Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.

PURPOSE: The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s Project Optimus initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed. METHODS: Model-predicted outcomes for each clinically relevant end point, informed by ER modeling, are converted to a CUS using a user-defined utility function. Thereafter, individual CUS is integrated into a single score with user-defined weighting for each end point. The user-defined weighting feature allows the user to incorporate expert knowledge/understanding into weighing the product's benefit versus risk profile. RESULTS: To validate the framework, data were leveraged from over 50 oncology programs from 2019 to 2023 on the basis of FDA new drug application/biologics license application review packages and/or related literature studies. Five representative cases were selected for in-depth evaluation. Results showed that the optimal benefit-risk ratio (highest CUS) was consistently observed at PK exposures synonymous with recommended doses. A recurring theme across cases was a greater emphasis on safety over efficacy in oncology drug dose determination. CONCLUSION: The ER-based CUS framework offers a strategic tool to navigate the complexities of dose selection in oncology programs. It serves as a pillar to the importance of integrative data analysis, aligning with the vision of Project Optimus, and demonstrates its potential in guiding dose optimization by balancing therapeutic benefits against risk.

[Diagnostic Value of Ultrasound for Thyroid Nodules With a Spoke-Wheel Blood Flow Pattern].

Objective To explore the diagnostic value of ultrasound for thyroid nodules with a spoke-wheel blood flow pattern.Methods The clinical data of the patients with thyroid nodules presenting a spoke-wheel blood flow pattern examined by ultrasound were collected,and the gray-scale ultrasound features of the nodules were recorded.The diagnostic performance of the Thyroid Imaging Reporting and Data System by American College of Radiology (ACR TI-RADS),Chinese Thyroid Imaging Reporting and Data System (C-TIRADS),and combined specific indicators for the thyroid nodules with a spoke-wheel blood flow pattern was evaluated by comparison with the pathological results,which was regarded as the gold standard.Results A total of 64 patients with thyroid nodules were finally included,including 47 patients with malignant nodules and 17 patients with benign nodules.In addition to the general ultrasound features,central scar mostly appeared in malignant nodules (χ2=5.968,P=0.015),while central coarse calcification was more common in benign nodules (χ2=10.899,P=0.001).After the combination of central scar and central gross calcification,the diagnostic performance of ACR TI-RADS and C-TIRADS was improved (both P<0.001).Conclusions When the thyroid nodule shows a spoke-wheel blood flow pattern,one should be cautious of the possibility of malignancy.Combining central scar and central coarse calcification can improve the accuracy of ultrasonic diagnosis.

Two-stage evolution of mammalian adipose tissue thermogenesis.

Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials.

Regulation of Interface Ion Transport by Electron Ionic Conductor Construction toward High-Voltage and High-Rate LiNi0.5Co0.2Mn0.3O2 Cathodes in Lithium Ion Battery.

Simultaneously achieving high-energy-density and high-power-density is a crucial yet challenging objective in the pursuit of commercialized power batteries. In this study, atomic layer deposition (ALD) is employed combined with a coordinated thermal treatment strategy to construct a densely packed, electron-ion dual conductor (EIC) protective coating on the surface of commercial LiNi0.5Co0.2Mn0.3O2 (NCM523) cathode material, further enhanced by gradient Al doping (Al@EIC-NCM523). The ultra-thin EIC effectively suppresses side reactions, thereby enhancing the stability of the cathode-electrolyte interphase (CEI) at high-voltages. The EIC's dual conduction capability provides a potent driving force for Li+ transport at the interface, promoting the formation of rapid ion deintercalation pathways within the Al@EIC-NCM523 bulk phase. Moreover, the strategic gradient doping of Al serves to anchor the atomic spacing of Ni and O within the structure of Al@EIC-NCM523, curbing irreversible phase transitions at high-voltages and preserving the integrity of its layered structure. Remarkably, Al@EIC-NCM523 displays an unprecedented rate capability (114.7 mAh g-1 at 20 C), and a sustained cycling performance (capacity retention of 74.72% after 800 cycles at 10 C) at 4.6 V. These findings demonstrate that the proposed EIC and doping strategy holds a significant promise for developing high-energy-density and high-power-density lithium-ion batteries (LIBs).

Assessment of CYP-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.

As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.

Isolation of Human Milk Difucosyl Nona- and Decasaccharides by Ultrahigh-Temperature Preparative PGC-HPLC and Identification of Novel Difucosylated Heptaose and Octaose Backbones by Negative-Ion ESI-MSn.

Despite their many important physiological functions, past work on the diverse sequences of human milk oligosaccharides (HMOs) has been focused mainly on the highly abundant HMOs with a relatively low degree of polymerization (DP) due to the lack of efficient methods for separation/purification and high-sensitivity sequencing of large-sized HMOs with DP ≥ 10. Here we established an ultrahigh-temperature preparative HPLC based on a porous graphitized carbon column at up to 145 °C to overcome the anomeric α/ß splitting problem and developed further the negative-ion ESI-CID-MS/MS into multistage MSn using a combined product-ion scanning of singly charged molecular ion and doubly charged fragment ion of the branching Gal and adjacent GlcNAc residues. The separation and sequencing method allows efficient separation of a neutral fraction with DP ≥ 10 into 70 components, among which 17 isomeric difucosylated nona- and decasaccharides were further purified and sequenced. As a result, novel branched difucosyl heptaose and octaose backbones were unambiguously identified in addition to the conventional linear and branched octaose backbones. The novel structures of difucosylated DF-novo-heptaose, DF-novo-LNO I, and DF-novo-LNnO I were corroborated by NMR. The various fucose-containing Lewis epitopes identified on different backbones were confirmed by oligosaccharide microarray analysis.

A Phase I, Open-Label, Mass Balance Study of [14C]-Iberdomide in Healthy Subjects.

BACKGROUND: Iberdomide is a novel potent cereblon modulator (CELMoD®) agent, which is currently under clinical development for hematological malignancies. A human mass balance study was conducted to characterize the biotransformation and excretion pathways of iberdomide. METHOD: After a single dose of radiolabelled [14C]-iberdomide (1 mg) in six healthy subjects. Blood, urine, and fecal samples were collected for pharmacokinetics, mass balance, and clinical laboratory assessments. RESULTS: Results showed that a single oral dose of 1 mg iberdomide was generally well tolerated in healthy subjects. The recovery of [14C]-iberdomide-derived radioactivity in humans was 45.9% in urine and 42.6% in feces. Based on exposure (area under the concentration-time curve [AUC0-24]), iberdomide and M12 (metabolites) accounted for approximately 59% and 14% of circulating total radioactivity (TRA) exposure, respectively. Of the 88.5% TRA excreted, approximately 27% was excreted as unchanged iberdomide and 62% as metabolites, with similar amounts of excreted metabolites in the urine (16%) and feces (11%). CONCLUSION: Biotransformation of iberdomide in humans included multiple oxidations of the morpholino moiety as well as glutarimide ring hydrolysis of parent and oxidized metabolites and a combination of these pathways. Iberdomide was the predominant component in human plasma, with metabolite M12 being the most prominent circulating metabolite. In excreta, similar iberdomide-derived radioactivity was found in urine and feces. TRIAL REGISTRATION NUMBER: NCT03294603.

Integrating Full Bayesian Inference and Student's t-Distribution Method for Enhanced Outlier Handling in Caffeine Population Pharmacokinetics: Assessing Drug-Drug Interactions with Enasidenib in Relapsed or Refractory AML and MDS Patients.

As the first-in-class, selective, and potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP) enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single-dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t-distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8-fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field.

Emotion-Aware Scene Adaptation: A Bandwidth-Efficient Approach for Generating Animated Shorts.

Semantic communication technology in the 6G wireless system focuses on semantic extraction in communication, that is, only the inherent meaning of the intention in the information. Existing technologies still have challenges in extracting emotional perception in the information, high compression rates, and privacy leakage due to knowledge sharing in communication. Large-scale generative-model technology could rapidly generate multimodal information according to user requirements. This paper proposes an approach that leverages large-scale generative models to create animated short films that are semantically and emotionally similar to real scenes and characters. The visual content of the data source is converted into text expression through semantic understanding technology; emotional clues from the data source media are added to the text form through reinforcement learning technology; and finally, a large-scale generative model is used to generate visual media, which is consistent with the semantics of the data source. This paper develops a semantic communication process with distinct modules and assesses the enhancements garnered from incorporating an emotion enhancement module. This approach facilitates the expedited generation of broad media forms and volumes according to the user's intention, thereby enabling the creation of generated multimodal media within applications in the metaverse and in intelligent driving systems.

Exploring Transformer Model in Longitudinal Pharmacokinetic/Pharmacodynamic Analyses and Comparing with Alternative Natural Language Processing Models.

There remains a substantial need for a comprehensive assessment of various natural language processing (NLP) algorithms in longitudinal pharmacokinetic/pharmacodynamic (PK/PD) modeling despite recent advances in machine learning in the space of quantitative pharmacology. We herein investigated the application of the transformer model and further compared the performance among several different NLP models, including long short-term memory (LSTM) and neural-ODE (Ordinary Differential Equation) in analyzing longitudinal PK/PD data using virtual data containing three different regimens. Results suggested that LSTM and neural-ODE, along with their respective variants provide a strong performance when predicting from training-included (seen) regimens, albeit with slight information loss for training-excluded (unseen) regimens. Similarly, as with neural-ODE, the transformer exhibited superior performance in describing time-series PK/PD data. Nonetheless, when extrapolating to unseen regimens, while outlining the general data trends, it encountered difficulties in precisely capturing data fluctuations. Remarkably, a small integration of unseen data into the training dataset significantly bolsters predictive performance for both seen and unseen regimens. Our study marks a pioneering effort in deploying the transformer model for time-series PK/PD analysis and provides a systematic exploration of the currently available NLP models in this field.

A CRISPR-Cas9 library screening identifies CARM1 as a critical inhibitor of ferroptosis in hepatocellular carcinoma cells.

Ferroptosis is an iron-catalyzed form of regulated cell death that results from the accumulation of lipid peroxidation products and reactive oxygen species to a lethal content. However, the transcriptional regulation of ferroptosis is not well understood. Sorafenib, a standard drug for hepatocellular carcinoma (HCC), induces ferroptosis in HCC cells. In this study, we conducted a CRISPR-Cas9 library screening targeting epigenetic factors and identified coactivator-associated arginine methyltransferase 1 (CARM1) as a critical inhibitor of ferroptosis. CARM1 depletion intensified Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione level, increased lipid peroxidation, and altered mitochondrial crista structure. Additionally, we investigated a CARM1 inhibitor (CARM1i) as a potential ferroptosis inducer. Combining the CARM1i with Sorafenib enhanced the induction of ferroptosis. Notably, both CARM1 knockdown and CARM1i showed cooperative effects with Sorafenib in inhibiting HCC growth in mice. The underlying mechanism involves CARM1-catalyzed H3R26me2a on the promoter of glutathione peroxidase 4, leading to its transcriptional activation and subsequent ferroptosis inhibition. Furthermore, Sorafenib treatment induced the transcription of CARM1 through the MDM2-p53 axis. In summary, our findings establish CARM1 as a critical ferroptosis inhibitor and highlight the potential of CARM1is as novel ferroptosis inducers, providing promising therapeutic strategies for HCC treatment.

The value of Korean, American, and Chinese ultrasound risk stratification systems combined with BRAF(V600E) mutation for detecting papillary thyroid carcinoma in cytologically indeterminate thyroid nodules.

PURPOSE: To investigate the value of Korean, American, and Chinese ultrasound risk stratification systems combined with BRAF(V600E) mutation in the detection of papillary thyroid carcinoma (PTC)within cytologically indeterminate thyroid nodules (CITNs). METHODS: A single-center retrospective study encompassed 511 CITNs selected from 509 patients between January 2020 and July 2023.Each nodule underwent surgical treatment and was classified according to three distinct systems. Receiver operating characteristic (ROC) curves were plotted using histopathological diagnosis as the reference standard, and diagnostic performance was compared. RESULTS: The three ultrasound stratification systems showed an elevated malignant risk with increasing grades (all P for trend2 < 0.001). The cut-off values for Korean, American, and Chinese systems were 5, 5, and 4c, and their respective area under the curves (AUCs) were 0.735, 0.778, and 0.783.The combination of BRAF (V600E) mutation significantly enhanced the diagnostic efficacy for the Korean(0.773vs0.735, P < 0.001), American (0.809vs0.778, P < 0.001) and Chinese (0.815vs0.783, P < 0.001) stratification systems in distinguishing CITNs without compromising specificity. When the three stratification systems were applied individually or combined with BRAF (V600E) mutation, the AUCs of the American and Chinese systems were similar (all P > 0.05), both of which were higher than the AUC of the Korean system (all P < 0.05). The American system exhibited higher specificity compared to the Chinese and Korean systems (all P < 0.001), whereas the Chinese system demonstrated higher sensitivity and accuracy when compared to the American and Korean systems (all P < 0.001). CONCLUSION: Korean, American and Chinese stratification systems present potential in the differential diagnosis of CITNs. BRAF (V600E) mutation can significantly improve the detection rate of malignant nodules within CTNs, particularly PTC. Notably, the American and Chinese systems demonstrate superior overall diagnostic performance among these systems.

Blood transcriptomics mirror regulatory mechanisms during hibernation-a comparative analysis of the Djungarian hamster with other mammalian species.

Hibernation enables many species of the mammalian kingdom to overcome periods of harsh environmental conditions. During this physically inactive state metabolic rate and body temperature are drastically downregulated, thereby reducing energy requirements (torpor) also over shorter time periods. Since blood cells reflect the organism´s current condition, it was suggested that transcriptomic alterations in blood cells mirror the torpor-associated physiological state. Transcriptomics on blood cells of torpid and non-torpid Djungarian hamsters and QIAGEN Ingenuity Pathway Analysis (IPA) revealed key target molecules (TMIPA), which were subjected to a comparative literature analysis on transcriptomic alterations during torpor/hibernation in other mammals. Gene expression similarities were identified in 148 TMIPA during torpor nadir among various organs and phylogenetically different mammalian species. Based on TMIPA, IPA network analyses corresponded with described inhibitions of basic cellular mechanisms and immune system-associated processes in torpid mammals. Moreover, protection against damage to the heart, kidney, and liver was deduced from this gene expression pattern in blood cells. This study shows that blood cell transcriptomics can reflect the general physiological state during torpor nadir. Furthermore, the understanding of molecular processes for torpor initiation and organ preservation may have beneficial implications for humans in extremely challenging environments, such as in medical intensive care units and in space.

2L polyethylene glycol combined with castor oil versus 4L polyethylene glycol for bowel preparation before colonoscopy among inpatients.

Inpatients are more likely to have inadequate bowel preparation compared to outpatients. Although experts recommend 4L split polyethylene glycol (PEG) preparation, bowel preparation with castor oil (CaO) was recently found to reduce the volume of solution required. The aim of the study was to evaluate the cleansing effect and safety of 2L-PEG with Cao in bowel preparation among inpatients. Our study retrospectively analyzed the medical records and colonoscopy reports of inpatients (n = 1251) who underwent colonoscopy in the Affiliated Changzhou No.2 People Hospital of Nanjing Medical University, and the inpatients were divided into 2L-PEG-CaO and 4L-PEG group according to different bowel preparation protocols. Boston Bowel Preparation Scale (BBPS) is used to assess bowel preparation efficacy before colonoscopy. Furthermore, we also calculated other outcomes, such as polyp or adenoma detection rates and adverse events. A total of 1251 patients undergoing colonoscopy were included in this study, 738 were taken 4L-PEG and 513 2L-PEG-CaO. Both inpatients groups were matched for baseline characteristics. The 2L-PEG-CaO group was significantly higher than the 4L-PEG group on both BBPS (7.26 ± 1.75 vs 7.06 ± 1.58, P = .043) and adequate bowel cleansing rates (83.2% vs 77.4%, P = .011). Regarding adverse events, the 4L-PEG group was significantly higher than the 2L-PEG-CaO group on the incidence of abdominal fullness (6.4% vs 9.6%, P = .045) and adverse events (33.7% vs 28.5%, P = .048). The 2L split PEG with CaO preparation increased quality of bowel cleansing and improved tolerance in inpatients. Bowel preparation with 2L-PEG-CaO is suitable alternative to traditional 4L split PEG bowel preparation for colonoscopy of inpatients.

A novel T-cell proliferation-associated gene predicts prognosis and reveals immune infiltration in patients with oral squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is a highly malignant tumour, and the prediction of its prognosis remains challenging. The prognostic value of T-lymphocyte proliferation regulators in OSCC remains to be explored. DESIGN: We integrated mRNA expression profiles and relevant clinical information of OSCC patients from The Cancer Genome Atlas database. The expression and function of T-lymphocyte proliferation regulators and their relationship with overall survival (OS) were analysed. The T-lymphocyte proliferation regulator signature was screened using univariate Cox regression and least absolute shrinkage and selection operator coefficients and used to construct models for prognosis and staging prediction as well as for immune infiltration analysis. Final validation was performed using single-cell sequencing database and immunohistochemical staining. RESULTS: Most T-lymphocyte proliferation regulators in the TCGA cohort exhibited different expression levels between OSCC and paracancerous tissues. A prognostic model constructed using the T-lymphocyte proliferation regulator signature (RAN, CDK1, and CDK2) was used to categorise patients into high- and low-risk groups. The OS was significantly lower in the high-risk group than the low-risk group (p < 0.01). The predictive ability of the T-lymphocyte proliferation regulator signature was validated by receiver operating characteristic curve analysis. Immune infiltration analysis revealed different immune statuses in both groups. CONCLUSIONS: We established a new T-lymphocyte proliferation regulator signature that can predict the prognosis of OSCC. The results of this study will contribute to studies of T-cell proliferation and the immune microenvironment in OSCC to improve prognosis and immunotherapeutic response.

Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Iberdomide.

Iberdomide is an orally available cereblon-modulating agent being developed for the treatment of hematologic malignancies and autoimmune-mediated diseases. To assess the potential concentration-QTc relationship in humans and to ascertain or exclude a potential QT effect by iberdomide, a plasma concentration and ΔQTcF (change from baseline of corrected QT interval using the Fridericia formula) model of iberdomide was developed. Iberdomide concentration and paired high-quality, intensive electrocardiogram signal from a single-ascending-dose study in healthy subjects (N = 56) were included in the analysis. The primary analysis was based on a linear mixed-effect model with ΔQTcF as the dependent variable; iberdomide plasma concentration and baseline QTcF as continuous covariates; treatment (active or placebo) and time as a categorical factor; and a random intercept per subject. The predicted change from baseline and placebo corrected (ΔΔQTcF) at the observed geometric mean maximum plasma concentration and 2-sided 90% confidence intervals at different dose levels were calculated. The upper bound of the 90% confidence interval of the model-predicted ΔΔQTcF effect at maximum concentration from the supratherapeutic dose of 6 mg (2.54 milliseconds) is <10-millisecond threshold, suggesting that iberdomide does not have a clinically relevant QT prolongation liability.

A Phase 1, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics of Iberdomide in Subjects with Mild, Moderate, or Severe Hepatic Impairment Compared with Healthy Subjects.

Introduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment. Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12. Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful. Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.

Hemolytic iron regulation in traumatic brain injury and alcohol use.

Hemorrhage is a major component of traumatic brain injury (TBI). Red blood cells, accumulated at the hemorrhagic site, undergo hemolysis upon energy depletion and release free iron into the central nervous system. This iron must be managed to prevent iron neurotoxicity and ferroptosis. As prior alcohol consumption is often associated with TBI, we examined iron regulation in a rat model of chronic alcohol feeding subjected to fluid percussion-induced TBI. We found that alcohol consumption prior to TBI altered the expression profiles of the lipocalin 2/heme oxygenase 1/ferritin iron management system. Notably, unlike TBI alone, TBI following chronic alcohol consumption sustained the expression of all three regulatory proteins for 1, 3, and 7 days post-injury. In addition, alcohol significantly affected TBI-induced expression of ferritin light chain at 3 days post-injury. We also found that alcohol exacerbated TBI-induced activation of microglia at 7 days post-injury. Finally, we propose that microglia may also play a role in iron management through red blood cell clearance.

Model-based analysis for the population pharmacokinetics of iberdomide and its major active metabolite in healthy subjects and patients with relapsed and refractory multiple myeloma.

AIMS: A parent-metabolite population pharmacokinetic (popPK) model of iberdomide and its pharmacologically active metabolite (M12) was developed and the influence of demographic and disease-related covariates on popPK parameters was assessed based on data from 3 clinical studies of iberdomide (dose range, 0.1-6 mg) in healthy subjects (n = 81) and patients with relapsed and refractory multiple myeloma (n 245). METHODS: Nonlinear mixed effects modelling was used to develop the popPK model based on data from 326 subjects across 3 clinical studies. RESULTS: The pharmacokinetics (PK) of iberdomide were adequately described with a 2-compartment model with first-order absorption and elimination. A first-order conversion rate was used to link the 1-compartment linear elimination metabolite model with the parent model. Subject type (multiple myeloma patients vs. healthy subject) was a statistically significant covariate on apparent clearance and apparent volume of distribution for the central compartment, suggesting different PK between patients with multiple myeloma and healthy subjects. Aspartate aminotransferase and sex were statistically but not clinically relevant covariates on apparent clearance. Metabolite (M12) PK tracked the PK of iberdomide. The metabolite to parent ratio was consistent across doses and combinations. CONCLUSION: The parent-metabolite population PK model adequately described the time course PK data of iberdomide and M12. Iberdomide and M12 PK exposure were not complicated by demographic factors (age [19-82 y], body weight [41-172 kg], body surface area [1.4-2.7 m2 ], body mass index [16.4-59.3 kg/m2 ]), combination (in combination with dexamethasone and daratumumab), mild hepatic, or mild and moderate renal impairments. The model can be used to guide the dosing strategy for special patient population and inform future iberdomide study design.