Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling.

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca2+) homeostasis, with its Ca2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-ß signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca2+ levels through a form of Ca2+ influx, named store-operated Ca2+ entry (SOCE), we examined whether moderating SOCE affected TGF-ß signaling. Interestingly, blocking SOCE had little effect on TGF-ß-induced gene expression. In contrast, inhibition of ER Ca2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-ß signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca2+ at the basal level. Indeed, adjusting Ca2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-ß-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca2+ concentrations and TGF-ß signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.

Positive Echocardiographic Association between Carotid Artery and Coronary Artery Diameter and Z-Score in a Mouse Model of Kawasaki Disease.

Kawasaki disease (KD) occurs in young children, has an unknown etiology, and can cause such life-threatening complications as coronary artery aneurysm. A mouse model using Lactobacillus casei cell wall extract (LCWE) with intraperitoneal injection was established for KD years ago. Histological examination of coronary artery lesions indicated features similar to those of vascular lesions of patients with KD. Since animals must be sacrificed during histological examination, the longitudinal survey of coronary artery lesions (CALs) is difficult. The aim of this study was to survey the vasculitis status of the coronary artery and the carotid artery in a KD mouse model. METHOD: LCWE was intraperitoneally injected into 5-week-old male C57BL/6 mice to induce CALs. We studied the longitudinal status of the carotid and coronary arteries and analyzed the Z-score of coronary artery diameter. RESULTS: Carotid artery wall thickness (day 7) and diameter (day 14) significantly increased in the LCWE group with a dose-dependent effect (p < 0.05). Aortic diameter and wall thickness demonstrated significant increases on day 28 and day 7, respectively (p < 0.05). Carotid artery outer diameter and wall thickness were positively associated with coronary artery diameter on day 28 (p < 0.01). Coronary artery diameter significantly increased in the LCWE group after day 7 (p < 0.05). The percentage of Z > 3.0 indicated was more than 80% in the high-dose LCWE group and 0% in the control group. CONCLUSIONS: This report is the first to use coronary artery Z-score in a mouse model of KD by echocardiography and to find a positive association between carotid artery and coronary artery diameter.

Molecular Hydrogen: Emerging Treatment for Stroke Management.

Ischemic stroke is a major cause of death and disability worldwide. However, only intravenous thrombolysis using mechanical thrombectomy or tissue plasminogen activator is considered an effective and approved treatment. Molecular hydrogen is an emerging therapeutic agent and has recently become a research focus. Molecular hydrogen is involved in antioxidative, anti-inflammatory, and antiapoptotic functions in normal physical processes and may play an important role in stroke management; it has been evaluated in numerous preclinical and clinical studies in several administration formats, including inhalation of hydrogen gas, intravenous or intraperitoneal injection of hydrogen-enriched solution, or drinking of hydrogen-enriched water. In addition to investigation of the underlying mechanisms, the safety and efficacy of using molecular hydrogen have been carefully evaluated, and favorable outcomes have been achieved. All available evidence indicates that molecular hydrogen may be a promising treatment option for stroke management in the future. This review aimed to provide an overview of the role of molecular hydrogen in the management of stroke and possible further modifications of treatment conditions and procedures in terms of dose, duration, and administration route.

Smoking cessation and influenza vaccination can reduce the healthcare burden of COPD.

INTRODUCTION: Influenza vaccination (INV) and smoking cessation (SC) have individual positive effects on COPD, but their synergistic impact has yet to be extensively studied. This retrospective study aimed to assess the combined effect of SC and IV on the medical burden of COPD, including medical visits, hospitalization, medical expenses, and the occurrence of respiratory failure. METHODS: Patients with COPD who visited our medical center between January and October 2018 were included in the study. The patients were categorized into four groups: Group I (no SC or INV), Group II (INV only), Group III (SC only), and Group IV (both SC and INV). The outcomes analyzed were emergency utilization, hospital utilization, and occurrence of respiratory failure. Airflow limitation was stratified according to GOLD guidelines, and successful smoking cessation was defined as not smoking for at least one year. RESULTS: A total of 357 patients were included in the study. Group I (119 patients) neither smoking cessation nor influenza vaccination; Group II (66 patients) had only influenza vaccination; Group III (94 patients), had only smoking cessation, Group IV (78 patients), with both smoking cessation and influenza vaccination. Group IV had lower odds of emergency utilization (OR=0.13; 95% CI: 0.07-0.25), hospital utilization (OR=0.13; 95% CI: 0.05-0.30, p<0.001), and occurrence of respiratory failure (OR=0.13; 95% CI: 0.04-0.40, p<0.001). CONCLUSIONS: Combined smoking cessation and influenza vaccination are more effective in reducing the medical burden of COPD compared to either intervention alone or neither. These findings highlight the importance of promoting both smoking cessation and influenza vaccination in the management of COPD.

Comparable bidirectional neutrophil immune dysregulation between Kawasaki disease and severe COVID-19.

Kawasaki disease (KD), a multisystem inflammatory syndrome that occurs in children, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) may share some overlapping mechanisms. The purpose of this study was to analyze the differences in single-cell RNA sequencing between KD and COVID-19. We performed single-cell RNA sequencing in KD patients (within 24 hours before IVIG treatment) and age-matched fever controls. The single-cell RNA sequencing data of COVID-19, influenza, and health controls were downloaded from the Sequence Read Archive (GSE149689/PRJNA629752). In total, 22 single-cell RNA sequencing data with 102,355 nuclei were enrolled in this study. After performing hierarchical and functional clustering analyses, two enriched gene clusters demonstrated similar patterns in severe COVID-19 and KD, heightened neutrophil activation, and decreased MHC class II expression. Furthermore, comparable dysregulation of neutrophilic granulopoiesis representing two pronounced hyperinflammatory states was demonstrated, which play a critical role in the overactivated and defective aging program of granulocytes, in patients with KD as well as those with severe COVID-19. In conclusion, both neutrophil activation and MHC class II reduction play a crucial role and thus may provide potential treatment targets for KD and severe COVID-19.

Expression of Eosinophilic Subtype Markers in Patients with Kawasaki Disease.

PURPOSE: Eosinophils may rise to a higher level in the acute phase of Kawasaki disease (KD) both before and after intravenous immunoglobulin (IVIG) therapy. A substantial body of research was carried out on the association between KD and allergic diseases. Eosinophils play an important role in type 2 inflammation. Recent studies have shown that there are two distinct subtypes of eosinophils. In addition to their role in inflammation, lung-resident eosinophils (rEOS) also regulate homeostasis. Inflammatory eosinophils (iEOS) reflect type 2 inflammation in tissues. iEOS were considered the primary eosinophils in non-severe allergic asthma, while rEOS were thought to be the primary eosinophils in severe non-allergic eosinophilic asthma. This case-control study aimed to investigate the marker expression of eosinophilic subtypes in KD patients. MATERIALS AND METHODS: The marker expressions of eosinophilic subtypes in the leukocytes of patients with KD were evaluated by the recently established KDmarkers online tool, a web server including gene expression data. Finally, the results were validated with a quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We analyzed the mRNA expression levels of SELL and IL10RA in leukocytes from KD patients and febrile children. RESULTS: Included in our screening tools were transcriptome arrays, which provided clues showing the importance of rEOS, whose role was identified by three genes (lower IL10RA, higher SELL, and SERPINB1 than controls). In contrast, the iEOS representative gene CD101 was not elevated in KD. It was found that the gene IL10RA, a marker of inflammatory eosinophilic leukocytes, was more highly expressed in the leukocytes of KD patients (n = 43) than febrile controls (n = 32), especially those without coronary artery lesions (CAL) (n = 26). Before treatment, SELL expression was higher in leukocytes of CAL patients (CAL, 1.33 ± 0.18, n = 39; non-CAL, 0.87 ± 0.12, n = 55; p = 0.012). SELL was significantly higher after half a year compared to febrile controls. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that KD patients have increased SELL than febrile controls after 6 months of treatment. We present evidence here that dynamically different eosinophilic involvement exists between KD patients with and without CAL. The role of eosinophilic subtypes in KD patients warrants further investigation.

Liver Graft MicroRNAs Expression in Different Etiology of Acute Jaundice after Living Donor Liver Transplantation.

Background: Acute jaundice remains a critical problem following liver transplantation. MicroRNAs (miRNAs) are involved in regulating gene expression related to various disease phenotypes and statuses. Aims: To differentiate acute jaundice etiology after living donor liver transplantation (LDLT), we examined the hepatic miRNA expression patterns in several liver graft pathologies. Methods: Eighty liver transplant recipients undergoing post-LDLT graft biopsy for the evaluation of acute jaundice were enrolled in this 1-year prospective study. Using a real-time quantitative reverse transcription-polymerase chain reaction profiling assay, we identified hepatic miRNA (miRNA-122, miRNA-301, miRNA-133a, and miRNA-21) signatures in various allografts pathologies. Results: Pathologic findings of the 80 recipients were as follows: acute cholangitis (AC), 37 (46%); acute rejection (AR), 20 (25%); recurrent hepatitis (RH), 12 (15%); non-specific pathological change, 6 (8%); and fatty change (FC), 5 (6%). None of these identified hepatic miRNAs expression pattern was significantly correlated with serum parameters, including neutrophil-lymphocyte ratio. In AC, hepatic miRNA-122, miRNA-301, miRNA-133a, and miRNA-21 expression was significantly downregulated (p < 0.05). MicroRNA-122 expression was elevated in cases of AR and RH (p < 0.05); miRNA-301 and miRNA-21 expression was higher in RH than in AC (p < 0.05); and miRNA-133a expression was higher in FC than in AR (p < 0.05). Conclusions: Our study suggests that specific hepatic miRNA expression patterns as a checklist may be useful for differential diagnosis of acute jaundice following liver transplantation.

Comparison of portal and capsular microscopic vascular invasion in the outcomes of early HCC after curative resection.

Microscopic vascular invasion (MVI) is a strong risk factor associated with tumor recurrence and poor overall survival (OS) among hepatocellular carcinoma (HCC) patients after resection. Two types of MVI are identified: portal vein and capsular vein invasion. However, little is known about the impact of different types of MVI on HCC recurrence. The present study aimed to compare HCC recurrence and OS between the portal vein and capsule vein MVI. Patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 were consecutively recruited. Factors that influenced OS and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models. Of the 857 eligible patients, 327 (38.2%) had MVI, and 530 (61.8%) were without MVI. Of the 327 patients with MVI, 85 (26.0%) were with portal vein, 178 (54.4%) with capsular vein, and 64 (19.6%) with both-MVI type. Patients with both-MVI type suffered from a higher proportion of BCLC stage A (P < 0.001), capsular invasion (P = 0.002), and satellite nodules (P < 0.001). Both-MVI type is an independent risk factor for HCC recurrence (hazard ratio [HR]: 1.69; 95% CI, 1.22-2.36, P = 0.002) and mortality (HR: 2.29; 95% CI, 1.59-3.29, P < 0.001) compared with non-MVI. We further found that both-MVI type was significantly associated with a higher risk of extrahepatic recurrence (EHR) (HR: 8.74; 95% CI, 2.38-32.03, P = 0.001). Among HCC patients after curative resection, concurrent portal and capsular MVI is a risk factor for HCC recurrence, especially for EHR, in comparison with non-MVI or only portal or capsular MVI alone.

Combination of Hemoglobin-for-Age Z-Score and Plasma Hepcidin Identified as a Novel Predictor for Kawasaki Disease.

Kawasaki disease (KD) is a febrile coronary vasculitis that affects younger children and includes complications such as coronary artery aneurysm. KD diagnoses are diagnosed based on clinical presentations, a process that still poses a challenge for front-line physicians. In the current study, we developed a novel predictor using the hemoglobin-for-age z-score (HbZ) and plasma hepcidin to differentiate Kawasaki disease (KD) from febrile children (FC). There were 104 FC and 115 KD subjects (89 typical KD; 26 incomplete KD) for this study, and data were collected on the biological parameters of hemoglobin and plasma hepcidin levels. A receiver operating characteristic curve (auROC), multiple logistics regression, and support vector machine analysis were all adopted to develop our prediction condition. We obtained both predictors, HbZ and plasma hepcidin, for distinguishing KD and FC. The auROC of the multivariate logistic regression of both parameters for FC and KD was 0.959 (95% confidence interval = 0.937-0.981), and the sensitivity and specificity were 85.2% and 95.9%, respectively. Furthermore, the auROC for FC and incomplete KD was 0.981, and the sensitivity and specificity were 92.3% and 95.2%, respectively. We further developed a model of support vector machine (SVM) classification with 83.3% sensitivity and 88.0% specificity in the training set, and the blind cohort performed well (78.4% sensitivity and 100% specificity). All data showed that sensitivity and specificity were 81.7% and 91.3%, respectively, by SVM. Overall, our findings demonstrate a novel predictor using a combination of HbZ and plasma hepcidin with a better discriminatory ability for differentiating from WBC and CRP between children with KD and other FC. Using this predictor can assist front-line physicians to recognize and then provide early treatment for KD.

Liver Graft Pathology and Low Serum 25-Hydroxyvitamin D after Living Donor Liver Transplantation.

BACKGROUND: Most cases of advanced liver diseases are associated with low serum 25-hydroxyvitamin D and vitamin D deficiency. This phenomenon may occur in living donor liver transplantation (LDLT). AIMS: We conducted this study to explore the interplay between VDR and CYP2R1 in liver graft and compared our findings with the pathological interpretation of serum 25(OH)D concentration. METHODS: In total, 60 patients received liver graft biopsy after LDLT and were separated (1:1) into two groups: graft rejection group and graft non-rejection group. We extracted both of the recipients' and donors' serum DNA to investigate the vitamin D receptor (VDR) rs2228530 and CYP2R1 rs10741657 single nucleotide polymorphisms (SNPs) using real-time polymerase chain reaction. We also extracted DNA from liver graft tissues to explore the genetic alleles of VDR rs2228530 and CYP2R1 rs10741657 after LDLT. Serum biochemistry profile and 25(OH)D concentrations were measured before and after LDLT. RESULTS: There were no significant differences in serum VDR rs2228530 and CYP2R1 rs10741657 genetic alleles between recipients and donors. The percentage of genetic modification was 33.4% (10/30) for the rejection and non-rejection groups in VDR rs2228530, and 66.7% (20/30) for both groups in CYP2R1 rs10741657. Serum 25(OH)D concentrations were significantly lower after LDLT D30 than that before LDLT in the rejection (p = 0.0001) and non-rejection graft pathology (p = 0.0017) groups. CONCLUSIONS: The presence of low serum 25(OH)D concentrations after LDLT suggested that post-transplant low serum 25(OH)D concentrations may develop with the homogenous phenomenon of VDR rs2228530 and CYP2R1 rs10741657 genetic modifications in recipients regardless of graft pathology.

KDmarkers: A biomarker database for investigating epigenetic methylation and gene expression levels in Kawasaki disease.

Kawasaki disease (KD) is a form of acute systemic vasculitis that primarily affects children and has become the most common cause of acquired heart disease. While the etiopathogenesis of KD remains unknown, the diagnostic criteria of KD have been well established. Nevertheless, the diagnosis of KD is currently based on subjective clinical symptoms, and no molecular biomarker is yet available. We have previously performed and combined methylation array (Illumina HumanMethylation450 BeadChip) and transcriptome array (Affymetrix GeneChip Human Transcriptome Array 2.0) to identify genes that are differentially methylated/expressed in KD patients compared with control subjects. We have found that decreased methylation levels combined with elevated gene expression can indicate genes (e.g., toll-like receptors and CD177) involved in the disease mechanisms of KD. In this study, we constructed a database called KDmarkers to allow researchers to access these valuable potential KD biomarkers identified via methylation array and transcriptome array. KDmarkers provides three search modes. First, users can search genes differentially methylated and/or differentially expressed in KD patients compared with control subjects. Second, users can check the KD patient groups in which a given gene is differentially methylated and/or differentially expressed. Third, users can explore the DNA methylation levels and gene expression levels in all samples (KD patients and controls) for a particular gene of interest. We further demonstrated that the results in KDmarkers are strongly associated with KD immune responses. All analysis results can be downloaded for downstream experimental designs. KDmarkers is available online at https://cosbi.ee.ncku.edu.tw/KDmarkers/.

Human Transcriptome Array Analysis Identifies CDR2 as a Novel Suppressed Gene for Kawasaki Disease.

Kawasaki disease (KD) is a febrile childhood vasculitis that involves the coronary arteries. Most previous studies have focused on the genes activated in the acute phase of KD. However, in this study, we focused on suppressed genes in the acute stage of KD and identified novel targets with clinical significance and potential prognostic value for KD patients. We enrolled 18 patients with KD, 18 healthy controls (HC), and 18 febrile controls (FC) for human transcriptome array analysis. Another 19 healthy controls, 20 febrile controls, and 31 patients with KD were recruited for RT-PCR validation of target mRNA expressions. The results of Human Transcriptome Array (HTA) 2.0 showed 461 genes that were significantly higher in KD and then normalized after IVIG, as well as 99 suppressed genes in KD. Furthermore, we identified the four genes in KD with the most downregulation, including BCL11B, DUSP2, DDX24, and CDR2, as well as the upregulation of their expression following IVIG administration. The mRNA expression of CDR2 by qRT-PCR was the most compatible with the pattern of the HTA2.0 results. Furthermore, we found higher DDX24 mRNA expression in KD patients with CAL when compared to those without CAL 3 weeks after IVIG administration. In summary, activated gene expression represented a majority in the immune response of KD. In this study, we identified CDR2 as a novel suppressed gene for Kawasaki disease via human transcriptome array analysis and DDX24 associated with CAL formation, which may contribute to further understanding of CAL pathogenesis in KD.

CD36 is Associated With the Development of Coronary Artery Lesions in Patients With Kawasaki Disease.

Kawasaki disease (KD) is an autoimmune-like vasculitis of childhood involving the coronary arteries. Macrophages require scavenger receptors such as CD36 to effectively clear cellular debris and induce self-tolerance. In this study, we hypothesized that CD36 plays an important role in the immunopathogenesis of KD, by aiding in the clearance of plasma mitochondrial DNA, and by amplifying the immune response by activating the inflammasome pathway via AIM2. Fifty-two healthy controls, 52 febrile controls, and 102 KD patients were recruited for RT-PCR of target mRNA expression and plasma mitochondrial DNA. Blood samples were obtained 24 hours prior and 21 days after the administration of intravenous immunoglobulin (IVIG) therapy. Patients with acute KD had higher plasma levels of cell-free mitochondrial DNA (ND1, ND4, and COX1), and higher mRNA expressions of CD36 and AIM2 when compared to both healthy and febrile controls. A greater decrease in both CD36 and AIM2 mRNA expression after IVIG therapy was associated with the development of coronary artery lesions. Coronary artery lesions were associated with a larger decrease of CD36 expression following IVIG therapy, which may indicate that prolonged expression of the scavenger receptor may have a protective effect against the development of coronary artery lesions in KD.

DNA Methylation Array Identifies Golli-MBP as a Biomarker for Disease Severity in Childhood Atopic Dermatitis.

In this study, we investigated the changes in global methylation status and its functional relevance in childhood atopic dermatitis (AD). Differences in epigenome-scale methylation events in peripheral blood associated with childhood AD were screened using DNA methylation arrays of 24 patients with AD compared with 24 control subjects. Of the 16,840 differentially methylated CpG regions between AD and control subjects, >97% CpG loci revealed hypomethylation in patients with childhood AD. Among the globally hypomethylated loci, we identified two CpG clusters within the golli-mbp locus of the MBP gene, which was functionally enriched by subnetwork enrichment analysis as an orchestrator among associated genes. The differential hypomethylation of the top-ranked cg24700313 cluster in the golli-mbp locus was validated by pyrosequencing in an independent cohort of 224 children with AD and 44 control subjects. DNA methylation was found to be negatively correlated with disease severity but showed no significant correlation with IgE levels after age adjustment. The multivariate correlation analysis represents a higher score in AD intensity with significantly increased IgE levels and decreased methylation levels in cg27400313. We concluded that methylation loss in the golli-mbp locus is an epigenetic factor associated with disease severity of childhood AD.

HCV RNA in serum and liver samples of patients undergoing living donor liver transplantation.

OBJECTIVE: To compare hepatitis C virus (HCV) RNA levels from serum and explanted native liver samples from patients undergoing living donor liver transplantation (LDLT). METHODS: This was a prospective observational study. Serum and liver samples were collected from consecutive serum anti-HCV-positive transplant recipients between February 2016 to August 2019. HCV RNA was extracted from liver samples and subjected to one-step reverse-transcription qPCR. using the TopScript One Step qRT-PCR Probe Kit with HCV qPCR probe assay and human GAPDH qPCR probe assay on a ViiA7 Real-Time PCR System. RESULTS: Among the 80 patients, 36% (29/80) were HCV RNA positive in serum and 85% (68/80) had positive hepatic HCV RNA. Post-liver transplantation, 4% (3/80) patients were serum positive. CONCLUSIONS: Our study suggests that pre-transplant serum HCV RNA levels may give an underestimate of the number of positive HCV RNA cases and that hepatic HCV RNA data may be more accurate.

Long-Term Hypermethylation of FcγR2B in Leukocytes of Patients with Kawasaki Disease.

The Fc gamma receptor family contains several activating receptors and the only inhibitory receptor, FcγR2B. In this study, we investigated the dynamic methylation change of FcγR2B in different stages of Kawasaki disease (KD). We enrolled a total of 116 participants, which included patients with febrile diseases as controls and KD patients. Whole blood cells of KD patients were collected prior to intravenous immunoglobulin (IVIG) treatment (KD1), three to seven days after IVIG (KD2), three weeks after IVIG treatment (KD3), six months after IVIG (KD4), and one year after IVIG treatment (KD5). In total, 76 KD patients provided samples in every stage. Leukocytes of controls were also recruited. We performed DNA extraction and pyrosequencing. FcγR2B methylation levels were higher in KD3 compared to both the controls and KD1. A significantly higher methylation of FcγR2B was found in KD5 when compared with KD1. FcγR2B methylation levels in the IVIG-resistant group were lower than those in the IVIG-responsive group at KD1-3 (p = 0.004, 0.004, 0.005 respectively). This study is the first to report the dynamic change of FcγR2B methylation and to demonstrate long-term hypermethylation one year after disease onset. Hypomethylation of FcγR2B is associated with IVIG resistance.

Chemical and Biochemical Aspects of Molecular Hydrogen in Treating Kawasaki Disease and COVID-19.

Kawasaki disease (KD) is a systemic vasculitis and is the most commonly acquired heart disease among children in many countries, which was first reported 50 years ago in Japan. The 2019 coronavirus disease (COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) has been a pandemic in most of the world since 2020, and since late 2019 in China. Kawasaki-like disease caused by COVID-19 shares some symptoms with KD, referred to as multisystem inflammatory syndrome in children, and has been reported in the United States, Italy, France, England, and other areas of Europe, with an almost 6-10 times or more increase compared with previous years of KD prevalence. Hydrogen gas is a stable and efficient antioxidant, which has a positive effect on oxidative damage, inflammation, cell apoptosis, and abnormal blood vessel inflammation. This review reports the chemical and biochemical aspects of hydrogen gas inhalation in treating KD and COVID-19.

Impact of metformin use on the recurrence of hepatocellular carcinoma after initial liver resection in diabetic patients.

BACKGROUND: Metformin is proposed to have chemopreventive effect of various cancer currently. However, the anti-cancer effect of metformin for diabetic patients with hepatocellular carcinoma (HCC) undergoing liver resection remains unclear. The aim of our cohort study was to assess whether metformin influence the recurrence of HCC. METHODS: We retrospectively enrolled 857 HCC patients who received primary resection from April 2001 to June 2016. 222 patients were diagnosed with diabetes mellitus (DM) from medical record. Factors influence the overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis. RESULTS: During the follow-up period (mean, 75 months), 471 (54.9%) patients experienced recurrence, and 158 (18.4%) patients died. Multivariate analysis revealed that DM (p = 0.015), elevated AST (p = 0.006), hypoalbuminemia (p = 0.003), tumor number (p = 0.001), tumor size (p < 0.001), vascular invasion (p <0.001), high Ishak fibrosis score (p <0.001), hepatitis B (p = 0.014), hepatitis C (p = 0.001) were independent predictors for RFS. In diabetic patients, only HbA1c>9% (p = 0.033), hypoalbuminemia (p = 0.030) and vascular invasion (p = 0.001) were independent risk factors for HCC recurrence; but the metformin use revealed no significance on recurrence. DM is a risk factor of HCC recurrence after resection. Adequate DM control can reduce the recurrence of HCC. However, the use of metformin does not reduce the risk of HCC recurrence in diabetic patient after initial resection. Hence, metformin may not have protective influences on HCC recurrence in diabetic patients who undergo initial liver resection.

The Perioperatively Altered Neutrophil-to-Lymphocyte Ratio Associates with Impaired DNA Damage Response in Liver Transplantation Recipients with Hepatocellular Carcinoma.

Increasing evidence has suggested that elevated systemic inflammation with a high neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis after liver transplantation (LT). The ongoing molecular events involved in poor survival remain unclear. This retrospective study evaluated LT recipients whose data was collected at Kaohsiung Chang Gung Memorial Hospital between 2005 and 2014. Clinical records of 347 patients with hepatocellular carcinoma from seven days before LT to 30 days after LT illustrated that longitudinal values of lymphocytes, RBC, and hemoglobin were persistently low in patients with peritransplant high NLR (PTH-NLR, pre-LT ≥ 4 and post-LT ≥ 5), which indicated a significantly worse survival rate in association with increased RDW-CV and pancytopenia when compared to other patients (p = 0.008). We further found that PTH-NLR patients had decreased DNA damage response (DDR) genes and detoxifying enzymes of ADH and ALDH families, and increased mitochondrial stress response genes in their liver tissues. Reduced lineage markers of liver progenitor cells were also observed in PTH-NLR patients signifying the presence of unresolved impairments after LT. Our results demonstrate the association between hematopoietic deficiencies and lack of protection against DDR with PTH-NLR in LDLT recipients with HCC and may imply abnormal hematological and organismal defects in those patients.