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Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information.
No full textMetabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints.Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable.Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance.This study developed a series of ML models of accuracy ranging from 71.9-99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means
Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone.
No full textCardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process.To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec).Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected.The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single‑lead ECGs collected from freely moving dogs and monkeys
In Vivo Genotoxicity Testing Strategies: Report from the 8th International Workshop on Genotoxicity Testing (IWGT)
No full textThe working group reached complete or majority agreement on many issues.
A negative in vivo erythrocyte MN study should be acceptable if dosing is conducted up to a dose level recommended by OECD TG 474, and if sufficient bone marrow exposure is demonstrated. Full consensus on the evidence required to demonstrate “sufficient” bone marrow exposure was not reached.
The liver MN test using six-week-old rats is sufficiently validated to develop an OECD Test Guideline, however, the impact of animal age warrants further study. Ki-67 is a reliable marker for cellular proliferation in hepatocytes.
The GI tract MN test is useful for the genotoxicity evaluation of in vitro aneugens that are poorly absorbed or rapidly degraded, and therefore unlikely to reach the bone marrow, or for metabolites formed in the colon. There are insufficient validation data to support the development of a new OECD guideline, however the methodologies are sufficiently advanced to consider creating an appendix to OECD TG 474.
Comparison of comet results to historical control data [HCD]) should not be used for data evaluation, unless it is demonstrated that the HCD distribution is stable, and animal not study factors are the predominant source of HCD variance. A universally acceptable negative control range of %TI for any tissue cannot be identified at this time. Methodological differences in comet studies could result in misleading conclusions, however, more data are required before best practice recommendations can be made. Hedgehogs alone are unreliable for the measurement of cytotoxicity and further discussion is required
Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity.
No full textThe recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan
Bioequivalence between a new omalizumab prefilled syringe with an autoinjector or with a needle safety device compared with the current prefilled syringe: a randomized controlled trial in healthy volunteers
No full textOmalizumab is an anti-IgE monoclonal antibody currently approved for the treatment of asthma, nasal polyps/chronic rhinosinusitis with nasal polyps, and chronic spontaneous urticaria. Omalizumab is available as an injection in a prefilled syringe (PFS) with a needle safety device (NSD). New product configurations were developed to reduce the number of injections per dose administration, improve patient convenience and treatment compliance. The objective of this randomized open-label 12-week study was to demonstrate pharmacokinetic bioequivalence between (i) new PFS with autoinjector (PFS-AI), (ii) new PFS-NSD configuration, and (iii) current PFS-NSD configuration. Each new configuration was considered bioequivalent to the current configuration if the confidence intervals (CIs) for the geometric mean ratios (GMR) were contained in the 0.80–1.25 range for maximum concentration (Cmax), area under the concentration-time curve until the last quantifiable measurement (AUClast), and AUC extrapolated to infinity (AUCinf). Safety was assessed throughout the study. In total, 193 healthy volunteers were randomized at 1:1:1 ratio to omalizumab 1x300mg/2mL via new PFS-AI (n=66), omalizumab 1x300mg/2mL via new PFS-NSD (n=64), or omalizumab 2x150mg/1mL via current PFS-NSD (n=63). Comparing new PFS-AI versus current PFS-NSD, the GMRs (95% CIs) were: Cmax, 1.085 (0.996–1.181); AUClast, 1.093 (0.997–1.199); AUCinf, 1.100 (1.001–1.209). Comparing new PFS-NSD versus current PFS-NSD, the GMRs (95% CIs) were: Cmax, 1.006 (0.923–1.096); AUClast, 1.016 (0.925–1.116); AUCinf, 1.027 (0.933–1.130). Safety findings were consistent with the known safety profile of omalizumab. Single-dose omalizumab administered as the new PFS-AI or new PFS-NSD was bioequivalent to the current PFS-NSD
Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality
No full textEnhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)−2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker
Meeting report of the 5th European Biotransformation Workshop
No full textChallenges, strategies and new technologies in the field of biotransformation were presented and discussed at the 5th European Biotransformation Workshop, which was held on March 14, 2024 on the Novartis Campus in Basel, Switzerland.
2. In this meeting report we summarise the presentations and discussions from this workshop.
3. The topics covered are listed below:
• Advances in understanding drug induced liver injury (DILI) risks of carboxylic acids and targeted covalent inhibitors
• Biotransformation of oligonucleotide-based therapeutics including automated software tools for metabolite identification
• Recent advances in metabolite synthesis
• Qualification and validation of a new compact Low Energy Accelerator Mass Spectrometry (LEA) system for metabolite profiling
Keywords: unusual biotransformation reactions, acyl glucuronides, acyl CoA conjugates, DILI risks, biotransformation of oligonucleotides, Genedata software for MS data processing of oligonucleotides, AMS, Mass spectrometry imagin
Protein destabilization underlies pathogenic missense mutations in ARID1B.
No full textARID1B is a SWI/SNF subunit frequently mutated in human Coffin-Siris syndrome (CSS) and it is necessary for proliferation of ARID1A mutant cancers. While most CSS ARID1B aberrations introduce frameshifts or stop codons, the functional consequence of missense mutations found in ARID1B is unclear. We here perform saturated mutagenesis screens on ARID1B and demonstrate that protein destabilization is the main mechanism associated with pathogenic missense mutations in patients with Coffin-Siris Syndrome