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Abstract Background We aimed to assess whether disease-free survival (DFS) could serve as a reliable surrogate endpoint for overall survival (OS) in adjuvant trials of pancreatic cancer. Methods We systematically reviewed adjuvant randomized trials for non-metastatic pancreatic cancer after curative resection that reported a hazard ratio (HR) for DFS and OS. We assessed the correlation between treatment effect (HR) on DFS and OS, weighted by sample size or precision of hazard ratio estimate, assuming fixed and random effects, and calculated the surrogate threshold effect (STE). We also performed sensitivity analyses and a leave-one-out cross validation approach to evaluate the robustness of our findings. Results After screening 450 relevant articles, we identified a total of 20 qualifying trails comprising 5170 patients for quantitative analysis. We noted a strong correlation between the treatment effects for DFS and OS, with coefficient of determination of 0.82 in the random effect model, 0.82 in the fixed effect model, and 0.80 in the sample size weighting; the robustness of this finding was further verified by the leave-one-out cross-validation approach. Sensitivity analyses with restriction to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy strengthened the correlation (0.75 to 0.88) between DFS and OS. The STE was 0.96 for DFS. Conclusions Therefore, DFS could be regarded as a surrogate endpoint for OS in adjuvant trials of pancreatic cancer. In future similar adjuvant trials, a hazard ratio for DFS of 0.96 or less would predict a treatment impact on OS.

Abstract Background Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet. Methods A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis. Results A circRNA consisting of exon 8–11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness. Conclusions Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.

An amendment to this paper has been published and can be accessed via the original article.

Background: We assessed the surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs). Methods: PubMed and EMBASE were searched for phase II/III RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings. Results: We included 8 RCTs (4110 patients; 11 comparisons). We did not identify strong correlations between ORR [coefficient of determination ( R 2 ): 0.09–0.25], DCR (0.41–0.57) and OS. However, we noted a strong correlation between PFS and OS, with R 2 of 0.82 in sample size, 0.75 in fixed effect and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover, phase III trials, large trials and first-line trials strengthened the correlation (0.78–0.94). The STE for PFS was 0.78. Conclusions: PFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.

Abstract Background Heart failure (HF) is a critical complication in elderly patients with atrial fibrillation (AF) and diabetes mellitus (DM). Recent preclinical studies suggested that non-vitamin K antagonist oral anticoagulants (NOACs) can potentially suppress the progression of cardiac fibrosis and ischemic cardiomyopathy. Whether different oral anticoagulants influence the risk of HF in older adults with AF and DM is unknown. This study aimed to evaluate the risk of HF in elderly patients with AF and DM who were administered NOACs or warfarin. Methods A nationwide retrospective cohort study was conducted based on claims data from the entire Taiwanese population. Target trial emulation design was applied to strengthen causal inference using observational data. Patients aged ≥ 65 years with AF and DM on NOAC or warfarin treatment between 2012 and 2019 were included and followed up until 2020. The primary outcome was newly diagnosed HF. Propensity score-based fine stratification weightings were used to balance patient characteristics between NOAC and warfarin groups. Hazard ratios (HRs) were estimated using Cox proportional hazard models. Results The study included a total of 24,835 individuals (19,710 NOAC and 5,125 warfarin users). Patients taking NOACs had a significantly lower risk of HF than those taking warfarin (HR = 0.80, 95% CI 0.74–0.86, p

Abstract We aimed to determine whether hospital admissions during an extended holiday period (Chinese New Year) and weekends were associated with increased mortality risk from pulmonary embolism (PE), compared to admissions on weekdays. We conducted a nationwide retrospective cohort study using Taiwan’s National Health Insurance Research Database. Data of newly diagnosed PEs during the months of January and February from 2001 to 2017 were obtained from patient records and classified into three admission groups: Chinese New Year (≥ 4 consecutive holiday days), weekends, and weekdays. The adjusted odds ratios (aORs) (95% confidence intervals [CIs]) for 7-day and in-hospital mortality were calculated using multivariable logistic regression models. The 7-day and in-hospital mortality risks were higher for patients admitted during the Chinese New Year holiday (10.6% and 18.7%) compared to those admitted on weekends (8.4% and 16.1%) and weekdays (6.6% and 13.8%). These higher mortality risks for holiday admissions compared to weekday admissions were confirmed by multivariable analysis (7-day mortality: aOR = 1.68, 95% CI 1.15–2.44, P = 0.007; in-hospital mortality: aOR = 1.41, 95% CI 1.05–1.90, P = 0.022), with no subgroup effects by sex or age. Hospital admission for PE over an extended holiday period, namely Chinese New Year, was associated with an increased risk of mortality.

A typical interband cascade laser wafer contains more than 2000 multilayers composed of InAs, AlSb, GaSb, and GaInSb. The lattice constants of the three materials except GaSb have a certain degree of mismatch with the GaSb substrate. Therefore, to grow a high-quality epitaxial layer, it is necessary to optimize the growth conditions to achieve strain balance in the entire epitaxial layer. In this work, the strained superlattice structure was characterized via scanning transmission electron microscopy and high-resolution x-ray diffraction. The strain distribution was mapped using geometric phase analysis of high-angle annular dark-field images. We demonstrate that strain compensation has been achieved in both the InAs/AlSb superlattice clad layers and the InAs/InGaSb/InAs W quantum well active region.

Abstract In this paper, an anomalous spectral data of distributed Bragg reflector (DBR) quantum cascade lasers (QCLs) emitting around 7.6 μm is presented. The two-section DBR lasers, consisting of a gain section and an unpumped Bragg reflector, display an output power above 0.6 W in continuous wave (CW) mode at room temperature. The anomalous spectral data is defined as a longitudinal mode which moves toward shorter wavelengths with increasing temperature or injection current, which is unexpected. Although the longer wavelength modes are expected to start lasing when raising device temperature or injection current, occasional mode hops to a shorter wavelength are seen. These anomalous mode transitions are explained by means of modal analysis. The thermal-induced change of the refractive index implied by an increase in the temperature or injection current yields nearly periodic transitions between cavity modes.

Abstract High-power, low-threshold stable single-mode operation buried distributed feedback quantum cascade laser by incorporating sampled grating emitting at λ ~ 4.87 μm is demonstrated. The high continuous wave (CW) output power of 948 mW and 649 mW for a 6-mm and 4-mm cavity length is obtained at 20 °C, respectively, which benefits from the optimized optical field distribution of sampled grating. The single-mode yields of the devices are obviously enhanced by controlling cleaved positions of the two end facets precisely. As a result, stable single-mode emission and mode tuning linearly without any mode hopping of devices are obtained under the different heat sink temperatures or high injection currents.

Abstract Background Stroke is a major risk factor for osteoporosis and fractures. No study has evaluated the association between diuretic use and risk of vertebral fracture in stroke patients, although a considerable proportion of stroke patients are prescribed diuretics for hypertension. Our study aimed to investigate whether treatment with thiazides or loop diuretics affects the risk of vertebral fracture after stroke. Methods A population-based propensity score-matched retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database. Patients with a new diagnosis of stroke between 2000 and 2011 were included. After propensity score matching, 9468 patients were included in the analysis of the effect of thiazides, of who 4734 received thiazides within 2 years after stroke. To analyze the loop diuretic effect, 4728 patients were included, of who 2364 received loop diuretics. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) of vertebral fractures among patients according to thiazide or loop diuretic use within 2 years following stroke. Sensitivity analyses based on the duration of thiazide or loop diuretic use were further conducted. Results There was no significant difference in vertebral fracture risk between thiazide users and non-users (adjusted HR [aHR] = 1.14, 95% confidence interval [CI] = 0.88–1.47, p = 0.316). Loop diuretic users had a significantly higher vertebral fracture risk than non-users (aHR = 1.45, 95% CI = 1.06–1.98, p = 0.019). However, the sensitivity analysis revealed that short-term thiazide use (exposure duration

Background Evidence on the differences in fracture risk associated with non‐vitamin K antagonist oral anticoagulants (NOAC) and warfarin is inconsistent and inconclusive. We conducted a systematic review and meta‐analysis to assess the fracture risk associated with NOACs and warfarin. Methods and Results We searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov from inception until May 19, 2020. We included studies presenting measurements (regardless of primary/secondary/tertiary/safety outcomes) for any fracture in both NOAC and warfarin users. Two or more reviewers independently screened relevant articles, extracted data, and performed quality assessments. Data were retrieved to synthesize the pooled relative risk (RR) of fractures associated with NOACs versus warfarin. Random‐effects models were used for data synthesis. We included 29 studies (5 cohort studies and 24 randomized controlled trials) with 388 209 patients. Patients treated with NOACs had lower risks of fracture than those treated with warfarin (pooled RR, 0.84; 95% CI, 0.77–0.91; P

Background A higher risk of developing dementia is observed in patients with atrial fibrillation (AF). Results are inconsistent regarding the risk of dementia when patients with AF use different anticoagulants. We aimed to investigate the risk of dementia in patients with AF receiving non‐vitamin K antagonist oral anticoagulants (NOACs) compared with those receiving warfarin. Methods and Results We conducted a nationwide population‐based cohort study of incident cases using the Taiwan National Health Insurance Research Database. We initially enlisted all incident cases of AF and then selected those treated with either NOACs or warfarin for at least 90 days between 2012 and 2016. First‐ever diagnosis of dementia was the primary outcome. We performed propensity score matching to minimize the difference between each cohort. We used the Fine and Gray competing risk regression model to calculate the hazard ratio (HR) for dementia. We recruited 12 068 patients with AF (6034 patients in each cohort). The mean follow‐up time was 3.27 and 3.08 years in the groups using NOACs and warfarin, respectively. Compared with the HR for the group using warfarin, the HR for dementia was 0.82 (95% CI, 0.73–0.92; P=0.0004) in the group using NOACs. Subgroup analysis demonstrated that users of NOAC aged 65 to 74 years, with a high risk of stroke or bleeding were associated with a lower risk of dementia than users of warfarin with similar characteristics. Conclusions Patients with AF using NOACs were associated with a lower risk of dementia than those using warfarin. Further randomized clinical trials are greatly needed to prove these findings.

BackgroundAcute aortic dissection is a life-threatening condition associated with high mortality rate. Findings from previous studies addressing the "weekend effect" on the mortality rate from an acute aortic dissection mortality have been inconsistent. Furthermore, the effect of admission for acute aortic dissection during the holiday season has not been previously investigated.ObjectiveOur aim was to evaluate the effect of admission for acute aortic dissection during holiday season or weekends on the risk of mortality.MethodsWe conducted a retrospective analysis of nationwide cohort data from the Taiwan's National Health Insurance Research Database. We collected data on all adult patients hospitalized for acute aortic dissection between 2001 and 2017 in Taiwan and classified them into the following three groups based on day of admission: holiday season (at least 4 consecutive days; n = 280), weekend (n = 1 041), and weekday (n = 3 109). The following three outcomes were evaluated: in-hospital mortality, 7-day mortality, and 180-day mortality.ResultsA multivariable logistic regression was used to adjust for possible cofounders on the measured outcomes. Compared to weekday admissions for acute aortic dissection, weekend admissions resulted in a 29% increase in the risk of in-hospital death (aOR = 1.29; 95% CI, 1.05-1.59; P = 0.0153), with a 25% increase in the 7-day (aOR = 1.25; 95% CI, 1.001-1.563; P = 0.0492) and 20% increase in the 180-day mortality risk (aOR = 1.20; 95% CI, 1.01-1.42; P = 0.0395). Of note, admission over the holiday season did not result in a higher mortality risk than for weekday admissions; this finding, however, might reflect insufficient statistical power on subgroup analysis.ConclusionPatients admitted for acute aortic dissection during the weekends are at higher risk of mortality compared to those admitted on weekdays. Our finding likely reflects inadequate staffing and team experience of weekend staff and can guide healthcare policy makers to improve patient outcomes.

Background Warfarin, a vitamin K antagonist, has been shown to affect bone mineral density and cause osteoporosis. However, studies investigating the relationship between non–vitamin K antagonist oral anticoagulants (NOACs) and osteoporosis are limited. We thus compared the risk of osteoporosis in patients with atrial fibrillation treated with either NOACs or warfarin. Methods and Results This nationwide, retrospective cohort study used Taiwan's National Health Insurance Research Database. All adult patients in Taiwan who were newly diagnosed with atrial fibrillation and treated with NOACs or warfarin between January 2012 and December 2015 were included and classified into their respective cohorts. Patients who received NOACs were subcategorized into the rivaroxaban, dabigatran, and apixaban subgroups. Propensity score matching was performed for each head‐to‐head comparison. Adjusted hazard ratios (aHRs) for the risk of osteoporosis were calculated using Cox proportional hazards regression models, with adjustment for confounders. Overall, 17 008 patients were included, with 8504 in each cohort. NOACs were associated with a lower osteoporosis risk than warfarin (aHR=0.82; 95% CI=0.68–0.97). A subgroup effect of treatment duration was identified (namely, the lower osteoporosis risk with NOAC compared with warfarin became stronger in those with longer treatment duration [P for interaction

Abstract Power scaling in broad area quantum cascade laser (QCL) usually leads to the deterioration of the beam quality with an emission of multiple lobes far-field pattern. In this letter, we demonstrate a tapered QCL array integrated with Talbot cavity at one side of the array. Fundamental supermode operation is achieved in the arrays with taper straight-end connected to the Talbot cavity. Lateral far-field of the fundamental supermode shows a near diffraction limited beam divergence of 2.7°. The output power of a five-element array is about three times as high as a single-ridge laser with an emission wavelength of around 4.8 μm. However, arrays with the taper-end connected to the Talbot cavity always show a high-order supermode operation whatever Talbot cavity length is.

Abstract In this work, quantum cascade lasers (QCLs) based on strain compensation combined with two-phonon resonance design are presented. Distributed feedback (DFB) laser emitting at ~ 4.76 μm was fabricated through a standard buried first-order grating and buried heterostructure (BH) processing. Stable single-mode emission is achieved under all injection currents and temperature conditions without any mode hop by the optimized antireflection (AR) coating on the front facet. The AR coating consists of a double layer dielectric of Al2O3 and Ge. For a 2-mm laser cavity, the maximum output power of the AR-coated DFB-QCL was more than 170 mW at 20 °C with a high wall-plug efficiency (WPE) of 4.7% in a continuous-wave (CW) mode.

Chronic kidney disease (CKD) is a commonly occurring complex renal syndrome that causes overall mortality in many diseases. The clinical manifestations of CKD include renal tubulointerstitial fibrosis and loss of renal function. Metallothionein-I/II (MT-I/II) is potentially expressed in the liver and kidney, and possesses antioxidant and metal detoxification properties. However, whether MT-I/II expression is associated with the prognosis of nephropathy remains unknown. In this study, we investigated the MT-I/II level in human CKD, using immunohistochemistry. MT-I/II is located on the proximal tubules and is notably reduced in patients with CKD. MT-I/II expression was significantly correlated with the functional and histological grades of CKD. In an aristolochic acid (AAI)-induced nephropathy mouse model, MT-I/II was abundantly increased after AAI injection for 7 days, but decreased subsequently compared to that induced in the acute phase when injected with AAI for 28 days. Furthermore, we found that ammonium pyrrolidinedithiocarbamate (PDTC) restored AAI-induced MT-I/II reduction in HK2 cells. The injection of PDTC ameliorated AAI-induced renal tubulointerstitial fibrosis and reduced the concentrations of blood urea nitrogen and creatinine in mouse sera. Taken together, our results indicate that MT-I/II reduction is associated with advanced CKD, and the retention of renal MT-I/II is a potential therapeutic strategy for CKD.

Abstract In the present work, an ultra-low power consumption substrate-emitting distributed feedback (DFB) quantum cascade laser (QCL) was developed. The continuous-wave (CW) threshold power dissipation is reduced to 0.43 W at 25 °C by shortening the cavity length to 0.5 mm and depositing high-reflectivity (HR) coating on both facets. As far as we know, this is the recorded threshold power dissipation of QCLs in the same conditions. Single-mode emission was achieved by employing a buried second-order grating. Mode-hop free emission can be observed within a wide temperature range from 15 to 105 °C in CW mode. The divergence angles are 22.5o and 1.94o in the ridge-width direction and cavity-length direction, respectively. The maximum optical power in CW operation was 2.4 mW at 25 °C, which is sufficient to spectroscopy applications.

Background The effect of holiday season admission for stroke on mortality has not been investigated. Thus, we aimed to evaluate whether “holiday season” and “weekend” effects exist on mortality risk for stroke admission. Methods and Results A nationwide cohort study was conducted using Taiwan's National Health Insurance Research Database. We identified all patients admitted for stroke between 2011 and 2015 in Taiwan, and categorized them according to the admission date: holiday season (at least 4 days off) (n=3908), weekend (n=13 774), and weekday (n=49 045). We analyzed in‐hospital, 7‐day, and 30‐day mortality using multivariable logistic regression, adjusting for stroke severity and other confounders. Compared with weekday admissions, holiday season admission for stroke was significantly associated with a 20%, 33%, and 21% increase in in‐hospital, 7‐day, and 30‐day mortality, respectively. Compared with weekend admissions, holiday season admissions were associated with a 24%, 30%, and 22% increased risk of in‐hospital, 7‐day, and 30‐day mortality, respectively. However, mortality did not differ significantly between weekend and weekday admissions. Subanalyses after stratification for age, sex, and stroke type also revealed similar trends. Conclusions We report for the first time a “holiday season effect” on stroke mortality. Patients admitted during holiday seasons had higher mortality risks than those admitted on weekends and weekdays. This holiday season effect persisted even after adjusting for stroke severity and other important confounders. These findings highlight the need for healthcare delivery systems with a consistent quality of round‐the‐clock care for patients admitted for stroke.

Partitioning defective 3 (Par-3), a crucial component of partitioning-defective complex proteins, controls cell polarity and contributes to cell migration and cancer cell epithelial-to-mesenchymal transition. However, the clinical relevance of Par-3 in tumor progression and metastasis has not been well elucidated. In this study, we investigated the impact and association of Par-3 expression and clinical outcomes with hepatocellular carcinoma (HCC). We first confirmed that Par-3 was abundantly expressed in HCC cell lines by Western blot analysis. We used immunohistochemistry to analyze the association of Par-3 expression and clinicopathological characteristics in primary and subsequent metastatic tumors of patients with HCC. Par-3 was overexpressed in 47 of 111 (42.3%) primary tumors. Increased expression of Par-3 in primary tumors predicted an increased five-year cumulative incidence of extrahepatic metastasis. In addition, multivariate analysis revealed that Par-3 overexpression was an independent risk factor of extrahepatic metastasis. Increased Par-3 expression in primary tumors was associated with poor five-year overall survival rates and was an independent prognostic factor on Cox regression analysis. In conclusion, we show for the first time that increased Par-3 expression is associated with distant metastasis and poor survival rates in patients with HCC. Par-3 may be a novel prognostic biomarker and therapeutic target for HCC.

A phase-locked quantum cascade laser (QCL) array consisting of one hundred elements that were integrated in parallel was achieved at λ ∼ 4.6 μm. The proposed Fraunhofer’s multiple slits diffraction model predicted and explained the far-field pattern of the phase-locked laser array. A single-lobed far-field pattern, attributed to the emission of an in-phase-like supermode, is obtained near the threshold (Ith). Even at 1.5 Ith, greater than 73.3% of the laser output power is concentrated in a low-divergence beam with an optical power of up to 40 W.

Inflammation is a major mediator of CKD progression and is partly driven by altered gut microbiome and intestinal barrier disruption, events which are caused by: urea influx in the intestine resulting in dominance of urease-possessing bacteria; disruption of epithelial barrier by urea-derived ammonia leading to endotoxemia and bacterial translocation; and restriction of potassium-rich fruits and vegetables which are common sources of fermentable fiber. Restriction of these foods leads to depletion of bacteria that convert indigestible carbohydrates to short chain fatty acids which are important nutrients for colonocytes and regulatory T lymphocytes. We hypothesized that a high resistant starch diet attenuates CKD progression. Male Sprague Dawley rats were fed a chow containing 0.7% adenine for 2 weeks to induce CKD. Rats were then fed diets supplemented with amylopectin (low-fiber control) or high fermentable fiber (amylose maize resistant starch, HAM-RS2) for 3 weeks. CKD rats consuming low fiber diet exhibited reduced creatinine clearance, interstitial fibrosis, inflammation, tubular damage, activation of NFkB, upregulation of pro-inflammatory, pro-oxidant, and pro-fibrotic molecules; impaired Nrf2 activity, down-regulation of antioxidant enzymes, and disruption of colonic epithelial tight junction. The high resistant starch diet significantly attenuated these abnormalities. Thus high resistant starch diet retards CKD progression and attenuates oxidative stress and inflammation in rats. Future studies are needed to explore the impact of HAM-RS2 in CKD patients.

14-3-3ε is implicated in regulating tumor progression, including hepatocellular carcinoma (HCC). Our earlier study indicated that elevated 14-3-3ε expression is significantly associated with higher risk of metastasis and lower survival rates of HCC patients. However, the molecular mechanisms of how 14-3-3ε regulates HCC tumor metastasis are still unclear.In this study, we show that increased 14-3-3ε expression induces HCC cell migration and promotes epithelial-mesenchymal transition (EMT), which is determined by the reduction of E-cadherin expression and induction of N-cadherin and vimentin expression. Knockdown with specific siRNA abolished 14-3-3ε-induced cell migration and EMT. Furthermore, 14-3-3ε selectively induced Zeb-1 and Snail expression, and 14-3-3ε-induced cell migration was abrogated by Zeb-1 or Snail siRNA. In addition, the effect of 14-3-3ε-reduced E-cadherin was specifically restored by Zeb-1 siRNA. Positive 14-3-3ε expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in HCC tumors. Analysis of 14-3-3ε/E-cadherin expression associated with clinicopathological characteristics revealed that the combination of positive 14-3-3ε and negative E-cadherin expression is significantly correlated with higher incidence of HCC metastasis and poor 5-year overall survival. In contrast, patients with positive 14-3-3ε and positive E-cadherin expression had better prognostic outcomes than did those with negative E-cadherin expression.Our findings show for the first time that E-cadherin is one of the downstream targets of 14-3-3ε in modulating HCC tumor progression. Thus, 14-3-3ε may act as an important regulator in modulating tumor metastasis by promoting EMT as well as cell migration, and it may serve as a novel prognostic biomarker or therapeutic target for HCC.

Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear.In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3σ isoform. Knockdown of 14-3-3σ with siRNA reduced embryonic stem cell proliferation, while only 14-3-3σ transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3σ was abrogated by β-catenin knockdown, we investigated the influence of 14-3-3σ overexpression on β-catenin/GSK-3β. 14-3-3σ bound GSK-3β and increased GSK-3β phosphorylation in a PI-3K/Akt-dependent manner. It disrupted β-catenin binding by the multiprotein destruction complex. 14-3-3σ overexpression attenuated β-catenin phosphorylation and rescued the decline of β-catenin induced by retinoid acid. Furthermore, 14-3-3σ enhanced Wnt3a-induced β-catenin level and GSK-3β phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3β/14-3-3σ binding.Our findings show for the first time that 14-3-3σ plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3β and enhancing Wnt-signaled GSK-3β inactivation. 14-3-3σ is a novel target for embryonic stem cell expansion.