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Soyeon Jang,1 Soyoung Jang,1 Si-Yong Kim,1 Jiwon Ko,1 Eungyung Kim,2 Ji Yeong Park,1 Hyejin Hyung,1 Jin Hong Lee,1 Su-Geun Lim,3 Sijun Park,3 Junkoo Yi,4 Heon-Jin Lee,5 Myoung Ok Kim,2 Hyun-Shik Lee,1 Zae Young Ryoo1 1School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea; 2Department of Animal Science and Biotechnology, Kyungpook National University, Daegu, Korea; 3School of Life Science, Kyungpook National University, Daegu, Korea; 4Gyeongsangbukdo Livestock Research Institute, Yeongju, Korea; 5Department of Microbiology and Immunology, School of Dentistry, Kyungpook National University, Daegu, 41940, KoreaCorrespondence: Zae Young Ryoo; Hyun-Shik LeeSchool of Life Science, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, KoreaTel +82-53-950-7361; +82-53-950-7367Fax +82-53-943-6925; +82-53-943-2762Email jaewoong64@knu.ac.kr; leeh@knu.ac.krPurpose: Psoriasis is a common and well-studied autoimmune skin disease, which is characterized by plaques. The formation of psoriasis plaques occurs through the hyperproliferation and abnormal differentiation of keratinocytes, infiltration of numerous immune cells into the dermis, increased subepidermal angiogenesis, and various autoimmune-associated cytokines and chemokines. According to previous research, Lin28 regulates the let-7 family, and let-7b is associated with psoriasis. However, the link between Lin28 and psoriasis is unclear. In this study, an association was identified between Lin28a and psoriasis progression, which promoted the pathological characteristic of psoriasis in epidermal keratinocytes.Patients and Methods: This study aims to investigate the role of Lin28a and its underlying mechanism in psoriasis through in vivo and in vitro models, which include the Lin28a-overexpressing transgenic (TG) mice and Lin28a-overexpressing human keratinocyte (HaCaT) cell lines, respectively.Results: In vivo and in vitro results revealed that overexpression of Lin28a downregulated microRNA let-7 expression levels and caused hyperproliferation and abnormal differentiation in keratinocytes. In imiquimod (IMQ)-induced psoriasis-like inflammation, Lin28a overexpressing transgenic (TG) mice exhibited more severe symptoms of psoriasis.Conclusion: Mechanistically, Lin28a exacerbated psoriasis-like inflammation through the activation of the extracellular-signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 signaling (STAT 3) by targeting proinflammatory cytokine interleukin-6 (IL-6).Keywords: psoriasis, keratinocyte, Lin28a, let-7

Directional differentiation is a key factor determining the result of stem cell therapy. Herein, we developed a polyethylenimine (PEI)-coated poly(lactic- co -glycolic) acid (PLGA) nanoparticle (mPDN) carrying both nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and dexamethasone (Dex) to human mesenchymal stem cells (hMSCs). The combination of Dex and Nrf2-mRNA delivered by mPDN promoted the osteogenic differentiation of hMSCs. In particular, Nrf2-mRNA rapidly reduced the DNA damage caused by ROS due to early and efficient gene expression at 3 h after treatment, which was not achieved in traditional pDNA systems. High and rapid transfection, effective ROS-scavenging effect, and protection of mitochondrial dynamics were observed in hMSCs after treatment with the resulting Nrf2-mPDN. Osteogenic differentiation was also observed in 3D pellets for up to 5 weeks. Finally, the effects of rapid DNA repair in hMSCs by Nrf2-mPDN and on in vivo bone regeneration were evaluated in a rat femoral bone defect model using CT. This study demonstrated the potential of an NP-based codelivery system and efficient transfection of mRNA at early stages in hMSCs for bone regeneration and stem cell therapy.

In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma patient-derived xenografts (HCC-PDX) encounter limitations in NK cell infiltration, hindering studies on NK cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 reinstated persistent NK cell reconstitution and infiltration in HCC-PDX in humanized mice. scRNA-seq revealed NK cell and T cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights., Competing Interests: Declaration of interests Q.C. is the scientific cofounder of two biotech companies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: The rapid urease test (RUT) is widely used to detect Helicobacter pylori infection; however, it is not preferred as a monitoring strategy after eradication owing to its low sensitivity. In this study, we evaluated the diagnostic performance of RUT using the sweeping method, which overcomes the limitations of conventional tissue sampling methods after eradication., Methods: Patients who received H pylori eradication treatment were enrolled. Each of the sweeping and conventional methods was performed on the same patients to compare diagnostic performance. Urea breath test (UBT), histology, and polymerase chain reaction were performed to determine true infection. Logistic regression analysis was conducted to investigate reasons for discrepancies between the results of the 2 methods., Results: In 216 patients, the eradication success rate was 68.1%, and the sensitivity and specificity of the sweeping method were 0.812 and 0.912, respectively, whereas those of the conventional method were 0.391 and 0.993, respectively (P < .05 for all). The area under the receiver operating characteristic curve for the sweeping method was higher than that for the conventional method (0.862 vs 0.692, P < .001). The mean time to H pylori detection for the sweeping method was 4.7 ± 4.4 minutes and 12.3 ± 16.1 minutes for the conventional method (P < .001). The risk for inconsistent results between the 2 methods was the highest for UBT values of 1.4‰ to 2.4‰ (odds ratio, 3.8; P = .016)., Conclusions: The RUT with the sweeping method could potentially replace the tissue sampling method as a test to confirm H pylori eradication and be an alternative option to UBT for patients requiring endoscopy., Competing Interests: Disclosure All authors disclosed no financial relationships. This work was partly supported by the Korean College of Helicobacter and Upper Gastrointestinal Research Foundation Grant (no. KCHUGR-202101002)., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background/aims: Early diagnosis of esophageal cancer (EC) remains challenging despite the increasing frequency of endoscopic screenings globally. The rapidly increasing number of endoscopic screenings performed over a certain period might influence diagnostic performance. This study evaluated the association between the number of endoscopic screenings and EC detection rates in a nationwide cohort., Methods: This retrospective population-based study used the Korean National Cancer Screening Program database, comprising 32,774,742 males and females aged ≥40 years between 2015 and 2019. Negative binomial regression model and least-squares mean evaluation were used to assess the association between month of the year and EC detection rates., Results: This study enrolled 28,032,590 participants who underwent upper endoscopy. The number of participants in the fourth quarter (October to December: 10,923,142 [39.0%]) was 2.1 times higher than that in the first quarter (January to March: 5,085,087 [18.1%]); this trend continued for all 5 years. Contrarily, detection rates for EC in the fourth quarter (0.08/1,000 person) were half that in the first quarter (0.15/1,000 person). The odds of detecting EC were lowest in November; in 2015 the odds were 0.57 (95% confidence interval, 0.41 to 0.79; p=0.001) times lower and in 2016, they were 0.51 (95% confidence interval, 0.37 to 0.68; p<0.001) times lower compared to January. The predicted detection rates showed a decreasing trend toward the end of the year (p>0.05 for all)., Conclusions: The workload of endoscopists increased excessively with the rising number of endoscopies toward the end of the year, which was reflected by the decreased EC detection rates during this period.

This study compared the thickness of each intraretinal layer in patients with neurofibromatosis 1 (NF1) and controls to analyze the association between intraretinal layer thickness and visual function. The macular spectral-domain optical coherence tomography volumetric dataset obtained from 68 eyes (25 adult eyes, 43 pediatric eyes) with NF1 without optic glioma and 143 control eyes (100 adult eyes, 43 pediatric eyes) was used for image auto-segmentation. The intraretinal layers segmented from the volumetric data included the macular retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer, outer plexiform layer, outer nuclear layer, and photoreceptor layer. Cases and controls were compared after adjusting for age, sex, refractive error, and binocular use. The association between retinal layer thickness and visual acuity was also analyzed. The GCIPL was significantly thinner in both adult and pediatric patients with NF1 compared with healthy controls. Average RNFL and GCIPL thicknesses were associated with visual acuity in adult patients with NF1. In pediatric patients, average GCIPL thickness was associated with visual acuity. These results suggest that changes in the inner retinal layer could be a biomarker of the structural and functional status of patients with NF1., (© 2024. The Author(s).)

Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging. [BMB Reports 2024; 57(9): 417-423].

Background/aim: Skin wound healing is a physiological process restoring the structural and functional integrity of injured skin. During this process, wound management preventing bacterial infection and complications is important for the regeneration of skin layers and adnexa, as well as the protective function of the skin. Therefore, the development of an effective ointment to promote wound healing without complications is beneficial., Materials and Methods: This study developed Raepenol™ cream, comprising a base cream and natural compounds including paeonol, D-panthenol and extract of Centella asiatica, and assessed its therapeutic effect in wound healing. A rat model of skin wound healing and a mouse model of imiquimod-induced pruritus were employed. The effect of Raepenol™ cream was evaluated by wound size and histological analysis, including the integrity of skin structures and inflammatory response., Results: Raepenol™ cream treatment effectively restored the structural integrity of the skin in rats, including wound closure, regeneration of skin adnexa, and reconstitution of collagen, comparable to commercial ointment. Additionally, Raepenol™ cream significantly suppressed pruritus by inhibiting mast cell infiltration or retention in the inflammatory site of mouse ears., Conclusion: Raepenol™ cream effectively promoted wound healing and relieved pruritus in animal models. These results suggest that it could be a promising option for wound care and pruritus relief, offering potential advantages over current ointments., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored., Materials and Methods: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death., Results: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF-α, IL-6, and IL-1β. Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins., Conclusion: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To investigate the efficacy of early surgical intervention in ameliorating aniseikonia among patients with epiretinal membrane., Methods: This prospective cohort study enrolled patients who underwent surgery for epiretinal membrane. Patients were divided into early (symptom onset within 1 year) and late (symptom onset ≥1 year) treatment groups. Changes in aniseikonia, best-corrected visual acuity, and tangential retinal displacement were assessed and compared at 6 and 12 months postoperatively., Results: Of the 56 patients, 30 (53.6%) belonged to the early treatment group and 26 (46.4%) to the late treatment group. The early treatment group demonstrated a significant reduction in aniseikonia score at 6- and 12-month follow-up visits (-1.10 ± 1.50 [P = 0.002] and -1.18 ± 1.79 [P = 0.003], respectively); however, no improvement was observed in the late treatment group (0.98 ± 4.62 [P = 0.310] and 1.52 ± 4.35 [P = 0.124], respectively). The early treatment group showed larger tangential retinal displacement at the 12-month postoperative follow-up visit. In addition, the amount of tangential retinal displacement was associated with postoperative changes in aniseikonia., Conclusion: Early surgical intervention is helpful in improving aniseikonia in patients with epiretinal membrane. The degree of recovery in inner retinal displacement was associated with the improvement of aniseikonia.

Malignant gastric outlet obstruction (GOO) is a condition characterized by blockage or narrowing where the stomach empties its contents into the small intestine due to primary malignant tumors or metastatic diseases. This condition leads to various symptoms such as nausea, vomiting, abdominal pain, and weight loss. To manage malignant GOO, different treatment options have been employed, including surgical gastrojejunostomy (SGJ), gastroduodenal stenting (GDS) using self-expandable metallic stent (SEMS), and endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ). This review focuses on comparing the clinical outcomes of endoscopic stenting (GDS and EUS-GJ) with SGJ for malignant GOO. Studies have shown that GDS with SEMS provides comparable clinical outcomes and safety for the palliation of obstructive symptoms. The choice between covered and uncovered SEMS remains controversial, as different studies have reported varying results. EUS-GJ, performed via endoscopic ultrasound guidance, has shown promising efficacy and safety in managing malignant GOO, but further studies are needed to establish it as the primary treatment option. Comparative analyses suggest that GDS has higher recurrence and reintervention rates compared to EUS-GJ and SGJ, with similar overall procedural complications. However, bleeding rates were lower with GDS than with SGJ. Randomized controlled trials are required to determine the optimal treatment approach for malignant GOO.

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management., (© 2024. The Author(s).)

Background and Aims: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6., Methods: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021., Results: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12., Conclusions: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%)., Competing Interests: FJ: Speaker fees: Gilead Sciences, MSD, and Ascletis. Consultancy: Gilead Sciences, MSD. FJ has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2023. YJW: Speaker fees: Gilead Science, AbbVie. Research Grant: Medicine Academic Clinical Program, SingHealth, Singapore. YJW has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2020. HT: Speaker fees: Gilead Science, AbbVie, Eisai, Fujifilm WAKO, Takeda, Kowa, Terumo, Astra Zeneca. VWSW: Consultancy: AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, Visirna. Speaker fees: Abbott, AbbVie, Gilead Sciences, Novo Nordisk, Unilab. Research grants: Gilead Sciences. Stock: Co-founder of Illuminatio Medical Technology Limited. MA: Speakers’ fees: AbbVie, Gilead Sciences. SD: Speakers fees: Gilead Sciences. MFY: Speakers’ fees: Fujirebio Incorporation, Gilead Sciences, Roche, Sysmex Corporation. Consulting or advisory board: AbbVie, Abbott Diagnostics, Aligos Therapeutics, AiCuris, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Precision BioSciences, Roche, Sysmex Corporation, Tune Therapeutics, Vir Biotechnology and Visirna Therapeutics. Research grant: AbbVie, Assembly Biosciences, Arrowhead Pharmaceuticals, Fujirebio Incorporation, Gilead Sciences, Immunocore, Sysmex Corporation and Roche. MFY has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2021. CW: Research grant: Gilead Sciences. MLYu: Research support (grant) from Abbvie, BMS, Gilead, Merck, and Roche diagnostics. Consultant of Abbvie, BMS, Gilead, Roche, and Roche diagnostics. Speaker of Abbvie, BMS, Eisai, Gilead, Roche, and Roche diagnostics. MLYu has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2023. MHN: Research grants via institution: Pfizer, Enanta, Astra Zeneca, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Vir Biotech, Helio Health, National Cancer Institute, Glycotest. Consulting/Advisory board: Intercept, Exact Science, Gilead, GSK. JL, MLYe, WLC and JFH have been Editorial Board Members of Journal of Clinical and Translational Hepatology since 2022. HR has been an Editor-in-Chief of Journal of Clinical and Translational Hepatology since 2013. The other authors have no conflict of interests related to this publication., (© 2024 Authors.)

Background & Aims: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium., Methods: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses., Results: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001)., Conclusions: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed., Impact and Implications: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy., Aim: To evaluate the use of serum biomarkers to predict HBeAg loss., Methods: HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated., Results: HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm., Conclusions: Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Daniel Q. Huang Advisory board: Eisai, Gilead. Liang Shen nil; Wah Phyo nil; Gavin Cloherty Employee of Abbott Diagnostics; Emily K. Butler Employee of Abbott Diagnostics; Mary C. Kuhns Employee of Abbott Diagnostics; Anne L. McNamara Employee of Abbott Diagnostics; Vera Holzmayer Employee of Abbott Diagnostics; Jeffrey Gersch Employee of Abbott Diagnostics; Mark Anderson Employee of Abbott Diagnostics; Wei Lyn Yang: Advisory board: Gilead, Abbie, Bristol Myers Squibb, MSD; Jing Hieng Ngu Advisory Board: Gilead Sciences; Speakers Bureau: Abbvie; Jason Chang nil; Jessica Tan nil; Taufique Ahmed nil; Yock Young Dan Advisory Board: BMS, Gilead, Novartis, Abbvie, MSD; Speaker's Bureau: Sanofi Aventis, Siemens; Research grants: BMS, Novartis and Johnson & Johnson; Yin Mei Lee nil; Guan Huei Lee nil; Poh Seng Tan nil; Htet Toe Wai Khine nil; Amy Tay nil; Seng Gee Lim: Advisory Board: Gilead Sciences, Roche, GSK, Janssen, Grifols, Assembly, Arbutus, Abbott, Sysmex. Speakers Bureau: Gilead Sciences, Abbott, Sysmex, Roche, GSK. Educational/research funding: Abbott, Gilead Sciences., (Copyright © 2024. Published by Elsevier B.V.)

Background & Aims: Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC., Methods: We combined single-cell transcriptomics (single-cell RNA sequencing) with multiparametric flow cytometry-based immune phenotyping, and multiplexed immunofluorescence to elucidate the immunopathological cell states associated with CHB vs. FC., Results: We found that the intrahepatic environment in CHB and FC displays specific cell identities and molecular signatures that are distinct from those found in matched PBMCs. FC is associated with the emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes, and an activated innate response represented by liver-resident natural killer cells, specific Kupffer cell subtypes and marginated neutrophils. Surprisingly, we found MHC class II-expressing hepatocytes in patients achieving FC, as well as low but persistent levels of covalently closed circular DNA and pregenomic RNA, which may play an important role in FC., Conclusions: Our study provides conceptually novel insights into the immuno-pathological control of HBV cure, and opens exciting new avenues for clinical management, biomarker discovery and therapeutic development. We believe that the discoveries from this study, as it relates to the activation of an innate and altered immune response that may facilitate sustained, low-grade inflammation, may have broader implications in the resolution of chronic viral hepatitis., Impact and Implications: This study dissects the immuno-pathological cell states associated with functionally cured chronic hepatitis B (defined by the loss of HBV surface antigen or HBsAg). We identified the sustained presence of very low viral load, accessory antigen-presenting hepatocytes, adaptive-memory-like natural killer cells, and the emergence of helper CD4 T cells with cytotoxic or effector-like signatures associated with functional cure, suggesting previously unsuspected alterations in the adaptive immune response, as well as a key role for the innate immune response in achieving or maintaining functional cure. Overall, the insights generated from this study may provide new avenues for the development of alternative therapies as well as patient surveillance for better clinical management of chronic hepatitis B., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression., Methods: We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I 2 ) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up., Results: We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse., Conclusions: While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/aims: This study aimed to investigate the clinical characteristics and treatment outcomes of patients with active central serous chorioretinopathy (CSC) and foveal atrophy., Methods: Patients diagnosed with active idiopathic CSC using multimodal imaging and followed up for at least 6 months were included. They were divided into two groups (foveal atrophy group vs foveal non-atrophy group) according to a cut-off central foveal thickness of 120 µm on baseline optical coherence tomography (OCT). Baseline characteristics, angiographic and tomographic features and treatment outcomes were compared between the two groups., Results: Of the 463 patients, 92 eyes of 92 patients (19.9%) were in the foveal atrophy group and 371 eyes of 371 patients (80.1%) were in the foveal non-atrophy group. The baseline subretinal fluid (SRF) height was 111.3±76.8 µm in the foveal atrophy group and 205.0±104.4 µm in the foveal non-atrophy group on OCT images (p<0.001). Complete resolution of SRF after treatment was noted in 60.4% and 93.5% of patients in the foveal atrophy and foveal non-atrophy groups at the final visit, respectively (p<0.001). The foveal atrophy group showed worse visual acuity at baseline (logarithm of the minimum angle of resolution, 0.43±0.33 vs 0.13±0.18, p<0.001) and final visit (0.41±0.32 vs 0.05±0.15, p=0.035)., Conclusions: CSC with foveal atrophy was associated with a shallow SRF height, low treatment efficacy and poor vision before and after treatment. We suggest that early active treatment should be considered for eyes with CSC accompanied by a persistent shallow SRF and foveal atrophy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Long intergenic non-coding RNA 346 (LINC00346) has been reported to be involved in the development of atherosclerosis and specific cancers by affecting signaling pathways. However, its function in inflammation has not been thoroughly studied. Therefore, its expression pattern and function were determined in the human macrophage-like cell line THP-1. Lipopolysaccharide (LPS) treatment induced the expression of LINC00346. LPS-induced NF-κB activation and proinflammatory cytokine expression were suppressed or enhanced by the overexpression or knockdown of LINC00346, respectively. Analyses using dual luciferase assay and decoy RNAs that could block RNA-RNA interactions indicated that LINC00346 improves phosphatase and tensin homolog (PTEN) expression by sponging miR-25-3p. Subsequently, PTEN suppresses phosphoinositide-3 kinase (PI3K)-mediated conversion of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) into phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ) as well as consequent activation of protein kinase B (AKT) and NF-κB. Interestingly, database analysis revealed that the expression levels of LINC00346 and PTEN were simultaneously decreased in breast cancer tissues. Further analyses conducted using a breast cancer cell line, MDA-MB-231, confirmed the functional relationship among LINC00346, miR-25-3p, and PTEN in LPS-induced activation of NF-κB. These results indicate that miR-25-3p-sponging activity of LINC00346 affects the balance between PTEN and PI3K as well as the downstream activation of AKT/NF-κB pathway in inflammatory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest. The funders had no role in the design of the study; collection, analyses, or interpretation of data; writing of the manuscript, or decision to publish the results., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Maintaining epidermal homeostasis relies on a tightly organized process of proliferation and differentiation of keratinocytes. While past studies have primarily focused on calcium regulation in keratinocyte differentiation, recent research has shed light on the crucial role of lysosome dysfunction in this process. TLR adaptor interacting with SLC15A4 on the lysosome (TASL) plays a role in regulating pH within the endo-lysosome. However, the specific role of TASL in keratinocyte differentiation and its potential impact on proliferation remains elusive. In our study, we discovered that TASL deficiency hinders the proliferation and migration of keratinocytes by inducing G1/S cell cycle arrest. Also, TASL deficiency disrupts proper differentiation process in TASL knockout human keratinocyte cell line (HaCaT) by affecting lysosomal function. Additionally, our research into calcium-induced differentiation showed that TASL deficiency affects calcium modulation, which is essential for keratinocyte regulation. These findings unveil a novel role of TASL in the proliferation and differentiation of keratinocytes, providing new insights into the intricate regulatory mechanisms of keratinocyte biology., (© 2024. The Author(s).)

As human society has advanced, nuclear energy has provided energy security while also offering low carbon emissions and reduced dependence on fossil fuels, whereas nuclear power plants have produced large amounts of radioactive wastewater, which threatens human health and the sustainability of water resources. Here, we demonstrate a hydrate-based desalination (HBD) technology that uses methane as a hydrate former for freshwater recovery and for the removal of radioactive chemicals from wastewater, specifically from Cs- and Sr-containing wastewater. The complete exclusion of radioactive ions from solid methane hydrates was confirmed by a close examination using phase equilibria, spectroscopic investigations, thermal analyses, and theoretical calculations, enabling simultaneous freshwater recovery and the removal of radioactive chemicals from wastewater by the methane hydrate formation process described in this study. More importantly, the proposed HBD technology is applicable to radioactive wastewater containing Cs + and Sr 2+ across a broad concentration range of low percentages to hundreds of parts per million (ppm) and even subppm levels, with high removal efficiency of radioactive chemicals. This study highlights the potential of environmentally sustainable technologies to address the challenges posed by radioactive wastewater generated by nuclear technology, providing new insights for future research and development efforts.

Background/aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients., Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks., Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported., Conclusion: 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.