Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(11), P. e005414 - e005414

Published: Nov. 1, 2022

Background Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and third-leading cause cancer-related death worldwide. Most patients with HCC are diagnosed at an advanced stage, median survival for treated modern systemic therapy less than 2 years. This leaves stage limited treatment options. Immune checkpoint inhibitors (ICIs) targeting programmed cell protein 1 (PD-1) or its ligand, widely used in associated durable responses a subset patients. ICIs cytotoxic T-lymphocyte-associated 4 (CTLA-4) also have clinical activity HCC. Combination nivolumab (anti-PD-1) ipilimumab (anti-CTLA-4) first option to be approved by Food Drug Administration that targets more one immune checkpoints. Methods In this study, we framework quantitative systems pharmacology (QSP) perform virtual trial Our model incorporates detailed biological mechanisms interactions cells leading antitumor response. To conduct trial, generate patient from cohort 5,000 proposed extending recent algorithms literature. The was calibrated using data CheckMate 040 (ClinicalTrials.gov number, NCT01658878 ). Results Retrospective analyses were performed different therapies as 040. Using machine learning approach, predict importance potential biomarkers blockade therapies. Conclusions QSP predictions consistent clinically observed outcomes. study demonstrates mechanistic understanding underlying pathophysiology, models can facilitate selection design trials improved success.

Language: Английский

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Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 7, 2024

SUMMARY Health is strongly affected by aging and lifespan-modulating interventions, but the molecular mechanisms of mortality regulation remain unclear. Here, we conducted an RNA-seq analysis mice subjected to 20 compound treatments in Interventions Testing Program (ITP). By integrating it with data from over 4,000 rodent tissues representing responses genetic, pharmacological, dietary interventions established survival data, developed robust multi-tissue transcriptomic biomarkers mortality, capable quantifying change lifespan both short-lived long-lived models. These tools were further extended single-cell human demonstrating common across cell types species. Via a network analysis, identified annotated 26 co-regulated modules longevity tissues, interpretable module-specific clocks that capture aging- mortality-associated phenotypes functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, extracellular matrix organization. captured characterized acceleration biological age induced progeria models chronic diseases rodents humans. They also revealed rejuvenation heterochronic parabiosis, early embryogenesis, cellular reprogramming, highlighting universal signatures shared age-related disease. included Cdkn1a Lgals3 , whose plasma levels demonstrated strong association all-cause disease incidence risk factors, such as obesity hypertension. Overall, this study uncovers hallmarks mammalian organs, types, species rejuvenation, exposing fundamental longevity.

Language: Английский

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Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases

Annals of the Rheumatic Diseases, Journal Year: 2024, Volume and Issue: 83(10), P. 1233 - 1253

Published: May 3, 2024

Due to optimised treatment strategies and the availability of new therapies during last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art cannot induce remission. Moreover, risk for flares strongly increases once anti-inflammatory therapy is tapered withdrawn, suggesting that underlying pathological processes remain active absence overt inflammation. It has evident tissues ability remember past encounters with pathogens, wounds other irritants, react more and/or persistently next occurrence. This priming tissue bears a paramount role defence from microbes, but on hand drives pathologies (the Dr Jekyll Mr Hyde aspect adaptation). Emerging evidence suggests long-lived tissue-resident cells, fibroblasts, macrophages, plasma cells memory T determine an interplay infiltrating immune lymphoid myeloid origin, systemically acting factors cytokines, extracellular vesicles antibodies. Here, we review current state science priming, focusing tissue-occupying SSc, reflect most promising options targeting maladapted response these diseases.

Language: Английский

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Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 4, 2023

Background Systemic sclerosis (SSc) belongs to the group of connective tissue diseases and is associated with occurrence disease-specific autoantibodies. Although it still controversial whether these antibodies contribute pathogenesis, there are new insights into development specific their possible pathophysiological properties. Interestingly, they clinical manifestations, but for some rarer this association not fully clarified. The aim study a comprehensive analysis serum autoantibody status in patients SSc followed by correlation analyses autoantibodies course disease. Methods Serum from was analyzed using line blot (EUROLINE, EUROIMMUN AG) SSc-related Autoantibodies centromere, Topo-1, antimitochondrial (AMA) M2 subunit, angiotensin II type 1 receptors (AT R) endothelin-1 type-A-receptors (ET A were also determined ELISA. We formed immunological clusters used principal components (PCA) assign characteristics clusters. Results total 372 included. 95.3% antinuclear antibody positive 333 at least one could be detected. Four found PCA. Centromere, Topo-1 RP3 all own clusters, which distinct phenotypes. that an inverted phenotype, such as limited cutaneous within cluster show increased risk interstital lung disease compared ACA patients. Anti-AT R anti-ET measured 176 patients; no manifestation found. AMA-M2 showed cardiovascular events. Conclusion In our large analysis, included extended profile, we able serologic provides important clues manifestation, co-morbidities complications. Line reliable technique detect detected 42%

Language: Английский

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Regulatory B Cells Contribute to the Clinical Response After Bone Marrow-Derived Mesenchymal Stromal Cell Infusion in Patients With Systemic Sclerosis

Stem Cells Translational Medicine, Journal Year: 2023, Volume and Issue: 12(4), P. 194 - 206

Published: March 16, 2023

Mesenchymal stromal cells (MSCs) have recently emerged as an interesting therapeutic approach for patients with progressive systemic sclerosis (SSc), a rare and life-threatening orphan autoimmune disease. Whereas MSC immunomodulatory potential is considered central mechanism their clinical benefit, very few data are available on the impact of MSCs immune cell subsets in vivo. In current extended study phase I/II trial exploring injection single dose allogeneic bone marrow-MSCs (alloBM-MSCs) severe SSc (NCT02213705), we performed longitudinal in-depth characterization circulating 19 MSC-treated patients, including 14 responders 5 non-responders. By combination flow cytometry transcriptomic analyses, highlighted increase CD24hiCD27posCD38lo/neg memory B cells, main IL-10-producing regulatory (Breg) subset, upregulation IL10 expression ex-vivo purified specifically responder early after alloBM-MSC infusion. addition, deeper alteration B-cell compartment before treatment, higher profibrotic cytokines IL6 TGFβ by sorted was associated non-responder status. Finally, BM-MSCs were able to directly upregulate IL-10 production activated vitro. These suggest that cytokine-producing particular Breg, pivotal effectors BM-MSC activity SSc. Their quantification biomarkers potency assays patient selection criteria may be reach optimal benefit when designing MSC-based trials.

Language: Английский

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Depletion-restitution therapy for autoimmune rheumatic diseases. Part 1. Fundamental prerequisites and efficacy of modern treatment technologies: anti-B-cell drugs and CAR-T therapy

Modern Rheumatology Journal, Journal Year: 2025, Volume and Issue: 19(2), P. 7 - 17

Published: April 22, 2025

The key element in the pathogenesis of systemic autoimmune rheumatic diseases is breakdown immunological tolerance and formation a pool autoreactive cells. This leads to uncontrolled activation effector arm cellular (T-lymphocytes) humoral (B-lymphocytes plasma cells) immunity, proliferation clones, persistence memory In this process, T-cells, B-cells, cells memory, interaction with complex pathogenic signals from microenvironment, ensure stability adaptability developing inflammatory process. modern clinical practice, prevailing approach prescribing medications "therapeutic pyramid" strategy, which involves gradual escalation treatment until remission achieved. does not address mechanisms and, as result, requires lifelong therapy associated numerous adverse effects. term “depletion-restitution therapy” proposed (from English “depletion” – exhaustion; Latin “restitutio ad integrum” restoration original state, complete recovery) describe an alternative approach. characterized by methods based on massive, shortterm cytotoxic impact, leading profound reduction followed repopulation "naive" elements. Consequently, restores enables ultra-long, drug-free remissions. Currently, principles depletion-restitution have already been integrated into oncology, hematology, neurology. Among most promising potential targets for such rheumatology are effectors immune system: plasmablasts, At present stage, implementing CAR-T therapeutic bispecific monoclonal antibodies.

Language: Английский

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Microplastics from disposable paper cups are enriched in the placenta and fetus, leading to metabolic and reproductive toxicity during pregnancy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 21, 2024

Abstract The health implications of microplastics (MPs), especially those originating from hot drinks in disposable paper cups (DPCs), are increasingly alarming. We investigated the accumulation and metabolic reproductive toxicological effects MPs DPCs filled with water various tissues a pregnant mouse model. Simulating human intake 0.3, 3.3, 33.3 daily, we found exposure-induced dose-responsive harmful on murine fetal development maternal physiology. were detected all 13 examined tissues, highest cecal contents, followed by significant depositions fetus, placenta, kidney, spleen, lung, heart. A higher proportion smaller (90.35% < 10 μm) was identified brain tissues. Dose-responsive changes functional microbiome gene pathways observed. Moderate 3.3 daily significantly altered composition functions. transcriptomic variations blood, mammary gland underscore impacts realistic exposure immune posing neurodegenerative miscarriage risks. benchmark dose framework analysis using tissue-specific biomarkers revealed safe limits at 2 to 4 cups/day during pregnancy. Our results indicate selective tissue potential toxicities levels presumed non-hazardous. Such risks remain unaddressed within current food safety regulations, impacting vulnerable groups such as women fetuses. Research Highlights Microplastics released showed preferential accumulations heart, adverse development. Microplastic led associated increased fatty acid biosynthesis elevated expressions genes related viral infections, diseases, oxidative stress, risk. consumption level sufficient elicit systemic toxicity, predicted limit pregnancy molecular biomarkers.

Language: Английский

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Multiple Sclerosis and Other Acquired Demyelinating Diseases of the Central Nervous System

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 17(3), P. a041374 - a041374

Published: May 28, 2024

Acquired demyelinating diseases of the central nervous system (CNS) comprise inflammatory conditions, including multiple sclerosis (MS) and related diseases, as well noninflammatory conditions caused by toxic, metabolic, infectious, traumatic, neurodegenerative insults. Here, we review spectrum producing acquired CNS demyelination before focusing on prototypical example MS, exploring pathologic mechanisms leading to myelin injury in relapsing progressive MS summarizing modulators remyelination. We highlight complex interplay between immune system, oligodendrocytes oligodendrocyte progenitor cells (OPCs), other glia such microglia astrocytes pathogenesis clinical course MS. Finally, emerging therapeutic strategies that exploit our growing understanding disease limit progression promote

Language: Английский

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Analytical approach of synchronous and asynchronous update schemes applied to solving biological Boolean networks

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Abstract Characterizing the minimum, necessary and sufficient components to generate dynamics of a biological system has always been priority understand its functioning. In this sense, canonical form systems modeled by Boolean networks accurately defines in charge controlling such systems. However, calculation might be complicated mathematical terms. addition, computing does not consider dynamical properties found when using synchronous asynchronous update schemes solve networks. Here, we analyze both their connection with We that scheme can expressed Chapman-Kolmogorov equation, being particular case Markov chains. also discovered any network easily obtained solving matrix equation. Finally, order generates set functions that, composed together, produce characteristic scheme, as conservation fixed-point attractors or variability basins attraction. concluded only for use which opens up new possibilities study.

Language: Английский

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Understanding and managing cardiac involvement in systemic sclerosis

Expert Review of Clinical Immunology, Journal Year: 2023, Volume and Issue: 19(3), P. 293 - 304

Published: Jan. 24, 2023

Cardiac involvement is common in systemic sclerosis occurring up to 80% of patients. Primary myocardial dysfunction results from impairment coronary microvascular circulation, inflammation and fibrosis with the prevalence atherosclerosis remaining contradictory.This review presents various aspects cardiac SSc a pathophysiological, clinical, diagnostic therapeutic standpoint. Imaging modalities emerging role understanding mechanisms prompt diagnosis namely magnetic resonance are also discussed.Cardiac - particularly primary disease remains challenge as clinical symptoms manifest advanced stages heart failure convey poor prognosis. Over last years introduction sophisticated imaging methods function has resulted better underlying pathophysiological processes damage such microvasculopathy, inflammation, diffuse or focal fibrosis. Such developments could contribute identification patients at higher risk for subclinical whom diligent surveillance initiation therapy cardioprotective and/or immunosuppressive drugs coupled invasive interventions radiofrequency ablation, implantable cardioverter-defibrillator when indicated, may improve long-term outcomes.

Language: Английский

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