Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response.

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

Multifunctional amorphous FeCoNiTixSi high-entropy alloys with excellent electromagnetic-wave absorption performances.

Amorphous high-entropy alloys (HEAs) as electromagnetic-wave absorbing materials have been rarely reported. In this work, amorphous FeCoNiTixSi HEAs were synthesized by introducing a high content of large-atom Ti using the high-energy ball-milling technique. This amorphous structure could improve the saturated magnetization and coercivity of HEAs, but slightly degraded the mechanical and oxidation resistance properties. In terms of electromagnetic properties, FeCoNiTi0.01Si and FeCoNiTiSi exhibit excellent electromagnetic-wave absorption performances, with significant absorptions of -68.4 dB at 6.14 GHz and -63.4 dB at 9.12 GHz, corresponding to bandwidths of 5.15 GHz (1.69 mm) and 3.64 GHz (1.43 mm), respectively. Overall, the prepared FeCoNiTixSi HEAs exhibited superior comprehensive performances compared to other HEA absorption materials. This work provided a novel strategy for the development of new electromagnetic-wave absorption materials with low weight, high absorption efficiency, and resistance to harsh environments.

Endoscopic transorbital approach for skull base lesions: a report of 16 clinical cases.

Due to the deep location, complex anatomy, and adjacent vital neurovascular structures, skull base surgery is challenging and requires specific approaches. The emerging endoscopic transorbital approach (eTOA) technique provides a new approach to the orbital content, spheno-orbital region, lateral cavernous sinus, and Meckel's cave. In this study, the clinical utility and effectiveness of the eTOA are reported. Sixteen cases who underwent the eTOA were included in the current study. The patients were divided into 3 groups according to tumor location: Group A (intraorbital, 6 cases), group B (spheno-orbital, 7 cases), and group C (cavernous sinus, and Meckel's cave, 3 cases). The clinical data and surgical results were analyzed. Eight meningiomas, 2 hemangiomas, 1 low-grade glioma, 1 instance of inflammatory hyperplasia tissue, 1 Langerhans cell histiocytosis, 1 epidermoid cyst, 1 trigeminal schwannoma, and 1 bone fibrosis hyperplasia were observed. The mean tumor diameter was 2.4 cm. A single case in Group A and Group C underwent biopsy (12.5%), and 1 case of fibrous dysplasia in Group B underwent sufficient orbit decompression (6.25%). The remaining 13 cases underwent gross total tumor resection (81.25%). No cerebral-spinal fluid leak or infection occurred. And no cosmetic problems or significant complications were observed during the follow-up. As a minimally invasive technique, the eTOA has unique advantages for carefully selected skull base lesions because of its direct route, short working distance, and distinct attack angle.

Overexpression of the SARS-CoV-2 receptor ACE2 is induced by cigarette smoke in bronchial and alveolar epithelia.

Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a target for disease prevention. However, the relationship between ACE2 expression and its clinical implications in SARS-CoV-2 pathogenesis remains unknown. Here, we explored the location and expression of ACE2, and its correlation with gender, age, and cigarette smoke (CS), in a CS-exposed mouse model and 224 non-malignant lung tissues (125 non-smokers, 81 current smokers, and 18 ex-smokers) by immunohistochemistry. Moreover, the correlations of ACE2 with CS-induced oxidative stress-related markers, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), and 4-hydroxynonenal (4-HNE) were investigated. Chromatin immunoprecipitation and luciferase reporter assays identified the cause of ACE2 overexpression in human primary lung epithelial cells. We demonstrated that ACE2 was predominantly overexpressed on the apical surface of bronchial epithelium, while reduced in alveolar epithelium, owing to the dramatically decreased abundance of alveolar type II pneumocytes in CS-exposed mouse lungs. Consistent with this, ACE2 was primarily significantly overexpressed in human bronchial and alveolar epithelial cells in smokers regardless of age or gender. Decreased ACE2 expression was observed in bronchial epithelial cells from ex-smokers compared with current smokers, especially in those who had ceased smoking for more than 10 years. Moreover, ACE2 expression was positively correlated with the levels of HIF-1α, iNOS, and 4-HNE in both mouse and human bronchioles. The results were further validated using a publicly available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus 2.0 microarray (AE-meta). Finally, our results showed that HIF-1α transcriptionally upregulates ACE2 expression. Our results indicate that smoking-induced ACE2 overexpression in the apical surface of bronchial epithelial cells provides a route by which SARS-CoV-2 enters host cells, which supports clinical relevance in attenuating the potential transmission risk of COVID-19 in smoking populations by smoking cessation. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Characterization of an endoplasmic reticulum stress-related signature to evaluate immune features and predict prognosis in glioma.

Endoplasmic reticulum (ER) stress has considerable impact on cell growth, proliferation, metastasis, invasion, angiogenesis and chemoradiotherapy resistance in various cancers. However, the effect of ER stress on the outcomes of glioma patients remains unclear. In this study, we established an ER stress risk model based on The Cancer Genome Atlas (TCGA) glioma data set to reflect immune characteristics and predict the prognosis of glioma patients. Survival analysis indicated that there were significant differences in the overall survival (OS) of glioma patients with different ER stress-related risk scores. Moreover, the ER stress-related risk signature, which was markedly associated with the clinicopathological properties of glioma patients, could serve as an independent prognostic indicator. Functional enrichment analysis revealed that the risk model correlated with immune and inflammation responses, as well as biosynthesis and degradation. In addition, the ER stress-related risk model indicated an immunosuppressive microenvironment. In conclusion, we present an ER stress risk model that is an independent prognostic factor and indicates the general immune characteristics in the glioma microenvironment.

Multi-center prospective study on central line-associated bloodstream infections in 79 ICUs of China.

BACKGROUND: China has not yet established a national surveillance network such as NHSN from America, so there is still no large-scale investigations on central line-associated bloodstream infection (CLABSI) incidence. Several retrospective studies in China reported that the incidence of CLABSI varied due to inconsistent diagnostic criteria. We performed a nationwide survey to investigate the utilization rate of central venous catheters (CVCs) and the incidence of CLABSI in ICUs of different areas of China. METHODS: This is a prospective multi-center study. Patients admitted to ICUs with the use of CVCs between January 1, 2014 and December 31, 2018 were enrolled in this study. Hospitals were given the definition of catheter-related bloodstream infection as: a laboratory-confirmed bloodstream infection where CVC was in place on the date of event or the day before. The characteristics of patients, information of catheterization, implementation rates of precautions, and CLABSIs were collected. The statistical analysis was performed by SPSS 25.0 software and website of Open Source Epidemiologic Statistics for Public Health. RESULTS: A total of 38,212 patients and 466,585 catheter days were involved in surveillance. The average CLABSI incidence in a thousand catheter days was 1.50, the lowest incidence unit was in pediatric ICU (0/1000 catheter days), and the lowest incidence area was in Northeast China (0.77/1000 catheter days), while the highest incidence unit was in cardiac ICU (2.48/1000 catheter days) and the highest incidence area was in Eastern China (1.62/1000 catheter days). The average utilization rate of CVC was 42.85%, the lowest utilization rate was in pediatric ICU (5.85%) and in Central China (38.05%), while the highest utilization rate was in surgical ICU (64.92%) and in Western China (51.57%). Among the 702 CLABSI cases reported, a total of 735 strains of pathogens were cultured. Staphylococcus spp. was the most common organism isolated (27.07%), followed by Enterobacteriaceae (22.31%). The implementation rates of all precautions showed an upward trend during the study period (P ≤ 0.001). CONCLUSION: The average incidence of CLABSI in ICUs in China is 1.5/1000 catheter days, similar to the rates reported in developed countries but lower than previous reports in China. CLABSI incidence showed regional differences in China. It is necessary to implement targeted surveillance of CLABSI cases by using standardized CLABSI surveillance definitions and methodologies.

Antiviral treatment and prognosis in patients undergoing maintenance hemodialysis due to hepatitis C virus. / ç»´æŒæ€§è¡€æ¶²é€æžä¸™åž‹è‚ç‚Žç— æ¯’æ„ŸæŸ“æ‚£è€ çš„æŠ—ç— æ¯’æ²»ç–—åŠé¢„åŽ.

OBJECTIVES: Maintenance hemodialysis (MHD) is one of the important renal replacement therapies for patients with end-stage renal disease. Hepatitis C virus (HCV) infection is a serious global public health problem. The proportion of MHD patients complicated with HCV infection and the risk of adverse prognosis are higher than those in the general population. Active antiviral treatment and prevention of reinfection is a combined treatment by nephrology and infection physicians. It is a widely accepted preventive measure to set hemodialysis buffer area for patients in treating HCV infection, but its effectiveness and safety still need to be further explored. Thus, the aim of this study is to explore the antiviral treatment and prognosis of MHD patients with HCV infection during hemodialysis. METHODS: A retrospective analysis for renal disease patients at 10 end-stage with long-term hemodialysis in the HCV area of the Blood Purification Center of Xiangya Hospital, Central South University. After standard antiviral drug treatment, the patient reached the cure standard for HCV infection. The buffer zone was set up in the Blood Purification Center by the Department of Nephrology of Xiangya Hospital since April 2017. Patients cured of HCV infection were transferred from the HCV area to the buffer zone for continuous dialysis, accompanied by monitoring serum HCV-RNA, anti-HCV antibody levels and changes in clinical biochemical indicators following the status of reinfection. RESULTS: Ten patients with HCV infection were finally cured after antiviral treatment, and there were no significant changes in clinical biochemical indicators before and after treatment. In the followed-up period after the transfer, the patient continued to be negative for HCV-RNA and positive for anti-HCV antibody. CONCLUSIONS: Direct antiviral therapy is safe and effective in MHD patients with HCV infection. Active antiviral therapy and transferring to the buffer area for dialysis are new and effective treatment modes for HCV patients during MHD.

Nasal myiasis in patients with disturbance of consciousness: A case report and literature review. / æ„è¯†éšœç¢æ‚£è€ å‘ç”Ÿé¼»è‡è›†ç— 1ä¾‹åŠæ–‡çŒ®å¤ä¹ .

Nasal myiasis is a rare parasitic disease. The growth of myiasis in the nasal cavity causes damage to the nasal cavity and paranasal sinuses. Once the dipeterous larvae are migrated, it causes damage to the surrounding structures such as eyes and skull cavity. Proper treatment and active prevention and control can reduce and avoid the occurrence of serious complications. On May 14, 2020, a patient with cerebral infarction and coma was admitted to Xiangya Hospital of Central South University and developed nasal myiasis. During the treatment of the primary disease, the patient was found to be infected with rhinomyiasis. The patient was treated with dehydration, cranial pressure reduction, brain protection, blood glucose control, blood pressure control, and anti-infection. Nasal endoscopy and nasal irrigation were carried out to treat nasal myiasis. The patient was properly placed and isolated for prevention and control so as to prevent the spread of myiasis in the ward. After 16 days, the patient regained consciousness, no worm was found in the nasal cavity, and was discharged from the hospital. The patient was followed-up for 6 months, no maggots were found in the nasal cavity of the patients, no complaints of nasal discomfort was occurred, and no other patients and medical staff were infected with myiasis. The prevention of myiasis is very important, and proper measures should be taken to reduce the risk of community and hospital infection.

Clinical characteristics of patients with listeriosis. / æŽæ–¯ç‰¹èŒç— æ‚£è€ çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: To investigate the clinical characteristics of patients with listeriosis and to provide a basis for diagnosis, treatment, prevention and control of hospital infection. METHODS: A total of 10 inpatients, who suffered from the listeriosis in Xiangya Hospital, Central South University from January 2013 to June 2019, were retrospectively collected for this study. The characteristics of the patients' age, gander, basic information, case type, clinical manifestations, first consultation department, days of diagnosis, infection indicator, specimen type, results of drug sensitivity, treatment plan, hospital infection or not, outcome, follow-up data were analyzed. RESULTS: Two cases were pregnant women and other were non-pregnant adults among 10 patients with listeriosis. Among them, there were 3 cases with hospital acquired infection. The age of patient onset was 27-71 years old, and the time from onset to diagnosis was 5-36 days. Five cases had fever, and other 5 cases had not fever. There were headache, fatigue, local pain, and other specialized symptoms in the 10 patients.The white blood cell count,the neutrophil ratio, the inflammatory index C-reactive protein, the procalcitonin were all increased, and the erythrocyte sedimentation was accelerated in the 10 patients.All the patients were sensitive to ampicillin, penicillin G, meropenem, and compound sinomine. CONCLUSIONS: Listeriosis often affects the patients with low immunity, which often leads to misdiagnosis or missed diagnosis in clinic.So early prevention, early diagnosis, and early treatment can reduce mortality; it is important for departments of nosocomial infection management to manage patients' diet for avoiding outbreaks of listeriosis in hospital.

Infection Control in the Era of Antimicrobial Resistance in China: Progress, Challenges, and Opportunities.

More than 3 decades have passed since infection control was implemented nationwide in China in 1986. A comprehensive set of regulations and guidelines has been developed, and almost all hospitals have established infection control teams. However, compliance is variable and is usually suboptimal. The incidence of certain multidrug-resistant organisms (MDROs), including carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Klebsiella pneumoniae (CRKP), is increasing, and associated infections are mainly hospital-acquired in China. Carbapenem-resistant Pseudomonas aeruginosa has remained relatively stable, whereas methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterobacter faecium have been decreasing. The spread of CRAB and CRKP in China is largely mediated by dominant high-risk lineages, namely, clonal complex 92 for CRAB and sequence type 11 for CRKP. However, challenges owing to MDROs bring opportunities for rethinking, taking coordinated action, building capacity, changing behavior, and performing studies that reflect everyday situations in the Chinese healthcare system.

In Vitro Activity of Imipenem/Relebactam Against Enterobacteriaceae Isolates Obtained from Intra-abdominal, Respiratory Tract, and Urinary Tract Infections in China: Study for Monitoring Antimicrobial Resistance Trends (SMART), 2015-2018.

BACKGROUND: Considering the increasing incidence of carbapenem-resistant Enterobacteriaceae in China, this study aimed to establish the in vitro effectiveness of imipenem/relebactam (IMI/REL) on clinical Enterobacteriaceae isolates derived from intra-abdominal infections (IAIs), respiratory tract infections (RTIs), and urinary tract infections (UTIs) in China between 2015 and 2018. METHODS: In total, 8781 Enterobacteriaceae isolates from IAI, RTI, and UTI samples were collected from 22 hospitals across 7 geographic regions of China. Susceptibility to antimicrobial drugs was tested using the Clinical and Laboratory Standards Institute broth microdilution and breakpoints, and IMI/REL activity was assessed using United States Food and Drug Administration guidelines. RESULTS: In 2015-2018, the most frequently identified Enterobacteriaceae species was Escherichia coli (n = 4676 [53.3%]), followed by Klebsiella pneumoniae (n = 2949 [33.6%]) and Enterobacter cloacae (n = 542 [6.2%]). The Enterobacteriaceae isolates showed 95.2% overall susceptibility to IMI/REL, of which the susceptibility rates in isolates from IAI, RTI, and UTI were 95.8%, 91.4%, and 96.6%, respectively. Overall, the susceptibilities of both intensive care unit (ICU) and non-ICU Enterobacteriaceae isolates to colistin were 92.9%, followed by IMI/REL (90.7% [95.9%]) and amikacin (83.3% [92.3%]). In addition, IMI/REL restored 66.3% susceptibility in imipenem-nonsusceptible Enterobacteriaceae. CONCLUSIONS: Given their high in vitro susceptibility, Enterobacteriaceae infections in China should be considered for IMI/REL treatment, especially with isolates that are not susceptible to carbapenems.

Diagnosis and Management of Intraabdominal Infection: Guidelines by the Chinese Society of Surgical Infection and Intensive Care and the Chinese College of Gastrointestinal Fistula Surgeons.

The Chinese guidelines for IAI presented here were developed by a panel that included experts from the fields of surgery, critical care, microbiology, infection control, pharmacology, and evidence-based medicine. All questions were structured in population, intervention, comparison, and outcomes format, and evidence profiles were generated. Recommendations were generated following the principles of the Grading of Recommendations Assessment, Development, and Evaluation system or Best Practice Statement (BPS), when applicable. The final guidelines include 45 graded recommendations and 17 BPSs, including the classification of disease severity, diagnosis, source control, antimicrobial therapy, microbiologic evaluation, nutritional therapy, other supportive therapies, diagnosis and management of specific IAIs, and recognition and management of source control failure. Recommendations on fluid resuscitation and organ support therapy could not be formulated and thus were not included. Accordingly, additional high-quality clinical studies should be performed in the future to address the clinicians' concerns.

Genomic landscape of the immune microenvironments of brain metastases in breast cancer.

BACKGROUND: This study was intended to investigate the genomic landscape of the immune microenvironments of brain metastases in breast cancer. METHODS: Three gene expression profile datasets (GSE76714, GSE125989 and GSE43837) of breast cancer with brain metastases were downloaded from Gene Expression Omnibus (GEO) database. After differential expression analysis, the tumor immune microenvironment and immune cell infiltration were analyzed. Then immune-related genes were identified, followed by function analysis, transcription factor (TF)-miRNA-mRNA co-regulatory network analysis, and survival analysis of metastatic recurrence. RESULTS: The present results showed that the tumor immune microenvironment in brain metastases was immunosuppressed compared with primary caner. Compared with primary cancer samples, the infiltration ratio of plasma cells in brain metastases samples was significantly higher, while the infiltration ratio of macrophages M2 cells in brain metastases samples was significantly lower. Total 42 immune-related genes were identified, such as THY1 and NEU2. CD1B, THY1 and DOCK2 were found to be implicated in the metastatic recurrence of breast cancer. CONCLUSIONS: Targeting macrophages or plasma cells may be new strategies for immunotherapy of breast cancer with brain metastases. THY1 and NEU2 may be potential therapeutic targets for breast cancer with brain metastases, and THY1, CD1B and DOCK2 may serve as potential prognostic markers for improvement of brain metastases survival.

Profiling pro-neural to mesenchymal transition identifies a lncRNA signature in glioma.

BACKGROUND: Molecular classification has laid the framework for exploring glioma biology and treatment strategies. Pro-neural to mesenchymal transition (PMT) of glioma is known to be associated with aggressive phenotypes, unfavorable prognosis, and treatment resistance. Recent studies have highlighted that long non-coding RNAs (lncRNAs) are key mediators in cancer mesenchymal transition. However, the relationship between lncRNAs and PMT in glioma has not been systematically investigated. METHODS: Gene expression profiles from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GSE16011, and Rembrandt with available clinical and genomic information were used for analyses. Bioinformatics methods such as weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis (GSEA), Cox analysis, and least absolute shrinkage and selection operator (LASSO) analysis were performed. RESULTS: According to PMT scores, we confirmed that PMT status was positively associated with risky behaviors and poor prognosis in glioma. The 149 PMT-related lncRNAs were identified by WGCNA analysis, among which 10 (LINC01057, TP73-AS1, AP000695.4, LINC01503, CRNDE, OSMR-AS1, SNHG18, AC145343.2, RP11-25K21.6, RP11-38L15.2) with significant prognostic value were further screened to construct a PMT-related lncRNA risk signature, which could divide cases into two groups with distinct prognoses. Multivariate Cox regression analyses indicated that the signature was an independent prognostic factor for high-grade glioma. High-risk cases were more likely to be classified as the mesenchymal subtype, which confers enhanced immunosuppressive status by recruiting macrophages, neutrophils, and regulatory T cells. Moreover, six lncRNAs of the signature could act as competing endogenous RNAs to promote PMT in glioblastoma. CONCLUSIONS: We profiled PMT status in glioma and established a PMT-related 10-lncRNA signature for glioma that could independently predict glioma survival and trigger PMT, which enhanced immunosuppression.

Identification of potential biomarkers and candidate small molecule drugs in glioblastoma.

BACKGROUND AND AIMS: Glioblastoma (GBM) is a common and aggressive primary brain tumor, and the prognosis for GBM patients remains poor. This study aimed to identify the key genes associated with the development of GBM and provide new diagnostic and therapies for GBM. METHODS: Three microarray datasets (GSE111260, GSE103227, and GSE104267) were selected from Gene Expression Omnibus (GEO) database for integrated analysis. The differential expressed genes (DEGs) between GBM and normal tissues were identified. Then, prognosis-related DEGs were screened by survival analysis, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed to explore the hub genes associated with GBM. The mRNA and protein expression levels of hub genes were respectively validated in silico using The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases. Subsequently, the small molecule drugs of GBM were predicted by using Connectivity Map (CMAP) database. RESULTS: A total of 78 prognosis-related DEGs were identified, of which10 hub genes with higher degree were obtained by PPI analysis. The mRNA expression and protein expression levels of CETN2, MKI67, ARL13B, and SETDB1 were overexpressed in GBM tissues, while the expression levels of CALN1, ELAVL3, ADCY3, SYN2, SLC12A5, and SOD1 were down-regulated in GBM tissues. Additionally, these genes were significantly associated with the prognosis of GBM. We eventually predicted the 10 most vital small molecule drugs, which potentially imitate or reverse GBM carcinogenic status. Cycloserine and 11-deoxy-16,16-dimethylprostaglandin E2 might be considered as potential therapeutic drugs of GBM. CONCLUSIONS: Our study provided 10 key genes for diagnosis, prognosis, and therapy for GBM. These findings might contribute to a better comprehension of molecular mechanisms of GBM development, and provide new perspective for further GBM research. However, specific regulatory mechanism of these genes needed further elaboration.

Nonfunctioning pituitary adenomas in pediatric and adolescent patients: a clinical analysis of a series of 14 patients.

PURPOSE: Nonfunctional pituitary adenomas (NFPAs) in pediatric and adolescent age are extremely rare. This study aimed to report a series of 14 pediatric and adolescent NFPAs to assist in its clinical management. METHODS: A total of 14 consecutive patients pathologically diagnosed with NFPAs (age ≤ 20 years) were retrospectively examined, and the clinical data were analyzed. RESULTS: NFPA is uncommon in pediatric and adolescent patients (0.4%). The most common clinical symptoms were a headache (6/14, 42.9%) and visual loss (4/14, 28.6%). Ten patients (71.4%) had preoperative hypopituitarism. All patients were diagnosed with macroadenoma including 8 (57.1%) invasive tumors, and the average tumor diameter was 2.8 cm. All patients underwent transsphenoidal surgery, and a near-total resection was achieved in nine (64.3%) patients. Postoperative visual acuity improved in three patients (75%). The results of immunohistochemistry showed 6 silent plurihormonal adenomas (42.9%), 3 null cell adenomas (21.4%), 3 silent lactotroph adenomas (21.4%), 1 silent gonadotroph adenoma (7.1%) and 1 silent corticotroph adenoma (7.1%). The mean follow-up was 54.8 months, and five patients had tumor recurrence. Tumors with Ki-67 ≧ 2% (28.6%) showed higher recurrence rate than those with lower index (P = 0.001). Two patients received secondary surgery and radiation for recurrent tumors suffered from panhypopituitarism. CONCLUSION: Pediatric and adolescent NFPA is clinically rare, and shows potential invasiveness. The silent plurihormonal adenoma is the most frequent phenotype. Transsphenoidal surgery is as safe and effective as in adults. However, individualized care and teamwork of neurosurgeons, pediatricians, endocrinologists, and radiation oncologists are important, especially for recurrent diseases.

Prognostic roles of time to positivity of blood cultures in patients with Escherichia coli bacteremia.

The time to positivity (TTP) of blood cultures has been considered a predictor of clinical outcomes for bacteremia. This retrospective study aimed to determine the clinical value of TTP for the prognostic assessment of patients with Escherichia coli bacteremia. A total of 167 adult patients with E.coli bacteremia identified over a 22-month period in a 3500-bed university teaching hospital in China were studied. The standard cut-off TTP was 11 h in the patient cohort. The septic shock occurred in 27.9% of patients with early TTP (⩽11 h) and in 7.1% of those with a prolonged TTP (>11 h) (P = 0.003). The mortality rate was significantly higher for patients in the early than in the late group (17.7% vs. 4.0%, P < 0.001). Multivariate analysis showed that an early TTP (OR 4.50, 95% CI 1.70-11.93), intensive care unit admission (OR 8.39, 95% CI 2.01-35.14) and neutropenia (OR 4.20, 95% CI 1.55-11.40) were independently associated with septic shock. Likewise, the independent risk factors for mortality of patients were an early TTP (OR 3.80, 95% CI 1.04-12.90), intensive care unit admission (OR 6.45; 95% CI 1.14-36.53), a Pittsburgh bacteremia score ⩾2 (OR 4.34, 95% CI 1.22-15.47) and a Charlson Comorbidity Index ⩾3 (OR 11.29, 95% CI 2.81-45.39). Overall, a TTP for blood cultures within 11 h appears to be associated with worse outcomes for patients with E.coli bacteremia.

Overexpression of oncostatin M receptor regulates local immune response in glioblastoma.

Glioblastoma (GBM) is the most lethal cancer in central nervous system. It is urgently needed to look for novel therapeutics for GBM. Oncostatin M receptor (OSMR) is a cytokine receptor gene of IL-6 family and has been reported to be involved in regulating GBM tumorigenesis. However, the role of OSMR regulating the disrupted immune response in GBM need to be further investigated. Three gene expression profiles, Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) data set (GSE16011), were enrolled in our study and used for OSMR expression and survival analysis. The expression of OSMR was further verified with immunohistochemistry and western blot analysis in glioma tissues. Microenvironment cell populations-counter (MCP-counter) was applied for analyzing the relationship between OSMR expression and nontumor cells. The functions of OSMR in GBM was investigated by Gene Ontology, Gene set enrichment analysis (GSEA), gene set variation analysis and so on. The analysis of cytokine receptor activity-related genes in glioma identifies OSMR as a gene with an independent predictive factor for progressive malignancy in GBM. Furthermore, OSMR expression is a prognostic marker in the response prediction to radiotherapy and chemotherapy. OSMR contributes to the regulation of local immune response and extracellular matrix process in GBM. Our findings define an important role of OSMR in the regulation of local immune response in GBM, which may suggest OSMR as a possible biomarker in developing new therapeutic immune strategies in GBM.

Is the presence of HCMV components in CNS tumors a glioma-specific phenomenon?

BACKGROUND: Human cytomegalovirus (HCMV) has been associated with malignant gliomas. The purpose of the present study was to investigate the presence of HCMV in common non-glial tumors of the central nervous system (CNS) and to determine whether it is a glioma-specific phenomenon. METHODS: Using HCMV-specific immunohistochemical staining, HCMV proteins IE1-72 and pp65 were examined in 65 meningiomas (benign, atypical and malignant), 45 pituitary adenomas, 20 cavernous hemangiomas, and 30 metastatic carcinomas specimens. HCMV DNA was also measured in these tumor tissues and the peripheral blood from patients using nested PCR. RESULTS: In meningioma, IE1-72 was detected in 3.1% (2/65) and pp65 was detected in 4.6% (3/65), whereas no IE1-72 and pp65 were detected in atypical and malignant meningioma. A low level of IE1-72 immunoreactivity 6.7% (2/30) was detected in metastatic carcinoma; pp65 was not detected. No HCMV components were detected in pituitary adenoma and cavernous hemangioma. The results of immunohistochemical staining were confirmed by HCMV-specific PCR. HCMV DNA was not detected in the peripheral blood of the non-glial CNS tumors patients. CONCLUSIONS: Our results demonstrate that the presence of HCMV components is not an entirely glioma-specific phenomenon, and that HCMV is present in a low percentage in some non-glioma CNS tumors. Comparing HCMV-positive non-glial CNS tumors with HCMV-positive gliomas may cast light on the mechanism and role of HCMV in CNS tumors.