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Background and Aim: Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin‐1 (IL‐1) regulates immunity and inflammation. We investigate the role of IL‐1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC. Methods: Hydrodynamics‐based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto‐oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen‐free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra‐hepatic immune cell flow cytometry were conducted. IL‐1β levels in human and mouse serum were assessed. Results: Interleukin‐1β levels were elevated in patients with HCC compared with those in non‐HCC controls. Hepatic IL‐1β levels were higher in HCC mouse models than those in non‐HCC mice, suggesting localized hepatic inflammation. IL‐1 receptor type 1 (IL‐1R1) knockout (IL‐1R1−/−) mice exhibited less severe HCC progression than that in wild‐type mice, despite the high intra‐hepatic IL‐1β concentration. IL‐1R1−/− mice exhibited increased hepatic levels of myeloid‐derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid‐derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver. Conclusions: Targeting IL‐1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced‐stage HCC. [ABSTRACT FROM AUTHOR]

Summary: Background: The benefits of HCV eradication on distinct recurrence patterns and long‐term hepatic outcomes in patients with hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) remain uncertain. This study aims to assess the impact of HCV eradication on HCC recurrence patterns and long‐term hepatic outcomes after RFA and to identify predictors of recurrence in patients achieving sustained virological response (SVR). Methods: We retrospectively enrolled 274 patients receiving RFA for HCV‐related HCC, including 73 and 88 patients treated with interferon‐based (IFN) and direct‐acting antivirals (DAA) therapy, respectively. We analysed factors associated with local tumour progression (LTP), distant recurrence, overall survival, and hepatic decompensation. Results: SVR was achieved in 49.3% of patients undergoing IFN therapy and 93.2% of patients undergoing DAA therapy. HCV eradication was not associated with LTP but significantly correlated with reduced risk of distant recurrence (by DAA: hazard ratio (HR) = 0.449, p = 0.006), overall survival (by IFN: HR = 0.242, p < 0.001; by DAA: HR = 0.274, p < 0.001) and hepatic decompensation (by IFN: HR = 0.313, p = 0.004; by DAA: HR = 0.281, p < 0.001). The benefits of achieving SVR in terms of overall survival and hepatic decompensation remained significant in subgroups of patients with and without recurrence. Patients with SVR showed a significant decline in FIB‐4 score and a higher proportion of ALBI grade improvement. Among SVR patients, the IMbrave050 criteria predicted LTP but not distant recurrence, whereas the FIB‐4 score after SVR, rather than the baseline FIB‐4, predicted distant recurrence. Conclusions: HCV eradication was associated with a significant reduction in distant recurrence, mortality and hepatic decompensation following RFA in patients with HCV‐related HCC. [ABSTRACT FROM AUTHOR]

Synthesis of ammonia by electrochemical nitrogen reduction reaction (NRR) is a promising alternative to the Haber–Bosch process. However, it is commonly obstructed by the high activation energy. Here, we report the design and synthesis of an Al−Al bonded dual atomic catalyst stabilized within an amorphous nitrogen‐doped porous carbon matrix (Al2NC) with high NRR performance. The dual atomic Al2‐sites act synergistically to catalyze the complex multiple steps of NRR through adsorption and activation, enhancing the proton‐coupled electron transfer. This Al2NC catalyst exhibits a high Faradaic efficiency of 16.56±0.3 % with a yield rate of 29.22±1.2 μg h−1 mgcat−1. The dual atomic Al2NC catalyst shows long‐term repeatable, and stable NRR performance. This work presents an insight into the identification of synergistic dual atomic catalytic site and mechanistic pathway for the electrochemical conversion of N2 to NH3. [ABSTRACT FROM AUTHOR]

The incidence of brain metastasis (BM) from colorectal cancer (CRC) is increasing. This study aims to identify the clinical prognosticators and evaluate the prognostic validity of common comorbidity indices in patients with BM from CRC. This retrospective single‐center study analyzed 93 patients with BM from CRC who received surgical excision and/or radiotherapy. The clinical characteristics and prognostic indices including the 5‐item modified frailty index (mFI‐5) and prognostic nutritional index (PNI) were calculated from the collected patient data and analyzed. In this study, 66 (71.0%), 10 (10.8%), and 17 (18.3%) patients received whole‐brain radiotherapy (WBRT) alone, surgery alone, and surgery plus WBRT, respectively. The median survival of all patients was 3.98 months (IQR: 1.74–7.99). The 2‐ and 3‐year survival rates were 7.4% and 3.7%, respectively. Controlled primary tumor (p = 0.048), solitary BM (p = 0.001), surgery + radiation (p < 0.001), and greater PNI (p = 0.001) were independent predictors of favorable survival. In surgically treated patients, uncontrolled primary tumor (p = 0.006), presence of multiple BM (p < 0.001), and MFI‐5 ≥ 2 (p = 0.038) were independent prognosticators. For patients who received WBRT, the presence of two (p = 0.004) or multiple (p < 0.001) BM and PNI (p < 0.001) were independent survival predictors MFI‐5, multiple BM, and the status of the primary tumor were independent prognosticators for patients who underwent surgery for CRCBM. For patients who received WBRT, the PNI and the number of BM were independent survival predictors. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non‐small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR–tyrosine kinase inhibitors (TKIs). Methods: The study included patients with stage IV EGFR‐mutated NSCLC who were receiving first‐line treatment with EGFR–TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. Results: The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression‐free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM. Conclusions: The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes. [ABSTRACT FROM AUTHOR]

A multifunctional bioreactor was fabricated in this study to investigate the facilitation efficiency of electrical and mechanical stimulations on myogenic differentiation. This bioreactor consisted of a highly stretchable conductive membrane prepared by depositing polypyrrole (PPy) on a flexible polydimethylsiloxane (PDMS) film. The tensile deformation of the PPy/PDMS membrane can be tuned by adjusting the channel depth. In addition, PPy/PDMS maintained its electrical conductivity under continuous cyclic stretching in the strain range of 6.5%-13% for 24 h. This device can be used to individually or simultaneously perform cyclic stretching and electrical stimulation. The results of single stimulation showed that either cyclic stretching or electrical stimulation upregulated myogenic gene expression and promoted myotube formation, where electrical stimulation improved better than cyclic stretching. However, only cyclic stretching can align C2C12 cells perpendicular to the stretching direction, and electrical stimulation did not affect cell morphology. Myosin heavy chain (MHC) immunostaining demonstrated that oriented cells under cyclic stretching resulted in parallel myotubes. The combination of these two stimuli exhibited synergetic effects on both myogenic gene regulation and myotube formation, and the incorporated electrical field did not affect the orientation effect of the cyclic stretching. These results suggested that these two treatments likely influenced cells through different pathways. Overall, the simultaneous application of cyclic stretching and electrical stimulation preserved both stimuli's advantages, so myo-differentiation can be highly improved to obtain abundant parallel myotubes, suggesting that our developed multifunctional bioreactor should benefit muscle tissue engineering applications. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the incidence rate and risk factors for anisometropia among young schoolchildren. Methods: A population‐based cohort study, the Myopia Investigation Study in Taipei, was conducted in primary schools in Taipei City. Children were recruited for biannual comprehensive eye examinations over 2 years. Cycloplegic autorefraction and slit lamp examinations were performed biannually. Data on demographic information, parental history, lifestyle and near‐work activities were collected using parent‐administered questionnaires at the first and final visits. Anisometropia was defined as ≥1 D difference in the spherical equivalent (SE) refractive error. Results: A total of 7035 8‐year‐old children completed the 2‐year follow‐up evaluations. The average annual incidence of anisometropia was 3.8%. Multivariable logistic regression analysis revealed that baseline SE (odds ratio [OR]: 0.87 95% CI: 0.80–0.95) and female sex (OR: 1.24, 95% confidence interval [CI]: 1.02–1.50) were significantly associated with incident anisometropia. Among lifestyle risk factors, spending <1 h per day in after‐school outdoor activities on weekdays (OR: 1.38, 95% CI: 1.08–1.76) and performing near work at a distance <30 cm (OR: 1.33, 95% CI: 1.08–1.64) were significantly associated with an increased risk of incident anisometropia. In the multiple linear regression analysis, the inter‐eye difference in SE increased significantly in children performing near work at distances <30 cm (adjusted β = 0.03; p = 0.02). Conclusions: This study indicated the annual incidence of anisometropia in Taiwanese schoolchildren. Less time spent outdoors and shorter eye‐to‐object distances during near work increased the risk of incident anisometropia. [ABSTRACT FROM AUTHOR]

Background: Little is known about the predictive value of soluble AXL (sAXL) in heart failure (HF). This study aimed to describe the prognostic value of plasma sAXL in patients with symptomatic HF. Methods: This is a multicentre observational prospective cohort study (Registration No. NCT03727828). Plasma sAXL were measured on admission. The primary endpoint is a composite of cardiovascular mortality and HF rehospitalization. Associations between plasma sAXL levels and clinical endpoints are described using Cox regression models and Kaplan–Meier methods. Results: A total of 1030 symptomatic HF patients were enrolled in the study; the mean age (65% men) was 71 ± 12 years, with a median follow‐up of 32 months (IQR: 26–41 months). The mean baseline sAXL levels were 20.03 ± 6.74 ng/mL. Plasma sAXL positively associated with NYHA classification and negatively associated with left ventricular ejection fraction (both P < 0.001). Cox regression showed that 1‐SD increment of sAXL was associated with primary endpoint [HR (CI): 1.128 (1.024–1.242)], cardiovascular mortality [1.112 (1.032–1.198)], all‐cause mortality [1.142 (1.057–1.234)], and HF rehospitalization [1.122 (1.030–1.224)] after adjustment for potential confounders including NT‐proBNP. Kaplan–Meier curves revealed that patients with the highest sAXL levels were at the highest risk of primary endpoint events, cardiovascular mortality, and all‐cause mortality (all P values < 0.001). Furthermore, both Kaplan–Meier method and Categorical analysis demonstrated that the combined use of sAXL and NT‐proBNP were more likely to predict all‐cause or cardiovascular mortality (both P < 0.001). Similar results were observed when separating patients with respect to left ventricular ejection fraction, namely, in HFrEF, HFmrEF, and HFpEF groups. Conclusions: Plasma sAXL concentrations are of great importance in predicting clinical outcomes in HF patients, independent of NT‐proBNP, suggesting that sAXL is a promising prognostic marker for further study. [ABSTRACT FROM AUTHOR]

The NanoString GeoMx digital spatial profiling is a new multiplexed platform that quantifies the abundance of tumor‐ and immune‐related proteins in a spatially resolved manner. We performed DSP for the simultaneous assessment of 52 analytes within spatially resolved tissue compartments defined by pan‐cytokeratin expression. We compared protein targets between 94 African American/Black and 65 European American/White cases, tumor and stromal tissue compartments, estrogen receptor alpha (ER)‐positive and ER‐negative cases, and explored potential biomarkers of survival. Of 33 analytes with robust signal for analysis, results were highly replicable. For a subset of markers, correlative analyses between DSP analytes and traditional immunohistochemistry scores revealed moderate to very strong associations between the two platforms. Similarly, DSP analytes and gene expression scores were concordant for 21 of 25 markers with overlap between the two datasets. Several analytes varied by ER status, and across the 25 immune markers surveyed, 14 had a significant inverse association with ER expression. B7 homolog 3 (B7‐H3; encoded by CD276) was the only analyte to show a significant difference by race, being lower in both the tumor and stromal compartments in Black women. DSP markers that were associated with survival included CD8, CD25, CD56, CD127, EpCAM, ER, Ki‐67, and STING. We conclude that DSP is an efficient tool for screening tumor‐ and immune‐related markers in a simultaneous fashion and yields results that are concordant with established immune profiling assays. DSP immune analytes were inversely associated with ER expression, in agreement with a substantial body of previous work that documents higher immune infiltration in ER‐negative breast cancers. This technology revealed that scores of the B7‐H3 protein were significantly lower in breast cancers from Black women compared with White women, an intriguing finding that requires replication in independent and racially diverse female populations. [ABSTRACT FROM AUTHOR]

Watershed ecological compensation has been widely accepted as a system to promote the cooperation of various stakeholders to solve the problem of transboundary water pollution, but the existing research does not fully consider the impact of compensation fee paid by different governments on stakeholders' decision-making. Therefore, this paper constructs a tripartite game model between upstream governments, downstream governments, and the central government by using evolutionary game theory and determines the influence of different factors on the decision-making process of each player through simulation. The results show the following: (1) the initial probability significantly affects the decision-making behavior of each player; (2) daily supervision of the central government and the reduction of the environmental protection cost can promote the implementation of watershed ecological compensation; (3) the fine to downstream governments makes the decisions of the central government and downstream governments change periodically; and (4) the increase of ecological compensation fee urges downstream governments to choose noncompensation, and compensation fee paid by the central government has a critical value. [ABSTRACT FROM AUTHOR]

The whale optimization algorithm (WOA) is a powerful swarm intelligence method which has been widely used in various fields such as parameter identification of solar cells and PV modules. In order to better balance the exploration and exploitation of WOA, we propose a novel modified WOA (MWOA) in which both the mutation strategy based on Levy flight and a local search mechanism of pattern search are introduced. On the one hand, Levy flight can make the algorithm get rid of the local optimum and avoid stagnation; thus, it is able to prevent the algorithm from losing diversity and to increase the global search capability. On the other hand, pattern search, a direct search method, has not only high convergence rate but also good stability, which can boost the local optimization ability of the WOA. Therefore, the combination of these two mechanisms can greatly improve the capability of WOA to obtain the best solution. In addition, MWOA may be employed to estimate parameters in single diode model (SDM), double diode model (DDM), and PV modules and to identify unknown parameters of two different types of PV modules under diverse light irradiance and temperature conditions. The analytical results demonstrate the validity and the practicality of MWOA for estimating parameters of solar cells and PV modules. [ABSTRACT FROM AUTHOR]

Background. There is increasing evidence that dietary intake of sugars may be a risk factor for prostate cancer (PCa) and elevate the concentration of serum prostate-specific antigen (PSA). However, there is limited evidence of the correlation between total dietary intake of sugars and serum PSA concentrations for adult American males. Herein, we evaluated the association between total dietary intake of sugars and serum PSA concentrations in men without a malignant tumor diagnosis in the United States (US) National Health and Nutrition Examination Survey (NHANES) database. Material and Methods. In this secondary data analysis, a total of 6,403 men aged ≥40 years and without malignant tumor history were included from 2003 to 2010. The independent variable of this study was the total dietary intake of sugars, and the dependent variable was serum PSA concentrations. Covariates included dietary, comorbidity, physical examination, and demographic data. Results. The average age of participants included in this study was 58.1 years (±13.6). After adjusting for the dietary, comorbidity, physical examination, and demographic data, we observed that a dietary intake increase of one gram of total dietary intake of sugars was associated with an increase of serum PSA concentrations by 0.003 ng/mL (after log2 transformed, 95% CI: 0.001 to 0.005) with a P value for trend less than 0.05. Sensitivity analysis using the generalized additive model (GAM) supported the linear association between total dietary intake of sugars and serum PSA concentrations. Conclusion. The total dietary intake of sugars is independently and positively associated with serum PSA concentrations in adult American males who are without a personal history of malignant tumors. [ABSTRACT FROM AUTHOR]

Care for patients with rheumatic diseases during COVID-19 pandemic: A position statement from APLAR The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China in December 2019. Health authorities should ensure adequate supply of these drugs since the HCQ shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases. On the other hand, rheumatologists are cautiously enthusiastic that a variety of immune-modulating drugs and targeted cytokine inhibitors available for rheumatic disease patients may also benefit patients as prophylaxis for COVID-19 or with COVID-19-induced CSS. [Extracted from the article]

C-type lectin domain family 5-member A (CLEC5A) associates with adaptor DAP12 (DNAX activation protein 12) to form receptor complexes involved in inflammatory responses. We postulated a potential role of CLEC5A in the pathogenesis of adult-onset Still's disease (AOSD) and aimed to investigate CLEC5A expression and its association with activity parameters and disease course. In 34 AOSD patients and 12 healthy controls (HC), circulating levels of CLEC5A-expressing monocytes or granulocytes were determined by flow cytometry analysis, the mRNA expression of CLEC5A and DAP12 on PBMCs by quantitative PCR, and plasma levels of proinflammatory cytokines by ELISA. AOSD patients had significantly higher percentages and mean fluorescence intensity (MFI) of CLEC5A-expressing monocytes (median 62.1% and 3.20, respectively) or granulocytes (72.6% and 3.22, respectively) compared with HC (in monocytes: 17.0% and 0.65, both p < 0.001; in granulocytes: 67.3%, p < 0.05 and 0.90, p < 0.001; respectively). Patients also had significantly higher levels of CLEC5A mRNA expression on PBMCs compared with HC (median 1.77 vs. 0.68, p < 0.05). The levels of CLEC5A-expressing monocytes or granulocytes were positively associated with activity scores and levels of IL-1β and IL-18 in AOSD patients. The patients with a systemic pattern had significantly higher levels of CLEC5A-expressing granulocytes and IL-18 compared to those with a chronic articular pattern of disease course. After 6 months of therapy, levels of CLEC5A-expressing monocytes and granulocytes significantly declined, paralleling the decrease of AOSD activity. Elevated CLEC5A levels and their positive association with activity parameters suggest that CLEC5A is involved in the pathogenesis and may serve as an activity indicator of AOSD. [ABSTRACT FROM AUTHOR]

Aim: To explore how different cultural values are connected to teamwork between doctors and nurses in emergency departments (EDs) in China. Background: China is a multicultural society, which leads to different cultural values being represented within its population. Doctors and nurses from different cultural backgrounds bring their own cultural values to their workplaces that influence teamwork. EDs are medical treatment facilities designed to provide episodic care to patients suffering from acute injuries and illnesses. Doctors and nurses in EDs should not only be highly skilled but also be able to work as a team. Studies have shown that different cultural values are often the cause of poor teamwork. However, there has been little focus on this phenomenon in the literature on ED. Therefore, this study aimed to identify how cultural values are connected to teamwork in EDs. Design: Phenomenological study. Methods: In‐depth interviews were conducted with 10 doctors and 10 nurses in EDs from September to December 2018 in three large general hospitals in Shanghai. Results: Four major themes emerged from the data: leadership, communication, mutual support and staffing. Twelve sub‐themes were identified (a) hierarchy between superiors and subordinates; (b) doctors as superiors; (c) Northerners are more powerful; (d) emphasizing etiquette; (e) traditionally feminine traits; (f) face‐to‐face communication; (g) collectivism; (h) being open‐minded; (i) tense doctor–patient relationships; (j) clique culture; (k) high pressure; and (l) home culture. Conclusions: Teamwork between doctors and nurses in EDs is influenced by different cultural values. Future research should be carried out to identify which factors are essential to improving teamwork among doctors and nurses in hospital EDs. Implications for Nursing Management: It is important to develop strategies to foster teamwork between doctors and nurses with different cultural values. [ABSTRACT FROM AUTHOR]

Adolescence is a developmental period with high vulnerability to sleep problems. However, research identifying distinct patterns and underlying determinants of sleep problems is scarce. This study investigated discrete subgroups of, changes in, and stability of sleep problems. We also examined whether peer victimization influenced sleep problem subgroups and transitions in patterns of sleep problems from late adolescence to young adulthood. Sex differences in the effects of peer victimization were also explored. In total, 1,455 male and 1,399 female adolescents from northern Taiwan participated in this longitudinal study. Latent transition analysis was used to examine changes in patterns of sleep problems and the effects of peer victimization on these changes. We identified three subgroups of sleep problems in males and two in females, and found that there was a certain level of instability in patterns of sleep problems during the study period. For both sexes, those with greater increases in peer victimization over time were more likely to change from being a good sleeper to a poor sleeper. The effects of peer victimization on baseline status of sleep problems, however, was only significant for males, with those exposed to higher levels of peer victimization more likely to be poor sleepers at baseline. Our findings reveal an important role of peer victimization in predicting transitions in patterns of sleep problems. Intervention programs aimed at decreasing peer victimization may help reduce the development and escalation of sleep problems among adolescents, especially in males. [ABSTRACT FROM AUTHOR]

Gross spreads received by underwriters on initial public offerings (IPOs) in the United States are much higher than in other countries. Furthermore, in recent years more than 90 percent of deals raising $20-80 million have spreads of exactly seven percent, three times the proportion of a decade earlier. Investment bankers readily admit that the IPO business is very profitable, and that they avoid competing on fees because they "don't want to turn it into a commodity business." We examine several features of the IPO underwriting business that result in a market structure where spreads are high. [ABSTRACT FROM AUTHOR]

Aims: The direct cost of operations and health care expenditure for treating pelvic floor dysfunction are substantial. In this study, we evaluate the number of inpatient surgical procedures and direct expenditures for treating pelvic organ prolapse and urinary incontinence under the coverage of National Health Insurance (NHI) in Taiwan. Methods: Thirteen years of population‐based NHI inpatient claims were used in this study. The number of surgical procedures and the average direct cost of inpatient fees for treating pelvic floor dysfunction for each patient from 1999 to 2011 were calculated. The patients were stratified based on age into a younger than 65 years group and 65 years or older group for comparisons. Results: The number of patients per year increased by 27%, increasing from 5278 patients in 1999 to 6706 patients in 2011. The total direct cost of inpatient (surgical and admission) fees for pelvic floor dysfunction increased by 57.2%, increasing from $6 674 968 USD in 1999 to $10 494 894 USD in 2011. However, while the expenditures for women 65 years or older increased by 102.2% from 1999 to 2011, there was only a 38.3% increase for those younger than 65 years when we stratified the patients by age. Conclusion: The increasing expenditures for inpatient surgery for pelvic floor dysfunction are mainly due to the escalating utilization of inpatient surgical procedures, especially those for pelvic organ prolapse in women aged 65 or older. [ABSTRACT FROM AUTHOR]

Background. Changes in the gut microbiota are associated with cardiovascular disease progression. Xiao-Qing-Long Tang (XQLT), a traditional herbal formula, has an anti-inflammatory effect and regulates the steady state of the immune system, which is also associated with the progression of heart failure with preserved ejection faction (HFpEF). In this study, we investigated whether XQLT could contribute to prevent the development of HFpEF and whether the modulation of the gut microbiota by this herbal formula could be involved in such effect. Methods. The gut microbiota, SCFAs, the histology/function of the heart, and systolic blood pressure were examined to evaluate the effect of XQLT on the gut microbiota and the progression of HFpEF after oral administration of XQLT to model rats. Furthermore, we evaluated, through fecal microbiota transplantation experiments, whether the favorable effects of XQLT could be mediated by the gut microbiota. Results. Oral administration of XQLT contributed to the reduction of elevated blood pressure, inflammation, and compensatory hypertrophy, features that are associated with the progression of HFpEF. The gut microbiota composition, SCFA levels, and intestinal mucosal histology were improved after treatment with XQLT. Moreover, fecal transfer from XQLT-treated rats was sufficient to prevent the progression of HFpEF. Conclusions. These data suggested that XQLT prevented the development of HFpEF in model rats by regulating the composition of the gut microbiota. [ABSTRACT FROM AUTHOR]

Whether the combination of inter-arm and inter-leg systolic blood pressure differences (BPDs) and ankle-brachial index is of clinical significance remains unclear. In this study, we aimed to investigate the association of the combination of inter-limb systolic BPDs with cardiovascular risk factors and hypertension-mediated organ damage (HMOD). A total of 2621 elderly subjects from the Northern Shanghai Study were divided into Group A, B, and C consisting of participants with 0, 1, and ≥2 abnormal inter-limb systolic BPDs, respectively. Comparisons of cardiovascular risk factors and parameters of cardiac, vascular, and renal damage between groups and logistic regression models were conducted. The proportions of subjects presenting 0, 1, and ≥2 abnormal inter-limb systolic BPDs were 60.9%, 25.1%, and 14.0%, respectively. Upward trends, from Group A, through Group B, to Group C, were observed for the level or prevalence of nearly all cardiovascular risk factors and HMOD (P for trend ≤0.007 for all). In multiple logistic regression, Group C showed significantly higher odds for carotid plaque (vs Group A: Odds ratio [OR] = 1.88, 95% confidence interval [CI] = 1.43-2.48; vs Group B: OR = 1.46, 95% CI = 1.08-1.97), arterial stiffness (vs Group A: OR = 1.26, 95% CI = 0.96-1.65; vs Group B: OR = 1.36, 95% CI = 1.01-1.83), and left ventricular hypertrophy (vs Group A: OR = 1.35, 95% CI = 1.04-1.76; vs Group B: OR = 1.25, 95% CI = 0.93-1.67), when compared with Group A and B. In conclusion, the combination of abnormal inter-limb systolic BPDs significantly associates with greater burden of cardiovascular risk factors and higher likelihood for HMOD, especially carotid plaque, arterial stiffness, and left ventricular hypertrophy. [ABSTRACT FROM AUTHOR]

We aim to compare 24-hour aortic blood pressure variability (BPV) with brachial BPV in relation to carotid damage as estimated by carotid intima-media thickness (CIMT) and cross-sectional area (CCSA). Four hundred and forty five individuals received brachial and aortic 24-hour ambulatory BP monitoring with a validated device (Mobil-O-Graph). Systolic BPV was estimated by average real variability (ARV) and time-weighted standard deviation (wSD). In multiple logistic regression analysis, CIMT > 900 μm was significantly and independently associated with aortic ARV (OR = 1.38; 95% CI: 1.04-1.84), aortic wSD (OR = 1.65; 95% CI: 1.19-2.29) and brachial ARV (OR = 1.53; 95% CI: 1.07-2.18), but not with brachial wSD. CCSA > 90th percentile was significantly and independently associated with aortic ARV (OR = 1.50; 95% CI: 1.07-2.10) and wSD (OR = 1.70; 95% CI: 1.12-2.56), but not with brachial BPVs. In receiver operator characteristics curve analysis, aortic wSD identified CCSA > 90th percentile better than brachial wSD (AUC: 0.73 vs 0.68, P < .01). In conclusion, aortic 24-hour systolic BPV showed a slightly stronger association with carotid damage than brachial BPV. [ABSTRACT FROM AUTHOR]

Background: We identified an autophagy-inducing areca nut (AN) ingredient (AIAI) in the 30-100 kDa fraction of AN extract (ANE 30-100K). This study was to analyze the role of endocytosis in ANE 30-100K-induced autophagy.Methods: We used benzyl alcohol, dynasore, and shRNA of clathrin and dynamin to assess whether ANE 30-100K-induced cytotoxicity and accumulation of microtubule-associated protein 1 light chain 3 (LC3)-II were affected in oral (OECM-1) and esophageal (CE81T/VGH) carcinoma cells.Results: Both benzyl alcohol and dynasore effectively reduced ANE 30-100K-induced cytotoxicity and LC3-II accumulation in OECM-1 and CE81T/VGH cells. Downregulated protein expression of both clathrin and dynamin by their shRNA also significantly attenuated ANE 30-100K-induced elevation of LC3-II levels in CE81T/VGH cells.Conclusions: These results indicate that AIAI may be engulfed by cells through clathrin-mediated endocytosis, which promotes the execution of the following autophagy program. [ABSTRACT FROM AUTHOR]

Nuclear factor-κB ( NF-κB) is an important nuclear transcription factor which regulates pro-inflammatory cytokines such as TNF-α, IL-6. Its role as immunoregulatory mediator makes it an attractive target in the development of treatments for inflammatory and autoimmune diseases. In this study, we synthesized derivatives of IMD0354, a known inhibitor for NF-κB, in attempt to understand the effect of benzanilide substitutions on its activity. The inhibition of these analogs on NF-κB activation was analyzed by luciferase assay. The inhibition of IKKβ phosphorylation and pro-inflammatory cytokines was determined by Western blot and real-time PCR. The structure activity relationships showed that the hydroxyl group on IMD0354 is a critical moiety that resulting in the inhibition of NF-κB. Derivatives 1m, 2b, and 2c were shown to inhibit pro-inflammatory cytokine production at low concentration. These newly synthesized compounds may be useful for the treatment of chronic inflammatory disorders or for cancer prevention. [ABSTRACT FROM AUTHOR]

To compare central and brachial blood pressure (BP) in the association of target organ damage (TOD) in a community-based elderly population, 1599 (aged 71.4 ± 6.1 years) participants in northern Shanghai were recruited. TOD included left ventricular hypertrophy (n = 1556), left ventricular diastolic dysfunction (n = 1524), carotid plaque (n = 1558), arteriosclerosis (n = 1485), and microalbuminuria (n = 1516). Both central and brachial BP significantly correlated with TOD. In full-model regression, central BP was significantly associated with all TOD (P ≤ .04), whereas brachial BP was only significantly associated with left ventricular hypertrophy and arteriosclerosis (P ≤ .01). Similarly, in stepwise regression, central BP was significantly associated with left ventricular hypertrophy, left ventricular diastolic dysfunction, arteriosclerosis, and microalbuminuria (P ≤ .04), while brachial BP was not associated with any TOD. Receiver operating characteristic analyses indicated that central BP identified arteriosclerosis and microalbuminuria better than brachial BP (P ≤ .01). In conclusion, central BP showed superiority over brachial BP in the association of hypertensive TOD in a community-based elderly population. [ABSTRACT FROM AUTHOR]

Burning incense to worship deities is a popular religious ritual in large parts of Asia, and is a popular custom affecting more than 1.5 billion adherents. Due to incomplete combustion, burning incense has been well recognized to generate airborne hazards to human health. However, the correlation between burning incense and lung cancer in epidemiological studies remains controversy. Therefore, we speculated that some unknown materials in incense smoke are involved in the initiation or progression of lung cancer. Based on this hypothesis, we identified a major compound auramine O (AuO) from the water-soluble fraction of incense burned condensate using mass spectrometry. AuO is commonly used in incense manufacture as a colorant. Due to thermostable, AuO released from burned incenses becomes an unexpected air pollutant. AuO is classified as a Group 2B chemical by the International Agency of Research on Cancer (IARC), however, the damage of AuO to the respiratory system remains elusive. Our study revealed that AuO has no apparent effect on malignant transformation; but, it dramatically promotes lung cancer malignancy. AuO accumulates in the nucleus and induces the autophagy activity in lung tumor cells. AuO significantly enhances migration and invasive abilities and the in vitro and in vivo stemness features of lung tumor cells through activating the expression of aldehyde dehydrogenase family 1 member A1 (ALDH1A1), and ALDH1A1 knockdown attenuates AuO-induced autophagy activity and blocks AuO-induced lung tumor malignancy. In conclusion, we found that AuO, an ingredient of incense smoke, significantly increases the metastatic abilities and stemness characters of lung tumor cells through the activation of ALDH1A1, which is known to be associated with poor outcome and progression of lung cancer. For public health, reducing or avoiding the use of AuO in incense is recommended. [ABSTRACT FROM AUTHOR]

Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP. sEH inhibitor (sEHI) N-[1-(oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy) phenyl)-urea (TPPU) and exogenous 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- or 14,15-EET-facilitated FSK-mediated LTP can be potentiated by an A1 adenosine receptor antagonist and a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. sEHI and 14,15-EET upregulated the activation of extracellular signal-regulated kinases (ERKs) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII). Phosphorylation of synaptic receptors NR2B and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 was increased by TPPU and 14,15-EET administration. These results indicated that EETs increased NMDAR- and FSK-mediated synaptic potentiation via the AC-cAMP-PKA signaling cascade and upregulated the ERKs and CaMKII, resulting in increased phosphorylation of NR2B and GluR1 in the hippocampus. [ABSTRACT FROM AUTHOR]

Aim There is little information on the relationship between uric acid (UA) and residual renal function (RRF) in continuous ambulatory peritoneal dialysis (CAPD). The aim of this research is to study the influence of UA on RRF decline in CAPD patients. Methods A retrospective observational cohort study of 304 patients who started CAPD without anuria between 2001 and 2010 was conducted at a single medical center. The outcomes measured in the study included the rate of RRF decline and anuria. A multiple ordinal logistic regression model with backward elimination was conducted to determine the independent factors of the slope of RRF decline. A Cox proportional hazard model was conducted to determine the independent variables of time to anuria. Results The average rate of RRF decline was −0.12 ± 0.22 mL/min per month. Multivariate analysis showed that lower UA group (<0.372 mmol/L), higher UA group (≧0.421 mmol/L), male gender, diabetes mellitus (DM), the use of calcium channel blocker (CCB), and RRF at baseline were linked positively with the rate of RRF decline; on the other hand, independence in dialysate exchanges and BUN were negatively associated with the risk of RRF decline. In addition, male gender, DM, diuretics, and CCB were associated with a higher risk of progression to anuria, whereas 24-h urine amount at baseline conferred a protective role in the development of anuria. Conclusions A U-shaped relationship was found between UA levels and the rate of RRF decline in patients on CAPD, with a faster decline rate in those of higher and lower UA groups. [ABSTRACT FROM AUTHOR]

Aim Chronic kidney disease (CKD) is always associated with hyperuricaemia. However, the studies evaluating the clinical implications of hyperuricaemia have shown conflicting results in these patients. Methods A retrospective observational study was conducted in 2408 stage 3-5 CKD patients. Instead of one baseline uric acid (UA) level, the averaged level of the two consecutive measurements for each participant was used as the predictor for the outcomes of the study, which included mortality, renal outcomes, and hospitalization risk. A multivariate Cox proportional hazards model and logistic regression model were performed to determine the independent risk factor. Results The mean UA level was 0.46 ± 0.106 mmol/L. Of the 2408 patients, there were 563 (23.3%) deaths, 143 (5.9%) cardiovascular deaths, 652 (27%) subjects commencing renal replacement therapy (RRT), 664 (27.5%) subjects with rapid renal progression, 1937 (58%) patients requiring hospitalization and 404 (16.7%) patients with CVD hospitalization during a mean follow-up of approximately 3.03 years. After multivariate adjustments, a 1-mg/dL increase in uric acid level was associated with a hazard ratio (HR) of 1.26 for RRT ( P = 0.002), an odds ratio (OR) of 1.27 for rapid renal progression ( P = 0.001), an HR of 1.19 for all-cause hospitalization ( P < 0.001), and an HR of 1.12 for cardiovascular disease (CVD) hospitalization ( P = 0.02), but not significantly with all-cause mortality and cardiovascular death at the end of follow-up. Conclusions In stage 3-5 CKD patients, hyperuricaemia was associated with a higher risk of renal replacement therapy, rapid renal progression and hospitalization for all causes or CVD, but not with all-cause mortality or cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Plants may affect the performance of neighboring plants either positively or negatively through interspecific and intraspecific interactions. Productivity of mixed-species systems is ultimately the net result of positive and negative interactions among the component species. Despite increasing knowledge of positive interactions occurring in mixed-species tree systems, relatively little is known about the mechanisms underlying such interactions. Based on data from 25-year-old experimental stands in situ and a series of controlled experiments, we test the hypothesis that a broadleaf, non-N fixing species, Michelia macclurei, facilitates the performance of an autotoxic conifer Chinese fir ( Cunninghamia lanceolata) through belowground chemical interactions. Chinese fir roots released the allelochemical cyclic dipeptide (6-hydroxy-1,3-dimethyl-8-nonadecyl-[1,4]-diazocane- 2,5-diketone) into the soil environment, resulting in self-growth inhibition, and deterioration of soil microorganisms that improve P availability. However, when grown with M. macclurei the growth of Chinese fir was consistently enhanced. In particular, Chinese fir enhanced root growth and distribution in deep soil layers. When compared with monocultures of Chinese fir, the presence of M. macclurei reduced release and increased degradation of cyclic dipeptide in the soil, resulting in a shift from self-inhibition to chemical facilitation. This association also improved the soil microbial community by increasing arbuscular mycorrhizal fungi, and induced the production of Chinese fir roots. We conclude that interspecific interactions are less negative than intraspecific ones between non-N fixing broadleaf and autotoxic conifer species. The impacts are generated by reducing allelochemical levels, enhancing belowground mutualisms, improving soil properties, and changing root distributions as well as the net effects of all the processes within the soil. In particular, allelochemical context alters the consequences of the belowground ecological interactions with a novel mechanism: reduction of self-inhibition through reduced release and increased degradation of an autotoxic compound in the mixed-species plantations. Such a mechanism would be useful in reforestation programs undertaken to rehabilitate forest plantations that suffer from problems associated with autotoxicity. [ABSTRACT FROM AUTHOR]

CeO2 films were prepared at deposition temperature ranged from 947 to 1096 K (corresponding laser power was from 52 to 185 W) on (100) LaAlO3 single crystal substrate by laser chemical vapor deposition. At deposition temperature of 1027-1096 K (laser power was from 115 to 185 W), highly (100)-oriented CeO2 films with wedge-caped columnar grains were prepared, whose epitaxial growth relationship was CeO2 [100]// LAO [100] (CeO2 [010]// LAO [011]). Their full width at half maximum of the ω-scan on the (200) reflection and that of the ϕ-scan on the (220) reflection were 0.8°-1.8° and 0.7°-1.2°, respectively. The highest deposition rate at which CeO2 film with pure (100) preferred orientation could be obtained was 30 μm h−1. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of potentially inappropriate medication (PIM) use on health care outcomes in elderly individuals using an instrumental variable (IV) approach.Data Sources/study Setting: Representative claim data from the universal health insurance program in Taiwan from 2007 to 2010.Study Design: We employed a panel study design to examine the relationship between PIM and hospitalization. We applied both the naive generalized estimating equation (GEE) model, which controlled for the observed patient and hospital characteristics, and the two-stage residual inclusion (2SRI) GEE model, which further accounted for the unobserved confounding factors. The PIM prescription rate of the physician most frequently visited by each patient was used as the IV.Principal Findings: The naive GEE models indicated that patient PIM use was associated with a higher likelihood of hospitalization (odds ratio [OR], 1.399; 95 percent confidence interval [CI], 1.363-1.435). Using the physician PIM prescribing rate as an IV, we identified a stronger significant association between PIM and hospitalization (OR, 1.990; 95 percent CI, 1.647-2.403).Conclusions: PIM use is associated with increased hospitalization in elderly individuals. Adjusting for unobserved confounders is needed to obtain unbiased estimates of the relationship between PIM and health care outcomes. [ABSTRACT FROM AUTHOR]

The authors aimed to investigate the superiority of angiotensin system blockade (angiotensin-converting enzyme [ACE] inhibitor/angiotensin receptor blocker [ARB]) plus a calcium channel blocker (CCB) (A+C) over other combination therapies in antihypertensive treatment. A meta-analysis in 20,451 hypertensive patients from eight randomized controlled trials was conducted to compare the A+C treatment with other combination therapies in terms of blood pressure (BP) reduction, clinical outcomes, and adverse events. The results showed that BP reduction did not differ significantly among the A+C therapy and other combination therapies in systolic and diastolic BP (P=.87 and P=.56, respectively). However, A+C therapy, compared with other combination therapies, achieved a significantly lower incidence of cardiovascular composite endpoints, including cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.70-0.91; P<.001), but similar all-cause mortality (RR, 0.90; 95% CI, 0.77-1.04; P=.15) and stroke rates (RR, 0.90; 95% CI, 0.77-1.04; P=.09). Moreover, A+C therapy yielded a 4.21 mL/min/1.73 m(2) lower estimated glomerular filtration rate reduction than other combinations (P<.001). Finally, A+C therapy showed a similar incidence of adverse events as other combination therapies (P=.34) but presented a significantly lower incidence of serious adverse events (RR, 0.85; 95% CI, 0.73-0.98; P=.03). In conclusion, A+C therapy is superior to other combinations of antihypertensive treatment as it shows a lower incidence of cardiovascular events and adverse events, while it has similar effects in lowering BP and preserving renal function. [ABSTRACT FROM AUTHOR]

Molecular averaging, including noncrystallographic symmetry (NCS) averaging, is a powerful method for ab initio phase determination and phase improvement. Applications of the cross-crystal averaging (CCA) method have been shown to be effective for phase improvement after initial phasing by molecular replacement, isomorphous replacement, anomalous dispersion or combinations of these methods. Here, a two-step process for phase determination in the X-ray structural analysis of a new coat protein from a betanodavirus, Grouper nervous necrosis virus, is described in detail. The first step is ab initio structure determination of the T = 3 icosahedral virus-like particle using NCS averaging (NCSA). The second step involves structure determination of the protrusion domain of the viral molecule using cross-crystal averaging. In this method, molecular averaging and solvent flattening constrain the electron density in real space. To quantify these constraints, a new, simple and general indicator, free fraction (ff), is introduced, where ff is defined as the ratio of the volume of the electron density that is freely changed to the total volume of the crystal unit cell. This indicator is useful and effective to evaluate the strengths of both NCSA and CCA. Under the condition that a mask (envelope) covers the target molecule well, an ff value of less than 0.1, as a new rule of thumb, gives sufficient phasing power for the successful construction of new structures. [ABSTRACT FROM AUTHOR]

Hard X-ray Fabry-Perot resonators (FPRs) made from sapphire crystals were constructed and characterized. The FPRs consisted of two crystal plates, part of a monolithic crystal structure of Al2O3, acting as a pair of mirrors, for the backward reflection (0 0 0 30) of hard X-rays at 14.3147 keV. The dimensional accuracy during manufacturing and the defect density in the crystal in relation to the resonance efficiency of sapphire FPRs were analyzed from a theoretical standpoint based on X-ray cavity resonance and measurements using scanning electron microscopic and X-ray topographic techniques for crystal defects. Well defined resonance spectra of sapphire FPRs were successfully obtained, and were comparable with the theoretical predictions. [ABSTRACT FROM AUTHOR]

Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p ≤ 0.05, particularly for ER- breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER- cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 ( p = 7 × 10−5, gene-wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 ( p = 1 × 10−4, corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes. [ABSTRACT FROM AUTHOR]

This study investigated errors in color judgment related to stimuli (cyan vs. magenta vs. yellow) printed on various materials (coated paper vs. cotton vs. polyester fiber) and occurring in a range of visual environments (color temperature × luminance: 4000 K × 1500 lx vs. 4000 K × 750 lx vs. 2700 K × 1500 lx vs. 2700 K × 750 lx) under illuminated light-emitting diodes. Participants included 16 female and 14 male Taiwanese college students [age range, 20-26 years (M = 21.92, SD = 2.13)]. Subjects were instructed to perform a series of comparative judgments in which they carefully observed a standard stimulus color under illuminated LEDs and judged which of five simultaneously presented colors under illuminant D65 was the most similar to the standard color. Data analysis revealed that the effect of visual environment on accuracy of color judgments against the standard was significant. Additionally, the accuracy of color judgments against the standard was significantly better for polyester printing material than it was for coated paper. The color of the standard also significantly affected color judgment accuracy: cyan yielded significantly worse accuracy rates than did magenta or yellow. These results have implications for lighting design and interior design. [ABSTRACT FROM AUTHOR]

Currently flash memory is widely used for data storage of mobile communication and automobile electronics. In this study the control program of multiple-execution has been designed to suppress the components and level of electromagnetic interference (EMI) noise generated during the data writing/reading of flash memory. The method designed by us can reduce the EMI noise levels of writing and reading operations by 4.39 dB and 2.91 dB respectively, while reducing the EMI noise components by 58.3% and 54.5% respectively, such that the noise interference by flash memory can be effectively reduced when it is used for various electronic devices. Especially for the automobile electronic systems, where the reduction of EMI noise interference can assure driving safety, and the reception sensitivity can be enhanced by suppressing the interference of RF module resulted from platform noise. [ABSTRACT FROM AUTHOR]

Aims To determine the significance of the epithelioid type and the corresponding molecular alterations in hepatic angiomyolipoma ( AML). Methods and results We retrieved 24 samples of hepatic AML to delineate the clinicopathological features and the immunohistochemical expression of components in the m TOR pathway, and employed microsatellite markers to analyse allelic imbalances in the TSC1 and TSC2 regions. Myomatous AML was the most common type, and a predominantly epithelioid cell population was observed in 50% of the samples. Two-thirds of all samples contained <20% of fat tissue. Four cases of monotypic epithelioid AML were discovered without prognostic implications. Elevated phospho-p70S6 kinase expression was noted in 19 samples in the absence of phospho- AKT activity. Loss of heterogeneity ( LOH) of TSC1/ TSC2 was found in 15 samples. As compared wityh syndromic AML samples, sporadic AML samples showed LOH of microsatellite markers to a limited extent. Only four samples had increased β-catenin expression in the context of concurrent high expression of phospho-p70S6 kinase and phospho-S6 ( P = 0.018). Conclusions The low fat content and epithelioid cytomorphology in hepatic AML potentially obstruct preoperative and pathological diagnosis. Alteration of the m TOR pathway and LOH of the tuberous sclerosis complex genes is a frequent pathogenesis in hepatic AMLs. [ABSTRACT FROM AUTHOR]

Background Early menarche is linked to higher incidence of adult asthma, suggesting that earlier puberty may influence type 2 immune response characteristics of allergic diseases. We examined the hypothesis that timing of breast and pubic hair development, which precede menarche, is associated with increased childhood atopic conditions. Methods Girls were enrolled at 6-8 yr of age (2004-2007) in the Breast Cancer and the Environment Research Program Puberty Study and were followed through 2011. Pubertal stages were assessed and atopic conditions were queried annually. Associations of age at pubertal stage 2 for breast or pubic hair development with atopic conditions were assessed using prevalence ratios ( PR) or odds ratios (OR) and 95% confidence intervals ( CI) from log-binomial regression and generalized estimating equation models, controlling for body mass index and other covariates. A total of 1055 girls with medical and pubertal stage data were included. Results Asthma (ever vs. never) was associated with younger pubarche (≤10 vs. >10 yr, PR = 1.15, CI: 1.04-1.28 adjusted for race/ethnicity and site; PR = 1.13, CI: 1.01-1.25 further adjusted for BMI), but not thelarche. In longitudinal models, risk of developing allergies increased with younger age at pubarche (adjusted OR = 1.60, CI: 1.10-2.34; ≤10 vs. >10 yr). Risks were highest among black girls with earlier pubarche (n = 248/326); for allergies, their fully adjusted OR was 2.35, CI: 1.06-5.19 for pubarche ≤10 vs. >10 yr. Conclusions Atopic conditions during childhood are associated with younger age at pubarche, independent of obesity, and these relationships may vary by racial/ethnic groups. [ABSTRACT FROM AUTHOR]

SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2 -silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells. [ABSTRACT FROM AUTHOR]