Identification of Two Long Noncoding RNAs, Kcnq1ot1 and Rmst, as Biomarkers in Chronic Liver Diseases in Mice.

This study investigates novel short-lived long noncoding RNAs (lncRNAs) in mice with altered expression in metabolic dysfunction-associated steatotic liver (MASH) and liver fibrosis. LncRNAs share similarities with mRNAs in their transcription by RNA polymerase II, possession of a 5' cap structure, and presence of a polyA tail. We identified two lncRNAs, Kcnq1ot1 and Rmst, significantly decreased in both conditions. These lncRNAs showed dramatic expression changes in MASH livers induced by Western diets and CCl4, and in fibrotic livers induced by CCl4 alone. The decrease was more pronounced in liver fibrosis, suggesting their potential as biomarkers for disease progression. Our findings are consistent across different fibrosis models, indicating a crucial role for these lncRNAs in MASH and liver fibrosis in mice. With MASH becoming a global health issue and its progression to fibrosis associated with hepatocarcinogenesis and poor prognosis, understanding the underlying mechanisms is critical. This research contributes to elucidating lncRNA functions in murine liver diseases and provides a foundation for developing novel therapeutic strategies targeting lncRNAs in MASH and liver fibrosis, offering new avenues for potential therapeutic interventions.

Impact of BMI and Body Composition on First-line Systemic Treatment for Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: The effects of body mass index (BMI) and body composition on the outcomes of systemic treatment for unresectable hepatocellular carcinoma (uHCC) remain unclear. PATIENTS AND METHODS: In this retrospective study, patients with uHCC treated with lenvatinib (LEN) or atezolizumab+bevacizumab, were classified into high- (≥25 kg/m2) and low- (<25 kg/m2) BMI groups and evaluated for prognosis. Prognostic impact of body composition was also evaluated. RESULTS: Patients with a high BMI had lower skeletal mass index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) compared to those in the low-BMI cohort. The baseline Child-Pugh scores and Barcelona Clinic Liver Cancer stages were comparable between the two cohorts. The overall survival (OS) was better in the high BMI group compared to the low BMI group (median, 913 vs. 484 days; p=0.008). SMI had a strong influence on OS. Additionally, low BMI, VATI, SATI, and visceral-to-subcutaneous fat ratio (VSR) in the LEN treatment group were associated with shorter progression-free survival (PFS). CONCLUSION: Following systemic treatment for uHCC, patients with low BMI have a poor prognosis. Among anthropometric factors, low SMI is associated with poor OS. In the LEN treatment group, low VATI may impact PFS negatively.

Predicting early rebleeding and mortality after endoscopic hemostasis of esophagogastric varices: Diagnostic performance of aspartate aminotransferase-to-platelet ratio index and model for end-stage liver disease-Na score.

BACKGROUND: Endoscopic variceal ligation and sclerotherapy are recommended for esophagogastric variceal bleeding (EGVB) in cirrhosis but can be complicated by early rebleeding and death. This study aimed to identify noninvasive markers accurately predicting early rebleeding and mortality after endoscopic hemostasis for EGVB. METHODS: Among 116 patients with endoscopically confirmed EGVB and endoscopic hemostasis, various noninvasive markers were calculated, and their predictive accuracy was compared by receiver-operating characteristic curve analysis. Endpoints included 5-day rebleeding, 5-day mortality, 6-week rebleeding, and 6-week mortality. RESULTS: The median age was 63 years. Child-Pugh class B and C patients accounted for 40.5% and 34.5%, respectively. Only the aspartate aminotransferase-to-platelet ratio index (APRI) significantly predicted 5-day rebleeding, with an area under the curve (AUC) of 0.777 (95% confidence interval [CI]: 0.537-1). The model for end-stage liver disease-Na (MELD-Na) score showed good predictive accuracy for 5-day mortality (AUC: 0.839, 95% CI: 0.681-0.997), 6-week rebleeding (AUC: 0.797, 95% CI: 0.663-0.932), and 6-week mortality (AUC: 0.888, 95% CI: 0.797-0.979). CONCLUSIONS: Patients with cirrhosis with a high APRI and MELD-Na score were at high risk of early rebleeding and death after EGVB. Allocating appropriate monitoring and care for those patients is necessary.

Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real­world practice.

Although durvalumab plus tremelimumab (Dur/Tre) has been approved as first-line therapy for patients with unresectable hepatocellular carcinoma (u-HCC), its outcomes in real-world clinical practice are unclear. The present study aimed to evaluate the efficacy and safety of Dur/Tre treatment. This multicenter study was conducted between March 2023 and January 2024, and included 120 patients with u-HCC treated with Dur/Tre. Among the patients, 44 had no history of systemic treatment. Progression-free survival (PFS), therapeutic response and adverse events (AEs) were assessed. The objective response rate (ORR) and disease control rates (DCR) were 15.8 and 53.3%, respectively. The median PFS was 3.9 months. The incidence rates of AEs of any grade and those grade 3 or higher were 83.3 and 36.7%, respectively. Liver injury was the most frequent AE of any grade and grade 3 or higher. Although there was no significant difference in ORR and PFS between the first and later line groups (ORR 15.8 vs. 15.7%, P=0.986; PFS 4.5 vs. 3.6 months, P=0.213), there was a significant difference in DCR between the two groups (65.8 vs. 45.9%, P=0.034). No significant differences were noted between the first- and later-line treatment groups regarding the incidence rate of AEs. Decision tree analysis revealed that poor liver function and advanced age were significant variables for discontinuation owing to AEs. In conclusion, Dur/Tre as first-line therapy had better disease control responses compared with later-line therapy; however, this regimen should be carefully administered to patients with deteriorating hepatic function or advanced age.

Initial tumor size and narrow-band image findings estimate growth speed in duodenal tumors.

INTRODUCTION: Recently, detection of superficial non-ampullary duodenal epithelial tumors (SNADETs) including adenomas and superficial duodenal carcinomas has increased. Various endoscopic treatment methods have also been reported for SNADETs, but there are few reports on the natural history. The aim of this study was to analyze factors related to tumor growth and determine the characteristics of SNADETs which need early therapeutic intervention. METHODS: A single-center, retrospective study was performed on medical records of 309 patients with SNADETs who underwent endoscopic or surgical resection between January 2010 and May 2021. Of these, 41 patients who were followed up for more than one year by endoscopy were analyzed. The primary outcome was analysis of the tumor growth speed. Secondary outcomes were the relationship between the tumor growth speed and mucin phenotype, tumor size and findings of magnifying endoscopy with narrow-band imaging (M-NBI). RESULTS: The observation period was 24 months (13-182). Tumor growth speed was 1.1 mm/year (0-21.6). Tumor diameter >10 mm at first detection (P=0.004; Odds ratio 19.5(2.03-186.96)) and mixed-type by M-NBI (p=0.036; Odds ratio 9.69(1.05-89.88)) were identified as risk factors of tumors growing at a rate of >3 mm/year. There was no statistically significant difference in the speed of tumor growth between the different mucin immunohistochemical phenotype. CONCLUSION: Initial tumor size and findings of M-NBI are useful to predict tumor growth and consider early intervention.

Analysis of Neuropeptides in the Intestinal Mucus of Patients with Ulcerative Colitis Using RNA Sequencing.

INTRODUCTION: Inflammation in ulcerative colitis (UC) originates in the colorectal mucosa. Transcriptome sequencing analysis of the colorectal mucosa allows the identification of potential neuropeptides related to local neurotransmission. The intestinal mucus lining the surface of the mucosa may harbor biomarkers of mucosal inflammation; however, this has not been sufficiently investigated, given the difficulty in obtaining human samples. We previously reported the feasibility of obtaining mucin samples for proteomic analysis by brushing during colonoscopy. Herein, we aimed to investigate the composition of the intestinal mucus and detect neuropeptides characteristic of UC. METHODS: Mucus and mucosal samples were collected from patients with UC from the colorectum in areas showing remission or active UC using a brush catheter and biopsy forceps during colonoscopy. RNA sequencing findings of mucus samples of active and remission areas were compared. RNA and protein expression levels of significantly upregulated neuropeptides were analyzed. RESULTS: Of the neuropeptides associated with UC, somatostatin (SST) was significantly elevated in areas of remission, according to RNA sequencing results of mucus and expression levels in mucus RNA and proteins. Conversely, SST expression in the mucosa was increased in the inflamed areas. Flow cytometry revealed that the fluorescence intensity of SST-positive cells in the remission zone was higher in the mucus than in the mucosa. CONCLUSION: SST expression in the mucus is considered to be an important factor associated with UC activity.

Risk factors for recurrent biliary obstruction following suprapapillary placement of a plastic stent as preoperative biliary drainage for perihilar biliary malignancy.

BACKGROUND/PURPOSE: The usefulness of endoscopic biliary stenting by deploying a plastic stent suprapapillary, called inside-stent (IS) placement, as preoperative biliary drainage (PBD) for perihilar biliary malignancy (PHBM) has been demonstrated. This study investigated risk factors for recurrent biliary obstruction (RBO) after IS placement. METHODS: Consecutive patients with potentially resectable PHBM treated with IS placement as PBD between 2017 and 2023 at Nagoya University Hospital were retrospectively reviewed. RESULTS: A total of 157 patients were included, with RBO occurring in 34 (22%) patients. The non-RBO rates were 83% at 30 days, 77% at 60 days, and 57% at 90 days. The most common cause of RBO was stent occlusion (n = 14), followed by segmental cholangitis (n = 12) and stent migration (n = 8). Stent migration and occlusion occurred more frequently within and after 1 week post-stenting, respectively. In multivariate analysis, biliary infection before IS was the sole risk factor for RBO, with a hazard ratio of 2.404 (95% confidence interval 1.163-4.972; p = .018). This risk was reduced by temporary endoscopic nasobiliary drainage prior to definitive IS placement. CONCLUSIONS: Biliary infection before IS was identified as an independent risk factor for RBO in patients with PHBM with IS as PBD. CLINICAL TRIAL REGISTER: Clinical trial registration number: UMIN000025631.

HNF6 and HNF4α expression in adenocarcinomas of the liver, pancreaticobiliary tract, and gastrointestinal tract: an immunohistochemical study of 480 adenocarcinomas of the digestive system.

Hepatocyte nuclear factors (HNF) 6 and 4α are master transcriptional regulators of development and maintenance of the liver and pancreaticobiliary tract in mice and humans. However, little is known about the prevalence of HNF6 and HNF4α expression in carcinomas of the hepatobiliary tract and pancreas. We aimed to reveal the diagnostic utility of HNF6 and HNF4α immunolabelling in adenocarcinomas of these organs. We investigated HNF6 and HNF4α expression by immunohistochemistry using a total of 480 adenocarcinomas of the digestive system, including 282 of the hepatobiliary tract and pancreas and 198 of the gastrointestinal tract. HNF6 expression was primarily restricted to intrahepatic cholangiocarcinomas (CCs) (63%, n=80) and gallbladder adenocarcinomas (43%, n=88), among others. Notably, small duct intrahepatic CCs almost invariably expressed HNF6 (90%, n=42), showing stark contrast to a low prevalence in large duct intrahepatic CCs (10%, n=21; p<0.0001). HNF6 expression was infrequent in extrahepatic CCs (9%, n=55) and pancreatic ductal adenocarcinomas (7%, n=58), and it was rare in adenocarcinomas of the gastrointestinal tract [oesophagus/oesophagogastric junction (EGJ) (2%, n=45), stomach (2%, n=86), duodenum (0%, n=25), and colorectum (0%, n=42)]. In contrast, HNF4α was widely expressed among adenocarcinomas of the digestive system, including intrahepatic CCs (88%), extrahepatic CCs (94%), adenocarcinomas of the gallbladder (98%), pancreas (98%), oesophagus/EGJ (96%), stomach (98%), duodenum (80%), and colorectum (100%). HNF6 was frequently expressed in and almost restricted to intrahepatic CCs of small duct type and gallbladder adenocarcinomas, while HNF4α was expressed throughout adenocarcinomas of the digestive system. HNF6 immunolabelling may be useful in distinguishing small duct intrahepatic CCs from other types of CC as well as metastatic gastrointestinal adenocarcinomas.

Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade.

BACKGROUND: The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs. METHODS: We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models. RESULTS: High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs. CONCLUSION: Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

Simultaneous Injection of Contrast and Saline Using Spiral Flow-Generating Tube for Hepatic Dynamic Computed Tomography: Effect on Enhancement of Liver Parenchyma and Metastases to the Liver.

PURPOSE: Recently, there have been a few reports regarding the usefulness of a novel saline injection technique using a spiral flow-generating tube. The purpose of this study was to evaluate whether simultaneous saline injection using a spiral flow-generating tube was able to improve hepatic contrast enhancement and lesion conspicuity of metastatic liver tumors. METHODS: We randomized a total of 411 patients with various liver diseases including metastases by total body weight (A, n = 204) and contrast dilution protocol (B, n = 207). Group A received 400 mgI/kg of contrast medium alone without a spiral flow-generating tube; group B received contrast medium 400 mgI/kg simultaneous with injection of a 0.57-ml/kg physiologic saline solution through a spiral flow-generating tube. Abdominal aorta computed tomography (CT) number, hepatic enhancement (ΔHU), percentage of tests demonstrating an enhancement effect of the liver parenchyma exceeding Δ50 HU in 3 measured segments (S2, S6, and S8), and the contrast-to-noise ratio of the metastatic liver tumors were measured. RESULTS: The mean aortic CT number of group B (417.0 HU ± 61.7; P < 0.01) was approximately 10% higher than that of group A (384.6 ± 79.1 HU). The average ΔHU was 59.8 ± 11.4 HU for group A and 61.7 ± 11.7 for group B. The ΔHU for group B was significantly higher than that for group A (P = 0.017). The percentage of tests demonstrating with the enhancement effect of group B was more than 80% in all subgroups; however, that of group A was less than 80% in all subgroups. The contrast-to-noise ratio of group B (7.8 ± 3.3 HU) was significantly higher compared to that of group A (6.5 ± 2.8 HU) (P < 0.05). CONCLUSIONS: Because of the volume effect, injecting a contrast medium diluted with normal saline improved the degree of hepatic and aortic contrast enhancement and achieved better visualization of liver metastases. CLINICAL IMPACT: The use of spiral flow-generating tube may help diagnostic of hepatic and aortic contrast enhancement and liver metastases. IMPORTANCE: The use of a spiral flow-generating tube improved the degree of hepatic and aortic contrast enhancement and achieve better visualization of liver metastases. POINTS: The use of low-concentration syringe formulations is limited by body weight. However, the use of spiral flow-generating tube provides low-concentration contrast medium regardless of body weight.

Clinical Outcomes of Use of the Porous Glass Membrane Pumping Emulsification Device During Transarterial Chemoembolization for Hepatocellular Carcinoma.

BACKGROUND/AIM: The porous glass membrane pumping emulsification device enhances local therapeutic effects of transarterial chemoembolization for hepatocellular carcinoma (HCC); however, limited clinical outcomes have been reported. This study aimed to investigate the efficacy and safety of transarterial chemoembolization using the glass membrane pumping emulsification device for HCC. PATIENTS AND METHODS: Between 2019 and 2023, 58 patients (median age=73 years) with unresectable HCC underwent 73 transarterial chemoembolizations using the glass membrane pumping emulsification device at the Nagoya University Hospital. Treatment effects were assessed using contrast-enhanced computed tomography 1-3 months after therapy and every 2-3 months thereafter. RESULTS: The median size of treated tumors was 25.5 mm (45 solitary nodules). The median dosage of ethiodized oil mixed with the epirubicin solution was 3 ml. Complete and partial response were observed in 73% and 11% of patients, respectively. Local control rates at 6 and 12 months were 82.8% and 59.8%, respectively. The median time to recurrence after treatment was 581 days. No major treatment-related complications occurred. The number of tumors and therapeutic effects of the initial transarterial chemoembolization were significantly associated with better local control. CONCLUSION: The glass membrane pumping emulsification device facilitated the accumulation of more concentrated ethiodized oil within the tumor and effective local control.

Long-Term Monitoring and Clinical Implications of Small Bowel Capsule Endoscopy in Patients with Crohn's Disease with Small Bowel Lesions: A Retrospective Analysis.

INTRODUCTION: Crohn's disease (CD) induces persistent inflammation throughout the gastrointestinal (GI) tract, potentially resulting in complications such as intestinal stenosis and fistulas, particularly in the small bowel. Small bowel capsule endoscopy (SBCE) is recommended for monitoring CD, especially when GI tract patency is maintained. This study aimed to retrospectively assess patients with CD who underwent SBCE to determine the timing of clinical changes and address the current lack of evidence regarding GI tract patency loss during CD treatment. METHODS: Of the 166 consecutive patients who underwent SBCE at our institution, 120 were followed up and included in this study. Forty-six patients were excluded due to colitis type or immediate treatment changes post-SBCE. This study focused on the primary and secondary endpoints, including the cumulative stricture-free rate of the GI tract, emergency hospitalization post-SBCE, and post-SBCE treatment strategies, at the discretion of the attending physicians. RESULTS: Demographic data revealed that the mean age of the study population was 43 years and that there was a male predominance (75%). The median disease duration was 12 years and the mean Crohn's Disease Activity Index was 98. During a 1,486-day observation period, 37% of patients experienced treatment changes. A Lewis score of >264 and perianal lesions were identified as independent risk factors for additional treatment needs. Emergency hospitalization occurred in 6% of patients and GI patency failure in 11%. Female sex and Lewis score>264 were associated with higher risks. GI patency rate declined 2 years after SBCE. CONCLUSIONS: For patients who experienced no treatment changes based on SBCE results, it is recommended to undergo SBCE monitoring at intervals of no longer than 2 years.

Lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli: Differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TLR4-related processes.

Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, activates Toll-like receptors (TLRs). Porphyromonas gingivalis (Pg) may be involved in the progression of periodontal disease. Mice exposed to a novel environment show hyperlocomotion that is inhibited by systemic administration of LPS derived from Escherichia coli (Ec-LPS). However, whether Pg-LPS influences novelty-induced locomotion is unknown. Accordingly, we carried out an open field test to analyse the effects of Pg-LPS. For comparison, effects of Ec-LPS were also studied. We additionally investigated the influence of systemic administration of Pg-LPS or Ec-LPS on IL-6, TNF-alpha, and IL-10 levels in blood, as they could be involved in the changes in locomotion. The TLR4 receptor antagonist TAK-242 was used to study the involvement of TLR4. Since Pg-LPS may block TLR4 in vitro, we analysed the effects of Pg-LPS on Ec-LPS-induced changes in behavioural and biochemical parameters. Male ddY mice were used. Pg- or Ec-LPS and TAK-242 were administered intraperitoneally. Ec-LPS (840 µg/kg), but not Pg-LPS (100, 500 and 840 µg/kg), inhibited novelty-induced locomotion, which was antagonized by TAK-242 (3.0 mg/kg). Ec-LPS (840 µg/kg) increased blood levels of IL-6 and IL-10, which were antagonized by TAK-242 (3.0 mg/kg). However, TAK-242 did not inhibit Ec-LPS-induced increases in TNF-alpha levels in blood. Pg-LPS (100, 500, and 840 µg/kg) did not alter blood IL-6, TNF-alpha, or IL-10 levels. The Ec-LPS-induced increase in blood IL-10, but not IL-6 and TNF-alpha, levels was inhibited by Pg-LPS (500 µg/kg). These results suggest that TLR4 stimulation mediates the inhibition of novel environment-induced locomotion in mice following systemic administration of Ec-LPS, while also increasing blood IL-6 and IL-10 levels. In contrast, Pg-LPS did not exhibit these effects. The present study also provides in vivo evidence that Pg-LPS can inhibit TLR4-mediated increases in blood levels of IL-10, a cytokine thought to prevent the development of periodontal disease.

A prospective study on the histological evaluation of type 1 autoimmune pancreatitis using endoscopic ultrasound-guided fine needle biopsy with a 19-gauge Franseen needle.

BACKGROUND/PURPOSE: To assess the diagnostic efficacy and safety of endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a 19-gauge Franseen needle for autoimmune pancreatitis (AIP). METHODS: Twenty patients suspected of having type 1 AIP were prospectively enrolled and underwent EUS-FNB with a 19-gauge Franseen needle. Their data were compared with those of historical controls: a total of 29 type 1 AIP patients had EUS-FNB with a 22-gauge Franseen needle. RESULTS: Specimens suitable for histological evaluation were obtained from 19 of the 20 patients (95%), and the median total tissue area was 11.9 mm2. The histological diagnosis rate of AIP was 65% (95% CI: 43.2%-82%). Adverse events were observed in three patients (15%), and a switch to 22-gauge needles occurred during transduodenal puncture in two patients. Compared to those punctured with 22-gauge needles, patients punctured with 19-gauge needles had greater prevalence of each characteristic feature of lymphoplasmacytic sclerosing pancreatitis, but the difference was not statistically significant. CONCLUSIONS: EUS-FNB using a 19-gauge Franseen needle demonstrated favorable performance for the histological diagnosis of AIP and allowed for large tissue samples, potentially facilitating pathological diagnosis. However, during transduodenal puncture, maneuverability is reduced; therefore, the needle may need to be selected according to the puncture site.

What is the appropriate method of pathological specimen collection for cholangiocarcinoma detection in primary sclerosing cholangitis?

BACKGROUND: In primary sclerosing cholangitis (PSC), it is important to understand the cholangiographic findings suggestive of malignancy, but it is difficult to determine whether cholangiocarcinoma is present due to modifications caused by inflammation. This study aimed to clarify the appropriate method of pathological specimen collection during endoscopic retrograde cholangiopancreatography for surveillance of PSC. METHODS: A retrospective observational study was performed on 59 patients with PSC. The endpoints were diagnostic performance for benign or malignant on bile cytology and transpapillary bile duct biopsy, cholangiographic findings of biopsied bile ducts, diameters of the strictures and upstream bile ducts, and their differences. RESULTS: The sensitivity (77.8% vs. 14.3%, P = 0.04), specificity (97.8% vs. 83.0%, P = 0.04), and accuracy (94.5% vs. 74.1%, P = 0.007) were all significantly greater for bile duct biopsy than for bile cytology. All patients with cholangiocarcinoma with bile duct stricture presented with dominant stricture (DS). The diameter of the upstream bile ducts (7.1 (4.2-7.2) mm vs. 2.1 (1.2-4.1) mm, P < 0.001) and the diameter differences (6.6 (3.1-7) mm vs. 1.5 (0.2-3.6) mm, P < 0.001) were significantly greater in the cholangiocarcinoma group than in the noncholangiocarcinoma group with DS. For diameter differences, the optimal cutoff value for the diagnosis of benign or malignant was 5.1 mm (area under the curve = 0.972). CONCLUSION: Transpapillary bile duct biopsy should be performed via localized DS with upstream dilation for the detection of cholangiocarcinoma in patients with PSC. Especially when the diameter differences are greater than 5 mm, the development of cholangiocarcinoma should be strongly suspected.

Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function.

BACKGROUND: Numerous biological interventions and small molecules are used to treat Crohn's disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn's disease. AIMS: The aim of this study was to elucidate the expression of precursor and mature IL-18 in patients with Crohn's disease who exhibited varied responses to cytokine-targeted treatments and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. METHODS: We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expression of precursor and mature IL-18 was analyzed in patients with Crohn's disease. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in an acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. RESULTS: Precursor and mature IL-18 expression was upregulated and goblet cell function was impaired in patients with Crohn's disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. CONCLUSIONS: The newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn's disease.

Risk factors for decreased bone mineral density in patients with metabolic dysfunction-associated steatotic liver disease: A cross-sectional study at a health examination center.

BACKGROUND & AIMS: Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. METHODS: Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below -1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. RESULTS: A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34-0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00-1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97-1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. CONCLUSION: The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma.

The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.