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At least 19 recordsLinked to original sources
PubMed2025

Efficacy of EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer with EGFR exon 19 insertions: clinical-genomic, preclinical analysis through LC-SCRUM-Asia (multi-institutional genomic screening registry).

BACKGROUND: EGFR exon 19 insertions (EGFRex19ins) are rare EGFR mutations. Their clinical-genomic characteristics and outcomes with EGFR-tyrosine kinase inhibitors (TKIs) remain uncertain. METHODS: We evaluated the clinical-genomic characteristics and outcomes of EGFR-TKIs for EGFRex19ins in the multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia). We also studied preclinical Ba/F3 models expressing EGFR-K745_E746insIPVAIK (Ba/F3-IPVAIK) to investigate their sensitivity to 1st-, 2nd-, 3rd-generation, and EGFR exon 20 insertion-active TKIs. RESULTS: In LC-SCRUM-Asia, 16,204 NSCLC patients were enrolled from March 2015 to December 2023. EGFRex19ins were detected in 13 samples (0.1 % of NSCLC). The median age was 72 years (range, 38-80); most patients were female (77 %), had adenocarcinoma (92 %), and were never-smokers (62 %). Twelve patients (93 %) had EGFR-K745_E746insIPVAIK, while one (7 %) had EGFR-K745_E746insVPVAIK. The most frequent co-mutation was TP53 (62 %); no patients had other driver alterations. Six patients (46 %) tested positive for EGFR exon 19 deletions with PCR-based Cobas EGFR test, likely due to cross-reactivity arising from sequence homology. Twelve patients received EGFR-TKIs; five (42 %) experienced partial response. In the preclinical study, Ba/F3-IPVAIK showed the highest sensitivity to 2nd-generation EGFR-TKIs compared to other EGFR-TKIs. Structural studies supported these consistent results. When broken down by EGFR-TKI generations, response rates for 1st-, 2nd-, and 3rd-generation TKIs were 50 % (1/2), 80 % (4/5), and 0 % (0/5), respectively. The median PFS for 1st-, 2nd-, and 3rd-generation TKIs were 8.7 (95 % CI, 7.4-NR), 14.7 (95 % CI, 8.0-NR), and 4.4 (95 % CI, 3.4-NR) months, respectively. CONCLUSION: Our preclinical, structural, and clinical findings indicate 2nd-generation EGFR-TKIs are more effective for EGFRex19ins compared to other TKIs.

Adult↗
PubMed2026

The molecular similarity landscape of preclinical cancer models to patient tumors.

Selecting appropriate preclinical models is fundamental for translational oncology, yet a large-scale, multi-omic quantitative comparison of their similarity to primary human tumors is lacking. To address this, we integrated transcriptomic, proteomic, and genomic profiles from over 10,000 primary tumors from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), alongside 4,000 preclinical models. Using a robust computational framework, we revealed a clear hierarchy of transcriptomic and proteomic similarity to patient tumors: with patient-dervied xenografts (PDXs) having greater transcriptomic and proteomic similarity to patient tumors (>) compared with patient-derived organoids (PDOs), which are equal in hierarchy to that of PDX-dervied organoids (PDXOs) > cell lines. We also quantified high molecular conservation (Pearson correlation coefficient = 0.96) across paired in vitro to in vivo platform (organoids to PDX) transitions. Furthermore, genomic analysis demonstrated that whole-exome sequencing (WES) outperforms RNA-seq in detecting DNA variants, and it identified a clonal complexity hierarchy (cell lines > PDXOs > PDXs > PDOs) reflecting the effect of passaging history on intratumor heterogeneity. Ultimately, this study delivers a comprehensive quantitative benchmark, establishing a population-level hierarchy of molecular similarity between preclinical models and primary tumors and providing a data-driven reference for model selection. These findings offer a data-driven framework for selecting models that balance biological representativeness with experimental practicality.

Humans↗
PubMed2026

Standardized Xenograft Models for Preclinical Cancer Research.

Xenograft models are the principal in vivo platform of preclinical oncology and the most established experimental link between cell culture and clinical investigation. From the carcinogen-exposed rabbit models of the early twentieth century through the current generation of humanized patient-derived xenograft (PDX) systems, these platforms have evolved in response to the demands of translational cancer research. This review critically examines the biological principles, methodological standards, and translational applications of the principal xenograft platforms in current use. Cell line-derived xenograft (CDX) models remain the most widely used and most cost-effective modality for preclinical efficacy testing, offering the reproducibility, scalability, and accessibility that have sustained their role across oncology drug development pipelines for decades. PDX models have emerged as the preferred platform for co-clinical trial design, predictive biomarker discovery, and personalized oncology applications, preserving the genomic landscape, intratumor heterogeneity, and histological architecture of the donor tumor across serial passages. The engraftment biology of PDX systems, including immunodeficient host strain selection, implantation site, tumor source, and passage biology, is reviewed, together with humanized and autologous humanized configurations that extend the platform to immune checkpoint inhibitors, bispecific T-cell engagers, and chimeric antigen receptor T (CAR-T) cell therapy evaluation. This review addresses preclinical-to-clinical translation as a function of immunological divergence, incomplete tumor microenvironment recapitulation, and standardization. Formal frameworks, including the PDX Model Minimal Information (PDX-MI) standard and the Minimal Information for Standardization of Humanized Mice (MISHUM), are examined alongside global biobank infrastructure and emerging AI-driven translational modeling approaches.

Animals↗
PubMed2026

Efferocytosis regulatory factors in atherosclerosis: A preclinical systematic review.

BACKGROUND: Impaired efferocytosis is a key driver of plaque instability during atherosclerosis progression. Efficient clearance of apoptotic cells through efferocytosis relies on the coordinated action of multiple regulatory factors. METHODS: PubMed, Web of Science, ScienceDirect, OVID MEDLINE, and Scopus were searched for studies published up to February 7, 2026. Eligible preclinical studies were systematically reviewed to identify endogenous factors that regulate efferocytosis in atherosclerosis. Clinical evidence was also incorporated to enable a preliminary translational assessment of these regulatory factors. RESULTS: Thirty-five endogenous regulatory factors were identified from 36 included studies, and their functional roles across distinct stages of efferocytosis were characterized. Notably, metabolic regulators such as PKM2, PFKFB3, GLS1, and Drp1 were involved in distinct efferocytosis stages. This suggests that metabolic reprogramming may provide the metabolic support require for efficient efferocytosis and inflammation resolution. Ten factors were supported by preliminary clinical evidence consistent with preclinical data. PKM2 was the only candidate biomarker with prospective observational data. However, its independent predictive value still requires validation in multicenter prospective studies. CONCLUSIONS: This review provides a systematic synthesis of 35 endogenous efferocytosis regulators and elucidates their regulatory network in atherosclerosis based on a functional stage framework. Metabolic reprogramming is identified as a central hub linking efferocytosis efficiency to inflammation resolution. This review offers a new theoretical basis for efferocytosis-targeted intervention strategies.

Animals↗
PubMed2026

Vitamin D Pathway Activation Reduces Cardiomyocyte DNA Damage and Improves Cardiac Contractility in Preclinical Models.

BACKGROUND: In heart failure (HF), DNA damage caused by various external stressors contributes to cardiac dysfunction through the activation of DNA damage response pathways. To date, no clinical strategies have been established to restore cardiac function by reducing accumulated DNA damage. We previously found that vitamin D improved contractility in lamin A/C (LMNA) p.Q353R-mutant induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPSCMs), but whether this effect extends to other LMNA variants and in vivo models remained uncertain. OBJECTIVES: The objective of the study was to evaluate the association of vitamin D pathway activation with cardiomyocyte phosphorylated histone H2AX (γH2AX) foci and contractile phenotypes in patient-derived iPSCMs and mouse models of HF. METHODS: iPS cell lines were generated from dilated cardiomyopathy patients carrying the LMNA p.R225X mutation, and the effects of vitamin D treatment on γH2AX foci and cardiomyocyte contractility were evaluated. In addition, the effects of the vitamin D analog paricalcitol were evaluated in Lmna p.R225X mice and in a pressure overload mouse model of HF. RESULTS: Consistent with previous findings, vitamin D treatment reduced γH2AX foci in cardiomyocytes derived from LMNA p.R225X mutant iPS cells through upregulating the expression of DNA repair factors, and improved contractility in these iPSCMs. Furthermore, paricalcitol reduced γH2AX foci and attenuated cardiac dysfunction in both Lmna p.R225X mice and pressure overload HF model mice. CONCLUSIONS: Vitamin D pathway activation improved contractile phenotypes across complementary preclinical models and was accompanied by reduced γH2AX foci or related transcriptional changes. These findings support further mechanistic and preclinical investigation.

DNA damage↗
PubMed2026

Subacute and long-term changes in cognitive functioning after administration of classic psychedelics, MDMA and ketamine: A systematic review of clinical and preclinical evidence.

Psychedelic agents induce a window of heightened neuroplasticity that extends beyond acute intoxication, during which neural circuits are more amenable to change. This period may facilitate changes in cognition relevant to the treatment of psychiatric disorders. This systematic review synthesised clinical and preclinical evidence of subacute and long-term (≥1 day) effects of classic and non-classic psychedelics on cognition. MEDLINE, EMBASE, APA PsycInfo and Web of Science were searched to identify human and animal studies investigating psychedelics and cognition (executive function, attention, decision-making). Sixty-seven (47 clinical, 20 preclinical) articles met inclusion criteria. Psilocybin demonstrated the most consistent evidence of subacute and longer-term cognitive improvement, particularly in cognitive flexibility and attention. Ketamine showed enhancement across cognitive domains, although findings were heterogeneous. LSD and DMT showed no consistent subacute changes, while MDMA was associated with transient cognitive impairments that resolved within days. Risk of bias assessments revealed selective outcome reporting, poor reporting of missing data and inadequate methodological detail, limiting the confidence of findings. Current evidence provides preliminary support for subacute changes in cognition following administration of select psychedelic agents. Cognitive improvements were more frequently seen in psychiatric populations than healthy subjects, which may reflect a remediation of existing cognitive deficit rather than enhancement above normal functioning. Adequately powered, controlled studies with standardised reporting of cognitive outcomes are required to determine the magnitude, durability and clinical relevance of psychedelic-associated cognitive change.

Hallucinogens↗
PubMed2026

Deep learning-assisted, pathogenesis-informed lung histopathology scoring in preclinical mouse models of SARS-CoV-2 and influenza A infection.

INTRODUCTION: SARS-CoV-2 and influenza A virus (IAV) cause viral pneumonia, yet their lung lesions evolve with distinct spatial organization and resolution-phase architecture. In preclinical murine studies, H&E histopathology is a primary endpoint, but burden-focused semiquantitative scoring can miss pathogen- and phase-specific differences in lesion topology, compartmental involvement, inflammatory organization, and repair. We aimed to define virus- and phase-specific morphologic signatures and translate them into a practical, pathogenesis-informed scoring guide, supported by whole-slide convolutional neural network (CNN) analysis with class activation mapping (CAM). METHODS: Mice were infected under standardized conditions and evaluated during the early, peak-injury, and late phases of infection, corresponding to 2~3, 5~8, and 14 days post-infection (dpi), respectively. Lungs were assessed by H&E with semiquantitative scoring and by immunostaining to map viral antigen distribution and epithelial tropism. Whole-slide CNN models were trained for virus- and phase-specific classification, and CAM localized discriminative regions. RESULTS: Dose titration established reproducible lethal and sublethal infection conditions for both viruses. Viral antigen kinetics diverged, with SARS-CoV-2 peaking early and declining toward clearance by the resolution phase, whereas IAV peaked later and declined by the resolution phase, paralleling distinct injury-repair trajectories. CNN/CAM analysis distinguished virus- and phase-specific histologic patterns across the early, peak-injury, and resolution phases of infection and highlighted spatial signatures consistent with expert review. At the peak-injury phase, SARS-CoV-2 lungs showed broad alveolar/interstitial involvement, whereas IAV exhibited bronchocentric inflammatory organization. During the resolution phase, IAV showed prominent epithelial regeneration with remodeling-forward architecture, while SARS-CoV-2 more often retained localized residual inflammatory foci. Across both infections, tissue inflammatory composition shifted over time, with higher neutrophil representation during the peak-injury phase and a relative increase in lymphocytic representation during the resolution phase. Integrating lesion topology/distribution, edema, epithelial injury-regeneration, remodeling features, and lymphocyte predominance, we proposed a pathogen-resolved, phase-informed histopathology scoring guide with recommended evaluation windows for each model. CONCLUSION: Together, these findings define virus- and phase-specific morphologic programs that inform respiratory virus pathogenesis in mice and can be translated into practical scoring criteria for preclinical respiratory virus studies.

Animals↗
PubMed1977

An evaluation system for preclinical and clinical endodontics.

One of the most difficult tasks, facing the dental educator is the evaluation of students' preclinical and clinical performance. This article describes the development of an evaluation system that eliminates some of the problems associated with the assessment of psychomotor skills including rater subjectivity and the validity of evaluation instruments. The evaluation system discussed is currently being used by the Department of Endodontics at the Louisiana State University School of Dentistry for both preclinical and clinical endodontics. The article focuses on the development of the system, use of the clinical rating scale, and an assessment of the system's effectiveness.

Clinical Competence↗
PubMed1979

Teaching clinical problem solving in preclinical occlusion courses.

The teaching of the basic principles and concepts of occlusion can be enhanced. Preclinical occlusion courses are made relevant to the clinical experience by introducing clinically related problem-solving exercises. These exercises develop a student's clinical problem-solving skill and create an excitement for active learning in the preclinical laboratory. Examples of these exercises are presented.

Clinical Competence↗
PubMed1977

Preclinical effects: learned behavior.

A review of the previous Marihuana and Health Reports (1971-1975) reveals that an extensive array of experimental procedures and contexts have been used to study the effects of cannabinoids on the performance of learned behavior in animals. These preclinical behavioral experiments have provided a framework for, and guided the design of, subsequent human experimentation. Compared to previous years, only a few experiments pertaining to cannabinoids and learned behavior have appeared during the past two years. By and large these more recent experiments confirm previous findings; no particularly novel procedures have been explored nor have there been dramatically unpredictable results. In part, the decrease in activity in cannabinoid preclinical animal research on learned behavior indicates an increase in human cannabinoid-learning investigations. Several detailed taxonomies of learned behavior are possible. However, for the purposes of the present report, learned behaviors will be categorized into those involving: avoidance learning and aversive control; reinforcement schedules and maze learning; and discrimination learning.

Animals↗
PubMed2026

Cine-derived mitral annular relaxation velocity for detection of preclinical left ventricular diastolic dysfunction.

OBJECTIVES: Imaging diastolic dysfunction in pre-clinical heart failure (HF) is challenging. We evaluated a novel cardiac MRI (CMR) biomarker, CMR e-prime (CMR-MARV), in patients at risk of HF. METHODS: In this substudy of the PARABLE trial (NCT04687111), 236 patients (71.6&#xa0;&#xb1;&#xa0;7.7&#xa0;years, 61.6% male) fulfilling trial-defined ALVDD citeria underwent CMR with measurement of mitral annular relaxation velocity (CMR-MARV) at four mitral annular anchor points. Diastolic strain rates from FT were also assessed. Twenty-five age- and sex-matched controls were included (73.8&#xa0;&#xb1;&#xa0;3.1&#xa0;years, 52% male). Group differences were tested with t-tests, diagnostic accuracy with ROC analysis, and predictors of diastolic dysfunction with adjusted logistic regression. RESULTS: Compared with controls, patients had significantly higher indexed maximal left atrial volume (LAVimax), LV end-diastolic and end-systolic volumes, and LV mass (all p&#xa0;<&#xa0;0.001). Of FT variables, only peak diastolic longitudinal velocity differed between groups (p&#xa0;<&#xa0;0.001). In multivariate models, CMR-MARV correlated with radial, circumferential, and longitudinal diastolic strain rates, radial and longitudinal diastolic velocities (all p&#xa0;<&#xa0;0.001), echocardiographic e' (r&#xa0;=&#xa0;0.20, p&#xa0;=&#xa0;0.007), LV mass (r&#xa0;=&#xa0;-0.18, p&#xa0;=&#xa0;0.008), LAVimax (r&#xa0;=&#xa0;-0.18, p&#xa0;=&#xa0;0.008), and NT-proBNP (r&#xa0;=&#xa0;-0.30, p&#xa0;<&#xa0;0.0001). LAVimax and CMR-MARV were strongly independently associated with ALVDD (AUC 0.89 and 0.76, respectively; p&#xa0;<&#xa0;0.0001). A combined model (LAVimax + CMR-MARV) achieved excellent discrimination (AUC 0.91, 95% CI 0.86-0.97, p&#xa0;<&#xa0;0.0001). Independent predictors included LAVimax, CMR-MARV, and peak diastolic longitudinal velocity (all p&#xa0;<&#xa0;0.001). CONCLUSION: CMR-MARV provides a simple cine-derived measure of longitudinal relaxation that correlates with established structural and biochemical markers of diastolic burden. Within an at-risk population, it offers incremental functional information beyond conventional parameters and may support multiparametric CMR phenotyping of preclinical diastolic dysfunction.

Aged↗
PubMed1977

Preclinical toxicological study of phosphonoacetic acid: determination in blood by selected ion monitoring.

Confirmed observations of the inhibition of oncogenic viruses by phosphonoacetic acid led to preclinical trials in animal model systems. Circulating phosphonoacetic acid was detected in the blood of mouse, rabbit and monkey after oral or subcutaneous administration of the drug. Phosphonoacetic acid is quantified in blood, after removing proteins and lipids, as the trimethylsilylated derivative, by monitoring the intensity of the protonated molecular ion and also that of phosphonopropionic acid (internal standard) using chemical ionization mass spectrometry combined with gas chromatography. The detection limit is 20 ng ml-1 when 0.2 ml serum is analyzed. A dosage of 230 mg kg-1 day-1 by continuous infusion is proposed for therapeutic trials in monkeys. This dose is well tolerated and results in slowly increasing blood levels of phosphonoacetic acid which reach a maximum of approximately 50 microgram ml-1 in a four day infusion, and decrease to 2 microgram ml-1 24 h after termination.

Animals↗
PubMedDate not supplied

Repeat laparotomy as a preclinical diagnostic and therapeutic method for treating ovarian carcinoma.

One hundred forty-two cases of epithelial ovarian carcinoma were treated from 1972 to 1976 in the Department of Obstetrics and Gynaecology, University Central Hospital, Turku, Finland. Repeat laparotomy was performed on 37 of the patients about six months after total extirpative surgery (group I). In addition, a second laparotomy was performed on 14 patients after partial surgery or exploratory laparotomy (group II). All patients were given external radiation therapy combined with cytostatic treatment prior to the repeat laparotomies. A preclinical carcinoma was detected in six of the 37 patients in group I. Two of them are asymptomatic after five years of follow-up. In group II, total surgery after initial partial or exploratory laparotomy succeeded in half of the cases. Serous and endometroid carcinomas appeared to respond best to conservative therapy preceding repeat laparotomy.

Female↗
PubMed2026

Large-Scale Plasma Proteomics Reveals Preclinical Biomarkers of Incident Severe Liver Disease.

The absence of robust biomarkers for early detection of severe liver disease (SLD) highlights the critical need for high-throughput proteomics-driven discovery. In this prospective cohort study, we aimed to identify plasma protein signatures associated with incident SLD and assess their clinical utility. Using the large-scale Olink Explore 1536 platform, we quantified 1461 plasma proteins in 46951 participants from the UK Biobank community-based cohort without baseline liver disease. Over a median follow-up of 14.1 years, we identified 490 proteins significantly associated with incident SLD risk. Growth differentiation factor 15 (GDF15) emerged as the strongest predictor, achieving a C-index of 0.80 and outperforming conventional clinical indices (LiverRisk score: 0.75; FIB-4: 0.68; APRI: 0.68). Temporal trajectories revealed that GDF15 levels began increasing up to 10 years before diagnosis, with progressive elevation as the diagnosis timepoint approached. Mendelian randomization analysis supported genetic associations linking higher protein levels of GDF15, FABP1, SPON2, CHI3L1, and PIGR with SLD risk. Our large-scale proteome-wide study not only reveals significant proteomic changes preceding SLD diagnosis but also establishes GDF15 as both a promising preclinical biomarker, opening new avenues for early intervention in at-risk individuals.

Humans↗
PubMed1979

The suitability of negative pions for radiotherapy: 4 years preclinical research with the biomedical PiE3-beam at SIN.

The radiobiological experiences over 4 years research with the biomedical pion channel of the 590 MeV proton-accelerator of the Swiss Institute for Nuclear Research (SIN) have been summarized. Mainly sensitive biological systems have been chosen (limiting factor: dose-rate not more than 10 rad/min, exceptionally till 30 rad/min). The RBE values in the peak region vary between 0.7-3.3 and in the plateau region between 0.4-1. The gain factors for pion radiotherapy of cancer are, beside the excellent physical dose distribution, irradiation in the same treatment with two types of radiation: sparsely ionizing (low LET) radiation in plateau (healthy tissue) region and densely ionizing (high LET) radiation in peak (tumor) region. The biological effectiveness ratio in peak and plateau as the clinically most important relation vary between 1.4-4.2. This is valid also for clinically limiting factors such as reaction of skin, of small intestine, vascular damage, dominant lethals in hypoxic cells, tumor induction. For peak pions the RBE in hypoxic cells (tumor cells) can be much higher than in euoxic cells (healthy tissue). This preclinical work supports the hope in a highly effective cancer therapy with negative pions.

Animals↗
PubMed2026

Are there any common effects in preclinical models of micro- and nanoplastic (MNP) exposure? A systematic review.

Micro- and nanoplastics (MNPs) are emerging contaminants detected in food sources and the marine food chain, raising concerns about human health. Although no causal relationship has been established between MNP exposure and specific diseases, growing evidence suggests adverse developmental, behavioral, cognitive and biochemical effects. This systematic review synthesized evidence from common preclinical neurotoxicology models, including C. elegans, D. rerio, D. melanogaster, in vitro systems and rodents, to identify convergent developmental, behavioral and biochemical outcomes. The protocol was preregistered in OSF, followed PRISMA-P guidelines, applied PICOS criteria, and assessed methodological quality using the European Commission's ToxRTool. Overall, 185 studies were included. Consistent findings showed impaired survival and disrupted development across all models. Behavioral alterations affecting anxiety, memory, learning, sociability and locomotor activity were also consistently reported. In addition, numerous studies identified disruptions in the serotonergic (5-HT) system, including changes in neurotransmitter levels, transporters and metabolic enzymes. Despite methodological heterogeneity, these findings indicate that MNP exposure produces reproducible neurodevelopmental and neurochemical alterations across experimental models. Future studies should improve methodological harmonization, strengthen cross-model comparability and identify robust biomarkers and key mechanisms underlying MNP-induced neurotoxicity, facilitating translation to human health risk assessment frameworks.

Animals↗
PubMed2025

A First-in-Class Chemical-Induced Proximity System Achieves Dose-Dependent Control of Tumor Protein P53 Gene Activation in Preclinical Models of Gastric Cancer.

The tumor protein P53 (TP53) gene has long been studied in cancer research with genomic and epigenetic aberrations playing a driving role in cancer pathology, yet even after decades of work, only a few methods have been developed to specifically target TP53 therapeutically. Some cancers are driven by loss-of-function TP53 mutations, while others have wild-type TP53 in a transcriptionally repressed state; the latter is exploitable by advances in epigenome editing. In our previous work, we demonstrated that deactivated CRISPR/Cas9 systems (dCas9), combined with an FK-506-binding protein (FKBP) recruitment protein tag and chemical epigenetic modifier (CEM) small molecules, can elicit gene-specific changes in expression in a dose-dependent manner. Here, we describe the development, application, and characterization of the dCas9-FKBP-CEM technology to increase TP53 expression. We demonstrate that catalyzing increased TP53 expression via dCas9-FKBP-CEM87 induced apoptosis, cell cycle arrest, and tumor growth inhibition in a dose-dependent manner in preclinical models of gastric cancer.

CRISPR↗