ABSTRACT
BACKGROUND: Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC. METHODS: Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios. RESULTS: Of 4824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (95% confidence interval [CI], 24.0%-37.7%) of HCC was alcohol associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male but were similar in age and comorbidities compared with other causes. A total of 20.8% (95% CI, 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared with 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P < .05). Alcohol-associated HCC had a lower likelihood of Barcelona Clínic Liver Cancer C stage (0/A) (OR, 0.7; 95% CI, 0.6-0.9; P = .018) and curative therapy (24.5% vs 33.9%; OR, 0.7; 95% CI, 0.5-0.9; P = .003), and higher mortality (HR, 1.3; 95% CI, 1.1-1.5; P = .012) when compared with other causes. CONCLUSIONS: Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.
ABSTRACT
BACKGROUND: Invariant natural killer T (iNKT) cells play protective or pathogenic roles in a variety of immune and inflammatory diseases. However, whether iNKT cells contribute to the progression of acute neuroinflammation remains unclear. Thus, we addressed this question with a mouse model of lipopolysaccharide (LPS)-induced acute neuroinflammation. METHODS: For induction of acute neuroinflammation, wild-type (WT) C57BL/6 (B6) mice were injected intraperitoneally (i.p.) with LPS for either three or five consecutive days, and then these mice were analyzed for brain-infiltrating leukocytes or mouse behaviors, respectively. To examine the role of iNKT cell activation in LPS-induced neuroinflammation, mice were injected i.p. with the iNKT cell agonist α-galactosylceramide (α-GalCer) seven days prior to LPS treatment. Immune cells infiltrated into the brain during LPS-induced neuroinflammation were determined by flow cytometry. In addition, LPS-induced clinical behavior symptoms such as depressive-like behavior and memory impairment in mice were evaluated by the open field and Y-maze tests, respectively. RESULTS: We found that iNKT cell-deficient Jα18 mutant mice display delayed disease progression and decreased leukocyte infiltration into the brain compared with WT mice, indicating that iNKT cells contribute to the pathogenesis of LPS-induced neuroinflammation. Since it has been reported that pre-treatment with α-GalCer, an iNKT cell agonist, can convert iNKT cells towards anti-inflammatory phenotypes, we next explored whether pre-activation of iNKT cells with α-GalCer can regulate LPS-induced neuroinflammation. Strikingly, we found that α-GalCer pre-treatment significantly delays the onset of clinical symptoms, including depression-like behavior and memory impairment, while decreasing brain infiltration of pro-inflammatory natural killer cells and neutrophils, in this model of LPS-induced neuroinflammation. Such anti-inflammatory effects of α-GalCer pre-treatment closely correlated with iNKT cell polarization towards IL4- and IL10-producing phenotypes. Furthermore, α-GalCer pre-treatment restored the expression of suppressive markers on brain regulatory T cells during LPS-induced neuroinflammation. CONCLUSION: Our findings provide strong evidence that α-GalCer-induced pre-activation of iNKT cells expands iNKT10 cells, mitigating depressive-like behaviors and brain infiltration of inflammatory immune cells induced by LPS-induced acute neuroinflammation. Thus, we suggest the prophylactic potential of iNKT cells and α-GalCer against acute neuroinflammation.
Subject(s)
Brain , Galactosylceramides , Lipopolysaccharides , Mice, Inbred C57BL , Natural Killer T-Cells , Neuroinflammatory Diseases , Animals , Galactosylceramides/pharmacology , Natural Killer T-Cells/immunology , Natural Killer T-Cells/drug effects , Brain/pathology , Brain/drug effects , Brain/immunology , Male , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/immunology , Neuroinflammatory Diseases/chemically induced , Mice , Cytokines/metabolismABSTRACT
BACKGROUND AND AIM: The Model for End-Stage Liver Disease (MELD) is a reliable prognostic tool for short-term outcome prediction in patients with end-stage liver disease. MELD 3.0 was introduced to enhance the predictive accuracy. This study assessed the performance of MELD 3.0, in comparison to MELD and MELD-Na, in patients with alcoholic liver cirrhosis. METHODS: This multicenter prospective cohort study comprised patients with alcoholic cirrhosis admitted for acute deterioration of liver function in the Republic of Korea between 2015 and 2019. This study compared the predictive abilities of MELD, MELD-Na, and MELD 3.0, for 30-day and 90-day outcomes, specifically death or liver transplantation, and explored the factors influencing these outcomes. RESULTS: A total of 1096 patients were included in the study, with a mean age of 53.3 ± 10.4 years, and 82.0% were male. The mean scores for MELD, MELD-Na, and MELD 3.0 at the time of admission were 18.7 ± 7.2, 20.6 ± 7.7, and 21.0 ± 7.8, respectively. At 30 and 90 days, 7.2% and 14.1% of patients experienced mortality or liver transplantation. The areas under the receiver operating characteristic curves for MELD, MELD-Na, and MELD 3.0 at 30 days were 0.823, 0.820, and 0.828; and at 90 days were 0.765, 0.772, and 0.776, respectively. Factors associated with the 90-day outcome included concomitant chronic viral hepatitis, prolonged prothrombin time, elevated levels of aspartate transaminase, bilirubin, and creatinine, and low albumin levels. CONCLUSION: MELD 3.0 demonstrated improved performance compared to previous models, although the differences were not statistically significant.
ABSTRACT
OBJECTIVES: To explore the course of lung function and RA disease activity and predictive factors for deteriorating lung function in patients with RA-interstitial lung disease (ILD). METHODS: The Korean Rheumatoid Arthritis-Interstitial Lung Disease cohort is a multicentre, prospective observational cohort. Patients with RA-ILD were enrolled and followed up annually for 3 years for RA disease activity and ILD status assessment. Group-based modelling was used to cluster a similar predicted percentage of forced vital capacity (FVC%) patterns into trajectories. RESULTS: This study included 140 patients who underwent at least two pulmonary function tests. Four distinctive trajectories for predicted FVC% were 'improving' [n = 11 (7.9%)], 'stable' [n = 68 (38.4%)], 'slowly declining' [n = 54 (48.6%)] and 'rapidly declining' [n = 7 (5.0%)]. Most (77.7%) patients maintained or improved to low RA disease activity. The lung function trajectory was not comparable to the RA disease activity trajectory. Age ≥70 years [relative risk (RR) 10.8 (95% CI 1.30, 89.71)] and early RA diagnosed within the preceding 2 years [RR 10.1 (95% CI 1.22, 84.2)] were associated with increased risk for rapidly declining predicted FVC%. The risk for deterioration or mortality increased in patients with a simultaneous diagnosis of RA and ILD within 24 weeks [RR 9.18 (95% CI 2.05, 41.0)] and the extent of lung involvement [RR 3.28 (95% CI 1.12, 9.60)]. CONCLUSION: Most patients with RA-ILD experienced stable or slowly declining lung function. In 5% of patients, predicted FVC% deteriorated rapidly, especially in older adults with early RA. The lung function trajectory was not comparable to the RA disease activity trajectory.
Subject(s)
Arthritis, Rheumatoid , Lung Diseases, Interstitial , Humans , Aged , Retrospective Studies , Arthritis, Rheumatoid/complications , Vital Capacity , LungABSTRACT
Interleukin-7 (IL-7) plays a vital role in the homeostasis of CD4+ and CD8+ T cells. Although IL-7 has been implicated in T helper (Th)1- and Th17-mediated autoinflammatory diseases, its role in Th2-type allergic disorders, such as atopic dermatitis (AD), remains unclear. Thus, to elucidate the effects of IL-7 deficiency on AD development, we generated IL-7-deficient AD-prone mice by backcrossing IL-7 knockout (KO) B6 mice onto the NC/Nga (NC) mouse strain, a model for human AD. As expected, IL-7 KO NC mice displayed defective development of conventional CD4+ and CD8+ T cells compared with wild type (WT) NC mice. However, IL-7 KO NC mice presented with enhanced AD clinical scores, IgE hyperproduction, and increased epidermal thickness compared with WT NC mice. Moreover, IL-7 deficiency decreased Th1, Th17, and IFN-γ-producing CD8+ T cells but increased Th2 cells in the spleen of NC mice, indicating that a reduced Th1/Th2 ratio correlates with severity of AD pathogenesis. Furthermore, significantly more basophils and mast cells infiltrated the skin lesions of IL-7 KO NC mice. Taken together, our findings suggest that IL-7 could be a useful therapeutic target for treating Th2-mediated skin inflammations, such as AD.
Subject(s)
Dermatitis, Atopic , Skin Diseases , Animals , Humans , Mice , CD8-Positive T-Lymphocytes/pathology , Cytokines , Dermatitis, Atopic/drug therapy , Disease Models, Animal , Interleukin-7/genetics , Interleukin-7/metabolism , Skin/pathology , Skin Diseases/pathology , Th2 CellsABSTRACT
Beta-glucan (ß-glucan) is a natural polysaccharide produced by fungi, bacteria, and plants. Although it has been reported that ß-glucan enhances innate immune memory responses, it is unclear whether different types of ß-glucans display similar immune effects. To address this issue, we employed zymosan (ß-1,3-glycosidic linkage) and pustulan (ß-1,6-glycosidic linkage) to investigate their in vivo effects on innate memory immune responses. We examined the changes of innate memory-related markers in macrophages and natural killer (NK) cells, two immune cell types that display innate memory characteristics, at two different time points (16 h and 7 days) after ß-glucan stimulation. We found that short-term (16 h) zymosan treatment significantly induced macrophages to upregulate IL15 production and increased surface IL15Rα expression on NK cells. In addition, long-term (7 days) zymosan treatment significantly induced macrophages to upregulate the expression of innate memory-related markers (e.g., TNFα, HIF1α, and mTOR) and induced NK cells to express enhanced levels of KLRG1, known as an innate memory-like marker. Our results provide support that zymosan can be an effective adjuvant to promote innate memory immune responses, providing a bridge between innate and adaptive immune cells to enhance various immune responses such as those directed against tumors.
Subject(s)
Interleukin-15 , beta-Glucans , Mice , Animals , Zymosan/pharmacology , Macrophages , beta-Glucans/pharmacology , Killer Cells, Natural , Immunity, InnateABSTRACT
BACKGROUND & AIMS: After hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains, and the optimal surveillance strategy has yet to be determined. Herein, we aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance. METHODS: A total of 1,443 patients with chronic hepatitis B who achieved HBsAg seroclearance between 1991 and 2020 were retrospectively screened for study eligibility. The data from 831 of these patients were included in the final analysis. A prediction model was developed based on multivariable Cox models. Harrell's C-index and a time-dependent AUROC were used for discrimination. Bootstrap analysis was performed for internal validation. RESULTS: Overall, 40 patients (4.8%) developed HCC after HBsAg seroclearance during a follow-up of 4,644 person-years (0.86%/year). Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop the prediction model. The C-index of the model was 0.804. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The score also showed good discrimination in the internal validation and sensitivity analysis. CONCLUSIONS: The novel prediction model based on age, cirrhosis, family history of HCC, and alcohol consumption enables reliable risk estimation of HCC after HBsAg seroclearance and may serve as a useful reference for decision-making in HCC surveillance for HBsAg-cleared patients. LAY SUMMARY: After spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently associated with HCC development after HBsAg seroclearance. The novel prediction model using these 4 variables enables reliable risk estimation of HCC and serves as a useful reference for decision-making in HCC surveillance and management for HBsAg-cleared patients.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B, Chronic , Liver Neoplasms , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/pathology , DNA, Viral , Hepatitis B Surface Antigens , Hepatitis B virus/genetics , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/epidemiology , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/epidemiology , Liver Cirrhosis/etiology , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Liver Neoplasms/pathology , Retrospective StudiesABSTRACT
The anticancer effect of statins is drawing attention. However, it is unclear whether statin use reduces the risk of hepatocellular carcinoma (HCC) recurrence in patients who undergo liver transplantation (LT) for HCC. Consecutive patients who underwent LT for HCC between 1995 and 2019 were enrolled. The effects of statins on HCC recurrence and mortality were compared between statin user and statin nonuser groups. We performed the analyses in a variety of ways, including inverse probability treatment weighting (IPTW) methods to balance any confounders and the landmark method to avoid immortal time bias. A total of 430 patients were enrolled, among whom 323 (75.1%) were statin nonusers and 107 (24.9%) were statin users. During a median of 64.9 months (IQR, 26.1-122.6 months) of follow-up, 79 patients (18.4%) had HCC recurrence and 111 (25.8%) died. Among those who died, 53 (47.7%) were identified as HCC-related mortalities. Statin use was a predictor of HCC recurrence (adjusted hazard ratio [HR], 0.3; 95% confidence interval [CI], 0.1-0.6; P = 0.002), all-cause mortality (adjusted HR, 0.3; 95% CI, 0.2-0.5; P < 0.001), and HCC-related mortality (adjusted HR, 0.4; 95% CI, 0.2-0.9; P = 0.03). The effects of statin use on clinical outcomes were also identified through IPTW analysis. There was a dose-dependent relationship between statin use and HCC recurrence. The anticancer effect of statins on HCC recurrence was consistently significant across multivariable-stratified and sensitivity analyses. Statin use significantly reduced the risk of HCC recurrence and improved the survival of patients who underwent LT for HCC.
Subject(s)
Carcinoma, Hepatocellular , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Liver Neoplasms , Liver Transplantation , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/surgery , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Liver Transplantation/adverse effects , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/prevention & control , Retrospective StudiesABSTRACT
PURPOSE: We quantified the familial risk of renal cell cancer (RCC) among first-degree relatives (FDRs) on a population level, and examined interactions between family history and body mass index or blood glucose. MATERIALS AND METHODS: Using the National Health Insurance database, which covers the entire Korean population, and the National Health Screening Program, we constructed a cohort of 5,524,403 individuals with blood-related FDRs and their lifestyle factors from 2002 to 2018. We calculated familial risk using incidence risk ratios (IRRs) with 95% confidence intervals, which compares the risk of individuals with and without FDR. The combined effect and interaction of a given risk factor and family history of RCC were measured by the relative excess risk due to interaction. RESULTS: Individuals with affected FDRs showed a 2.29-fold (95% CI 1.68-3.13) increased risk of disease. Familial risk adjusted for lifestyle factors showed minimal attenuation (IRR 2.25; 95% CI: 1.65-3.08), suggesting that genetic predisposition is the main contributor in the familial aggregation of RCC. Individuals with both a positive family history and overweight/obesity (IRR 3.71, 95% CI 2.50-4.92) or hyperglycemia (IRR 4.52, 95% CI 2.59-6.45) had a significantly higher risk that exceeded the sum of their individual risks, suggesting an interaction that was statistically significant (relative excess risk due to interaction 95% CI: 0.91, -0.21-2.12; 2.21, 0.28-4.14). CONCLUSIONS: Our findings suggest an interaction between genetic and environmental factors, namely obesity and hyperglycemia. Individuals with both factors should be considered a high-risk group and advised to undergo genetic counseling.
Subject(s)
Carcinoma, Renal Cell , Hyperglycemia , Kidney Neoplasms , Carcinoma, Renal Cell/etiology , Carcinoma, Renal Cell/genetics , Family , Genetic Predisposition to Disease , Humans , Hyperglycemia/epidemiology , Kidney Neoplasms/etiology , Kidney Neoplasms/genetics , Obesity/complications , Obesity/epidemiology , Obesity/genetics , Risk FactorsABSTRACT
Prunus japonica var. nakaii is used in traditional Korean medicine to treat various conditions; however, it has not been investigated for treating male infertility. In this study, we investigated the in vitro effects of the ethanolic extract of P. japonica seeds on human sperm motility and identified its mechanism of action. Eleven male volunteers were selected, and the effects of the extract on human spermatozoa were assessed through a computer-assisted semen analysis. The P. japonica seed extract increased the percentage of total and progressive motility of spermatozoa. To understand the mechanism of action, we monitored intracellular alkalization using flow cytometry and obtained electrophysiological recordings of human voltage-gated proton channels hHv1 that were overexpressed in HEK-293 cells. The extract shifted the activation curves in a concentration-dependent manner. Two major constituents of the extract, linoleic acid and oleic acid, exhibited proton channel activity. Our in vitro experiments suggested that P. japonica seed extract could be potentially used to rescue sperm motility in idiopathic infertility patients via pharmacological modulation of the proton channels during capacitation. Therefore, our results indicate the therapeutic potential of P. japonica seed extract for treating male infertility.
Subject(s)
Infertility, Male , Prunus , HEK293 Cells , Humans , Male , Plant Extracts/pharmacology , Protons , Sperm Capacitation , Sperm Motility , SpermatozoaABSTRACT
We have previously shown that a deficiency of CD1d-restricted invariant natural killer T (iNKT) cells exacerbates dextran sulfate sodium (DSS)-induced colitis in Yeti mice that exhibit IFNγ-mediated hyper-inflammation. Although iNKT cell-deficiency resulted in reduced Foxp3 expression by mesenteric lymph node (MLN) CD4+ T cells in DSS-treated Yeti mice, the cellular mechanisms that regulate Foxp3 expression by CD25+CD4+ T cells during intestinal inflammation remain unclear. We found that Foxp3-CD25+CD4+ T cells expressing Th1 and Th17 phenotypic hallmarks preferentially expanded in the MLNs of DSS-treated Yeti/CD1d knockout (KO) mice. Moreover, adoptive transfer of Yeti iNKT cells into iNKT cell-deficient Jα18 KO mice effectively suppressed the expansion of MLN Foxp3-CD25+CD4+ T cells during DSS-induced colitis. Interestingly, MLN dendritic cells (DCs) purified from DSS-treated Yeti/CD1d KO mice promoted the differentiation of naive CD4+ T cells into Foxp3-CD25+CD4+ T cells rather than regulatory T (Treg) cells, indicating that MLN DCs might mediate Foxp3+CD25+CD4+ T cell expansion in iNKT cell-sufficient Yeti mice. Furthermore, we showed that Foxp3-CD25+CD4+ T cells were pathogenic in DSS-treated Yeti/CD1d KO mice. Our result suggests that pro-inflammatory DCs and CD1d-restricted iNKT cells play opposing roles in Foxp3 expression by MLN CD25+CD4+ T cells during IFNγ-mediated intestinal inflammation, with potential therapeutic implications.
Subject(s)
Colitis , Dendritic Cells , Natural Killer T-Cells , Animals , Mice , Colitis/pathology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Interferon-gamma/metabolism , Mice, Inbred C57BL , Mice, Knockout , Natural Killer T-Cells/metabolism , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/metabolism , CD4-Positive T-Lymphocytes/immunology , Interleukin-2 Receptor alpha Subunit , Dendritic Cells/immunology , Dendritic Cells/metabolismABSTRACT
Although 3-aminopropyl functionalized magnesium phyllosilicate nanoparticles (hereafter aminoclay nanoparticles, ACNs) are well-known nanomaterials employed as drug carriers, their effects on immune cells remain unclear. To address this issue, we explored murine dendritic cells (DCs) as these cells belong to the innate arm of the immune system and function as antigen-presenting cells to elicit adaptive immune responses. We examined the in vitro effects of ACNs on DCs isolated from B6 mice. ACN treatment significantly down-regulated the expression of inflammasome-related markers, including NLRP3, caspase-1, and IL1ß. The ACNs-induced anti-inflammatory DC phenotype was further confirmed by down-regulation of the AKT/mTOR/HIF1α signaling pathway. Such anti-inflammatory effects of ACNs on DCs occurred independently of DC subtypes. To document the effects of ACNs on DCs more clearly, we examined their anti-inflammatory effects on lipopolysaccharide (LPS)-activated DCs. As expected, excessive inflammatory responses (increased mitochondrial ROS and Th1-type cytokines such as IL12 and IL1ß) of LPS-activated DCs were dramatically attenuated by ACN treatment. Furthermore, ACNs down-regulated IFNγ production by antigen-specific CD4+ T cells, which is consistent with a reduced inflammatory phenotype of DCs. Overall, our results provide support for employing ACNs as drug delivery materials with therapeutic potential to control inflammatory disorders.
Subject(s)
Lipopolysaccharides , Nanoparticles , Animals , Mice , Lipopolysaccharides/pharmacology , Cytokines/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/metabolism , Immunity , Dendritic CellsABSTRACT
BACKGROUND/AIMS: To assess the efficacy and safety of intra-articular sacroiliac glucocorticoid injection in ankylosing spondylitis (AS). METHODS: Patients with AS undergoing fluoroscopy-guided intra-articular sacroiliac glucocorticoid injection were enrolled between 2012 and 2018. Efficacy was assessed by numeric pain rating scale, acute phase reactants, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index, and Ankylosing Spondylitis Disease Activity Score (ASDAS). Patients who started biologics within 3 months despite the intervention were compared with those not starting biologics, hence: the nonbiologic group. RESULTS: A total of 96 patients were treated, with a total of 107 injections. After intervention, there were significant decreases in numeric pain rating scale (7.8 ± 1.8 vs. 3.3 ± 2.2, p < 0.001) and acute phase reactants level (erythrocyte sedimentation rate [ESR] 23.0 mm/h [10.0-47.0 mm/h] vs. 13.0 mm/h [4.0-27.0 mm/h], p < 0.001; C-reactive protein [CRP] 1.0 mg/dL [0.2-2.7 mg/dL] vs. 0.2 mg/dL [0.2-0.9 mg/dL], p < 0.001). Disease activity scores also decreased for BASDAI (6.2 ± 1.8 vs. 4.5 ± 2.5, p = 0.001), Bath Ankylosing Spondylitis Functional Index (5.5 [4.1-7.0] vs. 1.8 [0.5-4.1], p = 0.001), ASDAS-CRP (2.9 ± 1.0 vs. 2.3 ± 1.3, p = 0.046), and ASDAS-ESR (3.7 ± 1.1 vs. 2.4 ± 1.3, p < 0.001). However, 12 patients (12.5%) started biologics within 3 months. These patients showed higher ESR (91.0 mm/h [IQR 21.0-113.0 mm/h] vs. 21.5 mm/h [IQR 9.5-43.0 mm/h], p = 0.010), CRP (8.0 mg/dL [IQR 1.11-17.1 mg/dL] vs. 0.8 mg/dL [IQR 0.2-1.8 mg/dL], p = 0.002), BASDAI (7.4 ± 1.2 vs. 5.9 ± 1.8, p = 0.027), and ASDAS-CRP (4.0 ± 0.5 vs. 2.8 ± 1.0, p = 0.004) than the nonbiologic group. There was no serious adverse event. CONCLUSIONS: Intra-articular sacroiliac glucocorticoid injection can be a safe and effective treatment option for active sacroiliitis in AS.
Subject(s)
Glucocorticoids , Spondylitis, Ankylosing , Blood Sedimentation , C-Reactive Protein/analysis , Glucocorticoids/administration & dosage , Humans , Injections, Intra-Articular , Severity of Illness Index , Spondylitis, Ankylosing/diagnosis , Spondylitis, Ankylosing/drug therapyABSTRACT
The large-conductance calcium-activated potassium channel (BKCa channel) is expressed on various tissues and is involved in smooth muscle relaxation. The channel is highly expressed on urinary bladder smooth muscle cells and regulates the repolarization phase of the spontaneous action potentials that control muscle contraction. To discover novel chemical activators of the BKCa channel, we screened a chemical library containing 8364 chemical compounds using a cell-based fluorescence assay. A chemical compound containing an isoxazolyl benzene skeleton (compound 1) was identified as a potent activator of the BKCa channel and was structurally optimized through a structure-activity relationship study to obtain 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (CTIBD). When CTIBD was applied to the treated extracellular side of the channel, the conductance-voltage relationship of the channel shifted toward a negative value, and the maximum conductance increased in a concentration-dependent manner. CTIBD altered the gating kinetics of the channel by dramatically slowing channel closing without effecting channel opening. The effects of CTIBD on bladder muscle relaxation and micturition function were tested in rat tissue and in vivo. CTIBD concentration-dependently reduced acetylcholine-induced contraction of urinary bladder smooth muscle strips. In an acetic acid-induced overactive bladder (OAB) model, intraperitoneal injection of 20 mg/kg CTIBD effectively restored frequent voiding contraction and lowered voiding volume without affecting other bladder function parameters. Thus, our results indicate that CTIBD and its derivatives are novel chemical activators of the bladder BKCa channel and potential candidates for OAB therapeutics. SIGNIFICANCE STATEMENT: The novel BKCa channel activator CTIBD was identified and characterized in this study. CTIBD directly activates the BKCa channel and relaxes urinary bladder smooth muscle of rat, so CTIBD can be a potential candidate for overactive bladder therapeutics.
Subject(s)
Fluorobenzenes/pharmacology , Large-Conductance Calcium-Activated Potassium Channels/metabolism , Muscle, Smooth/physiology , Small Molecule Libraries/pharmacology , Urinary Bladder/physiology , Animals , Drug Evaluation, Preclinical , Female , Fluorobenzenes/chemistry , Male , Molecular Structure , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Rats , Structure-Activity Relationship , Urinary Bladder/drug effects , Urinary Bladder/metabolism , Urination/drug effects , Xenopus laevisABSTRACT
INTRODUCTION: Antiviral therapy improves hepatic fibrosis and reduces hepatocellular carcinoma (HCC) incidence. This study aimed to evaluate whether on-therapy changes in scores for fibrosis index based on 4 factors and aspartate aminotransferase-to-platelet ratio index are associated with HCC development and establish an HCC risk score model incorporating noninvasive fibrosis marker (NFM) response. METHODS: This multicenter study recruited 5,147 patients with chronic hepatitis B (4,028 for derivation cohort and 1,119 for validation cohort) who were given entecavir/tenofovir for >12 months between 2007 and 2018. A risk prediction model for HCC was developed using predictors based on multivariable Cox models, and bootstrapping was performed for validation. RESULTS: The 10-year cumulative HCC incidence rates were 12.6% and 13.7% in the derivation and validation cohorts, respectively. The risk of HCC significantly differed with early NFM response, with a marked reduction in HCC risk in patients achieving a significant decrease in NFM by 12 months (P < 0.001). NFM response, sex, age, and cirrhosis were independently predictive of HCC. We developed the Fibrosis marker response, Sex, Age, and Cirrhosis (FSAC) score based on regression coefficients of each variable. For the 10-year prediction of HCC, FSAC showed higher C-index values than PAGE-B, modified PAGE-B, CU-HCC, and REACH-B (0.84 vs 0.77, 0.80, 0.77, and 0.67, respectively; all P < 0.005). The predictive performance of FSAC was corroborated in the validation cohort, with higher C-index than other models (all P < 0.050). DISCUSSION: On-therapy changes in NFM are an independent indicator of HCC risk. FSAC incorporating NFM response is a reliable risk score for risk estimation for HCC with better performance than other models.
Subject(s)
Antiviral Agents/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/blood , Hepatitis B, Chronic/drug therapy , Liver Cirrhosis/blood , Liver Neoplasms/blood , Adult , Carcinoma, Hepatocellular/virology , Female , Humans , Incidence , Liver Cirrhosis/virology , Liver Neoplasms/virology , Male , Middle Aged , Predictive Value of Tests , Risk AssessmentABSTRACT
PURPOSE: We investigated whether serum testosterone levels vary monthly in middle-aged men. MATERIALS AND METHODS: A total of 8,367 middle-aged men who participated in a police officer urological health screening program at National Police Hospital were included. The participants were applicants. Total testosterone was measured early in the morning. Additionally, data on age, waist circumference, blood pressure and levels of fasting blood sugar, triglycerides and high density lipoprotein were collected as confounders. We also collected the monthly temperature and daylight duration in Seoul. We compared the mean testosterone level in each month before and after adjusting for confounders. RESULTS: Testosterone showed a monthly pattern with a nadir in May (4.4 ng/ml) and a peak in January (6.0 ng/ml). The mean testosterone level differed significantly across the months (p <0.001). After adjusting for confounders, testosterone still showed a monthly pattern with a nadir in May (4.5 ng/ml) and a peak in January (6.1 ng/ml). The trendlines of testosterone and the daylight duration in each month suggested a negative relationship, and the trendlines of testosterone and outdoor temperature suggested a negative relationship. CONCLUSIONS: The serum testosterone levels varied monthly, and this variation seems to be related to outdoor temperature and daylight duration. Our results warrant further investigation.
Subject(s)
Testosterone/blood , Humans , Male , Mass Screening , Middle Aged , Prospective Studies , Time FactorsABSTRACT
BACKGROUND & AIMS: Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. METHODS: A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6 months post-treatment and defined as achieving both <2000 IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg-positive group, and <2000 IU/mL HBV DNA in the HBeAg-negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off-therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. RESULTS: The median follow-up period was 7.2 years. Forty-three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P < .001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non-sustained responders (16.2% vs 2.5%, P = .01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. CONCLUSIONS: During long-term follow-up after PEG-IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B, Chronic , Liver Neoplasms , Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Disease Progression , Hepatitis B Surface Antigens , Hepatitis B e Antigens , Hepatitis B, Chronic/drug therapy , Humans , Interferon-alpha/therapeutic use , Liver Neoplasms/drug therapy , Polyethylene Glycols/therapeutic use , Recombinant Proteins/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: This retrospective study aimed to investigate the impact of positive hepatitis B core antibody (anti-HBc) and metabolic disorders on clinical characteristics of hepatocellular carcinoma (HCC) patients in an HBV-endemic area. METHODS: A total of 1950 consecutive patients newly diagnosed with HCC between 2002 and 2015 were included. Patient records were reviewed. We compared non-viral and non-alcoholic HCC patients with other etiological groups for HCC. In addition, we compared HCC patients with negative hepatitis B surface antigen (HBsAg) and positive anti-HBc to those with negative HBsAg and negative anti-HBc, and to those with HBV. RESULTS: The prevalence of non-viral and non-alcoholic HCC increased from 7% in 2002-2011 to 12% in 2012-2015. The proportion of non-viral and non-alcoholic HCC gradually increased with age. Patients with non-viral and non-alcoholic HCC exhibited higher rates of metabolic disorders and preserved liver function. The rate of anti-HBc positivity was similarly high in all HCC etiological groups. The clinical features of HCC patients with negative HBsAg and positive anti-HBc were similar to those with negative HBsAg and negative anti-HBc, but significantly different from those with HBV HCC. Regarding tumor characteristics, patients in the non-viral and non-alcoholic HCC group had more advanced stages of tumors (mUICC stage III-V and BCLC stage C/D). There was no significant difference in overall survival among the patient groups. The presence of anti-HBc did not affect patient survival. CONCLUSION: Patients with non-viral and non-alcoholic HCC had a relatively high prevalence of metabolic disorders and preserved liver function. However, they had advanced tumor stage compared to patients from other etiological groups. Anti-HBc positivity did not affect the clinical characteristics or prognosis of non-HBV HCC patients in this study.
Subject(s)
Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/pathology , Hepatitis B Antibodies/immunology , Liver Neoplasms/epidemiology , Liver Neoplasms/pathology , Metabolic Diseases/epidemiology , Adult , Age Factors , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/immunology , Female , Hepatitis B Antigens , Hepatitis B virus , Humans , Liver Neoplasms/immunology , Male , Middle Aged , Prognosis , Retrospective Studies , Risk FactorsABSTRACT
We have previously shown that CD1d-restricted iNKT cells suppress dysregulated IFNγ expression and intestinal inflammation in Yeti mice on the C57BL/6 background. Since type 3 innate lymphoid cells (ILC3s) in mesenteric lymph nodes (MLN) protect against intestinal inflammation in a CD1d-associated manner, we investigated whether crosstalk between iNKT cells and MLN ILC3s controls IFNγ-mediated intestinal inflammation in Yeti mice. We found that Yeti mice display increased levels of ILC3s and that iNKT cell deficiency in Yeti/CD1d KO mice decreases levels of IL22-producing ILC3s during DSS-induced colitis. This finding indicates that iNKT cells and ILC3s cooperate to regulate intestinal inflammation in Yeti mice. Yeti iNKT cells displayed a pronounced anti-inflammatory (IL4- or IL9-producing) phenotype during colitis. Their adoptive transfer to iNKT cell-deficient animals induced a significant increase in IL22 production by ILC3s, indicating that crosstalk between iNKT cells and ILC3s plays a critical role in modulating colitis in Yeti mice. Moreover, we showed that the IL9-producing subset of iNKT cells potently enhances IL22-producing ILC3s in vivo. Taken together, our results identify a central role of the iNKT cell-ILC3 axis in ameliorating IFNγ-mediated intestinal inflammation.
Subject(s)
Antigens, CD1d/genetics , Inflammation/genetics , Interferon-gamma/genetics , Interleukins/genetics , Lymphocytes/metabolism , Animals , Colitis/chemically induced , Colitis/genetics , Colitis/immunology , Dextran Sulfate/toxicity , Humans , Immunity, Innate/genetics , Inflammation/immunology , Inflammation/pathology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Intestines/pathology , Lymph Nodes/metabolism , Lymph Nodes/pathology , Lymphocytes/drug effects , Lymphocytes/immunology , Mice , Mice, Knockout , Natural Killer T-Cells/immunology , Natural Killer T-Cells/pathology , Splanchnic Circulation/genetics , Interleukin-22ABSTRACT
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70-80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.