One-Step Construction of Closed Pores Enabling High Plateau Capacity Hard Carbon Anodes for Sodium-Ion Batteries: Closed-Pore Formation and Energy Storage Mechanisms.

Closed pores play a crucial role in improving the low-voltage (<0.1 V) plateau capacity of hard carbon anodes for sodium-ion batteries (SIBs). However, the lack of simple and effective closed-pore construction strategies, as well as the unclear closed-pore formation mechanism, has severely hindered the development of high plateau capacity hard carbon anodes. Herein, we present an effective closed-pore construction strategy by one-step pyrolysis of zinc gluconate (ZG) and elucidate the corresponding mechanism of closed-pore formation. The closed-pore formation mechanism during the pyrolysis of ZG mainly involves (i) the precipitation of ZnO nanoparticles and the ZnO etching on carbon under 1100 °C to generate open pores of 0.45-4 nm and (ii) the development of graphitic domains and the shrinkage of the partial open pores at 1100-1500 °C to convert the open pores to closed pores. Benefiting from the considerable closed-pore content and suitable microstructure, the optimized hard carbon achieves an ultrahigh reversible specific capacity of 481.5 mA h g-1 and an extraordinary plateau capacity of 389 mA h g-1 for use as the anode of SIBs. Additionally, some in situ and ex situ characterizations demonstrate that the high-voltage slope capacity and the low-voltage plateau capacity stem from the adsorption of Na+ at the defect sites and Na-cluster formation in closed pores, respectively.

Rapid and Continuous Atmospheric Plasma Surface Modification of PAN-Based Carbon Fibers.

In this work, a continuous and rapid atmospheric plasma setup was developed for rapidly modifying the surface of PAN-based carbon fibers (CFs). The interlaminar shear strength (ILSS) of CFs increased from 64.9 to 80.0 MPa with 60 s plasma treatment. Further mechanical and surface structural characterizations revealed that the effect of plasma was different, depending on the treatment time. When the treatment time was lower than 15 s, the effect of plasma was mainly on physically etching the surface of CFs, and the ILSS of CFs increased rapidly. Further extending the plasma treatment time did not increase surface roughness but promoted the addition of oxygen-containing functional groups on the surface of CFs, corresponding to a slower growth rate of ILSS. The atmospheric plasma was generated via a dielectric barrier discharge (DBD) method, and its energy intensity was significantly lower than that of plasma generated under low pressure. Accordingly, a mechanism was proposed for the plasma treatment of CFs: atmospheric plasma was not strong enough to simultaneously etch all the carbon atoms on the surface of CFs; therefore, carbon atoms on the graphitic plane were selectively etched, followed by the attaching of oxygen-containing functional groups on the exposed carbon sites caused by etching.

A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma.

Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and "stepAIC" algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the "pRRophetic" and "TIDE" algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4+ T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4+ T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.

MicroRNA-4476 promotes glioma progression through a miR-4476/APC/ß-catenin/c-Jun positive feedback loop.

Glioma has been a major healthcare burden; however, the specific molecular regulatory mechanism underlying its initiation and progression remains to be elucidated. Although it is known that many miRNAs are involved in the regulation of malignant phenotypes of glioma, the role of miR-4476 has not been reported yet. In the present study, we identify miR-4476 as an upregulated microRNA, which promotes cell proliferation, migration, and invasion in glioma. Further mechanistic analyses indicate that the adenomatous polyposis coli (APC), a negative regulator of the Wnt/ß-catenin signaling pathway, is a direct target of miR-4476 and mediates the oncogenic effects of miR-4476 in glioma. C-Jun, a downstream effector of the Wnt/ß-catenin signaling, is upregulated by miR-4476 overexpression. In turn, c-Jun could positively regulate miR-4476 expression by binding to the upstream of its transcription start site (TSS). Furthermore, in our clinical samples, increased miR-4476 is an unfavorable prognostic factor, and its expression positively correlates with c-Jun expression but negatively correlates with that of APC. In conclusion, our study demonstrates that miR-4476 acts as a tumor enhancer, directly targeting APC to stimulate its own expression and promoting the malignant phenotypes of glioma.

CircZNF609/miR-134-5p/BTG-2 axis regulates proliferation and migration of glioma cell.

OBJECTIVES: MicroRNAs are abundant in eukaryotic cells and play key roles in cancers. Circular RNAs (CircRNAs) served as the competing endogenous RNAs (ceRNAs) in mediating multiple cell processes. This study aims to define the role of CircRNA CircZNF609/miR-134-5p in glioma as well as the underlying regulating mechanism. METHODS: Relative expression of miR-134-5p, CircZNF609 and BTG-2 mRNA was determined by quantitative real-time PCR. Cell proliferation was analysed by CCK-8 assay. Cell migration was assessed by cell wound scratch assay. The direct regulatory of miR-134-5p on BTG-2 and CircZNF609 was verified by luciferase report gene assay. KEY FINDINGS: MiR-134-5p was significantly upregulated in glioma cells. The overexpression of miR-134-5p inhibited cell proliferation and migration of glioma cell U251 and U87. Reversely, knock-down of miR-134-5p enhanced cell proliferation and migration. Both BTG-2 and CircZNF609 are the direct targets of miR-134-5p, and their expression could be negatively regulated by miR-134-5p. CircZNF609 was significantly upregulated in U251 and U87 cells and acted as an oncogene to promote cell proliferation and cell migration of glioma cell U251 and U87. CONCLUSIONS: These data proved that CircZNF609 served as a competing RNA to bind miR-134-5p that promoted BTG-2 expression leading to reduced proliferation and migration of glioma cell.

Bioactivity-based analysis and chemical characterization of hypoglycemic and antioxidant components from Artemisia argyi.

Diabetes is one of the metabolic disorders in the world. It is the prime reason of mortality and morbidity owing to hyperglycemia which is link with numerus obstacles. Artemisia argyi is commonly used as an ingredient in healthy foods as well as an herbal medicine in Asian countries. The present research aims to evaluate the hypoglycemic effects of A. argyi and reveal its the potentially active constituents. The chemical composition was identified by HPLC-DAD-Q-TOF-MS, and fractionation was performed by extraction. The fractions were assessed by the blood glucose level, oral glucose tolerance and small intestinal α-glucosidase inhibitory tests, and an analysis of the total phenolic content (TPC), antioxidant and α-glucosidase inhibitory activities. In our efforts to characterize the compounds responsible for hypoglycemic effect, bioactivity-guided fraction of the MeOH extract and chemical investigation of its active EtOAc fraction led to the successful identification of caffeoylquinic acids, which were elucidated by molecular docking, using the crystal structure of S. cerevisiae isomaltase (PD code: 3AXI). In summary, this bio-guided search revealed that caffeoylquinic acids from A. argyi as potential active constituents displayed with hypoglycemic activity, which provided a basis for further study of pharmacological activity.

Acupuncture for hearing loss after traumatic brain injury: A protocol for systematic review of randomized controlled trial.

BACKGROUND: This study aims to systematically assess the effectiveness and safety of acupuncture on hearing loss (HL) after traumatic brain injury (TBI). METHODS: In this study, the following databases will be retrieved from inception up to the May 1, 2019: PUBMED, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database. All databases will be retrieved without any language restrictions. Two reviewers will independently carry out article selection, data collection, and risk of bias evaluation. Any disagreements will be solved by a third reviewer through discussion. RESULTS: This study will systematically investigate the effectiveness and safety of acupuncture for treating HL after TBI through evaluating HL assessment, hearing threshold, quality of life, and adverse events. CONCLUSION: The expected findings of this study will provide latest evidence for assessing the effectiveness and safety of acupuncture for HL after TBI. ETHICS AND DISSEMINATION: This study is supposed to be published in a peer-reviewed journal. No ethical approval is needed because this study will based on the literature analysis, but not the individual patient. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019133417.

Vitellaria paradoxa nutshells from seven sub-Saharan countries as potential herbal medicines for treating diabetes based on chemical compositions, HPLC fingerprints and bioactivity evaluation.

The aim of the study was to determine the feasibility of the Vitellaria paradoxa nutshell as a new medicinal resource for treating diabetes. A total of forty-one compounds were identified by HPLC-DAD-Q-TOF-MS and phytochemical methods in V. paradoxa nutshell methanol extract. Based on HPLC fingerprints, four characteristic constituents were quantified and the origin of twenty-eight V. paradoxa nutshells from seven sub-Saharan countries was compared, which were classified into three groups with chemometric method. Twenty-eight samples contained high total phenolic content, and exhibited moderate-higher antioxidant activity and strong α-glucosidase inhibitory activity. Furthermore, all fractions and isolated compounds were evaluated for their antioxidant and α-glucosidase inhibitory activities, and α-glucosidase inhibitory action mechanism of four characteristic constituents including protocatechuic acid, 3, 5, 7-trihydroxycoumarin, (2R, 3R)-(+)-taxifolin and quercetin was investigated via molecular docking method, which were all stabilized by hydrogen bonds with α-glucosidase. The study provided an effective approach to waste utilization of V. paradoxa nutshell, which would help to resolve waste environmental pollution and provide a basis for developing potential herbal resource for treating diabetes.

Neuromuscular electrical stimulation on hearing loss caused by skull base fracture: A protocol for systematic review of randomized controlled trial.

BACKGROUND: This systematic review aims to investigate the effectiveness and safety of neuromuscular electrical stimulation (NMES) on hearing loss (HL) caused by skull base fracture (SBF). METHODS: We will retrieve the following electronic databases of Cochrane Library, PUBMED, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database from the inception to January 1, 2019 for relevant RCTs of NMES for HL caused by SBF. Two experienced authors will independently perform the study selection, data extraction, and methodology quality assessment. A 3rd author will solve any disagreements between 2 authors through discussion. RESULTS: This study will provide a high-quality synthesis of latest evidence of NMES for HL caused by SBF from comprehensive assessments, including hearing loss evaluation, hearing threshold, quality of life, and any relevant adverse events. CONCLUSION: The expected results of this systematic review will provide the up-to-date evidence to assess the effectiveness and safety of NEMS for patients with HL caused by SBF. ETHICS AND DISSEMINATION: The results of this study will be disseminated through publication in a peer-reviewed journal or will be presented at an associated conference meeting. This study will not use individual patient data, thus, the ethical approval is not needed. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019120195.

Efficacy of transsphenoidal surgery for pituitary tumor: A protocol for systematic review.

BACKGROUND: This systematic review aims to assess the efficacy and safety of transsphenoidal surgery (TPS) for patients with a pituitary tumor (PT). METHODS: We will retrieve the following electronic databases for randomized controlled trials or case-control studies to assess the effect and safety of TPS for PT: Cochrane Library, EMBASE, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database. Each database will be retrieved from the inception to December 20, 2018. The entire process consists of the study selection, data collection, methodology quality assessment, data pooled, and meta-analysis performance. The methodology quality will be assessed by using Cochrane risk of bias tool. The data pooled and meta-analysis will be conducted by using RevMan 5.3 software. RESULTS: This study will evaluate the efficacy and safety of TPS for PT. The primary outcome includes total tumor resection rate. The secondary outcomes consist of quality of life, total tumor resection rate, postoperative complication rate, and the rate of functional tumor hormone levels. CONCLUSION: The expected results may provide up-to-date evidence of TPS for the treatment of PT. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42018120194.

YB-1 modulates the drug resistance of glioma cells by activation of MDM2/p53 pathway.

BACKGROUND: Y-box-binding protein-1 (YB-1) is aberrantly expressed in a variety of cancers. However, the biological functional role of YB-1 in glioma is not yet clear. METHODS: The expression of MDM2 and YB-1 was analyzed by real time PCR. Overexpression and knockdown of YB-1 in glioma cells were created by transfection of pcDNA-YB-1 and siRNA against YB-1, respectively. Cell viability was performed by CCK8 assay. RESULTS: Our findings showed that glioma tissues had higher expressions of YB-1 than that in cancer-free tissues in 54 glioma patients, which were also positively correlated with Murine MDM2 expression. Overexpression of YB-1 or MDM2 renders a drug resistance feature in glioma cell exposed to temozolomide (TMZ), by directly targeting p53. Genetic or chemical inhibition of MDM2 significantly blocked YB-1-modulated response of glioma cells to TMZ. Moreover, inhibition of YB-1 or MDM2 reduced glioma cells metastasis and mortality in mice. CONCLUSION: YB-1 facilitates the resistance of glioma cells to TMZ by direct activation of MDM2/p53 signaling and represents a promising molecular target for glioma treatment.

Discriminating poststroke depression from stroke by nuclear magnetic resonance spectroscopy-based metabonomic analysis.

Poststroke depression (PSD), the most common psychiatric disease that stroke survivors face, is estimated to affect ~30% of poststroke patients. However, there are still no objective methods to diagnose PSD. In this study, to explore the differential metabolites in the urine of PSD subjects and to identify a potential biomarker panel for PSD diagnosis, the nuclear magnetic resonance-based metabonomic method was applied. Ten differential metabolites responsible for discriminating PSD subjects from healthy control (HC) and stroke subjects were found, and five of these metabolites were identified as potential biomarkers (lactate, α-hydroxybutyrate, phenylalanine, formate, and arabinitol). The panel consisting of these five metabolites provided excellent performance in discriminating PSD subjects from HC and stroke subjects, achieving an area under the receiver operating characteristic curve of 0.946 in the training set (43 HC, 45 stroke, and 62 PSD subjects). Moreover, this panel could classify the blinded samples from the test set (31 HC, 33 stroke, and 32 PSD subjects) with an area under the curve of 0.946. These results laid a foundation for the future development of urine-based objective methods for PSD diagnosis and investigation of PSD pathogenesis.

Sex Difference of Egfr Expression and Molecular Pathway in the Liver: Impact on Drug Design and Cancer Treatments?

Epidermal growth factor receptor (EGFR) has been used as the target in drug design for cancer treatment including the liver cancer. Men and women have different levels of EGFR expression during the life. The whole genome expression profiles of livers of recombinant inbred (RI) strains derived from C57BL/6J (B6) X DBA/2J (D2) were used to compare three major molecular aspects of Egfr gene: the relative expression levels, gene network and eQTLs that regulate the expression of Egfr between female and male mice. Our data suggest that there is a significant difference in the expression levels in the liver between female and male mice. Several important genes in the gene network of Egfr are differentially expressed between female and male mice. The regulatory elements for the expression levels of Egfr between female and male mice are also different. In summary, our data reveals an important sex difference in the Egfr pathways in the liver of the mice. These data may have substantial impact on drug development and dosage determinant for women and men in the clinical trials.

Thrombomodulin and High-Sensitive C-Reactive Protein Levels in Blood Correlate with the Development of Cerebral Infarction Among Asians.

Our meta-analysis was designed to obtain the correlation between thrombomodulin (TM) and high-sensitive C-reactive protein (hs-CRP) levels and the development of cerebral infarction (CI). Case-control studies relevant to the role plasma TM levels and serum hs-CRP levels in the development of CI were retrieved both electronically and manually and further screened according to a predetermined inclusion and exclusion criteria. All enrolled studies were analyzed for meta-regression analyses, sensitivity analyses, and assessments of publication bias. Comprehensive Meta-analysis 2.0 software (CMA 2.0) was used for statistical analysis. A total of 359 studies were initially retrieved, and 13 studies were eventually recruited into our meta-analysis with a total of 881 CI patients (plasma TM levels: n = 513; serum hs-CRP levels: n = 368) and 1067 healthy controls. The results of our meta-analysis suggested that plasma TM levels and serum hs-CRP levels in CI patients were significantly higher than those in healthy controls. In conclusion, increased plasma TM levels and serum hs-CRP levels in CI patients were associated with the development of CI in Asians.

MicroRNA involvement in a metastatic non-functioning pituitary carcinoma.

PURPOSE: Pituitary carcinomas are extremely rare neoplasms, and molecular events leading to malignant pituitary transformation are largely unknown. Enhanced understanding of molecular mechanisms driving malignant pituitary progression would be beneficial for pituitary carcinoma diagnosis and treatment. METHODS: Differential microRNA expression in paired primary and metastatic pituitary carcinoma specimens were detected using high-throughput human microRNA microarrays and TaqMan microRNA arrays. Three of significantly deregulated miRNAs were further confirmed using quantitative real-time PCR in the metastatic carcinoma, six atypical pituitary adenomas and eight typical pituitary adenomas. Target genes of microRNAs were bioinformatically predicated and verified in vitro by Western blotting and real-time PCR and in vivo by immunohistochemistry respectively. RESULTS: We present a case of a 50-year-old woman harboring non-functioning pituitary carcinoma with multiple intracranial metastases, and identified up-regulation of miR-20a, miR-106b and miR-17-5p in the metastatic carcinoma as compared to the primary neoplasm. Furthermore, miR-20a and miR-17-5p were increased in the metastatic carcinoma and six atypical pituitary adenomas as compared to eight typical pituitary adenomas as measured by quantitative real-time PCR. Both PTEN and TIMP2 were bioinformatically predicated and confirmed in vitro as target genes of these three microRNAs. As semi-quantified by immunohistochemistry, PTEN was absent and TIMP2 was decreased in the metastatic pituitary carcinoma as compared to pituitary adenomas. CONCLUSIONS: Our results suggest microRNA involvement in malignant pituitary progression, whereby increased miR-20a, miR-106b and miR-17-5p promote metastasis by attenuating PTEN and TIMP2 in pituitary carcinoma.

Influence of GNB3 C825T polymorphism on the efficacy of antidepressants in the treatment of major depressive disorder: A meta-analysis.

OBJECTIVE: We performed the present meta-analysis in order to evaluate the influence of a common polymorphism (C825T, rs5443 C>T) in the GNB3 gene on the efficacy of antidepressants in the treatment of major depressive disorder (MDD). METHOD: A relevant literature was searched using the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM and CNKI databases without any language restrictions. STATA Version 12.0 software (Stata Corporation, College Station, Texas USA) was used for this meta-analysis. Odds ratio (OR) and its corresponding 95% confidence interval (95% CI) were calculated. RESULTS: Our findings suggested that the GNB3 C825T polymorphism was significantly correlated with a higher response rate to antidepressants in MDD patients under the allele and dominant models. Furthermore, we found significant associations between GNB3 C825T polymorphisms and antidepressant-induced remission in MDD patients. Ethnicity-stratified analysis indicated that GNB3 C825T polymorphisms may be strongly related to the efficacy of antidepressants in the treatment of MDD among Asians, but not in Caucasians (all P>0.05). CONCLUSION: Our findings provide empirical evidence that GNB3 C825T polymorphisms may be correlated with the efficacy of antidepressants in the treatment of MDD, especially among Asians patients.

Improvement in diagnosis of metastatic pituitary carcinoma by 68Ga DOTATATE PET/CT.

Pituitary carcinoma is a rare disease with a challenge in both diagnosis and treatment. A 50-year-old female patient who underwent transsphenoidal resection of a pituitary tumor experienced progressive headache. For the evaluation, Ga DOTATATE PET/CT was used and compared with F-FDG PET/CT and enhanced MRI. Multiple lesions were detected by Ga DOTATATE PET/CT at the cerebral cortex, cerebellum, and cerebellopontine angle with a higher contrast than F-FDG PET/CT and enhanced MRI. With a biopsy, the patient was diagnosed as metastatic pituitary carcinoma. Moreover, it thus presents potential therapeutic implications on molecular-targeted therapy using somatostatin analogs and peptide receptor radionuclide therapy targeting the somatostatin receptors.

Comparison of (68)Ga DOTATATE to 18F-FDG uptake is useful in the differentiation of residual or recurrent pituitary adenoma from the remaining pituitary tissue after transsphenoidal adenomectomy.

AIM: The evaluation of the remaining pituitary tissue and recurrent or residual tumor after the pituitary adenoma resection is difficult. However, it is essential to assess the size of the recurrent tumor and remaining pituitary reserve before resurgery. This study aimed to distinguish the remaining pituitary tissue from pituitary adenoma with Ga 1,4,7,10-tetraazacyclododecane-N,N',N″,N″'-tetraacetic acid-D-Phe,Tyr3-octreotate (DOTATATE) and F-FDG PET imaging in patients status post transsphenoidal adenomectomy. METHODS: Thirty-five patients with suspected recurrent/residual pituitary tumors were retrospectively evaluated. All of these patients underwent DOTATATE and FDG PET/CT within 1 week before additional surgery. The DOTATATE and FDG uptake levels were compared. The image findings were then compared with pathology results after the additional surgery. RESULTS: Residual or recurrent pituitary adenoma were confirmed pathologically in all 35 patients. One recurrent pituitary adenoma did not have either DOTATATE or FDG uptake. In the remaining 34 adenomas, 33 had higher FDG uptake than DOTATATE uptake. In comparison, DOTATATE had significant higher uptake than FDG in the remaining pituitary tissues in all cases. CONCLUSIONS: Different degree of uptake of Ga DOTATATE and F-FDG PET/CT in the remaining pituitary tissue and recurrent/residual pituitary tumor indicated that combined analysis of Ga DOTATATE and F-FDG PET/CT might be of clinical value in differentiating recurrent/residual pituitary adenoma from the remaining pituitary tissue.

Correlations of pituitary tumor transforming gene expression with human pituitary adenomas: a meta-analysis.

OBJECTIVE: Pituitary tumor transforming gene (PTTG) is an important paracrine growth factor involved in early lactotrope transformation and early onset of angiogenesis in pituitary hyperplasia. Emerging evidences have shown that PTTG expression may contribute to the etiology of pituitary adenomas; but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the correlations of PTTG expression with human pituitary adenomas. METHODS: A range of electronic databases were searched: MEDLINE (1966∼2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980∼2013), CINAHL (1982∼2013), Web of Science (1945∼2013) and the Chinese Biomedical Database (CBM) (1982∼2013) without language restrictions. Meta-analysis was performed using the STATA 12.0 software. Crude odds ratio (OR) or standard mean difference (SMD) with its corresponding 95% confidence interval (95%CI) were calculated. RESULTS: Twenty-four clinical cohort studies were included with a total of 1,464 pituitary adenomas patients. The meta-analysis results revealed that patients with invasive pituitary adenomas had higher positive expression of PTTG than those of non-invasive patients (OR  = 6.68, 95%CI  = 3.72-11.99, P<0.001). We also found a significant difference in microvessel density between invasive and non-invasive patients (SMD  = 1.81, 95%CI  = 0.39-3.23, P = 0.013). However, there were no significant difference in PTTG expression between functional and non-functional patients with pituitary adenomas (OR  = 1.11, 95%CI  = 0.58-2.10, P = 0.753). No publication bias was detected in this meta-analysis (all P>0.05). CONCLUSION: This present meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas, while no correlations with functional status was found.

Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice.

Invasive pituitary adenomas (PAs) are often refractory to standard therapy and salvage treatment with temozolomide (TMZ). Hyperactivation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway contributes to chemotherapy resistance in many cancers. XL765, a novel dual-PI3K/mTOR inhibitor, has recently shown its efficacy as a monotherapy and in combination with conventional therapeutics in many cancers. The hyperactive PI3K/AKT/mTOR pathway frequently occurs in invasive PAs. In this study, we investigated whether XL765 sensitizes PA cells to TMZ in vitro and in vivo. Experiments were carried out to evaluate the effect of XL765 and TMZ alone or in combination on cell proliferation and apoptosis of PA cell lines (αT3-1, GH3, and MMQ) in vitro as well as the tumor growth and serum GH and prolactin secretions in a GH3 xenograft tumor model of female nude mice. XL765 and TMZ synergistically inhibited the growth of PA cell lines and induced apoptosis. Combination of XL765 and TMZ synergistically inhibited tumor growth, decreased serum GH and prolactin levels, and reduced the sacrifice rate of GH3 xenograft tumor models without increased systemic side effects. In addition, XL765 in combination with TMZ dramatically decreased phosphorylation of AKT and mTOR as well as the expression of Bcl-2. The increased expression of cleaved poly (ADP-ribose) polymerase and Bcl-2-associated X protein along with elevated caspase-3/7 activity were also observed in the combination group. Therefore, dual inhibitors of PI3K and mTOR may enhance alkylating agent-mediated cytotoxicity and provide a novel regimen in the treatment of invasive PAs.