Validation of Diagnostic Thresholds for Compensated Advanced Chronic Liver Disease Using Supersonic Shear Imaging.

Background The Society of Radiologists in Ultrasound (SRU) has proposed thresholds for acoustic radiation force impulse techniques to diagnose compensated advanced chronic liver disease (cACLD). However, the diagnostic performance of these thresholds has not been extensively validated. Purpose To validate the SRU thresholds in patients with chronic liver disease who underwent supersonic shear imaging and, if suboptimal diagnostic performance is observed, to identify optimal values for diagnosing cACLD. Materials and Methods This retrospective single-center study included high-risk patients with chronic liver disease who had liver stiffness (LS) measurements and had undergone endoscopy or liver biopsy between January 2018 and December 2021. Patients were randomly allocated to test and validation sets. cACLD was defined as varices at endoscopy and/or severe fibrosis or cirrhosis at liver biopsy. The diagnostic performance of the SRU guidelines was evaluated, and optimal threshold values were identified using receiver operating characteristic (ROC) curve analysis. Results A total of 1180 patients (median age, 57 years [IQR, 50-64 years]; 761 men), of whom 544 (46%) had cACLD, were included. With the SRU recommended thresholds of less than 9 kPa and greater than 13 kPa in the test set (n = 786), the sensitivity and specificity for ruling out and ruling in cACLD were 81% (303 of 374 patients; 95% CI: 77, 85) and 92% (380 of 412 patients; 95% CI: 89, 94), respectively. In ROC curve analysis, the identified optimal threshold values were less than 7 kPa and greater than 12 kPa, showing 91% sensitivity (340 of 374 patients; 95% CI: 88, 93) for ruling out cACLD and 91% specificity (373 of 412 patients; 95% CI: 87, 93) for ruling in cACLD, respectively. In the validation set (n = 394), the optimal thresholds showed 91% sensitivity (155 of 170 patients; 95% CI: 86, 95) and 92% specificity (206 of 224 patients; 95% CI: 88, 95). Conclusion Compared with the SRU guidelines, the dual LS threshold values of less than 7 kPa and greater than 12 kPa were better for diagnosing cACLD. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Barr in this issue.

The Association Between Cotinine-Verified Smoking Status and Risk of Gallstones: A Cohort Study.

BACKGROUND AND AIMS: Previous epidemiological data on the association between cigarette smoking and risk of gallstone development remain controversial, and most relevant studies have relied on self-reported questionnaires. We aimed to elucidate this association using both an objective biomarker of tobacco exposure (urinary cotinine) and a self-reported questionnaire. METHODS: We analyzed 221,721 asymptomatic adults who underwent abdominal ultrasonography and urinary cotinine measurement between January 2011 and December 2016. Cotinine-verified current smokers were defined as participants with urinary cotinine levels ≥50 ng/mL. RESULTS: The mean age of the study population was 35.9 years, and the proportion of men was 55.8%. The proportions of self-reported and cotinine-verified current smokers were 21.3% and 21.2%, respectively. After adjusting for confounding factors, self-reported current smoking was associated with an increased risk of gallstone development [adjusted odds ratio (aOR) 1.14; 95% confidence interval (95%CI), 1.04-1.25]. Moreover, among the current smokers, the risk of gallstone development increased with an increase in the amount of cigarette smoking (<20 and ≥20 pack-years vs. never smoked; aOR=1.11 and 1.25; 95%CI: 1.01-1.22 and 1.07-1.45, respectively). Cotinine-verified current smoking was also associated with an increased risk of gallstone development (aOR=1.16; 95%CI: 1.07-1.25). Among the self-reported never or former smokers, the cotinine-verified current smokers (aOR=1.20; 95%CI: 1.01-1.44) showed a significantly higher risk of gallstones than cotinine-verified never smokers. CONCLUSIONS: Cotinine-verified and self-reported current smoking were independent risk factors for gallstones, suggesting a distinct role of tobacco smoking in gallstone development.

Impact of nonalcoholic fatty liver disease on the risk of gallbladder polyps in lean and non-obese individuals: A cohort study.

BACKGROUND: The association between non-obese or lean nonalcoholic fatty liver disease (NAFLD) and gallbladder polyps (GBPs) has not yet been evaluated. We aimed to determine whether NAFLD is an independent risk factor for the development of GBPs, even in non-obese and lean individuals. METHODS: We analyzed a cohort of 331 208 asymptomatic adults who underwent abdominal ultrasonography (US). The risk of GBP development was evaluated according to the obesity and NAFLD status. RESULTS: The overall prevalence of NAFLD and GBPs ≥ 5 mm was 28.5% and 2.9%, respectively. The prevalence of NAFLD among 160 276 lean, 77 676 overweight and 93 256 obese participants was 8.2%, 31.2%, and 61.1%, respectively. Individuals with NAFLD had a significantly higher incidence of GBPs with a size of ≥ 5 mm [adjusted odds ratio (OR) = 1.18; 95% confidence interval (CI): 1.11-1.25]. A higher body mass index and its categories were also significantly associated with an increased risk of GBPs ≥ 5 mm. Moreover, risk of GBPs ≥ 5 mm was significantly increased even in NAFLD individuals who are not obese (lean: adjusted OR = 1.36, 95% CI: 1.19-1.54; overweight: adjusted OR = 1.14, 95% CI: 1.03-1.26, respectively). CONCLUSIONS: Non-obese/lean NAFLD is an independent risk factor for GBP development, suggesting that NAFLD may play an important role in the pathogenesis of GBPs regardless of the obesity status. Therefore, a more thorough evaluation for GBPs may be necessary when hepatic steatosis is detected on abdominal US, even in non-obese or lean individuals.

Impact of metabolic unhealthiness and its changes on the risk of erosive esophagitis: a cohort study.

BACKGROUND AND AIM: We aimed to compare the risk of erosive esophagitis (EE) among individuals with different phenotypes based on metabolic health status and obesity and investigate the role of changes in metabolic health in EE risk. METHODS: A cohort of 258 892 asymptomatic adults without EE at baseline who underwent ollow-up esophagogastroduodenoscopy (EGD) were categorized into the following four groups according to metabolic health and obesity status: (i) metabolically healthy (MH) non-obese; (ii) metabolically unhealthy (MU) non-obese; (iii) MH obese; and (iv) MU obese. EE was defined as the presence of grade A or higher mucosal breaks on EGD. RESULTS: During a median follow-up of 4.5 years, the incidence rates of EE were 0.6/103 person-years (PY), 1.7/103 PY, 1.7/103 PY, and 3.1/103 PY in the MH non-obese, MU non-obese, MH obese, and MU obese groups, respectively. The multivariable-adjusted hazard ratio (HR) (95% confidence intervals [CI]) for developing EE comparing the MH obese, MU non-obese, and MU obese groups with the MH non-obese group were 1.49 (1.29-1.71), 1.56 (1.25-1.94), and 2.18 (1.90-2.49), respectively. The multivariable-adjusted HR (95% CI) comparing the progression of MH to MU, regression of MU to MH, and persistent MU with the persistent MH group were 1.39 (1.10-1.76), 1.39 (1.09-1.77), and 1.86 (1.56-2.21), respectively. The increased risk of EE among the persistent MU group was consistently observed in individuals without obesity or abdominal obesity. CONCLUSION: Metabolic unhealthiness and obesity were independent risk factors for the development of EE, suggesting that maintaining both normal weight and metabolic health may help reduce the risk of EE.

Impact of hepatitis B virus infection on the risk of gallbladder polyps: a cohort study.

BACKGROUND/AIMS: We aimed to determine whether hepatitis B virus (HBV) or hepatitis C virus (HCV) infection remains an important risk factor for gallbladder polyps (GBPs) in the current context of reduced prevalence of these infections. METHODS: The cohort included 392,913 asymptomatic adults who underwent abdominal ultrasonography (US). RESULTS: The prevalence of GBP sized ≥ 5 mm, ≥ 10 mm, and overall (< 5, 5-9 and ≥ 10 mm) was 2.9%, 0.1%, and 12.8%, respectively. The prevalence of hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis C antibody (anti-HCV) positivity was 3.2%, 26.7%, and 0.1%, respectively. The GBP risk was significantly increased in HBsAg-positive individuals, with an adjusted odds ratio of 1.66 (95% confidence interval, 1.49-1.85) for GBP ≥ 5 mm, 2.39 (1.53-3.75) for GBP ≥ 10 mm, and 1.49 (1.41-1.59) for overall, whereas there was no significant association between anti-HCV positivity and GBP risk. The GBP risk did not increase significantly in individuals who tested negative for HBsAg but positive for HBcAb. CONCLUSION: The presence of HBsAg may be an independent risk factor for GBP development in the current context of a indecreasing prevalence of HBsAg positivity. A more comprehensive evaluation of GBP during abdominal US surveillance of HBsAg-positive individuals may be necessary.

Differences in the Impact of Obesity and Metabolic Unhealthiness on the Risk of Gallbladder Polyp.

PURPOSE: Differences in the impact of obesity and metabolic health status on the risk of gallbladder polyp (GBP) remain uncertain. Herein, we aimed to compare the risk of GBP ≥5 mm among individuals with different phenotypes based on obesity and metabolic health status. MATERIALS AND METHODS: A cohort of 253485 asymptomatic adults who underwent abdominal ultrasonography screening were categorized into the following four groups according to obesity and metabolic health status: 1) metabolically healthy non-obese (MHNO), 2) metabolically unhealthy and non-obese (MUNO), 3) metabolically healthy but obese (MHO), and 4) metabolically unhealthy obese (MUO). RESULTS: The prevalences of GBP ≥5 mm were 2.4%, 3.1%, 3.7%, and 4.0% in the MHNO, MUNO, MHO, and MUO groups, respectively. The multivariable-adjusted odds ratio (OR) values for prevalence of GBP ≥5 mm by comparing the MUNO, MHO, and MUO with the MHNO group were 1.11 [95% confidence interval (CI), 1.04-1.19], 1.30 (95% CI, 1.15-1.47), and 1.37 (95% CI, 1.28-1.45), respectively. The risk of GBP ≥5 mm in the MHO group was significantly higher than that in the MUNO group, but not significantly different from that in the MUO group. CONCLUSION: Obesity and metabolic unhealthiness appear to be independent risk factors for the prevalence of GBP, and the impact of obesity is greater than that of metabolic unhealthiness, suggesting that maintaining both normal weight and metabolic health may help reduce the risk of GBP.

Micellized protein transduction domain-bone morphogenetic protein-2 accelerates bone healing in a rat tibial distraction osteogenesis model.

The clinical application of growth factors such as recombinant human bone morphogenetic protein-2 (rh-BMP-2), for functional bone regeneration remains challenging due to limited in vivo efficacy and adverse effects of previous modalities. To overcome the instability and short half-life of rh-BMP-2 in vivo, we developed a novel osteogenic supplement by fusing a protein transduction domain (PTD) with BMP-2, effectively creating a prodrug of BMP-2. In this study, we first created an improved PTD-BMP-2 formulation using lipid nanoparticle (LNP) micellization, resulting in downsizing from micrometer to nanometer scale and achieving a more even distribution. The micellized PTD-BMP-2 (mPTD-BMP-2) demonstrated improved distribution and aggregation profiles. As a prodrug of BMP-2, mPTD-BMP-2 successfully activated Smad1/5/8 and induced mineralization with osteogenic gene induction in vitro. In vivo pharmacokinetic analysis revealed that mPTD-BMP-2 had a much more stable pharmacokinetic profile than rh-BMP-2, with a 7.5-fold longer half-life. The in vivo BMP-responsive element (BRE) reporter system was also successfully activated by mPTD-BMP-2. In the in vivo rat tibia distraction osteogenesis (DO) model, micro-computed tomography (micro-CT) scan findings indicated that mPTD-BMP-2 significantly increased bone volume, bone surface, axis moment of inertia (MOI), and polar MOI. Furthermore, it increased the expression of osteogenesis-related genes, and induced bone maturation histologically. Based on these findings, mPTD-BMP-2 could be a promising candidate for the next-generation osteogenesis drug to promote new bone formation in DO surgery. STATEMENT OF SIGNIFICANCE: This study introduces micellized bone morphogenetic protein-2 (mPTD-BMP-2), a next-generation osteogenic supplement that combines protein transduction domain (PTD) and nano-sized micelle formulation technique to improve transduction efficiency and stability. The use of PTD represents a novel approach, and our results demonstrate the superiority of mPTD-BMP-2 over rh-BMP-2 in terms of in vivo pharmacokinetic profile and osteogenic potential, particularly in a rat tibial model of distraction osteogenesis. These findings have significant scientific impact and potential clinical applications in the treatment of bone defects that require distraction osteogenesis. By advancing the field of osteogenic supplements, our study has the potential to contribute to the development of more effective treatments for musculoskeletal disorders.

Ultrasound LI-RADS Visualization Scores on Surveillance Ultrasound for Hepatocellular Carcinoma: A Systematic Review With Meta-analysis.

We performed a systematic review and meta-analysis to determine the proportions of each surveillance ultrasound (US) visualization score for hepatocellular carcinoma based on the US Liver Imaging Reporting and Data System (LI-RADS) and to identify the factors associated with visualization score C. Original publications reporting US LI-RADS visualization scores were identified in MEDLINE and EMBASE from January 1, 2017, to November 25, 2022. The meta-analytic pooled proportion of each visualization score based on US examination was calculated using the DerSimonian‒Laird random-effects model. Subgroup meta-regression analyses were performed to explore study heterogeneity. US LI-RADS visualization scores were reported from a total of 25,698 US examinations across 12 studies. The pooled proportions of visualization scores A, B and C were 56.7% (95% confidence interval [CI]: 38.6-73.2%, I2 = 99.2%), 30.3% (95% CI: 21.5-40.7%, I2 = 98.8%) and 6.9% (95% CI: 3.9-11.7%, I2 = 97.7%), respectively. Significantly higher proportions of visualization score C were found in studies that exclusively enrolled cirrhosis patients and a study in which the disease etiology was non-alcoholic fatty liver disease (NAFLD) (p < 0.05). In addition, the pooled proportion of visualization score C was higher in studies with a mean or median body mass index >25 kg/m2 (10.7%, 95% CI: 4.3-24.3%). In conclusion, a substantial proportion of surveillance US examinations exhibited moderate to severe limitations on visualization. There was a tendency toward higher proportions of US LI-RADS visualization score C in patients with cirrhosis, NAFLD and obesity.

Use of high-flow nasal cannula oxygen therapy for patients with terminal cancer at the end of life.

BACKGROUND: Few studies have focused on high-flow nasal cannula (HFNC) usage in the last few weeks of life. The aim of this study was to identify the status of HFNC use in patients with cancer at the end of life and the relevant clinical factors. METHODS: We performed a retrospective cohort study in a tertiary hospital in the Republic of Korea. Among patients with cancer who died between 2018 and 2020, those who initiated HFNC within 14 days before death were included. Patients were categorized based on the time from HFNC initiation to death as imminent (<4 days) and non-imminent (≥4 days). RESULTS: Among the 2191 deceased patients with terminal cancer, 329 (15.0%) were analyzed. The median age of the patients was 66 years, and 62.9% were male. The leading cause of respiratory failure was pneumonia (70.2%), followed by pleural effusion (30.7%) and aggravation of lung neoplasms (18.8%). Most patients were conscious (79.3%) and had resting dyspnea (76.3%) at HFNC initiation. Patients received HFNC therapy for a mean of 3.4 days in the last 2 weeks of life, and 62.6% initiated it within 4 days before death. Furthermore, female sex, no palliative care consultation, no advance statements in person on life-sustaining treatment, and no resting dyspnea were independently associated with the imminent use of HFNC. CONCLUSIONS: Many patients with cancer started HFNC therapy at the point of imminent death. However, efforts toward goal-directed use of HFNC at the end-of-life stage are required.

Inter-reader reliability of functional liver imaging score derived from gadoxetic acid-enhanced MRI: a meta-analysis.

PURPOSE: This study aimed to systematically determine the inter-reader reliability of the functional liver imaging score (FLIS) and explore the factors affecting it. METHODS: Original articles reporting the inter-reader reliability of FLIS derived from gadoxetic acid-enhanced magnetic resonance imaging (MRI) were systematically searched in the MEDLINE and EMBASE databases from January 2013 to June 2022. Data synthesis was performed to calculate the meta-analytic pooled estimates of the FLIS and its three subcategories, including enhancement quality score (EnQS), excretion quality score (ExQS), and portal vein sign quality score (PVsQS) using the DerSimonian-Laird random-effects model. To explore any cause of study heterogeneity, we conducted a meta-regression analysis. RESULTS: Six studies with data from 1419 patients were included. The meta-analytic pooled inter-reader reliability of FLIS was 0.93 (95% confidence interval [CI], 0.88-0.98). That of the three FLIS subcategories were 0.93 (95% CI, 0.85-1.00), 0.95 (95% CI, 0.91-1.00), and 0.90 (95% CI, 0.81-0.99) for EnQS, ExQS, and PVsQS, respectively. The pooled FLIS data was moderately heterogenous, but heterogeneity was not associated with the study methodology, MRI-related factors, and reader experience. CONCLUSION: The FLIS and its three subcategories showed almost perfect inter-reader reliability. Therefore, FLIS may be a reliable imaging parameter that reflects liver function and outcomes in patients with chronic liver disease. Further studies should be conducted to confirm any factors affecting the inter-reader reliability of FLIS.

Clinical pitfalls and serological diagnostics of MuSK myasthenia gravis.

BACKGROUND: We aimed to evaluate the diagnostic accuracy of enzyme-linked immunosorbent assay (ELISA) for anti-muscle specific tyrosine kinase (MuSK) antibody (Ab) in a large cohort of anti-acetylcholine receptor (AChR) Ab-negative generalized myasthenia gravis (MG), and also to investigate clinical contexts for the diagnosis of MuSK MG. METHODS: A retrospective study of 160 patients with a clinical suspicion of AChR Ab-negative generalized MG was performed. The serum samples were tested for anti-clustered AChR Ab by cell-based assay (CBA), anti-MuSK Ab by ELISA, CBA and/or radioimmunoprecipitation assay (RIPA). Clinical data were compared between anti-MuSK Ab-positive MG and double seronegative (AChR and MuSK) MG groups. RESULTS: After excluding non-MG and clustered AChR Ab-positive patients, we identified 89 patients as a cohort of AChR Ab-negative generalized MG. Anti-MuSK Ab was positive by ELISA in 22 (24.7%) patients. While CBA identified five additional anti-MuSK Ab-positive patients, the results of ELISA were mostly consistent with CBA and RIPA with Cohen's kappa of 0.80 and 0.90, respectively (p < 0.001). The most frequent differential diagnosis was motor neuron disease particularly of bulbar onset which showed remarkably overlapping clinical and electrophysiological features with MuSK MG at presentation. CONCLUSION: While confirming the highest sensitivity of CBA for detecting anti-MuSK Ab, our results highlight the clinical pitfalls in making a diagnosis of MuSK MG and may support a diagnostic utility of MuSK-ELISA in clinical practice.

A Pilot Study of Peritumor Administration of 5-FU for Preventing Bleeding in Advanced Gastric Cancer.

Five-FU is a potent chemotherapeutic agent for suppressing endothelial cell growth. The purpose of this study was to investigate the usefulness of local peritumor injection of 5-FU for patients with advanced gastric cancer (AGC) for the prevention of anemia. Between January 2020 and January 2022, patients aged 18 years or older with AGC and moderate anemia were included. A total of 200 mg of 5-FU was injected per session at ten points of the lesion (20 mg at each point) every 7 days for 4 to 12 weeks. Patients received a blood test for toxicity at every cycle. From one of these patients, endoscopic biopsy specimens were taken from gastric cancer before and after injecting 5-FU for immunostaining. A total of five AGC patients participated in this study. For most patients, hemoglobin levels were maintained without transfusions during 5-FU injection, and expression levels of thrombospondin-1 was increased after injection compared to those before injection. Blood test results during 5-FU injection showed no significant change in serum glutamic oxalacetic transaminase/glutamic pyruvic transaminase, total bilirubin, or creatinine level. The results of this study showed the possibility of local peritumor 5-FU injection as a treatment for relieving anemia of patients with gastric cancer.

The different prognostic impact of age according to individual molecular subtypes in breast cancer.

Purpose: Young age at diagnosis has been considered a poor prognostic factor. However, considering young age itself as an independent poor prognostic factor for all breast cancers is unwarranted. We analyzed the different prognostic effects of age as a prognostic factor according to molecular subtype. Methods: We retrieved data from 1,819 patients with primary breast cancer at the breast cancer center between 2007 and 2012. We classified each molecular subtype in 3 age cohorts (<40, 40-50, and >50 years). The associations of age and molecular subtypes with relapse-free survival (RFS) and disease-specific survival (DSS) were assessed. Results: Patients aged <40 years showed a poor histologic grade, hormone receptor negative expression than older patients, and had a higher proportion of triple-negative breast cancer (TNBC) (P < 0.001). This was thought to have led to a significantly shorter RFS than that of older patients (P < 0.001). In the subgroup analysis according to molecular subtypes, the poorer RFS was observed only in patients aged <40 years with luminal type breast cancer (P < 0.001). Age was an independent prognostic factor of RFS in luminal-type breast cancer (P = 0.001). However, no difference in RFS between age groups was found for patients with other subtypes (human epidermal growth factor receptor 2 overexpression, TNBC). No significant effect between age groups was found in DSS for patients with all molecular subtypes. Conclusion: Age at diagnosis of breast cancer affected prognosis differently according to molecular subtype. Age itself is not an independent prognostic factor. Age of <40 years showed a limited worse prognostic impact of recurrence in luminal type breast cancer only.

Potential anticancer effect of sodium caprate on human gastric cancer cells.

The role of sodium caprate (C10) in enhancing drug absorption is well established; however, little information is available on its role as an anticancer drug. This study aimed to evaluate the anticancer effect of C10 in gastric cancer cells. The mechanism of cytotoxicity of C10 was evaluated by western blotting following treatment of the gastric cancer cells with various concentrations of C10. C10 cytotoxicity was measured via MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium), lactate dehydrogenase (LDH), cAMP, and ATP assays. Gastric cancer cells were observed by electron microscopy following treatment with C10. Then, xenograft mice that were inoculated with gastric cancer cells were treated with C10 for 4 weeks, after which the changes in tumor size were measured. C10 triggered apoptosis in the gastric cancer cells through the mitochondrial pathway at concentrations of more than 0.2 mM. However, 15 mM of C10 induced necrosis in gastric cancer cells by causing cellular swelling and the formation of holes in the cell membrane. Levels of cAMP and ATP decreased significantly following exposure to 15 mM C10 for 1 h. Additionally, the size of the xenograft tumors was significantly reduced by 24% after 4 weeks of C10 treatment (p < 0.05). This study indicates that C10 induces apoptosis and necrosis in a concentration-dependent manner and has clear anticancer effects on gastric cancer cells.

Did expansion of insurance coverage for major diseases in Korea induce a positive spillover effect on dental service utilization?

Although people with serious major diseases are disproportionately likely to have poor oral health, they are also more likely to defer treatment for oral health conditions due to financial constraints. The South Korean government introduced a comprehensive benefit expansion policy covering four major disease categories in 2013: cancer, cardiac diseases, cerebrovascular diseases, and rare diseases. Meanwhile, a policy expanding benefits for dental prosthetic services for the elderly was also introduced during the same period. Using nationally representative Korean Health Panel data from 2012 to 2017, we performed a difference-in-difference (DID) analysis to examine the positive spillover effect of insurance expansion for the four major disease categories on encouraging dental service utilization (frequency of dental visits and dental out-of-pocket payments) or decreasing unmet dental needs. Additionally, a triple-difference (TD) analysis was performed to examine whether the effect of coverage expansion of dental prosthetic services on dental service utilization was larger among the beneficiaries of the expansion for the four major disease categories. Benefit expansion for the four major disease categories did not significantly affect dental service utilization among the beneficiaries (DID model) during all study years and slightly increased unmet dental needs in 2014 and 2015. However, the effect of expanded coverage for dental prosthetic services on encouraging dental service utilization was larger (TD model) among the beneficiaries of the policy for the four major disease categories than among non-beneficiaries when we defined the beneficiaries as individuals with two or more household members who had one of the four major diseases. Our results suggest a need to provide more intense coverage for those with comorbidities by embracing the concept of proportionate universalism in the coverage of dental services.

A micellized bone morphogenetic protein-7 prodrug ameliorates liver fibrosis by suppressing transforming growth factor-ß signaling.

Bone morphogenetic protein-7 (BMP-7) antagonizes transforming growth factor-ß (TGF-ß), which is critically involved in liver fibrogenesis. Here, we designed a micelle formulation consisting of a protein transduction domain (PTD) fused BMP-7 polypeptide (mPTD-BMP-7) to enhance endocytic delivery, and investigated its ability to ameliorate liver fibrosis. The mPTD-BMP-7 formulation was efficiently delivered into cells via endocytosis, where it inhibited TGF-ß mediated epithelial-mesenchymal transition. After successfully demonstrating delivery of fluorescently labeled mPTD-BMP-7 into the murine liver in vivo, we tested the mPTD-BMP-7 formulation in a murine liver fibrosis model, developed by repeated intraperitoneal injection of hepatotoxic carbon tetrachloride, twice weekly from 4 to 16 weeks. mPTD-BMP-7 effects were tested by injecting the mPTD-BMP-7 formulation (or vehicle control) into the lateral tail at a dose of 50 (n=8) or 500 µg/kg (n=10), also twice per week from 4 to 16 weeks. Vehicle-treated control mice developed fibrous septa surrounding the liver parenchyma and marked portal-to-portal bridging with occasional nodules, whereas mice treated with mPTD-BMP-7 showed only fibrous expansion of some portal areas, with or without short fibrous septa. Using the Ishak scoring system, we found that the fibrotic burden was significantly lower in mPTD-BMP-7 treated mice than in control mice (all P<0.001). Treatment with mPTD-BMP-7 protected tight junctions between hepatocytes and reduced extracellular matrix protein levels. It also significantly decreased mRNA levels of collagen 1A, smooth muscle α-actin, and connective tissue growth factor compared with that in control mice (all P<0.001). Collectively, out results indicate that mPTD-BMP-7, a prodrug formulation of BMP-7, ameliorates liver fibrosis by suppressing the TGF-ß signaling pathway in a murine liver fibrosis model.

Risk of developing metachronous colorectal neoplasia after the resection of proximal versus distal adenomas.

BACKGROUND: Current post-polypectomy guidelines do not consider adenoma location. We compared the risk of metachronous colorectal neoplasia (CRN) according to adenoma location. METHODS: We collected data from 9710 patients who underwent follow-up colonoscopy after adenoma removal. Patients were classified according to baseline adenoma location: distal only (n=4665), proximal only (n=3827), and both sides (n=1218). RESULTS: The risk of metachronous CRN in patients with proximal only adenomas was higher than that in those with distal only adenomas (adjusted hazard ratio [aHR]=1.12, 95% confidence interval [CI]=1.04-1.21), while the risk of metachronous advanced CRN (ACRN) was not different between the two groups. Among patients aged <50 years, the risk of metachronous CRN in those with proximal only non-advanced adenomas (NAAs) was higher than that in those with only distal NAAs, while among patients aged ≥ 50 years, the risk in those with proximal only advanced adenomas (AAs) was higher than that in those with distal only AAs. However, the risk of metachronous ACRN did not differ based on adenoma location in patients aged < 50 and ≥ 50 years. CONCLUSIONS: Proximal adenoma was associated with an increased risk of metachronous CRN, but not with an increased risk of metachronous ACRN, supporting the current guidelines recommending the same surveillance interval for distal and proximal adenoma without discrimination by adenoma location.

Metastatic breast cancer from a hepatocellular carcinoma: a case report.

Breast metastases from extramammary malignancies are rare. Here, we report a case of breast metastasis from hepatocellular carcinoma (HCC) after breast mass excision in a 63-year-old woman. A new breast nodule was noticed after transarterial chemoembolization, transarterial radioembolization, and stereotactic body radiation therapy for HCC. Breast ultrasound and core needle biopsy were performed to differentiate between the breast tumors. The biopsy result was invasive breast carcinoma, and wide excision of the breast was performed. The final pathological diagnosis was HCC breast metastasis based on histological findings and immunohistochemical staining results. After 9 months of follow-up, HCC and breast metastasis recurred. Despite palliative treatment, the patient died due to complications and general health deterioration. Although breast metastasis due to HCC is very rare, HCC breast metastasis should be considered when a new breast mass is discovered in a patient with a history of HCC for effective treatment and management.

Did Expanded Dental Insurance Improve Chewing Ability in the Older Korean Population? Results of an Interrupted Time-series Analysis.

BACKGROUND: In 2012, the Korean National Health Insurance extended its coverage to include denture services for older adults. We examined whether the new policy resulted in improved chewing ability in the eligible population. METHODS: We used interrupted time-series (ITS) analysis, a quasi-experimental design, to analyze the effect of the policy. We used data from the Korea National Health and Nutrition Examination Survey conducted from 2007 to 2016-2018. The study population consisted of two groups: the treatment group, aged 65 years or older and eligible for the dental insurance benefit; and the control group, those younger than 65 years and ineligible. The main evaluated outcome was self-reported chewing difficulty. RESULTS: The ITS analysis showed that chewing difficulty decreased annually by 0.93% (95% CI, -1.30 to -0.55%) and 0.38% (95% CI, -0.59 to -0.16%) after the policy extension in the older than 65 and younger than 65 groups, respectively. However, we could not conclude that the insurance extension affected chewing difficulty because there was a decrease in the control group as well. CONCLUSION: Chewing ability improved in both older and younger adults regardless of dental insurance coverage for older adults. Other exogenous factors probably led to the improvements in chewing ability as well as dental insurance benefits.

Competing Endogenous RNA of Snail and Zeb1 UTR in Therapeutic Resistance of Colorectal Cancer.

The epithelial-mesenchymal transition (EMT) comprises an important biological mechanism not only for cancer progression but also in the therapeutic resistance of cancer cells. While the importance of the protein abundance of EMT-inducers, such as Snail (SNAI1) and Zeb1 (ZEB1), during EMT progression is clear, the reciprocal interactions between the untranslated regions (UTRs) of EMT-inducers via a competing endogenous RNA (ceRNA) network have received little attention. In this study, we found a synchronized transcript abundance of Snail and Zeb1 mediated by a non-coding RNA network in colorectal cancer (CRC). Importantly, the trans-regulatory ceRNA network in the UTRs of EMT inducers is mediated by competition between tumor suppressive miRNA-34 (miR-34) and miRNA-200 (miR-200). Furthermore, the ceRNA network consisting of the UTRs of EMT inducers and tumor suppressive miRs is functional in the EMT phenotype and therapeutic resistance of colon cancer. In The Cancer Genome Atlas (TCGA) samples, we also found genome-wide ceRNA gene sets regulated by miR-34a and miR-200 in colorectal cancer. These results indicate that the ceRNA networks regulated by the reciprocal interaction between EMT gene UTRs and tumor suppressive miRs are functional in CRC progression and therapeutic resistance.