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Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN), causing bradykinesia and rest tremors. Although the molecular mechanism of PD is still not fully understood, neuroinflammation has a key role in the damage of dopaminergic neurons. Herein, we found that kurarinone, a unique natural product from Sophora flavescens, alleviated the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic neurotoxicity, including the losses of neurotransmitters and tyrosine hydroxylase (TH)-positive cells (SN and striatum [STR]). Furthermore, kurarinone attenuated the MPTP-mediated neuroinflammation via suppressing the activation of microglia involved in the nuclear factor kappa B signaling pathway. The proteomics result of the solvent-induced protein precipitation and thermal proteome profiling suggest that the soluble epoxide hydrolase (sEH) enzyme, which is associated with the neuroinflammation of PD, is a promising target of kurarinone. This is supported by the increase of plasma epoxyeicosatrienoic acids (sEH substrates) and the decrease of dihydroxyeicosatrienoic acids (sEH products), and the results of invitro inhibition kinetics, surface plasmon resonance, and cocrystallization of kurarinone with sEH revealed that this natural compound is an uncompetitive inhibitor. In addition, sEH knockout (KO) attenuated the progression of PD, and sEH KO plus kurarinone did not further reduce the protection of PD in MPTP-induced PD mice. These findings suggest that kurarinone could be a potential natural candidate for the treatment of PD, possibly through sEH inhibition.

Objective This study was performed to assess the clinical feasibility, safety, and effectiveness of a computed tomography (CT)–guided cyanoacrylate injection system and investigate the relationship between clinical features and pathologic characteristics of diminutive pulmonary lesions. Methods In total, 115 pulmonary nodules from 113 patients (63 female, 50 male) with a diameter of Results Of the pure ground-glass opacities (GGOs), 16.0% were atypical adenomatous hyperplasia (AAH), 18.7% were adenocarcinoma in situ (AIS), 49.3% were lung adenocarcinoma (ADC), and 16.0% were benign inflammatory fibrosis/fibrotic scars. Of the mixed GGOs, 18.2% were AAH, 22.7% were AIS, 22.7% were ADC, and 36.4% were benign lesions. Lesions of >10 mm and those located in relation to vessels were significantly more likely to be malignant. The success rate of both the cyanoacrylate injection system and video-assisted thoracoscopic surgery was 100% with no severe complications. Conclusions Preoperative localization of small pulmonary nodules using a cyanoacrylate injection system is a safe, simple, and useful technique.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aβ)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aβ-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aβ-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3β-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.

Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain.The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE).A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HTURE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HTU. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT

This study was performed to retrospectively evaluate the 10-year overall survival (OS), progression-free survival (PFS), and local control rates of patients with inoperable stage Ia non-small cell lung cancer (NSCLC) who underwent computed tomography (CT)-guided radiofrequency ablation (RFA) in a single center.Fifty patients with inoperable NSCLC underwent RFA between 2004 and 2016. Thoracic surgeons evaluated the patients and performed RFA under CT guidance. Follow-up CT and positron emission tomography/CT scans were obtained. Local control rates and recurrence patterns were analyzed.Seventy-three lesions in 50 patients (M:F = 22:28; median age: 73 years; range: 52-82 years) were treated with CT-guided RFA. The mean lesion size was 2.2 cm (range: 1-3 cm). No procedure-related deaths occurred. Low-grade fever was the most common post-ablation complication, with an incidence rate of 36%. The 1-, 2-, 3-, 5-, and 10-year OS rates of patients with Ia NSCLC were 96.0%, 86.5%, 67.1%, 36.3%, and 1%, respectively, and the 1-, 2-, 3-, and 5-year PFS rates were 94.0%, 77.5%, 43.5%, and 10.8%, respectively. The most common pattern of recurrence was local, and 15 patients with recurrence were treated with repeat RFA. Tumor size2.0 cm was associated with a significantly improved 3-year survival rate of 78.9%.CT-guided RFA is feasible and well tolerated by inoperable patients with inoperable stage Ia NSCLC.

Rationale and Objectives The aim of the study was to evaluate the overall survival (OS) rate, progression survival rate, and local control rate over 10 years of medically inoperable patients with lung cancer undergoing computed tomography (CT)-guided radiofrequency ablation (RFA). Materials and Methods Between September 2004 to March 2016, 668 neoplasms were treated in 476 medically inoperable patients (294 men, 60 women; median age 74 years; range 29–84) who underwent CT-guided RFA. All patients had clinical or pathologic evidence of the neoplastic lesion: 22.1% patients with primary non–small cell lung cancer (NSCLC), 22.3% patients with recurrent NSCLC, 45.2% with metastases, and 10.3% with small cell lung cancer. The mean size of the lesions was 3.8 cm (range of 1–16 cm). Twenty-one lesions were re-treated from one to as many as four times. Results The procedure was technically successful in all cases. No procedure-related deaths occurred in the RFA procedures. Major complications consisted in 104 (21.8%) cases of low-grade fever, 46 (9.6%) of the pneumothorax. The mean follow-up was 32 months. The probabilities of 1-, 2-, 3-, 5-, and 10-year OS rate were 98.1%, 86.6%, 68.9% 34.5%, and 9.5% for primary NSCLC; 59.7%, 18.5%, 8%, 3.4%, and 1.5% for metastases; 93.3%, 59.1%, 49.6%, 19.7%, and 0% for recurrence; and 89.4%, 67.5%, 39.1%, 16.5%, and 0% for small cell lung cancer. In primary NSCLC, progression-free survival (PFS) and OS were significantly related to tumor size, but there was no significant difference in recurrent NSCLC, metastasis, and peripheral SCLC. The median OS of metastases of NSCLC was significantly related to nodal or distant metastases. The most common pattern of recurrence was local; any type of recurrence at 1-year follow-up imaging was seen in 7.1% of primary NSCLC diameter less than 3 cm. Conclusions Our experience indicates that CT-guided RFA done by the thoracic surgeons is feasible and safe in high-risk patients. Maximum tumor diameter less than 3 cm and lack of extrapulmonary metastasis are all positive prognostic factors of survival after RFA. RFA offers good local control of recurrent NSCLC, lung metastases, and SCLC, also in the long-term period. RFA should continue to offer an alternative option in medically inoperable patients.

Background: Sophocarpine (SC) is a major alkaloid extracted from Sophora alopecuroides L. Our previous study showed that SC has analgesic effects on neuropathic pain induced by chronic constriction injury (CCI). However, the exact analgesic mechanism of SC on neuropathic pain has not yet been elucidated. Objectives: The current study aimed to examine the anti-neuropathic pain effects of SC on the HMGB1/TLR4/NF-κB signaling pathway to explore its analgesic mechanism in neuropathic pain. Methods: In this experimental study, the neuropathic pain mouse model was established by CCI of the sciatic nerve in a university-affiliated animal lab, China, 2016. Mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), cold withdrawal threshold (CWT), and tail-curling latency (TCL) were used to assess the antinociceptive effect of SC in neuropathic pain mice. The mRNA and protein expression levels of HMGB1, TLR4, NF-κB, p-NF-κB, TNF-α, and IL-6 in the spinal cord of neuropathic pain mice were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Results: Treatment with 40 and 20 mg/kg of SC was effective in increasing MWT, lengthening TWL, reducing CWT, and prolonging TCL in mice with neuropathic pain induced by CCI. Compared to the neuropathic-pain model group, treatment with 40 mg/kg of SC could effectively down-regulate HMGB1, TLR4, NF-κB, p-NF-κB, TNF-α, and IL-6 mRNA and protein expression levels in the spinal cord of mice with neuropathic pain induced by CCI. Conclusions: Our results showed that SC has analgesic effects on neuropathic pain induced by CCI, and its analgesic mechanism may be related to down-regulating the HMGB1/TLR4/NF-κB signaling pathway.

More women are delaying child-birth. Thus, the diagnosis of pregnancy-associated breast cancer (PABC) will continue to increase. The aim of this study was to identify core candidate genes of PABC, and the relevance of the genes on the prognosis of PABC. GSE31192 and GSE53031 microarray profile datasets were downloaded from the Gene Expression Omnibus database and differentially expressed genes were analyzed using the R package and GEO2R tool. Then, Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery. Moreover, the Search Tool for the Retrieval of Interacting Genes and the Molecular Complex Detection Cytoscape software plug-in were utilized to visualize protein–protein interactions and to screen candidate genes. A total of 239 DEGs were identified in PABC, including 101 up-regulated genes mainly enriched in fatty acid activation and the fibroblast growth factor signaling pathway, while 138 down-regulated genes particularly involved in activation of DNA fragmentation factor and apoptosis-induced DNA fragmentation. Fourteen hub genes with a high degree of connectivity were selected, including CREB1, ARF3, UBA5, SIAH1, KLHL3, HECTD1, MMP9, TRIM69, MEX3C, ASB6, UBE2Q2, FBXO22, EIF4A3, and PXN. Overall survival (OS) analysis of core candidate genes was performed using the Gene Expression Profiling Interactive Analysis and UALCAN websites. High ASB6 expression was associated with worse OS of PABC patients. Molecular subtypes and menopause status were also associated with worse OS for PABC patients. In conclusion, ASB6 could be a potential predictor and therapeutic target in patient with PABC.

Background Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain. Purpose The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE). Study design and methods A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system. Results URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 μg/ml. Conclusion U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor.

The aim of the study was to evaluate the overall survival (OS) rate, progression survival rate, and local control rate over 10 years of medically inoperable patients with lung cancer undergoing computed tomography (CT)-guided radiofrequency ablation (RFA).Between September 2004 to March 2016, 668 neoplasms were treated in 476 medically inoperable patients (294 men, 60 women; median age 74 years; range 29-84) who underwent CT-guided RFA. All patients had clinical or pathologic evidence of the neoplastic lesion: 22.1% patients with primary non-small cell lung cancer (NSCLC), 22.3% patients with recurrent NSCLC, 45.2% with metastases, and 10.3% with small cell lung cancer. The mean size of the lesions was 3.8 cm (range of 1-16 cm). Twenty-one lesions were re-treated from one to as many as four times.The procedure was technically successful in all cases. No procedure-related deaths occurred in the RFA procedures. Major complications consisted in 104 (21.8%) cases of low-grade fever, 46 (9.6%) of the pneumothorax. The mean follow-up was 32 months. The probabilities of 1-, 2-, 3-, 5-, and 10-year OS rate were 98.1%, 86.6%, 68.9% 34.5%, and 9.5% for primary NSCLC; 59.7%, 18.5%, 8%, 3.4%, and 1.5% for metastases; 93.3%, 59.1%, 49.6%, 19.7%, and 0% for recurrence; and 89.4%, 67.5%, 39.1%, 16.5%, and 0% for small cell lung cancer. In primary NSCLC, progression-free survival (PFS) and OS were significantly related to tumor size, but there was no significant difference in recurrent NSCLC, metastasis, and peripheral SCLC. The median OS of metastases of NSCLC was significantly related to nodal or distant metastases. The most common pattern of recurrence was local; any type of recurrence at 1-year follow-up imaging was seen in 7.1% of primary NSCLC diameter less than 3 cm.Our experience indicates that CT-guided RFA done by the thoracic surgeons is feasible and safe in high-risk patients. Maximum tumor diameter less than 3 cm and lack of extrapulmonary metastasis are all positive prognostic factors of survival after RFA. RFA offers good local control of recurrent NSCLC, lung metastases, and SCLC, also in the long-term period. RFA should continue to offer an alternative option in medically inoperable patients.

In the present work, mathematical modeling combined with measurement of the velocities near mold surface with rod deflecting method at the high temperature was carried out to optimize the flow field of slab continuous casting mold with medium width of 1230 mm for the production of an automobile exposed panel. The results show that the measured results of the velocities near the mold surface are in good agreement with the calculated results. The velocities near the mold surface increase with increasing the casting speed and decreasing the argon gas flow rate. When the casting speed is increased from 1.0, to 1.3, 1.5, and 2.0 m/min, the flow pattern in the mold is changed from single-roll flow (SRF), to unstable flow (UF), and then to double-roll flow (DRF), the top surface level fluctuations has the smallest value at 1.5 m/min. When the argon gas flow rate is 1 and 4 L/min, the velocity near the mold surface has a moderate value, and the flow pattern in the mold is DRF and the top surface level fluctuation is small and symmetrical. When the submerged entry nozzle (SEN) submergence depth is increased to 200 mm, the velocities near the mold surface decrease, and the top surface level fluctuation becomes small. The optimized flow field in the mold can be judged to be favorable to the surface quality of the automobile exposed panel, if the velocities near the mold surface are relatively small, the flow pattern in the mold is DRF and the top surface level fluctuation is small and symmetrical.

Oxidative stress is an important pathophysiological factor of asthma and chronic obstructive pulmonary disease (COPD). We hypothesized that procaterol and dexamethasone might treat inflammation through inhibiting oxidative stress in vitro. This study evaluated procaterol and dexamethasone in the hydrogen peroxide (H2O2)-induced immortal human bronchial epithelial cell model of oxidative stress and investigated the underlying mechanisms. Results showed that exposure to 125 μM H2O2 for 2 h led to a 50% reduction in the cell viability, significantly increased the percentage of apoptosis, and elevated levels of malondialdehyde and reactive oxygen species. Pretreatment with procaterol (25 – 200 nM) could reduce these effects in a dose-dependent manner. In contrast, pretreatment with dexamethasone (100 nM, 1000 nM) was inefficient. Pretreatment with procaterol plus dexamethasone (100 nM procaterol + 1000 nM dexamethasone) was effective, but the combined effect was not more effective than the sole pretreatment with 100 nM procaterol. The nuclear factor kappa-B (NF-κB) pathway was involved in the pathogenic mechanisms of H2O2. Procaterol may indirectly inhibit H2O2-induced activation of the NF-κB pathway due to its capability of antioxidation. Glucocorticoids may be not recommended to treat asthma or COPD complicated with severe oxidative stress. Keywords:: oxidative stress, procaterol, dexamethasone, nuclear factor kappa-B, hydrogen peroxide

Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of many respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). To evaluate the treatment responses of procaterol and CD38 inhibitors in an ozone-induced AHR mice model, we hypothesized that procaterol and two synthetic CD38 inhibitors (Compounds T and H) might have therapeutic effects on the ozone-induced AHR mice model, and the nuclear factor-kappaB (NF-κB) pathway and the CD38 enzymatic activity might be involved in the mechanisms. With the exception of the Control group, ozone exposure was used to establish an AHR model. Male Kunming mice in the Procaterol and CD38 inhibitors groups were treated with an emulsifier of procaterol hydrochloride, Compound T or H. Results indicated that (1) no drug showed severe toxicity in this study; (2) ozone exposure induced airway inflammation and AHR; (3) intragastric treatment with procaterol and Compound T achieved potent therapeutic effects, but Compound H did not show any therapeutic effect; (4) the NF-κB pathway was involved in both the pathogenic mechanisms of ozone and therapeutic mechanisms of procaterol and Compound T; (5) however, the in vivo effect of Compound T was not caused by its inhibitory activity on CD38. Taken together, procaterol and Compound T are potentially good drugs to treat asthma and COPD complicated with ozone exposure.

Translocated intimin receptor (Tir) is anEscherichia coli-encoded protein that is transported into the host cell through a sophisticated bacterial type III secretion system (T3SS). Tir anchors the infected cell membrane twice using both its N- and C-termini from inside the host cytoplasm for signalling. It plays a key role in enterohemorrhagicEscherichia coli(EHEC) infection, attaching and effacing (A/E) lesions and intracellular signal transduction. Here, the overexpression, purification and crystallization of its N-terminal intracellular domain are reported. The crystal belonged to the orthorhombic space groupI4122, with unit-cell parametersa=b= 59.79,c= 183.11 Å. The asymmetric unit contained one molecule, with a solvent content of 51% and aVMof 2.55 Å3 Da−1.

Rui-ping Zhai, Hong-mei Ying, Fang-fang Kong, Cheng-run Du, Shuang Huang, Jun-jun Zhou, Chao-su Hu Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China Aim: To evaluate the efficacy and safety of using nimotuzumab in combination with intensity-modulated radiotherapy (IMRT) in the primary treatment of locoregionally advanced nasopharyngeal carcinoma.Methods: Between December 2009 and December 2013, 38 newly diagnosed patients with stageIII–IV nasopharyngeal carcinoma were treated with IMRT and nimotuzumab concomitantly. The distribution of disease was stage III in 20 (52.6%), stage IV A in 9 (23.7%), and stage IV B in 9 (23.7%). All the patients received at least two cycles of cisplatin-based neoadjuvant chemotherapy followed by nimotuzumab 200 mg/week concurrently with IMRT. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of Radiation Therapy Oncology Group.Results: With a median follow-up of 39.7 months (range, 13.3–66.5 months), the estimated 3-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, progression failure-free survival, and overall survival rates were 92.8%, 92.9%, 89.5%, 78.7%, and 87.5%, respectively. The median cycle for nimotuzumab addition was 6 weeks. Grade 3 radiation-induced mucositis accounted for 36.8% of treated people. No skin rash and infusion reaction were observed, distinctly from what is reported in cetuximab-treated patients.Conclusion: Nimotuzumab plus IMRT showed promising outcomes in terms of locoregional control and survival, without increasing the incidence of radiation-related toxicities for patients. Keywords: nasopharyngeal carcinoma, intensity-modulated radiotherapy, nimotuzumab