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It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P <.01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P =.40) and HCC incidence rates (5.1% vs 4.4%; P =.64), but lower BR (84.0% vs 90.9%; P <.001) and CR (78.8% vs 83.4%; P =.016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17–1.46; P <.001) and CR (SHR, 1.16; 95% CI, 1.03–1.31; P =.016), but VR and HCC risks were similar. Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups. [ABSTRACT FROM AUTHOR]

• Developed a sensitive and fast analytical methodology for monitoring Remdesivir. • An improved vortex-assisted salt-induced liquid-liquid microextraction technique. • Short total run time in both UHPLC-PDA and UHPLC-MS/MS methods. • This method is simple, efficient, low-cost and eco-friendly sample preparation process. • This method can be used for accurate monitoring of Remdesivir in human plasma. • As a standard analytical tool for PK/TDM during clinical trials/COVID-19 treatment. To tackle the harmful consequences of the widespread COVID-19 pandemic, a broad-spectrum anti-viral drug remdesivir (RDV) has gained the utmost attention recently due to its promising application in treating COVID-19 patients. However, a fast and sensitive analytical methodology is important to monitor RDV drug profile in human plasma for pharmacokinetics (PK) and therapeutic drug monitoring (TDM). In this study, we demonstrate an improved vortex-assisted salt-induced liquid-liquid microextraction (VA-SI-LLME) technique coupled with UHPLC-PDA and UHPLC-MS/MS for rapid determination of RDV in human plasma. This technique involves simple one-step protein precipitation with hydrochloric acid and subsequent extraction with acetonitrile for analysis. Under the optimal VA-SI-LLME conditions (500 μL of acetonitrile with 2.5 g ammonium sulfate under 2 min vortex extraction), method validation results indicated an excellent correlation coefficient of 0.9969 for UHPLC-PDA (monitored at 254 nm) and 0.9990 for UHPLC-MS/MS (monitored at electrospray ionization with + ion mode transitions of m/z 603.1→ m/z 402.20 and m/z 603.1→ m/z 199.90). The detection and quantification limits were 1.5 and 5 ng/mL for UHPLC/PDA, and 0.3 and 1 ng/mL for UHPLC-MS/MS, respectively. The developed method showed excellent extraction recoveries between 90.79–116.74 % and 85.68–101.34 % with intraday and interday precision ≤ 9.59 for both methods. These results proved that the developed method is a simple, fast, and sensitive analytical method that can be applied as a standard analytical tool for PK and TDM studies of RDV in clinical trials during the current worldwide outbreak. [ABSTRACT FROM AUTHOR]

Background: The biochemical response is a crucial indicator of prognosis in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs). The impact of hepatitis D virus (HDV) infection on alanine aminotransferase normalization is elusive.Methods: The longitudinal study recruited 1185 CHB patients who received NAs. These patients were tested for anti-HDV antibody and HDV RNA at the initiation of anti-hepatitis B virus (HBV) therapy and annually for patients who were HDV-seropositive. ALT levels were examined at the first and second year of anti-HBV therapy. ALT abnormality was defined as ALT levels above 40 IU/mL in both male and female, and the risk factors associated with ALT abnormality were analysed.Results: Rates of seropositivity for anti-HDV and HDV RNA were 2.0% and 0.8% among 1185 NA-treated CHB patients, respectively. The strongest factor associated with ALT abnormality (>40 IU/mL) after first year treatment with NAs was HDV RNA seropositivity at year 1 (odds ratio [OR]/95% confidence interval [CI]: 31.44/3.49-283.56, P = 0.002), followed by liver cirrhosis (2.18/1.51-3.15, P < 0.001), detectable HBV DNA at year 1 (OR/CI: 1.99/1.36-2.92, P < 0.001), diabetes (OR/CI: 1.75/1.10-2.78, P = 0.02), body mass index (BMI) (OR/CI: 1.13/1.09-1.18, P < 0.001) and age (OR/CI: 0.97/0.96-0.98, P < 0.001). Among patients who were seronegative for HBV DNA at year 1, the strongest factor associated with ALT abnormality was HDV RNA seropositivity at year 1 (OR/CI: 30.00/3.28-274.05, P = 0.003), followed by liver cirrhosis (OR/CI: 1.83/1.21-2.75, P = 0.004), BMI (OR/CI: 1.16/1.11-1.21, P < 0.001) and age (OR/CI: 0.97/0.96-0.99, P < 0.001). Similarly, the impact of HDV RNA seropositivity on ALT abnormality was noted in patients without detectable HBV DNA but not in those with hepatitis B viremia at treatment year 2 (OR/CI: 10.16/1.33-77.74, P = 0.03).Conclusion: HDV infection played an important role in ALT abnormality in CHB patients receiving 1-year and 2-year NAs. The impact was particularly noted in patients who had successfully suppressed HBV DNA. [ABSTRACT FROM AUTHOR]

Background: The features and risk analysis of non-alcoholic fatty liver disease (NAFLD) in a community-based setting remain elusive. The predictors between obese and lean subjects need further clarification. We aimed to assess the characteristics of NAFLD during a community screening. The associated metabolic abnormalities and cardiovascular risk assessment were also analyzed.Methods: A total of 2483 subjects receiving multi-purpose health screening at 10 primary care centers were recruited. They received clinical assessment, including demographic data, laboratory examination, and abdominal sonography.Results: The prevalence of NAFLD and metabolic syndrome were 44.5%, and 15.8%, respectively. Among those NAFLD subjects, 1212 (48.8%) subjects were obese (BMI≥ 24 kg/m2). There was an increasing trend of NAFLD according to age, ranging from 25.8% of those aged <30 years to 54.4% of those aged 50-70 years (P for trend< 0.0001). High insulin resistance (IR) was the significant predictive factor for NAFLD in both obese (odds ratio [OR] = 3.85, 95% confidence interval [CI] = 1.87-8.36, P = 0.0002) and lean subjects (OR = 2.52, 95% CI = 1.13-5.54, p = 0.02). The prevalence of high Framingham Risk Score (≥7.5%) was 56.7% (211/372) among the male subjects, which was significantly higher than that (26%, 191/734) of the females (P < 0.001). There was a significant increase of high Framingham Risk Score according to BMI, ranging from 23.1% of BMI<24 kg/m2 to 45% of BMI>27 kg/m2 (P for trend< 0.0001).Conclusion: IR is predictive of NAFLD irrespective of BMI. The cardiovascular risk may exist in lean NAFLD subjects. [ABSTRACT FROM AUTHOR]

Background/purpose: Pegylated interferon (PegIFN) plus ribavirin (RBV) combination therapy has been the standard of care since 2002. Although a better viral response has been achieved among chronic hepatitis C (CHC) patients in Taiwan, approximately 25% of hepatitis C virus (HCV) genotype 1 (G1) patients and 15% of G2 patients failed to achieve a sustained virological response (SVR) at the first therapy. The actual cost-effectiveness of the retreatment remains elusive. The present study conducted a real-world cost-effectiveness analysis of a large cohort among different pre-specified subgroups of treatment-experienced CHC patients.Methods: A total of 117 patients with CHC who failed to achieve SVR at the first IFN-based therapy and received a second IFN-based therapy were enrolled. The inpatient and outpatient costs were acquired from National Health Insurance Research Database of Taiwan. The related medical care costs per treatment and per SVR were calculated.Results: We demonstrated that the average cost per SVR achieved was $13,722 in treatment-experienced CHC patients. Especially, patients with HCV G1 infection, baseline viral loads > 400,000 IU/mL, advanced hepatic fibrosis, not achieving a rapid viral response at week 4 or complete early viral response at week 12, had poorer cost-effectiveness for PegIFN/RBV retherapy, ranging from around $15,520 to as high as $72,546 per SVR achieved.Conclusion: In the current study, we explored the real-world cost-effectiveness data of PegIFN/RBV for different subgroups of treatment-experienced HCV patients. These findings provide information for policy-makers for making decisions on treatment strategies of costly direct-acting antiviral agents for retreating CHC patients. [ABSTRACT FROM AUTHOR]

Serum-based noninvasive tests (NITs) have been widely used to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). However, the diagnostic efficacy of NITs across ranges of age, body mass index (BMI), and presence of type 2 diabetes (T2DM) may vary and have not been well-characterized. We analyzed 1489 patients with biopsy-proven NAFLD from 6 centers in Japan, Taiwan, and Korea. Using histology as the gold standard, we compared the areas under the receiver operating characteristic (AUROCs) of Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and the new Hepamet fibrosis score (HFS), with a focus on performance in subgroups as stratified by age, BMI, and the presence of T2DM. By histology, 44.0% of the overall cohort (655/1489) had F2-4, and 20.6% (307/1489) had F3-4 fibrosis. FIB-4 had the highest AUROCs for both F2-4 (0.701 vs NFS 0.676 and HFS 0.682, P =.001) and F3-4 (0.767 vs NFS 0.736 and HFS 0.752, P =.002). However, for F3-4 fibrosis, the AUROCs of all 3 NITs were generally higher in older (>60 years), nonobese (BMI <25 kg/m2), and non-diabetic patients, although overall the best performance was observed with FIB-4 among nonobese (BMI<25) diabetic patients (AUROC, 0.92). The worst performance was observed in younger patients with T2DM for all NITs including FIB-4 (AUROC, 0.63–0.66). FIB-4 had higher diagnostic efficacy for F3-4 than NFS or HFS, but this varied greatly by age, BMI, and T2DM, with better performance in older, nonobese, and nondiabetic patients. However, all NITs including FIB-4 had unacceptably poor performance in young or obese diabetic patients. [Display omitted] [ABSTRACT FROM AUTHOR]

Breast cancer is a highly malignant carcinoma and most deaths of breast cancer are caused by metastasis. The epithelial-to-mesenchymal transition (EMT) has emerged as a pivotal event in the development of the invasive and metastatic potentials of cancer progression. Epidermal growth factor (EGF) and its receptor, EGFR, play roles in cancer metastasis. CTX III, a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity; however, the effect of CTX III on the EMT of cancer cells remains elusive. CTX III treatment resulted in morphological changes from elongated and spindle shape to rounded and epithelial-like shape, induced upregulation of E-cadherin and concurrent downregulation of N-cadherin and Vimentin protein levels, corresponding to observed decreases in cell migration and invasion. CTX III treatment also decreased the expression of Snail and Twist in EGF-induced MDA-MB-231 cells. Concurrently, CTX III efficiently inhibited the EGFR phosphorylation and downstream activation of phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2. The EGFR specific inhibitor AG1478 significantly suppressed ERK1/2 and Akt phosphorylation, cell migration and invasion, as well as the expressional changes associated with EMT markers in EGF-induced MDA-MB-231 cells. CTX III inhibitory effect on EGF-evoked invasion of MDA-MB-231 cells is mediated through suppressing EGF/EGFR activation and EMT process. [ABSTRACT FROM AUTHOR]

Highlights: [•] Development of a class II PHA synthase protein model for structure predition. [•] Identification of beneficial sites Gln481 and Ala547 for enhancing PHA production. [•] The residue Leu484 changes the substrate specificity of PhaC1 Pp from 8C shift to 4C. [ABSTRACT FROM AUTHOR]

Abstract: Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been demonstrated to display anticancer activity. Breast cancer is a highly malignant carcinoma and most deaths of breast cancer are caused by metastasis. In this study, we show that CTX III blocks migration and invasion of MDA-MB-231 breast cancer cells without affecting apoptosis or cell cycle arrest. CTX III caused significant block of Src kinase activity in MDA-MB-231 cells. Moreover, CTX III treatment was correlated with reduced phosphorylation of FAK at Tyr576, 861 and 925 sites, p130Cas at Tyr410, and paxillin at Tyr118. CTX III also suppressed the activation of extracellular signal-regulated kinase1/2 and phosphatidylinositol 3-kinase/Akt. Consistent with inhibition of these signaling pathways and invasion, CTX III inhibited the expression of matrix metalloproteinase-9. In addition, Src specific inhibitor PP2 caused a significant decrease in the phosphorylation of FAK, p130Cas, paxillin, PI3K/Akt, and ERK1/2. Taken together, CTX III significantly inhibited phosphorylation of Src and downstream molecules as well as cell migration and invasion. Our findings provide evidences that CTX III inhibits Src-mediated signaling pathways involved in controlling MDA-MB-231 cell migration and invasion, suggesting that it has therapeutic potential in breast cancer treatment. [Copyright &y& Elsevier]

Polyunsaturated fatty acids (PUFAs) consumption indicates beneficial effects on cardiovascular disease (CVD) and physiological processes in humans. However, the inappropriate ratio of omega-(ω)-PUFA levels in human blood is considered as raising the risk of CVD. Therefore, monitoring dietary ω-FAs in human serum is vital for early diagnosis for individuals to predict CVD risk. This work reports a fast green sample pre-treatment protocol for sensitive and simultaneous monitoring of ω-3-FAs and ω-6-FAs in serum by novel in-syringe-based ultrasonication-assisted alkaline hydrolysis coupled with vortex-induced liquid-liquid microextraction (IS-USAH-VI-LLME) technique connected with UHPLC–MS/MS analysis. Factors affecting extraction recoveries of ten ω-PUFAs by the presented method were well-studied. ω-3 and ω-6 PUFAs demonstrated excellent linearities between the concentrations between 0.1–10,000 ng mL−1 with good regression coefficients between 0.9910–0.9997. The detection and quantification limits were between 0.05–0.35 and 0.16–1.07 ng mL−1, demonstrating that the presented method is highly sensitive and versatile. The precision of the technique was <8.2% that deemed acceptable in clinical analysis. Further, the proposed method was applied for ω-PUFAs analysis in human blood samples, and spiked recoveries showed between 80.32–119.34% with <9.82% precision. Results proved that the developed method is green, sensitive, and reliable to simultaneously determine ten ω-PUFAs in human blood samples for clinical diagnosis applications for predicting health hazards. [Display omitted] • Trace level anaysis of environmentally healthy poly-unsaturated fatty acids in serum. • Sensitive and simultaneous biomonitoring of ω-PUFAs in human blood by LC-MS/MS. • In-syringe ultrasonication-assisted vortex-induced liquid-liquid microextraction. • This technique was employed for the real-time biomonitoring of human serum samples. • This method is green, and efficient for real-time analysis for health hazard assessment. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in the 5′ non-coding region of GJB1 are rarely reported in patients with Charcot–Marie–Tooth disease (CMT). We therefore aimed to assess the frequency and identities of the GJB1 5′ non-coding region mutations in a cohort of CMT. We analyzed the 5′ non-coding region of GJB1 (including the promoter P2 and exon 1b) in 91 unrelated CMT patients without an identified genetic cause. Two mutations, c.-529T>C, and c.-459C>T, were identified in one patient each. One polymorphism, c.-713G>A, was also identified in 53 patients and 73 of the 100 control subjects. The luciferase reporter assays showed that c.-459C>T significantly reduced the luciferase expression with or without SOX10 activation, whereas c.-529T>C impaired the expression only with SOX10 co-expression. c.-713G>A had no apparent functional effect. Mutations in the 5′ non-coding region of GJB1 account for 0.8% (2 of 251) of CMT and 2.2% (2 of 91) of genetically unassigned CMT in a Taiwanese cohort. As previously demonstrated, c.-459C>T and c.-529T>C may cause CMT through compromising GJB1 expression whereas c.-713G>A is a benign variant. This study highlights the pathogenic role of the GJB1 5′ non-coding region mutations in CMT, and suggests that their identification should be considered for CMT patients without commonly observed mutations. [Copyright &y& Elsevier]

Highlights: [•] We first noted that brazilein inhibited MDA-MB-231 cell migration and invasion. [•] Brazilein suppressed the expression, activation, and mRNA of MMP-2. [•] Brazilein decreased the nuclear protein level of NF-κB. [•] Brazilein suppressed the phosphorylation of p38 MAPK, PI3K and Akt. [Copyright &y& Elsevier]

Abstract: Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. [Copyright &y& Elsevier]

Abstract: Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity. Epidermal growth factor (EGF) and its receptor, EGFR, play roles in cancer metastasis in various tumors. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CTX III on cell migration. CTX III inhibited the EGF-induced activation of matrix metalloproteinase-9 (MMP-9), and further suppressed cell invasion and migration without obvious cellular cytotoxicity. CTX III suppressed EGF-induced nuclear factor-kappaB (NF-κB) nuclear translocation and also abrogated the EGF-induced phosphorylation of EGFR, phosphatidylinositol 3-kinase (PI3K)/Akt, and extracellular regulated kinase (ERK)1/2. In addition, CTX III similar to wortmannin (a PI3K inhibitor) and U0126 (an up-stream kinase regulating ERK1/2 inhibitor) attenuated cell migration and invasion induced by EGF. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of ERK1/2 and PI3K/Akt, suggesting that ERK1/2 and PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CTX III inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt, ERK1/2, and NF-κB signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CTX III as a potent anti-metastatic agent in MDA-MB-231 cells. [Copyright &y& Elsevier]

Abstract: Cancer metastasis is a primary cause of cancer death. Ovatodiolide, a bioactive cembrane-type diterpenoid isolated from Anisomeles indica (L.) Kuntze (Labiatae), has been shown to inhibit the growth and proliferation of cancer cells. However, the anti-metastatic effects of ovatodiolide on highly metastatic human breast cancer MDA-MB-231 cells remain unclear. In this study, we first noted that ovatodiolide inhibited MDA-MB-231 cell migration and invasion by wound-healing assay and Boyden chamber assay. Western blot, gelatin zymography and reversed transcription-PCR analysis showed that ovatodiolide significantly and selectively suppressed the expression, activation, and mRNA of matrix metalloproteinase-9 (MMP-9) in a concentration-dependent manner. Ovatodiolide significantly decreased the nuclear level of nuclear factor kappaB (NF-κB), increased inhibitor of kappaBα (IκBα) through preventing phosphorylation of upstream signal IκB kinase (IKK). Pretreatment with a specific NF-κB inhibitor (PDTC) and an IκB protease inhibitor (TPCK) also reduced MMP-9 activity, cell migration and cell invasion. Moreover, ovatodiolide can suppress activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase and Akt, while it did not affect phosphorylation of extracellular signal regulating kinases (ERK)1/2. Additionally, the treatment of inhibitors specific for PI3K (wortmannin), JNK (SP600125) or p38 MAPK (SB203580) to MDA-MB-231 cells could result in a reduced activation of MMP-9, concomitantly with a marked inhibition on cell migration and invasion. Taken together, these results demonstrate that ovatodiolide inhibits the metastatic ability of MDA-MB-231 cells by reducing MMP-9 activity through suppressing JNK, p38 MAPK and PI3K/Akt signaling pathways and inhibiting NF-κB activity. These results are the first to reveal the function of ovatodiolide in tumor metastasis and its underlying molecular mechanism, thus suggesting ovatodiolide to be a promising antimetastatic agent. [Copyright &y& Elsevier]

A follow-up study was designed to compare the 24-year overall and disease-specific mortality in Yucheng people who were highly exposed to polychlorinated biphenyls/dibenzofurans (PCBs/PCDFs) to that in the background population in Taiwan. In 1979, the Yucheng (oil-disease in Chinese) incident occurred in central Taiwan involving approximately 2000 victims due to ingestion of rice oil contaminated with PCBs/PCDFs. Long-term follow-up of these people has been continued for 24 years. Methods: Standardized mortality ratios were calculated using the Taiwan population as comparison group. Overall and disease-specific mortality was compared between Yucheng and background populations. Results: Mortality from chronic liver disease and cirrhoses was increased in the Yucheng men, but not in women, in the early period after exposure. Cancer mortality was not increased in the Yucheng population up to 24 years after exposure. SLE in females was highly increased in the later period after PCB/PCDF exposure. Mortality from disease in any other organ system was not significantly different between Yucheng and background populations. Conclusions: The study provided a long-term mortality picture after the Taiwanese PCB/PCDF exposure incident. In addition to re-confirming the increase in liver mortality, we found high mortality of SLE among exposed population. This finding highlights the importance of further investigating the immunological effects associated with PCB/PCDF exposure. [Copyright &y& Elsevier]

Summary: In this study, the genetic polymorphisms associated with breast cancer in southern Taiwan were investigated. Two categories of genes were analyzed: (1) BRCA1, BRCA2, and Rad51, the DNA repair factors involved in homologous recombinational repair; and (2) CYP1A1, COMT, GST, and NAT2, the xenobiotic-metabolizing enzymes (XME) involved in estrogen metabolism. We found that the number of deletions and/or mutations in the GST genes was highly correlated with the occurrence of breast cancer. These data suggest that the GST enzymes, which detoxify the catechol estrogen quinones, are important target molecules for screening in populations at high risk of breast cancer. [Copyright &y& Elsevier]

Abstract: Introduction: Polychlorinated biphenyls (PCBs) and dibenzofurans (PCDFs) are ubiquitous persistent pollutants in humans. Whether people with different genotypes are with different susceptibility to these chemicals are unknown. In a group of people highly exposed to PCBs/PCDFs, we tested the hypothesis that genotypic polymorphisms affected susceptibility for development of skin manifestations. Methods: In 1979, approximately 2000 people in central Taiwan ingested cooking oil contaminated with PCBs/PCDFs. Skin disorder such as chloracne, abnormal nail, hyperkeratosis and skin allergy were found in PCBs/PCDFs exposed group. We recruited exposed and community background exposure subjects for blood testing and telephone-interview. Single nucleotide polymorphisms, AhR Arg554Lys, CYP1A1 Ile462Val, CYP1A1 T6235C, and GSTM1/T1 deletion, were determined. Occurrence of skin manifestations was compared among people with different genotypes while stratified by PCB exposure levels by logistic regression. Results: Data on exposure, medical history, and genotypes were obtained from 393 exposed and 181 background exposure groups. Skin manifestations including chloracne, allergy, abnormal nail, and hyperkeratosis were more prevalent in exposed people in a dose-related manner. Among highly exposed individuals, combined CYP1A1-MspI mutant genotype and GSTM1-null genotype were associated with increased risk of chloracne (odds ratio 2.8, 95% confidence interval 1.1–7.6). Among intermediately exposed individuals, GSTM1 null genotype was associated with skin allergy. AhR Arg554Lys genotype and GSTT1 null genotype were not related to susceptibility to skin manifestations in PCB/PCDF-exposed population. Conclusion: CYP1A1 and GSTM1 genotypic polymorphisms might be related to the susceptibility to PCB/PCDF-induced skin manifestations. [Copyright &y& Elsevier]

In this work, a new semi-automated syringe infusion-pump assisted graphene nanosheets (GNSs) based pipette-tip micro-solid phase extraction (PT-μSPE) as a green sample preparation technique was demonstrated for the sensitive analysis of emerging environmental pollutant in environmental waters using HPLC-UV. Microwave-assisted synthesized GNSs powder was packed into a 100 μL pipette-tip (as PT-μSPE cartridge) connected with a commercial plastic syringe (contains water sample). This setup was attached to a programmable auto-syringe infusion pump for the GNSs-PT-μSPE process. Triclosan (TCS) is an emerging environmental pollutant chosen as a target analyte to examine the extraction capacity and feasibility of GNSs as a sorbent material for PT-μSPE. Parameters affecting the extraction capability were systematically evaluated and thoroughly optimized. At optimized experimental parameters, excellent linearity (r2 = 0.9979) was achieved over the concentration range of 2–250 ng mL−1 for TCS, with a detection limit of 0.5 ng mL−1. Applicability of the presented method was examined with real water samples, and extraction recoveries obtained were ranged between 94.6–102.4% with RSD less than 7.8%. The presented protocol is a simple, semi-automated, eco-friendly, low-cost, and efficient sample pretreatment technique for quick analysis of TCS in environmental wastewaters. ✓ New semi-automated graphene based pipette-tip assisted micro-solid phase extraction. ✓ This eco-friendly technique was applied for rapid analysis of triclosan by HPLC-UV. ✓ This method is easy, low-cost, efficient, and sensitive technique for water analysis. ✓ This method can be applied to real-time analysis of emerging pollutants in waters. [ABSTRACT FROM AUTHOR]

The GGGGCC hexanucleotide expansion in the C9ORF72 gene is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasian populations. The phenotypic spectrum of C9ORF72 hexanucleotide repeat expansion mutation has been reported to include parkinsonian syndrome, Huntington's disease-like syndrome and dementia syndrome. Although few individuals with cerebellar ataxia have also anecdotally been found to harbor the mutation, the relationship between the mutation and cerebellar ataxia awaits further clarification. We hereby screened for the presence of the C9ORF72 hexanucleotide repeat expansion in 331 patients with multiple system atrophy-cerebellar variant and 98 unrelated patients with molecularly un-assigned spinocerebellar ataxia in Taiwan utilizing a repeat-primed polymerase chain reaction assay. We found that none of the 429 patients had the C9ORF72 hexanucleotide repeat expansion mutation. Therefore, our study does not support that the mutation plays a significant role in cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Parahydroxybenzoates (parabens) are considered as emerging environmental contaminants because of their extensive usage in our daily life products, causing parabens contamination into environmental water systems and lead to toxic effects on environmental health. This study describes a greener extraction method using a new cationic polymer poly (ethyleneimine) functionalized acid-treated carbon nanofibers (PEI-CNFs) coated cellulose paper (CP) as solid-phase extraction (SPE) sorbent material for the extraction of parabens from environmental water samples. The fabrication of PEI-CNFs modified CP was confirmed using field-emission scanning electron microscope, transmission electron microscopy, and fourier-transformer infrared spectroscopy techniques. Various factors affecting the adsorption and desorption of parabens on PEI-CNFs@CP and its extraction efficiencies were studied using HPLC-UV analysis. Under the optimal experimental conditions, maximum extraction efficiencies were achieved for four target parabens, and PEI-CNFs@CP/HPLC-UV method exhibited excellent linearities ranged from 0.5–50 ng mL−1 with regression coefficient values were between 0.9952–0.9970. The presented method showed good sensitivity with quantification limits between 0.5–0.75 ng mL−1 and detection limits between 0.1–0.25 ng mL−1. The developed technique was applied for the real sample analysis (river, lake, domestic sewage water, and drinking tap water). The spiked recovery revealed good recoveries between 86.8–116.0% with RSD less than 8.8% for all the water samples. These results proved that it a simple, fast, efficient, low-cost, and eco-friendly method for the extraction and determination of parabens in environmental water samples and can be applied as a routine analytical tool in environmental monitoring and quality control laboratories. Image 1 • Poly (ethyleneimine)-Functionalized Carbon Nanofibers Coated Cellulose Paper was developed. • Applied as Low-Cost Disposable Efficient Solid Phase Extraction Sorbent Material. • Maximum Extraction Recovery of Parahydroxybenzoates were achieved from Environmental Waters. • Eco-friendly method can be employed as a routine method in wastewater treatment. [ABSTRACT FROM AUTHOR]

Fabrication of g-C 3 N 4 /Fe 2 O 3 /PdNPs/SPE nanocomposite modified electrode by electrochemical deposition method for the ethylene glycol oxidation. • Simple one-step fabrication of novel nanocomposite by electrodeposition technique. • Graphitic carbon nitride/iron oxide/palladium nanocomposite modified electrode. • Nanocomposite exhibited a three-dimensional nanoflower like structure. • Excellent catalytic activity over ethylene glycol oxidation compared with Pd/C catalyst. • Developed electrocatalyst is highly suitable for direct alcohol fuel cell applications. The design and development of highly efficient and environmental-friendly methods for the synthesis of electro-catalysts are highly significant for fuel cell applications. Herein, we demonstrate a facile technique for the synthesis of graphitic carbon nitride/iron oxide/palladium nanoparticles (g-C 3 N 4 /Fe 2 O 3 /PdNPs) composite towards efficient electro-catalytic oxidation of ethylene glycol. g-C 3 N 4 /Fe 2 O 3 /PdNPs nanocomposite was prepared using a one-step simultaneous electrochemical co-deposition process. The electro-deposition was performed on a single-disk carbon screen-printed electrode (SPE) under acidic electrolyte solution containing g-C 3 N 4 nanosheets, Fe 2 O 3 nanoparticles, and palladium chloride as precursors. The structural and elemental composition of the electrochemically fabricated g-C 3 N 4 /Fe 2 O 3 /PdNPs nanocomposites modified SPE was investigated using fourier-transform infrared spectroscopy, field-emission scanning electron microscopy, and X-ray photoelectron spectroscopy techniques and the results indicated that three-dimensional nanoflower-like Fe 2 O 3 and spherical shaped PdNPs were electro-deposited on the g-C 3 N 4 nanosheets to form the nanocomposite. The voltammetric behavior of the developed g-C 3 N 4 /Fe 2 O 3 /PdNPs/SPE showed excellent electro-catalytic response towards ethylene glycol and superior electro-oxidation with high durability when compared to commercial Pd/C and other recently reported electro-catalyst materials. Therefore, the proposed g-C 3 N 4 /Fe 2 O 3 /PdNPs nanocomposite is proved to be an efficient electro-catalyst and can be highly suitable for direct alcohol fuel cell applications. [ABSTRACT FROM AUTHOR]

Abstract Mutations in the annexin A11 gene (ANXA11) have been recently identified in British patients and Italian patients with amyotrophic lateral sclerosis (ALS), and their role in other ALS populations remains unclear. The aim of this study was to investigate the ANXA11 mutations in a Taiwanese ALS cohort. Mutational analysis of ANXA11 was performed in 286 unrelated Taiwanese patients with ALS by Sanger sequencing. Eight ANXA11 missense variants were identified initially, and only one of them was absent from population databases. This missense variant, p.Q362L, was identified in 1 single patient with apparently sporadic ALS, and no further strong evidence was available to support its pathogenicity. Therefore, it is classified as a variant of uncertain significance. Our data indicate that pathogenic ANXA11 mutations are absent or rare in ALS patients in Taiwan. [ABSTRACT FROM AUTHOR]

Mutations in the cyclin F gene ( CCNF ) have been recently identified in a small number of patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia, and their role in patients with ALS in Taiwan remains elusive. The aim of this study was to elucidate the frequency and spectrum of CCNF mutations in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of the CCNF gene were performed using Sanger sequencing in a cohort of 255 unrelated patients with ALS. Among these patients, the genetic diagnoses of 204 patients remained unclear after mutations in SOD1 , C9ORF72 , TARDBP , FUS , ATXN2 , OPTN , VCP , UBQLN2 , SQSTM1 , PFN1 , HNRNPA1 , HNRNPA2B1 , MATR3 , CHCHD10 , TUBA4A , and TKB1 had been investigated. Two novel heterozygous missense mutations in CCNF , p.S222P (c.664T>C) and p.S532R (c.1596C>T), were identified; 1 in each patient with apparently sporadic ALS. In vitro functional study demonstrated that both mutations result in a general and cyclin F-mediated ubiquitin-proteasome pathway dysfunction. The frequency of CCNF mutations in ALS patients in Taiwan is, therefore, approximately 0.8% (2/255). These findings expand the mutational spectrum of CCNF and also emphasize the pathogenic role of CCNF mutations in ALS. [ABSTRACT FROM AUTHOR]

The GGC repeat expansion in the 5′-untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID). To determine if the NIID repeat expansion contributes to amyotrophic lateral sclerosis (ALS), we screened 304 unrelated ALS patients and 637 healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. None of the ALS patients carried the GGC repeat expansion. The sizes of the GGC repeats ranged from 7 to 36 in the ALS patients and 4 to 46 in the controls. The distribution of the GGC repeat sizes did not differ between the two groups. Our findings indicate that the NOTCH2NLC GGC repeat expansion is absent or extremely rare in Taiwanese patients with ALS. [ABSTRACT FROM AUTHOR]