Performance of the new biological small- and wide-angle X-ray scattering beamline 13A at the Taiwan Photon Source.

Recent developments in the instrumentation and data analysis of synchrotron small-angle X-ray scattering (SAXS) on biomolecules in solution have made biological SAXS (BioSAXS) a mature and popular tool in structural biology. This article reports on an advanced endstation developed at beamline 13A of the 3.0 GeV Taiwan Photon Source for biological small- and wide-angle X-ray scattering (SAXS-WAXS or SWAXS). The endstation features an in-vacuum SWAXS detection system comprising two mobile area detectors (Eiger X 9M/1M) and an online size-exclusion chromatography system incorporating several optical probes including a UV-Vis absorption spectrometer and refractometer. The instrumentation and automation allow simultaneous SAXS-WAXS data collection and data reduction for high-throughput biomolecular conformation and composition determinations. The performance of the endstation is illustrated with the SWAXS data collected for several model proteins in solution, covering a scattering vector magnitude q across three orders of magnitude. The crystal-model fittings to the data in the q range ∼0.005-2.0 Å-1 indicate high similarity of the solution structures of the proteins to their crystalline forms, except for some subtle hydration-dependent local details. These results open up new horizons of SWAXS in studying correlated local and global structures of biomolecules in solution.

Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study.

To determine denosumab's effectiveness for fracture prevention among postmenopausal women with osteoporosis in East Asia, the risk of fracture was compared between patients continuing denosumab therapy versus patients discontinuing denosumab after one dose. The real-world effectiveness was observed to be consistent with the efficacy demonstrated in the phase III trial. INTRODUCTION: After therapeutic efficacy is demonstrated for subjects in global clinical trials, real-world evidence may provide complementary knowledge of therapeutic effectiveness in a heterogeneous mix of patients seen in clinical practice. This retrospective cohort study was conducted to compare the fracture risk in real-world clinical care received in Taiwan and Hong Kong between a treatment cohort (patients receiving denosumab 60 mg subcutaneously every 6 months) versus an off-treatment cohort (patients discontinuing after 1 dose of denosumab, which has no known clinical benefit) among real-world postmenopausal women. METHODS: This study included 38,906 and 2,835 postmenopausal women receiving denosumab in Taiwan and Hong Kong, respectively. The primary endpoint was hip fracture, and secondary endpoints were clinical vertebral and nonvertebral fractures. Propensity-score-matched analysis, adjusting for known covariates, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The robustness of findings was evaluated with a series of sensitivity and quantitative bias analyses. RESULTS: In this study, 554 hip fractures were included in the primary Taiwan population analysis. The crude incidence rate was 0.9 per 100 person-years in the treatment cohort (n = 25,059) and 1.7 per 100 person-years in the off-treatment cohort (n = 13,847). After adjusting for prognostic differences between cohorts, denosumab reduced the risk of hip fractures by 38% (HR = 0.62, CI:0.52-0.75). Risk reductions of similar magnitude were observed for the secondary endpoints and for the analysis of the smaller Hong Kong population. CONCLUSION: The effectiveness of denosumab for fracture reduction among real-world postmenopausal women with osteoporosis was consistent with the efficacy demonstrated in a global clinical trial. REGISTRATION: EnCePP registration number: EUPAS26372; registration date: 12/11/2018.

Cancer-related hypercalcemia in oral cancer.

Cancer-related hypercalcemia (CRH) is a critical paraneoplastic disorder in advanced cancer patients. In clinical practice, patients with CRH have a poor prognosis. The medical records of 3198 oral cancer patients with CRH diagnosed at Taichung Veterans General Hospital from 1 January 2003 to 31 December 2015 were reviewed. The criteria for patient enrolment were a diagnosis of hypercalcemia or the use of antihypercalcemia medication. Patients who met any of the following criteria were excluded: use of total parenteral nutrition, incomplete serum calcium data, and unknown date of death. The total incidence of CRH was 6.95‰ per year. A total of 91 patients were enrolled; their median survival time was 28 days. The patients were divided into two groups by survival time, with a cut-off point of 30 days. Reduced serum albumin, leucocytosis, and clodronate use had a statistically significant effect on survival in the univariate analysis (all P<0.05). Forty-five patients (49.5%) had recurrence of CRH, of whom nine died within 30days. These nine patients had a shorter interval to the first episode of CRH recurrence (median 13 days) than those who survived ≥30days (median 28 days) (P<0.001). It was observed that a short interval to the first episode of CRH recurrence is a poor prognostic factor.

High-free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independent of obesity and insulin resistance.

BACKGROUND/OBJECTIVE: Central obesity and insulin resistance (IR) are common conditions in women with polycystic ovary syndrome (PCOS) and in subjects with non-alcoholic fatty liver disease (NAFLD). However, few studies have addressed the association between hyperandrogenism (HA) and NAFLD. We aimed to determine whether variations in the free androgen index (FAI) might be associated with NAFLD prevalence. SUBJECTS/METHODS: A cross-sectional study was performed including 400 Chinese women with PCOS and 100 age, and body mass index (BMI)-matched women. The anthropometric and serum biochemical parameters related to sex steroids, glucose and lipid profiles were examined. Liver fat content (LFC) was measured by quantitative ultrasound. RESULTS: The prevalence of NAFLD was 56.23% in PCOS patients and 38% in controls (P=0.001), and this prevalence increased with FAI quartile independently of obesity and homeostasis model assessment of insulin resistance (HOMA-IR). The FAI level increased from non-NAFLD group to NAFLD group. The FAI was positively associated with the metabolic parameters LFC, BMI, waist circumference, alanine aminotransferases, aspartate, triglyceride, total cholesterol and low-density lipoprotein cholesterol, and was negatively associated with high-density lipoprotein. Moreover, in multivariate logistic regression analysis BMI, high-sensitivity C-reactive protein (hsCRP), FAI, LFC and HOMA-IR were significantly associated with NAFLD. The cut-off values of FAI, LFC, BMI and hsCRP to predict NAFLD were 9.86%, 17.19%, 24.38% and 0.72%, respectively. The area under the curve for predicting NAFLD in PCOS patients showed comparable sensitivity and specificity between BMI and a new index combining FAI with hsCRP. CONCLUSIONS: A higher FAI level is associated with increased LFC and NAFLD prevalence independent of obesity and IR.

A Novel Hybrid Viabahn-assisted Bypass Technique: Extra-arterial Flossing Wiring for Chronic Total Occlusion in Superficial Femoral Artery.

INTRODUCTION: A hybrid Viabahn-assisted bypass (VAB) technique is introduced for revascularizing chronic total occlusion (CTO) in superficial femoral artery (SFA) when bypass surgery is difficult or endovascular intervention fails. REPORT: This technique combines extra-arterial flossing wiring with antegrade-retrograde intervention via traditional open exposure of middle SFA and deploying a Viabahn from the proximal true lumen through the subintimal lumen and extra-arterial space, and back into distal true lumen to restore flow. It only needs a 3-5 cm incision to expose the mid-SFA without clamping or endarterectomy of the SFA. DISCUSSION: This hybrid procedure is an alternative technique to improve SFA revascularization in some difficult CTOs.

Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells.

The antitumor drug etoposide (ETO) is widely used in treating several cancers, including adrenocortical tumor (ACT). However, when used at sublethal doses, tumor cells still survive and are more susceptible to the recurring tumor due to centrosome amplification. Here, we checked the effect of sublethal dose of ETO in ACT cells. Sublethal dose of ETO treatment did not induce cell death but arrested the ACT cells in G2/M phase. This resulted in centrosome amplification and aberrant mitotic spindle formation leading to genomic instability and cellular senescence. Under such conditions, Chk2, cyclin A/CDK2 and ERK1/2 were aberrantly activated. Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells. In addition, autophagy was activated by ETO and was required for ACT cell survival. Chloroquine, the autophagy inhibitor, reduced ACT cell growth and inhibited ETO-induced centrosome amplification. Chloroquine alleviated CDK2 and ERK, but not Chk2, activation and thus inhibited centrosome amplification in either ETO- or hydroxyurea-treated ACT cells. In addition, chloroquine also inhibited centrosome amplification in osteosarcoma U2OS cell lines when treated with ETO or hydroxyurea. In summary, we have demonstrated that chloroquine inhibited ACT cell growth and alleviated DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrence of ACT.

Extreme Hyperlactatemia After Heart Transplantation: One Center's Experience.

INTRODUCTION: Hyperlactatemia may occur early after cardiac surgery and is correlated with prognosis. This study was conducted to analyze the perioperative variables and postoperative outcomes among heart transplant recipients with extremely high lactate levels (>15 mmol/L). METHODS: The single-center medical records of heart transplantation from June 2006 to May 2013 were retrospectively reviewed for patient characteristics, perioperative hemodynamic variables, arterial blood gas analysis data, and postoperative mortality. RESULTS: Among 58 consecutive heart transplant recipients, lactate levels over the detectable upper limit (>15 mmol/L) were identified in 12 patients after intensive care unit admission, with peak time at 1.9 ± 2.0 (range 0-6.1) hours. The maximal preoperative lactate level was 3.1 mmol/L, and most (11/12) postoperative lactate levels returned to <4 mmol/L at 27.5 ± 12.8 hours after surgery (range 15-58, median 24), displaying a trend toward delayed extubation time in 10 recipients (P < .01). Blood glucose levels elevated significantly from preoperative 148.9 ± 45.2 to 375.7 ± 96.9 mg/dL at peak lactate level (P < .01). Four patients died in the ICU (range 5-32 days), 4 died after discharge (range 5-57 months), with 6 in total surviving over 1 year. CONCLUSION: Extreme hyperlactatemia commonly occurred early after heart transplantation and mostly recovered within 30 hours; however, with delayed extubation time after operation.

Aerobic and resistance exercise training program intervention for enhancing gait function in elderly and chronically ill Taiwanese patients.

OBJECTIVES: This study aimed to develop an effective exercise training program for enhancing the postural stability and gait function of chronically ill patients to avoid falls. STUDY DESIGN: Pre training-post-training. Analyses were limited to those randomized to the exercise intervention. METHODS: The participants were chronically ill patients over 45 years old (47-89 years), of whom 25 completed the 12-week training regimen and assessment in the exercise group, whereas 29 completed the assessment in the control group, suffering from cardiovascular disease, diabetes mellitus, or osteoporosis. The average age of the participants was 67.56 ± 10.70 years in the intervention group. All patients in this study signed institutional review board (IRB) agreements before participating (IRB approval no: FEMH-IRB-101029-E, v. 02, date: 20120429). RESULTS: The results revealed the beneficial effects of regular aerobic and resistance training, which improved in elderly, chronically ill patients. According to our data, most of the gait function measurements exhibited significant differences between the exercise group and control group. The duration of the 'timed up-and-go' test decreased from 7.67 s to 6.76 s (P = 0.00013), and the 'the base of support area' increased from 392.0 cm(2) to 433.2 cm(2) (P = 0.0088). Women attained more significant differences than men in the exercise and control groups (P = 0.0008), and the participants aged 45-65 years had a more satisfactory outcome than those aged > 65 years (P = 0.0109). CONCLUSION: Regular exercise regimens, such as aerobic, resistance or combination exercise training, enhance the gait function and sense of postural stability in elderly, chronically ill patients. Younger patients attained more positive results than older patients, and women attained more positive results than men. Regular exercise is a means of preventing falls; thus, the government and hospitals should increase promotional measures in aging communities to encourage regular exercise among elderly, chronically ill outpatients.

MTAP is an independent prognosis marker and the concordant loss of MTAP and p16 expression predicts short survival in non-small cell lung cancer patients.

OBJECTIVES: Methylthioadenosine phosphorylase (MTAP), a ubiquitously expressed protein, plays important roles in purine biosynthesis. Locating near to each other on chromosome 9p21-22, codeletion of the MTAP and p16(Ink4A) genes have been reported in non-small cell lung cancer (NSCLC). The aim of this study is to determine the respective prognostic value of MTAP and p16 by considering their correlation in NSCLC patients. MATERIALS AND METHODS: We analyzed MTAP and p16 protein expression by immunohistochemical staining on 99 NSCLC tissue microarray samples. The association between MTAP and p16 expression levels and prognosis were analyzed using the Kaplan-Meier method and Cox proportional hazards model for prognosis. RESULTS: Patients with a low MTAP expression level had poor overall survival (P = 0.010) and disease-free survival (P = 0.002). Low p16 expression indicated a trend toward poor overall survival (P = 0.138) and disease-free survival (P = 0.199). There was a significant positive correlation between MTAP and p16 expression levels (Spearman's ρ = 0.402, P < 0.001). By multivariate analyses, the MTAP expression level retained its independent prognostic power and p16 expression loss of the correlation with prognosis. Concordant loss of MTAP and p16 expression was observed in 24 out of 99 patients (24.2%). Patients with concordant loss of MTAP and p16 expression had the worst prognosis compared to patients with high expression of both markers. CONCLUSION: MTAP expression is an independent prognostic factor and has greater prognostic significance than p16 expression in NSCLC. Concordant loss of MTAP and p16 expression indicates poor outcomes in lung cancer patients.

Incidence and risk of osteonecrosis of the jaw among the Taiwan osteoporosis population.

UNLABELLED: Evidence of the incidence and risk of osteonecrosis of the jaw (ONJ) in Asian osteoporosis populations receiving different osteoporosis medications is lacking. We found that there is no excess incidence of or risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin under real-world conditions in Taiwan. INTRODUCTION: To provide information on ONJ in Asian populations, this study compares the incidence and risk of ONJ between patients receiving alendronate and those receiving non-bisphosphonate osteoporosis medications in Taiwan. METHODS: Enrollees in the National Health Insurance Research Database (NHIRD) from 2003 to 2007, aged above 50 years, with vertebral/hip fracture, and new to osteoporosis therapy were recruited. Patients with Paget's disease or cancer during the baseline period were excluded. Patients were classified into either the alendronate or the calcitonin/raloxifene (control) group according to their exposure during follow-up. Previously proposed possible ONJ diagnosis codes were adopted as potential ONJ cases, but qualifying cases also had a repeated ONJ diagnosis within 8 weeks of the first diagnosis and received one or more broad-spectrum oral antibiotics. Cox modeling compared the risk of ONJ between the alendronate and the control groups, which were matched using propensity scores. Results were examined in series sensitivity analyses, including different cumulative dose groups. RESULTS: We found 25 potential ONJ cases in the alendronate (N = 18,030) and 21 in the control groups (N = 25,615). Over the 6-year follow-up period, no increased risk of ONJ in the alendronate group in the original (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.47-1.58) or propensity score-matched cohorts (HR, 0.86; 95% CI, 0.44-1.69) was found. All comparison groups exhibited a similar incidence of ONJ, ranging from 6.9 to 8.2/10,000 person-years. CONCLUSION: Under real-world conditions, there is no excess risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin.

Undular bore theory for the Gardner equation.

We develop modulation theory for undular bores (dispersive shock waves) in the framework of the Gardner, or extended Korteweg-de Vries (KdV), equation, which is a generic mathematical model for weakly nonlinear and weakly dispersive wave propagation, when effects of higher order nonlinearity become important. Using a reduced version of the finite-gap integration method we derive the Gardner-Whitham modulation system in a Riemann invariant form and show that it can be mapped onto the well-known modulation system for the Korteweg-de Vries equation. The transformation between the two counterpart modulation systems is, however, not invertible. As a result, the study of the resolution of an initial discontinuity for the Gardner equation reveals a rich phenomenology of solutions which, along with the KdV-type simple undular bores, include nonlinear trigonometric bores, solibores, rarefaction waves, and composite solutions representing various combinations of the above structures. We construct full parametric maps of such solutions for both signs of the cubic nonlinear term in the Gardner equation. Our classification is supported by numerical simulations.

Universal pharmacological thromboprophylaxis for total knee arthroplasty may not be necessary in low-risk populations: a nationwide study in Taiwan.

BACKGROUND: Thromboprophylaxis should be universally administered in major orthopedic surgery. However, epidemiology of venous thromboembolism (VTE) following major knee surgery in Asia is scarce. OBJECTIVE: To describe the use of thromboprophylaxis and calculate the incidence and risk factors of symptomatic VTE following major knee surgery in Taiwan. METHODS: We used Taiwan's National Health Insurance Research Database to retrospectively identify patients (≥45 years) who underwent major knee surgery from 1998 to 2007 and collected the medical records within 3 months after the discharge. Logistic regression analysis was used to determine the risk factors of symptomatic VTE after the surgery. RESULTS: We identified 113 844 patients (mean age, 69.0 ± 7.7 years; female, 75.2%) receiving major knee arthroplasties. The mean length of stay was 9.1 ± 3.3 days. The overall pharmacological thromboprophylaxis rate was 2.2%. The 3-month cumulative incidence of procedure-related symptomatic VTE was 0.46% (95% CI, 0.42­0.50%). The median time to the first post-operation VTE was 7 days, with 85.4% occurring within 2 weeks after the discharge.Logistic regression analysis showed that previous VTE, malignancy, heart failure and neurologic disorder with extremity paralysis or pararesis were independent risk factors (P < 0.05) for symptomatic VTE following major knee arthroplasties. CONCLUSIONS: The thromboprophylaxis rate is low, which may be due to the very low incidence of symptomatic VTE after the surgery in Taiwan. Most symptomatic VTE occurred within 2 weeks after the surgery. Universal thromboprophylaxis for knee arthroplasties may not be necessary in Taiwan, but it should be considered in some high-risk populations.

Impact of neck dissection in early tongue and buccal cancer without neck extension.

PROBLEM: The role of elective neck dissection in early stage tongue and buccal squamous cell carcinoma with negative neck lymph nodes is still controversial. METHODS: We retrospectively reviewed patients with T1-2N0M0 buccal and tongue cancer who underwent primary tumour excision with or without elective neck dissection between January 1997 and December 2006. RESULTS: Elective neck dissection specifically improved disease-free survival of T2N0M0 buccal cancer and overall survival of T2N0M0 tongue cancer. CONCLUSION: Elective neck dissection seems to improve the disease-free survival rate of T2N0M0 buccal cancer and the overall survival rate of T2N0M0 tongue cancer but has no beneficial effect on the survival rate of T1N0M0 buccal and tongue cancer.

Alendronate adherence and its impact on hip-fracture risk in patients with established osteoporosis in Taiwan.

A pharmacoepidemiology study was conducted using the health insurance database in Taiwan to assess compliance with osteoporosis drug regimens and the impact of compliance on the risk for secondary fractures. Patients >50 years of age with vertebral/hip fracture who had been started on alendronate therapy for the first time only after the fracture were included. Compliance was measured using the medication possession ratio (MPR) and was included as a time-dependent covariate in the Cox model to compare the difference between compliant (MPR ≥ 80%) and noncompliant patients (MPR <80%) with respect to risk for subsequent hip fractures. Only 38% of the study population remained compliant during the first year of treatment. Over the 4-year follow-up period, the risk of hip fracture among the compliant patients was 70% lower than that among the noncompliant ones (adjusted hazard ratio (HR) 0.30). Among patients with osteoporosis in Taiwan who had experienced a fracture and had started alendronate therapy, compliance with the dosage regimen was suboptimal. It was also found that compliance significantly reduced the risk of secondary hip fracture up to 4 years.

VEGF -460T → C polymorphism and its association with VEGF expression and outcome to FOLFOX-4 treatment in patients with colorectal carcinoma.

The -460T → C polymorphism of vascular endothelial growth factor (VEGF) gene significantly increases its promoter activity. A pilot study was conducted to assess the influence of this polymorphism on clinicopathological features of patients with colorectal carcinoma. In total, 228 patients were enrolled, including 100 with stage II/III colorectal carcinoma receiving curative surgery and 128 with metastatic disease. An excellent correlation in VEGF -460 genotypes based on white blood cells and tumor tissues existed, but there was no between-group difference in patients with or without colorectal carcinoma. A marked increase in intratumor and circulating VEGF levels were observed in patients with the T/C or C/C genotypes (P < 0.01), which was associated with increased extent of invasion, nodal involvement, poor histological differentiation, subsequent metastasis and shorter survival in stage II/III patients treated with curative surgery (P < 0.01). For patients with metastatic disease, this polymorphism was associated with a lower response rate to FOLFOX-4 (P = 0.03) and shorter survival (P < 0.001). By multivariate analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). These data suggest that -460T → C polymorphism of VEGF gene, by increasing VEGF expression and subsequent angiogenesis, could be a key determinant for increased tumor recurrence and a poor prognosis of patients with colorectal carcinoma. However, this study is exploratory and is not adjusted for multiple comparisons, requiring independent replication.

CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia.

Hypermethylation of the distal CEBPA promoter region has been reported to result in the downregulation of CEBPA expression in several malignancies. However, the clinical implication of CEBPA hypermethylation in acute myeloid leukemia (AML) remains unclear. To investigate the correlation between CEBPA hypermethylation and clinical features in AML, quantitative MassARRAY analyses for CEBPA methylation status were performed on a cohort of 193 patients. High CEBPA methylation group (CEBPA(high-meth), n=28) and low methylation group (CEBPA(low-meth), n=165) were defined by using two-way hierarchical clustering. With a median follow-up of 48 months, among the 125 patients receiving standard induction therapy, CEBPA(high-meth) was associated with better treatment response (complete remission rate 93.3% versus 73.6%, P=0.116). In patients with normal karyotype and without CEBPA and NPM1 mutations, the CEBPA(high-meth) had longer overall survival (OS) than the CEBPA(low-meth) (P=0.028). Multivariate analysis further supported that the CEBPA methylation was an independent prognostic factor for disease free-survival (hazard ratio=0.416; 95% confidence interval, 0.223-0.777, P=0.006) and OS (hazard ratio=0.406; 95% confidence interval, 0.166-0.996, P=0.050). We conclude that CEBPA methylation status is a useful prognostic biomarker for AML patients.