Substantiating evidence for the inflammation theory of depression is that interferon-alpha (IFN-α) induces clinical depression. Despite numerous researches on neurochemical and neuroendocrinological ...mechanisms from human and animal studies, the direct mechanisms of IFN-α at cellular levels are still lacking. In this study, we aimed to identify the cellular mechanisms for IFN-α-induced neuroinflammatory response with the murine BV-2 microglia cell line. IFN-α potently induced nitric oxide synthase (iNOS) and nitric oxide (NO) release and down-regulated haem oxygenase-1 (HO-1) expression, which could be dampened by Janus kinase 1 (JAK1) and c-Jun NH2-terminal kinase (JNK) inhibition, respectively. IFN-α activated JAK1, JNK, signal transducers and activators of transcription (STAT)1 and STAT3, but not extracellular signal-regulated kinases (ERK) and phosphoinositide 3 (PI3) kinase, signal pathways. The transfection with STAT1 and STAT3 siRNA also inhibited IFN-α-induced iNOS/NO expression and HO-1 down-regulation. The HO-1 activator, CoppIX, reversed iNOS/NO up-regulation and HO-1 down-regulation induced by IFN-α. On the other hand, a knockdown of HO-1 expression enhanced IFN-α-induced iNOS/NO expression. The effects of IFN-α-induced iNOS/NO up-regulation and HO-1 down-regulation in microglia are associated with JAK1/JNK/STAT1 and STAT3 signalling pathways. The different effects between IFN-α and IFN-γ on HO-1 regulation and ERK phosphorylation might provide a possible explanation of different risk in their induction of neuropsychiatric adverse effects in clinical and animal studies. The results from this study add the missing part of direct cellular mechanisms for IFN-α-induced depression.
Menopausal symptoms are common in midlife women and have broad impacts on their daily functioning and quality of life. Black cohosh extracts have been widely used to relieve menopausal symptoms. ...However, the comparative benefits of different combined black cohosh regimens remain inconclusive. The aim of the current updated meta-analysis is to address the comparative efficacies of different black cohosh regimens in improving menopausal symptoms.
Random-effect model pairwise meta-analysis of randomized controlled trials was conducted to investigate the treatment effect on menopausal symptoms by the black cohosh extract both alone or combined with other related active ingredients. The outcomes studied were changes in menopausal symptoms after treatment with black cohosh extracts in menopausal women.
Twenty-two articles including information on 2,310 menopausal women were included in the analyses. Black cohosh extracts were associated with significant improvements in overall menopausal symptoms (Hedges' g = 0.575, 95% CI = 0.283 to 0.867, P < 0.001), as well as in hot flashes (Hedges' g = 0.315, 95% CIs = 0.107 to 0.524, P = 0.003), and somatic symptoms (Hedges' g = 0.418, 95% CI = 0.165 to 0.670, P = 0.001), compared with placebo. However, black cohosh did not significantly improve anxiety (Hedges' g = 0.194, 95% CI = -0.296 to 0.684, P = 0.438) or depressive symptoms (Hedges' g = 0.406, 95% CI = -0.121 to 0.932, P = 0.131). The dropout rate for black cohosh products was similar to that for placebo (odds ratio = 0.911, 95% CI = 0.660 to 1.256, P = 0.568).
This study provides updated evidence regarding the potentially beneficial effects of black cohosh extracts for relieving menopausal symptoms in menopausal women.
Non-small cell lung cancer (NSCLC) carries a poor survival rate mainly because of metastasis. However, the molecular mechanisms that govern NSCLC metastasis have not been described. Because ...huntingtin-interacting protein-1 (HIP1) is known to play a role in tumorigenesis, we tested the involvement of HIP1 in NSCLC progression and metastasis.
HIP1 expression was measured in human NSCLC tumors, and correlation with survival outcome was evaluated. Furthermore, we investigated the ability of HIP1 to suppress metastasis. The molecular mechanism by which HIP1 contributes to suppress metastasis was investigated.
We used tissue arrays containing samples from 121 patients with NSCLC to analyze HIP1 expression by immunohistochemistry. To investigate the role of HIP1 expression on metastasis, we evaluated cellular mobility, migration, and invasion using lung adenocarcinoma (AdCA) cells with modified HIP1 expression levels. The human disease mouse models with the same cells were applied to evaluate the HIP1 suppressing metastasis and its mechanism in vivo.
HIP1 expression in AdCA progression was found to be an early-stage prognostic biomarker, with low expression correlated to poor prognosis. We also found HIP1 to be a metastatic suppressor in AdCA. HIP1 significantly repressed the mobility of lung cancer cells in vitro and in vivo and regulated the epithelial-mesenchymal transition by repressing AKT/glycogen synthase kinase-3β/β-catenin signaling.
HIP1 serves as an early-stage prognostic biomarker and a metastatic suppressor. Reduced expression during AdCA progression can relieve HIP1 suppression of Akt-mediated epithelial-mesenchymal transition and thereby lead to development of late metastases and poor prognosis.
This letter reports a new mechanism for the enhanced impact-ionization rate (I sub /I d ) present in short- channel uniaxial strained p-MOSFETs. Through the pinch-off voltage (V dsat ), we have ...assessed the impact of strain on the maximum channel electric field. Due to the strain-enhanced mobility, V dsat becomes lower, resulting in the observed V g -dependent enhancement in I sub /I d . This mechanism needs to be considered when one-to-one comparisons of the hot-carrier effect between strained and unstrained devices are made.
Hepatocellular Carcinoma (HCC) is rising in incidence worldwide, especially in areas endemic for chronic viral hepatitis. Distant metastases are common especially in lungs and bones. Subcutaneous or ...mucosal metastases, however, are rare. We report a case of both mucosal and subcutaneous metastases in the same patient.
This article investigates the impact of interface trapped-charge variations on the dimensional scaling of the ferroelectric field-effect transistor (FeFET) nonvolatile memory (NVM) under two ...scenarios: a uniform ferroelectric and random ferroelectric-dielectric (FE-DE) phase distribution. Our study indicates that both memory window (MW) and read margin decrease with increasing trap density (<inline-formula> <tex-math notation="LaTeX">{< }{n}_{T}{>} </tex-math></inline-formula>), and the MW of FeFET devices with scaled channel width can be more vulnerable to the trapped-charge variations than that with scaled gate length. Under the presence of the FE-DE phase variation, for low <inline-formula> <tex-math notation="LaTeX">{< }{n}_{T}{>} </tex-math></inline-formula>, the impact of trapped charges is mainly on the MW degradation for the high MW instances. As the <inline-formula> <tex-math notation="LaTeX">{< }{n}_{T}{>} </tex-math></inline-formula> continues to rise, the trapped charges can further worsen the worst case MW significantly. Besides, when down-scaling the interfacial layer thickness of the FeFET device to increase the MW, the increased <inline-formula> <tex-math notation="LaTeX"> \sigma </tex-math></inline-formula>MW due to the random interface trapped charges may also need to be considered. Our study may provide insights for device design with advanced FeFET NVMs.
Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are ...present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.
Suitable rescue path selection is very important to rescue lives and reduce the loss of disasters, and has been a key issue in the field of disaster response management. In this paper, we present a ...path selection algorithm based on Q-learning for disaster response applications. We assume that a rescue team is an agent, which is operating in a dynamic and dangerous environment and needs to find a safe and short path in the least time. We first propose a path selection model for disaster response management, and deduce that path selection based on our model is a Markov decision process. Then, we introduce Q-learning and design strategies for action selection and to avoid cyclic path. Finally, experimental results show that our algorithm can find a safe and short path in the dynamic and dangerous environment, which can provide a specific and significant reference for practical management in disaster response applications.
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