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Chao-Jen Li,1,* Hung-Wen Tsai,2,* Yi-Li Chen,3 Chun-I Wang,4 Yang-Hsiang Lin,5 Pei-Ming Chu,6,7 Hsiang-Cheng Chi,8,9 Yi-Ching Huang,3 Cheng-Yi Chen3 1Department of General & Gastroenterological Surgery, An Nan Hospital, China Medical University, Tainan, Taiwan; 2Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; 5Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan; 8Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Cheng-Yi Chen, Tel/Fax +886-6-2353535#5329, Email cychen@gs.ncku.edu.twIntroduction: Hepatocellular carcinoma (HCC) accounts for 80% of all liver cancers and is the 2nd leading cause of cancer-related death in Taiwan. Various factors, including rapid cell growth, a high recurrence rate and drug resistance, make HCC difficult to cure. Moreover, the survival rate of advanced HCC patients treated with systemic chemotherapy remains unsatisfactory. Hence, the identification of novel molecular targets and the underlying mechanisms of chemoresistance in HCC and the development more effective therapeutic regimens are desperately needed.Methods: An MTT assay was used to determine the cell viability after cisplatin or doxorubicin treatment. Western blotting, qRT‒PCR and immunohistochemistry were utilized to examine the protein tyrosine phosphatase IVA3 (PTP4A3) level and associated signaling pathways. ELISA was utilized to analyze the levels of the inflammatory cytokine IL-6 influenced by cisplatin, doxorubicin and PTP4A3 silencing.Results: In this study, we found that PTP4A3 in the cisplatin/doxorubicin-resistant microarray was closely associated with the overall and recurrence-free survival rates of HCC patients. Cisplatin or doxorubicin significantly reduced cell viability and decreased PTP4A3 expression in hepatoma cells. IL-6 secretion increased with cisplatin or doxorubicin treatment and after PTP4A3 silencing. Furthermore, PTP4A3 was highly expressed in tumor tissues versus adjacent normal tissues from HCC patients. In addition, we evaluated the IL-6-associated signaling pathway involving STAT3 and JAK2, and the levels of p-STAT3, p-JAK2, STAT3 and JAK2 were obviously reduced with cisplatin or doxorubicin treatment in HCC cells using Western blotting and were also decreased after silencing PTP4A3. Collectively, we suggest that cisplatin or doxorubicin decreases HCC cell viability via downregulation of PTP4A3 expression through the IL-6R-JAK2-STAT3 cascade.Discussion: Therefore, emerging evidence provides a deep understanding of the roles of PTP4A3 in HCC cisplatin/doxorubicin chemoresistance, which can be applied to develop early diagnosis strategies and reveal prognostic factors to establish novel targeted therapeutics to specifically treat HCC.Keywords: hepatocellular carcinoma, chemoresistance, cisplatin, doxorubicin, PTP4A3, IL-6

Han-Ni Chuang,1,* Chien-Hung Shih,1,* Hung-Wen Tsai,2 Rong-San Jiang,1 Tzu-Hung Hsiao,2– 4 Po-Yu Liu,5 Yee-Jee Jan,6 Jiunn-Min Wang6 1Department of Medical Research, Taichung Veterans General Hospital, Taichung, 407204, Taiwan; 2Medical Administration Department, Taichung Veterans General Hospital, Taichung, 47204, Taiwan; 3Department of Public Health, Fu Jen Catholic University, New Taipei City, 24205, Taiwan; 4Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 40227, Taiwan; 5Division of Infection, Taichung Veterans General Hospital, Taichung, 47204, Taiwan; 6Department of Pathology & Laboratory Medicine, Taichung Veterans General Hospital, Taichung, 407, Taiwan*These authors contributed equally to this workCorrespondence: Yee-Jee Jan; Jiunn-Min Wang, Department of Pathology & Laboratory Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 40705, Taiwan, Tel +886-4-23592525, Fax +886-4-2359-5046, Email yejan@vghtc.gov.tw; jmwang@vghtc.gov.twAbstract: The COVID-19 pandemic has reaffirmed the critical significance of effective diagnostics in outbreak response. In Taiwan, the COVID-19 wave in May 2021 led to a rapidly growing demand for SARS-CoV-2 diagnostic tests. To meet the challenge, an extensive system-wide emergency preparedness plan, hospital emergency incident command system (HEICS), was developed to deal with emergencies involving healthcare systems. During the wave of the COVID-19 outbreak, a 19.4-fold increase in SARS-CoV-2 PCR (polymerase chain reaction) diagnostic tests occurred in the hospital. The incident commander of TCVGH reviewed COVID-19 related events daily and purchased a high-throughput PCR machine for SARS-CoV-2 PCR diagnostic tests. In addition, the Department of Operations was responsible for staff scheduling and educational training. The turn-around times of SARS-CoV-2 diagnostic tests were shortened from 21.2 hours to 5.8 hours in the second week of the COVID-19 wave. Implementation of HEICS integrated resources could be helpful for expanding surge capacity during future outbreaks.Keywords: COVID-19, hospital emergency incident command system, pandemics

Yu-Chuan Chuang,1 Hung-Wen Tsai,2 Shih-An Liu,3 Ming-Ju Wu,1 Po-Yu Liu4 1Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Medical Administration Department, Taichung Veterans General Hospital, Taichung, Taiwan; 3Center of Quality Management, Taichung Veterans General Hospital, Taichung, Taiwan; 4Division of Infection, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, TaiwanCorrespondence: Po-Yu Liu, Division of Infection, Department of Internal Medicine, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Blvd., Xitun Dist., Taichung City, 407219, Taiwan, Tel +886 4 2359 2525, Email liupoyu@gmail.comAbstract: Veterans are a special population that has been largely ignored during the corona virus disease 2019 (COVID-19) pandemic. Veterans with COVID-19 not only suffered symptoms from the disease but also had a higher risk of further development of in-hospital complications involving multiple organs. This article aims to review the current literature on the epidemiology, risk factors, diagnosis, clinical presentation, treatment, and outcome in veterans who contracted COVID-19 during the pandemic, using papers published between January 1, 2020 and August 1, 2021. Forty published papers were considered relevant to this review study. The COVID-19 pandemic not only caused a burden on health-care facilities but also affected the veterans population. Veterans with COVID-19 not only suffered symptoms from the disease but also had a higher risk of further development of in-hospital complications involving multiple organs. The dismal outcome might be attributed to old age and multiple comorbidities among veterans. Symptoms that may be seen in veterans with COVID-19 are comparable to those in the general population with fever, cough, and dyspnea, the most commonly reported. There are several approaches, such as self-assessment tools and virtual or telephone triage strategies, that can initially provide adequate evaluation of the symptoms related to COVID-19 in veterans. Adequate risk stratification could be carried out using the VA COVID-19 (VACO) Index, which predicts the risk of 30-day all-cause mortality after COVID-19 infection. There are several COVID-19 specific treatments that have been given to veterans; however, none of them have been proven to reduce the overall mortality in veterans. The overall mortality rate among veterans showed a declining trend. However, veterans suffering from chronic COVID-19 are at risk of dependence on activities of daily living after recovering from the illness. In summary, veterans are a special population that requires more attention especially during the COVID-19 pandemic.Keywords: SARS-CoV-2, COVID-19, veterans, pandemic

The purpose was to compare the findings of multi-detector computed tomography (MDCT) in prosthetic valve disorders using the operative findings as a gold standard. In a 3-year period, we prospectively enrolled 25 patients with 31 prosthetic heart valves. MDCT and transthoracic echocardiography (TTE) were done to evaluate pannus formation, prosthetic valve dysfunction, suture loosening (paravalvular leak) and pseudoaneurysm formation. Patients indicated for surgery received an operation within 1 week. The MDCT findings were compared with the operative findings. One patient with a Björk-Shiley valve could not be evaluated by MDCT due to a severe beam-hardening artifact; thus, the exclusion rate for MDCT was 3.2% (1/31). Prosthetic valve disorders were suspected in 12 patients by either MDCT or TTE. Six patients received an operation that included three redo aortic valve replacements, two redo mitral replacements and one Amplatzer ductal occluder occlusion of a mitral paravalvular leak. The concordance of MDCT for diagnosing and localizing prosthetic valve disorders and the surgical findings was 100%. Except for images impaired by severe beam-hardening artifacts, MDCT provides excellent delineation of prosthetic valve disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Buckwheat flour and buckwheat sprouts possess antioxidant properties, and previous studies have reported on buckwheat flour displaying an inhibitory activity for angiotensin-I converting enzyme (ACE). Information is lacking on the bioactivity of other parts of the buckwheat, such as the seed hulls and plant stalks. This study investigates the ACE inhibitory activity and antioxidant activity of various parts of 2 types of buckwheat, namely, common buckwheat (Fagopyrum esculentum Moench) and tartary buckwheat (Fagopyrum tataricum Gaertn). Results The extract of common hulls extracted using 50% (v/v)-ethanol solvent presented a remarkable inhibitory activity. The value of IC50 is 30 μg ml-1. The extracts of both common and tartary hulls extracted using 50% (v/v)-ethanol solvent demonstrated an antioxidant activity that is superior to that of other extracts. Conclusion This study determined that the ethanolic extract of the hulls of common buckwheat presented more favorable antioxidant and ACE inhibitory abilities. However, the correlation of antioxidant activity and ACE inhibitory activity for all 18 types of extracts is low. The ACE inhibitory activity could have been caused by a synergistic effect of flavonoids or from other unidentified components in the extracts. The ethanolic extract of common hulls demonstrated remarkable ACE inhibitory activity and is worthy of further animal study.

There are no reported case series of common variable immunodeficiency (CVID) from southern Taiwan. A 20-year review was performed in adult CVID from a southern Taiwan medical center. Patients with ages of 18 years or older were enrolled from May, 2003 to April, 2023. Twelve patients were identified, 8 females/4 males aged 23 to 68 (38.9 ± 13.4) with one to 11 years (5.0 ± 3.3) delay of diagnosis after disease onset. There were concomitant autoimmune disorders in 7 (58 %), splenomegaly in 10 (83 %), lymphadenopathy in 4 (25 %) and B-cell lymphoma in 2 (17 %). All received intravenous immunoglobulin (IVIg) infusion with improved autoimmune-mediated arthritis in 2. Patients with higher IgG trough levels (above 500 mg/dL) had a better survival than those with lower IgG trough levels. Adult CVID in southern Taiwan has a high occurrence of autoimmune and lymphoproliferative manifestations. Early diagnosis with IVIg infusion might improve the presentations., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/aim: The dysregulation of matrix metalloproteinase (MMP) proteins has been reported to be involved in the etiology of pterygium. However, studies about the role of matrix metalloproteinase-11 (MMP-11) are lacking. This study is the first to examine the genomic role of MMP-11 in pterygium., Materials and Methods: The genotypes of MMP-11 rs738791, rs2267029, rs738792, and rs28382575 were determined in 140 pterygium cases and 280 non-pterygium controls by utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing., Results: The genotypic frequencies of MMP-11 rs738792 TT, CT and CC were 40.0%, 50.7%, and 9.3% in the pterygium group, significantly different from those in the non-pterygium group (55.0%, 37.1%, and 7.9%, respectively; p for trend=0.0139). Specifically, individuals carrying the variants CT and CC had a 1.88- and 1.63-fold odds ratio of pterygium risk [95% confidence interval (CI)=1.22-2.89 and 0.77-3.44, p=0.0054 and 0.2834, respectively]. In the dominant model, individuals carrying CT+CC had significantly higher pterygium risk (odds ratio=1.83, 95%CI=1.21-2.77, p=0.0052). No association was found for other MMP-11 polymorphisms. Allelic analysis showed that MMP-11 rs738792 C allele was significantly associated with pterygium risk (odds ratio=1.48, 95%CI=1.08-2.01, p=0.0169). for the variant alleles of other MMP-11 polymorphisms were not associated with pterygium risk., Conclusion: The MMP-11 rs738792 genotypes can serve as a predictive marker for pterygium risk in Taiwanese. Additionally, elucidating the role of MMP-11 in the pathogenesis of pterygium could inform targeted therapies based on MMP-11 modulation., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Liver dysfunction in systemic lupus erythematosus (SLE) is caused by disease activity or secondary conditions like coexistent autoimmune liver diseases. In Taiwan, despite sporadically reported cases of SLE-autoimmune hepatitis (AIH) overlap disease, larger-scale monocentric investigations for such overlapping patients are not available. Retrospective analyses were performed in a hospitalized SLE cohort with 805 patients for identifying co-existent AIH from 2014 to 2023, focusing on distinct therapeutic modalities and differential diagnosis between SLE-AIH overlap and lupus hepatitis (LH). There were 5 cases (a 0.6% occurrence), all females aged 25-58 years (44 ± 13). Ages for the SLE diagnosis were 19-51 years (30 ± 13), while ages for the AIH diagnosis were 22-57 years (36 ± 14). Contradictory to interface hepatitis in SLE-AIH overlap, liver biopsy only demonstrated non-specific abnormalities in LH. Liver cirrhosis was identified in SLE-AIH overlap but not in LH. After corticosteroids/azathioprine therapy, there were normalized liver function in all LH. In 2 SLE-AIH overlap cases refractory to such therapy, one received B-cell depletion therapy (annual rituximab infusion, 375 mg/m 2 weekly × 4) and another accepted living-donor liver transplantation from sibling due to advanced liver cirrhosis, leading to improved hepatic dysfunction in both., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

When a plant is infected by a pathogen, endogenous immune responses are initiated. When the initiation of these defense responses is induced by a pathogen-associated molecular pattern (PAMP) of a pathogen, it is called PAMP-triggered immunity (PTI). Previous studies have shown that Bacillus amyloliquefaciens PMB05 can enhance PTI signals and improve disease control of bacterial soft rot and wilt in Arabidopsis thaliana . In the context of controlling bacterial wilt disease, the involvement of a mitogen-activated protein kinase (MAPK) signaling pathway has been established. Nevertheless, it remains unclear whether this pathway is also required for B. amyloliquefaciens PMB05 in controlling bacterial soft rot. In this study, A. thaliana ecotype Columbia (Col-0) and its mutants on a MAPK pathway-related pathway were used as a model and established that the ability of B. amyloliquefaciens PMB05 to control soft rot requires the participation of the MAPK pathway. Moreover, the enhancement of disease resistance by PMB05 is highly correlated with the activation of reactive oxygen species generation and stomata closure, rather than callose deposition. The spray inoculation method was used to illustrate that PMB05 can enhance stomatal closure, thereby restricting invasion by the soft rot bacterium. This control mechanism has also been demonstrated to require the activation of the MAPK pathway. This study demonstrates that B. amyloliquefaciens PMB05 can accelerate stomata closure via the activation of the MAPK pathway during PTI, thereby reducing pathogen invasion and achieving disease resistance against bacterial soft rot.

We employed a straightforward microwave-assisted extraction technique to investigate the presence of carbon dots (CDs) in Chinese herbal extracts derived from fructus gardeniae and gardenia charcoal, designated as CDs-1 and CDs-2, respectively. The found CDs exhibited unique photoluminescence with quantum yields of 0.95% for CDs-1 and 1.81% for CDs-2, indicating significant potential for bioimaging applications. Both CD types maintain approximately 80% of their fluorescence intensity after 120 min of continuous 365 nm UV exposure, underscoring their stability and suitability for prolonged biological studies. Moreover, antioxidant activity tests showed that CDs-2 have a higher scavenging capacity, with an SC-50 value of 21.7 μg/mL, compared to 35.9 μg/mL for CDs-1, attributed to their higher content of surface functional groups during the extraction procedure. Notably, the results indicated that the carbonization process of fructus gardeniae leads to the formation of CDs, suggesting a potential link between traditional herbal treatments and modern nanotechnology. This research demonstrates that active compounds in Chinese herbal medicine could possess therapeutic properties when adsorbed on the surface of CDs.

Introduction: Sharing mental models is essential for high-performance teams, and speaking up is key for exchanging critical insights, especially during medical errors. Understanding how health providers and trainees voice their concerns is crucial for improving speaking-up behavior. This study aims to fill a gap in the literature by examining how medical students speak up when they encounter medical errors and assessing the impact of training on their speaking-up patterns., Method: A quasi-experimental study involving 146 students, who were divided into two groups, was conducted in Northern Taiwan. One group of students encountered life-threatening scenario before intervention, followed by a faculty-led personalized debriefing session, then a non-life-threatening scenario after the intervention. Another group of students underwent these sessions in the reverse order. Students' Speaking-up patterns, including expression style, form and attitude, and their speaking-up confidence were assessed at pre- and post-intervention scenarios., Results: During pre-intervention scenario, in expression style, 50 students (34.5%) addressed their concerns to medical errors with direct expression and 14 students (9.7%) utilized indirect hint to express their concerns. In expression form, 31 students (21.4%) addressed their concerns to medical errors with affirmative sentences and 33 students (22.8%) asked questions to express their concerns. In speaking-up attitude, 47 students (32.4%) used unoffensive words, while 17 students (11.7%) used offensive words. After intervention, significantly change of speaking-up styles, forms, and attitude were observed along with their speaking-up confidence ( p  < 0.001)., Discussion: Medical students are inclined to speak up in the event of medical errors using more direct expression and affirmative sentences, along with increased speaking-up confidence after simulation scenario learning and faculty-led personalized debriefing. Healthcare educators can focus more on discussing with students the advantages and disadvantages of various approaches of speaking-up in medical errors, helping them to develop effective speaking-up behaviors in a variety of medical contexts.

Objective: Although sporadic case reports have demonstrated successful management of eosinophilic granulomatosis with polyangiitis (EGPA) by anti-IL-5 therapy, larger-scale monocentric studies for the efficacy of mepolizumab (MEP), an IL-5 monoclonal antibody, are still lacking in Taiwan., Methods: Hospitalized EGPA patients aged at least 18 years were enrolled from November 1998 to October 2023, and analyzed for demographic, clinical, laboratory, medication and outcome data, focusing on the efficacy and safety of biologics use, particularly induction therapy with MEP., Results: Twenty-seven EGPA patients aged 10-70 years (43 ± 15) at disease diagnosis were recruited with 21 under combined corticosteroids/cyclophosphamide induction therapy. Seventeen patients received biologics with 13 under MEP therapy. Ten patients aged 19-71 years (48 ± 15) completed 12-month induction therapy with a 100 mg quadri-weekly subcutaneous injection regimen indicated for active or relapse disease. There were reduced BVAS with complete remission in 6 and partial remission in 4 patients, lower CRP levels, decreased eosinophil counts with an inhibition of 92∼96 %, and tapered prednisolone dosages from 5 to 25 (13.0 ± 6.3) to 0-10 (3.3 ± 3.1) mg/day. Only one patient had an adverse event of injection site reactions. Nine patients received the same regimen for annual maintenance therapy. All had a persistent clinical remission. In these patients, 13-56 injections (41 ± 15) were prescribed with a follow-up period of 12∼52 months (38 ± 14)., Conclusion: In this retrospective study, induction therapy with a 12-month 100 mg MEP quadri-weekly subcutaneous injection regimen demonstrates the efficacy and safety for active and relapsing EGPA patients., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Ovarian aging is characterized by the accumulation of free radicals, leading to tissue damage and affecting reproductive health. Intravascular laser irradiation of blood (ILIB, using a low-energy He-Ne laser) is known for its efficacy in treating vascular-related diseases by reducing free radicals and inflammation. However, its impact on ovarian aging remains unexplored. This study aimed to investigate the effects of ILIB on oxidative stress and energy metabolism in aging ovaries., Methods: Genetic analysis was conducted on 75 infertile patients with aging ovaries, divided into ILIB-treated and control (CTRL) groups. Patients underwent two courses of laser treatment, and clinical parameters were evaluated. Cumulus cells were collected for the genetic analysis of oxeiptosis, glycolysis, and the tricarboxylic acid (TCA) cycle., Results: The analysis of gene expression patterns revealed intriguing findings in ILIB-treated patients compared to the untreated group. Notably, ILIB treatment resulted in significant upregulation of oxeiptosis-related genes AIFM1 and NRF2, suggesting a potential protective effect against oxidative stress-induced cell death. Furthermore, ILIB treatment led to a downregulation of glycolysis-associated gene hexokinase 2 (HK2), indicating a shift away from anaerobic metabolism, along with an increase in PDHA levels, indicative of enhanced mitochondrial function. Consistent with these changes, ILIB-treated patients exhibited elevated expression of the key TCA cycle genes citrate synthase (CS), succinate dehydrogenase complex subunit A (SDHA), and fumarate hydratase (FH), signifying improved energy metabolism., Conclusion: The findings from this study underscore the potential of ILIB as a therapeutic strategy for mitigating ovarian aging. By targeting oxidative stress and enhancing energy metabolism, ILIB holds promise for preserving ovarian function and reproductive health in aging individuals. Further research is warranted to elucidate the underlying mechanisms and optimize the application of ILIB in clinical settings, with the ultimate goal of improving fertility outcomes in women experiencing age-related ovarian decline.

Sepsis-induced acute kidney injury (AKI) is a common complication in patients with severe illness and leads to increased risks of mortality and chronic kidney disease. We investigated the association between monocyte distribution width (MDW), red-blood-cell volume distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), sepsis-related organ-failure assessment (SOFA) score, mean arterial pressure (MAP), and other risk factors and sepsis-induced AKI in patients presenting to the emergency department (ED). This retrospective study, spanning 1 January 2020, to 30 November 2020, was conducted at a university-affiliated teaching hospital. Patients meeting the Sepsis-2 consensus criteria upon presentation to our ED were categorized into sepsis-induced AKI and non-AKI groups. Clinical parameters (i.e., initial SOFA score and MAP) and laboratory markers (i.e., MDW, RDW, and NLR) were measured upon ED admission. A logistic regression model was developed, with sepsis-induced AKI as the dependent variable and laboratory parameters as independent variables. Three multivariable logistic regression models were constructed. In Model 1, MDW, initial SOFA score, and MAP exhibited significant associations with sepsis-induced AKI (area under the curve [AUC]: 0.728, 95% confidence interval [CI]: 0.668-0.789). In Model 2, RDW, initial SOFA score, and MAP were significantly correlated with sepsis-induced AKI (AUC: 0.712, 95% CI: 0.651-0.774). In Model 3, NLR, initial SOFA score, and MAP were significantly correlated with sepsis-induced AKI (AUC: 0.719, 95% CI: 0.658-0.780). Our novel models, integrating MDW, RDW, and NLR with initial SOFA score and MAP, can assist with the identification of sepsis-induced AKI among patients with sepsis presenting to the ED.

Goal : The early diagnosis and treatment of hepatitis is essential to reduce hepatitis-related liver function deterioration and mortality. One component of the widely-used Ishak grading system for the grading of periportal interface hepatitis is based on the percentage of portal borders infiltrated by lymphocytes. Thus, the accurate detection of lymphocyte-infiltrated periportal regions is critical in the diagnosis of hepatitis. However, the infiltrating lymphocytes usually result in the formation of ambiguous and highly-irregular portal boundaries, and thus identifying the infiltrated portal boundary regions precisely using automated methods is challenging. This study aims to develop a deep-learning-based automatic detection framework to assist diagnosis. Methods : The present study proposes a framework consisting of a Structurally-REfined Deep Portal Segmentation module and an Infiltrated Periportal Region Detection module based on heterogeneous infiltration features to accurately identify the infiltrated periportal regions in liver Whole Slide Images. Results : The proposed method achieves 0.725 in F1-score of lymphocyte-infiltrated periportal region detection. Moreover, the statistics of the ratio of the detected infiltrated portal boundary have high correlation to the Ishak grade (Spearman's correlations more than 0.87 with p-values less than 0.001) and medium correlation to the liver function index aspartate aminotransferase and alanine aminotransferase (Spearman's correlations more than 0.63 and 0.57 with p-values less than 0.001). Conclusions : The study shows the statistics of the ratio of infiltrated portal boundary have correlation to the Ishak grade and liver function index. The proposed framework provides pathologists with a useful and reliable tool for hepatitis diagnosis., Competing Interests: VI.No conflict of interest., (© 2024 The Authors.)

Ground glass hepatocytes (GGHs) have been associated with hepatocellular carcinoma (HCC) recurrence and poor prognosis. We previously demonstrated that pre-S expression in some GGHs is resistant to current hepatitis B virus (HBV) antiviral therapies. This study aimed to investigate whether integrated HBV DNA (iDNA) is the primary HBV DNA species responsible for sustained pre-S expression in GGH after effective antiviral therapy. We characterized 10 sets of micro-dissected, formalin-fixed-paraffin-embedded, and frozen GGH, HCC, and adjacent hepatitis B surface antigen-negative stained tissues for iDNA, pre-S deletions, and the quantity of covalently closed circular DNA. Eight patients had detectable pre-S deletions, and nine had detectable iDNA. Interestingly, eight patients had integrations within the TERT and CCNE1 genes, which are known recurrent integration sites associated with HCC. Furthermore, we observed a recurrent integration in the ABCC13 gene. Additionally, we identified variations in the type and quantity of pre-S deletions within individual sets of tissues by junction-specific PacBio long-read sequencing. The data from long-read sequencing indicate that some pre-S deletions were acquired following the integration events. Our findings demonstrate that iDNA exists in GGH and can be responsible for sustained pre-S expression in GGH after effective antiviral therapy., (© 2024 Wiley Periodicals LLC.)

Objectives: To compare the intraoperative and postoperative outcomes of sublabial excision and transnasal endoscopic marsupialization, the two primary surgical approaches for nasolabial cysts., Design and Setting: A comprehensive meta-analysis of studies identified from PubMed, Embase, and the Cochrane Library., Participants: Patients diagnosed with nasolabial cysts who underwent surgical treatment., Main Outcome Measures: Operative time, postoperative pain, overall postoperative complications, admission rate, length of hospital stay, use of general anaesthesia, medical costs, and recurrence rate., Results: The pooled analysis revealed that the transnasal endoscopic marsupialization group had shorter operative time (mean differences [MD], -32.51; 95% confidence interval [CI], -38.52 to -26.51), reduced postoperative pain (MD, -4.25; 95% CI, -7.62 to -0.89), fewer overall postoperative complications (risk difference [RD], -0.68; 95% CI, -0.90 to -0.46), lower admission rates (RD, -0.86; 95% CI, -1.11 to -0.61), shorter hospital stays (MD, -1.74; 95% CI, -2.58 to -0.89), decreased use of general anaesthesia (RD, -0.40; 95% CI, -0.76 to -0.03), and reduced medical costs (MD, -229.69; 95% CI, -338.64 to -120.75). The recurrence rate between the two groups showed no significant difference (RD, -0.01; 95% CI, -0.05 to 0.04)., Conclusion: Transnasal endoscopic marsupialization presents as a promising alternative to sublabial excision in the treatment of nasolabial cysts. It offers advantages like reduced operative time, decreased postoperative pain, fewer complications, lower admission rates, shorter hospital stays, diminished need for general anaesthesia, and cost savings. Clinicians can leverage these findings to select the most suitable surgical approach for their patients., (© 2023 John Wiley & Sons Ltd.)

Background: The Wnt/β-catenin signaling pathway plays an important role in embryogenesis and tumorigenesis. In human cancer, abnormal activity of Wnt/β-catenin signaling pathway induces overexpressed of downstream genes, and initiate oncogene. There are several target genes known to be key players in tumorigenesis, such as c-myc, cyclin D1, MMPs or survivin. Therefore, identifying the target genes of Wnt/β-catenin signaling pathway is important to understanding Wnt/β-catenin-mediated carcinogenesis. In this study, we developed a combined bioinformatics and experimental approach to find potential target genes., Methods: Luciferase reporter assay was used to analyze the promoter activity of RMI2. WST1 cell proliferation assays and transwell assays were performed to determine the proliferation and migration capacities of RMI2 overexpressing or knockdown stable hepatic cells. Finally, xenograft experiments were performed to measure the tumor formation capacity in vivo., Results: The results showed that RMI2 mRNA was upregulated after LiCl treatment and Wnt3a-conditioned medium in a culture of SK-hep-1 cell lines. A chromatin immunoprecipitation (ChIP) assay showed that the β-catenin/T cell-specific factor (TCF) complex binds to the putative TCF binding site of the RMI2 promoter. We then found a TCF binding site at - 333/- 326 of the RMI2 promoter, which is crucial for β-catenin responsiveness in liver cell lines. RMI2 was overexpressed in hepatoma tissue and cell lines, and it promoted the migration and invasion of HCC cells. Moreover, RMI2 upregulated the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt3a/β-catenin-related genes, but silencing RMI2 had the opposite effects. Notably, the expression of RMI2 was positively correlated with the clinical data of HCC patients who had significantly shorter overall survival (OS) and disease-free survival (DFS) (Both: P < 0.05). In addition, a total of 373 HCC patients' data from the Caner Genome Atlas project (TCGA) were used to validate our findings., Conclusions: Taking all these findings together, we determined that RMI2 was a new target gene of the Wnt/β-catenin signaling pathway. We also found that RMI2 promotes EMT markers, HCC cell invasion, and metastasis, which indicated that RMI2 is a potential target for preventing or at least mitigating the progression of HCC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In this work, luminescent carbon dots with gardenia seeds as carbon precursors (GCDs) were synthesized using a one-step mild pyrolysis process and were then used as probes for imaging of bacterial ( Escherichia coli ). The GCDs showed a strong emission at 430 nm when excited at 370 nm. The relative fluorescence quantum yield of GCDs was found to be 1.13% in an aqueous medium. Rapid internalization of the GCDs by bacteria was confirmed by three colors (blue, green, and yellow) images that were obtained using confocal fluorescence microscopy. In addition, GCDs were noted to exhibit potent scavenging activities against DPPH˙, ˙OH, and ˙O 2 - free radicals. GCDs were also assayed as antioxidants in an oil sample by volumetric determination of the peroxide value. Thus, GCDs exhibited good antioxidant properties both in aqueous and oil media. In addition, a free fatty acid quantification kit in the presence of GCDs showed enhanced fluorescence detection of palmitic acid with a remarkably good limit of detection of 0.08 μM, which is lower than that in the absence of GCDs (0.76 μM). The proposed fluorescence method was then successfully used to determine the concentration of palmitic acid spiked in milk powder samples, with spiked recoveries of 82.6-109.6% and relative standard deviations of 0.9-4.6%., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The COVID-19 pandemic has caused millions of people to become infected worldwide. Some patients may have disease progression and may need treatment with an anti-COVID-19 agent, hospitalization, and even intensive care. The risk factors for disease progression include old age, diabetes mellitus, pulmonary disease, cardiac disease, immunodeficiency, and immunosuppressant treatment. Therefore, managing COVID-19 infection in transplant patients under immunosuppressant treatments needs specific consideration, especially the side effects of anti-COVID-19 agents and the interaction between immunosuppressants and anti-COVID-19 agents. In this report, we present the case of a small bowel transplant patient who had a COVID-19 infection. The patient was initially treated for paxlovid, and she developed bloody stools and dizziness. The treatment was then changed to molnupiravir without discontinuation of tacrolimus. The patient recovered smoothly after a 5-day treatment with molnupiravir. Here, we discuss the management experience of such patients and review the relevant literature., 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., (Copyright © 2023. Published by Elsevier Inc.)

Background: Dysregulated long noncoding RNA (lncRNA) expression with increased apoptosis has been demonstrated in systemic lupus erythematosus (SLE) patients with alveolar hemorrhage (AH). SNHG16, a lncRNA, can enhance pulmonary inflammation by sponging microRNAs, and upregulate toll-like receptor 4 (TLR4) expression via stabilizing its mRNAs. TRAF6, a TLR4 downstream signal transducer, can induce autophagy and NETosis formation. In this study, we investigated whether SNHG16 could regulate TLR4-mediated autophagy and NETosis formation in SLE-associated AH., Methods: Expression of SNHG16, TLR4 and TRAF6 and cell death processes were examined in lung tissues and peripheral blood (PB) leukocytes from AH patients associated with SLE and other autoimmune diseases, and in the lungs and spleen from a pristane-induced C57BL/6 mouse AH model. SNHG16-overexpressed or -silenced alveolar and myelocytic cells were stimulated with lipopolysaccharide (LPS), a TLR4 agonist, for analyzing autophagy and NETosis, respectively. Pristane-injected mice received the intra-pulmonary delivery of lentivirus (LV)-SNHG16 for overexpression and prophylactic/therapeutic infusion of short hairpin RNA (shRNA) targeting SNHG16 to evaluate the effects on AH. Renal SNHG16 expression was also examined in lupus nephritis (LN) patients and a pristane-induced BALB/c mouse LN model., Results: Up-regulated SNHG16, TLR4 and TRAF6 expression with increased autophagy and NETosis was demonstrated in the SLE-AH lungs. In such patients, up-regulated SNHG16, TLR4 and TRAF6 expression was found in PB mononuclear cells with increased autophagy and in PB neutrophils with increased NETosis. There were up-regulated TLR4 expression and increased LPS-induced autophagy and NETosis in SNHG16-overexpressed cells, while down-regulated TLR4 expression and decreased LPS-induced autophagy and NETosis in SNHG16-silenced cells. Pristane-injected lung tissues had up-regulated SNHG16, TLR4/TRAF6 levels and increased in situ autophagy and NETosis formation. Intra-pulmonary LV-SNHG16 delivery enhanced AH through up-regulating TLR4/TRAF6 expression with increased cell death processes, while intra-pulmonary prophylactic and early therapeutic sh-SNHG16 delivery suppressed AH by down-regulating TLR4/TRAF6 expression with reduced such processes. In addition, there was decreased renal SNHG16 expression in LN patients and mice., Conclusions: Our results demonstrate that lncRNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in the human and mouse AH lungs, and provide a therapeutic potential of intra-pulmonary delivery of shRNA targeting SNHG16 in this SLE-related lethal manifestation., (© 2023. National Science Council of the Republic of China (Taiwan).)

Background: Protein phosphatase 2A (PP2A) is one of the major protein phosphatases in eukaryotic cells and is essential for cellular homeostasis. PP2A is a heterotrimer comprising the dimeric AC core enzyme and a highly variable regulatory B subunit. Distinct B subunits help the core enzyme gain full activity toward specific substrates and contribute to diverse cellular roles of PP2A. PP2A has been thought to play a tumor suppressor and the B56γ3 regulatory subunit was shown to play a key tumor suppressor regulatory subunit of PP2A. Nevertheless, we uncovered a molecular mechanism of how B56γ3 may act as an oncogene in colorectal cancer (CRC)., Methods: Polyclonal pools of CRC cells with stable B56γ3 overexpression or knockdown were generated by retroviral or lentiviral infection and subsequent drug selection. Co-immunoprecipitation(co-IP) and in vitro pull-down analysis were applied to analyze the protein-protein interaction. Transwell migration and invasion assays were applied to investigate the role of B56γ3 in affecting motility and invasive capability of CRC cells. The sensitivity of CRC cells to 5-fluorouracil (5-FU) was analyzed using the PrestoBlue reagent assay for cell viability. Immunohistochemistry (IHC) was applied to investigate the expression levels of phospho-AKT and B56γ3 in paired tumor and normal tissue specimens of CRC. DataSets of TCGA and GEO were analyzed to investigate the correlation of B56γ3 expression with overall survival rates of CRC patients., Results: We showed that B56γ3 promoted epithelial-mesenchymal transition (EMT) and reduced the sensitivity of CRC cells to 5-FU through upregulating AKT activity. Mechanistically, B56γ3 upregulates AKT activity by targeting PP2A to attenuate the p70S6K-mediated negative feedback loop regulation on PI3K/AKT activation. B56γ3 was highly expressed and positively correlated with the level of phospho-AKT in tumor tissues of CRC. Moreover, high B56γ3 expression is associated with poor prognosis of a subset of patients with CRC., Conclusions: Our finding reveals that the B56γ3 regulatory subunit-containing PP2A plays an oncogenic role in CRC cells by sustaining AKT activation through suppressing p70S6K activity and suggests that the interaction between B56γ3 and p70S6K may serve as a therapeutic target for CRC. Video Abstract., (© 2023. The Author(s).)

Background: The aim of our study was to provide real-world data on outcomes for elderly Taiwanese patients who underwent transcatheter aortic valve replacement or surgical aortic valve replacement in different risk groups., Methods: From March 2011 through December 2021, 177 patients with severe aortic stenosis who were ≥70 years old and had undergone TAVI (transcatheter aortic valve implantation) or SAVR (surgical aortic valve replacement) in a single center were divided by STS score (<4%, 4-8% and >8%) into three different groups. Then, we compared their clinical characteristics, operative complications, and all-cause mortality., Results: In all risk groups, there were no significant differences in in-hospital mortality, or 1-year and 5-year mortality between patients in the TAVI and SAVR groups. In all risk groups, patients in the TAVI group had shorter hospital stay and higher rate of paravalvular leakage than the SAVR group. After univariate analysis, BMI (body mass index) < 20 was a risk factor for higher 1-year and 5-year mortality. In the multivariate analysis, acute kidney injury was an independent factor for predicting worse outcomes in terms of 1-year and 5-year mortality., Conclusions: Taiwan elderly patients in all risk groups did not have significant differences in mortality rates between the TAVI and the SAVR group. However, the TAVI group had shorter hospital stay and higher rate of paravalvular leakage in all risk groups.

Background/purpose: Periodical replacement of venous Hickman catheters is required for the nutritional care of patients with intestinal failure. The conventional de novo operation (DN-OP) involves inserting the catheter into a new venous tract in each replacement; however, this could result in fast consumption of functional central vessels in patients with intestinal failure. Recently, same-route operation (SR-OP) has been adopted as an alternative approach for retaining venous access., Methods: We conducted a retrospective study to compare the efficacy of Hickman catheters and the survival of venous vessels using two different operative strategies., Results: Overall, 181 catheters were inserted, 109 using DN-OP and 72 using SR-OP. The mean catheter duration was 11.9 ± 8.8 months in the DN-OP group and 10.5 ± 5.6 months in the SR-OP group; the infection rate was 0.74 in the DN-OP group and 0.44 in the SR-OP group. The vein accesses used in these insertions (n = 113) were classified: the DN-vein group for veins accessed only by DN-OP (n = 75) and the SR-vein group for veins accessed by an initial DN-OP and subsequent SR-OPs (n = 38). Mean working duration per vein access was 12.3 ± 10.1 months in the DN-vein group and 28.2 ± 14.8 months in the SR-vein group (p < 0.001); mean infection-free duration was 11.4 ± 10.1 months in the DN-vein group and 27.7 ± 15.3 months in the SR-vein group (p < 0.001)., Conclusion: Application of SR-OP in Hickman catheter replacement significantly extended the working duration of venous access by re-using the same venous route without compromising catheter efficacy in patients with IF having poor venous access., Competing Interests: Conflict of interest The authors have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier B.V.)

Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18-encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the Wnt-DVL3-β-catenin signaling axis. Functional studies verified that the ASPM-I1-regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1-mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target., Significance: ASPM promotes SCLC stemness and aggressiveness by stabilizing the expression of GLI1, DVL3, and SMO, representing a novel regulatory hub of Hh and Wnt signaling and targetable vulnerability., (©2023 American Association for Cancer Research.)

Background: Hepatocellular carcinoma (HCC) accounts for almost 80% of all liver cancer cases and is the sixth most common cancer and the second most common cause of cancer-related death worldwide. The survival rate of sorafenib-treated advanced HCC patients is still unsatisfactory. Unfortunately, no useful biomarkers have been verified to predict sorafenib efficacy in HCC., Results: We assessed a sorafenib resistance-related microarray dataset and found that anterior gradient 2 (AGR2) is highly associated with overall and recurrence-free survival and with several clinical parameters in HCC. However, the mechanisms underlying the role of AGR2 in sorafenib resistance and HCC progression remain unknown. We found that sorafenib induces AGR2 secretion via posttranslational modification and that AGR2 plays a critical role in sorafenib-regulated cell viability and endoplasmic reticulum (ER) stress and induces apoptosis in sorafenib-sensitive cells. In sorafenib-sensitive cells, sorafenib downregulates intracellular AGR2 and conversely induces AGR2 secretion, which suppresses its regulation of ER stress and cell survival. In contrast, AGR2 is highly intracellularly expressed in sorafenib-resistant cells, which supports ER homeostasis and cell survival. We suggest that AGR2 regulates ER stress to influence HCC progression and sorafenib resistance., Conclusions: This is the first study to report that AGR2 can modulate ER homeostasis via the IRE1α-XBP1 cascade to regulate HCC progression and sorafenib resistance. Elucidation of the predictive value of AGR2 and its molecular and cellular mechanisms in sorafenib resistance could provide additional options for HCC treatment., (© 2023. The Author(s).)

Urine-based cytology is non-invasive and widely used for clinical diagnosis of urothelial carcinoma (UC), but its sensitivity is less than 40% for low-grade UC detection. As such, there is a need for new diagnostic and prognostic biomarkers of UC. CUB domain containing protein 1 (CDCP1) is a type I transmembrane glycoprotein highly expressed in various cancers. Using tissue array analysis, we demonstrated that CDCP1 expression in UC patients (n = 133), especially in those with low-grade UC, was significantly higher than in 16 normal persons. In addition, CDCP1 expression in urinary UC cells could also be detected by using immunocytochemistry method (n = 11). Furthermore, in 5637-CD cells, overexpression of CDCP1 affected the expression of epithelial mesenchymal transition-related markers and increased matrix metalloproteinase 2 expression and migration ability. Conversely, the knockdown of CDCP1 in T24 cells had the opposite effects. Using specific inhibitors, we demonstrated the involvement of c-Src/PKCδ signaling in the CDCP1-regulated migration of UC. In conclusion, our data suggest that CDCP1 contributes to the malignant progression of UC and may have the potential as a urine-based biomarker for detecting low-grade UC. However, a cohort study needs to be conducted., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Seronegative spondyloarthropathy (SpA) usually starts in the third decade of life with negative rheumatoid factor, human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis, dactylitis, enthesitis and extra-articular manifestations (EAMs). Cases can be classified as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, or juvenile-onset spondyloarthritis. Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease (IBD), with shared genetic and immunopathogenic mechanisms. IBD is a common EAM in SpA patients, while extraintestinal manifestations in IBD patients mostly affect the joints. Although individual protocols are available for the management of each disease, the standard therapeutic guidelines of SpA-associated IBD patients remain to be established. Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA, whereas their use is controversial in IBD due to associated disease flares. Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy. Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD, and a drug of choice for treating SpA-associated IBD. Janus kinase inhibitors, approved for treating SpA and ulcerative colitis, are promising therapeutics in SpA coexistent with ulcerative colitis. A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: The cervicovaginal microbiota is essential for maintaining the health of the female reproductive tract. However, whether cervicovaginal microbiota status prior to frozen embryo transfer (FET) associates with pregnancy outcomes is largely unexplored., Methods: Cervical mucus from 29 women who had undergone FET was collected. Microbial composition was analyzed using 16 S rRNA gene sequence to assess the correlation to the pregnancy outcomes., Results: CST-categorized Lactobacillus was the most dominant (41.71%) in the pregnant group, while CST-IV-based and BV-related Gardnerella (34.96%) prevailed in the non-pregnant group. The average abundance of Gardnerella compared non-pregnant to pregnant women was the highest (34.96% vs. 4.22%, p  = 0.0015) among other CST-IV indicator bacteria. Multivariate analysis revealed that CST-IV-related bacteria have a significantly adverse effect on ongoing pregnancy outcomes (odds ratio, 0.083; 95% confidence index, 0.012-0.589, p  = 0.013*)., Conclusions: The study found that the CST-IV microbiota, with significantly increasing Gardnerella and the loss of Lactobacilli as the dominant bacteria, can potentially contribute to pregnancy failure. Therefore, dysbiotic microbiota may be a risk factor in women undergoing FET. Assessing the health of the cervicovaginal microbiota prior to FET would enable couples to make a more thoughtful decision on the timing and might improve pregnancy outcomes., Competing Interests: The authors declare no conflicts of interest related to the subject matter or materials discussed in this article., (© 2023 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Hepatocellular carcinoma (HCC) is among the most prevalent visceral neoplasms. So far, reliable biomarkers for predicting HCC recurrence in patients undergoing surgery are far from adequate. In the aim of searching for genetic biomarkers involved in HCC development, we performed analyses of cDNA microarrays and found that the DNA repair gene NEIL3 was remarkably overexpressed in tumors. NEIL3 belongs to the Fpg/Nei protein superfamily, which contains DNA glycosylase activity required for the base excision repair for DNA lesions. Notably, the other Fpg/Nei family proteins NEIL1 and NEIL2, which have the same glycosylase activity as NEIL3, were not elevated in HCC; NEIL3 was specifically induced to participate in HCC development independently of its glycosylase activity. Using RNA-seq and invasion/migration assays, we found that NEIL3 elevated the expression of epithelial-mesenchymal transition (EMT) factors, including the E/N-cadherin switch and the transcription of MMP genes, and promoted the invasion, migration, and stemness phenotypes of HCC cells. Moreover, NEIL3 directly interacted with the key EMT player TWIST1 to enhance invasion and migration activities. In mouse orthotopic HCC studies, NEIL3 overexpression also caused a prominent E-cadherin decrease, tumor volume increase, and lung metastasis, indicating that NEIL3 led to EMT and tumor metastasis in mice. We further found that NEIL3 induced the transcription of MDR1 (ABCB1) and BRAF genes through the canonical E-box (CANNTG) promoter region, which the TWIST1 transcription factor recognizes and binds to, leading to the BRAF/MEK/ERK pathway-mediated cell proliferation as well as anti-cancer drug resistance, respectively. In the HCC cohort, the tumor NEIL3 level demonstrated a high positive correlation with disease-free and overall survival after surgery. In conclusion, NEIL3 activated the BRAF/MEK/ERK/TWIST pathway-mediated EMT and therapeutic resistances, leading to HCC progression. Targeted inhibition of NEIL3 in HCC individuals with NEIL3 induction is a promising therapeutic approach. © 2022 The Pathological Society of Great Britain and Ireland., (© 2022 The Pathological Society of Great Britain and Ireland.)

Objective: Characterize and quantify epithelium in multiple etiologies of laryngotracheal stenosis (LTS) to better understand its role in pathogenesis., Study Design: Controlled in vitro cohort study., Methods: Endoscopic brush biopsy samples of both normal (non-scar) and scar were obtained in four patients with idiopathic subglottic stenosis (iSGS) and four patients with iatrogenic LTS (iLTS). mRNA expression of basal, ciliary, and secretory cell markers were evaluated using quantitative PCR. Cricotracheal resection tissue samples (n = 5 per group) were also collected, analyzed using quantitative immunohistochemistry, and compared with rapid autopsy tracheal samples., Results: Both iSGS and iLTS-scar epithelium had reduced epithelial thickness compared with non-scar control epithelium (P = .0009 and P = .0011, respectively). Basal cell gene and protein expression for cytokeratin 14 was increased in iSGS-scar epithelium compared with iLTS or controls. Immunohistochemical expression of ciliary tubulin alpha 1, but not gene expression, was reduced in both iSGS and iLTS-scar epithelium compared with controls (P = .0184 and P = .0125, respectively). Both iSGS and iLTS-scar had reductions in Mucin 5AC gene expression (P = .0007 and P = .0035, respectively), an epithelial goblet cell marker, with reductions in secretory cells histologically (P < .0001)., Conclusions: Compared with non-scar epithelium, the epithelium within iSGS and iLTS is morphologically abnormal. Although both iSGS and iLTS have reduced epithelial thickness, ciliary cells, and secretory cells, only iSGS had significant increases in pathological basal cell expression. These data suggest that the epithelium in iSGS and iLTS play a common role in the pathogenesis of fibrosis in these two etiologies of laryngotracheal stenosis., Setting: Tertiary referral center (2017-2020)., Level of Evidence: NA Laryngoscope, 132:2194-2201, 2022., (© 2022 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

The outcomes for patients with NASH-related HCC after curative resection have not been clarified. This study compared the overall survival (OS), time-to-tumor recurrence (TTR), and recurrence-free survival (RFS) associated with NASH-related HCC and virus-related HCC after resection. Methods: Patients with HCC who underwent curative resection were retrospectively enrolled. Baseline characteristics, including disease etiologies and clinical and tumor features, were reviewed. The primary outcomes were OS, TTR, and RFS. Results: Two hundred and six patients were enrolled (HBV: n = 121, HCV: n = 54, NASH: n = 31). Of those with virus-related HCC, 84.0% achieved viral suppression. In both the overall and propensity-score-matched cohorts, those with NASH-related HCC experienced recurrence significantly earlier than those with virus-related HCC (median TTR: 1108 days vs. non-reached; p = 0.03). Through multivariate analysis, NASH-related HCC (hazard ratio (HR), 2.27; 95% confidence interval (CI), 1.25-4.12) was independently associated with early recurrence. The unadjusted RFS rate of the NASH-related HCC group was lower than the virus-related HCC group. There was no difference in the OS between the two groups. Conclusions: NASH-related HCC was associated with earlier tumor recurrence following curative resection compared to virus-related HCC. Post-surgical surveillance is crucial for detecting early recurrence in patients with NASH-related HCC.

Objective: Tapered low-volume, low-pressure (LVLP) cuffs have been introduced to improve sealing and reduce injury from tracheostomy and endotracheal intubation compared to traditional cylindrical high-volume, low-pressure (HVLP) cuffs. The objective of this study is to develop a swine model of tracheostomy injury and to compare live tissue response following LVLP and HVLP tracheostomy placement., Study Design: In vivo animal study., Setting: Academic institution., Methods: Swine underwent tracheostomy followed by placement of LVLP and HVLP tracheostomy cuffs at 30 cm H 2 O. After 24 and 48 hours, tracheal specimens underwent histopathological analysis including cilia, lamina propria and epithelial thickness, and mucosal injury score., Results: In all cuff contact areas, mean epithelial thickness for both tracheostomy cohorts was decreased compared to control epithelium at 24 and 48 hours ( P < .01). HVLP proximal epithelium thickness was decreased at 24 and 48 hours relative to LVLP sections ( P < .05). Lamina propria thickness in proximal LVLP sections was less than HVLP sections at 24 hours and 48 hours ( P < .05). Mucosal injury score at areas of cuff contact was increased in tracheostomy cohorts relative to controls ( P < .001), with HVLP injury score greater than LVLP at the proximal cuff ( P < .05)., Conclusion: In a swine model, tracheostomy resulted in increased mucosal injury compared to normal tracheal mucosa. LVLP cuffs resulted in less injury than HVLP cuffs, with reduced mucosal inflammation and improved health of epithelium and lamina propria. The wider proximal LVLP cuff demonstrated improved mucosal health compared to the HVLP cylindrical cuff.

Background and Aims: Limited data are available for tumor immune microenvironment (TIME) in Epstein-Barr virus (EBV)-associated lymphoepithelioma-like cholangiocarcinoma (EBV-LELCC), a rare subtype of intrahepatic cholangiocarcinoma (IHCC). We aimed to investigate TIME features in EBV-LELCC and the correlation between the components of TIME and the clinical outcomes., Methods: Tumor tissues from five EBV-LELCC cases confirmed through EBER in situ hybridization and five stage-matched conventional IHCC (non-EBV IHCC) cases were collected. These samples were used to evaluate genetic alterations, TIME composition, and PD-L1 expression through ion AmpliSeq comprehensive cancer panel, PanCancer immune profiling panel, immunohistochemistry, and immunofluorescence staining. The correlation between clinical outcomes and TIME components was analyzed in the two EBV-LELCC cases receiving anti-PD-1 treatment., Results: The genetic mutations identified in EBV-LELCC were BARD1, CD19, CD79B, EPHA5, KDM5A, MUC6, MUC16, PTEN, RECQL4, TET1, and TNFAIP3. Both CD79B and TNFAIP3 mutations were involved in the NF-κB signaling pathway. PD-L1 was highly expressed in tumor-infiltrating immune cells, especially the T cells and macrophages. The TIME of EBV-LELCC displayed abundant immune cell infiltration with a stronger adaptive immune response. Increased Th1 cells, NK CD56 dim cells, and M1 macrophages, decreased M2 macrophages, exhausted CD8 T cell infiltration, and increased T cell activation signatures in TIME were associated with longer survival. Two patients with metastatic EBV-LELCC had good disease control after anti-PD-1 antibody treatment. A significantly larger TIME component made EBV-LELCCs more sensitive to immune checkpoint blockade (ICB)., Conclusion: A better understanding of the composition of TIME in EBV-LELCC is critical for predicting the clinical outcomes of ICB treatment., (© 2022. Asian Pacific Association for the Study of the Liver.)

Following a previously published paper in studying stone-skipping processes, detailed experimental figures are revealed in this paper. A mathematical model is also provided to explain the observed phenomena and measured data. The model separates the skipping process into several stages. It emphasizes, in particular, a hitting stage and a sliding stage, and also includes capillary-gravity wave resistance in its formulation. During these two stages, scale analysis is applied first to evaluate the relative importance among various forces acting on the stone. After reasonable simplification, a numerical algorithm is established to depict motion of the stone starting from its first hit of water to final sink. The total number of skips under specified initial throwing conditions can be predicted accordingly. The agreement between the analytical and experimental results indicates the applicability of the proposed model., (© 2022. The Author(s).)

Background: Artificial oocyte activation (AOA) is used to improve fertilization rate following fertilization failure after intracytoplasmic sperm injection (ICSI). Several studies have also shown that AOA may be involved in embryo development. Women with poor ovarian response are more likely to encounter in vitro fertilization (IVF) failure due to poor embryo quality. The aim of this study was to investigate whether AOA could improve embryo quality in older patients with diminished ovarian reserve undergoing IVF-ICSI cycles., Methods: The retrospective cohort study consisted of 308 patients who fulfilled the POSEIDON Group 4 criteria and received IVF-ICSI cycles. The study group included 91 patients receiving AOA with calcium ionophores following ICSI. A total of 168 patients in the control group underwent ICSI without AOA. The baseline and cycle characteristics and embryo quality were compared between the two groups., Results: At baseline, there were more IVF attempts, greater primary infertility, higher basal FSH levels and lower anti-Müllerian hormone (AMH) levels in the AOA group than in the non-AOA group. In terms of embryo quality, there were higher cleavage rates and top-quality Day 3 embryo (TQE) rates, as well as higher percentages of more than 1 TQE and TQE rates ≥50 in the AOA group than in the non-AOA group. The multivariate analysis revealed that AOA was positively associated with more than 1 TQE (adjusted OR 3.24, 95% CI 1.63-6.45, P = 0.001) and a TQE rate ≥ 50 (adjusted OR 2.14, 95% CI 1.20-3.80, P = 0.010). When the study population was divided into 2 subgroups based on the age of 40 years old, the beneficial effects of AOA on embryo quality were only observed in the subgroup of age ≥ 40 years old., Conclusions: Our data suggest that AOA with calcium ionophores may improve embryo quality in older patients with diminished ovarian reserve undergoing IVF-ICSI cycles, especially in women aged ≥40 years., (© 2022. The Author(s).)

Objectives: To evaluate the effectiveness of a question prompt list (QPL) in decision self-efficacy, decision-making participation, patient-physician communication, decisional conflict or regret, and health status in patients with breast cancer., Methods: A total of 240 patients with breast cancer were randomly assigned to a QPL group or control group (n = 120 each). The intervention and control groups received an additional educational QPL booklet and routine care, respectively., Results: The intervention group exhibited significant improvements in decision self-efficacy, perceived patient-physician interactions, and patient-physician communication compared with the control group. Multilevel modeling analyses revealed significant group-time interaction effects on decision self-efficacy (β = 9.99, P < 0.01), perceived patient-physician interactions (β = 8.10, P < 0.01), patient-physician communication (β = 5.02, P < 0.01), and anxiety status (β = -3.78, P < 0.05). The QPL intervention exerted more favorable effects than routine care, with repeated measurements of the same patients and the data of patients under the care of the same surgeons accounted for., Conclusions: The QPL intervention exerted multidimensional effects on decision-making outcomes among patients with breast cancer., Practical Implications: Clinicians can integrate a QPL into routine care for patients with breast cancer., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: To investigate the association between increased monocyte distribution width (MDW) and pediatric sepsis in the emergency department (ED)., Design: Retrospective cohort study., Setting: A single academic hospital study., Patients: Patients from birth to the age of 18 years who presented at the ED of an academic hospital with systemic inflammatory response syndrome (SIRS) were consecutively enrolled. Sepsis was diagnosed using the International Pediatric Surviving Sepsis Campaign criteria., Interventions: Antibiotic treatment was administrated once infection was suspected., Measurements and Main Results: Routine complete blood cell count, neutrophil-to-lymphocyte ratio (NLR), and MDW, a new inflammatory biomarker, were evaluated in the ED. Logistic regression models were used to explore associations with early pediatric sepsis. We included 201 patients with sepsis and 1,050 without sepsis. In the multivariable model, MDW greater than 23 U (odds ratio [OR], 4.97; 95% CI, 3.42-7.22; p < 0.0001), NLR greater than 6 (OR, 2.06; 95% CI, 1.43-2.94; p = 0.0001), WBC greater than 11,000 cells/µL (OR, 6.52; 95% CI, 4.45-9.53; p < 0.0001), and the SIRS score (OR, 3.42; 95% CI, 2.57-4.55; p < 0.0001) were associated with pediatric sepsis. In subgroup analysis, MDW greater than 23 U remained significantly associated with sepsis for children 6-12 years old (OR, 6.76; 95% CI, 2.60-17.57; p = 0.0001) and 13-18 years (OR, 17.49; 95% CI, 7.69-39.76; p = 0.0001) with an area under the receiver operating curve of 0.8-0.9., Conclusions: MDW greater than 23 U at presentation is associated with the early diagnosis of sepsis in children greater than or equal to 6 years old. This parameter should be considered as a stratification variable in studies of pediatric sepsis., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Increasing evidences have suggested an important role of microRNAs (miRNAs) in regulating cell death processes including NETosis and apoptosis. Dysregulated expression of miRNAs and increased formation of neutrophil extracellular traps (NETs) and apoptosis participate in autoimmune-mediated diffuse alveolar hemorrhage (DAH), mostly associated with pulmonary capillaritis in systemic lupus erythematosus (SLE) patients. In particular, besides the inhibition of apoptosis, miR-146a can control innate and acquired immune responses, and regulate the toll-like receptor pathway through targeting TRAF6 to reduce the expression of pro-inflammatory cytokines/chemokines like IL-8, a NETosis inducer., Methods: Expression of miR-146a, TRAF6 and NETs were examined in peripheral blood neutrophils (PBNs) and lung tissues from SLE-associated DAH patients, and in neutrophils and pristane-induced DAH lung tissues from C57BL/6 mice. To assess NETs formation, we examined NETosis-related DNAs morphology and crucial mediators including protein arginine deiminase 4 and citrullinated Histone 3. Expression of miR-146a and its endogenous RNA SNHG16 were studied in HL-60 promyelocytic cells and MLE-12 alveolar cells during NETosis and apoptosis processes, respectively. MiR-146a-overexpressed and CRISPR-Cas13d-mediated SNHG16-silenced HL-60 cells were investigated for NETosis. MiR-146a-overexpressed MLE-12 cells were analyzed for apoptosis. Pristane-injected mice received intra-pulmonary miR-146a delivery to evaluate therapeutic efficacy in DAH., Results: In DAH patients, there were down-regulated miR-146a levels with increased TRAF6 expression and PMA/LPS-induced NETosis in PBNs, and down-regulated miR-146a levels with increased TRAF6, high-mobility group box 1 (HMGB1), IL-8, NETs and apoptosis expression in lung tissues. HMGB1-stimulated mouse neutrophils had down-regulated miR-146a levels with increased TRAF6, IL-8 and NETs expression. PMA-stimulated HL-60 cells had down-regulated miR-146a levels with enhanced NETosis. MiR-146a-overexpressed or SNHG16-silenced HL-60 cells showed reduced NETosis. Apoptotic MLE-12 cells had down-regulated miR-146a expression and increased HMGB1 release, while miR-146a-overexpressed MLE-12 cells showed reduced apoptosis and HMGB1 production. There were down-regulated miR-146a levels with increased TRAF6, HMGB1, IL-8, NETs and apoptosis expression in mouse DAH lung tissues. Intra-pulmonary miR-146a delivery could suppress DAH by reducing TRAF6, IL-8, NETs and apoptosis expression., Conclusions: Our results demonstrate firstly down-regulated pulmonary miR-146a levels with increased TRAF6 and IL-8 expression and NETs and apoptosis formation in autoimmune-mediated DAH, and implicate a therapeutic potential of intra-pulmonary miR-146a delivery., (© 2022. The Author(s).)

Significant enhancement of segment-scale chirality, as measured by vibrational circular dichroism (VCD), is observed in the helical phase (H*) of polylactide-based chiral block copolymers (BCPs*) due to the mesoscale chirality of the microphase-separated domains. Here, we report a weaker, yet meaningful, enhancement on the VCD signal of a double gyroid phase (DG) as compared to a double diamond phase (DD) and disordered phase from the same diblock BCPs*. Residual VCD enhancement indicates a weak degree of chiral symmetry breaking, implying the formation of a chiral double gyroid (DG*) instead of the canonical achiral form. Calculations on the basis of orientational self-consistent field theory, comparing coupling between the segmental-scale preference of an intradomain twist and morphological chirality, show that a transition between DG and DG* takes place above the critical chiral strength, driving a weak volume asymmetry between the two enantiomeric single networks of DG*. The formation of nanostructures with controllable mesoscale chiral asymmetry indicates a pathway for the amplification of optical activity driven by self-assembly.

Acute rheumatic fever (ARF) is considered as a disorder of children, and attacks in adults are usually a recurrence of disease acquired in the child's life. Although the incidence of ARF in children has a decreasing trend in developed countries, resurgent and sporadic epidemics still occur in adults. The first attacks of ARF in adult patients without a childhood history can lead to a diagnostic dilemma. A medical record review in adults at least 18 years of age with an arthralgia complaint fulfilling 2015 revised Jones criteria was performed from January 1, 2000 to December 31, 2019. Eleven ARF patients were identified, including 8 with initial attacks (6 females aged 26-42 years, 33.9 ± 5.3) and 3 pre-existing valvular heart disease with recurrent attacks (2 females aged 38-52 years, 45.0 ± 7.0). In addition to febrile pharyngitis and migratory polyarthritis in initial attacks, pericarditis was encountered in 1, valvulitis in 2, prolong PR interval in 3 and skin involvement in 2 patients with erythema marginatum and IgA vasculitis. All responded to antibiotics and nonsteroidal anti-inflammatory drugs therapy with normalized clinical and laboratory abnormalities, no new-onset carditis, and no recurrent disease during a long-term follow-up (3.8-19.8 years, 12.7 ± 5.4). A sporadic occurrence of adult ARF is observed in southern Taiwan. This disease should be considered by physicians for the differential diagnosis of febrile pharyngitis with arthritis and/or carditis in adults, even in areas with a low incidence of ARF., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Systemic rheumatic diseases (SRDs) are chronic, inflammatory, autoimmune disorders with the presence of autoantibodies that may affect any organ or system. Liver dysfunction in SRDs can be associated with prescribed drugs, viral hepatitis, alternative hepatic comorbidities and coexisting autoimmune liver diseases (AILDs), requiring an exclusion of secondary conditions before considering liver involvement. The patterns of overlap diseases depend predominantly on genetic determinants with common susceptible loci widely distributing in both disorders. In AILDs, it is important to identify the overlapping SRDs at an early stage since such a coexistence may influence the disease course and prognosis. Commonly co-occurring SRDs in AILDs are Sjögren syndrome (SS), rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) in autoimmune hepatitis (AIH), and SS, RA or systemic sclerosis in primary biliary cholangitis. Owing to different disease complications and therapies, it is imperative to differentiate between SLE liver involvement and SLE-AIH overlap disease. Therapeutic options can be personalized to control coexisting conditions of liver autoimmunity and rheumatic manifestations in AILD-SRD overlap diseases. The collaboration between hepatologists and rheumatologists can lead to significant advances in managing such a complex scenario. In this review, we provide a comprehensive overview on coexisting AILDs in different SRDs and the therapeutic approach in managing these overlap diseases., Competing Interests: Conflict-of-interest statement: The authors declare having no real or potential conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: An increased risk of insulin resistance (IR) has been identified in rheumatoid arthritis (RA), a chronic inflammatory disorder with elevated levels of pathogenic cytokines. Biologics targeting proinflammatory cytokines can control the disease and improve insulin sensitivity in RA. Although Janus kinase (JAK) signaling can regulate cytokine receptors and participate in RA pathogenesis, it remains to be elucidated whether there is a reduction of IR in such patients under JAK inhibitor (JAKi) therapy., Aim: To study the effect of JAKi treatment on the reduction of IR in RA patients with active disease., Methods: A retrospective study was carried out from April 1, 2017 to March 31, 2021 in a population of non-diabetic patients with active RA who were undergoing tofacitinib (TOF) therapy with 5 mg twice-daily immediate-release formulation., Results: Fifty-six RA patients, aged 30 years to 75 years (mean ± SD: 52.3 ± 11.1) with disease activity score 28 values ranging from 4.54 to 7.37 (5.82 ± 0.74), were classified into high-IR (> 2.0) and low-IR (≤ 2.0) groups based on their baseline homeostatic model assessment (HOMA)-IR levels. They had no previous exposure to JAKi, and received TOF therapy for no less than 6 mo. In 30 patients who were naïve to biologics, after a 24-week therapeutic period, the high-IR group showed reduced HOMA-IR levels (3.331 ± 1.036 vs 2.292 ± 0.707, P < 0.001). In another 26 patients who were exposed to tumor necrosis factor-α or interleukin-6 blockers, the high-IR group, despite having achieved a decrease but with lower magnitude than in naïve patients, showed reduced HOMA-IR levels (2.924 ± 0.790 vs 2.545 ± 1.080, P = 0.018)., Conclusion: In this retrospective study, reduced IR was achieved in non-diabetic active RA patients following 24 wk of TOF therapy., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)