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Abstract To clarify the survival benefit of sequential curative treatment post transcatheter arterial chemoembolization (TACE) for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC), we retrospectively analyzed HCC patients at a hospital. From July 2017 to July 2020, 787 treatment-naïve HCC patients underwent initial treatment; 77 (9.8%) meeting inclusion criteria were enrolled. Their initial treatments were TACE only (n = 68, 88.3%) or TACE with other treatments (n = 9, 11.7%). Median survival of the TACE-only group was 30 months. Treatment response was evaluated after 2 or 3 consecutive TACEs for patients (54/68, 79.4%) with available pre-/post-TACE computerized tomography (CT) or magnetic resonance imaging (MRI). Treatment responses was divided into 4 groups: complete (n = 14, 26%, group (Gr) 1), incomplete without new tumor growth (n = 28, 52.0%, Gr2), incomplete with new growth (n = 6, 11%, Gr3), and progression (n = 6, 11%, Gr4). Of Gr2, further treatment after TACE were had radiofrequency ablation (n = 13, Gr2a), TACE (n = 9, Gr2b), other modalities (n = 6, Gr2c. Gr2a’s median survival was longer than Gr2b’s (> 60 vs. 20 months, p = 0.007). Nine patients in Gr2a (69%, 9/13) achieved a complete response, but none in Gr2b (p = 0.001). Conclusively, in TACE-suitable BCLC stage B HCC patients, a partial response without new tumor growth can serve as an indicator of treatment effectiveness following initial TACE treatment. This can facilitate the selection of appropriate candidates to receive RFA, potentially resulting in improved patient survival.

Abstract In 2008, sorafenib became the first approved systemic therapeutic agent for advanced HCC. Although its pharmacological efficacy has been established, reimbursement for such a new, high‐cost drug, as well as physicians' awareness and prescription practice, likewise contribute to its clinical effectiveness. We therefore conducted a retrospective study using 38 sorafenib‐eligible, advanced HCC patients when sorafenib was approved but not yet reimbursed as a control and 216 patients during the reimbursed era. Study group showed longer survival at 8.2 months versus the control's 4.9 months (p = 0.0063 hazard ratio: 0.612 [0.431 ~ 0.868], p = 0.0059). Among the 42 (19.4%) patients who survived more than 2 years, 50% had tumor rupture, and all 32 patients with portal vein tumor thrombus and/or extrahepatic metastasis received sorafenib (p = 0.003). Furthermore, during their first 2 years of HCC management, sorafenib had been given in 29.1% of the treatment courses among survivors between 2 and 5 years while it was prescribed in 55.8% among the more than 5 years survivor group (p

Background: /Purpose: To achieve the World Health Organization goal of eliminating viral hepatitis by 2030, a key strategy in resource-limited areas is to identify the areas with high prevalence and to prioritize screening and treatment intervention. We hypothesized that a hospital-based laboratory database could be used to estimate the township- and village-specific anti-hepatitis C virus (HCV) prevalence. Methods: Yunlin County Public Health Bureau has been collecting anti-HCV test data from eight major hospitals. Township- and village-specific screening testing rates and anti-HCV prevalence were calculated for residents 40 years or older. A township with a wide range of anti-HCV prevalence rates was selected for outreach universal screening and for validating the village-specific prevalence of anti-HCV in the analysis of the data from the hospitals. Results: The overall anti-HCV screening testing rate in Yunlin County was 30.4 %, whereas the anti-HCV prevalence rate for persons 40 years or older was 15.4 %. The village-specific anti-HCV prevalence rates ranged from 3.8 % to 85.8 %. Community-based screening was conducted in Kouhu Township. The village-specific anti-HCV prevalence rates ranged from 0 % to 18.8 %. Three of the four villages had the highest village-specific anti-HCV prevalence in the community-based study and the hospital-based study. Additionally, 95.8 % of the new HCV cases detected by universal screening received anti-HCV therapy. Conclusion: The hospital-based database provided a framework for identifying the villages with high anti-HCV prevalence. Additionally, community-based universal screening should be prioritized for villages with high prevalence in hospital-based databases.

Abstract Introduction Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). Methods The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. Results A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. Conclusion Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Background/Aims Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

臺灣於2019年5月24日正式成為亞洲第一個同性結婚合法化的國家，揆諸現況，相較於其他年齡群體，高齡者對於同志結婚和成家撫養小孩的反對意見最為強烈。本研究試圖對高齡者進行同志結婚成家議題教學，以及探討對高齡者進行同志結婚成家議題教學所遭遇的困難與反應。本研究參與者為東部陽光（化名）樂齡大學17位學員，課程設計期透過「接觸理論」 （contact theory）引發學員「同理心」（empathy），教學策略以故事敘說和課堂對話為主，邀請高齡同志親自敘說同志生命故事與同志結婚成家議題，進行兩次共6小時課程。研究結果顯示，課程有助於參與學員對同志有更多的認識，讓他們有更多角度思考同志結婚成家在臺灣社會所面臨的處境與困境。不過，17位學員對同志結婚成家的態度幾乎維持不變，只有兩位女學員從不同意轉成同意。本次同志課程教學行動雖未能立即改變多數高齡學員對同志結婚成家的態度，但鬆動高齡者對同志過去的看法，讓高齡者從更多元的角度看到性別的差異，以及同志個人對婚姻和成家的需求，透過這次的教學行動，啟動高齡者對同志的認識、瞭解並尊重別人「同志」有選擇自己生活方式的權利。本研究根據教學實踐歷程與結果，提出對高齡者實施同志教育課程應注意之原則。 Background Taiwan officially became the first country in Asia to legalize same-sex marriage on May 24, 2019. Despite this progressive step, many older adults in Taiwan continue to exhibit more resistance to same-sex marriage and families than do other age groups. The present study delineated the educational strategies employed in lesbian, gay, bisexual, and transgender (LGBT) education targeting older adults. In addition, the study analyzed the reactions and attitudinal shifts of older adults upon being exposed to the narratives of lesbian and gay individuals and the effects of these narratives on the older adults’ attitudes toward same-sex families. This study used action research (1) to gauge the responses of older adults to same-sex marriage and families through a specialized course and (2) to explore the pedagogical approaches that are effective in teaching older adults about same-sex marriage and families. Literature Review The Gender Equality Division of the Executive Yuan in Taiwan reported that as of 2022, 66.7% of Taiwanese older adults aged above 60 years were opposed to same-sex marriage being legal. In addition, 45.1% reported that they believed that “homosexuality is a disease that can be cured with treatment,” 59.6% believed that “marriage between same-sex couples destroys the family system and ethics,” and 46.7% believed that same-sex couples could not raise children as well as heterosexual couples could. These statistics reveal prevailing prejudices, stigmas, and misconceptions about the LGBT community among older Taiwanese adults. Contact theory, first introduced by Allport in 1954, posits that prejudices and stereotypes can be mitigated through meaningful contact between individuals. In his seminal work The Nature of Prejudice, Allport (1954) argued that direct and appropriate interactions can foster mutual understanding between mainstream (majority) and nonmainstream (minority) groups. The application of contact theory in educational settings can effectively reduce stereotypes, prejudices, and discrimination (Pettigrew, 2021; Pettigrew & Tropp, 2006). Such pedagogical approaches also promote empathy in individuals (Allport, 1954). Empirical studies have indicated that individuals who have had contact with the LGBT community demonstrate more positive attitudes and higher levels of empathy toward this community compared with those without such contact (Brown & Hewstone, 2005; Chang & You, 2012; Han et al., 2010; Norton & Herek, 2013). Specifically, individuals experience increased empathy levels after interacting with LGBT individuals who share information regarding their life experiences and personal narratives. Studies on this topic have primarily focused on younger populations, such as college students (Chang & Huang, 2018; Chang & You, 2012), revealing a substantial research gap in the literature on LGBT education for older adults. Methods The present study was conducted at Sunshine University (pseudonym) in Hualien, Taiwan. The criteria for study participation were (1) being 55 years of age or older and (2) self-identifying as heterosexual. The study spanned two sessions, each lasting 3 hours, with the sessions conducted in March and April 2021. The curriculum was designed around the principles of contact theory and empathy (Allport, 1954). In addition, we invited an older adult named Ah Hung (pseudonym), who identified as gay, to share personal stories related to life as a gay person and the problems same-sex families face. The pedagogical approach was primarily focused on storytelling and classroom dialogue (Lee & Lin, 2021). This approach is often employed to expose participants to different forms of family structures, such as those involving different social groups, new immigrants, single or single-parent households, heterosexual couples, gay and lesbian couples, and families with intergenerational caregiving. Data were collected through classroom observations, interviews, and reflective notes provided by the instructors. We used Miles and Huberman’s (1994) process for qualitative data analysis, which includes (1) streamlining data, (2) presenting data, (3) interpreting data, and (4) drawing conclusions. Results This study involved 17 individuals. After the course and subsequent data analysis were completed, three central themes emerged: (1) the participants developed a new understanding of the LGBT community, albeit incompletely; (2) the participants’ attitudes toward same-sex marriage and families remained unchanged; and (3) the participants were more willing to adjust their explicit discriminatory attitudes (e.g., I understand why we are different) than their implicit discriminatory attitudes (e.g., I still cannot accept same-sex marriage). We elaborate upon these findings in the following. The participants gained a new understanding of gay and lesbian people and empathized with the feelings and perceptions of these people through their interaction with Ah Hung. The participants reported a heightened understanding of the challenges gay and lesbian people face in Taiwanese society when marrying and forming families. Taken together, our findings indicate that the course led the participants to empathize with the emotional and cognitive experiences of gay and lesbian people. Despite the overall increase in empathy, of the 17 participants, only 2 female students experienced a change from disapproving to approving of same-sex families. Some comments from the participants included: “My empathy for homosexuals is not the same as approval of same-sex marriage;” “I respect [the LGBT population], but I still do not accept homosexuals coming out publicly because it can embarrass their parents;” “I understand [the LGBT population’s] difficulties in Taiwanese society, but they must also understand that homosexuals raising children will negatively affect the children.” These reflections indicate that the participants generally offered “politically correct” responses, such as expressions of understanding and respect; their responses often masked implicit discriminatory attitudes, such as the unfounded belief that children raised in gay families might also “become” gay. Moreover, the participants generally did not perceive themselves to be harboring discriminatory or prejudicial attitudes toward the LGBT community. Taken together, our findings indicate that the course did not lead to immediate changes in the attitudes of most participants toward same-sex marriage and families. However, it did soften the perspectives of the participants on gay and lesbian people, broaden their understanding of gender diversity, and increase their awareness of the needs and challenges related to the formation of gay and lesbian families. Discussion and Suggestions Although the education program led to minimal change in the attitudes of the participating older adults toward same-sex marriage and family concerns, it did provide insights into their true perspectives regarding the LGBT community. These insights distinguish the present study from other studies, which have primarily focused on university students or high school students. This study offers the following suggestions for future efforts toward and studies of LGBT education aimed at older adults: (1) initiating contact with a person who identifies as LGBT can be used as a starting point for fostering acceptance among older adults; (2) empathy and contact theory should be incorporated into curricula to broaden the heteronormative perspectives prevalent among older adults; and (3) strategies for combatting implicit discriminatory attitudes in older adults, such as those related to gay rights or relationships, should be incorporated into curricula. The education of this study established a channel of communication by exposing older adults to the narrative of a gay person, which led them to feel empathy. Through such pedagogical approaches, older adults may develop a better understanding of the experiences of gay and lesbian people and recognize these people’s right to make life choices. Our findings indicate that studies and educational practices should be more focused on the development of LGBT educational programs designed for an older population.

本研究旨在探討大學生在大學四年之教育抱負與職業抱負的改變情形，並分析性別與就讀領域對這兩種抱負影響的情形。本研究以1,090位大學生為對象，以四次的自填式問卷為工具，持續追蹤其大一至大四教育抱負與職業抱負的成長軌跡，以及性別與就讀領域對於抱負起始狀態及成長速率的影響。本研究採用階層線性分析模式，結果顯示：一、對於教育抱負與職業抱負的發展皆有相同的趨勢，大學生的教育抱負在大一至大三時逐漸下降，大四則有些微上升。二、性別與就讀領域的不同，會造成大學生在起始狀態中教育抱負的差異化，研究顯示男大一生的教育抱負顯著高於女大一生，理工領域大一生的教育抱負顯著高於人文社會領域大一生，但在職業抱負的初始狀態，性別與就讀領域並不會造成其差異。三、性別與就讀領域的差異不會造成教育抱負與職業抱負在成長速率的影響。依據上述分析結果，本研究提出對教育實務及未來研究的建議。 Background The universalization of higher education has presented college graduates with challenges related to underemployment and insufficient compensation. Understanding how the educational and occupational aspirations of college students develop is crucial to developing career counseling programs to help such students succeed in the competitive job market. Most studies of the educational and occupational aspirations of college students in Taiwan have relied on cross-sectional data. Cross-sectional studies assess variables at specific time points and are prone to biases because they cannot determine how variables change over time. Therefore, the current study explored how the educational and occupational aspirations of college students change over the 4 years of college study. Literature Review Aspirations are life goals that are often influenced by personal and social values (Wolbers et al., 2011). Research on social education has categorized aspirations into educational and occupational aspirations (Teravainen-Goff et al., 2020). Educational aspirations refer to educational desires or goals; occupational aspirations refer to occupational preferences and goals regarding future occupational roles (Hauser et al., 1983). Educational and occupational aspirations may change over the 4-year college period (Sharf, 2006). According to Gottfredson (1981), gender and academic field may influence the development of aspirations among college students. In sum, the current study examined the development trajectories of the educational and occupational aspirations of students from their first year to the fourth year of college as well as the effects of gender and academic field on aspiration development. Methods Stratified and purposive sampling was employed to select participants from different types of colleges (both national and private colleges) and academic fields (both science/technology/ engineering and social sciences/humanities). A total of 1,090 first-year students from 11 colleges agreed to share their educational and occupational aspirations via self-report questionnaires in 2011. These participants agreed to fill out follow-up questionnaires between March and May in 2012, 2013, and 2014. To assess the students’ educational aspirations, this study asked, “What kind of degree will you want to pursue?” (Chen & Hwang, 2011). The responses were coded as 16, 18, and 22 for a bachelor’s, master’s, or doctoral degree. Hwang’s (2008) improved Taiwanese occupational prestige and socioeconomic status scale was used to measure the participants’ occupational aspirations. The participants were provided with a list of jobs (e.g., administrative assistant, teacher, or technician) and asked to select one. The jobs were assigned continuous numerical values based on those used by Hwang (2008). Two-level hierarchical linear modeling (HLM) was conducted for assessing the development of educational and occupational aspirations over the 4 years. Additionally, the moderating effects of gender and academic fields on the development of educational and occupational aspirations were examined using statistical tests performed in HLM 7.0. Results The two-level HLM revealed the following results: First, both educational and occupational aspirations exhibited similar development trends: a linear decline from the first year to the third year followed by a linear increase in the final year. Second, differences in gender and academic field affect educational aspirations initially; specifically, educational aspirations among male first-year students were higher than those among female first-year students. Also, first-year students in the fields of science, technology, and engineering had higher educational aspirations than those in the fields of social sciences and the humanities. However, gender and academic field did not initially affect occupational aspirations. Finally, neither gender nor academic field affected the development of educational or occupational aspirations in the later years of college. Discussion and Suggestions Consistent with prior studies (Chen & Hwang, 2011; Pramod, 2021), the current study discovered that first-year students had the highest educational and occupational aspirations. The students’ aspirations gradually decreased and were the lowest during their third year of study. A potential explanation for this finding is that students tend to be idealistic when starting college. However, they begin to realize that their actual academic performance may not be as high as they expected, reducing their aspirations in their third and fourth years of study. In line with previous studies (Gottfredson, 1981; Teravainen-Goff, 2020; Wang, 2007), this study discovered that first-year students who were female or in the fields of social sciences or the humanities had lower educational aspirations than their counterparts who were male or in the fields of science, technology, or engineering. The gender-based difference in aspirations may be attributed to the social norms in Taiwan. Taiwanese society holds some negative stereotypes regarding women who completed advanced degrees. The difference in aspirations owing to the academic field may be explained by the fact that science, technology, and engineering students are expected to pursue higher education to prepare for rapid changes in technology. The results imply three suggestions for educational practitioners. First, focused counseling programs suitable for students in each year of college should be organized. Second, gender-equal education should be encouraged to bridge the gap between the aspirations of male and female students. Finally, career guidance focused on specific academic fields should be implemented early in students’ college careers to help them establish informed educational and occupational aspirations and accordingly develop their skills to excel in their respective academic and professional fields.

Background/purpose: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR. Methods: Patients enrolled in TACR from 2017–2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12). Results: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P

This research aimed to explore the correlation between Indonesian University students' conception of learning physics and their physics' self-efficacy. A total of 279 students who were majoring in physics education participated in this research and were invited to complete two instruments: the conception of learning physics (CLP) and the physics learning' self efficacy (PLSE). Both of the questionnaires, which were modified from [Lin, Liang, & Tsai (2015a) and Lin, Liang, & Tsai (2015b)]' instruments, had been translated into Indonesian language and validated through an exploratory factor analysis of participants' responses. The differences between student levels were explored for their significance using an ANOVA test in order to portray a clear line among different conceptions of learning physics and physics learning self-efficacy. The results indicated that, first, the instruments used in the research had satisfactory validity and reliability. Second, students in sophomore level were significantly lower on the conceptions of testing than those in other levels. Meanwhile, the conceptions of calculating-practicing and understanding were not significantly different. Third, university students in senior level performed more confident in four dimensions: science content, higher-order thinking, everyday application, and science communication than others. The research also depicted a moderate correlation among dimensions of CLP and PLSE.

Few studies have reported weight gain in patients with hepatitis C virus (HCV) infection treated with direct-acting antiviral agents (DAAs). This retrospective cohort study identified factors associated with substantial weight gain after DAA treatment in Taiwan. This study involved patients treated using DAAs at the Chiayi and Yunlin branches of Chang Gung Memorial Hospital from 1 January 2017 to 31 October 2020. Body weight data were collected at the start of DAA therapy and 2 years after the confirmation of a sustained virologic response. We performed multiple logistic regression to evaluate the clinical and laboratory parameters associated with a large body mass index (BMI) increase (≥5%). The mean BMI was 25.56 ± 4.07 kg/m2 at baseline and 25.77 ± 4.29 kg/m2 at the endpoint (p = 0.005). A considerable reduction in fibrosis-4 (FIB-4) score was a significant predictor of a large BMI increase (OR: 1.168; 95% CI: 1.047–1.304, p = 0.006). By contrast, older age (OR: 0.979; 95% CI: 0.963–0.996, p = 0.013) and a higher baseline BMI (OR: 0.907; 95% CI: 0.863–0.954, p < 0.001) were associated with a reduced risk of a large increase in BMI at the endpoint. In summary, a larger BMI increase was closely associated with a younger age, lower baseline BMI, and higher FIB-4 score reduction. Notably, differences in DAA regimens did not affect outcomes. Future studies are needed to elucidate the long-term effects and metabolic outcomes associated with this body weight change and investigate the exact underlying mechanisms.

Abstract The study evaluated the real-world treatment outcomes of Glecaprevir/pibrentasvir (GLE/PIB) including effectiveness, safety and healthcare resource utilization based on a nation-wide registry in Taiwan. The Taiwan HCV Registry (TACR) is a nation-wide platform organized and supervised by the Taiwan Association for the Study of the Liver. Data were analyzed for patients treated with GLE/PIB, including 3144 patients who had treatment outcome available. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA throughout 12 weeks of end-of-treatment). The overall SVR12 rate was 98.9% (3110/3144), with 98.8%, 99.4% and 100% in patients receiving 8 weeks, 12 weeks, and 16 weeks of GLE/PIB respectively. The SVR12 rate in the treatment-naïve cirrhotic patients receiving 8 weeks of GLE/PIB was 98.2% (108/110). The most common AEs were fatigue (7.5%), pruritus (6.7%) and dizziness (1.5%). The mean number of outpatient visits during the GLE/PIB was 5.94 visits for patients treated with 8 weeks, significantly different from the patients treated with 12 weeks of GLE/PIB (6.90 visits). The results support the effectiveness and safety of GLE/PIB treatment in real-world clinical practice, and provide further evidence that the shorter, 8-week GLE/PIB regimen is effective and cost-saving.

Abstract Clinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only

Abstract Introduction Real-world data regarding the impact of hepatic fibrosis on the effectiveness of sofosbuvir/velpatasvir (SOF/VEL) treatment is limited in the Asian population. Methods We analyzed data for all 823 patients with hepatitis C virus treated with SOF/VEL from June 2019 to September 2020 at Chang Gung Memorial Hospital in Chiayi, Taiwan. The degree of fibrosis was determined using the fibrosis-4 (FIB-4) index, with advanced fibrosis or cirrhosis defined as a FIB-4 score of > 3.25. The primary treatment outcome was the rate of sustained virologic response 12 weeks after treatment cessation (SVR). Adverse events (AEs) were also evaluated. Results SVR rates did not significantly differ (p > 0.05) between patients with FIB-4 scores of ≤ 3.25 and those with scores of > 3.25. In the per protocol analysis, 99.2% (593/598) of the FIB-4 ≤ 3.25 group and 100% (172/172) of the FIB-4 > 3.25 group achieved SVR; in the evaluable population analysis, 93.4% (593/635) of the FIB-4 ≤ 3.25 group and 91.5% (172/188) of the FIB-4 > 3.25 group achieved SVR. Five patients with FIB-4 scores of ≤ 3.25 did not attain SVR: two relapsed and three had no response. The most common AEs were comparable (p > 0.05) for the FIB-4 ≤ 3.25 group and the FIB-4 > 3.25 group and included abdominal discomfort (4.4% vs. 5.9%), fatigue (4.1% vs. 5.9%), and skin itching (3.6% vs. 3.2%). Laboratory abnormalities were more common in the FIB-4 > 3.25 group (p 3.25 had total bilirubin elevation > 3 × the upper normal limit (UNL). Alanine transaminase elevation > 5 × the UNL was observed in two patients with FIB-4 scores of ≤ 3.25 and one patient with a FIB-4 score of > 3.25. No AEs resulted in treatment discontinuation. Conclusions SOF/VEL treatment is well tolerated and achieves high SVR rates for patients of Taiwanese ethnicity with HCV, regardless of cirrhosis status.

6-Gingerol is a major phenolic compound within ginger (Zingiber officinale), often used in healthcare; however, its lower bioavailability is partly due to its poor solubility. Four bacterial glycosyltransferases (GTs) were tested to glycosylate 6-gingerol into soluble gingerol glucosides. BsUGT489 was a suitable GT to biotransform 6-gingerol into five significant products, which could be identified via nucleic magnetic resonance and mass spectrometry as 6-gingerol-4′,5-O-β-diglucoside (1), 6-gingerol-4′-O-β-glucoside (2), 6-gingerol-5-O-β-glucoside (3), 6-shogaol-4′-O-β-glucoside (4), and 6-shogaol (5). The enzyme kinetics of BsUGT489 showed substrate inhibition toward 6-gingerol for producing two glucosides. The kinetic parameters were determined as KM (110 μM), kcat (862 min-1), and KI (571 μM) for the production of 6-gingerol-4′-O-β-glucoside (2) and KM (104 μM), kcat (889 min-1), and KI (545 μM) for the production of 6-gingerol-5-O-β-glucoside (3). The aqueous solubility of the three 6-gingerol glucosides, compound (1) to (3), was greatly improved. However, 6-shogaol-4′-O-β-glucoside (4) was found to be a product biotransformed from 6-shogaol (5). This study first confirmed that the glucose moiety at the C-5 position of both 6-gingerol-4′,5-O-β-diglucoside (1) and 6-gingerol-5-O-β-glucoside (3) caused spontaneous deglucosylation through β-elimination to form 6-shogaol-4′-O-β-glucoside (4) and 6-shogaol (5), respectively. Moreover, the GTs could glycosylate 6-shogaol to form 6-shogaol-4′-O-β-glucoside (4). The assays showed 6-shogaol-4′-O-β-glucoside (4) had higher anti-inflammatory activity (IC50 value of 10.3 ± 0.2 μM) than 6-gingerol. The 6-gingerol-5-O-β-glucoside (3) possessed 346-fold higher solubility than 6-shogaol, in which the highly soluble glucoside is a potential prodrug of 6-shogaol via spontaneous deglucosylation. This unusual deglucosylation plays a vital role in influencing the anti-inflammatory activity. IMPORTANCE Both 6-gingerols and 6-shogaol possess multiple bioactivities. However, their poor solubility limits their application. The present study used bacterial GTs to catalyze the glycosylation of 6-gingerol, and the resulting gingerol glycosides were found to be new compounds with improved solubility and anti-inflammatory activity. In addition, two of the 6-gingerol glucosides were found to undergo spontaneous deglucosylation to form 6-shogaol or 6-shogaol glucosides. The unique spontaneous deglucosylation property of the new 6-gingerol glucosides makes them a good candidate for the prodrug of 6-shogaol. [ABSTRACT FROM AUTHOR]

Abstract It remains controversial whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) is associated with different clinical outcomes for chronic hepatitis B (CHB). This study aimed to compare the long-term risk of ETV versus TDF on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in CHB patients from a large multi-institutional database in Taiwan. From 2011 to 2018, a total of 21,222 CHB patients receiving ETV or TDF were screened for eligibility. Patients with coinfection, preexisting cancer and less than 6 months of follow-up were excluded. Finally, 7248 patients (5348 and 1900 in the ETV and TDF groups, respectively) were linked to the National Cancer Registry database for the development of HCC or ICC. Propensity score matching (PSM) (2:1) analysis was used to adjust for baseline differences. The HCC incidence between two groups was not different in the entire population (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.66–1.02, p = 0.078) and in the PSM population (HR 0.83; 95% CI 0.65–1.06, p = 0.129). Among decompensated cirrhotic patients, a lower risk of HCC was observed in TDF group than in ETV group (HR 0.54; 95% CI 0.30–0.98, p = 0.043, PSM model). There were no differences between ETV and TDF groups in the ICC incidence (HR 1.84; 95% CI 0.54–6.29, p = 0.330 in the entire population and HR 1.04; 95% CI 0.31–3.52, p = 0.954 in the PSM population, respectively). In conclusion, treatment with ETV and TDF showed a comparable long-term risk of HCC and ICC in CHB patients.

Background: The real-world data of glecaprevir/pibrentasvir (GLE/PIB) therapy for patients with chronic hepatitis C virus (HCV) genotype 2 infection remained limited. We aimed to evaluate the possible predictors of virological failure and side effects of GLE/PIB therapy for chronic genotype 2 HCV-infected patients in a real-world setting. Methods: A total of 326 compensated HCV genotype 2 patients treated with GLE/PIB 12 weeks for cirrhotic patients (n = 56) and 8 weeks for non-cirrhotic patients (n = 270) were enrolled. Results: The sustained virological response 12 weeks off therapy (SVR12) was 98.1%, 100%, and 97.7% in overall, GLE/PIB 12-week, and 8-week group, respectively. There were 6 (1.8%) patients with early withdrawal, and 14.1% patients had pruritus, the major adverse effect. In multivariate analyses, end-stage renal disease (odds ratio (OR) = 4.056, 95% confidence interval (CI) = 1.477–11.14, p = 0.007) and hypertension (OR = 2.325, 95% CI = 1.171–4.616, p = 0.016) were two significant factors associated with pruritus. There were 6 patients with virologic failure. In patients receiving 8-week GLE/PIB therapy, the SVR12 rate was significant lower in high baseline viral load (≥107 IU/ml) group compared to low viral load group (90.6% v.s 98.7%, p = 0.025). Multivariate analyses showed that HCV RNA≥107 IU/ml was one of the independent factors (OR = 0.134, 95% CI = 0.024–0.748; p = 0.022) associated with SVR12. Conclusion: GIE/PIB is an effective, tolerable and safe agent to treat genotype 2 HCV infected patients. However, high viral load (≥107 IU/ml) may predict virologic failure in non-cirrhotic patients receiving 8 weeks GIE/PIB treatment. This result should be further validated in a large cohort in the future.

Abstract Background Chronic hepatitis C virus (HCV), which is a concern in many countries, is the leading cause of liver cancer around the world. Since Taiwan launched its national health insurance system in 1995, it has managed to extend health coverage to 99% of the Taiwanese population, providing free but limited antiviral treatment each year since 2017. However, many people in rural areas are unaware that they have chronic HCV; nor do they realize that new drugs with high cure rates could drastically reduce their health burden. The aim of this study is to explore the implementation facilitators of and barriers to inviting potentially infected patients in rural areas to be transferred for HCV ribonucleic acid (RNA) confirmation and new drug treatment. Methods A descriptive and prospective study design with an interdisciplinary collaboration approach was implemented. After five elements of referral were developed, telephone counseling was conducted between August 2018 and May 2019 in Yunlin, Taiwan. The elements of referral developed by the research team were: (1) forming and coordinating physicians’ schedules, (2) recruiting and training volunteers, (3) training the nursing staff, (4) raising funds or resources, and (5) connecting with village leaders. Thereafter, we collaborated with two district health centers, a private local hospital, and health clinics. Based on the medical records provided by these agencies, community adults that were HCV antibody (anti-HCV) positive were invited to join the program. Results Of the 1795 adults who were serum anti-HCV positive, 1149 (64%) accepted transfer to a qualified hospital; of these, 623 (54.2%) had an HCV infection. 552 (88.6%) of those infected started receiving direct-acting antivirals (DAAs) treatment. The top four barriers to accepting transfer were: (1) they perceived themselves to be healthy (n = 98, 32.3%); (2) mistrust of treatment/healthcare (n = 60, 20.2%); (3) limited transportation to the hospital (n = 52, 17.5%); and (4) work conflict (n = 30, 10.1%). Conclusion An interdisciplinary collaboration approach significantly contributed to the invitation of CHC patients, as well as their acceptance of HCV RNA confirmation and free DAAs treatment. Using anti-HCV data from previous medical records for case-finding and collaborating with a hospital and health clinics proved to be an efficient strategy.

Early detection and prompt linkage to care are critical for hepatocellular carcinoma (HCC) care. Chang Gung Memorial Hospital (CGMH) Yunlin branch, a local hospital in a rural area, undertakes health checkup programs in addition to its routine clinical service. Patients with HCC are referred to CGMH Chiayi branch, a tertiary referral hospital, for treatment. This study enrolled 77 consecutive patients with newly diagnosed HCCs between 2017 and 2022, with a mean age of 65.7 ± 11.1 years. The screening group included HCC patients detected through health checkups, and those detected by routine clinical service served as the control group. Compared to the 24 patients in the control group, the 53 patients in the screening group had more cases with early stage cancer (Barcelona Clinic Liver Cancer or BCLC stage 0 + A 86.8% vs. 62.5%, p = 0.028), better liver reserve (albumin–bilirubin or ALBI grade I 77.3% vs. 50%, p = 0.031) and more prolonged survival (p = 0.036). The median survival rates of the 77 patients were >5 years, 3.3 years, and 0.5 years in the BCLC stages 0 + A, B, and C, respectively, which were above the expectations of the BCLC guideline 2022 for stages 0, A, and B. This study provides a model of HCC screening and referral to high-quality care in remote viral-hepatitis-endemic areas.

Real-world data on the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV infection and compensated cirrhosis is limited, especially for the 8-week regimen and in an Asian population. This retrospective study enrolled 159 consecutive patients with HCV and compensated cirrhosis who were treated with GLE/PIB at a single center in Taiwan. Sustained virological response (SVR) and adverse events (AEs) were evaluated. Among the 159 patients, 91 and 68 were treated with GLE/PIB for 8 and 12 weeks, respectively. In the per protocol analysis, both the 8- and 12-week groups achieved 100% SVR (87/87 vs. 64/64); and in the evaluable population analysis, 95.6% (87/91) of the 8-week group and 94.1% (64/68) of the 12-week group achieved SVR. The most commonly reported AEs, which included pruritus (15.4% vs. 26.5%), abdominal discomfort (9.9% vs. 5.9%), and skin rash (5.5% vs. 5.9%), were mild for the 8- and 12-week groups. Two patients in the 8-week group exhibited total bilirubin elevation over three times the upper normal limit. One of these two patients discontinued GLE/PIB treatment after 2 weeks but still achieved SVR. Both 8- and 12-week GLE/PIB treatments are safe and effective for patients of Taiwanese ethnicity with HCV and compensated cirrhosis.

The findings regarding changes in renal function in patients with hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs) are controversial. This study attempted to identify the factors associated with the large decline in renal function following DAA treatment. This retrospective cohort study included patients treated with DAAs at Chiayi and Yunlin Chang Gung Hospitals, Taiwan, from 1 January 2017 to 31 October 2020. Estimated glomerular filtration rate (eGFR) data were collected within 90 days prior to DAA therapy and 2 years after the confirmation of a sustained virologic response (SVR). We performed multiple logistic regression to evaluate the clinical or laboratory parameters associated with a large eGFR decline (≥10%). Among the enrolled 606 patients, the mean eGFR at the baseline and endpoint were 84.11 ± 24.38 and 78.88 ± 26.30 mL/min/1.73 m2, respectively (p < 0.001). The factors associated with a large eGFR decline 2 years after the SVR included hypertension (OR: 1.481; 95% CI: 1.010–2.173, p = 0.044) and a higher baseline eGFR (OR: 1.016; 95% CI: 1.007–1.024, p < 0.001). A higher albumin level reduced the risk of a large eGFR decline (OR: 0.546; 95% CI: 0.342–0.872, p = 0.011). In the patients with HCV treated with DAAs, a larger renal function decline was more commonly observed in those with hypertension, a lower (but within normal range) albumin level, and a higher baseline eGFR, while DAA treatment had no effect. The clinical significance of these findings has to be further defined. Although some risk factors associated with chronic kidney disease may be alleviated after DAA treatment, the regular control and follow-up of risk factors and renal function are still recommended in at-risk patients after HCV eradication.

The real-world benefits of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on the de novo occurrence and progression of esophageal varices (EV) remain unclear in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). This is a retrospective cohort study evaluating all patients with Child-Pugh class A HCV-related LC during 2013 to 2020 in the Chang Gung Medical System. A total of 215 patients fit the inclusion criteria and were enrolled. Of them, 132 (61.4%) patients achieved DAA induced-SVR and 83 (38.6%) did not receive anti-viral treatment. During a median follow-up of 18.4 (interquartile range, 10.1–30.9) months, the 2-year incidence of de novo EV occurrence was 8 (7.0%) in the SVR group and 7 (12.7%) in the treatment-naïve group. Compared to the treatment-naïve group, the SVR group was associated with a significantly lower incidence of EV occurrence (adjusted hazard ratio [aHR]: 0.47, p = 0.030) and a significantly lower incidence of EV progression (aHR: 0.55, p = 0.033). The risk of EV progression was strongly correlated with the presence of baseline EV (p < 0.001). To the best of our knowledge, this is the first study to demonstrate that DAA-induced SVR is associated with decreased risk of de novo EV occurrence and progression in the real world.

Background/Purpose: The major dose-limiting toxicity of ribavirin is hemolytic anemia. We investigated the incidence, risk factors and impact on virological response of anemia in chronic hepatitis C genotype 2 patients receiving sofosbuvir plus ribavirin therapy. Methods: This was a retrospective real-world analysis of a single center including 293 chronic hepatitis C genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks. Severe anemia was defined as hemoglobin concentration

Abstract Background The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear. Methods HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo. Results We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells. Conclusions The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b–mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.

Ha-Soo-Oh is a traditional Chinese medicine prepared from the roots of Polygonum multiflorum Thunb. The herb extract has been widely used in Asian countries as a tonic agent and nutritional supplement for centuries. To identify new bioactive compounds in Chinese herbs, the biotransformation-guided purification (BGP) process was applied to Ha-Soo-Oh with Bacillus megaterium tyrosinase (BmTYR) as a biocatalyst. The result showed that a major biotransformed compound could be purified using the BGP process with preparative high-performance liquid chromatography (HPLC), and it was confirmed as a new compound, 2,3,5,3′,4′-pentahydroxystilbene-2-O-β-glucoside (PSG) following mass and nucleic magnetic resonance (NMR) spectral analyses. PSG was further confirmed as a biotransformation product from 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside (TSG) by BmTYR. The new PSG exhibited 4.7-fold higher 1,1-diphenyl-2-picrylhydrazine (DPPH) free radical scavenging activity than that of TSG. The present study highlights the potential usage of BGP in herbs to discover new bioactive compounds in the future.

Objectives Community-based screening for hepatitis B virus (HBV) and hepatitis C virus (HCV) is essential for hepatitis elimination. This study attempted to increase screening accessibility and efficacy by using alternative tools.Design Population-based prospective cohort study.Setting Hepatitis elimination program at Yunlin County, Taiwan.Participants All 4552 individuals participated in 60 screening sessions of a community-based HBV and HCV screening project in five rural townships with approximately 95 000 inhabitants in central-western Taiwan.Interventions To increase accessibility, 60 outreach screening sessions were conducted in 41 disseminative sites. Quantitative HBV surface antigen (qHBsAg) and anti-HCV testing with reflex HCV core antigen (HCV Ag) tests were employed as alternative screening tools.Main outcome measures Calculate village-specific prevalence of HBsAg, anti-HCV and HCV Ag and establish patient allocation strategies according to levels of qHBsAg HCV Ag and alanine aminotransferase (ALT).Results Of 4552 participants, 553, 697 and 290 were positive for HBsAg, anti-HCV and HCV Ag, respectively; 75 of them had both HBsAg and anti-HCV positivity. The average (range) number of participants in each screening session was 98 (31–150). The prevalence rates (range) of HBsAg, anti-HCV and HCV Ag were 12.1% (4.3%–19.4%), 15.3% (2.6%–52.3%) and 6.4% (0%–30.2%), respectively. The HCV Ag positivity rate among anti-HCV-positive participants was 42% (0%–100%). Using cut-off values of >200 IU/mL for qHBsAg, >3 fmol/L for HCV Ag and >40 IU/mL for ALT as criteria for patient referral, we noted an 80.2% reduction in referral burden. Three villages had high anti-HCV prevalences of 52.3%, 53.8% and 63.4% with corresponding viraemic prevalences of 23.2%, 30.1% and 22% and thus constituted newly identified HCV-hyperendemic villages.Conclusion Outreach hepatitis screening increases accessibility for residents in rural communities. Screening HBV and HCV through qHBsAg and HCV Ag tests provides information concerning viral activities, which might be conducive to precise patient allocation in remote communities.

This study demonstrated the enzymatic hydroxylation of glycitin to 3′-hydroxyglycitin, confirming the structure by mass and nucleic magnetic resonance spectral analyses. The bioactivity assays further revealed that the new compound possessed over 100-fold higher 1,1-diphenyl-2-picrylhydrazine free-radical scavenging activity than the original glycitin, although its half-time of stability was 22.3 min. Furthermore, the original glycitin lacked anti-α-glucosidase activity, whereas the low-toxic 3′-hydroxyglycitin displayed a 10-fold higher anti-α-glucosidase activity than acarbose, a standard clinical antidiabetic drug. The inhibition mode of 3′-hydroxyglycitin was noncompetitive, with a Ki value of 0.34 mM. These findings highlight the potential use of the new soy isoflavone 3′-hydroxyglycitin in biotechnology industries in the future.

Puerarin (daidzein-8-C-glucoside) is an isoflavone isolated from several leguminous plants of the genus Pueraria. Puerarin possesses several pharmacological properties; however, the poor solubility of puerarin limits its applications. To resolve this poor solubility, Deinococcus geothermalis amylosucrase (DgAS) was used to modify puerarin into more soluble derivatives. The results showed that DgAS could biotransform puerarin into a novel compound: puerarin-4′-O-α-glucoside. The biotransformation reaction was manipulated at different temperatures, pH values, sucrose concentrations, reaction times, and enzyme concentrations. The results showed that the optimal reaction condition was biotransformed by 200 μg/mL DgAS with 20% (w/v) sucrose at pH 6 and incubated at 40 °C for 48 h, and the optimal production yield was 35.1%. Puerarin-4′-O-α-glucoside showed 129-fold higher solubility than that of puerarin and, thus, could be further applied for pharmacological use in the future.

PurposeThe purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer.MethodsMBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19).ResultsAs compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells in vitro and in vivo. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05).ConclusionsConstitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer.

A large community cohort of adults who participated in a health screening program from 2003 to 2013 were prospectively analyzed for the risk factors of non-B, non-C (NBNC) hepatocellular carcinoma (HCC). The serostatus of hepatitis B and C of 52,642 participants was linked to the mortality and cancer registration data of the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. During a median follow-up of 6 years, 35 of the 43,545 participants who were negative for both HBsAg and anti-HCV antibody developed HCC. Multivariate Cox regression analysis revealed that old age (hazard ratio, 95% CI: 1.058, 1.019–1.098, p = 0.003); male sex (2.446, 1.200–4.985, p = 0.014); high aspartate aminotransferase levels (6.816, 2.945–15.779, p < 0.001); fibrosis index based on four factor score (1.262, 1.154–1.381, p < 0.001); blood sugar (1.009, 1.002–1.015, p = 0.006); and alpha-fetoprotein ≥15 ng/mL (143.938, 43.094–480.760, p < 0.001) were independent risk factors for HCC. By contrast, triglyceride >150 mg/dL was associated with a decreased risk of HCC (0.216, 0.074–0.625, p = 0.005). This prospective community-based study provided insights into the potential HCC risk factors which may shed some light in HCC prevention and screening.

Glycosylation occurring at either lipids, proteins, or sugars plays important roles in many biological systems. In nature, enzymatic glycosylation is the formation of a glycosidic bond between the anomeric carbon of the donor sugar and the functional group of the sugar acceptor. This study found novel glycoside anomers without an anomeric carbon linkage of the sugar donor. A glycoside hydrolase (GH) enzyme, amylosucrase from Deinococcus geothermalis (DgAS), was evaluated to glycosylate ganoderic acid F (GAF), a lanostane triterpenoid from medicinal fungus Ganoderma lucidum, at different pH levels. The results showed that GAF was glycosylated by DgAS at acidic conditions pH 5 and pH 6, whereas the activity dramatically decreased to be undetectable at pH 7 or pH 8. The biotransformation product was purified by preparative high-performance liquid chromatography and identified as unusual α-glucosyl-(2→26)-GAF and β-glucosyl-(2→26)-GAF anomers by mass and nucleic magnetic resonance (NMR) spectroscopy. We further used DgAS to catalyze another six triterpenoids. Under the acidic conditions, two of six compounds, ganoderic acid A (GAA) and ganoderic acid G (GAG), could be converted to α–glucosyl-(2→26)-GAA and β–glucosyl-(2→26)-GAA anomers and α-glucosyl-(2→26)-GAG and β-glucosyl-(2→26)-GAG anomers, respectively. The glycosylation of triterpenoid aglycones was first confirmed to be converted via a GH enzyme, DgAS. The novel enzymatic glycosylation-formed glycoside anomers opens a new bioreaction in the pharmaceutical industry and in the biotechnology sector.

Screening and linkage to care are essential to achieve viral hepatitis elimination before 2030. The accurate identification of endemic areas is important for controlling diseases with geographic aggregation. Viral activity drives prognosis of chronic hepatitis B and hepatitis C virus infection. This screening was conducted in Chiayi County from 2018–2019. All residents aged 30 years or older were invited to participate in quantitative HBsAg (qHBsAg) and HCV Ag screening. Among the 4010 participants (male:female = 1630:2380), the prevalence of qHBsAg and HCV Ag was 9.9% (396/4010) and 4.1% (163/4010), respectively. High-prevalence townships were identified, three for qHBsAg > 15% and two for HCV Ag > 10%. The age-specific prevalence of qHBsAg was distributed in an inverse U-shape with a peak (16.0%, 68/424) for subjects in their 40 s; for HCV, prevalence increased with age. Concentrations of qHBsAg < 200 IU/mL were found in 54% (214/396) of carriers. The rate of oral antiviral treatment for HCV was 75.5% (114/151), with subjects younger than 75 years tending to undergo treatment (85.6% vs. 57.4%, p < 0.001). QHBsAg and HCV Ag core antigens can reflect the concentration of the viral load, which serves as a feasible screening tool. Using quantitative antigen screening for hepatitis B and C in community-based screening, two hyperendemic townships were identified from an endemic county.

To clarify the predictive factors of significant platelet count improvement in thrombocytopenic chronic hepatitis C (CHC) patients. CHC patients with baseline platelet counts of 3/μL receiving direct-acting antiviral (DAA) therapy with at least 12-weeks post-treatment follow-up (PTW12) were enrolled. Significant platelet count improvement was defined as a ≥10% increase in platelet counts at PTW12 from baseline. Platelet count evolution at treatment week 4, end-of-treatment, PTW12, and PTW48 was evaluated. This study included 4922 patients. Sustained virologic response after 12 weeks post-treatment was achieved in 98.7% of patients. Platelet counts from baseline, treatment week 4, and end-of-treatment to PTW12 were 108.8 ± 30.2, 121.9 ± 41.1, 123.1 ± 43.0, and 121.1 ± 40.8 × 103/μL, respectively. Overall, 2230 patients (45.3%) showed significant platelet count improvement. Multivariable analysis revealed that age (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.99–1.00, p = 0.01), diabetes mellitus (DM) (OR = 1.20, 95% CI: 1.06–1.38, p = 0.007), cirrhosis (OR = 0.66, 95% CI: 0.58–0.75, p < 0.0001), baseline platelet counts (OR = 0.99, 95% CI: 0.98–0.99, p < 0.0001), and baseline total bilirubin level (OR = 0.80, 95% CI: 0.71–0.91, p = 0.0003) were independent predictive factors of significant platelet count improvement. Subgroup analyses showed that patients with significant platelet count improvement and sustained virologic responses, regardless of advanced fibrosis, had a significant increase in platelet counts from baseline to treatment week 4, end-of-treatment, PTW12, and PTW48. Young age, presence of DM, absence of cirrhosis, reduced baseline platelet counts, and reduced baseline total bilirubin levels were associated with significant platelet count improvement after DAA therapy in thrombocytopenic CHC patients.

Background: The results of long-term renal evolution in HCV-infected patients using sofosbuvir and velpatasvir (SOF/VEL), with or without ribavirin (RBV), are lacking. Aims: We evaluated the renal safety for HCV-infected patients receiving SOF/VEL. Methods: Between 1 June 2019 and 6 July 2020, we included 594 HCV-infected patients receiving SOF/VEL +/− RBV for 12 weeks in Taiwan. Viral eradication rate (defined by sustained virological response at week 12 post-treatment; SVR12) and changes to renal function were considered. Results: SVR12 was achieved in 99.3% (590/594) upon per-protocol analysis. Patients saw improved hepatobiliary function and fibrosis after the start of SOF/VEL therapy. For renal function, those with baseline estimated glomerular filtration rate (eGFR) ≥ 60 (mL/min/1.73 m2) experienced transient on-treatment reduction in renal function that improved upon ending treatment, but recurrent eGFR degradation during one-year follow-up. The use of RBV (OR = 5.200, 95% CI: 1.983–13.634, p = 0.001) was a significant risk factor at SVR24, while diabetes mellitus (OR = 2.765, 95% CI: 1.104–6.922, p = 0.030) and the use of RBV (OR = 3.143, 95% CI: 1.047–9.435, p = 0.041) were identified as significant risk factors of worsening renal function at SVR48. SOF/VEL did not worsen renal function among those with stage 4–5 chronic kidney disease (CKD) who were not receiving dialysis. Conclusions: A trend of decline in eGFR at 1 year after SOF/VEL treatment was observed among diabetic patients with baseline eGFR ≥ 60 (mL/min/1.73 m2) and concomitant use of RBV. The close monitoring of renal function is warranted. Further study should be conducted in order to weigh the risks and benefit of RBV.

Mangiferin is a natural antioxidant C-glucosidic xanthone originally isolated from the Mangifera indica (mango) plant. Mangiferin exhibits a wide range of pharmaceutical activities. However, mangiferin’s poor solubility limits its applications. To resolve this limitation of mangiferin, enzymatic glycosylation of mangiferin to produce more soluble mangiferin glucosides was evaluated. Herein, the recombinant maltogenic amylase (MA; E.C. 3.2.1.133) from a thermophile Parageobacillus galactosidasius DSM 18751T (PgMA) was cloned into Escherichia coli BL21 (DE3) via the expression plasmid pET-Duet-1. The recombinant PgMA was purified via Ni2+ affinity chromatography. To evaluate its transglycosylation activity, 17 molecules, including mangiferin (as sugar acceptors), belonging to triterpenoids, saponins, flavonoids, and polyphenol glycosides, were assayed with β-CD (as the sugar donor). The results showed that puerarin and mangiferin are suitable sugar acceptors in the transglycosylation reaction. The glycosylation products from mangiferin by PgMA were isolated using preparative high-performance liquid chromatography. Their chemical structures were glucosyl-α-(1→6)-mangiferin and maltosyl-α-(1→6)-mangiferin, determined by mass and nucleic magnetic resonance spectral analysis. The newly identified maltosyl-α-(1→6)-mangiferin showed 5500-fold higher aqueous solubility than that of mangiferin, and both mangiferin glucosides exhibited similar 1,1-diphenyl-2-picrylhydrazyl free radical scavenging activities compared to mangiferin. PgMA is the first MA with glycosylation activity toward mangiferin, meaning mangiferin glucosides have potential future applications.

Vitexin is a C-glucoside flavone that exhibits a wide range of pharmaceutical activities. However, the poor solubility of vitexin limits its applications. To resolve this limitation, two glycoside hydrolases (GHs) and four glycosyltransferases (GTs) were assayed for glycosylation activity toward vitexin. The results showed that BtGT_16345 from the Bacillus thuringiensis GA A07 strain possessed the highest glycosylation activity, catalyzing the conversion of vitexin into new compounds, vitexin-4′-O-β-glucoside (1) and vitexin-5-O-β-glucoside (2), which showed greater aqueous solubility than vitexin. To our knowledge, this is the first report of vitexin glycosylation. Based on the multiple bioactivities of vitexin, the two highly soluble vitexin derivatives might have high potential for pharmacological usage in the future.

8-Hydroxydaidzein (8-OHDe) is a non-natural isoflavone polyphenol isolated from fermented soybean foods. 8-OHDe exhibits a wide range of pharmaceutical activities. However, both the poor solubility and instability of 8-OHDe limit its applications. To resolve the limitations of 8-OHDe, Deinococcus geothermalis amylosucrase (DgAS) has previously been used to glycosylate 8-OHDe to produce soluble and stable 8-OHDe-7-O-α-glucopyranoside (8-OHDe-7-G) in a 0.5 h reaction time. In this study, we aimed to use DgAS and an extended reaction time to produce 8-OHDe diglucosides. At least three 8-OHDe derivatives were produced after a 24 h reaction time, and two major products were successfully purified and identified as new compounds: 8-OHDe-7-O-[α-glucopyranosyl-(1→6)-α-glucopyranoside] (8-OHDe-7-G2) and 8-OHDe-7,4′-O-α-diglucopyranoside (8-OHDe-7-G-4′-G). 8-OHDe-7-G-4′-G showed a 4619-fold greater aqueous solubility than 8-OHDe. In addition, over 92% of the 8-OHDe diglucosides were stable after 96 h, while only 10% of the 8-OHDe could be detected after being subjected to the same conditions. The two stable 8-OHDe diglucoside derivatives have the potential for pharmacological usage in the future.

BACKGROUND:Hepatitis C virus core antigen (HCV Ag) assay has been proposed as a more economical alternative to HCV RNA detection. This study aimed to investigate the clinical utility of HCV Ag assay in the monitoring of direct-acting antivirals (DAAs) for chronic hepatitis C patients. METHODS:We analyzed serum samples from 110 patients treated with paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin. The levels for both HCV Ag and HCV RNA assessed by COBAS TaqMan HCV (CTM) Test or Abbott RealTime HCV (ART) assay were evaluated at baseline, week 2, 4, and 12 during treatment and 12 weeks after completion. RESULTS:Baseline HCV Ag levels showed good correlations with HCV viral load (r = 0.879; p

Current guidelines recommend antibiotic prophylaxis for all patients with various degrees of cirrhosis and upper gastrointestinal (UGI) bleeding. This study assessed the need for antibiotic prophylaxis in patients with low Child-Pugh scores. We retrospectively screened all patients with cirrhosis who underwent upper endoscopies for UGI bleeding in a referral hospital in Taiwan between 2003 and 2014, from which 913 patients were enrolled after excluding patients with active bacterial infections, recent antibiotic use, early death, and Child-Pugh class C cirrhosis. Among them, 73 (8%) received prophylactic antibiotics, and 45 (4.9%) exhibited 14-day bacterial infection. Neither Child-Pugh score nor model for end stage liver disease score were optimal for predicting bacterial infection because their areas under the curves were 0.610 (95% confidence interval [CI]: 0.529-0.691) and 0.666 (95% CI: 0.591-0.742), respectively. Antibiotic prophylaxis did not reduce the risks of 14-day bacterial infection (relative risk [RR]: 0.932, 95% CI: 0.300-2.891, P = 0.902), 14-day rebleeding (RR: 0.791, 95% CI: 0.287-2.181, P = 0.650), or 42-day mortality (RR: 2.710, 95% CI: 0.769-9.524, P = 0.121). The results remained similar after propensity score adjustment. On-demand antibiotic treatment might suffice for patients with Child-Pugh class A/B cirrhosis and UGI bleeding.