OBJECTIVE: The objective of this study was to explore the association of longitudinal CA-125 measurements with overall survival (OS) time by developing a flexible model for patient-specific CA-125 profiles, and to provide a simple and reliable prediction of OS. METHODS: A retrospective study was performed on 275 patients with ovarian cancer who underwent at least one cycle of primary chemotherapy in our institute. Serial measurements of patients' CA-125 levels were performed at different frequencies according to their clinical plans. A statistical model coupling the Cox proportional hazards and the mixed-effects models was applied to determine the association of OS with patient-specific longitudinal CA-125 values. Stage and residual tumor size were additional variables included in the analysis. RESULTS: A total of 1,601 values of CA-125 were included. Longitudinal CA-125 levels, stage, and the residual tumor size were all significantly associated with OS. A patient-specific survival probability could be calculated. Validation showed that, in average, 85.4% patients were correctly predicted to have a high or low risk of death at a given time point. Comparison with a traditional model using CA-125 half-life and time to reach CA-125 nadir showed that the longitudinal CA-125 model had an improved predicative value. CONCLUSION: Longitudinal CA-125 values, measured from the diagnosis of ovarian cancer to the completion of primary chemotherapy, could be used to reliably predict OS after adjusting for the stage and residual tumor disease. This model could be potentially useful in clinical counseling of patients with ovarian cancer.
Counseling ; Diagnosis ; Drug Therapy ; Half-Life ; Humans ; Models, Statistical ; Neoplasm, Residual ; Ovarian Neoplasms* ; Retrospective Studies

Background: Compared with the Western population, central demyelinating disorders are relatively rare while the data on the prognostic value of autoantibodies together with clinical characteristics and cognitive dysfunction has rarely been explored in neuromyelitis optica (NMO) and multiple sclerosis (MS). Methods: Nineteen patients with MS and 14 with NMO underwent clinical profiling and cognitive assessment. According to serology tests, they are divided into four subgroups for further analysis. Results: There was higher frequency of aquaporin-4 immunoglobulin G. sero-positivity (64.3% vs. 10.5%; p=0.003) and antinuclear antibodies (ANA) and/or antibodies to extractable nuclear antigens (anti-ENA) in NMO compared to MS (42.9% vs. 5.2%; p=0.026). The presence of anti-ENA represented a unique clinical phenotype, with longer segment of myelitis (p=0.049), female preponderance, and an inverse correlation between age-of-onset and annual relapse rate (ρ= -0.88, p=0.021). Among patients with anti-ENA positivity, comprehensive serology panels revealed Sjögren’s syndrome A antibodies as the most common (83%), in contrast to limited clinical documentation of Sjögren’s syndrome (16%). There was no significant difference in cognitive assessment by anti-ENA status. MS and NMO represent two different serologic entities. Conclusions: Anti-ENA may have prognostic value for its linkage to a unique clinical phenotype, which has longer initial segment of myelitis, female preponderance, and higher annual relapse rate on earlier age-of-onset, but has limited clinical impact on cognition. Further studies are warranted to investigate whether anti-ENA represents an epiphenomenon of myelitis or simply a systemic inflammatory state.

Background:Reports on the aquaporin-4 immunoglobulin G (AQP4-IgG) status for cognitive performance and neuroimaging correlations are limited in neuromyelitis optica (NMO) and multiple sclerosis (MS) literature. Methods: Cognitive results of 19 MS and 15 NMO patients were compared with 47 agematched controls. Apparent diffusion coeffi cient (ADC) values were used to delineate gray matter and white matter damages and correlate with neuropsychological results. Results: Verbal memory test showed signifi cant differences between MS and NMO in the late registration, early and delay recall (p<0.05), while their retention rates were even. In MS, ADC values were signifi cantly elevated in the dorsolateral prefrontal and occipital gray matter which was in contrast with NMO group that showed elevation in the dorsolateral prefrontal gray matter and parieto-occcipital white matter. AQP4-IgG status exerted a limited effect on ADC values and neuropsychological results. Conclusions: Verbal memory test might be helpful in differentiating NMO and MS. ADC values can be used as a surrogate marker for tissue injury in NMO and MS since they were in line with the cognition scores. Anatomical regions with elevated ADC values were different in NMO and MS.

BACKGROUND/OBJECTIVES: Coffee is a complex chemical mixture, with caffeine being the most well-known bioactive substance. The immunomodulatory and anti-inflammatory properties of coffee and caffeine impact health in various aspects, including the respiratory system. The objective is to investigate the effects of coffee and caffeine on airway hyperresponsiveness and allergic reactions, as well as to analyze and compare associated cytokine profiles.MATERIALS/METHODS: BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) and given OVA inhalation to induce airway hypersensitivity. Two weeks after sensitization, they were intragastrically gavaged with coffee or caffeine, both containing 0.3125 mg caffeine, daily for 4 weeks. Control mice were fed with double-distilled water. Serum OVAspecific antibody levels were measured beforehand and 5 weeks after the first gavage. Airway hyperresponsiveness was detected by whole body plethysmography after gavage. Cytokine levels of bronchoalveolar lavage and cultured splenocytes were analyzed. RESULTS: Coffee effectively suppressed T helper 2-mediated specific antibody response.Airway responsiveness was reduced in mice treated with either coffee or caffeine. Compared to the control, coffee significantly reduced OVA-specific immunoglobulin (Ig) G, IgG1 and IgE antibody responses (P < 0.05). Caffeine also attenuated specific IgG and IgG1 levels, though IgE level was unaffected. Coffee significantly reduced interleukin (IL)-4 and increased IL-10 concentration in spleen cells and bronchoalveolar lavage fluid (P < 0.05). CONCLUSIONS Coffee effectively attenuated airway hyperresponsiveness and systemic allergic responses induced by OVA food allergen in mice. As a complex composition of bioactive substances, coffee displayed enhanced immunomodulatory and anti-inflammatory effects than caffeine.

Background/Aims: Direct‐acting antivirals (DAAs) have been approved for hepatitis C virus (HCV) treatment in patients with end-stage renal disease (ESRD) on hemodialysis. Nevertheless, the complicated comedications and their potential drug-drug interactions (DDIs) with DAAs might limit clinical practice in this special population. Methods: The number, class, and characteristics of comedications and their potential DDIs with five DAA regimens were analyzed among HCV-viremic patients from 23 hemodialysis centers in Taiwan. Results: Of 2,015 hemodialysis patients screened in 2019, 169 patients seropositive for HCV RNA were enrolled (mean age, 65.6 years; median duration of hemodialysis, 5.8 years). All patients received at least one comedication (median number, 6; mean class number, 3.4). The most common comedication classes were ESRD-associated medications (94.1%), cardiovascular drugs (69.8%) and antidiabetic drugs (43.2%). ESRD-associated medications were excluded from DDI analysis. Sofosbuvir/velpatasvir/voxilaprevir had the highest frequency of potential contraindicated DDIs (red, 5.6%), followed by glecaprevir/pibrentasvir (4.0%), sofosbuvir/ledipasvir (1.3%), sofosbuvir/velpatasvir (1.3%), and elbasvir/grazoprevir (0.3%). For potentially significant DDIs (orange, requiring close monitoring or dose adjustments), sofosbuvir/velpatasvir/voxilaprevir had the highest frequency (19.9%), followed by sofosbuvir/ledipasvir (18.2%), glecaprevir/pibrentasvir (12.6%), sofosbuvir/velpatasvir (12.6%), and elbasvir/grazoprevir (7.3%). Overall, lipid-lowering agents were the most common comedication class with red-category DDIs to all DAA regimens (n=62), followed by cardiovascular agents (n=15), and central nervous system agents (n=10). Conclusions HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with currently available DAA regimens. Elbasvir/grazoprevir had the fewest potential DDIs, and sofosbuvir/velpatasvir/voxilaprevir had the most potential DDIs.

PURPOSE: Lovastatin is an effective inhibitor of cholesterol synthesis. A previous study demonstrated that lovastatin can also suppress airway hyperresponsiveness (AHR) in murine model of asthma. We aimed to investigate the effect of lovastatin on mucus secretion and inflammation-associated gene expression in the lungs of murine model of asthma. METHODS: Female BALB/c mice were sensitized and challenged with ovalbumin (OVA) by intraperitoneal injection, and orally administered lovastatin from days 14 to 27 post-injection. Gene expression in lung tissues was analyzed using real-time polymerase chain reaction. AHR and goblet cell hyperplasia were also examined. BEAS-2B human bronchial epithelial cells were used to evaluate the effect of lovastatin on the expression of cell adhesion molecules, chemokines, and proinflammatory cytokines in vitro. RESULTS: We showed that lovastatin inhibits the expression of Th2-associated genes, including eotaxins and adhesion molecules, in the lungs of murine model of asthma. Mucin 5AC expression, eosinophil infiltration and goblet cell hyperplasia were significantly decreased in the lung tissue of murine model of asthma treated with lovastatin. Furthermore, lovastatin inhibited AHR and expression of Th2-associated cytokines in bronchoalveolar lavage fluid. However, a high dose (40 mg/kg) of lovastatin was required to decrease specific IgE to OVA levels in serum, and suppress the expression of Th2-associated cytokines in splenocytes. Activated BEAS-2B cells treated with lovastatin exhibited reduced IL-6, eotaxins (CCL11 and CCL24), and intercellular adhesion molecule-1 protein expression. Consistent with this, lovastatin also suppressed the ability of HL-60 cells to adhere to inflammatory BEAS-2B cells. CONCLUSIONS: These data suggest that lovastatin suppresses mucus secretion and airway inflammation by inhibiting the production of eotaxins and Th2 cytokines in murine model of asthma.
Animals ; Asthma* ; Bronchoalveolar Lavage Fluid ; Cell Adhesion Molecules ; Chemokines ; Cholesterol ; Cytokines ; Eosinophils ; Epithelial Cells ; Female ; Gene Expression ; Goblet Cells ; HL-60 Cells ; Humans ; Hyperplasia ; Immunoglobulin E ; Inflammation* ; Injections, Intraperitoneal ; Intercellular Adhesion Molecule-1 ; Interleukin-6 ; Lovastatin* ; Lung ; Mice ; Mucin 5AC ; Mucus* ; Ovalbumin ; Ovum ; Real-Time Polymerase Chain Reaction

Objective: A meta-analysis of locus-based genome-wide association studies recently identified a relationship between AXIN1 and Parkinson’s disease (PD). Few studies of Asian populations, however, have reported such a genetic association. The influences of rs13337493, rs758033, and rs2361988, three PD-associated genetic variants of AXIN1, were investigated in the present study because AXIN1 is related to Wnt/β-catenin signaling. Methods: A total of 2,418 individuals were enrolled in our Taiwanese cohort for analysis of the genotypic and allelic frequency. Polymerase chain reaction–restriction fragment length polymorphism analysis was employed for rs13337493 genotyping, and the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA) was used for rs758033 and rs2361988 genotyping in 672 patients with PD and 392 controls. Taiwan Biobank data of another 1,354 healthy controls were subjected to whole-genome sequencing performed using Illumina platforms at approximately 30× average depth. Results: Our results revealed that rs758033 {odds ratios [OR] (95% confidence interval [CI]) = 0.267 [0.064, 0.795], p = 0.014} was associated with the risk of PD, and there was a trend toward a protective effect of rs2361988 (OR [95% CI] = 0.296 [0.071, 0.884], p = 0.026) under the recessive model. The TT genotype of rs758033 (OR [95% CI] = 0.271 [0.065, 0.805], p = 0.015) and the CC genotype of rs2361988 (OR [95% CI] = 0.305 [0.073, 0.913], p = 0.031) were less common in the PD group than in the non-PD group. Conclusion Our findings indicate that the rs758033 and rs2361988 polymorphisms of AXIN1 may affect the risk of PD in the Taiwanese population.

Objective: Problematic use of social media (PUSM) may affect sleep quality and self-stigma in people with schizophrenia and consequently reduce their quality of life (QoL). This longitudinal study investigated if sleep quality and self-stigma mediated relationships between PUSM and QoL. Methods: One-hundred-and-ninety-three outpatients with schizophrenia were recruited from a psychiatric center in Taiwan from April 2019 to August 2021 and participated in a longitudinal study at intervals of three months between measurements. QoL was assessed using the World Health Organization Quality of Life Questionnaire Brief Version; sleep quality using the Pittsburgh Sleep Quality Index; self-stigma using the Self-Stigma Scale-Short; and PUSM using the Bergen Social Media Addiction Scale. Via SPSS 20.0, general estimating equation models assessed temporal associations between variables. Via R software, mediating effects of self-stigma and sleep quality were examined through Monte Carlo simulations with 20,000 repetitions. Results: Mean scores of physical, psychological, social and environmental QoL ranged from 11.86 to 13.02. Mean scores of sleep quality and self-stigma were 9.1±4.5 and 2.2±0.8, respectively. Sleep quality and self-stigma were directly related to QoL (p<0.001) and mediated indirect relationships between PUSM and all components of QoL with a range of 95% confidence intervals spanning from -0.0591 to -0.0107 for physical QoL; -0.0564 to -0.0095 for psychological QoL; -0.0292 to -0.0035 for social QoL; and -0.0357 to -0.0052 for environmental QoL. Conclusion Sleep quality and self-stigma mediated relationships between PUSM and QoL in people with schizophrenia. Developing interventions targeting PUSM, sleep, and self-stigma may help improve QoL in people with schizophrenia.

Triple-negative breast cancer (TNBC) remains difficult to treat and urgently needs new therapeutic options. Nintedanib, a multikinase inhibitor, has exhibited efficacy in early clinical trials for HER2-negative breast cancer. In this study, we examined a new molecular mechanism of nintedanib in TNBC. The results demonstrated that nintedanib enhanced TNBC cell apoptosis, which was accompanied by a reduction of p-STAT3 and its downstream proteins. STAT3 overexpression suppressed nintedanib-mediated apoptosis and further increased the activity of purified SHP-1 protein. Moreover, treatment with either a specific inhibitor of SHP-1 or SHP-1-targeted siRNA reduced the apoptotic effects of nintedanib, which validates the role of SHP-1 in nintedanib-mediated apoptosis. Furthermore, nintedanib-induced apoptosis was attenuated in TNBC cells expressing SHP-1 mutants with constantly open conformations, suggesting that the autoinhibitory mechanism of SHP-1 attenuated the effects of nintedanib. Importantly, nintedanib significantly inhibited tumor growth via the SHP-1/p-STAT3 pathway. Clinically, SHP-1 levels were downregulated, whereas p-STAT3 was upregulated in tumor tissues, and SHP-1 transcripts were associated with improved disease-free survival in TNBC patients. Our findings revealed that nintedanib induces TNBC apoptosis by acting as a SHP-1 agonist, suggesting that targeting STAT3 by enhancing SHP-1 expression could be a viable therapeutic strategy against TNBC.
Apoptosis* ; Breast Neoplasms ; Disease-Free Survival ; Humans ; Protein-Tyrosine Kinases* ; RNA, Small Interfering ; Triple Negative Breast Neoplasms* ; Tyrosine*

Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician's clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms.
Antipsychotic Agents* ; Asian Continental Ancestry Group ; Bipolar Disorder* ; Consensus* ; Fluphenazine ; Haloperidol ; Humans ; Judgment ; Microspheres ; Patient Compliance ; Psychotic Disorders ; Recurrence ; Risperidone ; Schizophrenia ; Taiwan ; Aripiprazole ; Paliperidone Palmitate