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Background:. Multiple techniques are commonly used for posterior cruciate ligament (PCL) reconstruction. However, the optimum method regarding the fixation of PCL reconstruction after PCL tears remains debatable. The purpose of this study was to compare the biomechanical properties among three different tibial fixation procedures for transtibial single-bundle PCL reconstruction. Methods:. Thirty-six porcine tibias and porcine extensor tendons were randomized into three fixation study groups: the interference screw fixation (IS) group, the transtibial tubercle fixation (TTF) group, and TTF + IS group (n = 12 in each group). The structural properties of the three fixation groups were tested under cyclic loading and load-to-failure. The slippage after the cyclic loading test and the stiffness and ultimate failure load after load-to-failure testing were recorded. Results:. After 1000 cycles of cyclic testing, no significant difference was observed in graft slippage among the three groups. For load-to-failure testing, the TTF + IS group showed a higher ultimate failure load than the TTF group and the IS group (876.34 ± 58.78 N vs. 660.92 ± 77.74 N [P

Chemotherapy is widely used in a variety of solid tumors, such as lung cancer, gastric cancer and breast cancer. The genotoxic drugs, such as cisplatin, suppress cancer progression either by inhibition cell proliferation or facilitating apoptosis. However, the chemotherapy resistance remains an urgent challenge in cancer therapy, especially in advanced stages. Several studies showed that the activation of pro-survival pathways, such as PI3K-AKT, participated in mediating chemotherapy resistance. The insights into the molecular mechanisms for underlying chemotherapy resistance are of great importance to improve cancer patient survival in advanced stages. The HOIP protein belongs to the RING family E3 ubiquitin ligases and modulates several atypical ubiquitination processes in cellular signaling. Previous studies showed that HOIP might be an important effector in modulating cancer cell death under genotoxic drugs. Here, we report that HOIP associates with PTEN and facilitates PTEN degradation in cancer cells. Depletion of HOIP causes cell cycle arrest and apoptosis, which effects could be rescued by PTEN silencing. Besides, the survival data from public available database show that HOIP expression correlates with poor survival in several types of chemotherapy-treated cancer patients. In conclusion, our study establishes a novel mechanism by which HOIP modulates PTEN stability and facilitates chemotherapy resistance in malignancies.

Background Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. Methods TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT–PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT–PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. Results In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. Conclusion Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Graphical abstract

Autophagy has been shown to maintain neural system homeostasis during stroke. However, the molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. This study aims to investigate the regulatory mechanisms of the pathway consisting of MEG3 (maternally expressed gene 3), microRNA-378 (miR-378), and GRB2 (growth factor receptor-bound protein 2) in neuronal autophagy and neurological functional impairment in ischemic stroke. A mouse model of the middle cerebral artery occluded–induced ischemic stroke and an in vitro model of oxygen-glucose deprivation–induced neuronal injury were developed. To understand the role of the MEG3/miR-378/GRB2 axis in the neuronal regulation, the expression of proteins associated with autophagy in neurons was measured by Western blotting analysis, and neuron death was evaluated using a lactate dehydrogenase leakage rate test. First, it was found that the GRB2 gene, up-regulated in middle cerebral artery occluded–operated mice and oxygen-glucose deprivation–exposed neurons, was a target gene of miR-378. Next, miR-378 inhibited neuronal loss and neurological functional impairment in mice, as well as neuronal autophagy and neuronal death by silencing of GRB2. Confirmatory in vitro experiments showed that MEG3 could specifically bind to miR-378 and subsequently up-regulate the expression of GRB2, which in turn suppressed the activation of Akt/mTOR pathway. Taken together, these findings suggested that miR-378 might protect against neuronal autophagy and neurological functional impairment and proposed that a MEG3/miR-378/GRB2 regulatory axis contributed to better understanding of the pathophysiology of ischemic stroke.

Our aim was to investigate factors predicting blood pressure (BP) variability during diagnostic cerebral angiography and associations between BP variability and clinical outcomes in patients with acute and subacute ischemic stroke and intracranial artery stenosis. 114 patients with ischemic stroke and intracranial artery stenosis (stenosis rate >50%) were recruited. Patients who underwent cerebral angiography within 3 days and 3–14 days of disease onset are referred to be Group A and Group S, respectively. BP variability in Group A was defined as the coefficient of variance (CV) of BP. Univariate and multivariate regression analyses were used to identify predictors of CV of BP and associations between CV of BP and clinical outcomes at discharge. In Group A patients, advanced age was associated with increased CV of SBP and diastolic blood pressure (DBP), and antihypertensive use was associated with lower CV of SBP. Male was associated with lower CV of DBP. In Group S, higher CV of SBP was associated with hypertension and antihypertensive use. Males had lower CV of SBP than females. The calcium channel blocker was associated with lower CV of DBP. Higher scores of the Stroke Scale at admission were significantly associated with poor clinical outcomes for both groups, while BP variability was not. Factors associated with BP variability are significantly different between stroke patients undergoing angiography within 3 days vs. 3–14 days after disease onset. BP variability is not significantly associated with clinical outcomes at discharge.

Background: The important effect of regular blood flow surveillance on arteriovenous fistula maintenance is emphasized. The ultrasonic dilution technique for blood flow surveillance can be performed during hemodialysis, but there are some limitations. Blood flow is traditionally measured by duplex Doppler ultrasound during the nondialysis period. However, the surveillance workload for arteriovenous fistula has increased with the rapid increase in the hemodialysis population size. Efficient methods for blood flow surveillance during hemodialysis are needed. Methods: Eighty-four hemodialysis patients with a forearm radiocephalic arteriovenous fistula were enrolled in this cross-sectional study. Each received blood flow measurements using ultrasonic dilution technique and duplex Doppler ultrasound during hemodialysis. Duplex Doppler ultrasound measurements included the blood flow of the brachial artery and radial artery. The correlations between these variables were analyzed. Results: The correlation coefficients ( r) between flow measured by ultrasonic dilution technique and brachial artery flow measured by duplex Doppler ultrasound, between flow measured by ultrasonic dilution technique and radial artery flow measured by duplex Doppler ultrasound, and between brachial artery flow and radial artery flow measured by duplex Doppler ultrasound were 0.724, 0.784, and 0.749, respectively (all p < 0.001). Conclusion: Blood flow measured by ultrasonic dilution technique was positively correlated with blood flow measured by duplex Doppler ultrasound during hemodialysis, suggesting that duplex Doppler ultrasound can be used to monitor the trends in the blood flow of the brachial artery and radial artery for timely intervention to improve patency during hemodialysis.

Breast cancer is the most common malignancy for women worldwide, while Triple Negative Breast Cancer (TNBC) accounts for 20% in all patients. Compared with estrogen receptor positive breast cancer, which could be effectively controlled via endocrine therapy, TNBC is more aggressive and worse in prognosis. It is therefore urgent and necessary to develop a novel therapeutic strategy for TNBC treatment. Recent studies identified Hippo signaling is highly activated in TNBC, which could be a driving pathway for TNBC progression. In our study, we determine RNF187 as a negative regulator for Hippo signaling activation. RNF187 depletion significantly decreases cell migration and invasion capacity in TNBC. These effects could be rescued by further YAP depletion. Depletion of RNF187 increases the YAP protein level and Hippo signaling target genes, such as CTGF and CYR61 in TNBC. Immuno-precipitation assay shows that RNF187 associates with YAP, promoting its degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Interestingly, Our clinical data reveals that RNF187 reversely correlates with YAP protein level and Hippo target genes. RNF187 tends to correlate with good prognosis in TNBC patients. Our study provides evidence to establish a proteolytic mechanism in regulation Hippo signaling activation in TNBC.

Breast cancer is one of the most common malignancies worldwide, while the luminal types (ERα positive) accounts for two third of all breast cancer cases. Although ERα positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ERα signaling might be a critical factor, which makes it urgent and important to reveal the potential molecular mechanism of ERα signaling. In our current study, we identified a new deubiquitination enzyme USP1 through screening the whole DUB (Deubiquitinases) siRNA library. The expression of USP1 is elevated in human breast cancer compared with normal mammary tissues. Importantly, USP1 expression levels are specially correlated with poor survival in ERα positive patients. USP1 depletion inhibited breast cancer cell progression and ERα signaling activity. Immuno-precipitation assays indicate that USP1 associates with ERα and promotes its stability possibly via inhibiting ERα K48-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by USP1 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.

Aim: Studies have suggested that genetic and environmental factors do not account for all risks and mechanisms of intracranial atherosclerotic stenosis (ICAS). DNA methylation may play a role in the progression of ICAS. Methods: DNA methylation profiles of peripheral blood leucocytes from 7 patients with early-onset ICAS and 7 perfectly matched controls were interrogated for the first time using the Illumina Infinium Human MethylationEPIC BeadChip. Afterward, functional analysis for differentially methylated genes was conducted. In addition, pyrosequencing verification was performed in an independent cohort comprising 21 patients with earlyonset ICAS and 21 age- and gender-matched controls. Results: A total of 318 cytosine-phosphate-guanine sites were found to be differentially methylated based on the established standards. Functional analysis annotated differentially methylated sites to atherosclerosis-related processes and pathways, such as the negative regulation of hydrolase activity (GO 0051346), type II diabetes mellitus (KEGG hsa04930), and the insulin signaling pathway (KEGG hsa04910). In addition, a differentially methylated site was also validated, cg22443212 in gene Rnf213, which showed significant hypermethylation in patients with early-onset ICAS compared with controls 59.56% (49.77%, 88.55%) vs. 44.65% (25.07%, 53.21%), respectively; P = 0.010). Receiver operating characteristic curve analysis showed that the area under the curve value of cg22443212 was 0.744 (95% confidence interval, 0.586–0.866; P = 0.002). Conclusions: We revealed that altered DNA methylation may play a role in the occurrence and development of ICAS. These results provided new epigenetic insights into ICAS.

Background and aims Circulating microRNAs (miRNAs) have recently emerged as promising biomarkers for acute ischaemic stroke (AIS). However, the expression profiles of miRNAs in AIS patients receiving intravenous thrombolysis, and their associations with outcome have not been investigated. Methods In a prospective cohort study, a total of 84 AIS patients, who received intravenous thrombolysis (21.4% received combined reperfusion therapy) and completed 3 month follow-up visits, were included. Favourable and unfavourable outcomes were defined as modified Rankin Scale (mRS) scores of 0–1 and 2–6, respectively. Plasma samples were collected at 24 h after thrombolysis. We used RNA sequencing to study miRNA profiles in 5 patients with unfavourable outcomes and 5 matched patients with favourable outcomes. Differentially expressed miRNAs were further validated in all cohorts using quantitative real-time polymerase chain reaction assays. Results After identification and validation, we found that miR-124-3p, miR-125b-5p and miR-192-5p levels were higher in patients with unfavourable outcomes than in patients with favourable outcomes. Logistic regressions and receiver-operating characteristic curve analyses demonstrated that these altered miRNAs may function as predictive biomarkers for outcome in AIS patients receiving thrombolysis, whether combined with endovascular thrombectomy or not. In addition, miR-124-3p and miR-125b-5p were closely associated with stroke severity. Conclusions A set of circulating microRNAs (miR-124-3p, miR-125b-5p and miR-192-5p) are associated with unfavourable 3 month outcomes and might have clinical utility in AIS patients receiving thrombolysis.

Background Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated. Methods Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts. Results MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV). Conclusion MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura. Electronic supplementary material The online version of this article (10.1186/s10194-019-1045-5) contains supplementary material, which is available to authorized users.

Severe haemorrhagic transformation (HT), a common complication of recombinant tissue plasminogen activator (rtPA) treatment, predicts poor clinical outcomes in acute ischaemic stroke. The search for agents to mitigate this effect includes investigating biomolecules involved in neovascularization. This study examines the role of Cathepsin K (Ctsk) in rtPA-induced HT after focal cerebral ischaemia in mice. After knockout of Ctsk, the gene encoding Ctsk, the outcomes of Ctsk+/+ and Ctsk−/− mice were compared 24 h after rtPA-treated cerebral ischaemia with respect to HT severity, neurological deficits, brain oedema, infarct volume, number of apoptotic neurons and activated microglia/macrophage, blood–brain barrier integrity, vascular endothelial growth factor (VEGF) expression and Akt-mTOR pathway activation. We observed that haemoglobin levels, brain oedema and infarct volume were significantly greater and resulted in more severe neurological deficits in Ctsk−/− than in Ctsk+/+ mice. Consistent with our hypothesis, the number of NeuN-positive neurons was lower and the number of TUNEL-positive apoptotic neurons and activated microglia/macrophage was higher in Ctsk−/− than in Ctsk+/+ mice. Ctsk knockout mice exhibited more severe blood–brain barrier (BBB) disruption, with microvascular endothelial cells exhibiting greater VEGF expression and lower ratios of phospo-Akt/Akt and phospo-mTOR/mTOR than in Ctsk+/+ mice. This study is the first to provide molecular insights into Ctsk-regulated HT after cerebral ischaemia, suggesting that Ctsk deficiency may disrupt the BBB via Akt/mTOR/VEGF signalling, resulting in neurological deficits and neuron apoptosis. Ctsk administration has the potential as a novel modality for improving the safety of rtPA treatment following stroke.

Purpose Identifying previous chronic cerebral hemorrhage (PCH), especially asymptomatic cases in patients with ischemic stroke, is essential for proper antithrombotic management. The study aimed to further clarify the prevalence of PCH and the associated factors in patients with acute ischemic stroke using multi-modal neuroimaging including susceptibility-weighted MR imaging (SWI). Methods This was a retrospective cross-sectional study of 382 patients with acute ischemic stroke. All patients underwent 3.0-T MRI for cranial SWI, 1.5-T or 3.0-T conventional cranial MRI, and cranial CT. Patients found with PCH were matched 1:4 with patients without PCH. Clinical manifestation, computed tomography, conventional cranial MRI, and cranial SWI were used to determine PCH. Clinical and neuroimaging findings between the patients with symptomatic vs. asymptomatic PCH were compared. Results Thirty-six patients (36/382, 9.4%) were determined to have had a PCH. Of these 36 patients, 17 (17/36, 47.2%, or 17/382, 4.5%) had asymptomatic PCH. Multivariable analysis showed that serum total cholesterol (OR = 0.510, 95%CI 0.312–0.832, P = 0.007), cerebral microbleeds (OR = 6.251, 95%CI 2.220–17.601, P = 0.001), and antithrombotic drugs history (OR = 3.213, 95%CI 1.018–10.145, P = 0.047) were independently associated with PCH. Asymptomatic PCH had similar clinical and neuroimaging characteristics with symptomatic PCH. Conclusion PCH is not uncommon in acute ischemic stroke patients. Total serum cholesterol, cerebral microbleeds on SWI, and history of antithrombotic drugs were independently associated with PCH in patients with acute ischemic stroke. Asymptomatic PCH, which is easier to be missed and has similar characteristics with symptomatic PCH, should draw much attention. Electronic supplementary material The online version of this article (10.1007/s00234-018-2141-y) contains supplementary material, which is available to authorized users.

Background: This study aimed to evaluate the predictive potential of contrast-enhanced computed tomography (CT)-based imaging biomarkers (IBMs) for the treatment outcomes of oesophageal squamous cell carcinoma (OSCC) patients after definitive concurrent chemoradiotherapy (CCRT).Methods: A total of 151 ESCC patients who underwent definitive CCRT were included in this retrospective study. All patients were separated randomly to a training cohort (n=97) and the validation cohort (n=54). Pre-treatment contrast-enhanced CT scans were obtained for all patients and used for the extraction of IBMs. An IBM score was constructed by using the least absolute shrinkage and selection operator with logistic regression analysis in training cohort and tested in the validation cohort. IBMsnomograms were built based on IBM score. The concordance index (C-index) was used to assess the performance of the nomograms. Finally, decision curve analysis was performed to estimate the clinical usefulness of the nomograms.Results: A total of 96 IBMs were extracted from each contrast-enhanced CT scan. The IBM score were consisted of 13 CT-based IBMs and were significantly correlated with 3-year overall survival (OS) and 3-year progression-free survival (PFS). Multivariate analysis revealed that IBM score was the independent prognostic factor. In the training cohort, the IBM score yielded an area under the curves (AUCs) of 0.802 (95% CI: 0.713–0.891, pConclusions: TheIBM score based on pre-treatment contrast-enhanced CT could predict the 3-year OS and 3-year PFS for OSCC patients after definitive CCRT. Further multicenter studies with larger sample sizes are warranted.

Introduction: Patients with arteriovenous fistulas are advised to avoid carrying heavy objects draped over the fistula arm. Awareness gradually leads to overprotection and a reduction in the use of the fistula arm. However, restricting motion in the fistula arm leads to decreased quality of life and diminished muscle strength. The current safety recommendations regarding lifting heavy items with the fistula arm are primarily based on experience. Few studies have provided evidence clarifying the scope of safe activity and the influence of load bearing on the continued patency of arteriovenous fistulas. Methods: This prospective observation was based on a long-term follow-up study in which 86 hemodialysis recipients with arteriovenous fistulas were randomized into either a dumbbell group or a handgrip group. The dumbbell group exercised with 6-lb dumbbells, while the handgrip group squeezed rubber balls. Postintervention primary patency and adverse events at the 6-month follow-up were analyzed. Results: No significant difference in postintervention primary patency was observed between the dumbbell group and the handgrip group at 6 months (97.4% vs 95.0%). There were two participants with high-flow fistulas in the dumbbell group and three in the handgrip group, with no significant difference between the two groups (5.3% vs 7.5%). In both groups, there were no other adverse events reported regarding cardiac failure, aneurysm, puncture site hematoma, or hemorrhage. Conclusion: Hemodialysis patients can safely use their fistula arm to lift objects weighing less than 6 lb, which encourages increased motion and helps preserve the functionality of the fistula arm.

Objective: The platelet-to-lymphocyte ratio (PLR) is a new marker of atherosclerotic inflammation and has been identified as a predictive factor in cardiovascular diseases, but its significance in patients with acute ischaemic stroke (AIS) who have undergone intravenous thrombolysis (IVT) is still unknown.Methods: Consecutive patients who were treated with IVT using recombinant tissue plasminogen activator (rtPA) for AIS were included from May 2012 to August 2018. The PLR was calculated according to platelet and lymphocyte counts within 24 h after thrombolysis therapy. Functional outcomes were assessed by the modified Rankin Scale (mRS) at 3 months after thrombolysis. Stroke severity was assessed by National Institutes of Health Stroke Scale (NIHSS) scores. The primary endpoint was an unfavorable outcome (mRS > 2), and the secondary endpoint was death at 3 months.Results: A total of 286 patients were included in the study. The median age was 69.5 (59.0–80.0) years, and 59.1% of patients were men. A total of 120 (42.0%) patients had an unfavorable outcome, and 38 (13.2%) died. Patients with an unfavorable outcome had significantly higher PLR values compared with those with a favorable outcome [172.5 (105.3–239.0) vs. 139 (97.0–194.5), P = 0.008], and the PLR values of the patients who died at 3 months were higher than those of the surviving patients [189.5 (127.5–289.0) vs. 142.0 (98.0–215.5), P = 0.006]. After adjustment for other variables, the PLR was independently associated with the two endpoints: unfavorable outcome (OR 2.220, 95% CI 1.245–3.957, P = 0.007) and death (OR 2.825, 95% CI 1.050–7.601, P = 0.040) at 3 months after thrombolysis. In addition, PLR was correlated with the NIHSS score (R = 0.230, P < 0.001).Conclusions: Higher PLR levels were independently associated with an unfavorable outcome and death at 3 months in AIS patients treated with IVT.

// Ting Zhuang 1, 2, * , Sifan Yu 1, 2, 3 * , Lichen Zhang 1, 2, 4 * , Huijie Yang 1, 2 , Xin Li 1, 2 , Yingxiang Hou 1, 2 , Zhenhua Liu 1, 2, 5 , Yuanyuan Shi 1, 2 , Weilong Wang 6, 7 , Na Yu 6, 7 , Anqi Li 1, 2, 8 , Xuefeng Li 9 , Xiumin Li 6, 7 , Gang Niu 10, 11, 12 , Juntao Xu 10, 11, 12 , Muhammad Sharif Hasni 12, 13 , Kun Mu 14 , Hui Wang 1, 2 and Jian Zhu 1, 2, 15 1 Research Center for Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China 2 Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China 3 Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Renal Cancer and Melanoma, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China 4 Laboratory of Genetic Regulators in the Immune System, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China 5 Synthetic Biology Remaking Engineering and Application Laboratory, School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, Henan, China 6 Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China 7 Center for Cancer Research, Xinxiang Medical University, Xinxiang, Henan, China 8 School of International Education, Xinxiang Medical University, Xinxiang, Henan, China 9 Department of Medical Oncology, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China 10 Department of Cancer genomics, LemonData biotech (Shenzhen) Ltd, Shenzhen, Guangdong, China 11 Phil Rivers Technology (Beijing) Ltd. Beijing, China 12 Institute of Biochemistry University of Balochistan, Quetta, Pakistan 13 Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden 14 Department of Pathology, School of Medicine, Shandong University, Jinan, Shandong, China 15 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA * Ting Zhuang, Sifan Yu and Lichen Zhang contribute equally to this study Correspondence to: Jian Zhu, email: jian.zhu@utsouthwestern.edu Ting Zhuang, email: zhuangting_83@qq.com Hui Wang, email: wanghui@xxmu.edu.cn Kun Mu, email: mukun@sdu.edu.cn Keywords: SHARPIN, ER alpha, breast cancer, ubiquitination, protein stability Received: May 17, 2017 Accepted: June 29, 2017 Published: August 19, 2017 ABSTRACT Estrogen receptor α is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. In our study, we identified the novel E3 ubiquitin ligase SHARPIN function to facilitate ERα signaling. SHARPIN is highly expressed in human breast cancer and correlates with ERα protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ERα positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ERα signaling is a potential SHARPIN target. SHARPIN depletion significantly decreases ERα protein level, ERα target genes expression and estrogen response element activity in breast cancer cells, while SHARPIN overexpression could reverse these effects. SHARPIN depletion significantly decreases estrogen stimulated cell proliferation in breast cancer cells, which effect could be further rescued by ERα overexpression. Further mechanistic study reveals that SHARPIN mainly localizes in the cytosol and interacts with ERα both in the cytosol and the nuclear. SHARPIN regulates ERα signaling through protein stability, not through gene expression. SHARPIN stabilizes ERα protein via prohibiting ERα protein poly-ubiquitination. Further study shows that SHARPIN could facilitate the mono-ubiquitinaiton of ERα at K302/303 sites and facilitate ERE luciferase activity. Together, our findings propose a novel ERα modulation mechanism in supporting breast cancer cell growth, in which SHARPIN could be one suitable target for development of novel therapy for ERα positive breast cancer.

Purpose The association between intracranial internal carotid artery (IICA) calcification and lacunes, white matter hyperintensity (WMH), and cerebral microbleeds (CMBs) has been well researched. However, enlarged cerebral perivascular space (PVS) has not yet been reported to correlate with intracranial internal carotid artery calcification. Therefore, the primary aim of this study was to investigate the relationship between IICA calcification and enlarged PVS. Methods A total of 189 patients with ischemic stroke in the middle cerebral artery territory who presented within 7 days of ictus from 2012 to 2015 were enrolled respectively. All patients were required to have undergone head computed tomography, magnetic resonance imaging, susceptibility-weighted magnetic resonance imaging, magnetic resonance angiography, or computed tomography angiography. Clinical characteristics were recorded. IICA calcification and enlarged PVS were semi-quantitatively evaluated, and the presence of lacunes, WMH, and CMBs was recorded. Results Of the 189 patients, 63.5% were male. Mean age of the patients was 68.6 ± 12.2 years. There were 104 patients with IICA calcification. Age, diabetes mellitus, lacunes, and white matter hyperintensity were significantly associated with IICA calcification (P

Background: Arteriovenous fistulas (AVF) have been the main vascular accesses for haemodialysis patients, but the maintenance after maturation poses serious challenges. Arm exercises promote the maturation of AVFs. However, few studies have evaluated the effect of arm exercise on matured AVF and addressed the intervention for late fistula failure. Objectives: The study was conducted to explore the effect of dumbbell exercise on mature AVF. Methods: 86 participants undergoing haemodialysis with AVFs were randomized into the control group and experimental group. The experimental group held 6-pound dumbbells on non-dialysis days for 3 months, while the control group squeezed rubber balls. Results: For blood flow of draining vein (DV; primary outcome), the between-group effects, interaction effect and time effect showed significant differences. A significant increase in blood flow of DV was observed in the dumbbell group at the 3rd month (mean difference, 359.50 [111.90–829.05] mL/min; p = 0.001). The difference in blood flow of AVF proximal artery, blood flow of brachial artery, the diameter of DV and the incidence of adverse events at 3 months (secondary outcomes) between the 2 groups was insignificant. Conclusion: Prolonged training with arm exercises is essential for patients with AVFs though the fistula has matured. The designed dumbbell exercise is an economical, effective intervention to maintain the function of AVF, especially for patients with potential reduction of access blood flow and no percutaneous transluminal angioplasty indication.

The brainstem has been discussed as the main player in the pathogenesis of migraine. Dysfunctional brainstem nuclei and their abnormal connections to other key brain centers may contribute to headache and other symptoms of migraine. In the present study, 32 patients with migraine without aura (MWoA) and 32 age- and sex-matched healthy controls (HCs) underwent resting-state fMRI scans. We used masked independent analysis (mICA) to investigate whether patients with MWoA exhibited abnormal brainstem nuclei-cortical functional connectivity (FC). The mICA can suppress adjacent physiological noise and prevent results from being driven by the much stronger signals of the surrounding structures. Regional homogeneity (ReHo) was used to investigate whether the brainstem regions with abnormal FC to other brain areas exhibited abnormal regional neuronal activity. Patients with MWoA showed significantly weaker FC between the posterior pons and the left superior parietal lobule, the left middle temporal gyrus, and the left middle frontal gyrus. Furthermore, patients with MWoA exhibited significantly decreased ReHo values in the posterior pons compared with HCs, and the posterior pons ReHo value was significantly negatively correlated with HIT-6 scores in the MWoA group. Patients with MWoA exhibited functional abnormalities in the posterior pons and weakened connections between the posterior pons and several key cortical brain areas involved in pain processing during the resting state. PERSPECTIVE: This study provided increased evidence that the pons is involved in the pathophysiological mechanism of migraine, and weakened connections suggest that the touch and pain sensation of migraine sufferers may not be properly relayed to cortical processing areas, which may be associated with the pathogenesis of MWoA.

Parkinson’s disease (PD) is a progressive neurological degenerative disorder characterized by impaired motor function and non-motor dysfunctions. While recent studies have highlighted the role of the cerebellum in PD, our understanding of its role in PD remains limited. In the present study, we used resting-state fMRI to evaluate dysfunctions within the cerebellum in PD patients treated with medication and drug-naive PD patients. We applied amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) analysis methods. Thirty-one patients with early stage PD (22 drug-naive and 9 medicated patients) and 31 gender- and age-matched healthy controls were recruited in this study. ALFFs increased in the left cerebellar areas (lobules VI/VIIb/CruI/CruII and the dentate gyrus) and right cerebellar areas (lobules VI/VIIb/VIIIa/CruI/CruII and the dentate gyrus) of all PD patients and in the left and right cerebellar areas (lobules VI/VIIb/CruI and the dentate gyrus) of drug-naive PD patients but were not significantly changed in medicated PD patients. DC increased in the right cerebellar areas of all PD patients and medicated PD patients. All PD patients and all drug-naive PD patients showed significantly weaker functional connectivity (FC) between the left cerebellum and the left medial frontal gyrus. However, FC was significantly stronger between the right cerebellum and the left precentral and right middle occipital gyri in the medicated PD patients than in controls. Furthermore, a correlation analyses revealed that ALFF z scores in the left cerebellum (lobule VI) and right cerebellum (lobule VI/CruI and dentate gyrus) were negatively correlated with Mini-Mental State Examination (MMSE) scores in all PD patients and drug-naive patients. These results indicate that the cerebellum plays an important role in PD, mainly by exerting a compensatory effect in early stage PD. Additionally, antiparkinsonian medication would modified PD-induced changes in local neural activity and FC in PD patients. The results of this study offer novel insights into the roles of the cerebellum in early stage drug-naive PD.

BackgroundBotulinum toxin type A (BoNT-A) is generally considered safe and is widely used to treat a variety of clinical conditions involving muscle hyperactivity and for cosmetic purposes. However, the effects of BoNT-A poisoning (botulism) on brain function are poorly understood.Methodology/principal findingsHerein, we investigated brain functions in 9 patients who received illegal cosmetic injections of botulinum and 18 matched controls by combining the analysis methods of regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) based on resting-state fMRI. Compared with the controls, the patients with botulism exhibited significantly reduced ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum extending to the parahippocampal gyrus and right posterior lobe of the cerebellum. The patients with botulism also showed weakened ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum.Conclusions/significanceThe results indicate that BoNT-A may modulate cerebral activation in specific areas, which may play roles in both the adverse effects of botulism and the mechanism underlying clinical treatment with BoNT-A.

Rationale The capsular warning syndrome (CWS) is a rare and special type of transient ischemic attacks (TIAs) syndrome. The pathophysiology of CWS is very complicate, and intracranial atherosclerotic stenosis (ICAS) is rare cause. Moreover, the effective and standard therapy has not yet been established. Patient concerns A 47-year-old man experienced repeated and exacerbated TIAs of right hemiparesis and dysarthria. Fourteen hours after the first episode of TIAs, he developed more severe right hemiparesis and dysarthria, the National Institute of Health Stroke Scale (NIHSS) score was 12 points, and did not recover in a long time. Diagnosis The computed tomography (CT) angiography displayed high stenosis in the M1 segment of the left middle cerebral artery. The patient was diagnosed as CWS with ICAS. Interventions Loading dose of clopidogrel and aspirin were started but were ineffective, then we used recombinant tissue plasminogen (r-tPA) for thrombolysis therapy after repeat CT scan that showed small acute infarcts in the right putamen and no bleeding. Outcomes The patient was successfully treated by r-tPA intravenous thrombolysis after loading dose of dual-anti-platelet. He recovered rapidly, and the NIHSS score was 0 point, modified Rankin Scale score was 0 point, and Barthel Index score was 100 points at 3-month follow-up. Lessons r-tPA combined with loading dose of dual antiplatelet appears safe and effective in carefully selected CWS patients with ICAS. The collection of similar cases and further randomized controlled trial research would be desirable.

Interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) signaling is known to promote inflammation and the genesis and maintenance of neuropathic pain. However, it remained mostly unknown how IL-33/ST2 signaling can be enhanced by neuropathic stimulations. Here, we report that the chronic constriction nerve injury (CCI)-induced increases in the expression of IL-33 and ST2 and a decrease in microRNA (miRNA)-547-5p not only in the dorsal root ganglia (DRG) but also in spinal dorsal horn (SDH) ipsilateral to the CCI. We found that increasing endogenous miRNA-547-5p by the intrathecal (i.t.) infusion of agomir-miR-547-5p did not produce any effect in naive rats but blocked the CCI-induced increases in the IL-33 and ST2, and pain sensitivity. The reducing endogenous miRNA-547-5p by the i.t. delivering antagomir-miR-547-5p into naive rats caused significant changes in IL-33 and ST2 expressions in both the DRG and SDH, and pain sensitivity, which were similar to those induced by the CCI. Since increasing IL-33 by the i.t. infusion of recombinant IL-33 produced no change in the expression of miR-547-5p, and the CCI still reduced miR-547-5p expression in rats with the IL-33 knockdown, we conclude that the reduction of miR-547-5p can be an upstream event leading to the enhancement of IL-33/ST2 signaling induced by the CCI. The intravenous application of bone marrow stromal cells (BMSCs) reduced the depression of miR-547-5p in both the DRG and SDH, and pain hypersensitivity produced by the CCI or antagomir-miR547-5p application. However, the BMSC effect was significantly occluded by the pretreatment with miR-547-5p agomir or the IL-33 knockdown, demonstrating a novel mechanism underlying the BMSC therapy.

Breast cancer ranks No.1 in women cancer worldwide, while 60-70% are estrogen receptor alpha positive. The estrogen selective modulators, such as tamoxifen, become the effective drugs for controlling ER alpha breast cancer progression. However, tamoxifen resistance will develop during long-time treatment and cancer progression. Thus, further understanding of ER alpha signaling becomes necessary for the improvement of breast cancer therapy. Here, we identify TRIM56 as a novel regulatory factor in ER alpha signaling. TRIM56 expression is positive correlated with ER alpha and PR in breast cancer samples and is related to poor prognosis in endocrine therapy patients. TRIM56 depletion significantly decreases ER alpha signaling activity and ER alpha positive breast cancer proliferation in vitro and in vivo. TRIM56 associates with AF1 domain of ER alpha via its WD40 domain in the cytoplasm. TRIM56 prolongs ER alpha protein stability, possibly through targeting ER alpha K63 linked ubiquitination. In conclusion, our study reveals an interesting post-translational mechanism between TRIM56 and ER alpha in breast cancer progression. Targeting TRIM56 could be a promising approach for ER alpha positive breast cancer. Funding Statement: The project was supported by the National Science Foundation for Young Scientists of China (No. 8170110153, Ting Zhuang), the Joint Fund of the National Natural Science Foundation of China (No.U1604190, Jian Zhu; U1704169, Xiumin Li), the Program for Innovative Research Team (in Science and Technology) in University of Henan Province (No.15IRTSTHN025, Hui Wang), the National High Technology Research and Development Program of China (2012AA02A201-1), the Foundation of Henan Educational Committee (No.16A310014 and No.17A310025, Jian Zhu and Ting Zhuang), and the Program for Ph.D. starting research funding from Xinxiang Medical University (Ting Zhuang and Jian Zhu). This study is funded by graduate innovative practice base for clinical medicine of Xinxiang Medical University, Yashijie medical laboratory institute，School of laboratory medicine, Xinxiang Medical University Declaration of Interests: The authors claim no conflict of interest. Ethics Approval Statement: This study was reviewed and approved by the Ethical Board at Xinxiang Medical University. This usage of clinical samples was reviewed and approved by the Ethical Board at the Qilu Hospital of Shandong University with written informed consents from all the patients.

Long-term headache attacks may cause human brain network reorganization in patients with migraine. In the current study, we calculated the topologic properties of functional networks based on the Brainnetome atlas using graph theory analysis in 29 female migraineurs without aura (MWoA) and in 29 female age-matched healthy controls. Compared with controls, female MWoA exhibited that the network properties altered, and the nodal centralities decreased/increased in some brain areas. In particular, the right posterior insula and the left medial superior occipital gyrus of patients exhibited significantly decreased nodal centrality compared with healthy controls. Furthermore, female MWoA exhibited a disrupted functional network, and notably, the two sub-regions of the right posterior insula exhibited decreased functional connectivity with many other brain regions. The topological metrics of functional networks in female MWoA included alterations in the nodal centrality of brain regions and disrupted connections between pair regions primarily involved in the discrimination of sensory features of pain, pain modulation or processing and sensory integration processing. In addition, the posterior insula decreased the nodal centrality, and exhibited disrupted connectivity with many other brain areas in female migraineurs, which suggests that the posterior insula plays an important role in female migraine pathology.

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.

Alzheimer's disease (AD) is a typical hippocampal amnesia and the most common senile dementia. Many studies suggest that cognitive impairments are more closely correlated with synaptic loss than the burden of amyloid deposits in AD progression. To date, there is no effective treatment for this disease. Paeonol has been widely employed in traditional Chinese medicine. This compound improves learning behavior in an animal model; however, the mechanism remains unclear. In this study, Paeononlsilatie sodium (Pa), a derivative of Paeonol, attenuated D-galactose (D-gal) and AlCl3-induced behavioral damages in rats based on evaluations of the open field test (OFT), elevated plus maze test (EPMT), and Morris water maze test (MWMT). Pa increased the dendritic complexity and the density of dendritic spines. Correlation analysis indicated that morphological changes in neuronal dendrites are closely correlated with behavioral changes. Pa treatment reduced the production of Aβ, affected the phosphorylation and redistribution of cofilin1 and inhibited rod-like formation in hippocampal neurons. The induction of D-gal and AlCl3 promoted the expression of RAC1/CDC42 expression; however, the tendency of gene expression was inhibited by pretreatment with Pa. Taken together, our results suggest that Pa may represent a novel therapeutic agent for the improvement of cognitive and emotional behaviors and dendritic morphology in an AD animal model.

Purpose – Fixture design is a complicated task requiring both intensive knowledge and experience. This paper aims to present a computer-aided fixture design (CAFD) system framework based on design reuse technology. Design/methodology/approach – Fixture design domain ontology is constructed by analyzing fixture design document corpus. A design reuse engine is proposed to realize fixture design knowledge retrieval and fixture model retrieval based on ontology and find fixture design cases similar to fixture design problem, and then use evolutionary methods to modify the retrieved model to meet the design requirements and then generate a new fixture. Findings – The paper finds that the proposed framework is an efficient tool to improve efficiency of fixture design. Practical implications – Fixture design existing experience and cases can be used efficiently reused and to advance new fixture design processes. Originality/value – This paper presents a CAFD system framework capable of carrying out fixture design through full using of the existing fixture design resource and experienced knowledge.

// Cai Qun Bie 1, * , Xu You Liu 2, * , Ming Rong Cao 3, * , Qiu Yan Huang 4 , Hui Jun Tang 1 , Min Wang 4 , Guo Li Cao 4 , Ting Zhuang Yi 4 , Sheng Lan Wu 1 , Wei Jie Xu 4 , Shao Hui Tang 4 1 Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, China 2 Department of Gastroenterology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 3 Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China 4 Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Shao Hui Tang, email: tangshaohui206@163.com Keywords: IGF-1R, HCC, lentiviral vector, RNA interference, gene therapy Received: May 02, 2016 Accepted: October 26, 2016 Published: November 02, 2016 ABSTRACT The insulin-like growth factor-1 receptor (IGF-1R) overexpression contributes to the development of a variety of cancers. The present study explored the role of IGF-1R in the development and progression of hepatocellular carcinoma (HCC) and the possibility of IGF-1R silencing by lentivirus-mediated RNA interference (RNAi) as a therapeutic target for HCC. We showed that IGF-1R mRNA was up-regulated in Huh7 and Hep3B cells and human HCC tissues, and that IGF-1R knockdown by RNAi led to decreased proliferation, apoptosis induction, and decreased migration and invasion of Huh7 and Hep3B cells. Further, the in vivo study indicated that IGF-1R knockdown markedly diminished the tumorigenesis and metastasis of Huh7 xenograft. Moreover, the intratumoral administration of lentivirus-IGF-1R siRNA led to significant tumor growth inhibition in an established Huh7 xenograft model. Mechanistic investigations showed that midkine was found to be the most significantly down-regulated protein in Huh7 cells with IGF-1R knockdown, and ectopic overexpression of midkine significantly rescued inhibition of Huh7 cell proliferation, migration, and invasion caused by IGF-1R suppression. Collectively, these data suggest that IGF-1R inhibition by RNAi can significantly suppress HCC growth and invasion at least partially through down-regulating midkine expression, and IGF-1R is a potential target for HCC gene therapy.

This experiment collected sound signals of four different cars driving at different speeds on highway and replayed the noise samples with playback software HEAD Audio Recorder. The subjective evaluation tests were carried out with paired comparison method. Evaluating models between subjective evaluation and objective psychoacoustic parameters were established with SPSS analysis software.

The semantic retrieval of the engineering domain knowledge is critical in many engineering activities, e.g., product design and process planning. To address the problems with existing keyword-based and semantic-enable methods, we propose an ontology-based semantic retrieval scheme for knowledge search and retrieval from domain documents. In our scheme, domain ontology is first constructed using the graph-based approach to automating construction of domain ontology GRAONTO proposed by our group, and query semantic extension and retrieval are then adopted for semantic-based knowledge retrieval. For query semantic extension, latent semantic analysis is adopted to discover the latent semantic relationships between queries and ontology semantic features, and ontology semantic graph is used to represent the query. For semantic retrieval, a graph-based k-means method is proposed to partition the domain documents into several clusters, and a hierarchical searching strategy is employed for document retrieval. Finally, experimental results on the fixture design corpus verify the benefits of the proposed scheme.

In order to extract the pixels of teeth from 3D Cone Beam Computed Tomography (CBCT) image, in this paper, a novel 3D segmentation approach based on deformable surface mode is developed for 3D tooth model reconstruction. Different forces are formulated to handle the segmentation problem by using different strategies. First, the proposed method estimates the deformation force of vertex model by simulating the deformation process of a bubble under the action of internal pressure and external force field. To handle the blurry boundary, a “braking force” is proposed deriving from the 3D gradient information calculated by transforming the Sobel operator into three-dimension representation. In addition, a “border reinforcement” strategy is developed for handling the cases with complicate structures. Moreover, the proposed method combines affine cell image decomposition (ACID) grid reparameterization technique to handle the unstable changes of topological structure and deformability during the deformation process. The proposed method was performed on 510 CBCT images. To validate the performance, the results were compared with those of two other well-studied methods. Experimental results show that the proposed approach had a good performance in handling the cases with complicate structures and blurry boundaries well, is effective to converge, and can successfully achieve the reconstruction task of various types of teeth in oral cavity.

This paper proposes a carrier tracking method based on the Kalman Filter (KF) for the high dynamic target tracking. In the proposed method, the carrier tracking is achieved via the phase locked loop (PLL) serially assisted by the frequency locked loop (FLL). Furthermore, based on the KF theory, we analyse the carrier tracking loop and get the system equation of PLL and FLL. The proposed method can overcome high dynamic effects and achieve high accuracy tracking with good stability in low carrierto-noise ratio (CNR) circumstance. Compared to the traditional Infinite Impulse Response (IIR) filter tracking method, the proposed method has better tracking performance. Simulation results verify the effectiveness of the proposed method.

To compare the outcomes and treatment-related toxicities of two chemoradiotherapy schedules given to the patients with unresectable locally advanced non-small cell lung cancer (NSCLC): sequential chemotherapy with accelerated hypofractionated radiotherapy (SCRT), and concurrent chemotherapy with standard radiotherapy (CCRT), 68 patients from two prospective clinical trials were included. Thirty-four patients were treated with SCRT using an accelerated hypofractionated radiation schedule, 34 patients received CCRT with standard radiation. Between the two treatment groups there were no significant differences in terms of overall survival, progression-free survival (PFS), locoregional-PFS or distant metastasis-PFS. For the SCRT group, the median survival time and 2- and 4-year overall survival rates were 19 months, 38.2%, and 23.5%, respectively, and for the CCRT group these were 19 months, 44.1%, and 19.6%. Esophageal and constitutional toxicities were more pronounced in the CCRT group, while there was no significant difference in pulmonary toxicities. The results suggest that for unresectable stage III NSCLC, the outcomes of SCRT with accelerated hypofractionated radiotherapy and CCRT with standard radiotherapy are similar, but the toxicities associated with treatment are less in the SCRT group.

In recent years, e-learning system has become more and more popular and many effective assessment systems have been proposed to offer students for convenience of their self-assessment. However, conventional test systems simply provide students a score, and do not provide adaptive learning guidance for students. Thus, how to automatically diagnose student's learning status and provide learning help becomes an interesting issue. This study proposes an assessment model based on Bayesian Networks, which assesses learning status by knowledge map after absorbing and analyzing test results. In order to form adaptive and tailored feedback, rule inference and exact inference are applied to combine Knowledge map with teacher's experience rules. Experimental results have demonstrated that the novel model benefits students and deserves further investigation.

Plagiarism in students programming assignment submissions causes considerable difficulties for course designers. Efficient detection of plagiarism in programming assignments of students is important to the educational procedure. This paper proposes a metric, based on information distance, to measure similarity between two programs. Furthermore, clustering analysis, based on shared near neighbors, is applied in order to provide more beneficial and detailed information about the program plagiarism. Experimental results demonstrate that our software has clear advantages over other plagiarism detection systems and it is quite beneficial to teachers to get rid of time-consuming and toilsome tasks. Key words: Program plagiarism, Detection, Information distance, Clustering

A web-based operational skills examination and evaluation system is designed and implemented for computer courses. It consists of four systems, including preparation, examination, monitor and auto-grading subsystem. Various techniques involving DCOM, mark-method and fuzzy-match are adopted in this system, and a universal approach is generalized to enable auto-grading system suitable for different operated results. This system has been successfully applied in operational skills’ evaluation and training, such as programming, editing documents, using Microsoft Windows.

Rising chip densities have led to dramatic improvements in the costperformance ratio of processors. At the same time, software costs are burgeoning. Large software systems are expensive to develop and are riddled with errors. Certain types of defects (e.g., those related to memory access, concurrency, and security) are particularly difficult to locate and can have devastating consequences. We believe it is time to explore using some of the increasing silicon real estate to provide extra functionality to support software development. We propose dedicating a portion of these new transistors to provide hardware structures to enhance software development, make debugging more efficient, increase reliability, and provide run-time security.