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Na(v)1.5 sodium channels contribute to the generation of the rapid upstroke of the myocardial action potential and thereby play a central role in the excitability of myocardial cells. At present, the patch clamp method is the gold standard for ion channel inhibitor screening. However, this method has disadvantages such as high technical difficulty, high cost and low speed. In this study, novel machine learning models to screen chemical blockers were developed to overcome the above shortage. The data from the ChEMBL Database were employed to establish the machine learning models. Firstly, six molecular fingerprints together with five machine learning algorithms were used to develop 30 classification models to predict effective inhibitors. A validation and a test set were used to evaluate the performance of the models. Subsequently, the privileged substructures tightly associated with the inhibition of the Na(v)1.5 ion channel were extracted using the bioalerts Python package. In the validation set, the RF-Graph model performed best. Similarly, RF-Graph produced the best result in the test set in which the Prediction Accuracy (Q) was 0.9309 and Matthew's correlation coefficient was 0.8627, further indicating the model had high classification ability. The results of the privileged substructures indicated Sulfa structures and fragments with large Steric hindrance tend to block Na(v)1.5. In the unsupervised learning task of identifying sulfa drugs, MACCS and Graph fingerprints had good results. In summary, effective machine learning models have been constructed which help to screen potential inhibitors of the Na(v)1.5 ion channel and key privileged substructures with high affinity were also extracted.

Supplementary Data from Microsatellite Instability–High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles

Purpose:Microsatellite instability–high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph).Experimental Design:Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan–Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses.Results:Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively).Conclusions:MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.Experimental Design: We enrolled patients with metastatic HER2+ breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 17 months (95% CI: 16–28).Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR.

CCR Translation for This Article from HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab

PDF file, 37K, Human PBMCs Sample Preparation, Western Blot assay for Hsp90 Client Proteins, Luminex Assay for Hsp90 Client Proteins.

Purpose: We conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics of alvespimycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, given in combination with trastuzumab.Experimental Design: Patients were treated with trastuzumab followed by intravenous alvespimycin on a weekly schedule. Hsp90 client proteins were measured at baseline and serially in peripheral blood lymphocytes (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible.Results: Twenty-eight patients (25, breast; 3, ovarian) were enrolled onto three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m2 (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m2), and reversible grade III keratitis in two patients (80 mg/m2). Drug-related grade III toxicity included one episode each of fatigue, diarrhea, myalgia, and back pain. Common mild to moderate toxicities included diarrhea, fatigue, myalgia, arthralgia, nausea, blurry vision, headache, back pain, and dry eyes. There was one partial response and seven cases of stable disease (range, 4–10 months), all in HER2+ MBC. In addition, an ovarian cancer patient had complete resolution of ascites and pleural effusion that lasted 24.8 months. There was no change in PK upon weekly dosing. Hsp70 effect continued to increase across four weeks and was most pronounced at 80 and 100 mg/m2.Conclusion: The combination of alvespimycin and trastuzumab is safe and tolerable at MTD. Antitumor activity was seen in patients with refractory HER2+ MBC and ovarian cancer. The recommended dose of alvespimycin for further study in this combination is 80 mg/m2 weekly. Clin Cancer Res; 18(18); 5090–8. ©2012 AACR.

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Purpose: Microsatellite instability–high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). Experimental Design: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan–Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. Results: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). Conclusions: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

In the research and application of images, people are often only interested in the foreground or specific area of the image, so it is necessary to extract the specific area from the image, and image segmentation technology is the key to solving this problem. Aiming at the complex background and the color image with unclear target contour as the target image to be segmented, this paper first uses the texture and color of the image as the feature vector, and proposes an image segmentation algorithm based on SVM. The experimental results show that the segmentation accuracy is 91.23%. Secondly, in order to improve the accuracy of segmentation, the SVM algorithm is improved. The improved SVM algorithm is based on the grid search method to optimize the parameters C and g in the SVM. At the same time, the HIS color channel is added to the feature vector to obtain more Excellent SVM image segmentation model. Finally, the color image segmentation is verified and compared with the standard SVM algorithm. The experimental results show that the accuracy rate of the improved SVM algorithm reaches 97.263%, which improves the segmentation efficiency. It is verified that the improved model proposed in this paper can effectively segment complex color images.

This work was intended to explore the effect of circ-0005519 on the apoptosis of bronchial epithelial cells in children with severe asthma and its molecular mechanism. To this end, asthma’s inflammatory environment was simulated by using 1 mg/L lipopolysaccharide (LPS) to induce human bronchial epithelial 16HBE cells, which were considered the 16HBE model cells. After transfection, these 16HBE model cells were divided into following groups: control group, model+si-NC group, model+si-circ-0005519 group, model+miR-NC group, model+miR-625-5p group, model+si-circ-0005519+anti-miR-NC group, and model+si-circ-0005519+anti-miR-625-5p group. A series of experiments were then carried out, including RT-qPCR assay for testing circ-0005519 and miR-625-5p expressions, flow cytometry assay for analyzing cell apoptosis, western blot for testing protein expression, ELISA assay for detecting IL-6. TNF-α, IL-13, IL-8 expression, and dual-luciferase reporter confirm the targeted functions of circ-0005519 to miR-625-5p. The results displayed highly expressed circ-0005519 and lowly expressed miR-625-5p in 16HBE model cells induced by lipopolysaccharide. Furthermore, we also found increases in apoptosis, Bax expression, and levels of IL-6, TNF-α, IL-13, and IL-8, as well as a decrease in Bcl-2 expression. Additionally, our data revealed that silencing circ-0005519 or overexpressing miR-625-5p would affect these 16HBE model cells, including decreases in apoptosis, Bax expression, and levels of IL-6, TNF-α, IL-13, and IL-8, as well as an increase in Bcl-2 expression. The targeted binding function of circ-0005519 to miR-625-5p was also confirmed, in which interference miR-625-5p would weaken the influences of silencing circ-0005519 on 16HBE cells. These results suggested that silencing circ-0005519 could inhibit apoptosis of lipopolysaccharide-induced bronchial epithelial cells via targeted binding functions to miR-625-5p.

The interictal discharges of temporal lobe epilepsy (TLE) can be unilateral or bilateral. In addition, the ictal electroencephalogram (EEG) showed the discharges also tend to spread to the contralateral brain in TLE. The factors influencing unilateral and bilateral interictal discharges in TLE as well as ictal diffusion patterns in scalp EEG during onset of seizure were evaluated in the present study. This was a retrospective analysis of 129 patients with TLE. Cases were classified into unilateral and bilateral discharge groups based on interictal discharge patterns in the EEG. Differences between the two groups in age, gender, disease duration, seizure frequency, magnetic resonance imaging (MRI) findings, origin of TLE, antiepileptic drug (AED) administration, and ictal diffusion patterns during seizures were statistically analyzed. In addition, the differences in ictal diffusion patterns between left and right TLE were statistically analyzed. Statistically significant differences were not observed in gender, disease duration, seizure frequency, MRI findings, administration of AEDs, and ictal diffusion patterns between interictal unilateral and bilateral discharge groups but with statistically significant differences in age and side of origin of the TLE. In addition, whether the EEG-recorded diffusion pattern was confined to the same hemisphere or spread to both hemispheres was investigated and shown statistically significant differences between the left and right temporal lobes. Age and side of origin of TLE affects the TLE interictal discharge patterns. Older patients are more prone to bilateral discharges. Bilateral discharges are more common in right TLE, and the onset of EEG more likely to bilateral diffusion in right TLE.

Polydopamine/melamine composite microencapsulated red phosphorus (RP@PDA/MA) was prepared and applied as the flame retardant for epoxy resin (EP) in this work. For comparison, polydopamine (PDA) coated red phosphorus (RP@PDA) was also prepared. The microstructure, chemical composition and thermal decomposition of the as prepared samples were systematically characterized. The results showed that PDA and PDA/MA shell structures were fabricated successfully via convenient water-based processes at room temperature. The flame retardance of red phosphorus (RP), RP@PDA, and RP@PDA/MA on EP was evaluated. The results showed that EP blending with 7 wt% RP@PDA/MA passed V-0 degree in the vertical burning test (UL-94), reached a limited oxygen index (LOI) of 30.9% and decreased the peak heat release rate of EP by 65.1% in the cone calorimeter test. The satisfactory flame retardance can be attributed to the intumescent flame retardant system consisting of RP@PDA/MA. The PDA and PDA/MA shell structures also improved the compatibility between RP and EP, thus RP@PDA and RP@PDA/MA had less significant impact on the tensile–strain properties of EP.

Simple febrile convulsion (SFC) is a common disease that is mainly caused by fever from extracranial infections. In this study, we used proteomic approaches involving discovery and validation cohorts to examine the proteomes of serum from children who were diagnosed with SFC, children with fever but without convulsion, and healthy children (normal controls). We identified 86 proteins involved in different biological pathways that were significantly different between the SFC and normal control groups. Of these 86 proteins, 35 had higher expression in the SFC group compared with the normal control group, whereas 51 had lower expression. Notably, fibrinogen-related proteins involved in the coagulation system pathway were markedly decreased in the SFC group. Targeted and absolute quantification of fibrinogen-related proteins was performed and validated the potential of these proteins as biomarkers. Thus, fibrinogen-related proteins may participate in the pathophysiological process of SFC and may be potential biomarkers for the diagnosis of SFC.

Asthma is marked by chronic irritation in the airway lumen of the lungs due to the accretion of inflammatory cells that influence the regular inhalation process. An extended buildup of inflammation leads to oxidative pressure and the repression of antioxidant functions. In the current study, a potential compound, boldine, was tested for the containment of provocative markers along the path of antiasthmatic activity in an ovalbumin (OVA)-induced asthmatic mice model. As an effect, the boldine (10 and 20 mg/kg) treatment suppressed inflammatory cells such as eosinophil, macrophage, neutrophil, lymphocyte, and other inflammatory markers in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. Likewise, immunoglobulin E (IgE) levels were drastically condensed in the serum of boldine-treated animals. Levels of enzymatic and nonenzymatic antioxidants, such as superoxide dismutase (SOD) and glutathione (GSH), were upregulated in the boldine treatment group compared to the asthmatic control group, which displays the antioxidant effects of boldine on asthmatic animals. Interestingly, the reactive oxygen species (ROS) and malonaldehyde (MDA) levels were repressed in the BALF of boldine-treated mice groups. Therefore, the effects of boldine are significant for the management of asthma, reducing the accrual of inflammatory cells, along with other inflammatory markers, while improving antioxidant markers and containing ROS. Hence, boldine may be an option for clinical trials of chronic asthma management.

We consider the compressive sensing reconstruction for vibration signals, which are complex due to the harsh working environment. The recent fast iterative shrinkage-thresholding algorithm (FISTA) has paved the way for the signal reconstruction with a low complexity and high efficiency. Unfortunately, when extending to the vibration signals, the current algorithm still has some drawbacks such as the bad reconstruction effect. In this paper, we propose the improved fast iterative shrinkage-thresholding algorithm (IFISTA) to improve the reconstruction effect. Under the new scheme, the reconstruction is promoted by extracting information from the unstable signals in the process of iteration. Then the feature coefficients will be protected from shrinkage during iteration. The effectiveness of the IFISTA is verified by simulated signals and acquired signals. It is showed that the proposed scheme has superior performance in reconstruction and feature protection for vibration signals.

Objective: This study investigated whether pre-operative interictal discharge patterns detected by electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings affect the surgical prognosis in temporal lobe epilepsy (TLE) patients. Methods: A retrospective analysis of 115 cases of patients with refractory TLE was carried out from October 2010 to 2014 based on the classification of pre-operative interictal discharge patterns in EEG and MRI findings. The patients were followed up for 4 years after surgery. The ILAE method was used to assess differences in seizure-free rate among different types of interictal discharge pattern as well as in MRI findings. Results: A total of 115 cases were classified according to interictal discharge patterns in EEG, including normal cases, unilateral anterior discharge, unilateral multi-region discharge, and bilateral discharge. MRI findings were classified into negative results and positive results. Unilateral anterior and bilateral discharges showed statistically significant differences in post-operative seizure-free rates (p< 0.001). MRI-positive cases showed good overall post-operative outcome, irrespective of interictal discharge pattern in the EEG, whereas MRI-negative cases showed good overall prognosis if the interictal discharge pattern in EEG occurred in the unilateral anterior region. Conclusion: If the pre-operative interictal discharge pattern in EEG is confined to the unilateral anterior region, prognosis is good. If there are abnormalities in MRI findings, post-operative prognosis is good, regardless of pre-operative interictal discharge patterns in EEG. Surgical intervention is highly recommended for TLE patients with normal MRI findings and interictal discharge confined to the unilateral anterior region.

5584 Background: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States. Human epidermal growth factor 2 (HER2) overexpression or gene amplification occurs in 10-60% of EC. The addition of trastuzumab to carboplatin-paclitaxel chemotherapy improves survival in women with HER2-positive serous EC. However, criteria for assessment of HER2 status in EC are not standardized, and furthermore, intratumor heterogeneity may impact therapeutic efficacy. We aimed to identify factors associated with treatment response and survival outcomes in a retrospective cohort of ECs treated with anti-HER2 therapy. Methods: Patients with advanced/recurrent EC treated with trastuzumab or trastuzumab emtansine alone or in combination with chemotherapy from 2013-2021 at our institution were identified. Clinical and treatment information were retrieved from medical records. Central pathology review, HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) were performed. HER2 IHC was scored using modified ASCO/CAP 2007 guidelines for breast cancer. HER2 expression heterogeneity was defined as a 2-degree difference in staining intensity in ≥5% of tumor cells or discordant IHC score on different specimens. HER2 amplification (tumor/normal fold change) was also estimated from targeted next-generation sequencing (NGS). Best response was assessed by RECIST v1.1 as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), with clinical benefit defined as CR/PR/SD. Results: Among 39 patients included, median age was 69. Histologic subtypes included serous (n = 18, 46%), carcinosarcoma (n = 7, 18%), high-grade EC with ambiguous features (n = 13, 33%) and low-grade endometrioid carcinoma (n = 1, 3%). HER2 IHC results were 0 or 1+ (n = 2, 5%), 2+ (n = 17, 46%), 3+ (n = 18, 49%), with HER2 heterogeneity in 15 cases. By FISH, the HER2/CEP17 ratio was ≥2.0 in 34 (92%) and < 2.0 in 3 (8%); HER2 copy number (CN) was ≥6.0 in 25 (68%) and < 6.0 in 12 (32%). HER2 copy number ≥6.0 was significantly correlated with HER2 amplification by NGS ( p< 0.001). 18 (49%) patients had a co-existing somatic PIK3CA mutation. Amongst parameters assessed, only higher level of HER2 amplification by NGS was significantly associated with clinical benefit ( p= 0.036). None of these features were associated with progression-free survival. Notably, 2 patients with IHC 0/1+ had PD and 1 patient with IHC 3+, but non-amplified by FISH, achieved PR. Conclusions: In our cohort of EC patients treated with anti-HER2 therapy, higher level of HER2 amplification was associated with clinical benefit. Further studies with larger sample sizes are needed to determine whether any additional characteristics are associated with treatment response and survival.

Spasmodic torticollis is the most common focal dystonia and is characterized by aberrant involuntary contraction of muscles of the neck and shoulders, which greatly affects patients' quality of life. Consequently, patients with this condition often desire treatment to alleviate their symptoms. The common clinical treatments for spasmodic torticollis include interventions such as drug therapy, botulinum toxin injections, and surgery. Surgical treatment is feasible for patients who do not respond well to other treatments or who are resistant to drugs. The gradual improvement of surgeons' understanding of anatomy and the ongoing developments in surgical techniques since their advent in the 1640s have resulted in many innovative surgical approaches that have led to improvements in the treatment of spasmodic torticollis. Previously used surgical treatments that result in uncertain outcomes, various postoperative complications, and serious damage to motor functions of the head and neck have gradually been discontinued. Nerve dissection surgery is the most common surgical treatment for spasmodic torticollis. This article reviews existing research on nerve dissection surgery for the treatment of spasmodic torticollis and the history of its development, along with the advantages and disadvantages of various surgical improvements. This article aims to provide clinicians with practical advice.

Objective: To study whether there is a difference in peak and mean blood flow velocity between the left and right major cerebral vessels in patients with epilepsy.Methods: Sixteen patients with epilepsy underwent FDG18-PET-CT (PET) scan and electroencephalogram (EEG) examinations. Transcranial Doppler (TCD) was used to detect the peak flow velocity (PFV), mean flow velocity (MFV), and other hemodynamic indicators of bilateral anterior, middle, and posterior cerebral arteries in each patient. According to different patterns of the PET or interictal EEG, the differences in PFV, and MFV of corresponding vessels on both sides under different patterns were compared.Results: According to the PET of the low-metabolism region corresponding to the supplying artery, the PFV and MFV of the supplying artery in the low-metabolism region were lower than the value of the corresponding contralateral vessel. The PFV and MFV on the low metabolic side of PET were lower than that of the corresponding vessels on the opposite side. The PFV and MFV on the discharge side of interictal EEG were also lower than the PFV and MFV of the corresponding vessels on the opposite side. The MFV of posterior cerebral artery on the low metabolic side of PET or the interictal discharge side was significantly different from that of the contralateral vessels (P < 0.05). However, the other aforementioned differences in PFV and MFV did not achieve statistical significance.Conclusion: In epileptic patients, the PFV and MFV of main cerebral vessels on the PET hypometabolized side or the interictal discharge side was lower than that of corresponding vessels on the contralateral side. To some extent, the difference in the MFV of PCA between the bilateral sides can facilitate the lateral diagnosis of the epileptogenic zone.

Temporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE., Jingliang Zhang et al. examine how dysfunctional PKA signaling impacts neuronal activity and seizure susceptibility in a mouse model of temporal lobe epilepsy. Their data suggest that autophosphorylation of the RIIβ subunit regulates neuronal excitability, and may act as a future therapeutic target.

Background Lumbar cisterna drainage (LCD) is widely used in neurosurgery as an effective treatment for postoperative meningitis, vasospasm of subarachnoid hemorrhage and ventricular system hemorrhage, and for reducing intracranial pressure in patients with severe craniocerebral trauma. The purpose of this work was two-fold: to analyze the dynamic curve of cerebrospinal fluid (CSF) related indices in cases of postoperative meningitis after selective craniotomy and to provide reference data for the clinical treatment with LCD. Methods We conducted a retrospective study of LCD placement in patients who underwent either supratentorial craniotomy (n=23) or subtentorial craniotomy (m=28). Primary outcomes measured included pre-intervention and post-intervention dynamic changes of body temperature, and CSF biochemical parameters (white blood cell (WBC) count, polykaryocyte percentage, protein, glucose and chloride) over the course of 13 days of catheter placement. We also assessed the bivariate correlation between WBC count changes, polykaryocyte percentage, body temperature and daily CSF drainage volume. Finally, we analyzed the effect of average daily drainage volume, antibiotic choice, and surgical site on the WBC count change curves. Results After LCD, a trend of increased WBC count was observed on the first day of drainage, followed by an overall decrease in WBC count. There was a statistically significant ( P 0.05 ). Conclusions LCD is an effective method for the treatment of postoperative meningitis. The WBC count can decrease significantly by the fourth day after drainage, and placement of the LCD for six to seven days is ideal. An average drainage volume of 250-300 ml/d is safe and effective.

Objective Prospective data have demonstrated the efficacy of bevacizumab monotherapy in the treatment of advanced endometrial cancer. Bevacizumab is used off-label, and real-world data regarding the role of bevacizumab in endometrial cancer treatment are scant. In this largest single-institution retrospective study of its kind, we report our experience with bevacizumab monotherapy in the treatment of advanced/recurrent endometrial cancer. Methods All eligible patients (n = 101) had histologically confirmed endometrial cancer and were treated with bevacizumab at our institution from 2004 to 2017. Demographic data and tumor characteristics were obtained through chart review. Primary objective was response to therapy determined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Results Analysis included 13 grade 1/2 endometrioid, 15 grade 3 endometrioid, 44 serous, 8 carcinosarcoma, and 21 other/mixed histologies. No patients achieved complete (CR) or partial (PR) responses; 19 achieved stable disease (SD). The clinical benefit rate (CBR; CR + PR + SD) was 19% (95% CI: 12–28%). The CBRs were 7%, 17%, 21%, and 23% for patients with 1, 2, 3, and ≥ 4 prior treatment lines. Median PFS ranged from 2.6 months (2 lines) to 4.9 months (≥4 lines). The 3-year OS rate was 58% (95% CI: 47–67%). The median OS was 3.4 years (95% CI: 2.9–4.2), ranging from 2.5 years (2 lines) to 4.5 years (≥4 lines). The most common treatment-related adverse event was hypertension; 35 (78%) of 45 were grade 1 or 2. Conclusions In heavily pretreated advanced endometrial cancer, bevacizumab was associated with modest clinical efficacy and remains a viable palliative option in this setting.

Resume-job matching is one of the most important steps in recruitment chain. In big companies like Tencent, we routinely spend thousands of hours searching for potential candidates through internal and external recruiting platforms every day, which is tedious and passive. Besides, the traditional job descriptions are difficult to cover various hiring scenarios with surging diversified and personalized needs. To this end, in this paper, we propose an end-to-end deep neural network for active resume recommendation without dependence on job requirements. The key idea is to model latent preferences of recruiters by learning interactions of multi-field features with convolutional neural network. Based on real behavior data generated by the internal recruiting website, the experimental results show that our model improves resume click-through rate against a series of state-of-the-art methods. In this way, we find an effective approach to lower the time budgets for our recruiters.

Purpose The aim of the study was to investigate factors which may predispose patients to early neurological deterioration (END) and explore peripheral biomarkers for the prediction of END in cardiogenic cerebral embolism (CCE) patients. Methods Patients diagnosed with CCE within 24 hr of onset between January 2017 and January 2019 were included in this study. END was defined as an increase of ≥2 on the National Institutes of Health Stroke Scale (NIHSS) or the emergence of new neurological symptoms within 3 days of admission. Binary logistic regression was used to investigate the factors associated with END. Receiver operating characteristic (ROC) curves were then generated to determine the predictive value of the potential biomarkers and the optimal cutoff values. Results Of the 129 (male, 55.81%; mean age 71.85 ± 11.99 years) CCE patients, 55 patients with END were identified. Hemorrhage transformation (HT), coronary heart disease (CHD), diastolic blood pressure, cystatin C levels, NIHSS score, and platelet‐to‐lymphocyte ratio (PLR) at admission were independently associated with END. A peripheral cystatin C level ≥ 1.41 mg/L and a PLR ≥ 132.97 were predictive factors for END in CCE patients. The lymphocyte‐to‐monocyte ratio (LMR) was negatively independently associated with HT, and LMR, Early neurological deterioration (END) in the early phase of acute ischemic stroke (AIS) generally leads to a marked increase in poor prognosis due to diverse mechanisms. Cystatin C levels (cutoff value 1.41 mg/L, AUC 0.635, 95% CI 0.537–0.733, p = .009) and PLR (cutoff value 132.97, AUC 0.619, 95% CI 0.518–0.719, p = .02) were predictive of END, with high specificity and sensitivity. Hemorrhage transformation (HT) was independently associated with END, the lymphocyte‐to‐monocyte ratio (LMR) was negatively independently associated with HT, and LMR

Objective: To evaluate the relationship of the blood fibrinogen (FIB) degradation product (FDP) level and FDP/FIB ratio with seizure in young children with fever. Methods: A total of 35 children with simple febrile seizures and 80 children with fever but no seizure were selected. First, the differences in white blood cell (WBC), platelets (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), FIB, FDP, FDP/FIB ratio, and C-reactive protein (CRP) between 35 children with simple febrile seizures and 40 randomly selected children with fever but no seizure were retrospectively analyzed. Then, an ROC curve was used to determine the diagnostic utility of the FDP level, FDP/FIB ratio, and FDP+FDP/FIB ratio, and the best diagnostic cutoff points were selected. Finally, the diagnostic specificities of the three diagnostic indicators were verified by comparison with the results of all 80 children with fever but no seizure. Results: The FDP level and FDP/FIB ratio were significantly different between the two groups (P < 0.0001) and there was a positive correlation between the FDP and FIB levels. Both the FDP level and FDP/FIB ratio had good diagnostic value. An FDP ≥ 2.0 mg/L and FDP/FIB ratio ≥ 0.5 had good diagnostic specificities. Combined application of an FDP ≥ 2.0 mg/L and FDP/FIB ratio ≥ 0.5 improved the diagnostic power. Conclusions: The blood FDP level and FDP/FIB ratio may be related to seizures after fever, and an FDP ≥ 2.0 mg/L + FDP/FIB ratio ≥ 0.5 has good diagnostic specificity.

Given the available time and the maintenance degree, using the relationship between the maintenance degree and the maintenance time, this paper establishes an algorithm to judge whether the maintenance task can be completed within a certain time, and proposes a method for calculating the amount of equipment maintenance in the available time, which is extremely helpful for the maintenance decision making process especially with the support of computers.

Peng-Yu Chen, Xiao-Dong Li, Wei-Ning Ma, Han Li, Miao-Miao Li, Xin-Yu Yang, Shao-Yi Li Department of Neurosurgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Shao-Yi LiDepartment of Neurosurgery, Shengjing Hospital Affiliated to China Medical University, 39 Hua Xiang Road, Shenyang 110022, People’s Republic of ChinaEmail Dr_LSY2019@126.comPurpose: The recurrence and metastasis of glioma are closely related to complex regulatory networks among protein-coding genes, lncRNAs and microRNAs. The aim of this study was to investigate core genes, lncRNAs, miRNAs and critical ceRNA regulatory mechanisms, which are involved in lower-grade glioma (LGG) recurrence.Materials and Methods: We employed multiple datasets from Chinese Glioma Genome Atlas (CGGA) database and The Cancer Genome Atlas (TCGA) to perform comprehensive transcriptomic analysis. Further in vitro experiments including cell proliferation assay, luciferase reporter assay, and Western blot were performed to validate our results.Results: Recurrent LGG and glioblastoma (GBM) showed different transcriptome characteristics with less overlap of differentially expressed protein-coding genes (DEPs), lncRNAs (DELs) and miRNAs (DEMs) compared with primary samples. There were no overlapping gene in ontology (GO) terms related to GBM recurrence in the TCGA and CGGA databases, but there were overlaps associated with LGG recurrence. GO analysis and protein–protein interaction (PPI) network analysis identified three core genes: TIMP1, COL1A1 and COL6A2. By hierarchical cluster analysis of them, LGGs could be clustered as Low_risk and High_risk group. The High_risk group with high expression of TIMP1, COL1A1, and COL6A2 showed worse prognosis. By coexpression networks analysis, competing endogenous RNA (ceRNA) network analysis, cell proliferation assay and luciferase reporter assay, we confirmed that lncRNA HOXA-AS2 functioned as a ceRNA for miR-184 to regulate expression of COL6A2, which induced cell proliferation of low-grade glioma.Conclusion: In this study, we revealed a 3-hub protein-coding gene signature to improve prognostic prediction in LGG, and identified a critical ceRNA regulation involved in LGG recurrence.Keywords: lower-grade glioma, lncRNA, miRNA, HOXA-AS2, miR-184, COL6A2

Endothelial monocyte-activating polypeptide II (EMAP II) is a sensitive marker of neurotoxic injury, the expression of which increases significantly under conditions of stress, such as hypoxia or apoptosis. Studies have confirmed the extensive apoptosis of nerve cells in the brain following status epilepticus (SE), and the occurrence of SE can confer a hypoxic state on cells. The purpose of the present study was to observe the changes in the expression of EMAP II, and in the numbers and tight junction protein levels of micro-vascular endothelial cells in the hippocampus of rats with pilocarpine-induced SE. The protein expression levels of EMAP II, CD31, zonula occludens 1 (ZO-1) and occludin in the hippocampus were determined by immunofluorescence and western blot analyses. It was found that almost 75.6% of the rats in the SE group developed Racine stage IV-V seizures at approximately 44.7±18.8 min after the pilocarpine administration, and the 24-h mortality rate was almost 10.4%. The weight of the rats in the SE group was significantly decreased within 24 h following SE. Immunofluorescence staining revealed a low EMAP II expression in the hippo-campus of the rats in the control group; however, the numbers of EMAP II-positive cells were significantly increased in the SE group from 2 h to 21 days. The trend of EMAP II protein expression was consistent with that obtained with immunofluorescence staining. The numbers of CD31-positive microvascular endothelial cells were significantly increased from 24 h to 21 days compared with the levels in the control group. The protein expression of ZO-1 and occludin was most significantly decreased in the SE group. On the whole, the present study demonstrated that the expression of EMAP II in the rat hippocampus was upregulated in the SE model, which may promote angiogenesis and alter the TJ integrity of brain microvascular endothelial cells, with an increased number of CD31-positive microvascular endothelial cells and a decreased expression of ZO-1 and occludin.

Objective To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT). Methods All patients with EOC treated at our institution from 04/2015–08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score. Results Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS. Conclusions The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.