Polygenic Risk Score Predicts Earlier-Onset Adult Systemic Lupus Erythematosus and First-Year Renal Diseases in a Taiwanese Cohort.

OBJECTIVES: This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population. METHODS: Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE. RESULTS: In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III-IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis. CONCLUSIONS: PRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.

Effectiveness of the Huddles in Improving the Patient Safety Attitudes Among Clinical Team Members.

BACKGROUND AND OBJECTIVES: Huddles among members of interdisciplinary medical teams involve short stand-up sessions and allow team members to focus on existing or emerging patient safety issues, thereby facilitating team communication. Hospital managers are able to recognize the current situation of the organization through patient safety attitudes, strengthen team members' awareness of patient safety, and improve the quality of health care. The purpose of this study was to determine the effects of huddles on improving team members' attitudes toward patient safety. METHODS: We used a quasi-experimental design and selected 2 adult wards with similar properties as the experimental and comparison groups by convenience sampling. Data collection was from December 1, 2021, to June 30, 2022, at a teaching hospital in central Taiwan. Team members of the ward performing huddles formed the experimental group, and they participated 2 times per week in 15-minute huddles from 8:15 to 8:30 am for a total of 4 weeks. The comparison group adopted the routine team care process. Both groups completed the Safety Attitudes Questionnaire during the pre- and post-tests of the study. RESULTS: The experimental group scored significantly higher in the post-test than in the pre-test in all aspects of safety attitudes, with the exception of stress recognition. These improved aspects were teamwork climate (76.47 ± 15.90 vs 83.29 ± 13.52, P < .001), safety climate (75.94 ± 16.14 vs 82.81 ± 13.74, P < .001), job satisfaction (74.34 ± 20.22 vs 84.40 ± 17.22, P <.001), perceptions of management (78.02 ± 19.99 vs 85.51 ± 15.97, P < .001), and working conditions (78.85 ± 17.87 vs 86.81 ± 14.74, P < .001). CONCLUSION: Through the huddles, clinical team members improved their understanding of different aspects of safety attitudes. Such a study provided ward units with real-time improvement and adjustment in terms of patient safety during their medical work processes with better patient safety.

Association between HNF4A rs1800961 polymorphisms and gallstones in a Taiwanese population.

BACKGROUND AND AIM: A large genetic effect of a novel gallstone-associated genetic variant, the hepatocyte nuclear factor 4α (HNF4A) rs1800961 polymorphism, has been identified through recent genome-wide association studies. However, this effect has not been validated in Asian populations. We investigated the association between the rs1800961 variant and gallstones among a Taiwanese population. METHODS: A total of 20 405 participants aged between 30 and 70 years voluntarily enrolled in the Taiwan Biobank. Self-report questionnaires, physical examinations, biochemical tests, and genotyping were used for analysis. The association of the HNF4A rs1800961 variant and other metabolic risks with gallstone disease was analyzed using multiple logistic regression models. RESULTS: The minor T allele of HNF4A rs1800961 was associated with an increased risk of gallstone, and the association remained significant even after adjustment for other risk factors including age, body mass index (BMI), diabetes, hyperlipidemia, hypertension, and cigarette smoking (adjusted odds ratio [OR] = 1.90, 95% confidence interval [CI] = 1.31 to 2.75) in male participants. When further stratified by BMI and age, the lithogenic effect was the most significant in male participants with obesity (adjusted OR = 3.55, 95% CI = 1.92 to 6.56) and who were younger (adjusted OR = 2.45, 95% CI = 1.49 to 4.04). CONCLUSION: The novel gallstone-associated HNF4A rs1800961 variant was associated with the risk of gallstone in the Taiwanese men. Screening for the rs1800961 polymorphism may be particularly useful in assessing the risk of gallstone formation in younger or obese men.

Impacts of Huddle Intervention on the Patient Safety Culture of Medical Team Members in Medical Ward: One-Group Pretest-Posttest Design.

Objective: A huddle is a short, regular meetings to discuss existing or emerging patient safety issues. Hospital administrators can encourage healthcare staff to voluntarily examine the potential occurrence and severity of risks, thereby enhancing awareness of patient safety. The purpose of this study is to explore the effects of huddle intervention on patient safety culture among medical team members and related factors. Methods: We used a one-group pretest-posttest research design and convenience sampled 109 members of the general internal medicine ward team members from a medical center in central Taiwan. They participated 2 times per week in 15-min huddles from 08:15 to 08:30 in the morning, which lasted for a total of 4 weeks. The process was based on submitted ideas, approved ideas, research ideas and standardization, and data on the safety attitudes questionnaire (SAQ) were collected during the huddles' intervention pretest and posttest. Results: After the huddle intervention, we found significantly improved scores for safety attitude, teamwork climate (76.49±16.13 vs 83.26±13.39, p < 0.001), safety climate (75.07±16.07 vs 82.63±13.72, p < 0.001), job satisfaction (73.67±19.84 vs 83.39±17.21, p < 0.001), perceptions of management (77.87±19.99 vs 84.86±16.03, p < 0.001) and working conditions (78.96±18.16 vs 86.18±14.90, p < 0.001). Correlation analyses on the differences between pretest and posttest showed that age had a significant correlation with safety climate (r = 0.22, p = 0.022) and working conditions (r = 0.20, p = 0.035). The number of times to participate in a huddle had a significant correlation with teamwork climate (r = 0.33, p =<.001), safety climate (r = 0.30, p = 0.002), job satisfaction (r = 0.19, p = 0.043), and work conditions (r = 0.28, p = 0.003). Conclusion: Huddles improve clinical team members' understanding of different dimensions and relate factors of safety attitudes. Implementation of the huddles involved standardized process will help hospital administrators understand the steps to parallel expansion to other wards.

Distal Mean Nocturnal Baseline Impedance Predicts Pathological Reflux of Isolated Laryngopharyngeal Reflux Symptoms.

Background/Aims: Diagnosis of isolated laryngopharyngeal reflux symptoms (ILPRS), ie, without concomitant typical reflux symptoms (CTRS), remains difficult. Mean nocturnal baseline impedance (MNBI) reflects impaired mucosal integrity. We determined whether esophageal MNBI could predict pathological esophagopharyngeal reflux (pH+) in patients with ILPRS. Methods: In this cross-sectional study conducted in Taiwan, non-erosive or low-grade esophagitis patients with predominant laryngopharyngeal reflux symptoms underwent combined hypopharyngeal multichannel intraluminal impedance-pH monitoring when off acid suppressants. Participants were divided into the ILPRS (n = 94) and CTRS (n = 63) groups. Asymptomatic subjects without esophagitis (n = 25) served as healthy controls. The MNBI values at 3 cm and 5 cm above the lower esophageal sphincter (LES) and the proximal esophagus were measured. Results: Distal but not proximal esophageal median MNBI values were significantly lower in patients with pH+ than in those with pH- (ILPRS in pH+ vs pH-: 1607 Ω vs 2709 Ω and 1885 Ω vs 2563 Ω at 3 cm and 5 cm above LES, respectively; CTRS in pH+ vs pH-: 1476 vs 2307 Ω and 1500 vs 2301 Ω at 3 cm and 5 cm above LES, respectively, P < 0.05 for all). No significant differences of any MNBI exist between any pH- subgroups and healthy controls. The areas under the receiver operating characteristic curve in the ILPRS group were 0.75 and 0.80, compared to the pH- subgroup and healthy controls (P < 0.001 for both), respectively. Interobserver reproducibility was good (Spearman correlation 0.93, P < 0.0001). Conclusion: Distal esophageal MNBI predicts pathological reflux in patients with ILPRS.

The ABCG2 rs2231142 polymorphism and the risk of nephrolithiasis: A case-control study from the Taiwan biobank.

Background: Hyperuricemia and gout are risk factors of nephrolithiasis. However, it is unclear whether the ABCG2 gene contributes to the development of nephrolithiasis. We aimed to investigate the interaction between the ABCG2 rs2231142 variant and incident nephrolithiasis in the Taiwanese population. Methods: A total of 120,267 adults aged 30-70 years were enrolled from the Taiwan Biobank data-base in this retrospective case-control study and genotyped for rs2231142. The primary outcome was the prevalence of self-reported nephrolithiasis. The odds ratio (OR) of incident nephrolithiasis was analyzed by multivariable logistic regression models with adjustment for multifactorial confounding factors. Associations of the ABCG2 rs2231142 variant with serum uric acid levels, and the incident nephrolithiasis were explored. Results: The frequency of rs2231142 T allele was 53%, and 8,410 participants had nephrolithiasis. The multivariable-adjusted OR (95% confidence interval) of nephrolithiasis was 1.18 (1.09-1.28) and 1.12 (1.06-1.18) for TT and GT genotypes, respectively, compared with the GG genotype (p<0.001), specifically in the male population with hyperuricemia. Higher age, male sex, hyperlipidemia, hypertension, diabetes mellitus, hyperuricemia, smoking and overweight were independent risk factors for nephrolithiasis. In contrast, regular physical exercise is a protective factor against nephrolithiasis. Conclusions: ABCG2 genetic variation is a significant risk of nephrolithiasis, independent of serum uric acid levels. For rs2231142 T allele carriers, our result provides evidence for precision healthcare to tackle hyperuricemia, comorbidities, smoking, and overweight, and recommend regular physical exercise for the prevention of nephrolithiasis.

Validation of Pharyngeal Acid Reflux Episodes Using Hypopharyngeal Multichannel Intraluminal Impedance-pH.

Background/Aims: Hypopharyngeal multichannel intraluminal impedance-pH (HMII-pH) technology incorporating 2 trans-upper esophageal sphincter impedance channels has been developed to detect pharyngeal reflux. We used the HMII-pH technique to validate the candidate pharyngeal acid reflux (PAR) episodes based on the dual-pH tracings and determined the interobserver reproducibility. Methods: We conducted a cross-sectional study in tertiary centers in Taiwan. Ninety patients with suspected laryngopharyngeal reflux and 28 healthy volunteers underwent HMII-pH test when off acid suppressants. Candidate PAR episodes were characterized by pharyngeal pH drops of at least 2 units and reaching a nadir pH of 5 within 30 seconds during esophageal acidification. Two experts manually independently identified candidate PAR episodes based on the dual-pH tracings. By reviewing the HMII-pH tracings, HMII-pH-proven PAR episodes were subsequently confirmed. The consensus reviews of HMII-pH-proven PAR episodes were considered to be the reference standard diagnosis. The interobserver reproducibility was assessed. Results: A total of 105 candidate PAR episodes were identified. Among them 84 (80.0%; 95% CI, 71.0-87.0%) were HMII-pH-proven PAR episodes (82 in 16 patients and 2 in 1 healthy subject). Patients tended to have more HMII-pH-proven PAR episodes than healthy controls (median and percentile values [25th, 75th, and 95th percentiles]: 0 [0, 0, 3] vs 0 [0, 0, 0], P = 0.067). The concordance rate in diagnosing HMII-pH-proven PAR episodes between 2 independent observers was 92.2%. Conclusion: Our preliminary data showed that 80.0% (71.0-87.0%) of the proposed candidate PAR episodes were HMII-pH-proven PAR episodes, among which the interobserver reproducibility was good.

Anti-depressive-like and cognitive impairment alleviation effects of Gastrodia elata Blume water extract is related to gut microbiome remodeling in ApoE-/- mice exposed to unpredictable chronic mild stress.

ETHNOPHARMACOLOGY RELEVANCE: Gastrodia elata Blume (GE) is a traditional Chinese dietary therapy used to treat neurological disorders. Gastrodia elata Blume water extract (WGE) has been shown to ameliorate inflammation and improve social frustration in mice in a chronic social defeat model. However, studies on the anti-depressive-like effects and cognitive impairment alleviation related to the impact of WGE on the gut microbiome of ApoE-/- mice remain elusive. AIM OF THE STUDY: The present study aimed to investigate the anti-depressive-like effect and cognitive impairment alleviation and mechanisms of WGE in ApoE-/- mice subjected to unpredictable chronic mild stress (UCMS), as well as its impact on the gut microbiome of the mice. MATERIALS AND METHODS: Sixty ApoE-/- mice (6 months old) were randomly grouped into six groups: control, UCMS, WGE groups [5, 10, 20 mL WGE/kg body weight (bw) + UCMS], and a positive group (fluoxetine 20 mg/kg bw + UCMS). After four weeks of the UCMS paradigm, the sucrose preference, novel object recognition, and open field tests were conducted. The neurotransmitters serotonin (5-HT), dopamine (DA) and their metabolites were measured in the prefrontal cortex. Serum was collected to measure corticosterone and amyloid-42 (Aß-42) levels. Feces were collected, and the gut microbiome was analyzed. RESULTS: WGE restored sucrose preference, exploratory behavior, recognition ability, and decreased the levels of serum corticosterone and Aß-42 in ApoE-/- mice to alleviate depressive-like behavior and cognitive impairment. Furthermore, WGE regulated the monoamine neurotransmitter via reduced the 5-HT and DA turnover rates in the prefrontal cortex. Moreover, WGE elevated the levels of potentially beneficial bacteria such as Bifidobacterium, Akkermansia, Alloprevotella, Defluviitaleaceae_UCG-011, and Bifidobacterium pseudolongum as well as balanced fecal short-chain fatty acids (SCFAs). CONCLUSION: WGE demonstrates anti-depressive-like effects, cognitive impairment alleviation, and gut microbiome and metabolite regulation in ApoE-/- mice. Our results support the possibility of developing a functional and complementary medicine to prevent or alleviate depression and cognitive decline using WGE in CVDs patients.

Endoscopic features and clinical course of patients with asymptomatic cecal ulcers.

BACKGROUND: Cecal ulcers are sometimes encountered in asymptomatic individuals. Their clinical outcomes and management recommendations remain uncertain. METHODS: Asymptomatic patients who underwent a colonoscopic exam for colon cancer screening were retrospectively reviewed from July 2009 to November 2016. Patients with cecal ulcers were included. Patients who had colorectal symptoms, such as abdominal pain, had nonsteroidal anti-inflammatory drugs or were lost to follow-up were excluded. RESULTS: A total of 34,036 patients underwent colon cancer screening. Cecal ulcers were found in 35 patients. After exclusion, 24 patients (mean duration, 52 months) received follow-up colonoscopy. In 20 patients, (83.3%), cecal ulcer resolved without intervention, but 4 patients (16.7%) developed clinical significant diseases, including intestinal tuberculosis (n = 2), Crohn's disease (n = 1), and ulcerative colitis (n = 1). Patients who developed clinically significant diseases had a higher percentage of ulcers larger than 1 cm (75% vs. 15%, p = 0.035), terminal ileum involvement (100% vs. 15.4%, p = 0.006) and ulcers with irregular fold (75% vs. 5%, p = 0.008). CONCLUSIONS: In patients with asymptomatic cecal ulcers, the endoscopic features included larger ulcer size, terminal ileum involvement and ulcers with irregular fold may predict development of clinically significant diseases. If the above-mentioned features are present, even asymptomatic patients should be closely monitored.

The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases.

Oxidative stress is mainly caused by intracellular reactive oxygen species (ROS) production, which is highly associated with normal physiological homeostasis and the pathogenesis of diseases, particularly ocular diseases. Autophagy is a self-clearance pathway that removes oxidized cellular components and regulates cellular ROS levels. ROS can modulate autophagy activity through transcriptional and posttranslational mechanisms. Autophagy further triggers transcription factor activation and degrades impaired organelles and proteins to eliminate excessive ROS in cells. Thus, autophagy may play an antioxidant role in protecting ocular cells from oxidative stress. Nevertheless, excessive autophagy may cause autophagic cell death. In this review, we summarize the mechanisms of interaction between ROS and autophagy and their roles in the pathogenesis of several ocular diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and optic nerve atrophy, which are major causes of blindness. The autophagy modulators used to treat ocular diseases are further discussed. The findings of the studies reviewed here might shed light on the development and use of autophagy modulators for the future treatment of ocular diseases.

Interaction of Alcohol Consumption and ABCG2 rs2231142 Variant Contributes to Hyperuricemia in a Taiwanese Population.

BACKGROUND: ABCG2 rs2231142 is an important genetic factor that contributes to the development of gout and hyperuricemia (HUA). Epidemiologic studies have demonstrated that lifestyle risk factors of HUA (e.g., alcohol consumption) and genetic predisposition (e.g., ABCG2 gene) together, contribute to enhanced serum uric acid levels. However, the interaction between ABCG2 rs2231142, alcohol consumption, and HUA in the Taiwanese population is still unclear. Therefore, this study investigated whether the risk of HUA is associated with ABCG2 rs2231142 variants and how this is affected by alcohol consumption. METHOD: study subjects were selected from the participants of the Taiwan Biobank database. Overall, 114,540 participants aged 30 to 70 years were enrolled in this study. The interaction between ABCG2 rs2231142, alcohol consumption, and serum uric acid (sUA) levels was analyzed by multiple logistic regression models. RESULTS: the prevalence of HUA was 32.7% and 4.4 % in the male and female populations, respectively. In the whole study population, the minor T allele of ABCG2 rs2231142 was significantly associated with HUA risk, and the occurrence of HUA was high in TT genotype and TG genotype. The risk of HUA was significantly increased by the combined association of ABCG2 rs2231142 and alcohol consumption for TG/TT genotype compared to the GG genotype (wild-type genotype), especially among women. CONCLUSION: the ABCG2 rs2231142 is a crucial genetic locus for sUA levels in the Taiwanese population and our findings revealed that alcohol consumption combined with the ABCG2 rs2231142 risk allele contributes to increased HUA risk.

Association of ABCG2 rs2231142 Allele and BMI With Hyperuricemia in an East Asian Population.

Objectives: Genetic variants and obesity are risk factors for hyperuricemia (HUA). Recent genome-wide association studies have identified ABCG2 rs2231142 as one of the most prominent genetic variants for HUA in an East Asian population. Nevertheless, no large-scale studies have demonstrated any interactive effects between this variant and obesity on serum urate level in Asians. This study aimed to determine the interaction of ABCG2 rs2231142 variant and body mass index (BMI) and its effect on risk of HUA in an East Asian population. Methods: The study was conducted using the Taiwan Biobank database, a population-based biomedical research database of patients with Taiwanese Han Chinese ancestry aged 30-70years between September 2014 and May 2017. Detailed physical information on participants were collected by questionnaires and genotyping using Affymetrix TWB 650K SNP chip. The primary outcome was HUA, defined as a serum uric acid level>7.0mg/dl. Odds ratio (OR) of HUA was analyzed using logistic regression models and the effects of interaction between ABCG2 rs2231142 variants and BMI on serum uric acid level were explored. Results: We identified 25,245 subjects, 4,228 (16.75%) of whom had HUA. The prevalence of HUA was 30% in men and 3.8% in women. The risk of HUA was significantly associated with ABCG2 rs2231142 risk T allele, with more HUA in TT genotype (OR: 2.40, 95% CI: 2.11-2.72, p<0.001) and TG genotype (OR: 1.64, 95% CI: 1.51-1.78, p<0.001) in men, and TT genotype (OR: 2.42, 95% CI: 1.83-3.20, p<0.001) and TG genotype (OR: 1.82, 95% CI: 1.46-2.23, p<0.001) in women, compared with their counterparts. Moreover, we found a strong genetic-environmental interaction associated with the risk of HUA. There was increased risk of HUA by the interaction of ABCG2 rs2231142 variant and BMI for TT genotype (OR: 7.42, 95% CI: 2.54-21.7, p<0.001) and TG genotype (OR: 4.25, 95% CI: 2.13-8.47, p<0.001) in men compared with the GG genotype in men, and for TT genotype (OR: 25.43, 95% CI: 3.75-172.41, p<0.001) and TG genotype (OR: 3.05, 95% CI: 0.79-11.71, p=0.011) in women compared with the GG genotype in women. Conclusion: The risk of HUA was markedly increased by the interaction of ABCG2 rs2231142 variant and BMI, both in men and in women. Body weight control and reduction in BMI are recommended in high-risk patients with the ABCG2 rs2231142 risk T allele.

Long-Term Safety in HBsAg-Negative, HBcAb-Positive Patients with Rheumatic Diseases Receiving Maintained Steroid Therapy after Pulse Therapy.

The risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative, antibody to hepatitis B core antigen (anti-HBc)-positive patients after glucocorticoid (GC) pulse therapy remains unclear. AIMS: Our study aimed to examine the safety of GC pulse therapy in HBsAg-negative, anti-HBc-positive rheumatic patients. METHODS: Medical records of HBsAg-negative, anti-HBc-positive patients receiving GC pulse therapy to treat rheumatic diseases were reviewed. The primary outcome was HBV-associated hepatitis occurring within the first year after GC pulse therapy; the secondary outcome was HBsAg seroreversion occurring during the follow-up period. RESULTS: We identified 5222 HBsAg-negative, anti-HBc-positive patients with rheumatic diseases who had attended Taichung Veterans General Hospital from October 2006 to December 2018. A total of 689 patients had received GC pulse therapy, with 424 patients being analyzed. Hepatitis was noted in 28 patients (6.6%) within the first year after GC pulse therapy, but none had been diagnosed as HBV-associated hepatitis. Three patients (0.7%) later developed HBsAg seroreversion, with a median interval of 97 months from the first episode of GC pulse therapy. These cases concurrently had maintained high dose oral prednisolone (≥20 mg prednisolone daily for over 4 weeks). CONCLUSIONS: Amongst the HBsAg-negative, anti-HBc-positive rheumatic patients treated with GC pulse therapy, the risk of HBV-associated hepatitis within the first year was low. HBsAg seroreversion may have developed in the later stage, but only in those patients who had maintained high-dose oral steroid.

Electrospun Resveratrol-Loaded Polyvinylpyrrolidone/Cyclodextrin Nanofibers and Their Biomedical Applications.

Resveratrol is a naturally occurring polyphenol compound which has been shown to possess antioxidant and anti-inflammatory properties. However, its pharmaceutical applications are limited by its poor water solubility. In this study, we used electrospinning technology to synthesize nanofibers of polyvinylpyrrolidone (PVP) and hydroxypropyl-ß-cyclodextrin (HPBCD) loaded with resveratrol. We used X-ray diffractometry to analyze crystalline structure, Fourier transform infrared spectroscopy to determine intermolecular hydrogen bonding, antioxidant assays to measure antioxidant activity, and Franz diffusion cells to evaluate skin penetration. Our results showed that the aqueous solubility of resveratrol nanofibers was greatly improved (by more than 20,000-fold) compared to the pure compound. Analysis of physicochemical properties demonstrated that following nanofiber formation, resveratrol was converted from a crystalline to amorphous structure, and resveratrol formed new intermolecular bonds with PVP and HPBCD. Moreover, resveratrol nanofibers showed good antioxidant activity. In addition, the skin penetration ability of resveratrol in the nanofiber formulation was greater than that of pure resveratrol. Furthermore, resveratrol nanofibers suppressed particulate matter (PM)-induced expression of inflammatory proteins (COX-2 and MMP-9) in HaCaT keratinocytes. Therefore, resveratrol-loaded nanofibers can effectively improve the solubility and physicochemical properties of resveratrol, and may have potential applications as an antioxidant and anti-inflammatory formulation for topical skin application.

Sodium Iodate Disrupted the Mitochondrial-Lysosomal Axis in Cultured Retinal Pigment Epithelial Cells.

PURPOSE: Low doses of sodium iodate (NaIO3) impair visual function in experimental animals with selective damage to retinal pigment epithelium (RPE) and serve as a useful model to study diseases caused by RPE degeneration. Mitochondrial dysfunction and defective autophagy have been suggested to play important roles in normal aging as well as many neurodegenerative diseases. In this study, we examined whether NaIO3 treatment disrupted the mitochondrial-lysosomal axis in cultured RPE. METHODS: The human RPE cell line, ARPE-19, was treated with low concentrations (≤500 µM) of NaIO3. The expression of proteins involved in the autophagic pathway and mitochondrial biogenesis was examined with Western blot. Intracellular acidic compartments and lipofuscinogenesis were evaluated by acridine orange staining and autofluorescence, respectively. Mitochondrial mass, mitochondrial membrane potential (MMP), and mitochondrial function were quantified by MitoTracker Green staining, tetramethylrhodamine methyl ester staining, and the MTT assay, respectively. Phagocytosis and the degradation of photoreceptor outer segments (POS) were assessed by fluorescence-based approaches and Western blot against rhodopsin. RESULTS: Treatment with low concentrations of NaIO3 decreased cellular acidity, blocked autophagic flux, and resulted in increased lipofuscinogenesis in ARPE-19 cells. Despite increases in protein levels of Sirtuin 1 and PGC-1α, mitochondrial function was compromised, and this decrease was attributed to disrupted MMP. POS phagocytic activities decreased by 60% in NaIO3-treated cells, and the degradation of ingested POS was also impaired. Pretreatment and cotreatment with rapamycin partially rescued NaIO3-induced RPE dysfunction. CONCLUSIONS: Low concentrations of NaIO3 disrupted the mitochondrial-lysosomal axis in RPE and led to impaired phagocytic activities and degradation capacities.

The prevalence and risk factors of hepatitis B flares in chronic hepatitis B patients receiving glucocorticoid pulse therapy.

Background The frequency and risks of hepatitis B reactivation in patients receiving glucocorticoid pulse therapy has not been reported. Objective The aim of our study was to investigate the possibility of glucocorticoid pulse therapy related hepatitis B flare. Setting A Taiwanese tertiary hospital. Methods Chronic hepatitis B patients underwent glucocorticoid pulse therapy were retrospectively collected. The prevalence of hepatitis B flare was counted, and the statistic analysis with logistic regression was adapted to assess the associated risk factors. Main outcome measure The prevalence and associated risk factors of the individuals with hepatitis B flare after glucocorticoid pulse therapy were collected and analyzed. Results A total of 112 patients were identified. Forty patients had received prophylactic antiviral therapy and none of them developed hepatitis B flare. Among the 72 patients who had not received antiviral prophylaxis, 11 of them (15.3%) experienced hepatitis B flares. Those individuals with hepatitis B flares, comparing to those without, were younger (37.4 ± 13.3 vs. 46.0 ± 11.1, p = 0.038), had higher ratio of HBeAg positivity (50 vs. 15.9%, p = 0.017), higher percentage of high hepatitis B viral load (81.8 vs. 8.3%, p = 0.002), higher maintenance glucocorticoid dose (prednisone or equivalent 22.7 ± 14.9 vs. 10.7 ± 12.4 mg, p = 0.003) and higher ratio of cyclophosphamide use (27.3 vs. 1.6%, p = 0.010). After multivariate analysis, only higher dose of maintenance glucocorticoid was related to hepatitis B flare (odds ratio, 1.08; 95% CI, 1.01-1.16). Conclusion A higher maintenance glucocorticoid dosage is associated with the risk of hepatitis B flare after glucocorticoid pulse therapy. No hepatitis B flare occurred in patients receiving prophylactic antiviral therapy before glucocorticoid pulse therapy.

Efficacy and safety of recombinant human lymphotoxin-α derivative with cisplatin and fluorouracil in patients with metastatic esophageal squamous cell carcinoma: A randomized, multicenter, open-label, controlled, phase 2b trial.

BACKGROUND: Recombinant human lymphotoxin-α derivative (rhLTα-Da) is a lymphotoxin-α derivative that is missing 27 N-terminal amino acid residues. Previous studies indicated a benefit from the addition of rhLTα-Da to cisplatin-based treatment in patients with metastatic esophageal squamous cell carcinoma. The current study was conducted to evaluate the efficacy and safety of rhLTα-Da plus cisplatin and fluorouracil (PF) in patients with mESCC. METHODS: Patients from 15 centers in China were randomly assigned (1:1:1) to 3 arms (arm A, PF plus 10 µg/m2 daily rhLTα-Da; arm B, PF plus 20 µg/m2 daily rhLTα-Da; arm C, PF alone). The primary endpoints included progression-free survival (PFS) and the confirmed overall response rate (ORR). An exploratory analysis was performed to evaluate the role of serum tumor necrosis factor receptor II (TNFR II) in predicting the efficacy of rhLTα-Da. RESULTS: Between September 2010 and May 2013, 150 patients were enrolled. No significant differences in either PFS or ORR were observed between the 3 arms. However, in a small subset of patients who had low serum TNFR II levels, the median PFS was significantly longer for those in arm B than for these in other 2 arms (7.2 months [95% confidence interval, 5.1-8.6 months] for arm B vs 3.5 months [95% confidence interval, 1.7-5.5 months] for arm A [P = .022] and 4.0 months [95% confidence interval, 3.2-6.3 months] for arm C [P = .027]). The addition of rhLTα-Da significantly increased the incidence of chills (P < .001). CONCLUSIONS: rhLTα-Da combined with the PF regimen failed to improve PFS and ORR in patients with mESCC, except in a small subset that had low serum TNFR II concentrations. Cancer 2017;123:3986-94. © 2017 American Cancer Society.

[Study of sequence-dependent in vitro effects of zoledronic acid and paclitaxel upon human nasopharyngeal carcinoma cell line HNE1].

OBJECTIVE: To explore the in vitro effects of anti-proliferation and apoptosis-inducing with different sequence regimens of zoledronic acid plus paclitaxel in human nasopharyngeal carcinoma cell line HNE1 so as to explore the optimal sequence regimen of these two drugs and related mechanism. METHODS: The cytotoxic effects of different sequence schemes of zoledronic acid plus paclitaxel on HNE1 cells were detected by methyl-thiazol-tetrazolium (MTT) assay. Annexin V-FITC/PI double staining flow cytometry (FCM) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay were used to measure the effects of zoledronic acid plus paclitaxel upon apoptosis. The expressions of mRNA of Bcl-2, Bax, Caspase3 and Caspase9 gene were detected by real-time quantitative-polymerase chain reaction (PCR) and protein was detected by Western blot. RESULTS: All experiment groups enhanced the effect of anti-proliferation by MTT assay (P < 0.05); the treatment of zoledronic acid followed by paclitaxel was superior to the other two regimens (P < 0.05). As detected by FCM, the early apoptotic rate of control group was 2.59% ± 0.28% and the experiment groups were 13.89% ± 0.69%, 11.73% ± 0.54%, 23.97% ± 0.68%, 10.45% ± 0.16% and 8.59% ± 0.74% respectively (P < 0.05). TUNEL assay detected the late apoptosis of HNE1 cells and the experiment groups enhanced the effect of apoptosis-inducing (P < 0.05). The treatment of zoledronic acid followed by paclitaxel was superior to the other regimens (P < 0.05). Such an effect was due to the down-regulation of anti-apoptotic protein Bcl-2 and up-regulations of pro-apoptotic proteins Bax, Caspase3 and Caspase9 at the expression levels of mRNA and protein. There was a greater regulation in the group of zoledronic acid followed by paclitaxel. CONCLUSION: Zoledronic acid can enhance the in vitro effects of anti-proliferation and apoptosis-inducing for paclitaxel on HNE1 cell. The treatment of zoledronic acid followed by paclitaxel may be the optimal regimen. Synergistic induction of apoptosis is via the effects of Bcl-2 family and through the mitochondrial pathway.

Zoledronic acid inhibits human nasopharyngeal carcinoma cell proliferation by activating mitochondrial apoptotic pathway.

We investigated the apoptosis-inducing effect of zoledronic acid in human nasopharyngeal carcinoma cell HNE-1 and explore the potential mechanism. Human nasopharyngeal carcinoma cell HNE-1 was exposed to various concentrations (0-40 µmol/L) of zoledronic acid. Cell proliferation was studied by an MTT assay. Cell apoptosis was analyzed by flow cytometry and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Cell cycle was analyzed by flow cytometry. Gene expressions were investigated by quantitative real-time PCR, and protein expressions were investigated by Western blot. The results showed zoledronic acid decreased cell proliferation not in a time- or dose-dependent fashion. TUNEL assay, together with Annexin V/propidium iodide FACS analysis, confirmed the increase in apoptotic HNE-1 cells treated with zoledronic acid. Cell cycle analysis showed a larger number of treated cells occupied the S-phase. Quantitative RT-PCR and Western blot revealed that the pro-apoptotic genes, Bad, Bax, and Caspase-9, were upregulated in treated HNE-1 cells, whereas the anti-apoptotic gene, Bcl-2, was downregulated in both mRNA and protein levels. In conclusion, zoledronic inhibits human nasopharyngeal carcinoma cell proliferation by inducing apoptosis via the mitochondrial apoptotic pathway.

Zoledronic acid inhibits proliferation and impairs migration and invasion through downregulating VEGF and MMPs expression in human nasopharyngeal carcinoma cells.

To demonstrate the effect of zoledronic acid in proliferation, invasion, and migration of human nasopharyngeal carcinoma cell HNE-1 and explore the potential role of VEGF, MMP-2, and MMP-9 proteins in vitro. Human nasopharyngeal carcinoma cell HNE-1 was exposed to various concentrations (0-40 µmol/l) of zoledronic acid. Zoledronic acid inhibited proliferation of HNE-1 cells though not in a dose-dependent manner. Zoledronic acid had exerted a dose-dependent effect on the migration and invasion of HNE-1 cells. Both expressions of mRNA and protein of MMP2, MMP9, and VEGF were reduced, respectively, detected by RT-PCR and Western blot assays. These data suggested that zoledronic acid not only inhibited growth but also invasion and migration of HNE-1 cells in vitro. The anti-cancer action of zoledronic acid was partially associated with the suppression of VEGF expression and secretion and downregulating the expression of MMP2 and MMP9.