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Zhoumeng Lin,1– 4,* Wei-Chun Chou,1– 4,* Yi-Hsien Cheng,3,4 Chunla He,5 Nancy A Monteiro-Riviere,6,7 Jim E Riviere7,8 1Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA; 2Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, USA; 3Institute of Computational Comparative Medicine, Kansas State University, Manhattan, KS, USA; 4Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA; 5Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA; 6Nanotechnology Innovation Center of Kansas State, Kansas State University, Manhattan, KS, USA; 7Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, Raleigh, NC, USA; 8 1Data Consortium, Kansas State University, Olathe, KS, USA*These authors contributed equally to this workCorrespondence: Zhoumeng Lin, Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, 1225 Center Dr., Gainesville, FL, 32610, USA, Tel +1 352-273-6160, Email linzhoumeng@ufl.eduBackground: Low delivery efficiency of nanoparticles (NPs) to the tumor is a critical barrier in the field of cancer nanomedicine. Strategies on how to improve NP tumor delivery efficiency remain to be determined.Methods: This study analyzed the roles of NP physicochemical properties, tumor models, and cancer types in NP tumor delivery efficiency using multiple machine learning and artificial intelligence methods, using data from a recently published Nano-Tumor Database that contains 376 datasets generated from a physiologically based pharmacokinetic (PBPK) model.Results: The deep neural network model adequately predicted the delivery efficiency of different NPs to different tumors and it outperformed all other machine learning methods; including random forest, support vector machine, linear regression, and bagged model methods. The adjusted determination coefficients (R2) in the full training dataset were 0.92, 0.77, 0.77 and 0.76 for the maximum delivery efficiency (DEmax), delivery efficiency at 24 h (DE24), at 168 h (DE168), and at the last sampling time (DETlast). The corresponding R2 values in the test dataset were 0.70, 0.46, 0.33 and 0.63, respectively. Also, this study showed that cancer type was an important determinant for the deep neural network model in predicting the tumor delivery efficiency across all endpoints (19– 29%). Among all physicochemical properties, the Zeta potential and core material played a greater role than other properties, such as the type, shape, and targeting strategy.Conclusion: This study provides a quantitative model to improve the design of cancer nanomedicine with greater tumor delivery efficiency. These results help to improve our understanding of the causes of low NP tumor delivery efficiency. This study demonstrates the feasibility of integrating artificial intelligence with PBPK modeling approaches to study cancer nanomedicine.Graphical Abstract: Keywords: artificial intelligence, machine learning, physiologically based pharmacokinetic modeling, nanomedicine, drug delivery, nanotechnology

Wen-Chi Chou,1 Yen-Yang Chen,2 Chia-Yen Hung,1,3 Jen-Shi Chen,1 Chang-Hsien Lu,4 Pei-Hung Chang5 1Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 4Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan; 5Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan Background: Only 5-fluorouracil (5-FU), cisplatin, and gemcitabine have been reimbursed for metastatic pancreatic cancer (mPC) treatment in Taiwan since 2003. It is uncertain whether the reimbursement of S-1 in June 2014 might change the treatment pattern and improve the survival of mPC patients in Taiwan. Patients and methods: A total of 645 patients with newly diagnosed mPC who received palliative chemotherapy between 2010 and 2016 in Taiwan were analyzed retrospectively. Patients were stratified according to year at diagnosis of mPC for analysis of chemotherapeutic treatment pattern and survival. Results: Overall, the most common chemotherapeutic agents used for the treatment of mPC were gemcitabine (94.8%), followed by cisplatin (52.4%), S-1 (38.1%), and 5-FU (29.7%). The percentage of patients treated with S-1 between 2010 and 2016 increased from 2.6% to 74.0% (P

Hung-Chih Hsu,1,2 Wen-Chi Chou,1,2 Feng-Che Kuan,2,3 Kuan-Der Lee,4 Kun-Ming Rau,2,5 Jen-Seng Huang,2,6 Tsai-Sheng Yang1,2 1Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Guishan, Taoyuan, Taiwan, Republic of China; 2College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China; 3Division of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Puzi City, Taiwan, Republic of China; 4Division of Hematology and Oncology, Department of Medicine, Taipei Medical University Hospital and Taipei Medical University, Taipei, Taiwan, Republic of China; 5Division of Hematology and Oncology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China; 6Division of Hematology and Oncology, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China Purpose: Fewer treatment options are available for refractory metastatic colorectal cancer (mCRC). In early trials, S-1 monotherapy was effective for mCRC patients after chemotherapy failure and its combination with oral leucovorin therapy offers promising results in untreated mCRC. Hence, we conduct a Phase II trial to assess the efficacy of S-1 plus oral leucovorin (SL) in refractory mCRC that progressed after multiple prior standard therapies.Methods: In this open-label, single-arm study, we enrolled the refractory mCRC patients who received fluoropyrimidine, oxaliplatin, and irinotecan treatment and at least one targeted therapy previously. The doses of SL were 40–60 and 30 mg twice daily separately. They were administered for 7 days in a 2-week cycle. Treatment was continued until disease progression.Results: Of the 41 enrolled patients, 36 patients were evaluable with 61.1% disease control rate. The median progression-free survival and overall survival were 2.55 and 7.63 months, respectively. Regression change in tumor size stayed 10%–20% in five patients (13.9%) through 18 weeks after treatment, and two patients continued free from tumor progression at 30 and 42 weeks. Compared with moderate heavily pretreated mCRC patient subgroup (≤4 prior regimens), the severe heavily pretreated subgroup (≥5 prior regimens) showed similar disease control rate and survival benefit. Grade 3 or higher toxicities were documented only in 11 patients (26.8%).Conclusion: SL shows potential as a salvage regimen in refractory mCRC patients especially in the severe heavily pretreated setting and is well tolerated in these patients. Keywords: refractory metastatic colorectal cancer, S-1, oral leucovorin, Phase II, survival and safety

Yi-Hsien Cheng,1 Shu-Han You,2 Yi-Jun Lin,3 Szu-Chieh Chen,4,5 Wei-Yu Chen,6 Wei-Chun Chou,2 Nan-Hung Hsieh,7 Chung-Min Liao3 1Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA; 2National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, 3Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 4Department of Public Health, 5Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, 6Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA Background: The interaction between influenza and pneumococcus is important for understanding how coinfection may exacerbate pneumonia. Secondary pneumococcal pneumonia associated with influenza infection is more likely to increase respiratory morbidity and mortality. This study aimed to assess exacerbated inflammatory effects posed by secondary pneumococcal pneumonia, given prior influenza infection. Materials and methods: A well-derived mathematical within-host dynamic model of coinfection with influenza A virus and Streptococcus pneumoniae (SP) integrated with dose–response relationships composed of previously published mouse experimental data and clinical studies was implemented to study potentially exacerbated inflammatory responses in pneumonia based on a probabilistic approach. Results: We found that TNFα is likely to be the most sensitive biomarker reflecting inflammatory response during coinfection among three explored cytokines. We showed that the worst inflammatory effects would occur at day 7 SP coinfection, with risk probability of 50% (likely) to develop severe inflammatory responses. Our model also showed that the day of secondary SP infection had much more impact on the severity of inflammatory responses in pneumonia compared to the effects caused by initial virus titers and bacteria loads. Conclusion: People and health care workers should be wary of secondary SP infection on day 7 post-influenza infection for prompt and proper control-measure implementation. Our quantitative risk-assessment framework can provide new insights into improvements in respiratory health especially, predominantly due to chronic obstructive pulmonary disease (COPD). Keywords: chronic obstructive pulmonary disease, pneumonia, influenza, coinfection, modeling, risk assessment

Wei-Yu Chen,1 Yi-Hsien Cheng,2 Nan-Hung Hsieh,3 Bo-Chun Wu,2 Wei-Chun Chou,4 Chia-Chi Ho,4 Jen-Kun Chen,5 Chung-Min Liao,2,* Pinpin Lin4,* 1Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 2Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 3Institute of Labor, Occupational Safety and Health, Ministry of Labor, New Taipei City, 4National Institute of Environmental Health Sciences, 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan *These authors contributed equally to this work Abstract: Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of 65ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm 65ZnO NPs and zinc nitrate (65Zn(NO3)2) in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of 65ZnO NPs were greater than those of 65Zn(NO3)2, particularly the lung partition coefficient of 10 nm 65ZnO NPs. Sensitivity analysis revealed that 71 nm 65ZnO NPs and 65Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for 65ZnO NPs and 65Zn(NO3)2. The simulation of 65Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of 65ZnO NPs with those of 65Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to 65ZnO NPs

Objective: We presented a rare case of drug-induced thrombotic microangiopathy (DI-TMA) following chemotherapy with the regimen of bleomycin, etoposide, and cisplatin (BEP) in a patient with malignant ovarian germ cell tumor (MOGCT). The objective is to highlight the difficulty in diagnosing and treating DI-TMA associated with BEP chemotherapy., Case Report: A 21-year-old woman presented with a pelvic mass. Fertility-sparing staging surgery was performed, and a diagnosis of endodermal sinus tumor was confirmed. The patient received the first course of adjuvant chemotherapy with BEP regimen, but she developed symptoms of anemia, thrombocytopenia, and acute kidney injury. DI-TMA was diagnosed after thorough examinations, and she improved gradually by three courses of plasma exchange. Adjuvant chemotherapy was discontinued due to DI-TMA, and she kept disease-free for 17 months after the operation., Conclusion: DI-TMA, a rare lethal complication in MOGCT patients receiving the BEP regimen, requires prompt diagnosis and appropriate treatments., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The (ECOG) performance status (PS) is commonly used to evaluate the functional ability of patients undergoing antitumor therapy. An ECOG PS of 2, indicating patients capable of self-care but restricted strenuous activity, can complicate treatment decisions owing to concerns regarding treatment-related toxicity. We investigated whether frailty assessment could help discriminate treatment tolerance and survival outcomes in patients with an ECOG PS of 2., Methods: We prospectively included 45 consecutive patients, aged ≥65 years, with an ECOG PS of 2, and newly diagnosed solid cancer scheduled for chemotherapy. Frailty was assessed using an eight-indicator geriatric assessment. The primary outcome was overall survival (OS) based on frailty status; secondary outcomes included treatment tolerance and toxicity., Results: The median patient age was 73 years (range 65-94), and 71% had stage IV disease. Predominant frailty-related deficits were functional decline (96%), malnutrition (78%), and polypharmacy (51%). The median OS was 12.6 months (95% confidence interval [CI]: 6.8-18.4). Patients with 4-6 deficits had significantly lower OS than those with 1-3 deficits (9.9 months vs. 20.0 months, adjusted hazard ratio 2.51, 95% CI: 1.16-5.44, P = .020). Frailty significantly correlated with reduced 12-week chemotherapy competence (52% vs. 85%, adjusted odds ratio [OR] .14, 95% CI: .03-.70, P = .016) and enhanced risk of unexpected hospitalization (60% vs. 20%, adjusted OR 6.80, 95% CI: 1.64-28.1, P = .008)., Conclusion: Our findings highlight the multifaceted nature of patients with an ECOG PS of 2 and emphasize the importance of frailty assessment for treatment outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Flunixin meglumine is a nonsteroidal anti-inflammatory drug (NSAID). Banamine® Transdermal is a pour-on formulation of flunixin approved for pain control in beef and dairy cattle, but not for calves and some classes of dairy cattle or swine. Violative flunixin residues in edible tissues in cattle and swine have been reported and are usually attributed to non-compliant drug use or failure to observe an appropriate withdrawal time. This project aimed to develop a physiologically based pharmacokinetic (PBPK) model for flunixin in cattle and swine to predict withdrawal intervals (WDI) after exposures to different therapeutic regimens of Banamine® Transdermal. Due to the lack of comprehensive skin physiological data in cattle, the model was initially developed for swine and then adapted for cattle. Monte Carlo simulation was employed for population variability analysis. The model predicted WDIs were rounded to 1 and 2 days for liver and muscle in cattle, respectively, under FDA tolerance levels, while under EU maximum residue limits (MRLs), the WDIs were rounded to 1, 3, 2, and 2 days for liver, kidney, muscle, and fat, respectively, following a labeled single transdermal 3.3 mg/kg dose in cattle. The model was converted into a user-friendly interactive PBPK (iPBPK) interface. This study reports the first transdermal absorption model for drugs in cattle. This iPBPK model provides a scientifically based tool for the prediction of WDIs in cattle and swine administered with flunixin in an extra-label manner, especially by the transdermal route., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Coral reefs are facing threats from a variety of global change stressors, including ocean warming, acidification, and deoxygenation. It has been hypothesized that growing corals near primary producers such as macroalgae or seagrass may help to ameliorate acidification and deoxygenation stress, however few studies have explored this effect in situ. Here, we investigated differences in coral growth rates across a natural gradient in seawater temperature, pH, and dissolved oxygen (DO) variability in a nearshore seagrass bed on Dongsha Atoll, Taiwan, South China Sea. We observed strong spatial gradients in temperature (5°C), pH (0.29 pH units), and DO (129 μmol O2 kg-1) across the 1-kilometer wide seagrass bed. Similarly, diel variability recorded by an autonomous sensor in the shallow seagrass measured diel ranges in temperature, pH, and DO of up to 2.6°C, 0.55, and 204 μmol O2 kg-1, respectively. Skeletal cores collected from 15 massive Porites corals growing in the seagrass bed at 4 sites revealed no significant differences in coral calcification rates between sites along the gradients. However, significant differences in skeletal extension rate and density suggest that the dynamic temperature, pH, and/or DO variability may have influenced these properties. The lack of differences in coral growth between sites may be because favorable calcification conditions during the day (high temperature, pH, and DO) were proportionally balanced by unfavorable conditions during the night (low temperature, pH, and DO). Alternatively, other factors were simply more important in controlling coral calcification and/or corals were acclimated to the prevailing conditions at each site., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pezner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Compared to functional magnetic resonance imaging (fMRI), source localization of a scalp-recorded electroencephalogram (EEG) provides higher temporal resolution and frequency synchronization to better understand the potential neurophysiological origins of disrupted functional connectivity (FC) in major depressive disorder (MDD). The present study aimed to investigate EEG-sourced measures to examine the FC in drug-free patients with MDD., Method: Resting-state 32-channel EEG were recorded in 84 drug-free patients with MDD and 143 healthy controls, and the cortical source signals were estimated. Exact low-resolution brain electromagnetic tomography (eLORETA) was used to compute the intracortical activity from regions within the default mode network (DMN) and frontoparietal network (PFN). Lagged phase synchronization was used as a measure of functional connectivity., Results: Compared with control subjects, the MDD group showed greater within-DMN alpha 1 and 2 bands and within-FPN alpha 1, 2, and beta 3 bands. Furthermore, the MDD group showed hyperconnectivity between the DMN and the FPN in the alpha 1 and 2 bands. Finally, higher levels of anhedonia were associated with higher between-network DMN and FPN connectivity in the alpha-1 band., Limitations: Due to the inherent limitations of eLORETA with predefined seeds, we could not exclude connectivity between regions of interest (ROIs), which may be related to the activity from regions adjacent to the ROIs., Conclusions: The present findings support the importance of phase-lagged functional dysconnectivity in the neurophysiological mechanisms underlying MDD. Exploring the potential of these patterns as surrogates for treatment responses may advance targeted interventions for depression., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Chlorinated polyfluorinated ether sulfonic acid (F-53B), a commonly utilized alternative for perfluorooctane sulfonate, was detected in pregnant women and cord blood recently. However, the lack of detailed toxicokinetic information poses a significant challenge in assessing the human risk assessment for F-53B exposure. Our study aimed to develop a physiologically based pharmacokinetic (PBPK) model for pregnant mice, based on toxicokinetic experiments, and extrapolating it to humans. Pregnant mice were administered 80 μg/kg F-53B orally and intravenously on gestational day 13. F-53B concentrations in biological samples were analyzed via ultraperformance liquid chromatography-mass spectrometry. Results showed the highest F-53B accumulation in the brain, followed by the placenta, amniotic fluid, and liver in fetal mice. These toxicokinetic data were applied to F-53B PBPK model development and evaluation, and Monte Carlo simulations were used to characterize the variability and uncertainty in the human population. Most of the predictive values were within a 2-fold range of experimental data (>72%) and had a coefficient of determination (R 2 ) greater than 0.68. The developed mouse model was then extrapolated to the human and evaluated with human biomonitoring data. Our study provides an important step toward improving the understanding of toxicokinetics of F-53B and enhancing the quantitative risk assessments in sensitive populations, particularly in pregnant women and fetuses.

The development of an excellent multifunctional electrocatalyst that is based on non-precious metal is critical for improving the electrochemical processes of the hydrogen evolution reaction (HER), the oxygen evolution reaction (OER), and the urea oxidation reaction (UOR) in alkaline media. This study demonstrates that incorporating Mo into Co 3 O 4 facilitated the formation of rich oxygen vacancies (Vo), which promotes effective nitrate adsorption and activation in urea electrolysis. Subsequently, in situ/operando X-ray absorption spectroscopy is used to explore the active sites in Mo-Co 3 O 4 -3 under OER, indicating the oxygen vacancies are first filled with OH • in Mo-Co 3 O 4 ; facilitated the pre-oxidation of low-valence Co, and promoted the reconstruction/deprotonation of intermediate Co-OOH • . Mo-Co 3 O 4 -3 electrocatalysts show impressive HER, OER, and UOR with low overpotentials of 141 mV, 220 mV, and 1.32 V, respectively, at 10 mA cm -2 in an alkaline medium. Furthermore, in situ/Operando Raman spectroscopy results reveal the importance of CoOOH active sites for enhanced electrochemical performance in Mo-Co 3 O 4 -3 compared to the pure Co 3 O 4 . The urea electrolyzer with Mo-Co 3 O 4 electrocatalysts acts as an anode and the cathode delivers 1.42 V at 10 mA cm -2 . A viable approach to creating effective UOR electrocatalysts involves synergistic engineering exploiting doping and oxygen vacancies., (© 2024 Wiley‐VCH GmbH.)

Objectives: Given increasing research suggesting the utility of positron emission tomography/magnetic resonance imaging (PET/MRI) in identifying the pain generator of low back pain, our study aims to assess its effectiveness in evaluating the source of pain in patients with failed back surgery syndrome (FBSS) by comparing the performance of fluorine-18-labeled fluorodeoxyglucose ( 18 F-FDG) PET/MRI with conventional MRI., Methods: We retrospectively analyzed data from patients with FBSS who underwent 18 F-FDG PET and MRI of the lumbar vertebrae and lower extremities for undetermined sources of pain. We assessed 1) The diagnostic reliability and efficacy of MRI and 18 F-FDG PET/MRI according to correct differential diagnosis, affected level, and affected side of the pain source compared to the findings of selective root or peripheral nerve block or revision lumbar spine surgery; and 2) The association between standardized uptake value (SUV) and standardized uptake value ratio (SUVR) threshold and accuracy of the suspected pathology on 18 F-FDG PET/MRI., Results: Among 30 included patients, the diagnostic accuracy of pain source recognition was higher for 18 F-FDG PET/MRI than for MRI alone (1.0 vs. 0.4 in spinal disease and 0.8 vs. 0 in lower extremity disease, both p < 0.05). SUVR values of 1.4-1.5 showed the highest accuracy (0.93), higher than the accuracy obtained using the SUV threshold (0.87)., Conclusion: 18 F-FDG PET/MRI added value to MRI alone in detecting of hypermetabolic activity associated with pain from spinal and non-spinal sources., (© 2024. The Author(s) under exclusive licence to Japan Radiological Society.)

Ovarian clear cell carcinoma (OCCC) has a high incidence in Asia, with frequent occurrence at an early stage, but without sufficient data on molecular stratification for high-risk patients. Recently, immune-hot features have been proposed as indicators of poor prognosis in early stage OCCC. Specific patterns of intratumoral heterogeneity associated with immune-hot features must be defined. NanoString Digital Spatial Profiling technology was used to decipher the spatial distribution of the 18-plex protein panel. ROIs were collected based on the reference hematoxylin and eosin (H&E)-stained morphology. Areas of illumination (AOIs) were defined according to the ROI segmentation using the fluorescence signals of the visualization markers pan-cytokeratin (PanCK), CD45, or DNA. Unsupervised hierarchical clustering of 595 AOIs from 407 ROIs showed that the PanCK segments expressed different combinations of immune markers, suggestive of immune mimicry. Three immune-hot clusters were identified: granzyme B high (GZMB), immune signal high (IH), and immune-like cells (IL); two immune-cold clusters were identified: fibronectin high (FN) and immune checkpoint high cells (IC). In tumor samples at FIGO stage IC1/2 experiencing recurrence, there was an increased occurrence of PanCK+ AOIs with IH and IL groups in the papillary morphology surrounded by macrophage lineage tumor-infiltrating immune cells (TIIs). In contrast, for tumor samples at FIGO stage IC3/II with recurrence, PanCK + AOIs were prevalent in the FN group, particularly those with tubulocystic morphology surrounded by lymphoid lineage non-TIIs. Our work on the spatial profiling of early stage OCCC tumors revealed that the immune mimicry of tumor cells, presence of TIIs, and morphological patterns were associated with recurrence, which switched during tumor progression., (Copyright © 2024. Published by Elsevier Inc.)

In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1 Q157 ), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs., Methods: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined., Results: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63 + basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE., Conclusions: This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Nanoparticles (NPs) can be designed for targeted delivery in cancer nanomedicine, but the challenge is a low delivery efficiency (DE) to the tumor site. Understanding the impact of NPs' physicochemical properties on target tissue distribution and tumor DE can help improve the design of nanomedicines. Multiple machine learning and artificial intelligence models, including linear regression, support vector machine, random forest, gradient boosting, and deep neural networks (DNN), were trained and validated to predict tissue distribution and tumor delivery based on NPs' physicochemical properties and tumor therapeutic strategies with the dataset from Nano-Tumor Database. Compared to other machine learning models, the DNN model had superior predictions of DE to tumors and major tissues. The determination coefficients (R 2 ) for the test datasets were 0.41, 0.42, 0.45, 0.79, 0.87, and 0.83 for DE in tumor, heart, liver, spleen, lung, and kidney, respectively. All the R 2 and root mean squared error (RMSE) results of the test datasets were similar to the 5-fold cross validation results. Feature importance analysis showed that the core material of NPs played an important role in output predictions among all physicochemical properties. Furthermore, multiple NP formulations with greater DE to the tumor were determined by the DNN model. To facilitate model applications, the final model was converted to a web dashboard. This model could serve as a high-throughput pre-screening tool to support the design of new and efficient nanomedicines with greater tumor DE and serve as an alternative tool to reduce, refine, and partially replace animal experimentation in cancer nanomedicine research., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Anionic redox allows the direct formation of O─O bonds from lattice oxygens and provides higher catalytic in the oxygen evolution reaction (OER) than does the conventional metal ion mechanism. While previous theories have predicted and experiments have suggested the possible O─O bond, it has not yet been directly observed in the OER process. In this study, operando soft X-ray absorption spectroscopy (sXAS) at the O K-edge and the operando Raman spectra is performed on layered double CoFe hydroxides (LDHs) after intercalation with [Cr(C 2 O 4 ) 3 ] 3- , and revealed a three-step oxidation process, staring from Co 2+ to Co 3+ , further to Co 4+ (3d6L), and ultimately leading to the formation of O─O bonds and O 2 evolution above a threshold voltage (1.4 V). In contrast, a gradual oxidation of Fe is observed in CoFe LDHs. The OER activity exhibits a significant enhancement, with the overpotential decreasing from 300 to 248 mV at 10 mA cm -2 , following the intercalation of [Cr(C 2 O 4 ) 3 ] 3- into CoFe LDHs, underscoring a crucial role of anionic redox in facilitating water splitting., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

MoSSe is a semiconducting material with a layered structure similar to MoS 2 and MoSe 2 , which shows potential applications in optoelectronics, solar cells, sensing, and catalysis. Synthesis of this material with a controllable structure and chemical composition represents a great challenge. Herein, we report a new method for the synthesis of MoSSe by employing an [Et 4 N] 2 [Mo 3 S 4 Se 3 Br 6 ] complex as the sole precursor. Thermal annealing of this complex under an Ar atmosphere at moderate temperatures ranging from 350 °C to 650 °C resulted in the formation of pure MoSSe. The morphology and structure of MoSSe were characterized using SEM, HRTEM, XRD, Raman spectroscopy, X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS). The effects of annealing temperature on the structure of MoSSe were also examined.

A critical review of the current state-of-the-science for the physiologically based pharmacokinetic (PBPK) modeling of metal nanoparticles and their application to human health risk assessment for inhalation exposures was conducted. A systematic literature search was used to identify four model groups (defined as a primary publication along with multiple supplementary publications) subject to review. Using a recent guideline document from the Organization for Economic Cooperation and Development (OECD) for PBPK model evaluation, these model groups were critically peer-reviewed by an independent panel of experts to identify those to be considered for modeling and simulation application. Based upon the expert panel input, model confidence scores for the four model groups ranged from 30 to 41 (out of a maximum score of 50). The three highest-scoring model groups were then applied to compare predictions to a different metal nanoparticle (i.e. not specifically used to parameterize the original models) using a recently published data set for tissue burdens in rats, as well as predicting human tissue burdens expected for corresponding occupational exposures. Overall, the rat models performed reasonably well in predicting the lung but tended to overestimate systemic tissue burdens. Data needs for improving the state-of-the-science, including quantitative particle characterization in tissues, nanoparticle-corona data, long-term exposure data, interspecies extrapolation methods, and human biomonitoring/toxicokinetic data are discussed.

Plasma half-life is a crucial pharmacokinetic parameter for estimating extralabel withdrawal intervals of drugs to ensure the safety of food products derived from animals. This study focuses on developing a quantitative structure-activity relationship (QSAR) model incorporating multiple machine learning and artificial intelligence algorithms, and aims to predict the plasma half-lives of drugs in six food animals, including cattle, chickens, goats, sheep, swine, and turkeys. By integrating four machine learning algorithms with five molecular descriptor types, 20 QSAR models were developed using data from the Food Animal Residue Avoidance Databank (FARAD) Comparative Pharmacokinetic Database. The deep neural network (DNN) algorithm demonstrated the best prediction ability of plasma half-lives. The DNN model with all descriptors achieved superior performance with a high coefficient of determination (R  2) of 0.82±0.19 in 5-fold cross-validation on the training sets and a R  2 of 0.67 on the independent test set, indicating accurate predictions and good generalizability. The final model was converted to a user-friendly web dashboard to facilitate its wide application by the scientific community. This machine learning-based QSAR model serves as a valuable tool for predicting drug plasma half-lives and extralabel withdrawal intervals in six common food animals based on physicochemical properties. It also provides a foundation to develop more advanced models to predict the tissue half-life of drugs in food animals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Scarce research explores factors of concurrent psychologic distress (prolonged grief disorder [PGD], post-traumatic stress disorder [PTSD], and depression). This study models surrogates' longitudinal, heterogenous grief-related reactions and multidimensional risk factors drawing from the integrative framework of predictors for bereavement outcomes (intrapersonal, interpersonal, bereavement-related, and death-circumstance factors), emphasizing clinical modifiability., Design: Prospective cohort study., Setting: Medical ICUs of two Taiwanese medical centers., Subjects: Two hundred eighty-eight family surrogates., Interventions: None., Measurements and Main Results: Factors associated with four previously identified PGD-PTSD-depressive-symptom states (resilient, subthreshold depression-dominant, PGD-dominant, and PGD-PTSD-depression concurrent) were examined by multinomial logistic regression modeling (resilient state as reference). Intrapersonal: Prior use of mood medications correlated with the subthreshold depression-dominant state. Financial hardship and emergency department visits correlated with the PGD-PTSD-depression concurrent state. Higher anxiety symptoms correlated with the three more profound psychologic-distress states (adjusted odds ratio [95% CI] = 1.781 [1.562-2.031] to 2.768 [2.288-3.347]). Interpersonal: Better perceived social support was associated with the subthreshold depression-dominant state. Bereavement-related: Spousal loss correlated with the PGD-dominant state. Death circumstances: Provision of palliative care (8.750 [1.603-47.768]) was associated with the PGD-PTSD-depression concurrent state. Surrogate-perceived quality of patient dying and death as poor-to-uncertain (4.063 [1.531-10.784]) correlated with the subthreshold depression-dominant state, poor-to-uncertain (12.833 [1.231-133.775]), and worst (12.820 [1.806-91.013]) correlated with the PGD-PTSD-depression concurrent state. Modifiable social-worker involvement (0.004 [0.001-0.097]) and a do-not-resuscitate order issued before death (0.177 [0.032-0.978]) were negatively associated with the PGD-PTSD-depression concurrent and the subthreshold depression-dominant state, respectively. Apparent unmodifiable buffering factors included surrogates' higher educational attainment, married status, and longer time since loss., Conclusions: Surrogates' concurrent bereavement distress was positively associated with clinically modifiable factors: poor quality dying and death, higher surrogate anxiety, and palliative care-commonly provided late in the terminal-illness trajectory worldwide. Social-worker involvement and a do-not-resuscitate order appeared to mitigate risk., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: The management of diffuse large B-cell lymphoma (DLBCL) in elderly patients is complicated by an increased risk of treatment-related toxicity associated with aging. This study aimed to validate the effectiveness of the Cancer Aging and Research Group (CARG) model in elderly patients with DLBCL receiving rituximab-based chemotherapy., Methods: In this prospective study, elderly DLBCL patients (aged 65 years or older) receiving rituximab-based chemotherapy were consecutively assessed between August 2016 and December 2021 at one medical center in Taiwan using the CARG model to predict treatment-related toxicity. Patients were categorized into low-, medium-, and high-risk groups based on their CARG scores. Comparisons were made regarding toxicities and survival rates among these groups., Results: Ninety-one patients, with a median age of 70 years (range 65-96), were included. A substantial 81 % (74 patients) experienced grade 3-5 toxicity. The overall 2-year survival rate was 63.8 % after a median follow-up of 28 months (range, 2-46). The risk of grade 3-5 toxicity was 83 %, 78 %, and 87 %, respectively, among the low-, medium-, and high-risk groups (p = 0.60). The receiver operating characteristic (ROC) curve for CARG was 0.521 (95 % CI, 0.376-0.666), which was significantly lower than that for the Eastern Cancer Oncology Group score (ROC = 0.701, 95 % CI, 0.571-0.831). Similarly, compared with those of low-risk patients, hazard ratios for overall survival were 9.22 (95 % CI, 1.23-69.1; p = 0.031) and 14.6 (95 % CI, 1.90-112; p = 0.010) for medium- and high-risk patients, respectively., Conclusion: While CARG exhibited limitations in predicting treatment-related toxicity in elderly DLBCL patients, it demonstrated potential efficacy in predicting survival outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution., (© 2024. The Author(s).)

Background: This retrospective study analyzed tumor tissue profiling data to assess the potential of comprehensive genomic profiling (CGP) for patient care across diverse solid tumors., Material and Methods: Patients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with a null immunophenotype and esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included. One cohort was a part of the National Biobank Consortium of Taiwan project, whereas the other consisted of patients undergoing routine clinical practice. Tumor samples were subjected to CGP using FoundationOne®CDx, with therapeutic implications determined using OncoKB classification., Results: FoundationOne®CDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients with evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancers. Based on CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7-35.5 months) and 10.6 months (95% CI, 8.1-13.1 months; hazard ratio, 0.28, 95% CI, 0.14-0.55, p < 0.001), respectively., Conclusions: This study provides comprehensive insights into the genomic profiles of diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Purpose: Tissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis., Materials and Methods: We enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor ( EGFR ) mutations or anaplastic large-cell lymphoma kinase ( ALK ) rearrangement-positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK -negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted., Results: Cohort 1: EGFR TKI-pretreated EGFR -mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK -positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK -negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK -negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients., Conclusion: This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

Background: Health-related quality of life (HRQoL) is a predictor of treatment outcomes in cancer patients. This study aimed to evaluate the effect of pretreatment HRQoL on treatment tolerance and survival outcomes in patients with HNC planned for concurrent chemoradiotherapy (CCRT) in Taiwan., Methods: This study included 461 patients with HNC planned for definitive CCRT at three medical centers in Taiwan between August 2017 and December 2018. HRQoL was assessed using the QLQ-HN35 one week before the initiation of CCRT. Patients were grouped based on the sum scores of QLQ-HN35 (

The ascomycete filamentous fungus Neurospora intermedia is commonly used in the food industry and considered nonpathogenic to humans. This study characterizes four N. intermedia isolates recovered from three patients. The first patient had a mediastinal germ cell tumor with multiple metastases. N. intermedia was recovered from his endotracheal aspirate and from the endobronchial mass obtained by bronchoscopic forceps biopsy. Histopathology of the biopsy tissue revealed necrotic tissue mixed with septate fungal hyphae with right-angle branching. An endobronchial mass caused by N. intermedia was thus diagnosed. Another two N. intermedia isolates were recovered from the endotracheal aspirates of two critically ill patients. In vitro, N. intermedia grows rapidly and forms orange, conidiating colonies composed of septate hyphae. Two isolates from the first patient belong to mating type a; the other two isolates belong to mating type A. Coculture of isolates of opposite mating types yielded dark ascomata containing ascospores, supporting that N. intermedia is a heterothallic fungus. N. intermedia isolates cross-reacted with the Aspergillus galactomannan antigen assay and were susceptible to amphotericin B and voriconazole. In conclusion, this report describes the first human infection (endobronchial mass) caused by N. intermedia, highlighting its potential to invade the human respiratory tract., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Taiwan has pledged to achieve net-zero carbon emissions by 2050, but the current extent of carbon sinks in Taiwan remains unclear. Therefore, this study aims to first review the existing nature-based carbon sinks on land and in the oceans around Taiwan. Subsequently, we suggest potential strategies to reduce CO 2 emissions and propose carbon dioxide removal methods (CDRs). The natural carbon sinks by forests, sediments, and oceans in and around Taiwan are approximately 21.5, 42.1, and 96.8 Mt-CO 2 y -1 , respectively, which is significantly less than Taiwan's CO 2 emissions (280 Mt-CO 2 y -1 ). Taiwan must consider decarbonization strategies like using electric vehicles, renewable energy, and hydrogen energy by formulating enabling policies. Besides more precisely assessing both terrestrial and marine carbon sinks, Taiwan should develop novel CDRs such as bioenergy with carbon capture and storage, afforestation, reforestation, biochar, seaweed cultivation, and ocean alkalinity enhancement, to reach carbon neutrality by 2050., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aberrant alternative splicing (AS) contributes to leukemogenesis, but reports on the clinical and biological implications of aberrant AS in acute myeloid leukaemia (AML) remain limited. Here, we used RNA-seq to analyse AS in AML cells from 341 patients, comparing them to healthy CD34 + haematopoietic stem cells (HSCs). Our findings highlight distinct AS patterns in the nuclear transcription factor Y subunit alpha (NFYA) gene, with two main isoforms: NFYA-L (Long) and NFYA-S (Short), differing in exon 3 inclusion. Patients with lower NFYA-L but higher NFYA-S expression, termed NFYA-S predominance, displayed more favourable characteristics and better outcomes following intensive chemotherapy, regardless of age and European LeukemiaNet risk classification, compared to those with higher NFYA-L but lower NFYA-S expression, termed NFYA-L predominance. The prognostic effects were validated using The Cancer Genome Atlas cohort. Transcriptome analysis revealed upregulated cell cycle genes in NFYA-S predominant cases, resembling those of active HSCs, demonstrating relative chemosensitivity. Conversely, NFYA-L predominant cases, as observed in KMT2A-rearranged leukaemia, were associated with relative chemoresistance. NFYA-S overexpression in OCI-AML3 cells promoted cell proliferation, S-phase entry and increased cytarabine sensitivity, suggesting its clinical and therapeutic relevance in AML. Our study underscores NFYA AS as a potential prognostic biomarker in AML., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood., Methods: To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines., Results: In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7-most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or -7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66-3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56-3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25-4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33-4.04]; P = 0.003). By contrast, IDH2-mutated patients (9%) displayed prolonged OS (HR, 0.51 [95% CI 0.30-0.88]; P = 0.0015) and durable responses (RFS: HR, 0.5 [95% CI 0.26-0.96]; P = 0.036)., Conclusion: This work unraveled formerly underestimated genetic lesions and provides a comprehensive overview of the spectrum of recurrent gene mutations and their clinical relevance in AML with abn(7). KMT2C mutations are among the most frequent gene mutations in this heterogeneous AML subgroup and warrant further functional investigation., (© 2024. The Author(s).)

Background: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer., Methods: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics., Results: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%)., Conclusions: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals., Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016., (© 2024. The Author(s).)

Background: Many patients with dysfunctional uterine bleeding (DUB) seek traditional medicine consultations. This study intended to investigate the association of complementary Chinese herbal medicine (CHM) with the surgery rate in patients with DUB in Taiwan., Methods: We enrolled 43,027 patients with newly diagnosed DUB (ICD-9-CM codes 626.8) from the National Health Insurance Research Database in Taiwan during the period of 1997 to 2010. Among them, 38,324 were CHM users, and 4703 did not receive CHM treatment. After performing a 1:1 propensity-score match based on patients' age (per 5 years), comorbidities, conventional drugs, childbirth status, duration from the diagnosis year of DUB and index year, there were an equal number (n=4642) of patients in the CHM cohort and non-CHM cohort. The outcome measurement was the comparison of incidences of surgical events, including hysterectomy and endometrial ablation, in the two cohorts before the end of 2013., Results: CHM users had a lower incidence of surgery than non-CHM users (adjusted HR 0.27, 95% CI: 0.22-0.33). The cumulative incidence of surgery was significantly lower in the CHM cohort during the follow-up period (Log rank test, p < 0.001). A total of 146 patients in the CHM cohort (4.99 per 1000 person-years) and 485 patients in the non-CHM cohort (20.19 per 1000 person-years) received surgery (adjusted HR 0.27, 95% CI: 0.22-0.33). CHM also reduced the risk of surgery in DUB patients with or without comorbidities. Regardless of childbirth status or whether patients took NSAIDs, tranexamic acid or progesterone, fewer patients in the CHM cohort underwent surgery than in the non-CHM cohort. The most commonly prescribed single herb and formula were Yi-Mu-Cao (Herba Leonuri) and Jia-Wei-Xiao-Yao-San, respectively., Conclusion: The real-world data revealed that CHM is associated with a reduced surgery rate in DUB patients. This information may be provided for further clinical investigations and policy-making., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2024 Lin et al.)

Considering the frequency of ethylene oxide (EtO) residues found in food, the health effects of EtO have become a concern. Between 2022 and 2023, 489 products were inspected using the purposive sampling method in Taiwan, and nine unqualified products were found to have been imported; subsequently, border control measures were enhanced. To ensure the safety of all imported foods, the current study used the K-means clustering method for identifying EtO residues in food. Data on finished products and raw materials with EtO residues from international public opinion bulletins were collected for analysis. After matching them with the Taiwan Food Cloud, 90 high-risk food items with EtO residues and 1388 manufacturers were screened. The Taiwan Food and Drug Administration set up border controls and grouped the manufacturers using K-means clustering in the unsupervised learning algorithm. For this study, 37 manufacturers with priority inspections and 52 high-risk finished products and raw materials with residual EtO were selected for inspection. While EtO was not detected, the study concluded the following: 1. Using international food safety alerts to strengthen border control can effectively ensure domestic food safety; 2. K-means clustering can validate the risk-based purposive sampling results to ensure food safety and reduce costs.

Background and Objectives : Genomic studies have identified several SNP loci associated with schizophrenia in East Asian populations. Environmental factors, particularly urbanization, play a significant role in schizophrenia development. This study aimed to identify schizophrenia susceptibility loci and characterize their biological functions and molecular pathways in Taiwanese urban Han individuals. Materials and Methods : Participants with schizophrenia were recruited from the Taiwan Precision Medicine Initiative at Tri-Service General Hospital. Genotype-phenotype association analysis was performed, with significant variants annotated and analyzed for functional relevance. Results : A total of 137 schizophrenia patients and 26,129 controls were enrolled. Ten significant variants ( p < 1 × 10 -5 ) and 15 expressed genes were identified, including rs1010840 ( SOWAHC and RGPD6 ), rs11083963 ( TRPM4 ), rs11619878 (LINC00355 and LINC01052), rs117010638 ( AGBL1 and MIR548AP), rs1170702 (LINC01680 and LINC01720), rs12028521 ( KAZN and PRDM2 ), rs12859097 ( DMD ), rs1556812 ( ATP11A ), rs78144262 (LINC00977), and rs9997349 ( ENPEP ). These variants and associated genes are involved in immune response, blood pressure regulation, muscle function, and the cytoskeleton. Conclusions : Identified variants and associated genes suggest a potential genetic predisposition to schizophrenia in the Taiwanese urban Han population, highlighting the importance of potential comorbidities, considering population-specific genetic and environmental interactions.

This Special Issue contains articles on applications of various new approach methodologies (NAMs) in the field of toxicology and risk assessment. These NAMs include in vitro high-throughput screening, quantitative structure-activity relationship (QSAR) modeling, physiologically based pharmacokinetic (PBPK) modeling, network toxicology analysis, molecular docking simulation, omics, machine learning, deep learning, and "template-and-anchor" multiscale computational modeling. These in vitro and in silico approaches complement each other and can be integrated together to support different applications of toxicology, including food safety assessment, dietary exposure assessment, chemical toxicity potency screening and ranking, chemical toxicity prediction, chemical toxicokinetic simulation, and to investigate the potential mechanisms of toxicities, as introduced further in selected articles in this Special Issue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study examines diatom assemblages in the Matsu Archipelago, an area influenced by Minjiang River runoff. It focuses on harmful algal blooms (HABs) that occurred between August 2021 and July 2022. Utilizing 18S rRNA metabarcoding and microscopic analysis, we observed a significant diatom bloom during early summer runoff, peaking at 5 × 10 5 cells L -1 . The research reveals dynamic community changes during the runoff season, with dominant genera including Pseudo-nitzschia, Chaetoceros, and Skeletonema. Skeletonema cell density correlated with NO 3 levels, Chaetoceros had a slight PO 4 affinity, and Pseudo-nitzschia showed a negative correlation with Skeletonema. Pseudo-nitzschia, which prefers high light and pH conditions, had notably high concentrations in the flood season and in the autumn. In both, it was dominated by potential toxin-producing species - P. multistriata and P. pungens during the flooding, and P. cuspidate in the autumn. These findings highlight the intricate relationship between diatom dynamics and environmental factors, providing essential insights for managing HABs, especially Pseudo-nitzschia species, amidst environmental changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Phytoplankton blooms are common along the Chinese coast in the East China Sea, driven by various nutrient sources including river discharge, bottom water regeneration, and Kuroshio subsurface water intrusion. A notable 2014 summer bloom off the Zhejiang coast, exhibiting a Chl a concentration of 20.1 μg L -1 , was significantly influenced by Changjiang River discharge, and high nutrient concentrations are often observed in the region's surface water. During blooms, primary production peaks at 1686.3 mg C m -3 d -1 , indicating substantial CO 2 absorption, with surface water fCO 2 declining to 299.5 μatm, closely linked to plankton activities. Hypoxia often coincides with these frequent bloom occurrences, implicating marine-derived organic matter decomposition as a pivotal factor. Elevated particulate organic carbon concentrations further support this assumption, alongside increased nutrient levels, fCO 2 , and low pH in hypoxic waters. These findings underscore the intricate interplay between phytoplankton, nutrient cycling, and hypoxia formation, essential for effective coastal ecosystem management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear., Methods: In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2 R172K transgenic mice., Results: We found that thrombopoietin (TPO)-overexpressed Idh2 R172K ( Idh2 R172K + TPO) mice had accelerated progression to MF, compared with TPO-overexpressed Idh2- wild (WT + TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single-cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2 R172K + TPO group. Furthermore, Idh2 R172K mice at age of 18 months had larger spleens, increased S100a8/a9-Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations., Conclusion: Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2 R172K + TPO mice., Competing Interests: The authors declare they have no conflicts of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: The combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC., Methods: ECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C., Results: 178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7-36.7) than the PBO + P + C group (44.8%; 95% CI 34.1-55.9), with a difference of - 18.5% (95% CI - 32.0 - (- 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C., Conclusions: Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination., Trial Registration: NCT03322566. Registered October 26, 2017., (© 2023. The Author(s).)

Various first-line gemcitabine-based or fluorouracil-based combination regimens were approved in patients with advanced pancreatic cancer. Recent randomized clinical trials (RCTs) have investigated chemotherapy backbones in combination with novel investigational drugs, including chemotherapy agents or targeted drugs. However, the comparative efficacy of these different combination therapies remains limited. This systematic review and network meta-analysis aimed to assess the efficacy of first-line combination therapies for advanced pancreatic cancer. The study included 46 RCTs with 10,499 patients and 47 distinct regimens, using data sources from MEDLINE, EMBASE, Cochrane Clinical Trials, and ClinicalTrials.gov from January 1, 2010 to April 23, 2024. The primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included overall response rate (ORR) and disease control rate (DCR). The analysis revealed that gemcitabine+nab-paclitaxel (GA), GA with platinum and fluorouracil (GA+Plat+FU), gemcitabine with fluorouracil (G+FU), G+Plt+FU, and FOLFIRINOX were associated with superior OS and PFS compared to gemcitabine monotherapy. Triplet or quadruplet polychemotherapy combinations, such as GA+Plat+FU, G+Plt+FU, and FOLFIRINOX, demonstrated better OS benefit with hazard ratios of 0.42 (95% CI, 0.26-0.68), 0.41 (95% CI, 0.24-0.71), and 0.58 (95% CI, 0.48-0.71), respectively, compared to doublet regimens like GA and G+FU, which had hazard ratios of 0.70 (95% CI, 0.59-0.82) and 0.82 (95% CI, 0.72-0.95), respectively. Notably, no targeted drugs, monoclonal antibodies, or other medications showed improved survival when added to chemotherapy backbones. These findings support the use of gemcitabine-based or fluorouracil-based triplet or quadruplet regimens for better survival outcomes in patients with advanced pancreatic cancer. Further research is warranted to explore the potential benefits of adding chemotherapy agents, such as fluorouracil, to the GA doublet regimen., Competing Interests: None., (AJCR Copyright © 2024.)

Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)-expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA-binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude-greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.

Importance: Improving end-of-life care in the intensive care unit (ICU) is a priority, but clinically modifiable factors of quality of dying and death (QODD) are seldom identified., Objectives: To comprehensively identify factors associated with QODD classes of dying ICU patients, emphasizing clinically modifiable factors based on the integrative framework of factors associated with for bereavement outcomes., Design, Setting, and Participants: This observational cohort study was conducted at medical ICUs of 2 Taiwanese medical centers from January 2018 to March 2020 with follow-up through December 2022. Eligible participants included primary family surrogates responsible for decision making for critically ill ICU patients at high risk of death (Acute Physiology and Chronic Health Evaluation II score >20) but who survived more than 3 days after ICU admission. Data analysis was conducted from July to September 2023., Main Outcomes and Measures: QODD was measured by the 23-item ICU-QODD questionnaire. Factors associated with patient membership in 4 previously determined QODD classes (high, moderate, poor to uncertain, and worst) were examined using a 3-step approach for latent class modeling with the high QODD class as the reference category., Results: A total of 309 family surrogates (mean [SD] age, 49.83 [12.55] years; 184 women [59.5%] and 125 men [40.5%]) were included in the study. Of all surrogates, 91 (29.4%) were the patients' spouse and 66 (53.7%) were the patients' adult child. Patient demographics were not associated with QODD class. Two family demographics (age and gender), relationship with the patient (spousal or adult-child), and length of ICU stay were associated with QODD classes. Patients of surrogates perceiving greater social support were less likely to be in the poor to uncertain (adjusted odds ratio [aOR], 0.89; 95% CI, 0.83-0.94) and worst (aOR, 0.92; 95% CI, 0.87-0.96) QODD classes. Family meetings were associated with the poor to uncertain QODD class (aOR, 8.61; 95% CI, 2.49-29.74) and worst QODD class (aOR, 7.28; 95% CI, 1.37-38.71). Death with cardiopulmonary resuscitation was associated with the worst QODD class (aOR, 7.51; 95% CI, 1.12-50.25). Family presence at patient death was uniformly negatively associated with the moderate QODD class (aOR, 0.16; 95% CI, 0.05-0.54), poor to uncertain QODD class (aOR, 0.21; 95% CI, 0.05-0.82), and worst QODD class (aOR, 0.08; 95% CI, 0.02-0.38). Higher family satisfaction with ICU care was negatively associated with the poor to uncertain QODD class (aOR, 0.93; 95% CI, 0.87-0.98) and worst QODD class (aOR, 0.86; 95% CI, 0.81-0.92)., Conclusions and Relevance: In this cohort study of critically ill patients and their family surrogates, modifiable end-of-life ICU-care characteristics played a more significant role in associations with patient QODD class than did immutable family demographics, preexisting family health conditions, patient demographics, and patient clinical characteristics, thereby illuminating actionable opportunities to improve end-of-life ICU care.

Influenza viruses can cause highly infectious respiratory diseases, posing noteworthy epidemic and pandemic threats. Vaccination is the most cost-effective intervention to prevent influenza and its complications. However, reliance on embryonic chicken eggs for commercial influenza vaccine production presents potential risks, including reductions in efficacy due to HA gene mutations and supply delays due to scalability challenges. Thus, alternative platforms are needed urgently to replace egg-based methods and efficiently meet the increasing demand for vaccines. In this study, we employed a baculovirus expression vector system to engineer HA, NA, and M1 genes from seasonal influenza strains A/H1N1, A/H3N2, B/Yamagata, and B/Victoria, generating virus-like particle (VLP) vaccine antigens, H1N1-VLP, H3N2-VLP, Yamagata-VLP, and Victoria-VLP. We then assessed their functional and antigenic characteristics, including hemagglutination assay, protein composition, morphology, stability, and immunogenicity. We found that recombinant VLPs displayed functional activity, resembling influenza virions in morphology and size while maintaining structural integrity. Comparative immunogenicity assessments in mice showed that our quadrivalent VLPs were consistent in inducing hemagglutination inhibition and neutralizing antibody titers against homologous viruses compared to both commercial recombinant HA and egg-based vaccines (Vaxigrip). The findings highlight insect cell-based VLP vaccines as promising candidates for quadrivalent seasonal influenza vaccines. Further studies are worth conducting.

This study aimed to define the role of heterogeneity of liver parenchymal enhancement on computed tomography (CT) in the survival of patients with hepatocellular carcinoma (HCC) after hepatic resection. The medical records of patients with HCCs and who had undergone hepatic resection were retrospectively reviewed. The standard deviation (SD) of three different enhanced CT scan images was used to estimate the heterogeneity of liver parenchymal enhancement: SD of > 5.6, heterogenous enhancement, and SD of ≤ 5.6, homogeneous enhancement. A total of 57 patients had heterogenous enhancement, and 143 patients had homogeneous enhancement. The patients with heterogenous enhancement had longer disease-free and overall survivals than those with other enhancements (log-rank test, P < 0.001 and P = 0.036). The pathologic exam showed that heterogenous enhancement tended to develop septa in the peritumoral liver tissues. The prevalence of CD8 + cells was significantly higher in the peritumor liver tissues with septa than in those without (0.83% vs. 0.26%, P < 0.001). The peritumoral CD8/Foxp3 ratio was higher in the liver tissues with septa than in those without (1.22 vs. 0.47, P = 0.001), and patients with CD8/Foxp3 of > 0.8 had better overall survival than those with CD8/Foxp3 of ≤ 0.8 (log-rank test, P = 0.028). In conclusion, patients who had undergone hepatic resection with a heterogenous liver parenchymal enhancement tended to develop hepatic septa, which was associated with a higher CD8/Foxp3 ratio and longer survival. Therefore, contrast-enhanced CT scans might be a useful tool to predict the outcome of HCC., Competing Interests: None., (AJCR Copyright © 2024.)