morbidities are highly prevalent among patients initiating VEGFR TKI therapies, and baseline hypertension and Black race represent the primary clinical factors associated with VEGFR TKI-related early significant hypertension. However, early on-treatment hypertension was not associated with MACE, and cancer-specific CV risk algorithms may be warranted for patients initiating VEGFR TKIs.

Photoinduced Nitroarenes as Versatile Anaerobic Oxidants for Accessing Carbonyl and Imine Derivatives.

Herein, we report a protocol for the anaerobic oxidation of alcohols, amines, aldehydes, and imines promoted by photoexcited nitroarenes. Mechanistic studies support the idea that photoexcited nitroarenes undergo double hydrogen atom transfer (HAT) steps with alcohols and amines to provide the respective ketone and imine products. In the presence of aldehydes and imines, successive HAT and oxygen atom transfer (OAT) events occur to yield carboxylic acids and amides, respectively. This transformation is amenable to a continuous-photoflow setup, which led to reduced reaction times.

Cardiovascular toxicities after anthracycline and VEGF-targeted therapies in adolescent and young adult cancer survivors.

BACKGROUND: Cancer survival rates have been steadily improving in the adolescent and young adult (AYA) population, but survivors are at increased risk for cardiovascular disease (CVD). The cardiotoxic effects of anthracycline therapy have been well studied. However, the cardiovascular toxicity associated with newer therapies, such as the vascular endothelial growth factor (VEGF) inhibitors, is less well understood. OBJECTIVE: This retrospective study of AYA cancer survivors sought to gain insight into their burden of cardiovascular toxicities (CT) following initiation of anthracycline and/or VEGF inhibitor therapy. METHODS: Data were extracted from electronic medical records over a fourteen-year period at a single institution. Cox proportional hazards regression modeling was used to examine risk factors for CT within each treatment group. Cumulative incidence was calculated with death as a competing risk. RESULTS: Of the 1,165 AYA cancer survivors examined, 32%, 22%, and 34% of patients treated with anthracycline, VEGF inhibitor, or both, developed CT. Hypertension was the most common outcome reported. Males were at increased risk for CT following anthracycline therapy (HR: 1.34, 95% CI 1.04-1.73). The cumulative incidence of CT was highest in patients who received both anthracycline and VEGF inhibitor (50% at ten years of follow up). CONCLUSIONS: CT was common among AYA cancer survivors who received anthracycline and/or VEGF inhibitor therapy. Male sex was an independent risk factor for CT following anthracycline treatment. Further screening and surveillance are warranted to continue understanding the burden of CVD following VEGF inhibitor therapy.

Adding Pharmacist-Led Home Blood Pressure Telemonitoring to Usual Care for Blood Pressure Control: A Systematic Review and Meta-Analysis.

Health systems have been quickly adopting telemedicine throughout the United States, especially since the onset of the COVID-19 pandemic. However, there are limited data on whether adding pharmacist-led home blood pressure (BP) telemonitoring to office-based usual care improves BP. We searched PubMed/MEDLINE and Embase for randomized controlled trials from January 2000 until April 2022, comparing studies on pharmacist-led home BP telemonitoring with usual care. Six randomized controlled trials, including 1,550 participants, satisfied the inclusion criteria. There were 774 participants in the pharmacist-led telemonitoring group and 776 in the usual care group. The addition of pharmacist-led telemonitoring to usual care was associated with a significant decrease in systolic BP (mean difference -8.09, 95% confidence interval -11.15 to -5.04, p <0.001, I2 = 72%) and diastolic BP (mean difference -4.19, 95% confidence interval -5.58 to -2.81, p <0.001, I2 = 42%) compared with usual care. In conclusion, this meta-analysis showed that adding pharmacist-led home BP telemonitoring to usual care achieves better BP control than usual care alone.

Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart's energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage.

Iodide uptake by forest soils is principally related to the activity of extracellular oxidases.

129I is a nuclear fission decay product of concern because of its long half-life (16 Ma) and propensity to bioaccumulate. Microorganisms impact iodine mobility in soil systems by promoting iodination (covalent binding) of soil organic matter through processes that are not fully understood. Here, we examined iodide uptake by soils collected at two depths (0-10 and 10-20 cm) from 5 deciduous and coniferous forests in Japan and the United States. Autoclaved soils, and soils amended with an enzyme inhibitor (sodium azide) or an antibacterial agent (bronopol), bound significantly less 125I tracer (93%, 81%, 61% decrease, respectively) than the untreated control soils, confirming a microbial role in soil iodide uptake. Correlation analyses identified the strongest significant correlation between 125I uptake and three explanatory variables, actinobacteria soil biomass (p = 6.04E-04, 1.35E-02 for Kendall-Tau and regression analysis, respectively), soil nitrogen content (p = 4.86E-04, 4.24E-03), and soil oxidase enzyme activity at pH 7.0 using the substrate L-DOPA (p = 2.83E-03, 4.33E-04) and at pH 5.5 using the ABTS (p = 5.09E-03, 3.14E-03). Together, the results suggest that extracellular oxidases, primarily of bacterial origin, are the primary catalyst for soil iodination in aerobic, surface soils of deciduous and coniferous forests, and that soil N content may be indicative of the availability of binding sites for reactive iodine species.

Clinicopathological classification of immune checkpoint inhibitor-associated myocarditis: possible refinement by measuring macrophage abundance.

BACKGROUND: Immune checkpoint inhibitor (ICI) myocarditis is associated with high morbidity and mortality. While endomyocardial biopsy (EMB) is considered a gold standard for diagnosis, the sensitivity of EMB is not well defined. Additionally, the pathological features that correlate with the clinical diagnosis of ICI-associated myocarditis remain incompletely understood. METHODS: We retrospectively identified and reviewed the clinicopathological features of 26 patients with suspected ICI-associated myocarditis based on institutional major and minor criteria. Seventeen of these patients underwent EMB, and the histopathological features were assessed by routine hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for CD68, a macrophage marker. RESULTS: Only 2/17 EMBs obtained from patients with suspected ICI myocarditis satisfied the Dallas criteria. Supplemental IHC staining and quantification of CD68+ macrophages identified an additional 7 patients with pathological features of myocardial inflammation (> 50 CD68+ cells/HPF). Macrophage abundance positively correlated with serum Troponin I (P = 0.010) and NT-proBNP (N-terminal pro-brain natriuretic peptide, P = 0.047) concentration. Inclusion of CD68 IHC could have potentially changed the certainty of the diagnosis of ICI-associated myocarditis to definite in 6/17 cases. CONCLUSIONS: While the Dallas criteria can identify a subset of ICI-associated myocarditis patients, quantification of macrophage abundance may expand the diagnostic role of EMB. Failure to meet the traditional Dallas Criteria should not exclude the diagnosis of myocarditis.

Real-World Efficacy of Tafamidis in Patients With Transthyretin Amyloidosis and Heart Failure.

Tafamidis was associated with a reduction in cardiovascular hospitalizations and all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the ATTR-ACT trial. However, real-world data on the efficacy of tafamidis are limited. We conducted a retrospective, observational cohort study using the TriNetX research network. Patients with wild-type TTR amyloidosis and heart failure (HF) were divided into 2 groups based on treatment with tafamidis. Propensity score matching (PSM) was performed, and rates of heart failure exacerbations (HFE) and all-cause mortality at 12 months were compared. After PSM, 421 patients were in each group (tafamidis vs nontafamidis). During the 12-month follow-up period, patients treated with tafamidis experienced significantly less HFE and all-cause mortality. A higher probability of event-free survival for HFE and all-cause mortality was noted with tafamidis. This real-world analysis supports that tafamidis use is associated with reduced HFE and all-cause mortality in patients with wild-type TTR amyloidosis and HF. Longer-term follow-up is needed to better understand the utility of tafamidis, given the increasing recognition of ATTR-CM and the high cost of tafamidis.

Recent Advances in Serum Biomarkers for Risk Stratification and Patient Management in Cardio-Oncology.

PURPOSE OF REVIEW: Following significant advancements in cancer therapeutics and survival, the risk of cancer therapy-related cardiotoxicity (CTRC) is increasingly recognized. With ongoing efforts to reduce cardiovascular morbidity and mortality in cancer patients and survivors, cardiac biomarkers have been studied for both risk stratification and monitoring during and after therapy to detect subclinical disease. This article will review the utility for biomarker use throughout the cancer care continuum. RECENT FINDINGS: A recent meta-analysis shows utility for troponin in monitoring patients at risk for CTRC during cancer therapy. The role for natriuretic peptides is less clear but may be useful in patients receiving proteasome inhibitors. Early studies explore use of myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and others as novel biomarkers in CTRC. Biomarkers have potential to identify subclinical CTRC and may reveal opportunities for early intervention. Further research is needed to elucidate optimal biomarkers and surveillance strategies.

Cascade Synthesis of Phenanthrenes under Photoirradiation.

We report a photoinduced phenanthrene synthesis from aryl iodides and styrenes through an arylation/cyclization cascade. Compared to prior methods, this approach obviates the need for hazardous reagents and provides access to unsymmetrical phenanthrenes with good functional group tolerance. Mechanistic studies revealed that photoexcitation of aryl iodides leads to homolytic C-I bond cleavage. Arylation of styrenes with the formed aryl radical species furnishes stilbene derivatives, which undergo photoinduced cyclization promoted by iodine generated in situ to yield phenanthrene products.