Changes in smoking patterns and characteristics of Koreans using the Korea National Health and Nutrition Examination Survey 2013-2021 data.

OBJECTIVES: This study explored factors related to Korean adults' smoking patterns and also the reasons for using new types of tobacco products. STUDY DESIGN: Cross-sectional survey. METHODS: Data from the Korea National Health and Nutrition Examination Survey from 2013 to 2021 were used. The prevalence of the use of electronic cigarettes (e-cigarettes) or heated tobacco products (HTPs) alone or in combination with conventional cigarettes (CC) and the reasons for using new tobacco products are presented. Factors associated with using new types of tobacco products alone or in combination with CC compared to exclusive CC users were identified using multinomial logistic regression analysis. RESULTS: The prevalence of current smoking was 25.54% in 2013 and 23.05% in 2021, with no significant change. The prevalence of CC decreased from 23.39% in 2013 to 15.77% in 2021. The prevalence of new tobacco use in combination with CC did not show a definite trend. The prevalence of exclusive use of new tobacco was <1% until 2018 and has rapidly increased thereafter. Of the HTPs users, 46.68% responded with 'no cigarette smell' as the main reason for HTPs use, followed by 'It seems less harmful than cigarette' (19.19%), and 'It seems to be helpful for quitting smoking' (15.04%). Of the e-cigarette users, 45.19% responded 'It seems to be helpful for quitting smoking' as the main reason for e-cigarette use, followed by 'It is less harmful than cigarettes' (19.98%). Compared to CC users, new tobacco users were younger, had a higher household income or education, and used more nutritional supplements. CONCLUSION: Regulations for newer tobacco products are more lenient than for traditional cigarettes, leading to misunderstandings, especially among women and young people. To increase awareness of the risks of these products, specific policies such as disclosure of ingredients, ban on online sales, and increase in consumption tax, are needed.

Search for Boosted Dark Matter in COSINE-100.

We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.

Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration.

BACKGROUND AND AIMS: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. APPROACH AND RESULTS: Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients. CONCLUSIONS: Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.

Enhanced spectral-domain optical coherence tomography (SD-OCT) using in situ ultrasonic virtual tunable optical waveguides.

A conventional optical lens can enhance lateral resolution in optical coherence tomography (OCT) by focusing the input light onto the sample. However, the typical Gaussian beam profile of such a lens will impose a tradeoff between the depth of focus (DOF) and the lateral resolution. The lateral resolution is often compromised to achieve a mm-scale DOF. We have experimentally shown that using a cascade system of an ultrasonic virtual tunable optical waveguide (UVTOW) and a short focal-length lens can provide a large DOF without severely compromising the lateral resolution compared to an external lens with the same effective focal length. In addition, leveraging the reconfigurability of UVTOW, we show that the focal length of the cascade system can be tuned without the need for mechanical translation of the optical lens. We compare the performance of the cascade system with a conventional optical lens to demonstrate enhanced DOF without compromising the lateral resolution as well as reconfigurability of UVTOW for OCT imaging.

Characterization of Clozapine-Responsive Human T Cells.

Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and the association with HLA variants are characteristic of an immunological mechanism. The objective of this study was to generate clozapine-specific T cell clones (TCC) and characterize pathways of T cell activation and cross-reactivity with clozapine metabolites and olanzapine. TCC were established and characterized by culturing PBMCs from healthy donors and patients with a history of clozapine-induced agranulocytosis. Modeling was used to explore the drug-HLA binding interaction. Global TCC protein changes were profiled by mass spectrometry. Six well-growing clozapine-responsive CD4+ and CD8+ TCC were used for experiments; activation of TCC required APC, with clozapine interacting directly at therapeutic concentrations with several HLA-DR molecules. TCC were also activated with N-desmethylclozapine and olanzapine at supratherapeutic concentrations. Marked changes in TCC protein expression profiles were observed when clozapine treatment was compared with olanzapine and the medium control. Docking of the compounds into the HLA-DRB1*15:01 and HLA-DRB1*04:01 binding clefts revealed that clozapine and olanzapine bind in a similar conformation to the P4-P6 peptide binding pockets, whereas clozapine N-oxide, which did not activate the TCC, bound in a different conformation. TCC secreted Th1, Th2, and Th22 cytokines and effector molecules and expressed TCR Vß 5.1, 16, 20, and 22 as well as chemokine receptors CXCR3, CCR6, CCR4, and CCR9. Collectively, these data show that clozapine interacts at therapeutic concentrations with HLA-DR molecules and activates human CD4+ T cells. Olanzapine only activates TCC at supratherapeutic concentrations.

Validation of the Anti-Inflammatory Effect of Tenebrio Molitor Larva Oil in a Colitis Mouse Model.

Ulcerative colitis is caused by various external factors and is an inflammatory disease that causes decreased intestinal function. Tenebrio molitor larvae contain more than 30 % fat, and the fat component consists of 45 % oleic acid, 20 % linoleic acid and 20 % polyunsaturated fatty acids. In this study, after administering Tenebrio molitor larva oil (TMLO) in a dextran sodium sulphate (DSS)-induced ulcerative colitis mouse model, the pathological findings and inflammatory markers of colitis were analysed to assess whether a colitis mitigation effect was achieved. In the TMLO-administered group, the colon length increased, the spleen weight decreased, and the body weight increased compared with that in the DSS group. In addition, the disease activity index level decreased, the mRNA expression level of inflammatory cytokines in the colon decreased, and the myeloperoxidase activity level significantly decreased. Also, the activity of the NF-κB pathway involved in the regulation of the inflammatory response was lower in the TMLO group than in the DSS group. Taken together, these results suggest that TMLO suppresses occurrence of acute ulcerative colitis in the DSS mouse model. Therefore, TMLO has the potential to be developed as a health food for the prevention and treatment of ulcerative colitis.

Increased risk of cardiovascular diseases in patients with chronic rhinosinusitis: a longitudinal follow-up study using a national health screening cohort.

BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common chronic inflammatory diseases and is characterized by sinonasal inflammation that lasts longer than 12 weeks. Whether the effect of chronic inflammation caused by CRS on cardiovascular diseases (CVDs) is similar to its effect on other inflammatory disorders has not been thoroughly evaluated. We aimed to demonstrate whether CRS patients have a higher prevalence of CVDs, including stroke and ischemic heart disease (IHD). METHODOLOGY: We compared the prevalence of various comorbidities between CRS and control participants through a case-control cohort study from 2002 to 2015 that included 514,866 participants. CRS (n=6,552) and control (n=26,208) participants who were over 40 years old were selected by matching age, sex, income, and area of residence at a 1:4 ratio. RESULTS: A stratified Cox proportional hazards model was utilized to assess the hazard ratio (HR) of CRS for stroke and IHD. The HRs for stroke and IHD were significantly increased in CRS patients compared to controls after adjusting for obesity, alcohol consumption, smoking, systolic and diastolic blood pressure, fasting blood glucose, total cholesterol, hemoglobin, and Charlson Comorbidity Index (CCI) scores. The HR of stroke was significantly higher in the absence of nasal polyps than in the presence of nasal polyps. The HR of IHD was significantly increased in the CRS group regardless of the presence of nasal polyps. CONCLUSIONS: This study showed that CRS participants had a significantly higher prevalence of stroke and IHD.

Temporal change in the diagnosis and treatment rates of osteoporosis: results from the Korea National Health and Nutrition Examination Survey.

To compare the diagnosis andtreatment rates of osteoporosis and diabetes in Korea, a nationwide database was used. The results showed that although osteoporosis management is improving, it is still lower compared with that of diabetes; thus, further efforts are needed in this regard. INTRODUCTION: This study aimed to re-evaluate the diagnosis and treatment of osteoporosis from the KNHANES 2016-2017 and compare the temporal change of the rate with those of diabetes as another prevalent chronic disease in South Korea. METHODS: The prevalence of osteoporosis in 2016 was estimated using the previous data classified by age groups (50-59,60-69, and ≥70years) and the 2016 Korean census data. The physician diagnosis and treatment rates of osteoporosis in adults aged ≥50years were estimated using the 2016-2017 KNHANES data. The physician diagnosis and treatment rates of diabetes were evaluated using the KNHANES 2008-2009 and 2016-2017 data. RESULTS: The estimated physician diagnosisrate of osteoporosis increased from 29.9% in females and 5.8% in males in 2008-2009 to 62.8% in females and 22.8% in males in 2016-2017. The treatment rate for the estimated total number of patients with osteoporosis increased from 14.4% in females and 3.8% in males in 2008-2009 to 32.2% in females and 9.0% in males in 2016-2017. An increasing trend in the estimated treatment rateof physician-diagnosed osteoporosis patients was not observed (48.3% [2008-2009] vs 51.5% [2016-2017] in females; 42.6% [2008-2009] vs 42.2% [2016-2017] in males). The physician diagnosis and treatment rates of diabetes were considerably better and more stable than those of osteoporosis. CONCLUSION: Osteoporosis management in South Korea is improving but is insufficient compared with diabetes management. More extensive efforts are needed to improve the diagnosis and treatment rates of osteoporosis.

Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine.

AIMS: Carbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11-epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates. METHODS: A combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11-epoxide. Nonlinear mixed effects modelling was used to build a population-PK model. RESULTS: In total, 248 observations were collected from 80 subjects. A 1-compartment PK model with first-order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h-1 . Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1-416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11-epoxide. CONCLUSION: Our data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11-epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.

Radiomics-based model for predicting pathological complete response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

AIM: To develop and validate a radiomics-based model for predicting response to neoadjuvant chemotherapy (NAC) using baseline computed tomography (CT) images in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: A radiomics signature for predicting pathological complete response (pCR) was developed using radiomics features selected by a random forest classifier on baseline CT images, and imaging predictors were identified in the training set (87 patients). By incorporating imaging predictors and radiomics signature, an imaging-based model was constructed using multivariate logistic regression analysis and validated in an independent validation set consisting of 48 patients with CT from outside institutions. The performance and clinical usefulness of the imaging-based model for predicting pCR were evaluated using area under the receiver operating characteristic curve (AUC) and decision curve analysis. Using a cut-off determined in the training set, the positive likelihood ratios of the imaging-based model were calculated and compared with imaging and histological predictors. RESULTS: The radiomics signature was developed based on six stable radiomics features. An imaging-based model incorporating radiomics signature, tumour shape, tumour size, and clinical stage showed good performance for predicting pCR in both the training (AUC, 0.85; 95% confidence interval [CI], 0.78-0.93) and validation (AUC, 0.75; 95% CI, 0.60-0.86) sets, providing a larger net benefit in decision curve analysis. The imaging-based model showed a higher positive likelihood ratio (1.91) for pCR than imaging and histological predictors (1.33-1.63). CONCLUSIONS: The radiomics-based model using baseline CT images may predict the response of patients with MIBC to NAC.

Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification.

Hepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10-1000 µM) and irinotecan (1-100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

Systems analysis of miRNA biomarkers to inform drug safety.

microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.

3D wide-field multispectral photoacoustic imaging of human melanomas in vivo: a pilot study.

BACKGROUND: The Breslow depth is an important parameter to determine the excision margin and prognosis of melanoma. However, it is difficult to accurately determine the actual Breslow depth before surgery using the existing ocular micrometer and biopsy technique. OBJECTIVES: To evaluate the use of 3D wide-field multispectral photoacoustic imaging to non-invasively measure depth and outline the boundary of melanomas for optimal surgical margin selection. METHODS: Six melanoma patients were examined in vivo using the 3D multispectral photoacoustic imaging system. For five cases of melanomas (one in situ, three nodular, and one acral lentiginous type melanoma), the spectrally unmixed photoacoustic depths were calculated and compared against histopathological depths. RESULTS: Spectrally unmixed photoacoustic depths and histopathological depths match well within a mean absolute error of 0.36 mm. In particular, the measured minimum and maximum depths in the in situ and nodular type of melanoma were 0.6 and 9.1 mm, respectively. In the 3D photoacoustic image of one metastatic melanoma, feeding vessels were visualized in the melanoma, suggesting the neovascularization around the tumour. CONCLUSIONS: The 3D multispectral photoacoustic imaging not only provides well-measured depth and sizes of various types of melanomas, it also visualizes the metastatic type of melanoma. Obtaining accurate depth and boundary information of melanoma before surgery would play a useful role in the complete excision of melanoma during surgery.

Interferometric mapping of material properties using thermal perturbation.

Optical phase changes induced by transient perturbations provide a sensitive measure of material properties. We demonstrate the high sensitivity and speed of such methods, using two interferometric techniques: quantitative phase imaging (QPI) in transmission and phase-resolved optical coherence tomography (OCT) in reflection. Shot-noise-limited QPI can resolve energy deposition of about 3.4 mJ/cm2 in a single pulse, which corresponds to 0.8 °C temperature rise in a single cell. OCT can detect deposition of 24 mJ/cm2 energy between two scattering interfaces producing signals with about 30-dB signal-to-noise ratio (SNR), and 4.7 mJ/cm2 when SNR is 45 dB. Both techniques can image thermal changes within the thermal confinement time, which enables accurate single-shot mapping of absorption coefficients even in highly scattering samples, as well as electrical conductivity and many other material properties in biological samples at cellular scale. Integration of the phase changes along the beam path helps increase sensitivity, and the signal relaxation time reveals the size of hidden objects. These methods may enable multiple applications, ranging from temperature-controlled retinal laser therapy or gene expression to mapping electric current density and characterization of semiconductor devices with rapid pump-probe measurements.

Association between air pollution and chronic rhinosinusitis: a nested case-control study using meteorological data and national health screening cohort data.

BACKGROUND: Inconsistent results about the effect of air pollution on chronic rhinosinusitis (CRS) have been reported. This study aimed to evaluate the impact of meteorological conditions/air pollution on the prevalence of CRS in adult Koreans. METHODOLOGY: The data from the Korean National Health Insurance Service-Health Screening Cohort from 2002 through 2015 were used. A CRS group (defined as ICD-10 codes J32, n=6159) was matched with a control group (n=24,636) in 1:4 ratios by age, sex, income, and region of residence. The meteorological conditions and air pollution data included the daily mean, highest, and lowest temperature (°C), daily temperature range (°C), relative humidity (%), ambient atmospheric pressure (hPa), sunshine duration (hr), and the rainfall (mm), SO2 (ppm), NO2 (ppm), O3 (ppm), CO (ppm), and PM10 (λg/m3) levels before the CRS diagnosis. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for CRS were analyzed using logistic regression analyses. RESULTS: When the NO2 level increased by 0.1 ppm, the odds for CRS increased 5.40 times, and when the CO level increased by 1 ppm and PM10 increased by 10 λg/m3, the odds for CRS decreased 0.75 times and 0.93 times, respectively. Other meteorological conditions, such as the mean/highest/lowest temperature, temperature range, rainfall and other air pollution, such as SO2 and O3, were not statistically significant. NO2 for 90 days before the index date increased the risk of CRS in all subgroups, except for the nasal polyp and older age subgroups. CONCLUSION: CRS is related to high concentrations of NO2.

Increased risk of chronic otitis media in chronic rhinosinusitis patients: a longitudinal follow-up study using a national health screening cohort.

BACKGROUND: Chronic rhinosinusitis (CRS) and chronic otitis media (COM) share pathophysiological mechanisms such as bacterial infection, biofilm, and persistence of the obstruction state of ventilation routes. However, only a few studies have investigated the relationship between these two diseases nationwide and in the general population. The purpose of this study was to determine whether the incidence of COM in patients with CRS differed from that of a matched control from the national health screening cohort. METHODS: Data from the Korean Health Insurance Review and Assessment Service-National Patient Samples were collected from 2002 to 2015. Participants who were treated ≥ ≥ ≥2 times and underwent head and neck computed tomography evaluation were selected. A 1:4 matched CRS group (n=8,057) and a control group (n=32,228) were selected. The control group included participants who were never treated with the ICD-10 code J32 from 2002 to 2015. The CRS group included CRS patients with/without nasal polyps. RESULTS: The incidence of COM was significantly higher in the CRS group than in the control group. In a subgroup analysis, the incidence of COM in all age groups and in men and women was significantly higher in the CRS group than in the control group. More, CRS increased the risk of COM. CONCLUSIONS: A significant association was observed between CRS and COM. This indicates that CRS patients have a high risk of developing COM.

Treatment with K6PC-5, a selective stimulator of SPHK1, ameliorates intestinal homeostasis in an animal model of Huntington's disease.

Emerging evidence indicates that Huntington's disease (HD) may be described as multi-organ pathology. In this context, we and others have contributed to demonstrate that the disease is characterized by an impairment of the homeostasis of gastro-intestinal (GI) tract. Sphingolipids represent a class of molecules involved in the regulation and maintenance of different tissues and organs including GI system. In this study, we investigated whether the alteration of Sphingosine-1-phosphate (S1P) metabolism, previously described in human HD brains and animal models, is also detectable peripherally in R6/2 HD mice. Our findings indicate, for the first time, that sphingolipid metabolism is perturbed early in the disease in the intestinal tract of HD mice and, its modulation by K6PC-5, a selective activator of S1P synthesis, preserved intestinal integrity and homeostasis. These results further support the evidence that modulation of sphingolipid pathways may represent a potential therapeutic option in HD and suggest that it has also the potential to counteract the peripheral disturbances which may usually complicate the management of the disease and affect patient's quality of life.

Alternatively activated macrophages promote resolution of necrosis following acute liver injury.

BACKGROUND & AIM: Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI). METHODS: Several phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. RESULTS: BMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. CONCLUSION: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury. LAY SUMMARY: After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.

Expression of Concern to: Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatoxicity.

The Editors-in-Chief would like to alert readers that this article [1] is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1.

Exosomal Transport of Hepatocyte-Derived Drug-Modified Proteins to the Immune System.

Idiosyncratic drug-induced liver injury (DILI) is a rare, often difficult-to-predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are immune-mediated and may involve the activation of drug-specific T cells. Exosomes are cell-derived vesicles that carry RNA, lipids, and protein cargo from their cell of origin to distant cells, and they may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid, and nitroso-sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50 and 100 nm and expressed enriched CD63. Liquid chromatography-tandem mass spectrometry (LC/MS-MS) identified 2,109 proteins, with 608 proteins being quantified across all exosome samples. Data are available through ProteomeXchange with identifier PXD010760. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso-sulfamethoxazole-treated hepatocytes selectively packaged a specific subset of proteins. LC/MS-MS also revealed the presence of hepatocyte-derived exosomal proteins covalently modified with amoxicillin, flucloxacillin, and nitroso-sulfamethoxazole. Uptake of exosomes by monocyte-derived dendritic cells occurred silently, mainly through phagocytosis, and was inhibited by latrunculin A. An amoxicillin-modified 9-mer peptide derived from the exosomal transcription factor protein SRY (sex determining region Y)-box 30 activated naïve T cells from human leukocyte antigen A*02:01-positive human donors. Conclusion: This study shows that exosomes have the potential to transmit drug-specific hepatocyte-derived signals to the immune system and provide a pathway for the induction of drug hapten-specific T-cell responses.