Negative regulation of SH2B3 by SMYD5 controls epithelial-mesenchymal transition in lung cancer.

The main cause of death in lung cancer patients is metastasis. Thus, efforts to suppress micrometastasis or distant metastasis in lung cancer, identify therapeutic targets and develop related drugs are ongoing. In this study, we identified SMYD5 as a novel metastasis regulator in lung cancer and found that SMYD5 was overexpressed in lung cancer based on both RNA-sequencing (RNA-seq) analysis results derived from the TCGA portal and immunohistochemical analysis results; knockdown of SMYD5 inhibited cell migration and invasion by changing EMT (epithelial-mesenchymal transition) markers and MMP9 expression in NCI-H1299 and H1703 cell lines. Additionally, SMYD5 knockdown increased SH2B3 expression by decreasing the level of H4K20 trimethylation. Furthermore, in an in vitro EMT system using TGF-ß treatment, SMYD5 knockdown resulted in reduced cell migration and invasion in the highly invasive NCI-H1299 and H1703 cell lines. Based on these findings, we propose that SMYD5 could serve as a potential therapeutic target for lung cancer treatment and that cotreatment with an SMYD5 inhibitor and chemotherapy may enhance the therapeutic effect of lung cancer treatment.

Re-assessing the diagnostic value of the enhancing "capsule" in hepatocellular carcinoma imaging.

Background/Aims: The enhancing "capsule" (EC) in hepatocellular carcinoma (HCC) diagnosis has received varying degrees of recognition across major guidelines. This study aimed to assess the diagnostic utility of EC in HCC detection. Methods: We retrospectively analyzed patients who underwent pre-surgical computed tomography (CT) and hepatobiliary agent-enhanced magnetic resonance imaging (HBA-MRI) between January 2016 and December 2019. A single hepatic tumor was confirmed based on the pathology of each patient. Three radiologists independently reviewed the images according to the Liver Imaging Reporting and Data System (LIRADS) v2018 criteria and reached a consensus. Interobserver agreement for EC before reaching a consensus was quantified using Fleiss κ statistics. The impact of EC on the LI-RADS classification was assessed by comparing the positive predictive values for HCC detection in the presence and absence of EC. Results: In total, 237 patients (median age, 60 years; 184 men) with 237 observations were included. The interobserver agreement for EC detection was notably low for CT (κ=0.169) and HBA-MRI (κ=0.138). The presence of EC did not significantly alter the positive predictive value for HCC detection in LI-RADS category 5 observations on CT (94.1% [80/85] vs. 94.6% [88/93], P=0.886) or HBA-MRI (95.7% [88/92] vs. 90.6% [77/85], P=0.178). Conclusions: The diagnostic value of EC in HCC diagnosis remains questionable, given its poor interobserver agreement and negligible impact on positive predictive values for HCC detection. This study challenges the emphasis on EC in certain diagnostic guidelines and suggests the need to re-evaluate its role in HCC imaging.

Ultrasound-based steatosis grading system using 2D-attenuation imaging: an individual patient data meta-analysis with external validation.

BACKGROUND AND RATIONALE: Non-invasive tools assessing steatosis, such as ultrasonography-based 2D-attenuation imaging (ATI), are needed to tackle the worldwide burden of steatotic liver disease. This one-stage individual patient data (IPD) meta-analysis aimed to create an ATI-based steatosis grading system. MAIN RESULTS: A systematic review (EMBASE+MEDLINE, 2018-2022) identified studies, including patients with histologically or MRI-PDFF-verified ATI for grading steatosis (S0 to S3). One-stage IPD meta-analyses were conducted using generalized mixed models with a random study-specific intercept. Created ATI-based steatosis grading system (aS0 to aS3) was externally validated on a prospective cohort of patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD; n=174, histologically and MRI-PDFF verified steatosis). Eleven enrolled studies included 1374 patients, classified into S0, S1, S2, and S3 in 45.4%, 35.0%, 9.3%, and 10.3% of the cases. ATI was correlated with histological steatosis (r=0.60; 95%CI:0.52,0.67; p<0.001), and MRI-PDFF (r=0.70; 95%CI:0.66,0.73; p<0.001) but not with liver stiffness (r=0.03; 95%CI:-0.04,0.11, p=0.343). Steatosis grade was an independent factor associated with ATI (Coefficient: 0.24; 95%CI [0.22, 0.26]; p<0.001). ATI marginal means within S0, S1, S2, and S3 subpopulations were 0.59 (95%CI [0.58, 0.61]), 0.69 (95%CI [0.67, 0.71]), 0.78 95%CI [0.76, 0.81] and 0.85 95%CI [0.83, 0.88] dB/cm/MHz; all contrasts between grades significant (p<.0001). Three ATI thresholds were calibrated to create a new ATI-based steatosis grading system (aS0 to aS3, cut-offs: 0.66, 0.73, and 0.81 dB/cm/MHz). Its external validation showed Obuchowski measures of 0.84 ±0.02 and 0.82±0.02 with histologically- and MRI-PDFF-based references. CONCLUSIONS: ATI is a reliable, non-invasive marker of steatosis. This validated ATI-based steatosis grading system could be valuable in assessing MASLD patients.

Visceral adipose tissue reduction measured by deep neural network architecture improved reflux esophagitis endoscopic grade.

BACKGROUND AND AIMS: Visceral obesity is a risk factor for reflux esophagitis (RE). We investigated the risk of RE according to visceral adipose tissue (VAT) measured by deep neural network architecture using computed tomography and evaluated the longitudinal association between abdominal adipose tissue changes and the disease course of RE. METHODS: Individuals receiving health checkups who underwent esophagogastroduodenoscopy (EGD) and abdominal computed tomography (CT) at Seoul National University Healthcare System Gangnam Center between 2015 and 2016 were included. Visceral and subcutaneous adipose tissue areas and volumes were measured using a deep neural network architecture and CT. The association between the abdominal adipose tissue area and volume and the risk of RE was evaluated. Participants who underwent follow-up EGD and abdominal CT were selected; the effects of changes in abdominal adipose tissue area and volume on RE endoscopic grade were investigated using Cox proportional hazards regression. RESULTS: We enrolled 6570 patients who underwent EGD and abdomen CT on the same day. RE was associated with male sex, hypertension, diabetes, excessive alcohol intake, current smoking status, and levels of physical activity. The VAT area and volume increased the risk of RE dose-dependently. A decreasing VAT volume was significantly associated with improvement in RE endoscopic grade (HR:3.22, 95%CI:1.82-5.71). Changes in subcutaneous adipose tissue volume and the disease course of RE were not significantly correlated. CONCLUSIONS: Visceral obesity is strongly associated with RE. VAT volume reduction was prospectively associated with improvement in RE endoscopic grade dose-dependently. Visceral obesity is a potential target for RE treatment.

Comparison of non-contrast abbreviated MRI and ultrasound as surveillance modalities for HCC.

BACKGROUND AND AIMS: Ultrasonography (US) is recommended for HCC surveillance in high-risk patients, but has limited performance in detecting early-stage HCC. We aimed to compare the diagnostic performance of biannual US and annual non-contrast abbreviated magnetic resonance imaging (NC-AMRI) as HCC surveillance modalities in high-risk patients. METHODS: This prospective, multicenter cohort study enrolled participants with an estimated annual risk of HCC greater than 5% between October 2015 and April 2017. Participants underwent six rounds of HCC surveillance at 6-month intervals, with both US and NC-AMRI at rounds 1, 3, and 5, and only US at rounds 2, 4, and 6. The sensitivity, diagnostic yield (DY), and false referral rate (FRR) for HCC detection by US and NC-AMRI were compared. RESULTS: In total, 208 participants underwent 980 US and 516 NC-AMRI examinations during 30 months of follow-up. Among them, 34 HCCs were diagnosed in 31 participants, with 20 (64.5%) classified as very early and 11 (35.5%) as early-stage. The sensitivity of annual NC-AMRI (71.0%, 22/31) was marginally higher than that of biannual US (45.2%, 14/31; p = 0.077). NC-AMRI showed a significantly higher DY than US (4.26% vs. 1.43%, p < 0.001), with a similar FRR (2.91% vs. 3.06%, p = 0.885). A simulation of alternating US and NC-AMRI at 6-month intervals yielded a sensitivity of 83.0% (26/31), significantly exceeding that of biannual US (p = 0.006). CONCLUSIONS: Annual NC-AMRI showed a marginally higher sensitivity than biannual US for HCC detection in high-risk patients. The DY of annual NC-AMRI was significantly higher than that of biannual US, without increasing the FRR. Alternating US and NC-AMRI at 6-month intervals could be an optimal surveillance strategy for high-risk patients. IMPACT AND IMPLICATIONS: Current guidelines permit the use of magnetic resonance imaging (MRI) as a surveillance tool for hepatocellular carcinoma (HCC) in patients in whom ultrasonography (US) is inadequate. However, the specific indications, imaging sequences, and surveillance intervals for MRI surveillance remain unclear. In our study, we found that annual non-contrast (NC)-abbreviated MRI (AMRI) exhibited marginally higher sensitivity and significantly better diagnostic yield than biannual US in high-risk patients for HCC. Adopting alternating US and NC-AMRI at 6-month intervals demonstrated significantly improved sensitivity compared to biannual US, making it a potentially optimal surveillance strategy for high-risk patients. CLINICAL TRIAL NUMBER: ClinicalTrials.gov Identifier: NCT02551250.

Comparison of Four Diagnostic Guidelines for Hepatocellular Carcinoma Using Gadoxetic Acid-enhanced Liver MRI.

Background Noninvasive diagnostic guidelines for hepatocellular carcinoma (HCC) vary across different global geographic areas, especially regarding criteria about gadoxetic acid-enhanced MRI. Purpose To compare the diagnostic performance of four different international HCC diagnosis guidelines and readers' judgment in diagnosing HCC using gadoxetic acid-enhanced MRI in patients at high risk for HCC. Materials and Methods This retrospective study included patients who had not undergone treatment, were at risk for HCC, and who underwent gadoxetic acid-enhanced MRI from January 2015 to June 2018 from 11 tertiary hospitals in South Korea. Four radiologists independently reviewed focal liver lesions (FLLs) according to four guidelines: American Association for the Study of Liver Diseases (AASLD)/Liver Imaging Reporting and Data System (LI-RADS), Korean Liver Cancer Association-National Cancer Center (KLCA-NCC), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). Reader judgment (HCC or not HCC) was also recorded. Malignant FLLs were confirmed at pathology, and histologic and clinical follow-up data were used for benign FLLs. The guidelines' diagnostic performance was compared using generalized estimating equations. Additionally, the diagnostic odds ratio was assessed. Results A total of 2445 FLLs (median size, 27.4 mm) were analyzed in 2237 patients (mean age, 59 years ± 11 [SD]; 1666 male patients); 69.3% (1694 of 2445) were HCCs. KLCA-NCC showed the highest accuracy (80.0%; 95% CI: 78.7, 81.2; P = .001), with high sensitivity in Eastern guidelines (APASL, 89.1% [95% CI: 87.8, 90.3]; KLCA-NCC, 78.2% [95% CI: 76.6, 79.7]) and high specificity in Western guidelines (AASLD/LI-RADS, 89.6% [95% CI: 87.8, 91.2]; EASL, 88.1% [95% CI: 86.2, 89.9]) (P = .001). The diagnostic odds ratios were 20.7 (95% CI: 17.0, 25.3) for AASLD/LI-RADS, 18.9 (95% CI: 15.8, 22.6) for KLCA-NCC, 16.8 (95% CI: 13.8, 20.4) for EASL, and 8.9 (95% CI: 7.4, 10.7) for APASL. The readers' judgment demonstrated higher accuracy than that of the guidelines (accuracy, 86.0%; 95% CI: 84.9, 86.9; P = .001). Conclusion Among four different international HCC diagnosis guidelines, Eastern guidelines demonstrated higher sensitivity, whereas Western guidelines displayed higher specificity. KLCA-NCC achieved the highest accuracy, and AASLD/LI-RADS exhibited the highest diagnostic odds ratio. © RSNA, 2024 Supplemental material is available for this article.

No-Touch Radiofrequency Ablation Using Twin Cooled Wet Electrodes for Recurrent Hepatocellular Carcinoma Following Locoregional Treatments.

OBJECTIVE: To evaluate the therapeutic outcomes of no-touch radiofrequency ablation (NT-RFA) using twin cooled wet (TCW) electrodes in patients experiencing recurrent hepatocellular carcinoma (HCC) after undergoing locoregional treatments. MATERIALS AND METHODS: We conducted a prospective, single-arm study of NT-RFA involving 102 patients, with a total of 112 recurrent HCCs (each ≤ 3 cm). NT-RFA with TCW electrodes was implemented under the guidance of ultrasonography (US)-MR/CT fusion imaging. If NT-RFA application proved technically challenging, conversion to conventional tumor puncture RFA was permitted. The primary metric for evaluation was the mid-term cumulative incidence of local tumor progression (LTP) observed post-RFA. Cumulative LTP rates were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard regression was used to explore factors associated with LTP. Considering conversion cases from NT-RFA to conventional RFA, intention-to-treat (ITT; including all patients) and per-protocol (PP; including patients not requiring conversion to conventional RFA alone) analyses were performed. RESULTS: Conversion from NT-RFA to conventional RFA was necessary for 24 (21.4%) out of 112 tumors. Successful treatment was noted in 111 (99.1%) out of them. No major complications were reported among the patients. According to ITT analysis, the estimated cumulative incidences of LTP were 1.9%, 6.0%, and 6.0% at 1, 2, and 3 years post-RFA, respectively. In PP analysis, the cumulative incidence of LTP was 0.0%, 1.3%, and 1.3% at 1, 2, and 3 years, respectively. The number of previous locoregional HCC treatments (adjusted hazard ratio [aHR], 1.265 per 1 treatment increase; P = 0.004), total bilirubin (aHR, 7.477 per 1 mg/dL increase; P = 0.012), and safety margin ≤ 5 mm (aHR, 9.029; P = 0.016) were independently associated with LTP in ITT analysis. CONCLUSION: NT-RFA using TCW electrodes is a safe and effective treatment for recurrent HCC, with 6.0% (ITT analysis) and 1.3% (PP analysis) cumulative incidence of LTP at 2 and 3-year follow-ups.

Enhancing gadoxetic acid-enhanced liver MRI: a synergistic approach with deep learning CAIPIRINHA-VIBE and optimized fat suppression techniques.

OBJECTIVE: To investigate whether a deep learning (DL) controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA)-volumetric interpolated breath-hold examination (VIBE) technique can improve image quality, lesion conspicuity, and lesion detection compared to a standard CAIPIRINHA-VIBE technique in gadoxetic acid-enhanced liver MRI. METHODS: This retrospective single-center study included 168 patients who underwent gadoxetic acid-enhanced liver MRI at 3 T using both standard CAIPIRINHA-VIBE and DL CAIPIRINHA-VIBE techniques on pre-contrast and hepatobiliary phase (HBP) images. Additionally, high-resolution (HR) DL CAIPIRINHA-VIBE was obtained with 1-mm slice thickness on the HBP. Three abdominal radiologists independently assessed the image quality and lesion conspicuity of pre-contrast and HBP images. Statistical analyses involved the Wilcoxon signed-rank test for image quality assessment and the generalized estimation equation for lesion conspicuity and detection evaluation. RESULTS: DL and HR-DL CAIPIRINHA-VIBE demonstrated significantly improved overall image quality and reduced artifacts on pre-contrast and HBP images compared to standard CAIPIRINHA-VIBE (p < 0.001), with a shorter acquisition time (DL vs standard, 11 s vs 17 s). However, the former presented a more synthetic appearance (both p < 0.05). HR-DL CAIPIRINHA-VIBE showed superior lesion conspicuity to standard and DL CAIPIRINHA-VIBE on HBP images (p < 0.001). Moreover, HR-DL CAIPIRINHA-VIBE exhibited a significantly higher detection rate of small (< 2 cm) solid focal liver lesions (FLLs) on HBP images compared to standard CAIPIRINHA-VIBE (92.5% vs 87.4%; odds ratio = 1.83; p = 0.036). CONCLUSION: DL and HR-DL CAIPIRINHA-VIBE achieved superior image quality compared to standard CAIPIRINHA-VIBE. Additionally, HR-DL CAIPIRINHA-VIBE improved the lesion conspicuity and detection of small solid FLLs. DL and HR-DL CAIPIRINHA-VIBE hold the potential clinical utility for gadoxetic acid-enhanced liver MRI. CLINICAL RELEVANCE STATEMENT: DL and HR-DL CAIPIRINHA-VIBE hold promise as potential alternatives to standard CAIPIRINHA-VIBE in routine clinical liver MRI, improving the image quality and lesion conspicuity, enhancing the detection of small (< 2 cm) solid focal liver lesions, and reducing the acquisition time. KEY POINTS: • DL and HR-DL CAIPIRINHA-VIBE demonstrated improved overall image quality and reduced artifacts on pre-contrast and HBP images compared to standard CAIPIRINHA-VIBE, in addition to a shorter acquisition time. • DL and HR-DL CAIPIRINHA-VIBE yielded a more synthetic appearance than standard CAIPIRINHA-VIBE. • HR-DL CAIPIRINHA-VIBE showed improved lesion conspicuity than standard CAIPIRINHA-VIBE on HBP images, with a higher detection of small (< 2 cm) solid focal liver lesions.

Artificial intelligence in liver cancer research: a scientometrics analysis of trends and topics.

Background and aims: With the rapid growth of artificial intelligence (AI) applications in various fields, understanding its impact on liver cancer research is paramount. This scientometrics project aims to investigate publication trends and topics in AI-related publications in liver cancer. Materials and Methods: We employed a search strategy to identify AI-related publications in liver cancer using Scopus database. We analyzed the number of publications, author affiliations, and journals that publish AI-related publications in liver cancer. Finally, the publications were grouped based on intended application. Results: We identified 3950 eligible publications (2695 articles, 366 reviews, and 889 other document types) from 1968 to August 3, 2023. There was a 12.7-fold increase in AI-related publications from 2013 to 2022. By comparison, the number of total publications on liver cancer increased by 1.7-fold. Our analysis revealed a significant shift in trends of AI-related publications on liver cancer in 2019. We also found a statistically significant consistent increase in numbers of AI-related publications over time (tau = 0.756, p < 0.0001). Eight (53%) of the top 15 journals with the most publications were radiology journals. The largest number of publications were from China (n=1156), the US (n=719), and Germany (n=236). The three most common publication categories were "medical image analysis for diagnosis" (37%), "diagnostic or prognostic biomarkers modeling & bioinformatics" (19%), and "genomic or molecular analysis" (18%). Conclusion: Our study reveals increasing interest in AI for liver cancer research, evidenced by a 12.7-fold growth in related publications over the past decade. A common application of AI is in medical imaging analysis for various purposes. China, the US, and Germany are leading contributors.

Brown Algae Dictyopteris divaricata Attenuates Adipogenesis by Modulating Adipocyte Differentiation and Promoting Lipolysis through Heme Oxygenase-1 Activation in 3T3-L1 Cells.

The present study aims to explore the probable anti-adipogenesis effect of Dictyopteris divaricata (D. divaricata) in 3T3-L1 preadipocytes by regulating heme oxygenase-1 (HO-1). The extract of D. divaricata retarded lipid accretion and decreased triglyceride (TG) content in 3T3-L1 adipocytes but increased free glycerol levels. Treatment with the extract inhibited lipogenesis by inhibiting protein expressions of fatty acid synthase (FAS) and lipoprotein lipase (LPL), whereas lipolysis increased by activating phosphorylation of hormone-sensitive lipase (p-HSL) and AMP-activated protein kinase (p-AMPK). The extract inhibited adipocyte differentiation of 3T3-L1 preadipocytes through down-regulating adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1). This is attributed to the triggering of Wnt/ß-catenin signaling. In addition, this study found that treatment with the extract activated HO-1 expression. Pharmacological approaches revealed that treatment with Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, resulted in an increase in lipid accumulation and a decrease in free glycerol levels. Finally, three adipogenic transcription factors, such as PPARγ, C/EBPα, and SREBP1, restored their expression in the presence of ZnPP. Analysis of chemical constituents revealed that the extract of D. divaricata is rich in 1,4-benzenediol, 7-tetradecenal, fucosterol, and n-hexadecanoic acid, which are known to have multiple pharmacological properties.

Prognostic value of initial and longitudinal changes in body composition in metastatic pancreatic cancer.

BACKGROUND: Sarcopenia or visceral adipose tissue has been reported to be related to pancreatic cancer prognosis. However, clinical relevance of the comprehensive analysis of body compositions and their longitudinal changes is lacking. This study analysed the association between body composition changes after chemotherapy and survival in patients with metastatic pancreatic cancer. METHODS: We retrospectively included 456 patients (mean age ± standard deviation, 61.2 ± 10.0 years; 272 males and 184 females) with metastatic pancreatic cancer who received palliative chemotherapy from May 2011 to December 2019. Using deep learning-based, fully automated segmentation of contrast-enhanced computed tomography (CT) at the time of diagnosis, cross-sectional areas of muscle, subcutaneous adipose tissue and visceral adipose tissue were extracted from a single axial image of the portal venous phase at L3 level. Skeletal muscle index (SMI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI) and mean skeletal muscle attenuation (MA) were calculated, and their effect on overall survival (OS) was analysed. Longitudinal changes in body composition and prognostic values were also analysed in a subgroup of patients with 2- and 6-month follow-up CT (n = 349). RESULTS: A total of 452 deaths occurred during follow-up in the entire cohort. The survival rate was 49.3% (95% confidence interval [CI], 44.9-54.2) at 1 year and 3.7% (95% CI, 2.0-6.8) at 5 years. In multivariable analysis, higher MA (≥44.4 HU in males and ≥34.8 HU in females) at initial CT was significantly associated with better OS in both males and females (adjusted hazard ratio [HR], 0.706; 95% CI, 0.538-0.925; P = 0.012 for males, and HR, 0.656; 95% CI, 0.475-0.906; P = 0.010 for females), whereas higher SATI (≥42.8 cm2/m2 in males and ≥65.8 cm2/m2 in females) was significantly associated with better OS in female patients only (adjusted HR, 0.568; 95% CI, 0.388-0.830; P = 0.003). In longitudinal analysis, SMI, VATI and SATI significantly decreased between initial and 2-month follow-up CT, whereas mean MA significantly decreased between 2- and 6-month follow-up CT. In multivariable Cox regression analysis of longitudinal changes, which was stratified by disease control state, SATI change was significantly associated with OS in male patients (adjusted HR, 0.513; 95% CI, 0.354-0.745; P < 0.001), while other body composition parameters were not. CONCLUSIONS: In patients with metastatic pancreatic cancer, body composition mostly changed during the first 2 months after starting chemotherapy, and the prognostic factors associated with OS differed between males and females. Initial and longitudinal changes of body composition are associated with OS of metastatic pancreatic cancer.

Inter-platform reproducibility of ultrasound-based fat fraction for evaluating hepatic steatosis in nonalcoholic fatty liver disease.

OBJECTIVES: To evaluate the inter-platform reproducibility of ultrasound-based fat fraction examination in nonalcoholic fatty liver disease (NAFLD). METHODS: Patients suspected of having NAFLD were prospectively enrolled from January 2023. Ultrasound-based fat fraction examinations were performed using two different platforms (ultrasound-derived fat fraction [UDFF] and quantitative ultrasound-derived estimated fat fraction [USFF]) on the same day. The correlation between UDFF and USFF was assessed using Pearson correlation coefficient. Intraclass correlation coefficient (ICC), Bland-Altman analysis with 95% limits of agreement (LOAs), and the coefficient of variation (CV) were used to assess inter-platform reproducibility. RESULTS: A total of 41 patients (21 men and 20 women; mean age, 53.9 ± 12.6 years) were analyzed. Moderate correlation was observed between UDFF and USFF (Pearson's r = 0.748; 95% confidence interval [CI]: 0.572-0.858). On Bland-Altman analysis, the mean difference between UDFF and USFF values was 1.3% with 95% LOAs ranging from -8.0 to 10.6%. The ICC between UDFF and USFF was 0.842 (95% CI: 0.703-0.916), with a CV of 29.9%. CONCLUSION: Substantial inter-platform variability was observed among different ultrasound-based fat fraction examinations. Therefore, it is not appropriate to use ultrasound-based fat fraction values obtained from different vendors interchangeably. CRITICAL RELEVANCE STATEMENT: Considering the substantial inter-platform variability in ultrasound-based fat fraction assessments, caution is imperative when interpreting and comparing fat fraction values obtained from different ultrasound platforms in clinical practice. KEY POINTS: • Inter-platform reproducibility of ultrasound-based fat fraction examinations is important for its clinical application. • Significant variability across different ultrasound-based fat fraction examinations was observed. • Using ultrasound-based fat fraction values from different vendors interchangeably is not advisable.

Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict CYP3A-Mediated Drug Interaction between Saxagliptin and Nicardipine: Bridging Rat-to-Human Extrapolation.

The aim of this study was to predict the cytochrome P450 3A (CYP3A)-mediated drug-drug interactions (DDIs) between saxagliptin and nicardipine using a physiologically based pharmacokinetic (PBPK) model. Initially, in silico and in vitro parameters were gathered from experiments or the literature to construct PBPK models for each drug in rats. These models were integrated to predict the DDIs between saxagliptin, metabolized via CYP3A2, and nicardipine, exhibiting CYP3A inhibitory activity. The rat DDI PBPK model was completed by optimizing parameters using experimental rat plasma concentrations after co-administration of both drugs. Following co-administration in Sprague-Dawley rats, saxagliptin plasma concentration significantly increased, resulting in a 2.60-fold rise in AUC, accurately predicted by the rat PBPK model. Subsequently, the workflow of the rat PBPK model was applied to humans, creating a model capable of predicting DDIs between the two drugs in humans. Simulation from the human PBPK model indicated that nicardipine co-administration in humans resulted in a nearly unchanged AUC of saxagliptin, with an approximate 1.05-fold change, indicating no clinically significant changes and revealing a lack of direct translation of animal interaction results to humans. The animal-to-human PBPK model extrapolation used in this study could enhance the reliability of predicting drug interactions in clinical settings where DDI studies are challenging.

Direct delivery of stabilized Cas-embedded base editors achieves efficient and accurate editing of clinically relevant targets.

Over the last 5 years, cytosine base editors (CBEs) have emerged as a promising therapeutic tool for specific editing of single nucleotide variants and disrupting specific genes associated with disease. Despite this promise, the currently available CBE's have the significant liabilities of off-target and bystander editing activities, in part due to the mechanism by which they are delivered, causing limitations in their potential applications. In this study we engineeredhighly stabilized Cas-embedded CBEs (sCE_CBEs) that integrate several recent advances, andthat are highly expressible and soluble for direct delivery into cells as ribonucleoprotein (RNP) complexes. Our resulting sCE_CBE RNP complexes efficiently and specifically target TC dinucleotides with minimal off-target or bystander mutations. Additional uracil glycosylase inhibitor (UGI) protein in trans further increased C-to-T editing efficiency and target purity in a dose-dependent manner, minimizing indel formation to untreated levels. A single electroporation was sufficient to effectively edit the therapeutically relevant locus for sickle cell disease in hematopoietic stem and progenitor cells (HSPC) in a dose dependent manner without cellular toxicity. Significantly, these sCE_CBE RNPs permitted for the transplantation of edited HSPCs confirming highly efficient editing in engrafting hematopoietic stem cells in mice. The success of the designed sCBE editors, with improved solubility and enhanced on-target editing, demonstrates promising agents for cytosine base editing at other disease-related sites in HSPCs and other cell types.

Image Quality and Diagnostic Performance of Low-Dose Liver CT with Deep Learning Reconstruction versus Standard-Dose CT.

Purpose To compare the image quality and diagnostic capability in detecting malignant liver tumors of low-dose CT (LDCT, 33% dose) with deep learning-based denoising (DLD) and standard-dose CT (SDCT, 100% dose) with model-based iterative reconstruction (MBIR). Materials and Methods In this prospective, multicenter, noninferiority study, individuals referred for liver CT scans were enrolled from three tertiary referral hospitals between February 2021 and August 2022. All liver CT scans were conducted using a dual-source scanner with the dose split into tubes A (67% dose) and B (33% dose). Blended images from tubes A and B were created using MBIR to produce SDCT images, whereas LDCT images used data from tube B and were reconstructed with DLD. The noise in liver images was measured and compared between imaging techniques. The diagnostic performance of each technique in detecting malignant liver tumors was evaluated by three independent radiologists using jackknife alternative free-response receiver operating characteristic analysis. Noninferiority of LDCT compared with SDCT was declared when the lower limit of the 95% CI for the difference in figure of merit (FOM) was greater than -0.10. Results A total of 296 participants (196 men, 100 women; mean age, 60.5 years ± 13.3 [SD]) were included. The mean noise level in the liver was significantly lower for LDCT (10.1) compared with SDCT (10.7) (P < .001). Diagnostic performance was assessed in 246 participants (108 malignant tumors in 90 participants). The reader-averaged FOM was 0.880 for SDCT and 0.875 for LDCT (P = .35). The difference fell within the noninferiority margin (difference, -0.005 [95% CI: -0.024, 0.012]). Conclusion Compared with SDCT with MBIR, LDCT using 33% of the standard radiation dose had reduced image noise and comparable diagnostic performance in detecting malignant liver tumors. Keywords: CT, Abdomen/GI, Liver, Comparative Studies, Diagnosis, Reconstruction Algorithms Clinical trial registration no. NCT05804799 © RSNA, 2024 Supplemental material is available for this article.

Cultured meat with enriched organoleptic properties by regulating cell differentiation.

Research on cultured meat has primarily focused on the mass proliferation or differentiation of muscle cells; thus, the food characteristics of cultured meat remain relatively underexplored. As the quality of meat is determined by its organoleptic properties, cultured meat with similar sensory characteristics to animal-derived meat is highly desirable. In this study, we control the organoleptic and nutritional properties of cultured meat by tailoring the 2D differentiation of primary bovine myoblasts and primary bovine adipose-derived mesenchymal stem cells on gelatin/alginate scaffolds with varying stiffness. We assess the effect of muscle and adipose differentiation quality on the sensory properties of cultured meat. Thereafter, we fabricate cultured meat with similar sensory profiles to that of conventional beef by assembling the muscle and adipose constructs composed of highly differentiated cells. We introduce a strategy to produce cultured meat with enriched food characteristics by regulating cell differentiation with scaffold engineering.

Contrast-enhanced ultrasonography-CT/MRI fusion guidance for percutaneous ablation of inconspicuous, small liver tumors: improving feasibility and therapeutic outcome.

BACKGROUND: Percutaneous radiofrequency ablation (RFA) is pivotal for treating small malignant liver tumors, but tumors often remain inconspicuous on B-mode ultrasound (US). This study evaluates the potential of CEUS-CT/MRI fusion imaging (FI) to improve tumor visibility and the associated RFA outcomes for small (≤ 3 cm) malignant liver tumors that were inconspicuous on US. METHODS: Between January 2019 and April 2021, a prospective study enrolled 248 patients with liver malignancies (≤ 3 cm) that were poorly visible on B-mode US. Tumor visibility and ablation feasibility were assessed using B-mode US, US-CT/MRI FI, and CEUS-CT/MRI FI, and graded on a 4-point scale. CEUS was employed post-registration of US and CT/MRI images, utilizing either SonoVue or Sonazoid. Comparisons between US-based and CEUS-based fusion visibility and feasibility scores were undertaken using the Friedman test. Moreover, rates of technical success, technique efficacy, local tumor progression (LTP), and major complications were assessed. RESULTS: The cohort included 223 hepatocellular carcinomas (HCCs) (89.9%) and 23 metastases (9.3%), with an average tumor size of 1.6 cm. CEUS-CT/MRI FI demonstrated a significant advantage in tumor visibility (3.4 ± 0.7 vs. 1.9 ± 0.6, P < 0.001) and technical feasibility (3.6 ± 0.6 vs. 2.9 ± 0.8, P < 0.001) compared to US-FI. In 85.5% of patients, CEUS addition to US-FI ameliorated tumor visibility. Technical success was achieved in 99.6% of cases. No severe complications were reported. One and two-year post CEUS-CT/MRI FI-guided RFA estimates for LTP were 9.3% and 10.9%, respectively. CONCLUSIONS: CEUS-CT/MRI FI significantly improves the visualization of tumors not discernible on B-mode US, thus augmenting percutaneous RFA success and delivering improved therapeutic outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05445973. Registered 17 June 2022 - Retrospectively registered, http://clinicaltrials.gov/study/NCT05445973?id=NCT05445973&rank=1 .

Application of a deep learning algorithm for three-dimensional T1-weighted gradient-echo imaging of gadoxetic acid-enhanced MRI in patients at a high risk of hepatocellular carcinoma.

PURPOSE: To evaluate the efficacy of a vendor-specific deep learning reconstruction algorithm (DLRA) in enhancing image quality and focal lesion detection using three-dimensional T1-weighted gradient-echo images in gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) in patients at a high risk of hepatocellular carcinoma. MATERIALS AND METHODS: In this retrospective analysis, 83 high-risk patients with hepatocellular carcinoma underwent gadoxetic acid-enhanced liver MRI using a 3-T scanner. Triple arterial phase, high-resolution portal venous phase, and high-resolution hepatobiliary phase images were reconstructed using conventional reconstruction techniques and DLRA (AIRTM Recon DL; GE Healthcare) for subsequent comparison. Image quality and solid focal lesion detection were assessed by three abdominal radiologists and compared between conventional and DL methods. Focal liver lesion detection was evaluated using figures of merit (FOMs) from a jackknife alternative free-response receiver operating characteristic analysis on a per-lesion basis. RESULTS: DLRA-reconstructed images exhibited significantly improved overall image quality, image contrast, lesion conspicuity, vessel conspicuity, and liver edge sharpness and reduced subjective image noise, ringing artifacts, and motion artifacts compared to conventionally reconstructed images (all P < 0.05). Although there was no significant difference in the FOMs of non-cystic focal liver lesions between the conventional and DL methods, DLRA-reconstructed images showed notably higher pooled sensitivity than conventionally reconstructed images (P < 0.05) in all phases and higher detection rates for viable post-treatment HCCs in the arterial and hepatobiliary phases (all P < 0.05). CONCLUSIONS: Implementing DLRA can enhance the image quality in 3D T1-weighted gradient-echo sequences of gadoxetic acid-enhanced liver MRI examinations, leading to improved detection of viable post-treatment HCCs.

Poly(vinyl alcohol)/chitosan hydrogel incorporating chitooligosaccharide-gentisic acid conjugate with antioxidant and antibacterial properties as a potential wound dressing.

The design and development of wound dressing with antioxidant and antibacterial properties to accelerate wound healing remain challenging. In this study, we synthesize a chitooligosaccharide-gentisic acid (COS-GSA) conjugate using the free-radical grafting method, and fabricate a poly(vinyl alcohol) (PVA)/chitosan (CH)/COS-GSA (PVA/CH/CG) hydrogel using a freeze-thaw method. We characterize the synthesized COS-GSA conjugates using through polyphenol assay, absorbance, and 1H NMR spectroscopy and evaluate their antioxidant properties. The COS-GSA conjugates are successfully synthesized and exhibit better antioxidant properties than pristine COSs. Subsequently, the fabricated hydrogel is characterized based on its morphological analysis, rheological properties, water contact angle, swelling, degradation, water retention properties, and COS-GSA release profiles. Finally, the biocompatibility of the fabricated hydrogel is evaluated on HDF and HaCaT cells through indirect and direct cytotoxicity. The PVA/CH/CG hydrogel exhibited significantly higher antioxidant properties (DPPH, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and hydrogen peroxide (H2O2) scavenging activities) and antibacterial activities (Staphylococcus aureus and Pseudomonas aeruginosa) compared to other fabricated hydrogels such as PVA, PVA/CH, and PVA/CH/COS (PVA/CH/C). These results provide evidence that PVA/CH/CG hydrogels with antioxidant, antibacterial, and non-cytotoxic properties have great potential for wound-dressing applications.