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Background: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients., Methods: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded., Results: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217)., Conclusions: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration., Trial Registration: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892., (© 2024. The Author(s).)

Background: Although the traditional contingent screening strategy is effective, there are still undetected low-risk trisomy 21. This study aims to define appropriate cut-off values of serum biochemical markers at low-risk and develop a strategy for sequential prenatal testing associated with first-trimester screening to increase the detection rate of trisomy 21., Methods: This was a 9-year retrospective analysis of singleton pregnant women who underwent serum biochemical screening or combined first-trimester screening (CFTS) in the first trimester. For the low-risk group, the cut-off values of the serum biochemical markers were adjusted to determine the appropriate detection efficiency. Gravidas with abnormal serum biochemical markers at low-risk were advised to undergo further non-invasive prenatal screening (NIPS), whereas others continued with routine prenatal care., Results: When cut-off values of free beta subunit of human chorionic gonadotropin (free β-hCG) multiples of the median (MoM) or pregnancy-associated plasma protein A (PAPP-A) MoM were defined with ≥ 2.75 or ≤ 0.5, 7.72% (2,194/28,405) in the serum biochemical screening group and 12.36% (4,005/32,403) in CFTS group could be detected as abnormal results for further NIPS. Finally, 55.56% (5/9) and 85.71% (6/7) of trisomy 21 cases with false-negative results were detected, and the overall detection rate for trisomy 21 was improved by 10.64% (5/47) and 12.77% (6/47), respectively., Conclusions: The new contingent screening strategy can increase the detection rate of trisomy 21 compared with the traditional contingent screening strategy., (© 2023. The Author(s).)

During the service period, asphalt materials are affected by various natural factors, including heat, ultraviolet light, oxygen and moisture, etc., resulting in the reduction of pavement performance, the increase of pavement distress and shortening of service life. This study aims to investigate the aging performance of asphalt under multiple aging conditions of heat, UV and aqueous solution. Thermal-oxygen aging, UV aging and hydrostatic erosion tests were carried out sequentially on asphalt. The rheological properties, chemical structure and element composition of asphalt were characterized before and after aging, and the effect mechanism of multiple conditions was discussed. The results show that the multiple conditions of heat and UV can increase the rutting resistance and weaken the cracking resistance of asphalt. However, the effect degree of UV decreases gradually with the deepening of aging degree. Additionally, the effect of water on the physicochemical properties is less than that of UV; however, water can increase the sensitivity of physicochemical properties to UV. In summary, this study explored the short-term cycling effect of heat, light and water on asphalt and provided an idea for simulation test of asphalt under multiple aging condition.

Background: Studies have shown that lymphocyte dysfunction can occur during the early stages of sepsis and that cell dysfunction is associated with mitochondrial dysfunction. Therefore, quantifying the mitochondrial function of lymphocytes in patients with sepsis could be valuable for the early diagnosis of sepsis., Methods: Seventy-nine patients hospitalized from September 2020 to September 2021 with Sepsis-3 were retrospectively analyzed and subsequently compared with those without sepsis., Results: Univariate analysis showed statistical differences between the data of the two groups regarding age, neutrophil/lymphocyte, procalcitonin (PCT), C-reactive protein, total bilirubin, serum creatinine, type B natriuretic peptide, albumin, prothrombin time, activated partial thromboplastin time, lactic acid, single-cell mitochondrial mass (SCMM)-CD3, SCMM-CD4, SCMM-CD8, and Acute Physiology and Chronic Health Evaluation II score ( P < 0.05). Multivariate logistic regression analysis performed on the indicators mentioned above demonstrated a statistical difference in PCT, lactic acid, SCMM-CD4, and SCMM-CD8 levels between the two groups ( P < 0.05). The receiver operating characteristic curves of five models were subsequently compared [area under the curve: 0.740 (PCT) vs. 0.933 (SCMM-CD4) vs. 0.881 (SCMM-CD8) vs. 0.961 (PCT + SCMM-CD4) vs. 0.915 (PCT+SCMM-CD8), P < 0.001]., Conclusion: SCMM-CD4 was shown to be a better diagnostic biomarker of early sepsis when compared with the traditional biomarker, PCT. Furthermore, the value of the combination of PCT and SCMM-CD4 in the diagnosis of early sepsis was better than that of SCMM-CD4 alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pang, Cai, Chen, Fu, Xia, Li and Li.)

Objective: To evaluate whether sirolimus treatment could relieve the later burden of new-onset seizures in patients with tuberous sclerosis complex (TSC) prior to epilepsy., Methods: A real-world matched case-control study was nested in another registry cohort study. Infants with TSC (<12 months old) without seizures whose parents agreed on sirolimus treatment for other symptoms were eligible for inclusion to the early sirolimus (ES) group. These patients were enrolled from 2015 to 2018. Controls in the late sirolimus (LS) group were matched from the registry cohort database for 2015-2018. Age and genotype were used as the initial stratifying criteria and other symptoms as the greedy matching criteria at a matching ratio of 1:4. None of the preventive drugs were introduced before seizure onset or before 2 years of age in the LS group. Both groups were followed up until June 2020. The primary objective was a comparison of the characteristics of the first seizure between the two groups. The secondary objective was the assessment of the final seizure status at the endpoint., Results: There were 42 and 168 patients with TSC in the ES and LS groups, respectively. Early sirolimus treatment significantly reduced the seizure onset, especially in the patients aged <6 months. The mean onset-age was significantly delayed by sirolimus treatment (11.34±7.93 months vs. 6.94±6.03 months, P<0.001). The subtype of seizures that benefited the most was spastic (onset) seizures (all were infantile spasms) [5/42 (11.90%) vs. 73/168 (43.45%), P<0.001]; these seizures were either eliminated or alleviated. The sirolimus treatment addition prior to seizures was more effective than its addition after seizures in reducing drug-resistant epilepsy [10/42 (23.81%) vs. 70/147 (47.62%), P=0.004]., Conclusion: Early sirolimus treatment for TSC effectively modified the disease by preventing infantile spasms, delaying seizure onset, and relieving its severity. The anti-epileptogenic effect of sirolimus may be time- and dose-dependent., (Copyright © 2022. Published by Elsevier Ltd.)

Objectives: Recurrent bacterial meningitis (RBM) is a rare but life-threatening disease. This study aims to analyze the clinical features, potential causes, and therapeutic outcomes of RBM in children., Methods: This article retrospectively reviews the clinical characteristics, etiologies, and treatments in children with RBM hospitalized in Hebei children's hospital from 2012 to 2020., Results: A total of 10 children with RBM, five males and five females, were included in this study. The age of RBM in children spans from the neonatal stage to the childhood stage. The underlying illnesses were identified and classified as cerebrospinal fluid rhinorrhea (1 case), humoral immunodeficiency with Mondini dysplasia (1 case), common cavity deformity with cerebrospinal fluid ear leakage (1 case), Mondini malformations (2 cases), incomplete cochlear separation type I with a vestibular enlargement (2 cases), local inflammation of the sphenoid bone caused by cellulitis (1 case), congenital skull base defects (1 case), and congenital dermal sinus with intraspinal abscess (1 case). 6 patients chose targeted therapy for potential reasons., Conclusions: Congenital abnormalities or acquired injuries lead to intracranial communication with the outside world, which can quickly become a portal for bacterial invasion of the central nervous system, resulting in repeated infections., Competing Interests: All the authors declare that they have no conflict of interest., (Copyright © 2022 Xin Li et al.)

The rate of decline in the levels of neutralizing antibodies (NAbs) greatly varies among patients who recover from Coronavirus disease 2019 (COVID-19). However, little is known about factors associated with this phenomenon. The objective of this study is to investigate early factors at admission that can influence long-term NAb levels in patients who recovered from COVID-19. A total of 306 individuals who recovered from COVID-19 at the Tongji Hospital, Wuhan, China, were included in this study. The patients were classified into two groups with high (NAb high , n = 153) and low (NAb low , n = 153) levels of NAb, respectively based on the median NAb levels six months after discharge. The majority (300/306, 98.0%) of the COVID-19 convalescents had detected NAbs. The median NAb concentration was 63.1 (34.7, 108.9) AU/mL. Compared with the NAb low group, a larger proportion of the NAb high group received corticosteroids (38.8% vs. 22.4%, p = 0.002) and IVIG therapy (26.5% vs. 16.3%, p = 0.033), and presented with diabetes comorbidity (25.2% vs. 12.2%, p = 0.004); high blood urea (median (IQR): 4.8 (3.7, 6.1) vs. 3.9 (3.5, 5.4) mmol/L; p = 0.017); CRP (31.6 (4.0, 93.7) vs. 16.3 (2.7, 51.4) mg/L; p = 0.027); PCT (0.08 (0.05, 0.17) vs. 0.05 (0.03, 0.09) ng/mL; p = 0.001); SF (838.5 (378.2, 1533.4) vs. 478.5 (222.0, 1133.4) μg/L; p = 0.035); and fibrinogen (5.1 (3.8, 6.4) vs. 4.5 (3.5, 5.7) g/L; p = 0.014) levels, but low SpO 2 levels (96.0 (92.0, 98.0) vs. 97.0 (94.0, 98.0)%; p = 0.009). The predictive model based on Gaussian mixture models, displayed an average accuracy of 0.7117 in one of the 8191 formulas, and ROC analysis showed an AUC value of 0.715 (0.657-0.772), and specificity and sensitivity were 72.5% and 67.3%, respectively. In conclusion, we found that several factors at admission can contribute to the high level of NAbs in patients after discharge, and constructed a predictive model for long-term NAb levels, which can provide guidance for clinical treatment and monitoring.

Introduction: A large number of COVID-19 patients are in recovery, and millions of people are vaccinated for COVID-19 globally. This calls for a rapid screening strategy of SARS-CoV-2 protective antibodies, generated in rehabilitated and vaccinated populations., Methods: Serum samples collected over a follow-up period of six months from 306 COVID-19 cases discharged from Wuhan Tongji Hospital were analyzed. Anti-S Abs were detected by colloidal gold immunochromatographic assay (GICA), and neutralizing antibodies (nAbs) were detected by chemiluminescent microparticle immunoassay (CMIA)., Results: Most COVID-19 survivors tested positive for anti-S Abs (83.7%) and nAbs (98.0%) 6 months after being discharged from the hospital, and the levels of anti-S Abs in the blood were highly positively correlated with nAbs (r = 0.652, P < 0.0001). The positivity rate of nAbs for patients with anti-S Abs positive was 100%., Conclusions: There is a good agreement between anti-S Abs detected by GICA and nAbs detected by CMIA. It indicates that anti-S Abs detected by GICA may be used as a cheaper screening strategy for detectable SARS-CoV-2 nAbs in COVID-19 convalescent individuals., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the prevalence of dysphagia among an older population and patients with stroke, head and neck cancers (HNCs) or neurodegenerative diseases (NDDs) in China, to identify the factors associated with this condition, and to explore the relationship between dysphagia and nutritional status., Methods: This study included participants 65 years and older living in the community or in nursing homes and patients who had sustained a stroke, HNC, or NDD also recruited in hospitals from 14 provinces of China. The presence of dysphagia was determined by use of a questionnaire, water swallowing test, and/or a videofluoroscopic swallowing study. Logistic regression analysis was used to assess the possible associated risk factors. Body mass index was assessed as an indicator of malnutrition., Results: A total of 5943 persons met the inclusion criteria and 2341 (39.4%) were identified with dysphagia, including the following: 51.14% of patients with stroke, 34.4% in HNCs, 48.3% in NDDs, and 19.2% of otherwise healthy older adults. The elderly with comorbidity (OR = 2.90, p < 0.01) and stroke patients (OR = 2.27, p < 0.01) were significantly more likely to exhibit signs of dysphagia. Dysphagic participants were at significantly greater risk of malnutrition (OR = 1.91, p < 0.01) compared to those without dysphagia., Conclusion: Dysphagia is prevalent in China among older individuals and people who have suffered a stroke, HNCs, or NDDs. The prevalence of dysphagia increases steadily with increasing age and presence of comorbid disease. People with dysphagia are more likely to suffer from malnutrition.

Objectives: To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups., Study Design: The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described., Results: A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis., Conclusions: Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Myocardial ischemia-reperfusion injury (MIRI) is the main pathological manifestation of cardiovascular diseases such as myocardial infarction. The potential therapeutic effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) and the participation of regulatory T cells (Tregs) in MIRI remains to be defined., Methods: We used the experimental acute MIRI that was induced in mice by left ascending coronary ischemia, which were subsequently randomized to receive immunoglobulin G (IgG) or anti-CD25 antibody PC61 with or without intravenously injected BM-MSCs. The splenectomized mice underwent prior to experimental MIRI followed by intravenous administration of BM-MSCs. At 72 h post-MIRI, the hearts and spleens were harvested and subjected to cytometric and histologic analyses., Results: CD25 + Foxp3 + regulatory T cells were significantly elevated after MIRI in the hearts and spleens of mice receiving IgG + BM-MSCs and PC61 + BM-MSCs compared to the respective control mice (all p < 0.01). This was accompanied by upregulation of interleukin 10 and transforming growth factor β1 and downregulation of creatinine kinase and lactate dehydrogenase in the serum. The post-MIRI mice receiving BM-MSCs showed attenuated inflammation and cellular apoptosis in the heart. Meanwhile, splenectomy compromised all therapeutic effects of BM-MSCs., Conclusion: Administration of BM-MSCs effectively alleviates MIRI in mice through inducing Treg activation, particularly in the spleen.

To discuss combinations of traditional screening and noninvasive prenatal screening (NIPS) and to compare which traditional screening is the most suitable first-line screening approach to NIPS, pregnant women were recruited in this retrospective observational study. Pregnant women underwent one of four traditional screening tests. The 9 contingent models were combined by high risk cut-offs of 1:50, 1:100, 1:270 and intermediate risk cut-offs of 1:1000, 1:1500, 1:2000. We analyzed cost and performance of various screening models with contingent screening of different risk cut-offs. Compared with other screening tests, combined first-trimester screening (CFTS) had the lowest proportion of high risk (≥1:270) with the highest detection rate (DR) (78.79%) and the lowest proportion of intermediate risk (1:271~1:1000). When intermediate risk was 1:51 ~1:1500, CFTS as first-line screening had the lowest cost with DR of 93.94%. Other screening tests as the first-line screening with intermediate risk of 1:51~1:1000 had the lowest cost, there DR were 90.91%, 84.62%, 91.67%, respectively. Our study demonstrated if only one traditional screening was allowed to screen pregnant women, CFTS was recommended as the first choice. According to local health and economic conditions, adopting appropriate traditional screening with suitable cut-offs as first-line screening will contributed to a cost-effective screening model.

Objective: To compare the effect of different first-trimester screening programmes for Down syndrome in Sichuan Province., Methods: We retrospectively collected the data of singleton pregnancies that were screened by serum biochemistry markers combined with nuchal translucency screening tests in the first trimester in Prenatal Diagnosis Center of West China Second University Hospital of Sichuan University from January 2011 to December 2017. The fetal chromosome results were obtained by amniocentesis or by telephone follow-up. The screening effect of maternal age, nuchal translucency thickness, maternal serum biochemistry markers and combined screening in the first trimester were analyzed., Results: Among the 21 723 singleton pregnancies, 33 cases were diagnosed as Down syndrome, and 19 cases were diagnosed as trisomy 18 sex chromosome abnormalities were found in 4 cases, and other chromosome abnormalities were found in 8 cases. For the combined screening, the detection rate of Down syndrome was 72.73%, and the false positive rate was 2.49%; the detection rate of trisomy 18 syndrome was 73.68% with the false positive rate of 0.39%. With a 5% false positive rate, maternal age, nuchal translucency thickness, serum biochemistry markers and combined screening would respectively detect 15.15%, 57.58%, 60.61% and 87.88% of Down syndrome fetuses., Conclusion: Compared with the other three screening programmes, the combined screening can effectively screen fetuses with Down syndrome and other chromosomal abnormalities., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Purpose: To evaluate the associations between BADL/IADL disability and depressive symptoms from the perspective of gender among older adults in China., Methods: This cross-sectional study used the data from the second wave of the China Health and Retirement Longitudinal Study (CHARLS). The sample included 3463 older adults aged 60 years and older across China. Multivariable logistic regression models were conducted., Results: Among 3463 older adults, 1240 (35.8%) were classified as depressed, the prevalence of BADL and IADL disabilities were 756 (21.8%) and 1194 (34.5%), respectively. After controlling for covariates, BADL/IADL disability was significantly associated with an increased risk of depression prevalence both in men and women among older adults. Compared with IADL independent, IADL disability was about two times more likely to develop depressive symptoms in men (OR = 2.165, 95% CI = 1.661-2.822), which was much higher than that in women (OR = 1.748, 95% CI = 1.415-2.160). In contrast, the odds of being depressed for women with BADL disability (OR = 1.824, 95% CI = 1.447-2.299) were much higher than the odds for men with BADL disability (OR = 1.791, 95% CI = 1.348-2.379)., Conclusions: Older adults with BADL/IADL disability were more likely to have depressive symptoms both for men and women. However, the associations between depressive symptoms and BADL/IADL disability were different in gender. Our results suggest that differential institutional care service and appropriate strategies for improvement in mental health are required., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: To explore the application effects of whole course high-quality nursing on patients with liver cancer during radiotherapy., Methods: One hundred and five patients with liver cancer who received radiotherapy in Liaocheng People's Hospital, Liaocheng, China from March 2010 to February 2012 were selected and divided into a control group (42 cases with routine nursing) and an experimental group (63 cases with whole course high-quality nursing). The two groups of patients were observed and compared in terms of clinical data and the Activity of Daily Living (ADL) score before and after nursing (1 course of treatment/6 week). The Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used to evaluate and compare the patients' anxiety and depression before and after nursing. Adverse reactions during radiotherapy and nursing satisfactory of patients were observed and compared between the two groups., Results: After nursing, the ADL score and the nursing satisfaction in the experimental group was significantly higher than that in the control group ( P <0.05). The SDS and SAS scores in the 2 groups before nursing were significantly higher than those after nursing ( P <0.05). The total incidence of adverse reactions in the control group was significantly higher than that in the experimental group ( P <0.05)., Conclusion: Whole course high-quality nursing can improve the negative emotions, quality of life and nursing satisfaction, and reduce adverse reactions of patients with liver cancer during radiotherapy., (Copyright© Iranian Public Health Association & Tehran University of Medical Sciences.)

Breast cancer (BC) has a complex etiology and pathogenesis, and is the most common malignant tumor type in females, in USA in 2018, yet its relevant molecular mechanisms remain largely unknown. The collagen type V α‑1 chain (COL5A1) gene is differentially expressed in renal and ovarian cancer. Using bioinformatics methods, COL5A1 was determined to also be a significant gene in BC, but its association with BC has not been sufficiently reported. COL5A1 microarray and relevant clinical data were collected from the Gene Expression Omnibus, The Cancer Genome Atlas and other databases to summarize COL5A1 expression in BC and its subtypes at the mRNA and protein levels. All associated information was comprehensively analyzed by various software. The clinical significance of the mutation was obtained via the cBioPortal. Furthermore, Gene Ontology functional annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were also performed to investigate the mechanism of COL5A1 in BC. Immunohistochemistry was also conducted to detect and confirm COL5A1 expression. It was determined that COL5A1 was highly expressed in BC tissues, compared with normal tissues at the mRNA level [standard mean difference, 0.84; 95% confidence interval (CI), 0.60‑1.07; P=0.108]. The area under the summary receiver operator characteristic curve for COL5A1 was 0.87 (95% CI, 0.84‑0.90). COL5A1 expression was altered in 32/817 (4%) sequenced samples. KEGG analysis confirmed the most notable pathways, including focal adhesion, extracellular matrix‑receptor interaction and regulation of the actin cytoskeleton. Immunohistochemical detection was used to verify the expression of COL5A1 in 136 selected cases of invasive BC tissues and 55 cases of adjacent normal tissues, while the rate of high expression of COL5A1 in BC was up to 90.4%. These results indicated that COL5A1 is highly expressed at the mRNA and protein levels in BC, and the prognosis of patients with BC with high COL5A1 expression may be reduced; therefore, COL5A1 may be used independently or combined with other detection factors in BC diagnosis.

When a fire occurs in a tunnel, the instantaneous high temperature and smoke cause great danger to people. Therefore, the asphalt pavement material in the tunnel must have sufficient fire resistance. In this study, the effects of aluminum hydroxide and layered double hydroxide on the fire resistance of styrene-butadiene-styrene (SBS) polymer-modified asphalt was investigated. The fire resistance of the asphalt was evaluated by using a limiting oxygen index (LOI). The impact of aluminum hydroxide (ATH), layered double hydroxide (LDHs), and mixed flame retardant (MFR) on LOI was studied. The synergistic fire resistance mechanism of ATH and LDHs in asphalt binder was analyzed by using an integrated thermal analyzer‒mass spectrometry combined system (TG-DSC-MS) and Fourier transform infrared spectrometer (FTIR). The experimental results indicated that the main active temperature range of these flame retardants was 221⁻483 °C. The main components of smoke were methane, hydroxyl, water, carbon monoxide, aldehyde, carbon dioxide, etc. The addition of flame retardants could inhibit the production of methane, carbon monoxide, and aldehyde. Moreover, due to the good synergistic effects of ATH and LDHs, 20 wt % MFR had the best fire resistance.

Purpose: Tuberous sclerosis (TSC) is an autosomal dominant inherited disease caused by mutations in the TSC1 or TSC2 gene and results in the over-activation of the mammalian target of the rapamycin (mTOR) signaling pathway. Rapamycin, an mTOR inhibitor, is clinically used to treat hamartomatous lesionsas in TSC and its effect on controlling epilepsy is also reported in many studies. This study aims to evaluate the risk factors of pharmacoresistant epilepsy in patients with TSC receiving long-term rapamycin treatment., Method: A total of 108 patients with TSC taking rapamycin for over 1 year were enrolled in this study. Factors that might influence seizure control were statistically analyzed by multiple factor analysis. A subgroup analysis was also conducted to access the relationship between calcified epileptic foci and pharmacoresistant epilepsy. (Clinical trial registration number: ChiCTR-OOB-15006535(2015-05-29))., Results: Seizure was controlled in 53 patients but was not managed in 55 patients considered to be drug resistant. Logistic regression analysis showed that calcification in the cerebral parenchyma was a risk factor of pharmacoresistant epilepsy [P = 0.006, odds ratio (OR) = 4.831 (1.577, 14.795)]. Fifteen of 17 patients with calcified epileptic foci suffered from pharmacoresistant epilepsy (88.2%). Seizures in patients with calcified epileptic foci were probably pharmacoresistant (P = 0.010)., Conclusion: Calcification in epileptic foci strongly indicates pharmacoresistant epilepsy in patients with TSC even when treated with appropriate anti-epilepsy drugs (AEDs) and rapamycin. Calcification can be used to evaluate pharmacoresistant epilepsy in patients with TSC., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The properties of asphalt pavement are damaged under the effects of moisture. The pH value and salt concentration of water are the key factors that affect the chemical and rheological properties of asphalt during moisture damage. Four kinds of water solutions, including distilled water, an acidic solution, alkaline solution and saline solution were used to investigate the effects of aqueous solute compositions on the chemical and rheological properties of asphalt. Thin-layer chromatography with flame ionization detection (TLC-FID), Fourier transform infrared (FTIR) spectroscopy and dynamic shear rheometer (DSR) were applied to investigate the components, chemistry and rheology characteristics of asphalt specimens before and after water solute exposure. The experimental results show that moisture damage of asphalt is not only associated with an oxidation process between asphalt with oxygen, but it is also highly dependent on some compounds of asphalt dissolving and being removed in the water solutions. In detail, after immersion in water solute, the fraction of saturates, aromatics and resins in asphalt binders decreased, while asphaltenes increased; an increase in the carbonyl and sulphoxide indices, and a decrease in the butadiene index were also found from the FTIR analyzer test. The rheological properties of asphalt are sensitive to water solute immersing. The addition of aqueous solutes causes more serious moisture damage on asphalt binders, with the pH11 solution presenting as the most destructive during water solute exposure.

Diatomite is an inorganic natural resource in large reserve. This study consists of two phases to evaluate the effects of diatomite on asphalt mixtures. In the first phase, we characterized the diatomite in terms of mineralogical properties, chemical compositions, particle size distribution, mesoporous distribution, morphology, and IR spectra. In the second phase, road performances, referring to the permanent deformation, crack, fatigue, and moisture resistance, of asphalt mixtures with diatomite were investigated. The characterization of diatomite exhibits that it is a porous material with high SiO₂ content and large specific surface area. It contributes to asphalt absorption and therefore leads to bonding enhancement between asphalt and aggregate. However, physical absorption instead of chemical reaction occurs according to the results of FTIR. The resistance of asphalt mixtures with diatomite to permanent deformation and moisture are superior to those of the control mixtures. But, the addition of diatomite does not help to improve the crack and fatigue resistance of asphalt mixture.

Rationale: Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by multiple venous malformations. The gastrointestinal bleeding and secondary iron deficiency anemia are the most common complications. There are currently no effective treatments for BRBNS. Here, we report a case of successful treatment with a small dose of sirolimus of a BRBN patient with a de novo gene mutation., Patient Concerns: A 12-year-old female was admitted to our hospital with multiple hemangiomas for 12 years. The patient often displayed melena; she recently received transfusion of 2 units of red blood cells once every 2 weeks. Multiple fist-sized hemangiomas were piled up on both sides and back of the neck, and were also noted on the arms, legs, chest, back, and on the tip of the tongue. The laboratory findings demonstrated severe anemia. Blood sample sequencing detected a heterozygous de novo mutation c.2545C > Tin the TEK gene., Diagnoses: Based on these findings, final diagnosis of Blue rubber bleb nevus syndrome (BRBNS) was made., Interventions: After the diagnosis, low-dose sirolimus was orally administered., Outcomes: The patient's hemoglobin was increased after treatment with sirolimus for 1 month. Since the initial treatment with sirolimus, she had not received any blood transfusions. The skin and mucosal hemangioma decreased significantly, and new digestive tract hemorrhage, muscle hematoma, or adverse drug reactions were not observed., Lessons: we report a case of a mutation in exon 15 of the TEK gene leading to BRBN. It was successfully treated with a small dose of sirolimus as an alternative to blood transfusion in order to save the of BRBN patient's life.

The novel obesity-associated protein Phosphotyrosine Interaction Domain containing 1 (PID1) inhibits insulin-PI3K/Akt signaling pathway and insulin-stimulated glucose uptake in vitro. In this study, we generated fat tissue-specific aP2-PID1 transgenic (aP2-PID1 tg ) mice and PID1 knockout (PID1 -/- ) mice to explore how PID1 affects glucose metabolism in vivo. We observed insulin resistance and impaired insulin-PI3K/Akt signaling in aP2-PID1 tg mice. Consistent with these data, the PID1 -/- mice displayed improved glucose tolerance and insulin sensitivity under chow diet, with increased Akt phosphorylation in white adipose tissue (WAT). We further demonstrated that PID1 could interact with low density lipoprotein receptor-related protein 1 (LRP1) but not the insulin receptor (IR) in adipocytes, and its overexpression could lead to decreased GLUT4 level. Our results thus indentify PID1 as a critical regulator of glucose metabolism in adipocytes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mental retardation (MR) is one of the most common cognitive comorbidities in children with tuberous sclerosis, and there are enormous studies about its risk factors. The genetic difference and the severity of epilepsy are the two main factors, but their weight in the occurrence of MR is still unclear. Two hundred twenty-three patients with tuberous sclerosis who received intelligence assessment, genetic mutation analysis, and the epilepsy severity assessment were included in our study. Genotype-neurocognitive phenotype correlations and epilepsy-neurocognitive phenotype correlations were analyzed by binary logistic regression analysis. No statistical significant result was found on genotype-neurocognitive phenotype correlations, which contrasted the previous report. The prevalence of MR was 50.0% for the patients with tuberous sclerosis complex-1 (TSC1) mutation, 54.5% for TSC2 (p=0.561), 54.7% for patients with protein-truncating (PT) and 50.0% for patients with nontruncating (NT) (p=0.791), and 54.3% for patients with family history and 53.7% for patients without family history (p=0.748). Statistical significant results were found on epilepsy-neurocognitive phenotype correlations, both on E-chess score (p=0.01) and the occurrence of infantile spasms (p=0.014), which was consistent to the previous study. For children with tuberous sclerosis, instead of genetic factors, epilepsy may play the main role for the presence of mental retardation. Patients with mental retardation tend to have earlier seizure attack, take more AEDs, have more seizure types, and have higher seizure frequency. Among the four cognitive functions in Denver II, social ability and language ability are more vulnerable to be influenced than fine and gross motor ability., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: Pulmonary arterial hypertension (PAH), a deadly disorder is associated with excessive growth of human pulmonary artery endothelial (HPAECs) and smooth muscle (HPASMCs) cells. Current therapies primarily aim at promoting vasodilation, which only ameliorates clinical symptoms without a cure. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous aryl hydrocarbon receptor (AhR) ligand, and mediates many cellular function including cell growth. However, the roles of ITE in human lung endothelial cells remain elusive. Herein, we tested a hypothesis that ITE inhibits growth of human pulmonary artery endothelial cells via AhR., Materials and Methods: Immunohistochemistry was performed to localize AhR expression in human lung tissues. The crystal violet method and MTT assay were used to determine ITE's effects on growth of HPAECs. The AhR activation in HPAECs was confirmed using Western blotting and RT-qPCR. The role of AhR in ITE-affected proliferation of HPAECs was assessed using siRNA knockdown method followed by the crystal violet method., Results: Immunohistochemistry revealed that AhR was present in human lung tissues, primarily in endothelial and smooth muscle cells of pulmonary veins and arteries, as well as in bronchial and alveolar sac epithelia. We also found that ITE dose- and time-dependently inhibited proliferation of HPAECs with a maximum inhibition of 83% at 20 µM after 6 days of treatment. ITE rapidly decreased AhR protein levels, while it increased mRNA levels of cytochrome P450 (CYP), family 1, member A1 (CYP1A1) and B1 (CYP1B1), indicating activation of the AhR/CYP1A1 and AhR/CYP1B1 pathways in HPAECs. The AhR siRNA significantly suppressed AhR protein expression, whereas it did not significantly alter ITE-inhibited growth of HPAECs., Conclusions: ITE suppresses growth of HPAECs independent of AhR, suggesting that ITE may play an important role in preventing excessive growth of lung endothelial cells.

Background: Acute autonomic neuropathy (AAN) is rare disorder with anecdotal report, especially for childhood onset patients. Misdiagnosis or delays in treatment can always be found in clinical practice. We conducted this study to give a description of the manifestations and treatment of AAN in children and therefore help clinicians to make the accurate diagnosis early so that the prognosis of the patients can be improved., Methods: A systematic record from 3 clinical centers was used to identify 11 subject, 3 males and 8 females, with clinical diagnosed AAN., Result: The age ranged from 2 years and 4 months to 14 years and 6 months (mean, 9 ± 3.6 years old) and the course from onset to diagnosis ranged from 7 days to 8 months. All children shared prominent initial symptoms, 7 with frequent vomiting and 4 with motor dysfunctions. The condition of 9 patients improved after treatment of IVIg and intravenous glucocorticoid., Conclusion: The clinical manifestations of AAN are diverse, generalized, and non-specific. Gastrointestinal disorders were the most common initial symptoms. Symptoms of gastrointestinal system and abnormal secretion of glands were severe and more common than other symptoms. The mechanism of AAN remains unknown. Although IVIg and intravenous glucocorticoid can be used in clinical practice, there is still no treatment recommendation and further study is needed.

SBS (styrene-butadiene-styrene block copolymer) modified bitumen is one of most widely used polymer modified bitumens in China. It is also not satisfactory when subjected to extreme conditions. Multiple-walled carbon nanotubes, as a type of advanced nanomaterial, are investigated extensively because of their strong adsorption capacity. Little research has been done about MWCNTs/SBS modified bitumen, and in view of this, the performance and modification mechanism of MWCNTs/SBS modified bitumen was investigated in this paper. Conventional bitumen tests, Brookfield viscosity, bending beam rheometer, and dynamic shear rheometer tests showed improved performance at high and low temperature. The optimum MWCNTs content was determined as 1.0%. FT-IR, bitumen four components, and thermal analysis tests were conducted and revealed that the addition of MWCNTs led to a decrease in the content of light components. In addition, the rate of decomposition and volatilization of saturates and aromatics was reduced and better thermal stability of bitumen was found. Fluorescence microscopy tests showed that MWCNTs improved the dispersion of SBS and storage stability of the binder. Finally a schematic was proposed to explain how MWCNTs improved the performance of SBS modified bitumen through their strong adsorption property created by π-π intermolecular forces.

[Purpose] This study examined the measurement of the thickness of the transverse abdominal muscle in different tasks. [Subjects and Methods] The subjects were eleven healthy adult females. Thicknesses of transverse abdominal muscle were measured in seven tasks in the supine position. The tasks were: 1) Resting state, 2) Maximal contraction of transverse abdominal muscle, 3) Maximal contraction of levator ani muscle, 4) Maximal simultaneous contraction of both transverse abdominal muscle and levator ani muscle, 5) Maximal simultaneous contraction of both transverse abdominal muscle and levator ani muscle with front side resistance added to both knee, 6) Maximal simultaneous contraction of both transverse abdominal muscle and levator ani muscle with diagonal resistance added to both knees, and 7) Maximal simultaneous contraction of both transverse abdominal muscle and levator ani muscle with lateral resistance added to both knees. [Results] The thicknesses of transverse abdominal muscle during maximal simultaneous contraction and maximal simultaneous contraction with resistance were greater than during the resting state. [Conclusion] The muscle output during simultaneous contraction and resistance movement were larger than that of each individual muscle.

In the advanced research fields of solar cell and energy storing materials, graphene and graphene oxide (GO) are two of the most promising materials due to their high specific surface area, and excellent electrical and physical properties. However, they was seldom studied in the traditional materials because of their high cost. Nowadays, graphene and GO are much cheaper than before with the development of production technologies, which provides the possibility of using these extraordinary materials in the traditional construction industry. In this paper, GO was selected as a nano-material to modify two different asphalts. Then a thin film oven test and a pressure aging vessel test were applied to simulate the aging of GO-modified asphalts. After thermal aging, basic physical properties (softening point and penetration) were tested for the samples which were introduced at different mass ratios of GO (1% and 3%) to asphalt. In addition, rheological properties were tested to investigate how GO could influence the asphalts by dynamic shearing rheometer tests. Finally, some interesting findings and potential utilization (warm mixing and flame retardants) of GO in asphalt pavement construction were explained.

In cancer drug discovery, it is important to investigate the genetic determinants of response or resistance to cancer therapy as well as factors that contribute to adverse events in the course of clinical trials. Despite the emergence of new technologies and the ability to measure more diverse analytes (e.g., circulating tumor cell (CTC), circulating tumor DNA (ctDNA), etc.), tumor tissue is still the most common and reliable source for biomarker investigation. Because of its worldwide use and ability to preserve samples for many decades at ambient temperature, formalin-fixed, paraffin-embedded tumor tissue (FFPE) is likely to be the preferred choice for tissue preservation in clinical practice for the foreseeable future. Multiple analyses are routinely performed on the same FFPE samples (such as Immunohistochemistry (IHC), in situ hybridization, RNAseq, DNAseq, TILseq, Methyl-Seq, etc.). Thus, specimen prioritization and optimization of the isolation of analytes is critical to ensure successful completion of each assay. FFPE is notorious for producing suboptimal DNA quality and low DNA yield. However, commercial vendors tend to request higher DNA sample mass than what is actually required for downstream assays, which restricts the breadth of biomarker work that can be performed. We evaluated multiple genomics service laboratories to assess the current state of NGS pre-analytical processing of FFPE. Significant differences in pre-analytical capabilities were observed. Key aspects are highlighted and recommendations are made to improve the current practice in translational research., Competing Interests: The authors declare no conflict of interest. The authors are all Merck employees.

Aims: In this paper, the effect of the size gradations of basic oxygen furnace (BOF) slag on the functional performances of stone mastic asphalt (SMA) mixture including skid and deformation resistances was investigated., Methods: The industrially produced BOF slag coarse aggregates (BSCA) with size gradations of 4.75-9.5 mm and 9.5-16 mm were used. SMA mixtures were designed according to Marshall procedure. British pendulum number (BPN), indicating the skid resistance of asphalt mixture, was measured by a British pendulum skid resistance device. Flow number (FN) and Marshall quotient (MQ), reflecting the deformation resistance of asphalt mixture, were determined, respectively, based on the results of dynamic creep test and Marshall test (stability and flow value)., Results: Showed that BSCA with a size gradation of 9.5-16 mm performed better in improving the skid and deformation resistance of SMA mixture than BSCA with a size gradation of 4.75-9.5 mm. Furthermore, BSCA with combined size gradations, namely, 4.75-16 mm, worked the best., Conclusions: These conclusions would benefit the future extensive utilization of BSCA in asphalt pavement.

Tetrandrine is a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra, a traditional Chinese herbal medicine, which has been observed to exert anti‑inflammatory effects. The aim of the current study was to investigate whether tetrandrine was able to ameliorate sevoflurane‑induced cognitive impairment in aged rats. Male 20‑month‑old Sprague‑Dawley rats underwent sevoflurane‑induction in an environment containing 2% sevoflurane for 5 h. The Morris water maze test was used to measure the effect of tetrandrine on learning and memory in sevoflurane‑treated aged rats. Western blot analysis of the protein expression levels of cyclooxygenase‑2 (COX‑2), inducible nitric oxide synthase (iNOS) and Bcl‑2 was conducted. ELISAs were used to measure the levels of interleukin (IL)‑1β, tumor necrosis factor (TNF‑α), nuclear factor‑κB (NF‑κB) and caspase‑3. In the present study, tetrandrine improved the learning and memory deficits observed in sevoflurane‑treated aged rats. Treatment with tetrandrine reduced the expression levels of COX‑2, IL‑1β, TNF‑α, NF‑κB, iNOS and caspase‑3, and increased the Bcl‑2 protein expression in sevoflurane‑treated aged rats. In conclusion, the current study indicated that tetrandrine ameliorates sevoflurane‑induced cognitive impairment via the suppression of inflammation and apoptosis in aged rats. Thus, tetrandrine may be a potential novel candidate to protect against the effects of sevoflurane anesthesia on cognitive function.

Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. Several independent studies suggest that higher non-synonymous mutational burden assessed by whole exome sequencing (WES) in tumors is associated with improved objective response, durable clinical benefit, and progression-free survival in immune checkpoint inhibitors treatment. Next-generation sequencing (NGS) is a promising technology being used in the clinic to direct patient treatment. Cancer genome WES poses a unique challenge due to tumor heterogeneity and sequencing artifacts introduced by formalin-fixed, paraffin-embedded (FFPE) tissue. In order to evaluate the data interoperability of WES data from different sources to survey tumor mutational landscape, we compared WES data of several tumor/normal matched samples from five commercial vendors. A large data discrepancy was observed from vendors' self-reported data. Independent data analysis from vendors' raw NGS data shows that whole exome sequencing data from qualified vendors can be combined and analyzed uniformly to derive comparable quantitative estimates of tumor mutational burden.

Diurnal frequent urination is a common condition in elementary school children who are especially at risk for associated somatic and behavioral problems. Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that has been used in both partial and generalized seizures and less commonly adverse effects including psychiatric and behavioral problems. Diurnal frequent urination is not a well-known adverse effect of LEV. Here, we reported 2 pediatric cases with epilepsy that developed diurnal frequent urination after LEV administration. Case 1 was a 6-year-old male patient who presented urinary frequency and urgency in the daytime since the third day after LEV was given as adjunctive therapy. Symptoms increased accompanied by the raised dosage of LEV. Laboratory tests and auxiliary examinations did not found evidence of organic disease. Diurnal frequent urination due to LEV was suspected, and then the drug was discontinued. As expected, his frequency of urination returned to normal levels. Another 13-year-old female patient got similar clinical manifestations after oral LEV monotherapy and the symptoms became aggravated while in stress state. Since the most common causes of frequent micturition had been ruled out, the patient was considered to be diagnosed with LEV-associated psychogenic frequent urination. The dosage of LEV was reduced to one-third, and the frequency of urination was reduced by 60%. Both patients got the Naranjo score of 6, which indicated that LEV was a "probable" cause of diurnal frequent urination. Although a definite causal link between LEV and diurnal urinary frequency in the 2 cases remains to be established, we argue that diurnal frequent urination associated with LEV deserves clinician's attention.

Two novel porous luminescent metal-organic frameworks (MOFs, 1 and 2) have been constructed using 3,4-di(3,5-dicarboxyphenyl)phthalic acid using a hydrothermal method. Both MOFs can work as highly sensitive sensors to Fe(3+) by luminescent quenching. Analyses of the structures indicate a higher quenching efficiency of 2 because of the existence of active -COOH groups. Based on this consideration, the quenching mechanisms are studied and the processes are controlled by multiple mechanisms in which dynamic and static mechanisms of MOFs are discussed. Besides, the corresponding dynamic and static quenching constants are calculated, achieving the quantification evaluation of the quenching process. As expected, experimental data show that compound 2 possesses an overall quenching efficiency 6.9 times that of compound 1. Additionally, time-dependent intensity measurements, the shifts of the excitation spectrum and the appearance of a new emission peak all give visual proofs of the distinct mechanisms between the two MOFs.

Brown adipose tissue (BAT) functions to dissipate energy in response to cold exposure or overfeeding. Counteracting obesity has been extensively considered as a promising target. Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. However, the potential biological functions of lncRNAs during mouse brown fat cell differentiation have not been fully understood. Here, we performed lncRNA and mRNA expression profile analysis using microarray technology and identified 1064 lncRNAs with differential expression (fold change| ≥4, p ≤ 0.01) on day 0 and day 8 during differentiation. Furthermore, candidate lncRNAs were characterized by comprehensive examination of their genomic context, gene ontology (GO) enrichment of their associated protein-coding genes and pathway analysis. We identified three lncRNAs (Gm15051, Tmem189 and Cebpd) associated with their flanking coding genes (Hoxa1, C/EBPβ and C/EBPδ), which participated in adipose commitment. Collectively, our findings indicated lncRNAs are involved in mouse BAT development and provide potential targets for obesity therapy.

Aim: To preliminarily investigate the prognostic significance of the platelet to lymphocyte ratio (PLR) in patients with gallbladder carcinoma (GBC)., Methods: Clinical data of 316 surgical GBC patients were analyzed retrospectively, and preoperative serum platelet and lymphocyte counts were used to calculate the PLR. The optimal cut-off value of the PLR for detecting death was determined by the receiver operating characteristic (ROC) curve. The primary outcome was overall survival, which was estimated by the Kaplan-Meier method. The log-rank test was used to compare the differences in survival. Then, we conducted multivariate Cox analysis to assess the independent effect of the PLR on the survival of GBC patients., Results: For the PLR, the area under the ROC curve was 0.620 (95%CI: 0.542-0.698, P = 0.040) in detecting death. The cut-off value for the PLR was determined to be 117.7, with 73.6% sensitivity and 53.2% specificity. The PLR was found to be significantly positively correlated with CA125 serum level, tumor-node-metastasis (TNM) stage, and tumor differentiation. Univariate analysis identified carcinoembryonic antigen (CEA), CA125 and CA199 levels, PLR, TNM stage, and the degree of differentiation as significant prognostic factors for GBC when they were expressed as binary data. Multivariate analysis showed that CA125 > 35 U/mL, CA199 > 39 U/mL, PLR ≥ 117.7, and TNM stage IV were independently associated with poor survival in GBC. When expressed as a continuous variable, the PLR was still an independent predictor for survival, with a hazard ratio of 1.018 (95%CI: 1.001-1.037 per 10-unit increase, P = 0.043)., Conclusion: The PLR could be used as a simple, inexpensive, and valuable tool for predicting the prognosis of GBC patients.

MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of gene expression. MiR-1908 is a recently identified miRNA that is highly expressed in human adipocytes. However, it is not known what role of miR-1908 is involved in the regulation of human adipocytes. In this study, we demonstrate that the level of miR-1908 increases during the adipogenesis of human multipotent adipose-derived stem (hMADS) cells and human preadipocytes-visceral. Overexpression of miR-1908 in hMADS cells inhibited adipogenic differentiation and increased cell proliferation, suggesting that miR-1908 is involved in the regulation of adipocyte cell differentiation and metabolism, and, thus, may have an effect on human obesity.

Tanshinone IIA is a lipophilic abietane diterpene compound, which exhibits protective effects against ischaemia/reperfusion injury; however, the pathways responsible for the myocardial protective activities of tanshinone IIA remain to be elucidated. The aim of the present study was to investigate the effect of tanshinone IIA on the Janus‑activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, which is associated with cardiac dysfunction during ischemia/reperfusion. The results demonstrated that tanshinone IIA protected myocardial cells from hypoxia/ischemia‑induced injury in vitro and recovered decreased cell viability due to activation of the JAK2/STAT3 pathway, with 10 µM tanshinone IIA exhibiting the most potent protective effects. Flow cytometric analysis revealed that tanshinone IIA reversed the apoptotic aggravation induced by JAK2/STAT3 inhibitors following hypoxic ischemia. However, JAK2 inhibitors promoted the myocardial protective effect of tanshinone IIA from hypoxic‑ischemic injury. Furthermore, tanshinone IIA and JAK2/STAT3 inhibitors in combination augmented the protection of myocardial cells from apoptosis induced by ischemia/reperfusion preconditioning in vivo. In conclusion, the results of the present study indicated that JAK2/STAT3 inhibitors may enhance the protective effect of tanshinone IIA on cardiac myocytes from hypoxic ischemia-induced injury, therefore suggesting that JAK2/STAT3 inhibitors may have a potential application in combination therapies with tanshinone IIA.

Visceral obesity is an independent risk factor for metabolic syndrome, and abnormal fat accumulation is linked to increases in the number and size of adipocytes. MiR-146b was a miRNA highly expressed in mature adipocytes while very lowly expressed in human mesenchymal stem cells (hMSCs) and human visceral preadipocytes (vHPA). In this paper, we mainly focused on the roles of miR-146b in adipogenesis. We found miR-146b could inhibit the proliferation of visceral preadipocytes and promote their differentiation. MiR-146b in human visceral adipocytes inhibited the expression of KLF7, a member of the Kruppel-like transcription factors, as demonstrated by a firefly luciferase reporter assay, indicating that KLF7 is a direct target of the endogenous miR-146b. MiR-146b expression was significantly altered in visceral and subcutaneous adipose tissues in human overweight and obese subjects, and in the epididymal fat tissues and brown fat tissues of diet-induced obese mice. Our data indicates that miR-146b may be a new therapeutic target against human visceral obesity and metabolic dysfunction., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Pancreatic neuroendocrine tumors (PNETs) are rare, accounting for approximately 2% of primary malignant tumors of the pancreas. Compared with common pancreatic ductal adenocarcinomas, they grow more slowly, are less invasive and have a better prognosis. At present, surgery is the preferred method of treatment of PNETs, and offers the only chance of a cure. However, owing to the occult onset of PNETs, once diagnosed they are often inoperable when the diagnosis is established, and the optimal treatment of patients with inoperable liver metastases remains uncertain. In recent years, targeted drug therapies have emerged and have proved effective in prolonging progression-free survival in patients with advanced well-differentiated PNETs, but hardly any progress has been made in the treatment of poorly differentiated PNETs. In the patient described in this report, who had a poorly differentiated PNET with multiple hepatic metastases and had refused cytotoxic chemotherapy, oral sunitinib malate treatment for 22 months with regular follow-ups proved tolerable and effective in significantly reducing the size of the intrahepatic masses.

Objective: To observe the change of apelin and its receptor (APJ) in the lung tissue of rats with pulmonary hypertension induced by monocrotaline and to explore its significance., Methods: Twenty-five male SD rats were randomly divided into control group (n = 10) and monocrotaline group (n = 15). On the twenty-first day after the rats were intraperitoneally injected 60 mg/kg monocrotaline for monocrotaline group or equal volume vehicle for control group, the mean pulmonary artery pressure was measured by right heart catheterization. Histopathological study of lung tissue was done with hematoxylin-eosin (HE) and Masson's trichrome staining. The concentration of apelin in the plasma was measured by radioimmunoassay. The expressions of apelin/APJ proteins and genes in lung tissue were measured respectively by Western blot and reverse transcription polymerase chain reaction (RT-PCR)., Results: The mean pulmonary arterial pressure, right ventricular hypertrophy, pulmonary vascular remodeling index, content of apelin protein in lung tissue of monocrotaline group were higher than those in control group. APJ protein and gene expression in monocrotaline group were significantly lower than those in control group (P < 0.01, P < 0.05), but apelin gene expression in the lung tissue between the two groups had no significant difference., Conclusion: Endogenous apelin/APJ dysfunction may play an important role in the development of pulmonary hypertension induced by monocrotaline.

Aim: Chronic kidney disease (CKD) is increasingly recognized as a predictor of end-stage renal and cardiovascular disease. There is no data on CKD prevalence in numerous minority communities of China such as the Guangxi Jing community. We determined CKD prevalence and related risk factors in Jing adults., Methods: A stratified cluster random sampling method was used in this study comprising 757 Jing adults. Questionnaires, physical examinations and laboratory tests including measurements of urinary albumin and hematuria, were performed. Estimated glomerular filtration rate (eGFR) was calculated using the improved Chinese population MDRD formula. CKD-related risk factors were also examined., Results: After standardization for age and gender, the prevalence of albuminuria, haematuria and eGFR < 60 ml/min per 1.73 m2 was 12.5%, 3.8% and 0.4%, respectively Overall CKD prevalence was 15.3%, while the awareness rate was only 11.6%. Females had a significantly higher (p < 0.05) prevalence of albuminuria, hematuria and eGFR < 60 ml/min compared to males. CKD prevalence tended to increase significantly (< 0.05) with increase in age. Using the standardized age and gender ratios, the prevalence of hypertension, diabetes, hyperlipidemia and hyperuricemia was 14.8%, 5.2%, 38% and 16.2%, respectively, with awareness of 41.0%, 41.2%, 6.6% and 0.9%. Prevalence of overweight or obesity status and metabolic syndrome was 12.1% and 3.0%. Females showed a significantly higher prevalence of hyperuricemia and obesity or overweight status. CKD prevalence was also significantly higher in people with risk diseases. Regression analysis showed that age, gender, hypertension, high cholesterol and diabetes were CKD-related risk factors, while culture (higher education level) was a protective factor., Conclusion: Jing adults showed a high CKD prevalence of 15.3%, with a low awareness rate of 11.6%. Older subjects and females were more susceptible with a high prevalence of hypertension, diabetes, hyperlipidemia, metabolic syndrome etc. being associated closely with CKD.

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice.

Many flavonoids were demonstrated to possess the antiallergic effect. Here we detected whether apigenin, a flavonoid, can attenuate allergen-induced airway inflammation and what is the possible mechanism in a murine model of asthma. Apigenin decreased the degree of the inflammatory cell infiltration, airway hyperresponsiveness, and total immunoglobulin E levels compared with the ovalbumin group. In addition, apigenin triggered the switching of the immune response to allergens toward a T-helper type 1 (Th1) profile. Our data clearly demonstrated that apigenin exhibits an anti-inflammatory activity in a murine asthma model, and can switch the immune response to allergens toward the Th1 profile.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) induces degradation of low-density lipoprotein receptor (LDLR) in the liver. It is being pursued as a therapeutic target for LDL-cholesterol reduction. Earlier genome-wide gene expression studies showed that PCSK9 over-expression in HepG2 cells resulted in up-regulation of genes in cholesterol biosynthesis and down-regulation of genes in stress response pathways; however, it was not known whether these changes were directly regulated by PCSK9 or were secondary to PCSK9-induced changes to the intracellular environment. In order to further understand the biological function of PCSK9 we treated HepG2 cells with purified recombinant wild type (WT) and D374Y gain-of-function PCSK9 proteins for 8, 24, and 48 h, and used microarray analysis to identify genome-wide expression changes and pathways. These results were compared to the changes induced by culturing HepG2 cells in cholesterol-free medium, mimicking the intracellular environment of cholesterol starvation. We determined that PCSK9-induced up-regulation of cholesterol biosynthesis genes resulted from intracellular cholesterol starvation. In addition, we identified novel pathways that are presumably regulated by PCSK9 and are independent of its effects on cholesterol uptake. These pathways included "protein ubiquitination," "xenobiotic metabolism," "cell cycle," and "inflammation and stress response." Our results indicate that PCSK9 affects metabolic pathways beyond cholesterol metabolism in HepG2 cells., ((c) 2010 Wiley-Liss, Inc.)

Objective: To investigate the inhibitory effects and mechanism of apigenin (APG) on dominant response of Th2 cells in asthma model of mice., Methods: Thirty-two 6-week-old healthy BALB/c mice, SPF grade, were randomly divided into four groups equally, the normal control group (A), the asthma model group (B), and the two APG groups (C and D) consisted of asthma model mice treated respectively with high-dose (20 mg/kg per day) and low-dose (2 mg/kg per day) APG given by dissolving in 1% dimethyl sulphoxide via intraperitoneal injection. The murine asthma model was established by ovalbumin (OVA) sensitization and provocation. Twenty-four hours after the last airway provocation, acetylcholine (Ach) was administered via caudalis vein for measuring airway resistance by pulmonary function detector; levels of IL- 4 and IL-13 in bronchoalveolar lavage fluid (BALF) and total IgE in serum were determined by enzyme-linked immunosorbent assay (ELISA); total and differential cell counts in BALF were measured by light microscopy; the airway inflammatory infiltration was detected by haematoxylin and eosin (HE) staining; and the signal transducer and activator of transcription 3 (GATA-3) in the lung tissue was determined by Western blot analysis., Results: As compared with Group A, the airway hyper-reactivity, airway inflammation, cell count and eosinophil percentage in BALF, levels of total serum IgE and BALF IL-4 and IL-13, and GATA-3 protein expression in the lung tissue were significantly increased in Group B (P < 0.05). As compared with Group B, all the above-mentioned indices in Group C and D were lower, showing respective significant difference (P < 0.05), and significant difference was also shown between the two APG treated groups (P < 0.05)., Conclusion: APG could reduce the airway inflammation and hyper-reactivity by down-regulating the expressions of pulmonary GATA-3 and Th, cytokines, which is a potential drug for asthma therapy.