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Genistein is an isoflavone extracted from soybean (Glycine max). This compound has anti-inflammatory, anti-oxidative, and anti-cancer effects; however, the mechanism underlying the effects of genistein on IL-1β-stimulated human osteoarthritis (OA) chondrocytes remains unknown. Our objectives in this study were to explore the anti-inflammatory effects of genistein on IL-1β-stimulated human OA chondrocytes and to investigate the potential mechanisms which underlie them. Our results from an in-vitro model of osteoarthritis indicate that genistein inhibits the IL-1β-induced expression of the catabolic factors nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX-2), and matrix metalloproteinases (MMPs). Genistein was shown to stimulate Ho-1 expression, which has been associated with Nrf-2 pathway activation in human chondrocytes. In a rat model, genistein was also shown to attenuate the progression of traumatic osteoarthritis. Taken together, these results demonstrate the effectiveness of genistein in mediating the inflammation associated with joint disorders. Our results also indicate that genistein could potentially serve as an alternative therapeutic treatment for OA.

Aflatoxins are carcinogenic secondary metabolites of fungi that contaminate many staple crops and foods. Aflatoxin contamination is a worldwide problem, especially in developing countries, posing health hazards, e.g., causing aflatoxicosis and hepatocellular carcinoma, and even death. Biological solutions for aflatoxin detoxification are environmentally friendly and a cheaper alternative than chemical methods. The aims of the current study were to investigate: (1) the ability of MSMEG_5998, an aflatoxin-degrading F 420 H 2 -dependent reductase from Mycobacterium smegmatis , to degrade aflatoxin B1 (AFB1) and reduce AFB1-caused damage in HepG2 cell culture model; and (2) whether a thioredoxin (Trx) linkage of MSMEG_5998 enhanced the enzyme activity. We show that Trx-linked MSMEG_5998 degraded 63% AFB1 and native MSMEG_5998 degraded 31% after 4 h at 22 °C, indicating that the Trx-linked enzyme had a better AFB1-degrading ability. In a HepG2 cell culture model, Trx-linked MSMEG_5998 reduced DNA damage and p53-mediated apoptosis caused by AFB1 to a greater extent than the native enzyme. These findings suggest that Trx-linked MSMEG_5998 could potentially be developed to protect the liver from AFB1 damage, or as a candidate protein to reduce AFB1-related toxicity in animals.

Background: Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is well known as an important technique for diagnosis and staging of lung cancer. But a standard protocol to deal with patients who have a negative pathology result still needs to be defined. Herein, we describe the subsequent procedures of these patients in a single center., Methods: A total of 1,412 patients with clinical suspected lung cancer and mediastinal metastasis who underwent EBUS-TBNA were collected between September 2010 and December 2016. Among them, 51 patients with nonspecific pathology result were included and retrospectively analyzed., Results: The 51 patients were stratified into five groups by clinical characterize and follow-up procedures: (1) Diagnosed by other bronchoscopy procedures group (9 cases). Abnormalities of tracheobronchial tree were found during visual examination in the majority of patients (8 cases). Biopsy, endobronchial brushing, bronchoalveolar lavage, and transbronchial lung biopsy (TBLB) were used to get a specific diagnosis. (2) EBUS-TBNA re-biopsy group (11 cases). Patients in this group had normal mucosal appearance and airway lumen. Re-biopsy were performed on patients in this group. (3) Surgery group (6 cases). Patients underwent surgery after negative result of EBUS-TBNA. Five of them were confirmed with non-nodal metastasis after surgery. (4) Underwent other pathology diagnosis group (15 cases). patients in this group had other metastasis sites besides midiastinal lymph node. Computed tomography (CT)-guided fine-needle aspiration and lymph node biopsy were performed. (5) Follow-up group (10 cases). None invasive procedure was used in this group. The median follow up time was 38 months. One patient was diagnosed lymphoma during the follow up., Conclusions: Diagnostic procedures should be chosen based on the clinical character in EBUS-TBNA negative patients with suspected lung cancer. Long time follow-up is very important in patients whose diagnosis is apparently unknown.

Background: Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) has emerged as an innovative technique for diagnosis and staging of lung cancer. But whether the procedure can provide enough tissue for the detection of gene mutations is still to be defined. Here we evaluated the efficacy of lung cancer diagnosis and gene analysis using samples obtain via EBUS-TBNA., Methods: Patients with suspected lung cancer and mediastinal lesions were referred for EBUS-TBNA. Diagnosis and sub-classifications were made by pathologists. Samples with non-squamous non small cell lung cancer sub type were tested for the EGFR and/or ALK mutations., Results: A total of 377 patients were included in this study. The median needle passes were 2.07. Lung cancer was diagnosed in 213 patients. The diagnosis accuracy for malignancy was 92%. Epidermal growth factor receptor (EGFR) mutations, anaplasticlymphoma kinase (ALK) fusion genes and double genes analysis were successfully preformed in 84 (90%), 105 (95%) and 79 (90%) patients. The number of needle passes and the diameters of lymph node were not associated with the efficacy of gene testing in univariate analysis. However, samples of adenocarcinoma sub type showed a tendency associated with higher genotyping efficacy., Conclusions: Tissue samples obtained through EBUS-TBNA are sufficient for pathological diagnosis and genetic analysis of lung cancer. The pathology type of sample affected genotyping efficacy.

Background: Treatment options are limited for infections due to multidrug-resistant Gram-positive pathogens. Daptomycin is a lipopeptide antibiotic with concentration-dependent killing characteristic and dose-dependent post-antibiotic effect. To achieve optimized pharma-codynamic effect, some experts advocated using a high dose of daptomycin (≥9 mg/kg) for severe infections. However, the safety of high-dose therapy in patients with renal impairment remains unknown. This study was aimed to evaluate the safety of daptomycin in patients with severe renal impairment., Methods: This was a retrospective study performed by reviewing electronic medical records. Patients with severe renal impairment who were treated with daptomycin in a tertiary teaching hospital between January 1, 2013, and June 30, 2016, were included for evaluation. The incidence rates of creatine kinase (CK) elevation between high-dose (≥9 mg/kg) and standard-dose (<9 mg/kg) groups were compared., Results: Overall, 164 patients met the inclusion criteria, and 114 (69.5%) of them were on renal replacement therapy. Vancomycin-resistant enterococci were the most common pathogens (61.3%) of the patients with documented pathogens. The treatment success rate was 51.6% in the 91 patients with bacteremia. The average dose of daptomycin was 8.0±2.3 mg/kg, and 37 (22.6%) patients received ≥9 mg/kg. CK levels were followed in 108 (65.9%) patients. Significantly higher incidence of CK elevation was found in the high-dose group compared with that in the standard-dose group (10.8% vs 1.6%, P <0.05). Moreover, patients with elevated CK received a higher dose of daptomycin than those without (9.3±1.2 vs 7.9±2.3 mg/kg, P <0.05). There was no significant difference in the rate of CK elevation between patients treated with different dosing frequency or with the concurrent use of statins, fibrate, or colchicine., Conclusions: In patients with severe renal impairment, high-dose (≥9 mg/kg) daptomycin therapy may result in a significantly higher incidence of CK elevation. More frequent CK monitoring is warranted to avoid potential harm in this population., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

A nickel catalyzed cross-coupling protocol for the straightforward C-S bond formation has been developed. Various mercaptans and a wide range of ester and amide substrates bearing various substituents were tolerated in this process which afforded products in good to excellent yields. Furthermore, an intramolecular protocol for the synthesis of thioethers starting from thioesters has been developed. The utility of this protocol has been demonstrated in a new synthetic protocol of benzothiophene., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Novel series of limonin derivatives (V-A-1-V-A-8, V-B-1-V-B-8) were synthesized by adding various tertiary amines onto the C (7)-position of limonin. The synthesized compounds possessed favorable physicochemical property, and the intrinsic solubility of the novel compounds were significantly improved, compared with limonin. Different pharmacological models were used to evaluate the analgesic and anti-inflammatory activities of the target compounds. Compound V-A-8 exhibited the strongest in vivo activity among the novel limonin analogs; its analgesic activity was more potent than aspirin and its anti-inflammatory activity was stronger than naproxen under our testing conditions., (Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Bladder cancer is one of the most common urinary tract carcinomas in the world. Urine metabolomics is a promising approach for bladder cancer detection and marker discovery since urine is in direct contact with bladder epithelia cells; metabolites released from bladder cancer cells may be enriched in urine samples. In this study, we applied ultra-performance liquid chromatography time-of-flight mass spectrometry to profile metabolite profiles of 87 samples from bladder cancer patients and 65 samples from hernia patients. An OPLS-DA classification revealed that bladder cancer samples can be discriminated from hernia samples based on the profiles. A marker discovery pipeline selected six putative markers from the metabolomic profiles. An LLE clustering demonstrated the discriminative power of the chosen marker candidates. Two of the six markers were identified as imidazoleacetic acid whose relation to bladder cancer has certain degree of supporting evidence. A machine learning model, decision trees, was built based on the metabolomic profiles and the six marker candidates. The decision tree obtained an accuracy of 76.60%, a sensitivity of 71.88%, and a specificity of 86.67% from an independent test.

An inexpensive nickel(II) catalyst and a hydrosilane were used for the efficient reductive defunctionalization of aryl and heteroaryl esters through a decarbonylative pathway. This versatile method could be used for the removal of ester and amide functional groups from various organic molecules. Moreover, a scale-up experiment and a synthetic application based on the use of a removable carboxylic acid directing group highlight the usefulness of this reaction., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To evaluate the role of bronchoscopy in the diagnosis of sarcoidosis., Methods: A retrospective analysis was conducted for 200 patients who were diagnosed to have sarcoidosis and underwent bronchoscopy from June 2009 to June 2014 in Peking Union Medical College Hospital. The diagnostic value of different bronchoscopic procedures was analyzed., Results: Of the 200 patients, 145 were finally confirmed to have sarcoidosis by pathology through bronchoscopic sampling techniques. The diagnostic yields of endobronchial biopsy (EBB), transbronchial lung biopsy (TBLB), and EBUS-TBNA were 71.14%, 46.77%, 46.80%, respectively. The yields among the 3 techniques were statistically different. In those with mucosal lesions, the yield of EBB was 80.80%, while that of the combination of EBB, TBLB and EBUS-TBNA was 83.3%, the difference being not significant. In those without mucosal lesions, the yields of EBB, and the combination of EBB, TBLB and EBUS-TBNA were 20.8% and 48.0% respectively, with significant difference(χ(2)=4.463, P=0.035)., Conclusions: EBB is a preferred approach for the diagnosis of sarcoidosis with endobronchial abnormalities, while for cases without mucosal lesions, combined TBLB, EBUS-TBNA and bronchoalveolar lavage can improve the diagnostic yield.

This letter demonstrates a p-type raised source-and-drain (raised S/D) junctionless thin-film transistors (JL-TFTs) with a dual-gate structure. The raised S/D structure provides a high saturation current (>1 μA/μm). The subthreshold swing (SS) is 100 mV/decade and the drain-induced barrier lowering (DIBL) is 0.8 mV/V, and the I on/I off current ratio is over 10(8) A/A for L g = 1 μm. Using a thin channel structure obtains excellent performance in the raised S/D structure. Besides the basic electrical characteristics, the dual-gate structure can also be used to adjust V th in multi-V th circuit designs. This study examines the feasibility of using JL-TFTs in future three-dimensional (3D) layer-to-layer stacked high-density device applications.

Objective: To improve understanding of the clinical characteristics and diagnosis of hypersensitivity pneumonitis (HP)., Methods: We retrospectively analyzed the clinical data, including clinical symptoms, laboratory tests, exposure, pulmonary function tests, chest CT imaging and cytological classification of bronchoalveolar lavage (BAL) of 96 patients with HP from Jan 2001 to Jun 2011 in Peking Union Medical College Hospital. We divided the patients into 2 groups: a pathologically-confirmed group and a clinically-suspected group., Results: There were 58 females and 41 males. The median age at the diagnosis was 53 years. The most common exposures were low-molecular-weight chemicals (42.7%) and animal proteins (37.5%). Common clinical symptoms included dyspnea on exertion (90.6%) and cough (76.0%). Pulmonary function test showed diffusion abnormality (73.5%) and restrictive ventilatory impairment (59.7%). Chest CT scan revealed patchy or diffuse bilateral ground-glass opacities (64.6%), centrilobular nodules (21.9%), and air trapping (15.6%). Reticulation (45.8%), traction bronchiectasis (21.9%) and honeycombing(9.4%) were present in chronic HP. BAL lymphocyte counts > 0.2 and CD4/CD8 < 0.9 were more commonly seen in patients with a disease course of less than 1 year. The pathologically-confirmed group and the clinically-suspected group shared many similar characteristics including age at diagnosis, gender, clinical manifestation, pulmonary function impairments and imaging findings, but significant differences existed in certain parameters. In the pathologically- confirmed group, the duration of disease was longer (24 months vs 6 months, Z = -2.492, P = 0.013) and clubbed fingers were more common (23.4% vs 8.2%, χ(2) = 4.227, P = 0.040). Diffusion abnormality was present in more patients of this group (90.7% vs 44.0%, χ(2) = 35.219, P < 0.01). By CT scan, reticulation, traction bronchiectasis and honeycombing (57.5% vs 26.5%, χ(2) = 9.434, P < 0.01) were more evident as compared to the clinically-suspected group. The value of transbronchial lung biopsy for diagnosing HP was limited, with a positive result of only 8.2%. Surgical lung biopsy was needed in uncertain cases., Conclusion: The diagnosis of HP was difficult. In some cases a clinical diagnosis can be made by combination of history of exposure, CT manifestations and cell classification of BAL. For atypical cases a multi-disciplinary approach including pathologists, radiologists and pulmonologists is needed.

Background: Given the favorable impact of α1-blockers on lipid and glucose metabolism, this study was designed to compare the efficacy of two extended-release α1-blockers (bunazosin and doxazosin) as an add-on treatment in subjects with stage 1 or 2 essential hypertension which was inadequately controlled by valsartan 80 mg/day., Methods: After a 5-week treatment of valsartan monotherapy, subjects with inadequately controlled hypertension were randomized to receive either extended-release bunazosin (n = 47) or doxazosin (n = 46) after breakfast for 8 weeks. Office sitting blood pressure (BP), 24-hour ambulatory BP, and metabolic profiles were measured at baseline, start of study drug, and study end., Results: In the intention-to-treat population (n = 93), the average daily doses of bunazosin and doxazosinwere 2.8 mg and 3.6 mg, respectively. The two add-on treatments achieved significant and similar BP reductions from monotherapy (bunazosin, 13.2/9.3 mmHg; doxazosin, 9.2/8.5 mmHg, all p < 0.001). However, in patients with stage 2 hypertension, patients randomized to the bunazosin group, compared to those in the doxazosin group, achieved a significantly greater reduction in sitting systolic BP (14.4 ± 8.1 vs. 6.6 ± 13.8 mmHg, p = 0.015). In addition, patients who received bunazosin had significant changes in night-day systolic and diastolic BP ratios compared with those who received doxazosin (-0.02 vs. 0.02, p = 0.04 and 0 vs. 0.04, p = 0.04). No significant changes in metabolic profiles were observed in both add-on groups. Both drugs were well-tolerated, but adverse events related to the study drugs were marginally more frequent in the doxazosin group than in the bunazosin group (20% vs. 6%, p = 0.058)., Conclusions: Both extended-release bunazosin and doxazosinwerewell-tolerated and similarly effective as add-on therapy in hypertensive patients uncontrolled by valsartan monotherapy. However, add-on treatment with bunazosin seemed to be associated with favorable night-day BP ratio and greater sitting systolic BP reductions in stage 2 hypertensive patients., Key Words: Combination therapy; Hypertension; α1-blocker.

Serratia marcescens strain JPP1 was isolated from peanut hulls in Huai'an city, Jiangsu Province, China. Its potential to inhibit the mycelial growth of Aspergillus parasiticus and the subsequent aflatoxin production was evaluated. The strain JPP1 could produce chitinase to degrade fungal cell walls, which was the main mechanism of strain JPP1 for biocontrol. Scanning electron microscopy of fungi treated with the crude chitinase revealed abnormal morphological changes. While the strain was grown in the peanut hulls-based medium, the chitinase activity reached 7.39 units. RT-PCR analysis showed that the crude chitinase repressed the transcription of genes involved in the aflatoxin gene cluster, such as aflR, aflC (pksL1), and aflO (dmtA) genes. By visual agar plate assay and tip culture method, the strain JPP1 exhibited remarkable inhibitory effect on mycelia growth (antifungal ratio >95%) and subsequent aflatoxin production (antiaflatoxigenic ratio >98%). An in vitro assay with seed coating agent of bacterial suspension showed that strain JPP1 effectively reduced fungal growth and subsequent aflatoxin production on peanut seeds, and its antagonistic effect was superior to the common agricultural fungicide of carbendazim. These characteristics suggest that S. marcescens JPP1 strain could potentially be utilized for the biological control of phytopathogenic fungi and aflatoxin in Chinese peanut main producing areas.

Background: Protein-losing enteropathy (PLE) is a serious complication of a Fontan operation and has a very high mortality rate. The purpose of this study was to investigate the incidence, clinical manifestations, diagnostic approaches, laboratory findings, therapeutic modalities and outcome of patients with PLE at our institution., Methods: The diagnosis of PLE was based on clinical manifestations and laboratory studies. We reviewed medical records of patients who received a Fontan operation at our hospital form July 1985 to October 2005., Results: A total 101 patients underwent various modifications of the Fontan procedure during this period. Nine of the 75 patients (12%) who survived 30 days after surgery developed PLE, including 4 boys and 5 girls. The median time interval between the Fontan operation and onset of PLE was 3.7 years (range 1.2 to 9.7 years). Laboratory examination showed low serum albumin levels and increased fecal alpha-1-antitrypsin excretion. Lymphangiectasia was found on intestinal biopsy. Six patients had cardiac catheterization after development of PLE which demonstrated an elevated mean right atrium pressure (22.5 +/- 6.4 mmHg, range 16 to 33 mmHg) and mean pulmonary artery pressure (22.3 +/- 6.4 mmHg, range 16 to 33 mmHg). Treatment included diet modification, albumin infusion, diuretics, inotropes, corticosteroids, heparin, and surgery. Four patients received medical treatment only. Two of these patients died due to sepsis and heart failure and 2 survived with partial relief of PLE. The remaining five received surgery for PLE after medical treatment failure. Three of them died after the operation and the two survivors were free of PLE, but one died of ventricular tachycardia 8 years later. The overall mortality rate was 67% (6/9)., Conclusions: The current treatment for PLE is associated with a very high mortality rate. Further investigation is needed to determine the exact mechanism of the disease and to develop new therapeutic approaches.