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Background This study is aimed at estimating the unbiased effectiveness of population-based breast cancer service screening based on case survival information alone rather than large-scale individual screening data pursuant to the intention-to-treat principle of a randomized–controlled trial. Methods A novel time-dependent switched design with two modalities of cancer detection (screen-detected vs clinically detected) was proposed to evaluate the effectiveness of breast cancer screening. We used data on 767 patients from Kopparberg in the Swedish Two-County trial and on 78 587 patients in the Taiwan population-based service screening. We estimated the relative rate of the screen-detected vs the clinically detected with adjustment for both truncation and lead-time biases. The absolute effectiveness in terms of the number needed to screen (NNS) for averting one death from breast cancer was estimated. Results The relative rate of effectiveness was estimated as 33%, which was consistent with the 37% reported from the original Swedish randomized–controlled trial. The corresponding estimate for the Taiwan screening programme was 42%, which was also very close to that estimated using individual screening history data (41%). Both relative estimates were further applied to yield 446 and 806 of NNS for averting one death from breast cancer for the corresponding two data sets. Conclusion The proposed time-dependent switched design and analysis with two modalities of case survival information provides a very efficient means for estimating the unbiased estimates of relative and absolute effectiveness of population-based breast cancer service screening dispensing with a large amount of individual screening history data.

History of alcohol abuse is a predictive factor for posttransplant delirium. We aimed to investigate whether preoperative abstinence was associated with posttransplant delirium in liver transplant recipients with alcohol-related cirrhosis.From January 2014 to December 2019, 84 patients with alcohol-related cirrhosis who received living donor liver transplant were retrospectively reviewed and divided into a delirium group (n = 46, 54.8%) and a nondelirium group (n = 38, 45.2%) using the Richmond Agitation- Sedation Scale and the Confusion Assessment Method for the Intensive Care Unit.In the delirium group versus the nondelirium group, patients were more likely to have preoperative hepatic encephalopathy (58.7% vs 31.6%; P = .013), more likely to have higher Model for End-Stage Liver Disease scores (27.05 ± 10.56 vs 18.85 ± 7.96; P.001), less likely to have preoperative alcohol abstinence (43.5% vs 68.4%%; P = .022), had longer duration of mechanical ventilation (7.57 ± 7.82 vs 2.50 ± 5.96 days; P = .001), and had longer stays in the intensive care unit (14.85 ± 15.01 vs 8.84 ± 7.84 days; P = .021) and in the hospital (37.89 ± 18.85 vs 27.15 ± 10.43 days; P = .002). Multivariate analysis revealed that preoperative alcohol abstinence (odds ratio 4.953; 95% CI, 1.519-16.152; P = .008) was a significant predictor and that more patients had abstinence durations3 months (60.9% vs 34.2%; P = .048) in the delirium group.A high incidence of posttransplant delirium in liver transplant recipients with alcohol- related cirrhosis was associated with preoperative abstinence. Abstinence6 months before living donor liver transplant is suggested to reduce the risk of posttransplant delirium.

Introduction Efficient evaluation with an early surrogate endpoint, taking into account the process of disease evolution, may not only clarify inconsistent or underpowered results but also provide a new insight into the exploration of a new antiviral therapy for treating COVID-19 patients. Methods We assessed the dynamics of COVID-19 disease spectrum, commencing from low-risk (no or low oxygen supplement), medium-risk (non-invasive ventilator or high oxygen supplement), and high-risk (extracorporeal membrane oxygenation or invasive ventilator) risk state on enrollment, and then the subsequent progression and regression of risk states until discharge or death. The efficacy of antiviral therapy in altering the dynamics was assessed by using the high-risk state as a surrogate endpoint based on the data retrieved from the two-arm Adaptive Covid-19 Treatment Trial. Results Using the high-risk state as a surrogate endpoint, remdesivir treatment led to a decrease in the high-risk COVID-19 state by 34.8% (95% CI 26.7–42.0%) for a 14-day period and 29.3% (95% CI 28.8–29.8%) up to 28 days, which were consistent with a statistically significant reduction of death by 30.5% (95% CI 6.6, 50.9%) up to a 28-day period. The estimates of numbers needed to be treated were 100.9 (95% CI 88.1, 115.7) for using the high-risk COVID-19 state as a surrogate endpoint for a 14-day period and 133.3 (95% CI 112.5, 158.0) were required for averting one death from COVID-19 up to 28 days. Conclusions We demonstrate the expedient use of the high-risk COVID-19 disease status as a surrogate endpoint for evaluating the primary outcome of the earliest death. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00431-9.

ObjectiveAlthough mass eradication ofHelicobacter pylorihas been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear.DesignMass eradication ofH. pyloriinfection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalentH. pyloriinfection. Test positives for the13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively.ResultsAfter six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates ofH. pylorifell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, pH. pylori.ConclusionPopulation-based eradication ofH. pylorihas significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period.Trial registration numberNCT00155389

In the face of rapid emerging variants of concern (VOCs) with potential of evading immunity from Beta to Omicron and uneven distribution of different vaccine brands, a mix-match strategy has been considered to enhance immunity. However, whether increasing immunogenicity using such a mix-match can lead to high clinical efficacy, particularly when facing Omicron pandemic, still remains elusive without using the traditional phase 3 trial. The aim of this study is to demonstrate how to evaluate correlates of protection (CoP) of the mix-match vaccination.Data on neutralizing antibody (NtAb) titers and clinical efficacy against Wuhan or D614G strains of homologous ChAdOx1 nCov-19 or mRNA-1273 and heterologous vaccination were extracted from previous studies for demonstration. The reductions in NtAb titers of homologous vaccination against Beta, Delta, and Omicron variants were obtained from literatures. A Bayesian inversion method was used to derive CoP from homologous to mix-match vaccine. Findings The predicted efficacy of ChAdOx1 nCov-19 and mRNA-1273 for Wuhan or D614G strains was 93 % (89 %-97 %). Given 8 ∼ 11-fold, 2 ∼ 5.5-fold, and 32.5 ∼ 36-fold reduction of NtAb for Beta, Delta, and Omicron variants compared with D614G, the corresponding predictive efficacy of the mix-match ranged from 75.63 % to 73.87 %, 84.87 % to 81.25 %, and 0.067 % to 0.059 %, respectively. Interpretations While ChAdOx1 nCov-19 and mRNA-1273 used for demonstrating how to timely evaluate CoP for the mix-match vaccine still provides clinical efficacy against Beta and Delta VOCs but it appears ineffective for Omicron variants, which highlights the urgent need for next generation vaccine against Omicron variant.

ObjectivesTwo kinds of epidemic surveillance models are presented for containing the spread of SARS-CoV-2 variants so as to avert and stamp out a community-acquired outbreak (CAO) with non-pharmaceutical interventions (NPIs), tests, and vaccination.DesignThe surveillance of domestic cluster infections transmitted from imported cases with one-week time lag assessed by the Poisson model and the surveillance of whether, how and when NPIs and test contained the CAO with the SEIR model.SettingsBorder and Community of Taiwan.Main Outcome MeasurementsThe expected number and the upper bound of the 95% credible interval (CrI) of weekly covid-19 cases compared with the observed number for assessing the threshold of a CAO; effective reproductive number (Rt) and the effectiveness of NPIs for containing a CAO.ResultsFor the period of January-September 2020 when the wild type and the D614G period were prevailing, an increase in one imported case prior to one week would lead to 9.54% (95% CrI 6.44% to 12.59%) higher risk of domestic cluster infection that provides a one-week prior alert signal for more stringent NPIs and active testing locally. Accordingly, there was an absence of CAO until the Alpha VOC period of February 2021. However, given level one of NPI alert the risk of domestic cluster infections was gradually elevated to 14.14% (95% CrI 5.41% to 25.10%), leading to the Alpha VOC CAOs of six hotspots around mid-May 2021. It took two-and-half months for containing this CAO mainly with level three of NPI alert and rapid test and partially by the rolling out of vaccination. By applying the SEIR model, the Rt decreased from 4.0 at beginning to 0.7 on 31 July 2021 in parallel with the escalating NPIs from 30% to 90%. Containing a small outbreak of Delta VOC during this CAO period was also evaluated and demonstrated. After controlling the CAO, it again returned to imported-domestic transmission for Delta VOC from July until September 2021, giving an estimate of 10.16% (95% CrI: 7.01% to 13.59%) for the risk of several small cluster infections. However, there was an absence of CAO that resulted from the effectiveness of NPIs and tests, and the rapid expansion of vaccination.ConclusionsAverting and containing CAOs of SARS-CoV-2 variants are demonstrated by two kinds of epidemic surveillance models that have been applied to Taiwan scenario. These two models can be accommodated to monitor the epidemic of forthcoming emerging SARS-CoV-2 VOCs with various circumstances of vaccine coverage, NPIs, and tests in countries worldwide.

The aim of this study was to analyze patients who underwent endoscopic resection (ER) for gastric subepithelial tumors (SETs) with a high probability of surgical intervention. Between January 2013 and January 2021, 83 patients underwent ER at the operation theater and 27 patients (32.5%) required backup surgery mainly due to incidental perforation or uncontrolled bleeding despite endoscopic repairing. The tumor was predominantly located in the upper-third stomach (81%) with a size ≤ 2 cm (69.9%) and deep to the muscularis propria (MP) layer (92.8%) but there were no significant differences between two groups except tumor exophytic growth as a risk factor in the surgery group (37% vs. 0%, p &lt, 0.0001). Patients in the ER-only group had shorter durations of procedure times (60 min vs. 185 min, p &lt, 0.0001) and lengths of stay (5 days vs. 7 days, p &lt, 0.0001) but with a higher percentage of overall morbidity graded III (0% vs. 7.1%, p = 0.1571). After ER, five patients (6%) had delayed perforation and two (2.4%) required emergent laparoscopic surgery. Neither recurrence nor gastric stenosis was reported during long-term surveillance. Here, we provide a minimally invasive strategy of endoscopic resection with backup laparoscopic surgery for gastric SETs.

To call attention to a highly fatal breast cancer subtype arising from the major lactiferous ducts that is currently underdiagnosed as ductal carcinoma in situ (DCIS) with or without microinvasion.All breast cancers diagnosed at the Department of Mammography, Falun Central Hospital, Sweden, since 1977 have been classified according to their mammographic tumour features (imaging biomarkers) and followed up at regular intervals for the past four decades. The imaging biomarkers characteristic of breast cancers apparently arising from the major lactiferous ducts have been correlated with large format thin and thick section histopathology and long-term patient outcome.Breast cancers arising within the major lactiferous ducts propagate intraductally and produce continuously branching neoducts through epithelial-mesenchymal transformation (EMT), an invasive process termed neoductgenesis, which eventually forms a massive tumour burden. The high fatality of this breast cancer subtype indicates its truly invasive nature, although it is conventionally termed ductal carcinoma in situ, DCIS, terminology which is at odds with its poor long-term patient outcome. The neoducts are filled with multiple layers of malignant cells, have no attached lobules, and propagate by forming multiple invasive side branches. These newly formed duct-like structures are surrounded by a desmoplastic reaction (cancer associated fibroblasts, CAFs) and periductal lymphocytic infiltration. The neoducts are tightly packed together in irregular formations bearing no resemblance to the paniculate branching structure of normal lactiferous ducts. Cancers originating from the major ducts have six imaging biomarkers which can be easily recognized at breast imaging. These are described in detail in an accompanying article.Neoductgenesis in the breast, DAB, is similar in appearance and prognosis to ductal adenocarcinoma of the prostate, DAP. We propose the term ductal adenocarcinoma of the breast, DAB, to facilitate its recognition as a distinct invasive breast cancer subtype. The high fatality rates associated with neoductgenesis reflect the failure of current histopathologic diagnostic criteria to effectively guide therapeutic practice. When the neoducts are associated with small stellate/spiculated or spherical/oval-shaped invasive cancers arising from the terminal ductal lobular units (TDLUs), the prognosis and management are erroneously estimated according to the smaller invasive tumour(s), giving a false sense of security often resulting in undertreatment. Recognition that neoductgenesis is an invasive malignancy is a prerequisite for preventing treatment failure.

This chapter asks and examines two questions: what are the major factors that impact the role of management and leadership in police service delivery in Taiwan, and how do they relate to the high citizen satisfaction with police services? The authors take a legal-institutional perspective and identify several important factors that impact the role of management and leadership in police service delivery. This chapter identifies six legal-institutional factors that are important to police service delivery in Taiwan, including police enforcement laws, standard operating procedures (SOPs), command and control systems, appointment system of police chiefs, local autonomous actions, and shifting structural characteristics of communities. These factors affect the management and leadership of the local police department and impact the first-line police officer’s service delivery. Lastly, this chapter offers a discussion on how these factors contribute to the high citizen satisfaction rate with police service delivery in Taiwan.

Background: Survival of colorectal cancer detected within a screening program may largely affect the effectiveness of the screening program. Long-term outcomes of interval cancers after a fecal immunochemical test (FIT) and colonoscopy (interval type post-colonoscopy colorectal cancer; PCCRCi) within a FIT screening program are, however, rarely reported. Methods: The interval cancers occurring within a Taiwan Colorectal Cancer Screening Program in 2004-2012 comprised the study cohort and were followed until 2016. The incidence of FIT interval cancers and PCCRCi was calculated, and PCCRCi were stratified by adenoma detection rate (ADR) levels [ 42% (high)]. The survival status of those with FIT interval cancers and different PCCRCi categories were compared. Findings: In total, 2,746,478 subjects received at least one FIT screening with 1,825 (86·4%) FIT interval cancers and 288 (13·6%) PCCRCis developing during the study period. Hospitals with low ADR levels had a significantly higher incidence of PCCRCi (0·93 per 1000 person-years) than those with middle and high ADR levels (0·70 and 0·58 per 1000 person-years, respectively) (p

While the efficacy of population-based screening for colorectal cancer (CRC) with the fecal occult blood test (FOBT) has been demonstrated in several randomized controlled trials the results on cost-effectiveness analysis using a probabilistic approach has been barely investigated. In this chapter, we first proposed the framework of economic evaluation for population-based screening for CRC and then reviewed the results in literature on various screening methods. We also demonstrate a case study with the application of the analytical Markov decision model to evaluating different screening strategies with particular emphasis on fecal immunochemical test (FIT) that has been implemented in Taiwan since 2000. The probabilistic cost-effectiveness analysis was performed to evaluate annual, biennial, and triennial FIT as opposed to no screening. We found biennial FIT was cost saving compared with the annual g-FOBT test. The probability of being cost-effective was up to 80% given 20,000 WTP. Performing cost-effective analysis with a probabilistic approach plays a crucial in evidence-based medicine for population-based screening policy.

Evaluating the performance of serum prostate-specific antigen (PSA) test in population-based screening with receiver operating characteristics (ROC) curve often neglects the time dimension. Asymptomatic cases with negative PSA test would have been missed if sojourn time is not taken into account to allow for cases surfacing into the clinical phase. Data included 20,796 men with PSA test at the first screening round was used from population-based Finnish prostate cancer screening trial during 1996–1999. Cancers detected at the first screen, together with interval cancers ascertained during 4-year follow-up were expediently used to estimate sensitivity and specificity. A sojourn-time-corrected model was applied to estimating the possible false negative cases for those with PSA

Background: The impact of remdesivir on length of stay of hospitalization, high-risk state, and death stratified by the severity of COVID-19 at enrollment is controversial. Methods: We applied a simulated two-arm controlled study design to the data on compassionate use of remdesivir as a secondary analysis. Dynamics of risk states and death from COVID-19 patients defined by the six-point disease severity recommended by the WHO R&D and the time to discharge from hospital were used to evaluate the efficacy of remdesivir treatment compared with standard care. Results: Stratified by the risk state at enrollment, low-risk patients exhibited the highest efficacy of remdesivir in reducing subsequent progression to high-risk state by 67% (relative risk (RR)=0.33,95% CI: 0.30-0.35) and further to death by 55% (RR=0.45, 95%CI: 0.39-0.50). For the medium-risk patients, less but still statistically significant efficacy results were noted in reducing progression to high-risk state by 52% (RR=0.48, 95% CI: 0.45-0.51) and further to death by 40% (RR=0.60, 95% CI:0.54-0.66). High-risk state patients treated with remdesivir led to a 25% statistically significant reduction in death (RR=0.75, 95% CI: 0.69-0.82). Regarding the outcome of discharge, remdesivir treatment was most effective for medium-risk patients at enrollment (RR: 1.41, 95% CI: 1.35-1.47) followed by high- (RR=1.34, 95% CI: 1.27-1.42) and low-risk patients (RR=1.28, 95% CI: 1.25-1.31). Conclusion: Our results with a simulated two-arm controlled study have provided a new insight into the precision treatment of remdesivir for COVID-19 patients based on risk-stratified efficacy.

Identification of heavy health care users among community-dwelling older adults can lead to strategic care planning and management that positively impacts health care use and costs. This study aims to identify risk factors associated with heavy users of acute care and long-term care (LTC) in Changhua County, Taiwan. Study participants (n=8,090) included residents (age 65+) of Changhua County. Data were collected from 4/1/2017-10/26/2018. Linked hospitalization and LTC use information was provided by the Changhua County Public Health Bureau. Hospitalization was grouped into 1 vs. 2+. Univariate and multivariate logistic models will be used to address the study aim. Preliminary results show the average age was 81 years ranging from 65-105. Of this population, 56% are female, and 10% live alone. The average length of hospital stay was 9.7 days. Risk factors associated with heavy health care users identified in multivariate analysis will be presented and intervention strategies will be discussed. Part of a symposium sponsored by International Comparisons of Healthy Aging Interest Group.

The aim was to evaluate how the inter-screening interval affected the performance of screening by mammographic appearances. This was a Swedish retrospective screening cohort study with information on screening history and mammography features in two periods (1977&ndash, 1985 and 1996&ndash, 2010). The pre-clinical incidence and the mean sojourn time (MST) for small breast cancer allowing for sensitivity by mammographic appearances were estimated. The percentage of interval cancer against background incidence (I/E ratio) was used to assess the performance of mammography screening by different inter-screening intervals. The sensitivity-adjusted MSTs (in years) were heterogeneous with mammographic features, being longer for powdery and crushed stone-like calcifications (4.26, (95% CI, 3.50&ndash, 5.26)) and stellate masses (3.76, (95% CI, 3.15&ndash, 4.53)) but shorter for circular masses (2.65, (95% CI, 2.06&ndash, 3.55)) in 1996&ndash, 2010. The similar trends, albeit longer MSTs, were also noted in 1977&ndash, 1985. The I/E ratios for the stellate type were 23% and 32% for biennial and triennial screening, respectively. The corresponding figures were 32% and 43% for the circular type and 21% and 29% for powdery and crushed stone-like calcifications, respectively. Mammography-featured progressions of small invasive breast cancer provides a new insight into personalized quality assurance, surveillance, treatment and therapy of early-detected breast cancer.

Background: Survival of colorectal cancer detected within a screening program may largely affect effectiveness of screening. Survival of colorectal cancer by different detection modes within fecal immunochemical test (FIT)-based screening program is, however, rarely reported. Methods: Colorectal cancers with various detection modes within a population-based FIT screening program comprise the study cohort. Totally 8 992 colorectal cancers were identified from the cohort who were considered as eligible for screening during 2004-2012 in Taiwanese Colorectal Cancer Screening Program and were followed up until 2016. Their survival status was compared and stratified by different detection modes. Multivariable analyses were conducted with Cox proportional hazards regression models. Findings: Colonoscopy interval cancer, FIT interval cancer, and colorectal cancer in colonoscopy noncompliers presented at a more advanced compared with screen-detected colorectal cancers. The 5-years survival rate was higher for subsequent screen-detected colorectal cancers and worst in FIT interval cancer and colorectal cancer in colonoscopy noncompliers. In multivariable analysis, when compared with subsequent screen-detected colorectal cancers, colorectal cancers in colonoscopy noncompliers, the adjusted hazard ratio and its 95% confidence interval for colorectal cancer death was 1·25(1·04-1·50) for prevalent screen-detected colorectal cancers, 1·62(1·21-2·18) for colonoscopy interval cancers, 1·79(1·48-2·15) for FIT interval cancers, and 1·95(1·61-2·37) for colorectal cancer in colonoscopy noncompliers even after adjusting for stage. Interpretation: Interval colorectal cancer and colorectal cancers in colonoscopy noncompliers had worse survival than screen-detected colorectal cancers and factors other than stage might have affected survival and screening organizers should elaborate on relevant aspects. Funding Statement: This study was supported by the Health Promotion Administration, Ministry of Health and Welfare (A1011119, A1021227, A1031135, A1041122, A1051013, and A1061224). Declaration of Interests: The authors stated: "None." Ethics Approval Statement: This study was approved by Health Promotion Administration of the Ministry of Health and Welfare of the Taiwanese government.

Allyl isothiocyanate (AITC), a volatile and water-insoluble compound present in several cruciferous vegetables, has been shown to possess several biological qualities such as anti-bacterial, anti-fungal, and anti-cancer activity. In this study, water-soluble allyl isothiocyanate nanoparticles (AITC-NPs) were prepared by oil dispersed in water (O/W) microemulsion and complex coacervation techniques and evaluated for their anti-inflammatory activity towards macrophage cell RAW 264.7 and anti-cancer effect on human bladder cancer cell HT1376. RESULTS The AITC-NPs with a particle size of 9.4?nm were stable during heating up to 110?°C or three freeze-thawing cycles. No significant cytotoxicity was shown on Caco-2 and intestine epithelial IEC-6 cells at AITC-NP doses ranging from 0.25 to 2?g?L?1 (8.75?70?mg?L?1 AITC). However, at 2?g?L?1 dosage, AITC-NPs could inhibit the growth of human bladder cancer cells HT1376 by 90%, while their low dosage at 0.25?g?L?1 could inhibit migration ability by 83.7, 71.3, 58.4 and 31.4% after 4, 8, 12, and 24?h of incubation, respectively. Compared to AITC and NPs, AITC-NPs showed a better inhibition on lipopolysaccharide (LPS)-induced TNF-α, IL-6, NO and iNOS production in RAW 264.7 macrophage cells. CONCLUSION The results demonstrate the potential of AITC-NPs as therapeutic agents for the treatment of bladder cancer and the enhancement of immune function. ? 2018 Society of Chemical Industry

Aristolochic acid (AA) is a component of Chinese medicinal herbs, including asarum and aristolochia and has been used in Traditional Chinese Medicine for a long time. Recent studies found that AA has a cytotoxic effect resulting in nephropathy. These studies indicated that AA‑induced cytotoxicity is associated with increases in oxidative stress and caspase‑3 activation. The present study further demonstrated that AA mainly elevates the H2O2 ratio, leading to increases in oxidative stress. Furthermore, the results indicated that AA induces cell death can via caspase‑dependent and ‑independent pathways. It is desirable to identify means of inhibiting AA‑induced renal damage; therefore, the present study applied an anti‑oxidative nutrient, vitamin C, to test whether it can be employed to reduce AA‑induced cell cytotoxicity. The results showed that vitamin C decreased AA‑induced H2O2 levels, caspase‑3 activity and cytotoxicity in renal tubular cells. In conclusion, the present study was the first to demonstrate that AA‑induced increases of the H2O2 ratio resulted in renal tubular cell death via caspase‑dependent and ‑independent pathways, and that vitamin C can decrease AA‑induced increases in H2O2 levels and caspase‑3 activity to attenuate AA‑induced cell cytotoxicity.

Retinoic acid (RA), vitamin D and 12-O‑tetradecanoyl phorbol-13-acetate (TPA) can induce HL-60 cells to differentiate into granulocytes, monocytes and macrophages, respectively. Similar to RA and vitamin D, ascorbic acid also belongs to the vitamin family. High‑dose ascorbic acid (>100 µM) induces HL‑60 cell apoptosis and induces a small fraction of HL‑60 cells to express the granulocyte marker, CD66b. In addition, ascorbic acid exerts an anti‑oxidative stress function. Oxidative stress is required for HL‑60 cell differentiation following treatment with TPA, however, the effect of ascorbic acid on HL‑60 cell differentiation in combination with TPA treatment remains to be fully elucidated. The aim of the present study was to investigate the cellular effects of ascorbic acid treatment on TPA-differentiated HL-60 cells. TPA-differentiated HL-60 cells were used for this investigation, this study and the levels of cellular hydrogen peroxide (H2O2), caspase activity and ERK phosphorylation were determined following combined treatment with TPA and ascorbic acid. The results demonstrated that low‑dose ascorbic acid (5 µM) reduced the cellular levels of H2O2 and inhibited the differentiation of HL‑60 cells into macrophages following treatment with TPA. In addition, the results of the present study further demonstrated that low‑dose ascorbic acid inactivates the ERK phosphorylation pathway, which inhibited HL‑60 cell differentiation following treatment with TPA.

Acetaminophen (APAP), is a safe analgesic and antipyretic drug at therapeutic dose, and is widely used in the clinic. However, high doses of APAP can induce hepatotoxicity and nephrotoxicity. Most studies have focused on high‑dose APAP‑induced acute liver and kidney injury. So far, few studies have investigated the effects of the therapeutic dose (1/10 of the high dose) or of the low dose (1/100 of the high dose) of APAP on the cells. The aim of this study was to investigate the cellular effects of therapeutic- or low‑dose APAP treatment on hepatoma cells and kidney fibroblasts. As expected, high‑dose APAP treatment inhibited while therapeutic and low‑dose treatment did not inhibit cell survival of kidney tubular epithelial cells. In addition, therapeutic-dose treatment induced an increase in the H2O2 level, activated the caspase‑9/‑3 cascade, and induced cell apoptosis of hepatoma cells. Notably, APAP promoted fibroblast proliferation, even at low doses. This study demonstrates that different cellular effects are exerted upon treatment with different APAP concentrations. Our results indicate that treatment with the therapeutic dose of APAP may exert an antitumor activity on hepatoma, while low‑dose treatment may be harmful for patients with fibrosis, since it may cause proliferation of fibroblasts.

Squalene synthase (SQS) is a divalent metal-ion-dependent enzyme that catalyzes the two-step reductive `head-to-head' condensation of two molecules of farnesyl pyrophosphate to form squalene using presqualene diphosphate (PSPP) as an intermediate. In this paper, the structures of human SQS and its mutants in complex with several substrate analogues and intermediates coordinated with Mg2+or Mn2+are presented, which stepwise delineate the biosynthetic pathway. Extensive study of the SQS active site has identified several critical residues that are involved in binding reduced nicotinamide dinucleotide phosphate (NADPH). Based on mutagenesis data and a locally closed (JK loop-in) structure observed in thehSQS-(F288L)–PSPP complex, an NADPH-binding model is proposed for SQS. The results identified four major steps (substrate binding, condensation, intermediate formation and translocation) of the ordered sequential mechanisms involved in the `1′–1' isoprenoid biosynthetic pathway. These new findings clarify previous hypotheses based on site-directed mutagenesis and biochemical analysis.

Japanese encephalitis virus (JEV), a mosquito‑borne flavivirus, causes acute encephalitis and nervous damage. Previous studies have demonstrated that JEV induces apoptosis in infected cells. However, to date the mechanisms of JEV‑induced apoptosis are unclear. In order to identify the viral proteins associated with JEV‑induced apoptosis, pEGFP‑non‑structural protein 3 (NS3) 1‑619 (expressing the JEV NS3 intact protein, including the protease and helicase domains), pEGFP‑NS3 1‑180 (expressing the protease domain) and pEGFP‑NS3 163‑619 (expressing the helicase domain) were transfected into target cells to study cell death. Results demonstrate that the JEV NS3 intact protein and protease and helicase domains induce cell death. In addition, cell death was identified to be significantly higher in cells transfected with the NS3 protease domain compared with the intact protein and helicase domain. Caspase activation was also analyzed in the current study. NS3 intact protein and NS3 protease and helicase domains activated caspase‑9/‑3‑dependent and ‑independent pathways. However, caspase‑8 activity was not found to be significantly different in NS3‑transfected cells compared with control. In summary, the present study demonstrates that the NS3 helicase and protease domains of JEV activate caspase‑9/‑3‑dependent and ‑independent cascades and trigger cell death.

Nuclear existence of epidermal growth factor receptor (EGFR) has been documented for more than two decades. Resistance of cancer to radiotherapy is frequently correlated with elevated EGFR expression, activity, and nuclear translocation. However, the role of nuclear EGFR (nEGFR) in radioresistance of cancers remains elusive. In the current study, we identified a novel nEGFR-associated protein, polynucleotide phosphorylase (PNPase), which possesses 3' to 5' exoribonuclease activity toward c-MYC mRNA. Knockdown of PNPase increased radioresistance. Inactivation or knock-down of EGFR enhanced PNPase-mediated c-MYC mRNA degradation in breast cancer cells, and also increased its radiosensitivity. Interestingly, the association of nEGFR with PNPase and DNA-dependent protein kinase (DNAPK) increased significantly in breast cancer cells after exposure to ionizing radiation (IR). We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. The phospho-mimetic S776D mutant of PNPase impaired its ribonuclease activity whereas the nonphosphorylatable S776A mutant effectively degraded c-MYC mRNA. Here, we uncovered a novel role of nEGFR in radioresistance, and that is, upon ionizing radiation, nEGFR inactivates the ribonuclease activity of PNPase toward c-MYC mRNA through DNAPK-mediated Ser-776 phosphorylation, leading to increase of c-MYC mRNA, which contributes to radioresistance of cancer cells.

Purpose As the hospital industry continues to undergo significant change and becomes an increasingly competitive environment, the concept of competitive advantage has received a considerable degree of attention in the healthcare literature. Using a multilevel modeling approach, this study evaluated the contributions of hospital characteristics and market competition on perceived competitive advantage of hospital managers in Taiwan. Methods Data for this study were mainly collected using a questionnaire that was mailed to the top executives of 432 accredited hospitals in Taiwan in 2009. Valid responses were obtained from182 hospitals for an effective response rate of 42.1%. Results Respondents indicated relatively moderate assessment of perceived competitive advantage (mean = 3.5, standard deviation = 0.72, on a five-point Likert scale). There were no significant correlations between the group-level predictor (competition of local healthcare market) and the individual-level ones. Results of multilevel analysis to simultaneously examine the effects of individual-level (hospital characteristics; level 1) and group-level (competition of local healthcare market; level 2) predictors on perceived competitive advantage indicated that the predictors at hospital level had a statistically significant effect on respondents' perception of competitive advantage of their hospitals. Nonetheless, there was insignificant market competition variation in perceived competitive advantage among respondents. Conclusion We conducted a multilevel analysis that reflected the hierarchical structure of our data, where hospitals were nested within healthcare markets of different intensities of competition. Our results join a body of healthcare literature suggesting that hospital level is a significant predictor of hospital performance. However, we found no evidence of a strong relationship between the degree of local market competition and perceived competitive advantage of respondents. Taken together, the results of our empirical study shed light on some interesting issues regarding competitive advantage.

Zaragozic acids (ZAs) belong to a family of fungal metabolites with nanomolar inhibitory activity toward squalene synthase (SQS). The enzyme catalyzes the committed step of sterol synthesis and has attracted attention as a potential target for antilipogenic and antiinfective therapies. Here, we have determined the structure of ZA-A complexed with human SQS. ZA-A binding induces a local conformational change in the substrate binding site, and its C-6 acyl group also extends over to the cofactor binding cavity. In addition, ZA-A effectively inhibits a homologous bacterial enzyme, dehydrosqualene synthase (CrtM), which synthesizes the precursor of staphyloxanthin in Staphylococcus aureus to cope with oxidative stress. Size reduction at Tyr(248) in CrtM further increases the ZA-A binding affinity, and it reveals a similar overall inhibitor binding mode to that of human SQS/ZA-A except for the C-6 acyl group. These structures pave the way for further improving selectivity and development of a new generation of anticholesterolemic and antimicrobial inhibitors.

Carbon supported Pt–Ru/C (1:1) alloy catalysts supplied by E-TEK are widely used for fuel cell research. Heat treatments in various atmospheres are conducted for the promotion of the methanol oxidation reaction (MOR) and the investigation of the structure–activity relationship (SAR) of the catalysts. The alloy structures, surface compositions, surface species, and electro-catalytic activities of the alloy catalysts are characterized by X-ray diffraction (XRD), temperature-programmed reduction (TPR), X-ray photoelectron spectroscopy (XPS), and cyclic voltammetry (CV), respectively. The as-received Pt–Ru/C catalysts have a Ru rich in the inner core and Pt rich on the outer shell structure. Thermal treatments on the catalysts induce Ru surface segregation in different extents and thereby lead to their alteration of the alloying degrees. O2 treatment results in obvious Ru segregation and formation of RuO2. Catalysts treated in H2 have the highest If/Ib value in the CV scans among all samples, indicating the catalysts have the excellent CO de-poisoning ability as evidenced by anodic CO stripping experiments. N2 treatment may serve as an adjustment process for the surface composition and structure of the catalysts, which can suppress the surface Pt depletion (∼60% Pt on the surface), make the components stable and hence promote the MOR significantly.

β-Glucosidases (EC 3.2.1.21) cleave β-glucosidic linkages in disaccharide or glucose-substituted molecules and play important roles in fundamental biological processes. β-Glucosidases have been widely used in agricultural, biotechnological, industrial and medical applications. In this study, a high yield expression (70–250 mg/l) in Escherichia coli of the three functional β-glucosidase genes was obtained from the bacterium Clostridium cellulovorans (CcBglA), the fungus Trichoderma reesei (TrBgl2), and the termite Neotermes koshunensis (NkBgl) with the crystal structures of CcBglA, TrBgl2 and NkBgl, determined at 1.9 A, 1.63 A and 1.34 A resolution, respectively. The overall structures of these enzymes are similar to those belonging to the β-retaining glycosyl hydrolase family 1, which have a classical (α/β)8-TIM barrel fold. Each contains a slot-like active site cleft and a more variable outer opening, related to its function in processing different lengths of β-1,4-linked glucose derivatives. The two essential glutamate residues for hydrolysis are spatially conserved in the active site. In both TrBgl2 and NkBgl structures, a Tris molecule was found to bind at the active site, explaining the slight inhibition of hydrolase activity observed in Tris buffer. Manganese ions at 10 mM exerted an approximate 2-fold enzyme activity enhancement of all three β-glucosidases, with CcBglA catalyzing the most efficiently in hydrolysis reaction and tolerating Tris as well as some metal inhibition. In summary, our results for the structural and functional properties of these three β-glucosidases from various biological sources open important avenues of exploration for further practical applications.

Objective The molecular mechanism of major burn-induced gut damage is not clear. This study is to determine whether IkappaB-kinase (IKK)/nuclear factor-kappaB signaling in intestinal mucosa maintains gut function through the regulation of the c-Jun NH2-terminal kinase (JNK) and p38 phosphorylation. Design Prospective, experimental study. Setting Research laboratory at a university hospital. Subjects Thermal injury models in mice. Interventions Conditional intestinal epithelial cell IKKbeta knockout (Vil-Cre/Ikkbeta(F/Delta) mice and control (Ikkbeta(F/Delta) mice were subjected to 30% total body surface area third-degree burn. JNK inhibitor (SP600125) or p38 inhibitor (SB203580) was given to mice immediately after burn injury. Measurements and main results Thermal injury induced a significant increase of intestinal permeability, nuclear factor-kappaB DNA-binding activity, phosphorylated JNK, phosphorylated p38, and caspase 3 expression of intestinal mucosa in Vil-Cre/Ikkbeta(F/Delta) mice compared with those of Ikkbeta(F/Delta) mice. BCL-xL and cellular FLICE inhibitory protein, but not GADD45beta (growth arrest and DNA damage-inducing protein beta), cellular inhibitor of apoptosis 1, Bfl-1, or TRAIL, messenger RNA expression was significantly decreased in Vil-Cre/Ikkbeta(F/Delta) mice compared with that of Ikkbeta(F/Delta) mice. SP600125 decreased intestinal permeability and increased phosphorylated p38 and tumor necrosis factor receptor-associated factor 2 expression of intestinal mucosa in Vil-Cre/Ikkbeta(F/Delta) mice. SB203580 treatment enhanced thermal injury-induced gut damage in Vil-Cre/Ikkbeta(F/Delta) mice. Conclusions Thermal injury induces nuclear factor-kappaB activation of intestinal mucosa and IKK protects intestinal mucosa from thermal injury-induced gut damage. IKK blocks caspase 3 expression by up-regulating BCL-xL and cellular FLICE inhibitory protein expression. IKK inhibits JNK and p38 but not p44/42 phosphorylation of intestinal mucosa. JNK inhibition increases p38 and tumor necrosis factor receptor-associated factor 2 expression and decreases thermal injury-induced gut damage. Taken together with the enhanced thermal injury-induced gut damage by p38 inhibition, we conclude that IKK maintains gut function by inhibiting JNK phosphorylation, which suppresses p38 phosphorylation and induces gut damage.

Background: This study was to estimate the incidence rate of cleft lip and/or cleft palate (CL/P) in Taiwan from 1994 to 2013, and to assess the time trend over these years. Methods: Retrospective data analysis was performed on records of all newborns with CL/P treated at Chang Gung Craniofacial Center, the only treatment center for CL/P in Taiwan, from 1994 to 2013. Three-year moving average rates were computed and linear regression was used to explore the annual average percentage change. Results: From 1994 to 2013, 7282 newborns with CL/P were identified, corresponding to an annual rate of 1.48‰ (95% confidence interval (CI) = 1.45‰–1.52‰). There was a significant decline of rate of cleft lip with or without cleft palate (CL ± P) (−2.9% ± 0.2%, p

Human glioblastoma multiforme is one of the most aggressive malignant brain tumor types, and the mean survival time of patients with a brain tumor is

Retinoic acid (RA), vitamin D and 12-O‑tetradecanoyl phorbol-13-acetate (TPA) can induce HL-60 cells to differentiate into granulocytes, monocytes and macrophages, respectively. Similar to RA and vitamin D, ascorbic acid also belongs to the vitamin family. High‑dose ascorbic acid (100 µM) induces HL‑60 cell apoptosis and induces a small fraction of HL‑60 cells to express the granulocyte marker, CD66b. In addition, ascorbic acid exerts an anti‑oxidative stress function. Oxidative stress is required for HL‑60 cell differentiation following treatment with TPA, however, the effect of ascorbic acid on HL‑60 cell differentiation in combination with TPA treatment remains to be fully elucidated. The aim of the present study was to investigate the cellular effects of ascorbic acid treatment on TPA-differentiated HL-60 cells. TPA-differentiated HL-60 cells were used for this investigation, this study and the levels of cellular hydrogen peroxide (H2O2), caspase activity and ERK phosphorylation were determined following combined treatment with TPA and ascorbic acid. The results demonstrated that low‑dose ascorbic acid (5 µM) reduced the cellular levels of H2O2 and inhibited the differentiation of HL‑60 cells into macrophages following treatment with TPA. In addition, the results of the present study further demonstrated that low‑dose ascorbic acid inactivates the ERK phosphorylation pathway, which inhibited HL‑60 cell differentiation following treatment with TPA.

Methotrexate (MTX) has been widely used for rheumatoid arthritis therapy for a long time. MTX is also used as an anticancer drug for various tumors. However, many studies have shown that high-dose MTX treatment for cancer therapy may cause liver and renal damage. Alhough the mechanisms involved in MTX-induced liver and renal damage require further research, many studies have indicated that MTX-induced cytotoxicity is associated with increases in oxidative stress and caspase activation. In order to reduce MTX-induced side-effects and increase anticancer efficiency, currently, combination treatments of low-dose MTX and other anticancer drugs are considered and applied for various tumor treatments. The present study showed that MTX induces increases in H2O2 levels and caspase-9/-3 activation leading to cell death in hepatocellular carcinoma Hep3B cells. Importantly, this study is the first to demonstrate that vitamin C can efficiently aid low-dose MTX in inducing cell death in Hep3B cells. Therefore, the present study provides a possible powerful therapeutic method for tumors using a combined treatment of vitamin C and low-dose MTX.

Frog ribonucleases have been demonstrated to have anticancer activities. However, whether RC-6 ribonuclease exerts anticancer activity on human embryonal carcinoma cells remains unclear. In the present study, RC-6 induced cytotoxicity in NT2 cells (a human embryonal carcinoma cell line) and our studies showed that RC-6 can exert anticancer effects and induce caspase-9 and -3 activities. Moreover, to date, there is no evidence that frog ribonuclease-induced cytotoxicity effects are related to cellular senescence. Therefore, our studies showed that RC-6 can increase p16 and p21 protein levels and induce cellular senescence in NT2 cells. Notably, similar to retinoic acid-differentiated NT2 cells, neuron-like morphology was found on some remaining live cells after RC-6 treatment. In conclusion, our study is the first to demonstrate that RC-6 can induce cytotoxic effects, caspase-9/-3 activities, cellular senescence and neuron-like morphology in NT2 cells.

EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. Previously, we showed that EZH2 downregulation enhances neuron differentiation of human mesenchymal stem cells (hMSCs); however, the underlying mechanisms of EZH2-regulated neuron differentiation are still unclear. Here, we identify Smurf2 as the E3 ubiquitin ligase responsible for the polyubiquitination and proteasome-mediated degradation of EZH2, which is required for neuron differentiation. A ChIP-on-chip screen combined with gene microarray analysis revealed that PPARγ was the only gene involved in neuron differentiation with significant changes in both its modification and expression status during differentiation. Moreover, knocking down PPARγ prevented cells from undergoing efficient neuron differentiation. In animal model, rats implanted with intracerebral EZH2-knocked-down hMSCs or hMSCs plus treatment with PPARγ agonist (rosiglitazone) showed better improvement than those without EZH2 knockdown or rosiglitazone treatment after a stroke. Together, our results support Smurf2 as a regulator of EZH2 turnover to facilitate PPARγ expression, which is specifically required for neuron differentiation, providing a molecular mechanism for clinical applications in the neurodegenerative diseases.

Glioblastoma is the most aggressive primary brain tumor and its prognosis remains poor despite different treatment modalities including surgery, radiotherapy and chemotherapy. Therefore, more useful treatments for glioblastoma patients are required. Human interleukin 15 (hIL15) is an immunomodulator that has antitumor activities. hIL15 combined with gene therapy method is also currently under cosideration as a treatment option. Since recombinant adeno-associated virus serotype 2 (rAAV2) with low immunogenicity and long-term gene expression in human clinical trials has been demonstrated, rAAV2 encoding hIL15 (rAAV2-hIL15) were used to inhibit human glioblastoma growth in the present study. rAAV2-hIL15, which is able to express IL15 protein with bioactivity, was successfully produced and purified. Data of this study demonstrated that the long-term expression of rAAV2-hIL15 enhances immunoglobulin (Ig) production and the cytotoxic activity of lymphokine-activated killer (LAK) cells. In addition, results of the present study showed that rAAV2-hIL15 delays tumor growth on a xenografted human glioblastoma mice model. Taken together, these results indicated that rAAV2-hIL15 constitutes a powerful and potent gene immunotherapy method for human glioblastoma treatment.