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Brain functional connectivity (FC) networks derived from resting-state functional magnetic resonance imaging (rs-fMRI) have been widely applied to automated identification of brain disorders, such as Alzheimer's disease (AD) and attention deficit hyperactivity disorder (ADHD). To generate compact representations of FC networks, various thresholding strategies have been developed to analyze brain FC networks. However, existing studies usually employ predefined thresholds or percentages of connections to threshold FC networks, thus ignoring the diversity of temporal correlation (particularly strong associations) among brain regions in same/different subject groups. Also, it is usually challenging to decide the optimal threshold or connection percentage in practice. To this end, in this paper, we propose a distribution-guided network thresholding (DNT) method for functional connectivity analysis in brain disorder identification with rs-fMRI. Specifically, for each functional connectivity of a pair of brain regions, we proposed to compute its specific threshold based on the distribution of connection strength (i.e., temporal correlation) between subject groups (e.g., patients and normal controls). The proposed DNT can adaptively yield FC-specific threshold for each connection in brain networks, thus preserving the diversity of temporal correlation among brain regions. Experiment results on both ADNI and ADHD-200 datasets demonstrate the effectiveness of our proposed DNT method in fMRI-based identification of AD and ADHD.

Introduction In this study, we performed a consecutive macropathologic analysis to assess microscopic extension (ME) in high-grade glioma (HGG) to determine appropriate clinical target volume (CTV) margins for radiotherapy. Materials and methods The study included HGG patients with tumors located in non-functional areas, and supratotal resection was performed. The ME distance from the edge of the tumor to the microscopic tumor cells surrounding brain tissue was measured. Associations between the extent of ME and clinicopathological characteristics were evaluated by multivariate linear regression (MVLR) analysis. An ME predictive model was developed based on the MVLR model. Results Between June 2017 and July 2019, 652 pathologic slides obtained from 30 HGG patients were analyzed. The mean ME distance was 1.70 cm (range, 0.63 to 2.87 cm). The MVLR analysis identified that pathologic grade, subventricular zone (SVZ) contact and O6-methylguanine-DNA methyltransferase (MGMT) methylation, isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion status were independent variables predicting ME (all P ME = 0.672 + 0.513XGrade + 0.380XSVZ + 0.439XMGMT + 0.320XIDH + 0.333X1p/19q. The R-square value of goodness of fit was 0.780. The receiver operating characteristic curve proved that the area under the curve was 0.964 (P Conclusion ME was heterogeneously distributed across different grades of gliomas according to the tumor location and molecular marker status, which indicated that CTV delineation should be individualized. The model could predict the ME of HGG, which may help clinicians determine the CTV for individual patients. Trial registration The trial was registered with Chinese Clinical Trial Registry (ChiCTR2100046106). Registered 4 May 2021-Retrospectively registered.

The efficacy of crizotinib for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) patients with brain metastasis is controversial. Real-world research data are needed as further evidence. We conducted a multicenter, retrospective study to explore how crizotinib affects the control of brain metastasis and the survival outcomes among Chinese patients. We reviewed the medical records of unselected ALK-rearranged NSCLC patients treated with crizotinib at five hospitals in China from January 1, 2013 to November 30, 2017. Patients developing brain metastasis either before or during crizotinib treatment were included. Survival outcomes were analyzed by the Kaplan–Meier method, and prognostic factors were analyzed by multivariate Cox regression. A total of 174 patients were included in the analysis; 95 of these patients had baseline brain metastasis, while 79 patients developed brain metastasis during crizotinib treatment. Among patients with baseline brain metastasis, the median intracranial time to progression was 19.3 months (95% confidence interval [CI] 12.5–26.2) and the median overall survival (OS) was 53.4 months (95% CI not reached). A total of 135 patients experienced intracranial progression, and 94 of these patients continued crizotinib beyond progressive disease (CBPD). There was no significant difference in the median OS between patients with CBPD and without CBPD (48.3 months vs 53.4 months; p = 0.296). ALK-rearranged advanced NSCLC patients with baseline brain metastasis can still achieve OS benefits from crizotinib treatment. However, patients with intracranial progression may not obtain a long-term survival benefit from continuation of CBPD.

Background Crizotinib is associated with a favorable survival benefit in patients with ALK‐positive non‐small cell lung cancer (NSCLC); however, a subset of patients harboring ALK rearrangement shows a poor response. Methods We collected the clinical features and survival outcomes of 28 primary‐resistant responders (PRR) with progression‐free survival (PFS) of < 3 months on crizotinib and compared these with 78 long‐term responders (LTR) that achieved > 24 months PFS (control). Results Primary resistance was observed in 6.5% of the patients. The median PFS of the PRR and LTR groups was 1.2 months (95% confidence interval [CI] 0.70–1.73) and 47.0 months (95% CI 34.39–59.64), respectively. A better Eastern Cooperative Oncology Group performance status score was significantly associated with longer PFS (odds ratio 0.06, 95% CI 0.01–0.33; P = 0.001). The median overall survival (OS) of the PRR group was 8.4 months (95% CI 3.47–13.42) and crizotinib as first‐line treatment was an independent predictive factor for survival outcome (P = 0.005). Patients administered ALK‐tyrosine kinase inhibitors after crizotinib progression had significantly longer survival than the PRR group treated with best supportive care (P = 0.007), but no significant difference was found between ALK‐tyrosine kinase inhibitor treatment and single chemotherapy (P = 0.944). Conclusion Patients with primary resistance to crizotinib displayed unfavorable survival outcomes and the underlying mechanism cannot be identified in clinical features. Nevertheless, next‐generation ALK inhibitors and chemotherapy after crizotinib progression could confer a therapeutic and survival benefit in this population.

Objective: Glioma is one of the leading causes of death worldwide with high incidence, recurrence, and mortality. Interleukin-10 (IL-10) is a cytokine with dual function in many types of tumors. Although IL-10 is overexpressed and promotes tumor progression in human primary brain tumor, the mechanisms are largely unknown. Materials and Methods: Glioma cells were treated with different dosages of IL-10. The cell growth was detected by CCK-8, and the invasion was measured by Transwell. The relative expression of messenger RNAs was detected by quantitative real-time polymerase chain reaction. Results: We found that IL-10 treatment significantly enhanced glioma cell growth and invasion. Moreover, KPNA2 was significantly upregulated after treatment with IL-10. By performing knockdown experiments, we found that the glioma cell growth and invasion were significantly declined. Conclusions: The results indicated that knockdown of KPNA2 significantly inhibited the growth and invasion of glioma cells. Moreover, IL-10 promotes glioma progression via upregulation of KPNA2. This study will be of important significance and provides a potential target for treatment of patients with glioma.

Objective Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in clinical trials. We conducted this retrospective multicenter study to assess the outcomes of crizotinib therapy in, to our knowledge, a large sample cohort of patients with ALK-positive advanced NSCLC. Methods We reviewed the medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at 5 cancer centers in China from January 2013 to November 2017. Clinical data were collected from the initiation of crizotinib therapy to Response Evaluation Criteria in Solid Tumors (RECIST)-defined progressive disease (PD). Results A total of 428 eligible ALK-positive NSCLC patients were enrolled, 273 (63.8%) of whom received crizotinib as first-line treatment. The median progression-free survival (PFS) and overall survival (OS) from the initiation of crizotinib treatment were 14.4 [95% confidence interval (95% CI), 12.4−16.4] months and 53.4 (95% CI, 33.7−73.1) months, respectively. In subgroup analyses, patients who received crizotinib as first-line treatment showed a higher disease control rate (DCR) and a longer median OS compared with second-/later-line crizotinib treatment (94.8% and OS not reachedvs. 89.0% and 40.5 months, respectively). For 261 patients with RECIST-defined PD, multivariate Cox analysis revealed that in patients who received first-line crizotinib therapy, continued crizotinib beyond progressive disease (CBPD) and next-generation ALK inhibitors after crizotinib failure were associated with improved survival. Conclusions This study has demonstrated the clinically meaningful benefit of crizotinib treatment in a large cohort of Chinese ALK-positive NSCLC patients. CBPD and next-generation ALK inhibitor treatment may provide improved survival after RECIST-defined progression on crizotinib.

BackgroundGlioma is one of the highly fatal primary tumors in the central nervous system. As a major component of tumor microenvironment (TME), immune cell has been proved to play a critical role in the progression and prognosis of the diffuse lower-grade gliomas (LGGs). This study aims to screen the key immune-related factors of LGGs by investigating the TCGA database.MethodsThe RNA-sequencing data of 508 LGG patients were downloaded in the TCGA database. ESTIMATE algorithm was utilized to calculate the stromal, immune, and ESTIMATE scores, based on which, the differentially expressed genes (DEGs) were analyzed by using “limma” package. Cox regression analysis and the cytoHubba plugin of Cytoscape software were subsequently applied to screen the survival-related genes and hub genes, the intersection of which led to the identification of SERPINE1 that played key roles in the LGGs. The expression patterns, clinical features, and regulatory mechanisms of SERPINE1 in the LGGs were further analyzed by data mining of the TCGA database. What’s more, the above analyses of SERPINE1 were further validated in the LGG cohort from the CGGA database.ResultWe found that stromal and immune cell infiltrations were strongly related to the prognosis and malignancy of the LGGs. A total of 54 survival-related genes and 46 hub genes were screened out in the DEGs, within which SERPINE1 was identified to be significantly overexpressed in the LGG samples compared with the normal tissues. Moreover, the upregulation of SERPINE1 was more pronounced in the gliomas of WHO grade III and IDH wild type, and its expression was correlated with poor prognosis in the LGG patients. The independent prognostic value of SERPINE1 in the LGG patients was also confirmed by Cox regression analysis. In terms of the functions of SERPINE1, the results of enrichment analysis indicated that SERPINE1 was mainly enriched in the immune‐related biological processes and signaling pathways. Furthermore, it was closely associated with infiltrations of immune cells in the LGG microenvironment and acted synergistically with PD1, PD-L1, PD-L2.ConclusionThese findings proved that SERPINE1 could serve as a prognostic biomarker and potential immunotherapy target of LGGs.

Ceritinib shows efficacy in ALK+ NSCLC patients with BM. However, the disease will inevitably progress over time due to acquired resistance. We now report a case with BM from advanced lung adenocarcinoma with ALK mutations who exhibited a surprising and long-term response to treatment of ceritinib combined with bevacizumab.

Background Family with sequence similarity 111 member A (FAM111A), as a replication factor required for proliferating cell nuclear antigen (PCNA) loading, has been demonstrated a possible association with carcinogenesis. However, the role of FAM111A in lower-grade glioma (LGG) remains unclear. We aim at investigating the expression and function of FAM111A in lower-grade glioma at the molecular and clinical levels. Methods In total, 711 lower-grade glioma samples were analyzed in our research, including 182 RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) dataset and 529 RNA-seq data from The cancer Genome Atlas (TCGA) dataset. R language and the GraphPad software were used for the majority of statistical analysis and graphical work. Results FAM111A expression was overexpressed in WHO grade III and IDH-wildtype lower-grade glioma. FAM111A was significantly downregulated in the IDHmut-Codel molecular subtype. Univariate and multivariate Cox analysis demonstrated that FAM111A was an independent prognostic factor in LGG patients. Functional characterization of FAM111A revealed that it was associated with inflammatory response and immune response to tumor cells. FAM111A could also act as an indicator of the stromal and immune population, especially for monocytic lineage, myeloid dendritic cells and fibroblasts. It was positively correlated with macrophages, especially the M2 macrophage cells. Furthermore, FAM111A revealed predictive value for the immune subtypes and immune checkpoint blockade therapy. Conclusion FAM111A expression was closely related to the malignant phenotype, molecular pathology and immune response of lower-grade glioma. It might be a promising target for LGG immunotherapeutic strategies.

Background The A type of carotid-cavernous fistulas (CCF-A) is characterized by direct communication between the internal carotid artery (ICA) with a very low incidence. But it severely endangers the health and even the life of patients, not only causes insufferable symptoms but also can induce fatal epistaxis, intracranial hemorrhages or even death. So, this disease needs therapy as early as possible. The ideal treatment for CCF-A is to exclude the fistula from circulation, preserving the carotid flow. Interventional therapy has become the chief method for CCF-A especially in recent years, but the prerequisite, that the microwire or and microcatheter in ICA can be navigated across the orificium fistulae and into distal ICA, is necessary. Otherwise it is difficult to reserve the communication of seriously injured ICA and the orificium fistulae could simultaneously be reliably closed. The authors used a series of new and novel CCF with good result. Methods The authors experienced a patient of TCCF-A, whose ICA was seriously injured and customary method failed in the first treatment because the microwire and microcatheter could not cross the segment of orificium fistulae. Then, the authors applied military (outflanking techniques, aerial refueling, and retrograde navigation) to manage this case. Results Finally, the CCF-A was completely cured and the parent artery was perfect preserved without any complication. Conclusions For patients of TCCF-A with severe ICA injury, these strategies may be very important for some patients whose affected ICA cannot tolerant to be blocked.

The overexpressed soluble fms-like tyrosine kinase 1 (sFLT-1) in placenta is considered to be a potential therapeutic target for preeclampsia (PE). How to achieve efficient intervention of sFLT1 expression in the placenta is an urgent problem to be solved. PEG-PLA nanoparticle generated by double-emulsion methods is a novel siRNA delivery system. Synthetic placental CSA binding peptide (P-CSA-BP) is effective for targeting lipid-polymer nanoparticle to the placenta. We conjugated P-CSA-BP to the surface of PEG-PLA nanoparticle to create a novel placenta specific sFLT1 siRNA delivery system for the therapy of PE. Nanoparticles were synthesized using double emulsion method and characterized by dynamic light scattering and transmission electron microscopy (TEM). RT-PCR was employed to evaluate mRNA level and protein level was analyzed by ELISA kit. The tissue distribution of nanoparticles was observed through ex vivo images. The concentrations of nanoparticles in organs were measured using high-performance liquid chromatography. T-NPsi sFLT1 had higher efficiency than NPsi sFLT1 in accumulating in HTR-8/SVneo cells and significantly decreased the expression of sFLT1. Intravenously administered T-NPsi sFLT1 specifically accumulated in placentas of mice. sFLT1 mRNA level in placenta and protein level in serum were declined by T-NPsi sFLT1 . T-NPsi sFLT1 shown no obvious toxic effect on both mother and fetus. The utility of T-NPsisFLT1 nanoparticles as a sFLT1 siRNA placenta specific delivery system significantly silenced sFLT1 in mice and is safe for both mother and fetus. This nanoparticle is a novel potential therapeutic strategy for PE.

The CAPTRA-Lung study (NCT03334864) is a prospective observational study that will capture real-world data of patients with advanced or metastatic non-small cell lung cancer (NSCLC) across China. The study aims to complement the results from current therapeutic regimens to improve the standard of diagnosis and treatment, evaluate the effectiveness and safety of systemic therapy, and determine the factors influencing the outcomes and responses to treatment. From January 2018 to December 2023, eligible patients with advanced or metastatic NSCLC who are receiving treatment and participating in follow-up at 16 institutions in China, will be enrolled. The demographic, clinical, laboratory, and treatment characteristics and responses to treatment will be recorded in a case report form and transcribed into an electronic data capture system. Overall survival, progression-free survival, overall response rate, and incidence of adverse events will be calculated from the time of initial enrolment until progression evaluated by physicians, last contact, date of death, or analysis cutoff date, respectively. Based on the disease characteristics and treatment strategies, four sub-cohorts will also be established. This study cohort could serve as a pool of patients with advanced or metastatic NSCLC to support further research.

Amphihevir, a benzofuran derivative, is the first reported hepatitis C virus (HCV) nonstructural protein 4B (NS4B) inhibitor that has advanced to clinical trials (currently in phase Ib trial [CTR20170632]). Here, we report the results of a preclinical study of its potency, toxicity, selectivity, drug metabolism and pharmacokinetics (DMPK), and safety profiles. Amphihevir displayed good antiviral activities against genotype 1a (50% effective concentration [EC(50)] of 0.34 nM) and genotype 1b (EC(50) of 1.97 nM) replicons and no cytotoxicity in 12 cell lines derived from animals and humans. Amphihevir was found to be inactive against other viruses, human kinases, and G protein-coupled receptors (GPCRs), which implies its good selectivity. A 9-day long-term treatment of genotype 1b replicons with amphihevir resulted in a 3.8 Log(10) decline of the hepatitis C viral RNA at a concentration of 25× EC(90). Drug resistance screening showed that mutations occurred at H94, F98, and V105 of NS4B, which mediated the resistance to amphihevir. This result suggests that NS4B is the main target of amphihevir. There was no cross-resistance between amphihevir and NS5A, NS3/4A, and NS5B inhibitors, suggesting that amphihevir in combination with other anti-hepatitis C virus drugs could be used to treat hepatitis C, as proven by studies of amphihevir and other hepatitis C virus inhibitors. Pharmacokinetic studies demonstrated that amphihevir has good oral bioavailability and appropriate half-life (t(1/2)) in rats and dogs, thereby supporting its use once per day. Finally, amphihevir showed good safety profiles in rats and dogs. The results shed light on the use of amphihevir as a potential treatment option for chronic hepatitis C patients.

Background Cancer cells maintain energy metabolism mainly by glycolysis, even under sufficient oxygen conditions. It gives cancer cells better growth advantages under complicated internal environment. KPNA2 is a novel oncogene that has received much attention in recent years, but the exact mechanisms of KPNA2 in tumorigenesis and progression are largely unknown. Especially its potential roles in the metabolic transformation of tumors still remain to be explored. Methods The expressions of KPNA2 in glioblastoma and normal human brain samples were analyzed by immunohistochemical analysis. The activities of key enzymes in glycolysis, the production of lactate acid and glucose uptake were investigated by colorimetry. GLUT-1 expression was measured by flow cytometry. CCK8 was used to examine the cell viability in vitro, and the xenograft models in nude mice were established to explore the roles of KPNA2 in vivo. In addition, Co-IP, subcellular fractionation, western blot, immunofluorescence and luciferase assay were used to investigate the internal connection between KPNA2, c-myc and E2F1. Results In the present study, we found that KPNA2 was highly expressed in the glioma compared to the normal brain tissues. Level of KPNA2 was an independent predictor of prognosis in the glioma patients. Knockdown of KPNA2 in the glioblastoma cell lines U87 and U251 decreased deoxyglucose uptake, activities of the key glycolytic enzymes and lactate production. The level of oxidative phosphorylation (OXPHOS) was moderately decreased. Additioanlly, tumor proliferation and invasiveness were concomitantly downregulated. We have identified c-myc as a potential mediator of KPNA2. Aberrant expression of KPNA2 significantly changed the subcellular distribution of c-myc as well as its expression level. E2F1, another key cargo protein of KPNA2, was further identified to play a potential role in regulating the transcription of c-myc by KPNA2. Conclusions Our findings suggested that KPNA2, a potential tumor oncogene, performs its function in part via regulating cellular metabolism through c-myc signaling axis. It would provide a possible explanation for Warburg effect and thus offer a new perspective to the roles of KPNA2 in gliomagenesis. Electronic supplementary material The online version of this article (10.1186/s13046-018-0861-9) contains supplementary material, which is available to authorized users.

Hao Xu, Shangchen Xu, Rui Zhang, Tao Xin, Qi Pang Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China Purpose: SIL1 is a ubiquitous protein localized to the endoplasmic reticulum and functions as a cochaperone of BiP. Previous studies have shown that function loss of SIL1 is often associated with neurological diseases, such as Marinesco-Sjögren Syndrome. However, no studies have investigated the function of SIL1 in tumors. In this study we aim to reveal functions of SIL1 and the underlying mechanisms in glioma. Materials and methods: First, by searching on Gene Expression Profiling Interactive Analysis, we examined SIL1 expression and prognostic value in glioblastoma multiforme (GBM) and brain lower grade glioma (LGG). Immunohistochemical analysis (IHC) was also performed to determine the endogenic SIL1 level. Cell counting kit-8 (CCK8) and clone formation assays were used to detect cell proliferation of U251 cells. Cell migration was detected by transwell assay and cell cycle and apoptosis were detected by flow cytometry. Western blot was performed to determine protein expression. Results: We found that the expression of SIL1 was increased by approximately 1.5-fold in GBM and 1.3-fold in LGG compared with normal controls (P

This study was conducted to investigate the mechanism of action and extent of selective dopaminergic neurodegeneration caused by exposure to trichloroethylene (TCE) leading to the endogenous formation of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) in rodents. Beginning at 3 months of age, male C57BL/6 mice received oral TCE dissolved in vehicle for 8 months. Dopaminergic neuronal loss was assessed by nigral tyrosine hydroxylase (TH) immunoreactivity. Selective dopaminergic neurodegeneration was determined based on histological analysis of non-dopaminergic neurons in the brain. Behavioral assays were evaluated using open field activity and rotarod tests. Mitochondrial complex I activity, oxidative stress markers, and microglial activation were also examined in the substantia nigra. The level of TaClo was detected using HPLC-electrospray ionization tandem mass spectrometry. Dopaminergic neurotoxicity of TaClo was determined in midbrain organotypic cultures from rat pups. Following 8 months of TCE treatment, there was a progressive and selective loss of 50% of the dopaminergic neurons in mouse substantia nigra (SN) and about 50% loss of dopamine and 72% loss of 3,4-dihydroxyphenylacetic acid in the striatum, respectively. In addition, motor deficits, mitochondrial impairment, oxidative stress, and inflammation were measured. TaClo content was quantified in the brain after TCE treatment. In organotypic cultures, TaClo rather than TCE induced dopaminergic neuronal loss, similar to MPP+. TCE exposure may stimulate the endogenous formation of TaClo, which is responsible for dopaminergic neurodegeneration. However, even prolonged administration of TCE was insufficient for producing a greater than 50% loss of nigral dopamine neurons, indicating that additional co-morbid factors would be needed for mimicking the profound loss of dopamine neurons seen in Parkinson’s disease.

Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb repressive complex 2, which epigenetically represses genes involved in tumorigenesis and is highly expressed in tumors. However, no studies have investigated EZH2 expression and its clinical significance in human pituitary adenomas (PAs). Therefore, we examined the expression pattern of EZH2 in PAs and studied the correlations between protein expression and invasiveness, proliferation, angiogenesis, hormone functioning, and some other factors. We measured EZH2 and MMP-14 protein and EZH2 mRNA expression in 62 samples of PAs by immunohistochemistry staining and quantitative real-time polymerase chain reaction and correlated protein expression relative to clinicopathologic features. The immunopositive rate of EZH2 was 88.7% (55/62). The extent of expression was associated with invasiveness, microvessel density, and proliferation (Ki-67 index). Moreover, EZH2 expression correlated with MMP-14 expression. We did not find any correlation between EZH2 overexpression and hormone-secreting function or patient age or sex. The quantitative real-time polymerase chain reaction analysis revealed that the amount of EZH2 mRNA was significantly higher in invasive than in noninvasive adenomas. This is the first report to describe EZH2 overexpression in human PAs, especially invasive adenomas. Thus, EZH2 is a potentially useful diagnostic marker and pharmacotherapeutic target for invasive PAs.

We verified the advantages of using magnetic resonance imaging (MRI) for improving the diagnostic quality of growth hormone deficiency (GHD) in children with short stature caused by pituitary lesions. Clinical data obtained from 577 GHD patients with short stature caused by pituitary lesions were retrospectively analyzed. There were 354 cases (61.3%) with anterior pituitary dysplasia; 45 cases (7.8%) of pituitary stalk interruption syndrome (PSIS); 15 cases (2.6%) of pituitary hyperplasia due to primary hypothyroidism; 38 cases (6.6%) of Rathke cleft cyst; 68 cases (11.8%) of empty sella syndrome; 16 cases (2.8%) of pituitary invasion from Langerhans cell histiocytosis; 2 cases (0.3%) of sellar regional arachnoid cyst and 39 cases (6.8%) of craniopharyngioma. MRI results showed that the height of anterior pituitary in patients was less than normal. Location, size and signals of posterior pituitary and pituitary stalk were normal in anterior pituitary dysplasia. In all cases pituitary hyperplasia was caused by hypothyroidism. MRI results showed that anterior pituitary was enlarged, and we detected upward apophysis and obvious homogeneous enhancement. There were no pituitary stalk interruption and abnormal signal. We also observed that after hormone replacement therapy the size of pituitary gland was reduced. Anterior pituitary atrophy was observed in Rathke cleft cyst, empty sella syndrome, sellar regional arachnoid cyst and craniopharyngioma. The microstructure of hypophysis and sellar region was studied with MRI. We detected pituitary lesions, and the characteristics of various pituitary diseases of GHD in children with short stature. It was concluded that in children with GHD caused by pituitary lesions, MRI was an excellent method for early diagnosis. This method offers clinical practicability and we believe it can be used for differential diagnosis and to monitor the therapeutic effects.

Eleated expression of NIMA-related kinase 2 (NEK2) was frequently observed in a variety of malignant cancers, and it appears to be involved in the initiation, maintenance, progression, metastasis of cancer and is positively associated with poor prognosis. We sought to investigate NEK2 expression and its predictive roles in malignant gliomas, and study the correlation of NEK2 protein expression with proliferation, clinical parameters, overall survival and some other parameters. We investigate NEK2 protein expression in 99 samples of malignant gliomas, including 35 WHO grade II, 22 grade III, and 42 grade IV gliomas, by immunohistochemistry and western blot (n = 50). We then made correlative analysis of protein overexpression using the Kaplan-Meier method, Log rank test, and Cox proportional-hazards model analysis. NEK2 protein was overexpressed in malignant gliomas, but not in normal brain tissues. Overexpression of NEK2 correlated with malignancy, proliferation and adverse overall survival in gliomas. Moreover, chemotherapy, resection extent and WHO grade also correlate with overall survival in gliomas. However, within WHO grade II glioma subgroup, NEK2 overexpression showed no impact on overall survival. The present study firstly reveals that NEK2 protein is widely overexpressed in gliomas. NEK2 overexpression correlates significantly with malignancy (WHO grades), proliferation (Ki-67) and prognosis in malignant gliomas. NEK2 is a potential gene therapy target and prognostic indicator.

BACKGROUND The aim of this study is to explore the application of magnetic resonance imaging (MRI) and computed tomography (CT) image indexing in the assessment of cerebral injury of hypoxic-ischemic encephalopathy (HIE) neonate. METHODS The clinical data of 100 HIE children, who were admitted to the Department of Radiology, Xuzhou Children's Hospital, Jiangsu, from June 2013 to June 2014, were statistically analyzed. RESULTS Among the imaging data of 100 HIE children, the detection rate and false negative rate were 91.4% and 8.6%, respectively. The MRI detection rate was 100%. There was significant correlation between clinical indexing and CT indexing and MRI indexing (coefficient of contingency 0.731 and 0.723, P

α-synuclein is a predominantly expressing neuronal protein for understanding the neurodegenerative disorders. A diagnosing system with aggregated α-synuclein encoded by SNCA gene is necessary to make the precautionary treatment against Parkinson’s disease (PD). Herein, gold-nanourchin conjugated anti-α-synuclein antibody was desired as the probe and seeded on single-walled carbon nanotube (SWCN) integrated interdigitated electrode (IDE). The surface morphology of SWCN-modified IDE and gold urchin-antibody conjugates were observed under FESEM, FETEM and AFM, the existing elements were confirmed. Voltammetry analysis revealed that the limit of fibril-formed α-synuclein detection was improved by 1000 folds (1 fM) with gold-nanourchin-antibody modified surface, compared to the surface with only antibody (1 pM). Validating the interaction of α-synuclein by Enzyme-linked Immunosorbent Assay was displayed the detection limit as 10 pM. IDE has a good reproducibility and a higher selectivity on α-synuclein as evidenced by the interactive analysis with the control proteins, PARK1 and DJ-1.

Hyperglycemia was proved to cause neuron death in both animal experiments and poor outcome of hemorrhage patients, but the predictive ability of admission blood glucose level for early hematoma growth in patients with intracranial hemorrhage (ICH) is still controversial. Spot sign is a well-established imaging predictor for early hematoma growth, implying active microvascular bleeding. Here, we aim to assess associations between admission serum glucose and early hematoma expansion in ICH patients, as well as spot sign. We retrospectively reviewed all the patients with ICH from January 2017 to March 2018 in West China Hospital, Sichuan University. Admission blood glucose, clinical variables, radiological characteristics, and laboratorial parameters were obtained from medical record. According to computed tomography (CT) and computed tomography angiography (CTA) scan results, hematoma expansion and spot sign were identified by 2 experienced neuroradiologists. Multivariate logistic regression analyses were employed to adjust the associations of hematoma expansion and spot sign with other clinical parameters. Around 42 patients exhibited early hematoma expansions and 26 exhibited spot signs over 138 enrolled patients. The average level of admission blood glucose was 7.55 mmol/L. Multivariate logistic regression analyses revealed that Glasgow Coma Scale (GCS) score on admission, hematoma volume, spot sign, and hyperglycemia were associated with hematoma expansion, whereas admission serum glucose and hematoma size were only associated with spot sign, respectively. Admission blood glucose level is correlated with hematoma growth and incidence of spot sign. These results indicated that hyperglycemia probably plays a critical role in the pathological process of the active bleeding. Further studies should be drawn urgently to understand the potential molecular mechanism of systemic hyperglycemia in affecting prognosis of patients with ICH.

Several in vitro studies have revealed the neurotoxicity of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo). However, the underlying mechanism has not been completely elucidated, particularly in vivo. This study was designed to study the neurotoxicity of TaClo in vivo by stereotactically injecting TaClo into the striatum of Wistar rats. After the TaClo injections, rats were subjected to an open field test, and their distance travelled and tracks showed decreasing trends over time. The results of liquid chromatography-mass spectrometry analysis showed that the motor dysfunction of the TaClo-treated rats was accompanied by reduced dopamine levels in the striatum. Based on the diffusion tensor imaging data, the apparent diffusion coefficient of the nigrostriatal pathway was significantly increased, and subsequent histological staining revealed the demyelination of nigrostriatal fibres after the TaClo treatment. TaClo induced a loss of tyrosine hydroxylase-positive cells in the substantia nigra compacta. Regarding the underlying mechanism, TaClo caused oxidative stress in the nigrostriatal system by increasing the production of reactive oxygen species and reducing the mitochondria membrane potential. Meanwhile, the elevated expression of Iba-1, TNF-α, IL-6, Cox-2, and iNOS indicated microglial activation and a strong innate immune response in the nigrostriatal system. In addition, activated caspase-3 levels were increased. Thus, both mitochondrial impairments and the innate immune response are involved in TaClo-induced neurotoxicity.

This paper explores how personality factors affect substance use disorders (SUDs) using explanatory item response modeling (EIRM). A total of 606 Chinese illicit drug users participated in our study. After removing the cases with missing values on the covariate measures, a final sample of 573 participants was used for data analysis. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was used to measure the illicit drug users’ SUD level. Four personality factors–anxiety sensitivity, impulsivity, sensation seeking and hopelessness–along with gender and alcohol use were included in EIRM as person covariates. The results indicated that gender, alcohol use, and their interaction significantly predicted the SUD level. The only personality factor that strongly predicted the SUD level was sensation seeking. In addition, the interaction between gender and hopelessness was also found to be a significant predictor of the SUD level, indicating that the negative effect of hopelessness on SUD is stronger for women than for men. The findings suggest that sensation seeking plays an important role in influencing SUDs, and thus, it should be considered when designing intervention or screening procedures for potential illicit drug users. In addition, several DSM-5 SUD symptoms were found to exhibit differential effects by gender, alcohol use, and personality factors. The possible explanations were discussed.

An alarming number of students drop out of junior high school in developing countries. In this study, we examine the impacts of providing a social–emotional learning (SEL) program on the dropout behavior and learning anxiety of students in the first two years of junior high. We do so by analyzing data from a randomized controlled trial involving 70 junior high schools and 7,495 students in rural China. After eight months, the SEL program reduces dropout by 1.6 percentage points and decreases learning anxiety by 2.3 percentage points. Effects are no longer statistically different from zero after 15 months, perhaps due to decreasing student interest in the program. However, we do find that the program reduces dropout among students at high risk of dropping out (older students and students with friends who have already dropped out), both after eight and 15 months of exposure to the SEL program.

Nivolumab prolonged disease control in a patient with advanced squamous lung cancer that was refractory to multiple treatments. The rapid eradication of cancer after the administration of nivolumab caused hemoptysis and repeated infection. Six months after immunotherapy, mediastinal lymph node metastasis developed and afatinib effectively relieved dysphonia associated with nerve paralysis.

Background: Parkinson's disease (PD) is one of the foremost neurological disorders which is differentiated next to the progressive dopamine (DA) loss, especially in the area of substantia nigra pars compacta (SNpc). Aberrant neuroinflammation, as well as excessive reactive oxygen species (ROS) generation, have exposed to stimulate neuronal defeat in the gradual developing PD. The current study investigated whether fucoxanthin could attenuate the pathophysiology seen in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated PD model. Materials and Methods: C57BL/6 mice received 30 mg/kg of MPTP (i.p.) every day for 5 consecutive days to establish PD, subsequently everyday treatment with fucoxanthin intended for 7 days. Intraperitoneal injection of MPTP, resulted in impaired motor functions, dopaminergic neuronal loss, decreased DA, Tyrosine hydroxylase (TH) levels, and microglial activation-mediated neuroinflammation. Results: Fucoxanthin administration ameliorated α-synuclein abnormal accumulation and motor impairment in MPTP-induced chronic PD mouse model. Our observed findings revealed that fucoxanthin administration reverses the MPTP-mediated decline of DA neuron, TH along with microglial activation predominantly in the SNpc region. The Western blot analysis exposed that fucoxanthin suppressed the expression patterns of proinflammatory cytokines following MPTP administration. Conclusion: In conclusion, Fucoxanthin exerts neuroprotective potential in opposition to MPTP-mediated PD mice through repressing α-synuclein expression, oxidative stress and gliosis, recommended that fucoxanthin might perform as a beneficial remedy toward PD amelioration.

The poor prognosis in non-small-cell lung cancer has driven the development of novel targeted therapies. Vascular endothelial growth factor is the most potent force in mediating tumor angiogenesis, and many angiogenesis inhibitors have been developed for oncology treatment. We performed a study to characterize the efficacy, safety and tumor suppression of three lung cancer related anti-angiogenic drugs (bevacizumab, endostar and apatinib) using transgenic zebrafish embryo and human lung cancer xenotransplantation model. All three drugs demonstrated remarkable angiogenesis and tumor inhibition effect in the zebrafish model, within the nonlethal dose range. Endostar and bevacizumab showed competitive anti-tumor efficacy. The anti-tumor performance of apatinib was hamstrung by its elevated toxicity at 35 °C. The addition of pemetrexed to anti-angiogenesis therapy had no obvious additional benefit in tumors.

Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (β1, β2, β5), while β5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of β1 or β2 with β5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective β2/β5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of β5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the β5/β2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM.

Proteasomes are therapeutic targets for various cancers and autoimmune diseases. Constitutively expressed proteasomes have three active sites, β1c, β2c, and β5c. Lymphoid tissues also express the immunoproteasome subunits β1i, β2i, and β5i. Rapid and simultaneous measurement of the activity of these catalytic subunits would assist in the discovery of new inhibitors, improve analysis of proteasome inhibitors in clinical trials, and simplify analysis of subunit expression. In this work, we present a cocktail of activity-based probes that enables simultaneous gel-based detection of all six catalytic human proteasome subunits. We used this cocktail to develop specific inhibitors for β1c, β2c, β5c, and β2i, to compare the active-site specificity of clinical proteasome inhibitors, and to demonstrate that many hematologic malignancies predominantly express immunoproteasomes. Furthermore, we show that selective and complete inhibition of β5i and β1i is cytotoxic to primary cells from acute lymphocytic leukemia (ALL) patients.

The aim of this study was to explore the difference in high mobility group A1 (HMGA1) expression and isocitrate dehydrogenase (IDH) 1 R132H point mutation in initial and recurrent glioblastoma multiforme (GBM), and to further identify whether the expression of HMGA1 has a role in the malignant progression of GBM. Paired initial and recurrent GBM specimens from the same patient were evaluated using immunohistochemical analysis. The association between HMGA1 expression and progression-free survival time (PFST) was analyzed. Three patients were confirmed with IDH-1 R132H mutations in both initial and recurrent groups (3/25, 12%). There was a significant difference in HMGA1 expression between initial and recurrent GBM ( P = 0.002), and patients with tumors expressing HMGA1 at higher level had a significantly shorter PFST (7.3 months versus 11.1months; P = 0.044). Our study indicates that recurrent GBM express HMGA1 at a higher level and that HMGA1 overexpressoin is associated with shorter PFST in patients with GBM. These findings suggest that HMGA1 potentially plays an important role in the treatment of GBM.

AIM Patients with advanced nonsquamous nonsmall cell lung cancer (NSCLC) who experienced progression with two or more lines chemotherapy have no treatment options that clearly confer a survival benefit. As a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, apatinib has a certain antitumor effect for various solid tumors. The present study evaluated the efficacy and safety of apatinib in advanced nonsquamous NSCLC as salvage treatment in Chinese real-world practice. METHODS Twenty-eight patients were enrolled in this observational study from October 2015 to May 2017. Progression-free survival (PFS) and overall survival (OS) were graphed by Kaplan-Meier curve and intergroup comparisons were carried out by log-rank test. Objective response rate (ORR), disease control rate (DCR) and adverse effects (AEs) were also evaluated. RESULTS Seven patients obtained partial response, and 18 obtained stable disease, representing an ORR of 26% and a DCR of 93%. Median PFS and OS were 3 (95% confidence interval [CI] 2.6-3.4) and 7.4 (95% CI 1.3-13.5) months, respectively. The efficacy analysis showed that Eastern Cooperative Oncology Group (ECOG) performance status 0-1 was correlated with prolonged OS and PFS (P

Survivin has multiple functions in the progression of cancer. The aim of the present study was to investigate the influence of YM155, a specific survivin inhibitor, on the biological behavior of U87 glioblastoma cells. The proliferative activity and growth rate of U87 cells were determined by colony formation assay and mononuclear cell direct cytotoxicity assay (MTT assay). The reconstituted basement membrane penetrating capacity was determined by cell invasion assay. The cell movement and migratory capacity were detected by wound-healing repair assay. We found that inhibition of survivin by YM155 dramatically decreased the invasive and metastatic capacities of the cells, suppressed the proliferation, decelerated the rate of growth, and reduced the number of clones on soft agar. In conclusion, YM155 has the potential to be used in the clinical treatment of GBM.

As one of the prototypical intracranial hemorrhage (ICH), spontaneous cerebellar hemorrhage (SCH) is treated with different strategies by comparing with supratentorial hemorrhage (SH). Additionally, SCH patients usually suffer from worse prognosis than patients with other types of ICH. It is well documented that the unique anatomic structures of posterior cranial fossa lead to a higher risk for brainstem compression and/or brain edema in SCH patients. Recently, neutrophil to lymphocyte ratio (NLR) was reported to possess an excellent predictive ability for the prognosis of patients with ICH, and most of those cases are SH. Thus, the potential association between NLR and the prognosis of SCH patients remains to be elucidated. Here, we aim to assess the predictive role of admission NLR and other available inflammatory parameters for the outcomes of patients with SCH. All patients with acute SCH admitting to West China Hospital from February 2010 to October 2017 were retrospectively enrolled. According to the absolute neutrophil count, absolute lymphocyte count, white blood count and absolute monocyte count extracted from electronic medical records, NLR was calculated. The multivariable logistic regression analysis was applied to analyze the associations between disease outcome and laboratory biomarkers. The comparisons of predictive powers of each biomarker were assessed by receiver operating curves (ROCs). The spearman analyses and multiple linear analyses were also conducted to identify the independent predictors for admission NLR. Admission NLR independently associated with 30-day status (odds ratio [OR] 1.785, 95% confidence interval [CI] 1.463–2.666, P

Summary Background Post-traumatic seizures (PTS) is a well-known sequela of traumatic brain injury (TBI). The risk factors for PTS are still controversial. Studies on PTS in China are rare and no large prospective, multicenter-based studies are available. Methods Data were collected from 15 hospitals prospectively using standardized structured questionnaires in Shandong, a province in China with a follow-up of 2 years. Results A total of 3093 traumatic brain injury patients were validated and entered in this analysis. After 6 months of follow-up, 181 (59.9%) patients were identified as having PTS. The number were 236 (78.1%) and 302 after 1 year and 2 years’ follow-up, respectively. The cumulative 24-month-rate of PTS is 9.8%. Among these 302 patients, 242 were male (80.1%) and 60 female (19.9%). A marked peak was seen in the young people group aged 15–24 (27.8%). Three factors were identified as significant in the multivariate model of PTS: Frontal–temporal lobar contusion, Linear fracture and Severity of TBI measured by initial Glasgow Coma Scale (GCS). Conclusion This prospective cohort study shows the epidemiologic features and risk factors of PTS in China. Frontal–temporal lobar contusion, linear fracture and severity of TBI measured by initial Glasgow Coma Scale (GCS) are risk factors for PTS. It is essential to establish a standard surveillance system for PTS.

The knockdown of Bmi-1 could effectively suppress cancer cell proliferation and tumourigenicity in several cancers. This study aims to investigate whether or not Bmi-1 plays a causative role in the proliferation of ovarian epithelial cancer cells and telomerase activity. The messenger RNA (mRNA) and protein expression levels of Bmi-1 in the human ovarian carcinoma cell line OVCAR-3 were downregulated by Bmi-1 siRNA, as confirmed by real-time polymerase chain reaction (PCR) and Western blot. Cell viability was analysed by MTT assay, and telomerase activity was analysed by a modified telomeric repeat amplification protocol. Targeting Bmi-1 with siRNA inhibited Bmi-1 mRNA over five-fold compared with the control cells, and inhibited Bmi-1 protein expression over three-fold compared with control cells. The viability of the OVCAR-3 ovarian cancer cell line was reduced by Bmi-1 mRNA compared to control cells. Telomerase activity was decreased 22.73% (from 0.33 to 0.255) by Bmi-1 siRNA treatment compared to control cells. As Bmi-1 siRNA depressed telomerase activity, cell immortalisation may be prevented; thus, silencing Bmi-1 may be a potential therapy to manage ovarian cancer.

The CAPTRA-Lung study (NCT03334864) is a prospective observational study that will capture real-world data of patients with advanced or metastatic non-small cell lung cancer (NSCLC) across China. The study aims to complement the results from current therapeutic regimens to improve the standard of diagnosis and treatment, evaluate the effectiveness and safety of systemic therapy, and determine the factors influencing the outcomes and responses to treatment. From January 2018 to December 2023, eligible patients with advanced or metastatic NSCLC who are receiving treatment and participating in follow-up at 16 institutions in China, will be enrolled. The demographic, clinical, laboratory, and treatment characteristics and responses to treatment will be recorded in a case report form and transcribed into an electronic data capture system. Overall survival, progression-free survival, overall response rate, and incidence of adverse events will be calculated from the time of initial enrolment until progression evaluated by physicians, last contact, date of death, or analysis cutoff date, respectively. Based on the disease characteristics and treatment strategies, four sub-cohorts will also be established. This study cohort could serve as a pool of patients with advanced or metastatic NSCLC to support further research.

e23524Background: Soft tissue sarcomas (STS) are rare and aggressive malignancies that develop from the mesenchymal tissue. Despite advances in treatment methods, the prognosis of STS is very poor....

Background. In early September 2009, an outbreak of influenza occurred at a college campus in Beijing, China, in which both pandemic H1N1 and seasonal H3N2 viruses were detected. Methods. Outbreak investigation was performed in the campus. Epidemiologic, clinical data were collected by interviewing patients and retrieving medical records. Individual contact tracing was performed for detailed contact information. Viruses were identified by reverse-transcription polymerase chain reaction assays followed by sequence analysis. The hemagglutination inhibition test was used to detect antibodies to both viruses for paired serum samples. Results. Forty of 45 people with influenza-like illness had laboratory-confirmed influenza A infection; 22 of these 40 people were infected with pandemic H1N1 virus, 12 were infected with seasonal H3N2 virus, and 6 were coinfected with both viruses. In the subsequent generation of cases with mixed infection, we detected pandemic H1N1 virus infection more often than seasonal H3N2 virus infection. The clinical patterns were essentially similar for patients with different virus infections. No substantial differences in sequences were observed in either pandemic H1N1 or seasonal H3N2 virus between patients with mixed and single infection. Sequence analyses revealed that all of the detected viruses were susceptible to oseltamivir but resistant to adamantane. Hemagglutination inhibition tests of paired serum samples confirmed mixed infection in the outbreak. Conclusions. Cocirculation of pandemic H1N1 virus and seasonal H3N2 virus led to a mixed infection in patients. Pandemic H1N1 virus, however, took prevalence over seasonal influenza virus in the course of transmission. Therefore, competitive circulation of seasonal influenza A virus with the pandemic H1N1 virus seems less likely.

Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide; formerly harkoseride, SPM 927; Vimpat), has been recently approved by US and European regulatory authorities for use as add-on therapy for partial-onset seizures in adults. Because a number of anti-epileptic drugs are used to treat conditions beyond epilepsy, including anxiety, in the present study we investigated the anxiolytic potential of lacosamide in a conditioned emotional response (CER) model in rat, and the mouse marble burying assay. In each test lacosamide produced a significant effect consistent with anxiolysis, i.e. lacosamide increased suppression ratio in the CER test, and reduced the number of marbles buried in the marble burying assay. The doses necessary for an anxiolytic effect were higher than those necessary for efficacy in seizure tests conducted in the same species. For example in the mouse, the lacosamide oral ED(50) in the maximal electroshock seizure (MES) and 6 Hz tests was 5.3 and 9.6 mg/kg respectively, and the minimal effective dose in the marble burying assay was 30 mg/kg. In both seizure and anxiety tests, the (S)-enantiomer of lacosamide was inactive suggesting a similar mechanism of action, possibly use-dependent inhibition of sodium channel function (Errington et al., 2008). Efficacy in the CER model was equivalent to diazepam and pregabalin (Lyrica). In tests of side-effects, lacosamide had no effect on choice accuracy in the delayed match to position task of working memory, although at the 30 mg/kg dose, response rates and response latencies were significantly affected. In sum, the present results identify for the first time, an anxiolytic potential of lacosamide.

Objective To explore the expression of the glucocorticoid receptor α (GR α ) and its significance in the occurrence and progress of meningiomas. Materials and Methods By the use of flow cytometry, the proliferative index (PI), S-phase fraction (SPF) and DNA ploidy were detected to evaluate the proliferation of tumor cells in 58 meningioma specimens. The expressions of GR α in all meningiomas and seven normal dura samples were studied by means of reverse transcription-polymerase chain reaction to compare the difference in GR α between meningiomas and normal dura. The relation between GR α and histological grades, PI, SPF and DNA ploidy were also analyzed. Results The mean PI was 9.32% ± 4.41% while the mean SPF was 2.79% ± 2.43% in 58 meningioma specimens. DNA was diploid in 51 cases and aneuploid in the remaining seven cases, with the aneuploid rate being 12.1%. Nine of 58 meningiomas were GR α - negative and the rest were GR α -positive with a GR α -positive rate of 84.5%. The GR α -positive meningiomas included 13 ‘+’, 15 ‘++’, 9 ‘+++’ and 12 ‘++++’. GR α was negative in normal dura samples. The GR α -positive rate of meningiomas was significantly greater than that of normal dura. There were no significant differences in PI and SPF among GR α -negative, GR α -weak positive and GR α -strong positive meningiomas. The difference in aneuploid rate between GR α -positive and GR α -negative meningiomas was also not significant. Conclusion GR α is of significance in meningiomas, which are a target tissue for glucocorticoid. However, GR α ’s expression had no obvious effect on the proliferative activity of meningiomas, so it may not be a major control of this process.

Objective: Endoscopic endonasal (transnasal) transsphenoidal approach (EETA) for management of sellar lesions has gained popularity as a reliable and atraumatic method. Most reported studies of EETA have focused on surgical outcome in adult patients; and there are few reports to describe outcome in pediatric patients. The authors report our early experience of 11 patients aged 14 to 18 years managed with EETA to evaluate the safety and effectiveness of EETA in the pediatric. Methods: Retrospective review of hospital records of 11 pediatric patients who underwent endonasal endoscopic transsphenoidal approach for resection of sellar region lesion over 2 years. Age, sex, symptoms, tumor size, extent of tumor resection, clinical outcome, and surgical complications were reviewed. Results: Total resection was achieved in 9 (81.8%) patients, subtotal resection in 2 (18.2%), and no patient had partial or insufficient resection. All (100%) patients achieved visual remission, 7 (87.5%) of 8 patients with hyperhormone preoperative had endocrinological remission. Two (18.2%) patients incurred temporary diabetes insipidus (DI) postoperatively. One (9.1%) patient incurred postoperative cerebrospinal fluid (CSF) leakage which resolved following lumbar drainage. Three (27.3%) patients developed hypopituitarism needed hormone replacement therapy. There were no cases of meningitis, intracranial hematoma, or death. Conclusions: Endoscopic endonasal (transnasal) transsphenoidal approach (EETA) provides a safe and effective surgical option with low morbidity and mortality in pediatric patients.

Objective Abnormal telomere shortening has been observed in a subset of individuals with aplastic anemia (AA). We hypothesized that genetic variation in two genes critical in telomere biology, TERF1 and TERF2 , could be a risk factor for AA. Methods The proximal promoter and all coding regions of TERF1 and TERF2 were sequenced in 47 individuals with acquired AA. Regions with genetic variation were sequenced in an additional 95 AA patients and 289 healthy controls. Single nucleotide polymorphism (SNP) frequencies were analyzed using co-dominant and dominant models and haplotypes determined. Functional studies evaluated telomerase activity, telomere and telomeric overhang lengths, and TRF2 protein expression in select patients. Results Two nonsynonymous amino acid changes were detected, one in exon 9 of TERF1 and another in exon 6 of TERF2 . These sequence variants resulted in conservative amino acid changes and were not predicted to alter TRF1 or TRF2 protein expression or function. SNP and haplotype analyses in acquired AA patients suggested that one variant allele, in intron 9 of TERF1 , and haplotype could be associated with increased risk for aplastic anemia (OR 1.59, 95% confidence interval 1.06–2.39, p = 0.033). TERF2 SNPs and haplotypes were not significantly associated with aplastic anemia. Conclusions It is possible that a common genetic variant in TERF1 is associated with risk for AA but additional studies are required. Highly penetrant, non-synonymous, or insertion-deletion mutations in TERF1 and TERF2 were not identified and therefore are not likely to be major genetic risk factors for the development of AA.

In a cohort study of 56 convalescent patients with severe acute respiratory syndrome (SARS), titers of immunoglobulin G (IgG) antibodies and neutralizing antibodies (NAbs) against SARS-associated coronavirus were assessed at regular intervals (at 1, 4, 7, 10, 16, and 24 months after the onset of disease) by use of enzyme-linked immunosorbent assay and neutralization assay. IgG antibody and NAb titers were highly correlated, peaking at month 4 after the onset of disease and decreasing thereafter. IgG antibodies remained detectable in all patients until month 16, and they became undetectable in 11.8% of patients at month 24. The finding that NAbs remained detectable throughout follow-up is reassuring in terms of protection provided against reinfection; however, NAb titers decreased markedly after month 16

In light of the barrage of recent reviews on 5-HT7 receptor agonists and antagonists, this article will highlight and review the research advances published in the patent literature between January 1997 and December 2003. The article is supplemented with selected references on the design, synthesis and development of novel 5-HT7 agents to treat central and peripheral nervous system diseases. Emphasis is placed on recent advances in the possible involvement of 5-HT7 serotonergic agents in the treatment of learning and memory, depression, schizophrenia and migraine. By no means has any attempt been made to exhaustively review the literature, but rather, primary references together with citations to recent literature reviews have been included in each section.

Guided by Perry and Weinstein's (1998) conceptual model of school adjustment, first-generation Chinese-American adolescents' school adjustment was compared with that of Mainland Chinese and European American adolescents in two domains of functioning, academic (attitudes to school and teacher; their sense of academic adequacy) and behavioral (depression, anxiety and social stress), using the Behavioral Assessment System for Children (BASC). Results indicated that Chinese-American adolescents reported more negative attitudes toward teachers than European American and Mainland Chinese students, had more negative perceptions of the school environment than students in Mainland China, and reported more feelings of inadequacy in academics than European American students. Chinese-American adolescents reported higher levels of depression and social stress than the other two groups, and more anxiety than Mainland Chinese students. Feelings of academic inadequacy were related to depression, anxiety and social stress for all three cultural groups. In addition, Chinese-American adolescents reported that they did not trust their teachers and their peers who were not Chinese-American, and felt that adults at school and home did not understand them. This feeling coupled with their fear, anger and frustration at being bullied frequently in school could be related to Chinese-American adolescents' negative perception of school and teachers. Implications of the study are discussed. © 2003 Wiley Periodicals, Inc. Psychol Schs 40: 71–84, 2003.

The aim of this investigation was to compare clinical pathological characteristics and prognosis of very young and older triple-negative breast cancer (TNBC) patients in order to assess their relevance to TNBC in an younger population. Data of TNBC patients diagnosed between 2002 and 2007 were retrospectively analyzed by computer based chart information. Baseline tumor characteristics, biological markers, and patients' prognosis were compared between very young (≤ 35 years) and older (>35 years) TNBC patients. In the 216 cases of operable TNBC patients, 48 (22.2%) were ≤ 35 years and 168 (77.8%) were >35 years. Very young TNBC patients had showed a high clinical stage, more positive lymph nodes, Ck5/6 and/or EGFR expression (P = 0.049, 0.006, and 0.011, respectively). Compared to older TNBC patients, very young TNBC patients have short disease-free survival (P = 0.031), while no significant difference was found in overall survival (OS) (P = 0.075). In multivariate analysis, lymph node metastatic status was a significant predictor of OS. TNBC of very young patients is an aggressive breast cancer subtype, but the overall survival of both young and older TNBC patients did not have significant differences.

Glioma, the most common type of primary central nervous system cancers, was progressive with poor survival. MicroRNA, as a novel biomarker, was suspected to be novel biomarkers for glioma diagnosis and prognosis. The study aimed at investigating the diagnostic and predictive value of miR-221/222 family for glioma. In the first phase, we compared plasma miR-221/222 family levels between 50 glioma patients and 51 healthy controls by real-time qRT-PCR amplification. Meanwhile, a meta-analysis based on published studies and presents study was performed to explore the diagnostic performance of miR-221/222 family in human cancers. In the second phase, we correlated the miR-221/222 family expression level with prognosis of glioma using Kaplan-Meier survival curves. The plasma miR-221/222 family levels were found to be significantly upregulated in glioma patients (P = 0.001). The ROC curve analysis yielded an AUC values of 0.84 (95 % confidence interval (CI): 0.74–0.93) for miR-221 and 0.92 (95 % CI 0.87–0.94) for miR-222. In the meta-analysis, the summary receiver operating characteristic (sROC) was plotted with an AUC of 0.82 (95 % CI 0.78–0.85) for miR-221/222 family. It was also demonstrated that high positive plasma miR-221 and miR-222 were both correlated with poor survival rate (miR-221: HR = 2.13; 95 % CI, 1.05–4.31; miR-222: HR = 2.09; 95 % CI, 1.00–4.37). This study demonstrated that the detection of the miRNA-221/222 family should be considered as a new additional tool to better characterize glioma.