Integrative transcriptomic and genomic analyses unveil the IFI16 variants and expression as MASLD progression markers.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD. APPROACH AND RESULTS: RNA-Seq profiling (n = 146) and whole-exome sequencing (n = 132) of MASLD liver tissue samples identified 3 transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key feature for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A>T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals through mitochondrial dysfunction-related signaling of the IFI16-PYCARD-CASP1 pathway. CONCLUSIONS: This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.

Identification of signature gene set as highly accurate determination of metabolic dysfunction-associated steatotic liver disease progression.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat accumulation in the liver. MASLD encompasses both steatosis and MASH. Since MASH can lead to cirrhosis and liver cancer, steatosis and MASH must be distinguished during patient treatment. Here, we investigate the genomes, epigenomes, and transcriptomes of MASLD patients to identify signature gene set for more accurate tracking of MASLD progression. METHODS: Biopsy-tissue and blood samples from patients with 134 MASLD, comprising 60 steatosis and 74 MASH patients were performed omics analysis. SVM learning algorithm were used to calculate most predictive features. Linear regression was applied to find signature gene set that distinguish the stage of MASLD and to validate their application into independent cohort of MASLD. RESULTS: After performing WGS, WES, WGBS, and total RNA-seq on 134 biopsy samples from confirmed MASLD patients, we provided 1,955 MASLD-associated features, out of 3,176 somatic variant callings, 58 DMRs, and 1,393 DEGs that track MASLD progression. Then, we used a SVM learning algorithm to analyze the data and select the most predictive features. Using linear regression, we identified a signature gene set capable of differentiating the various stages of MASLD and verified it in different independent cohorts of MASLD and a liver cancer cohort. CONCLUSION: We identified a signature gene set (i.e., CAPG, HYAL3, WIPI1, TREM2, SPP1, and RNASE6) with strong potential as a panel of diagnostic genes of MASLD-associated disease.

Sonographic appearances of juvenile fibroadenoma of the breast.

OBJECTIVES: The purpose of this study was to evaluate characteristic features of juvenile fibroadenoma of the breast on sonography. METHODS: Our study included 34 juvenile fibroadenomas confirmed by surgical biopsy or sonographically guided 8-gauge vacuum-assisted biopsy in 23 patients (age range, 15-47 years; mean age, 25 years). Sonographic findings of the lesions were analyzed retrospectively by 2 radiologists in consensus according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) lexicon. The BI-RADS final assessment category was also established. RESULTS: On sonography, all fibroadenomas presented as masses. The mean size was 30 mm. Regarding shape, there were 29 oval, 2 round, and 3 irregular masses. The margins were circumscribed in 24, indistinct in 5, microlobulated in 4, and angular in 1. Regarding echogenicity, 16 masses were hypoechoic, 16 isoechoic, and 2 complex echoic. Posterior acoustic characteristics included posterior acoustic enhancement in 22 masses (65%), posterior shadowing in 1, and no posterior acoustic features in 9; this information was not available in 2. The lesion boundary presented as an abrupt interface in 32 and an echogenic halo in 2. The orientation was parallel in 32 and nonparallel in 2. Calcifications were present in 3 cases and absent in 31. On color Doppler sonography, the masses were usually hypervascular with vessel counts of 5 or more (87%). The BI-RADS final assessment categories were 3 in 24 and 4a in 10. CONCLUSIONS: The dominant sonographic presentation of juvenile fibroadenoma is a circumscribed oval hypoechoic or isoechoic mass, which resembles that of simple fibroadenoma. Juvenile fibroadenomas frequently show posterior acoustic enhancement and hypervascularity on color Doppler sonography.

Fluoroscopically guided balloon dilation for patients with esophageal stricture after radiation treatment.

PURPOSE: To evaluate the safety and clinical effectiveness of fluoroscopically guided balloon dilation in patients with esophageal stricture after radiation therapy (RT). MATERIALS AND METHODS: From April 1993 through December 2004, fluoroscopically guided balloon dilation was performed in 15 patients with esophageal strictures secondary to previous RT. Technical success, clinical success, recurrence of dysphagia, primary and secondary patency rates, and complications related to the procedure were retrospectively evaluated. RESULTS: Twenty-five balloon dilations were performed in 15 patients, with a mean of 1.7 dilations per patient (range, 1-5). Technical success was achieved in all procedures. One patient was immediately lost to follow-up and another underwent elective esophageal surgery 13 days after the procedure. Of the remaining 13 patients, clinical success was achieved 11 (85%). Two of 13 patients exhibited recurrence of dysphagia before 1 month after balloon dilation. Among the 11 patients in whom clinical success was achieved, seven exhibited maintained initial improvement of dysphagia until their last follow-up (mean, 174 days) and four exhibited recurrence of dysphagia after the first balloon dilation. Dysphagia recurred 2-128 days (mean, 67.2 d) after the first balloon dilation in six of the 13 patients (46%), who underwent further balloon dilation and/or stent placement. The primary and secondary patency rates at 1, 3, and 6 months were 86%, 68%, and 47% and 100%, 92%, and 62%, respectively. There were no major complications. Type 1 and 2 esophageal ruptures occurred after 12 dilations in nine patients; they were treated conservatively. CONCLUSION: Fluoroscopically guided balloon dilation for esophageal stricture after RT can be safe and effective. However, the high rate of recurrent dysphagia requires repeated dilations.

Influence of a dexamethasone-eluting covered stent on tissue reaction: an experimental study in a canine bronchial model.

This study was designed to evaluate the feasibility and efficacy of a dexamethasone (DXM)-eluting, covered, self-expanding metallic stent to reduce tissue reaction following stent placement in a canine bronchial model. We placed a DXM-eluting, polyurethane-covered, self-expanding metallic stent (drug stent, DS) and a polyurethane-covered, self-expanding metallic stent (control stent, CS) alternately in each left main bronchus and left lower lobe bronchus in 12 dogs. The stents were 20 mm in diameter and length when fully expanded. The dose of DXM was approximately 36.7 mg in each DS, but was absent in the CS. The dogs were euthanased 1 week (n=4), 2 weeks (n=4) or 4 weeks (n=4) after stent placement. Histologic findings, such as epithelial erosion/ulcer or granulation tissue thickness, were obtained from the mid-portion of the bronchus, where the stent had been placed, and evaluated between DS and CS. There were no procedure-related complications or malpositioning of any of the bronchial stents. Stent migration was detected in one dog just before euthanasia 1 week following stent placement. Stent patency was maintained until euthanasia in all dogs. Epithelial erosion/ulcer (%) was significantly less in the DS (mean+/-standard deviation, 46.88+/-23.75) than in the CS (73.75+/-14.08) (P=0.026) for all time-points. There was a decrease in epithelial erosion/ulcer as the follow-up period increased in both DS and CS. The granulation tissue thickness (mm) was less in DS (2.63+/-2.05) than in CS (3.49+/-2.95), although the difference was not significant (P=0.751) for all time-points. There was a tendency toward an increase in granulation tissue thickness and chronic lymphocytic infiltration as the follow-up period increased in both DS and CS. In conclusion, DXM-eluting, covered, self-expanding metallic stent seems to be effective in reducing tissue reaction secondary to stent placement in a canine bronchial model.