Carbon Quantum Dots: In vitro and in vivo Studies on Biocompatibility and Biointeractions for Optical Imaging.

BACKGROUND: Understanding the biocompatibility and biointeractions of nano-carbon quantum dots (nano-CQDs) in vitro and in vivo is important for assessing their potential risk to human health. In the previous research, the physical properties of CQDs synthesized by the laser ablation in liquid (LAL) method were analyzed in detail; however, possible bioapplications were not considered. MATERIALS AND METHODS: CQDs were prepared by LAL and characterized by atomic force microscopy, fluorescence lifetime, absorption spectrum, Fourier-transform infrared spectroscopy, and dynamic light scattering. Their biocompatibility was evaluated in vitro using assays for cytotoxicity, apoptosis, and biodistribution and in vivo using immunotoxicity and the relative expression of genes. Cells were measured in vitro using fluorescence-lifetime imaging microscopy to analyze the biointeractions between CQDs and intracellular proteins. RESULTS: There were no significant differences in biocompatibility between the CQDs and the negative control. The intracellular interactions had no impact on the optical imaging of CQDs upon intake by cells. Optical imaging of zebrafish showed the green fluorescence was well dispersed. CONCLUSION: We have demonstrated that the CQDs have an excellent biocompatibility and can be used as efficient optical nanoprobes for cell tracking and biomedical labeling except for L929 and PC-3M cells.

A Meta-Analytic Review of the Value of miRNA for Multiple Sclerosis Diagnosis.

Backgrounds and Purpose: Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system. The etiology of MS is unclear, disease diagnosis mainly based on symptoms, and lacks effective laboratory test index. Circulating microRNAs (miRNAs) as sensitive biomarkers have been widely studied, the expression levels of certain miRNAs are dynamically changed in MS patients. This meta-analysis aims to assess the overall diagnostic accuracy of circulating miRNAs for MS. Methods: We searched PubMed, EMBASE, Cochrane Library, CNKI databases as of July 20, 2019. QUADAS was used to assess the quality of included studies. All studies were processed by Stata 15.0 software. Eleven articles with 600 patients with MS and 389 controls were included. Results: The sensitivity and specificity, PLR, NLR, and DOR of the overall studies were 0.81 (95% CI 0.77-0.84), 0.75 (95% CI 0.68-0.81), 3.3 (95% CI 2.5-4.3), 0.25 (95% CI 0.20-0.32), 13 (95% CI: 8-20), and 0.85 (95% CI 0.82-0.88). Subgroup analysis indicated that miRNA assay had higher diagnostic accuracy for relapsing-remitting MS (RRMS) when compared with other MS subtypes. Conclusion: Our study performed a meta-analysis to generate an estimate of the relevance of miRNA change and the occurrence of MS, and revealed circulating miRNAs has the potential to be used for MS diagnosis, especially for RRMS. Future studies should clarify to which specific miRNAs can accurately diagnose disease subtypes. The miRNA-related pathogenesis may provide theoretical basis for drug development for early intervention.

The correlation between serum apolipoprotein B/apolipoprotein A1 ratio and brain necrosis in patients underwent radiotherapy for nasopharyngeal carcinoma.

INTRODUCTION: The apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio is recognized as a clinical indicator of cardiovascular disease and ischemic cerebral disease. Cerebrovascular dysfunction is also involved in head and neck radiotherapy. The aim of this study was to investigate the correlation between ApoB/ApoA1 ratio and the severity of radiation-induced brain necrosis (RN) in patients who underwent radiotherapy after nasopharyngeal carcinoma (NPC). METHODS: In this retrospective study, 191 NPC patients diagnosed with RN were evaluated. Clinical characteristics, serum lipid, apolipoproteins, and brain magnetic resonance imaging findings were collected. Serum lipid and apolipoproteins were quantified using standard diagnostic assays, and the quality of life (QOL) was assessed by the World Health Organization quality of life abbreviated instrument (WHOQOL-BREF). RESULTS: ApoB/ApoA1 ratio was positively correlated with lesion volume (r = .18, p = .03) and negatively correlated with WHOQOL-BREF scores (r = -.28, p < .01). The ApoB/ApoA1 ratio and intensity-modulated radiation therapy (IMRT) were independent risk factor of RN volume. Moreover, ApoB/ApoA1 ratio was significantly negatively correlated with physical health (r = -.29, p < .01), psychological (r = -.27, p < .01), social relationships (r = -.17, p = .02), and environment (r = -.27, p < .01) domains of WHOQOL-BREF. CONCLUSIONS: Serum ApoB/ApoA1 ratio is positively correlated with RN volume, which indicated serum ApoB/ApoA1 ratio as an independent risk factor for lesion volume in patients with RN after radiotherapy for NPC, suggesting a bright intervention target in RN treatment.

Tanshinone IIA attenuates demyelination and promotes remyelination in A. cantonensis-infected BALB/c mice.

BACKGROUND: Angiostrongylus cantonensis infection can cause demyelination in the central nervous system, and there is no effective treatment. METHODS: We used dexamethasone, Tanshinone IIA (TSIIA) and Cryptotanshinone(Two traditional Chinese medicine monomers) in combination with albendazole (AB, a standard anti-helminthic compound) to observe their therapeutic effect on demyelination in A. cantonensis-infected mice. Luxol fast blue staining and electron microscope of myelin sheath, Oligodendrocyte (OL) number and myelin basic protein (MBP) expression in brain was detected in above groups. RESULTS: TSIIA+AB facilitated OL proliferation and significantly increased both myelin sheath thickness and the population of small-diameter axons. In addition, TSIIA treatment inhibited the expression of inflammation-related factors (interleukin [IL]-6, IL-1ß, tumor necrosis factor [TNF]-α, inducible nitric oxide synthase [iNOS]) rather than inhibiting eosinophil infiltration in brain. TSIIA also decreased microglial activation and shifted their phenotype from M1 to M2. CONCLUSIONS: Taken together, these results provide evidence that TSIIA combined with AB may be an effective treatment for demyelination caused by A. cantonensis infection and other demyelinating diseases.

IL-17A neutralizing antibody attenuates eosinophilic meningitis caused by Angiostrongylus cantonensis by involving IL-17RA/Traf6/NF-κB signaling.

BACKGROUND: Angiostrongylus cantonensis (A. cantonensis) is a foodborne parasite that can invade the central nervous system (CNS), resulting in eosinophilic meningitis (EM). However, the mechanism by which A. cantonensis causes eosinophilic infiltration into CNS is not well understood. METHODS: In this study eosinophilic infiltration into the CNS caused by A. cantonensis was assessed based on eosinophil counts and evaluation of interleukin (IL)-5 and -13 levels by real-time PCR in brain of Balb/c mice. The expression and activation of IL-17A, IL17 receptor (IL-17R A), and IL-17RC and the related signaling molecules nuclear factor (NF)-κB1, NF-κB2, NF-κB activator (Act)1, tumor necrosis factor receptor-associated factor (Traf)5, and Traf6 during A. cantonensis infection in brain tissue of Balb/c mice were examined by real-time, western blotting and immunofluroence. A. cantonensis-infected Balb/c mice were treated with IL-17A neutralizing antibody to evaluate the role of IL17A in eosinophil accumulation in the CNS. RESULTS: Our results showed A. cantonensis infection caused eosinophil accumulation and alterations in IL-5 and -13 levels. The expression of IL-17A and -17RA, Act1, and Traf6 but not of IL-17RC and Traf5 was upregulated during infection; this was accompanied by NF-κB1 and -κB2 activation. Importantly, application of IL-17A neutralizing antibody attenuated eosinophil accumulation in CNS and reversed the changes in IL-5 and -13 expression caused by A. cantonensis infection. Additionally, IL-17RA and Traf6 levels decreased, which was accompanied by NF-κB inactivation. CONCLUSION: IL-17A plays an important role in EM caused by A. cantonensis, possibly through activation of NF-κB via the IL-17RA/Traf6 signaling pathway. These findings highlight the potential for using IL-17A neutralizing antibody as a therapeutic strategy for the treatment of EM.

Comparison between high-dose and low-dose intravenous methylprednisolone therapy in patients with brain necrosis after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy is the standard radical treatment for nasopharyngeal carcinoma (NPC) and may cause radiation-induced brain necrosis (RN). Intravenous steroids have been considered as an effective treatment for RN. However, evidence concerning the efficacy of different doses of intravenous steroid therapy remains insufficient to establish the optimal regimen for NPC patients with RN. METHODS: We retrospectively reviewed charts of 169 patients who were diagnosed with RN after radiotherapy for NPC, treated with low-dose or high-dose intravenous methylprednisolone (IVMP) and followed up for 12 months. We collected the clinical data, including the Late Effects of Normal Tissue (LENT)/Subjective, Objective, Management, Analytic (SOMA) scales score and Montreal Cognitive Assessment (MoCA) score. Magnetic resonance imaging (MRI) was performed pre- and post-treatment to define the radiographic response. RESULTS: There were no significant differences in the treatment response based on MRI, or changes in clinical symptoms and cognitive function between low and high-dose groups. Thirty of 93 low-dose patients (32.3%) and 21 of 76 high-dose patients (27.6%) presented effective response in MRI, with no significant differences between groups (P = 0.515). Neither group showed a significant difference in the effective rate based on the MoCA total score and LENT/SOMA score. The most commonly reported grade 3 adverse events in the high-dose group (n = 76) were infections and infestations (3 [3.9%] vs. none for low-dose group). CONCLUSIONS: We found low-dose IVMP was not inferior to high-dose IVMP for NPC patients with RN. In addition, treatment-related infections and infestations were likewise more common with high-dose steroid than low-dose steroid.

Magnetic and fluorescent Gd2O3:Yb3+/Ln3+ nanoparticles for simultaneous upconversion luminescence/MR dual modal imaging and NIR-induced photodynamic therapy.

The development of upconversion nanoparticles (UCNs) for theranostics application is a new strategy toward the accurate diagnosis and efficient treatment of cancer. Here, magnetic and fluorescent lanthanide-doped gadolinium oxide (Gd2O3) UCNs with bright upconversion luminescence (UCL) and high longitudinal relaxivity (r1) are used for simultaneous magnetic resonance imaging (MRI)/UCL dual-modal imaging and photodynamic therapy (PDT). In vitro and in vivo MRI studies show that these products can serve as good MRI contrast agents. The bright upconversion luminescence of the products allows their use as fluorescence nanoprobes for live cells imaging. We also utilized the luminescence-emission capability of the UCNs for the activation of a photosensitizer to achieve significant PDT results. To the best of our knowledge, this study is the first use of lanthanide-doped Gd2O3 UCNs in a theranostics application. This investigation provides a useful platform for the development of Gd2O3-based UCNs for clinical diagnosis, treatment, and imaging-guided therapy of cancer.

α1-Adrenergic receptors mediate combined signals initiated by mechanical stretch stress and norepinephrine leading to accelerated mouse vein graft atherosclerosis.

OBJECTIVE: The molecular mechanism underlying how hypertension with increased norepinephrine (NE) accelerates vascular remodeling is unknown. The present study examined the hypothesis that the additive effects of mechanical stretch stress (SS) and NE on vascular remodeling are mediated by α1-adrenergic receptors (α1-ARs). METHODS: In vitro quiescent mouse vascular smooth muscle cells were cultivated on a flexible membrane and treated by mechanical SS (10% elongation) with or without NE (10(-7) mol/L) in the absence or presence of prazosin, a selective antagonist of α1-ARs (Praz; 10(-7) mol/L). In vivo mouse vena cava segments were grafted into carotid arteries, the mice were treated by prazosin (1 mg/kg/d, intraperitoneally) or saline for 2 weeks and 4 weeks, and wall thickness of the vein grafts was quantified. RESULTS: Mechanical SS could induce Gαq translocation; increase expression of α1B-ARs, α1D-ARs, and Ki67; and rapidly activate extracellular signal-regulated kinases (ERKs) compared with negative controls (P < .05). However, the peak levels of ERK activation and Ki67 expression in vascular smooth muscle cells were stimulated by combining SS and NE (ratio of phosphorylated ERK [pERK]/ß-actin and Ki67 positive rates, SS+NE [1.07 ± 0.04 and 73% ± 3%]; SS [0.83 ± 0.07 and 53% ± 2%]; NE [0.63 ± 0.11 and 42% ± 2%]), which could be partially inhibited by prazosin (ratio of pERK/ß-actin and Ki67 positive rates, SS+NE+Praz [0.83 ± 0.08 and 40% ± 7% vs SS+NE; P < .05], SS+Praz [0.60 ± 0.04 and 26% ± 2% vs SS; P < .05], NE+Praz [0.32 ± 0.12 and 23% ± 2% vs NE; P < .05]) or small interfering RNAs of α1B-ARs and α1D-ARs (P < .05 vs siRNA control). Significantly increased wall thickness was seen in the vein grafts (VG2W, 39.20 ± 3.10 µm; VG4W, 60.35 ± 4.94 µm) compared with control veins (negative controls, 9.90 ± 0.38 µm; P < .05). The effect was partially inhibited by prazosin (VGP2W, 26.22 ± 1.84 µm, and VGP4W, 42.17 ± 1.75 µm vs VG2W and VG4W; P < .05). CONCLUSIONS: These results suggest that α1-ARs may partially mediate the intracellular signals induced by mechanical SS with or without NE via Gαq protein/ERKs pathway triggering increased proliferation of vascular smooth muscle cells and leading to accelerated neointima formation of vein grafts.

Gadolinium(3+)-doped mesoporous silica nanoparticles as a potential magnetic resonance tracer for monitoring the migration of stem cells in vivo.

We investigated the tracking potential of a magnetic resonance imaging (MRI) probe made of gadolinium-doped mesoporous silica MCM-41 (Gd(2)O(3)@MCM-41) nanoparticles for transplanted bone mesenchymal stem cells (MSCs) and neural stem cells (NSCs) in vivo. The nanoparticles, synthesized using a one-step synthetic method, possess hexagonal mesoporous structures with appropriate assembly of nanoscale Gd(2)O(3) clusters. They show little cytotoxicity against proliferation and have a lower effect on the inherent differentiation potential of these labeled stem cells. The tracking of labeled NSCs in murine brains was dynamically determined with a clinical 3T MRI system for at least 14 days. The migration of labeled NSCs identified by MRI corresponded to the results of immunofluorescence imaging. Our study confirms that Gd(2)O(3)@MCM-41 particles can serve as an ideal vector for long-term MRI tracking of MSCs and NSCs in vivo.

The properties of Gd2O3-assembled silica nanocomposite targeted nanoprobes and their application in MRI.

The feasibility of the gadolinium-doped mesoporous silica nanocomposite Gd(2)O(3)@MCM-41 as a safe, effective MRI nanoprobe has been validated in the current investigation systematically from atomistic and molecular modeling to its synthesis and characterization on in vivo MR imaging and biocompatibility. The first-principles calculation indicates that it is nearly impossible for toxic Gd ions to dissociate freely from silica. The biocompatibility studies confirm that the nanocomposite is lack of any potential toxicity; the biodistribution studies reveal a greater accumulation of the nanocomposite in liver, spleen, lung and tumor than in kidney, heart and brain; the excretion studies show that the nanocomposite can be cleared nearly 50% via the hepatobiliary transport mechanism after 1.5 months of injection. A larger water proton relaxivity r(1) and a better T(1)-weighted phantom MR imaging capability were detected in the nanocomposite than in the commercially available gadolinium diethylenetriaminepentaacetate. The results demonstrate that the nanocomposite is superior to the commercial counterpart in terms of contrast enhancement with a satisfactory biocompatibility, and it has a high potential to be developed into a safe and effective targeted probe for in vivo molecular imaging of cancer.

Efficiency of ferritin as an MRI reporter gene in NPC cells is enhanced by iron supplementation.

BACKGROUND: An emerging MRI reporter, ferritin heavy chain (FTH1), is recently applied to enhance the contrast and increase the sensitivity of MRI in the monitoring of solid tumors. However, FTH1-overexpression-related cytotoxicity is required to be explored. METHODS: By using the Tet-Off system, FTH1 overexpression was semi-quantitativiely and dynamicly regulated by doxycycline in a NPC cell line. Effects of FTH1 overexpression on the proliferation, cytotoxicity, apoptosis and migration of NPC cells were investigated in vitro, and MR relaxation rate was measured in vitro and in vivo. RESULTS: In vitro and in vivo overexpression of FTH1 significantly increased the transverse relaxivity (R(2)), which could be enhanced by iron supplementation. In vitro, overexpression of FTH1 reduced cell growth and migration, which were not reduced by iron supplementation. Furthermore, cells were subcutaneously inoculated into the nude mice. Results showed FTH1 overexpression decreased tumor growth in the absence of iron supplementation but not in the presence of iron supplementation. CONCLUSION: To maximize R(2) and minimize the potential adverse effects, supplementation of iron at appropriate dose is recommended during the application of FTH1 as a reporter gene in the monitoring of NPC by MRI.

Effects of decabrominated diphenyl ether (PBDE-209) in regulation of growth and apoptosis of breast, ovarian, and cervical cancer cells.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs), commonly used in building materials, electronics, plastics, polyurethane foams, and textiles, are health hazards found in the environment. OBJECTIVE: In this study we investigated the effects of PBDE-209, a deca-PBDE, on the regulation of growth and apoptosis of breast, ovarian, and cervical cancer cells as well as the underlying protein alterations. METHODS: We used MCF-7 and MCF-7/ADR (multidrug-resistant MCF-7) breast cancer cell lines, the HeLa cervical cancer cell line, the OVCAR-3 ovarian cancer cell line, and the normal CHO (Chinese hamster ovary) cell line to assess the effects of PBDE-209 using cell viability, immunofluorescence, and flow cytometric assays. Western blot assays were used to detect changes in protein expression. To assess the effects of PBDE-209 on apoptosis, we used the protein kinase Cα (PKCα) inhibitor Gö 6976, the extracellular signal-regulated kinase (ERK) inhibitor PD98059, and tamoxifen. RESULTS: Our data indicate that PBDE-209 increased viability and proliferation of the tumor cell lines and in CHO cells in a dose- and time-dependent manner. PBDE-209 also altered cell cycle distribution by inducing the S phase or G2/M phase. Furthermore, PBDE-209 partially suppressed tamoxifen-induced cell apoptosis in the breast cancer cell lines (MCF-7 and MCF-7/ADR) but suppressed Gö 6976- and PD98059-induced apoptosis in all cell lines. At the molecular level, PBDE-209 enhanced PKCα and ERK1/2 phosphorylation in the cell lines. CONCLUSIONS: Our data demonstrate that PBDE-209 is able to promote proliferation of various cancer cells from the female reproductive system and normal ovarian CHO cells. Furthermore, it reduced tamoxifen, PKCα, and ERK inhibition-induced apoptosis. Finally, PBDE-209 up-regulated phosphorylation of PKCα and ERK1/2 proteins in tumor cells and in CHO cells.

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells.

This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-positive human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-negative) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric analysis. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot analysis revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-positive MCF-7 cells; while ER-negative MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we observed that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells.

PKCα inhibited apoptosis by decreasing the activity of JNK in MCF-7/ADR cells.

The development of multidrug resistance (MDR) in breast cancer patients is a serious therapeutic problem. The role of signal transduction in the development of MDR has drawn intensive attention recently. In this study, the role of c-Jun N-terminal kinase (JNK) pathway in MDR, specifically regulated by PKCα, was investigated in MCF-7/ADR cells. MTT, DNA ladder and flow cytometry were used to detect cell growth inhibition or apoptosis while Western blot was used to detect the activation of proteins. Compared with MCF-7 cells, the cell growth inhibition and apoptosis induced by tamoxifen (TAM) could not be detected in MCF-7/ADR cells, but the expression of PKCα in MCF-7/ADR cells was higher. And, Western blot results showed that JNK was activated by TAM in MCF-7 cells while not in MCF-7/ADR cells, even at very high doses. In addition, sp600125, the inhibitor of JNK, decreased the percentage of apoptosis induced by TAM in MCF-7 cells. These data showed that PKCα and JNK were key regulators in the apoptosis of MCF-7/ADR cells. Furthermore, PKCα being the upstream of JNK in inhibiting apoptosis was suggested by using Go6976, the specific PKCα inhibitor, in the presence or absence of sp600125. This study highlighted an important signaling pathway involved in MDR regulated by PKCα in MCF-7/ADR breast cancer cells and implied that JNK might be an important downstream target of PKCα in this cellular context.

Development and applications of a nasopharyngeal carcinoma Tet-Off cell line.

The conditional activation and inactivation of target gene expression in a nasopharyngeal carcinoma (NPC) cell line is beneficial for the study of the roles of NPC-related genes. Based on the Tet-Off Advanced system, a NPC S18 Tet-Off cell line was developed by stable transfection of a pTet-Off Advanced vector (regulator plasmid in Tet-Off Advanced system) into NPC S18 cells. Doxycycline-dependent regulators expressed in the S18 Tet-Off cells were examined by transient and stable transfection of pTRE-Tight-Luc. The S18 Tet-Off-Luc clone selected by stable transfection of pTRE-Tight-Luc into S18 Tet-Off cells expressed firefly luciferase under tight control of doxycycline in a time- and dose-dependent manner. To test applications of the S18 Tet-Off cell line in the study of gene function, the impact of ferritin heavy chain (FTH1) gene on NPC cell growth was examined. The S18 Tet-Off-FTH1 clone was developed by stably transfecting pTRE-Tight-FTH1 (response plasmid harboring FTH1) into S18 Tet-Off cells. FTH1 levels in the S18 Tet-Off-FTH1 clone were semi-quantitatively regulated in response to varying concentrations of doxycycline. A cell proliferation assay showed that a high expression of FTH1 (cells grown in the absence of doxycycline) reduced cell growth, while moderate FTH1 overexpression (cells grown in 0.1 ng/ml doxycycline) had no adverse effect on cell growth. In conclusion, the S18 Tet-Off cell line provides a proven genetic background for convenient access to controllable gene expression in NPC.

Tamoxifen-induced apoptosis of rat C6 glioma cells via PI3K/Akt, JNK and ERK activation.

To elucidate the mechanism of TAM treatment on gliomas, we hypothesised that PI3K/Akt and MAPK signaling pathway may play important roles on TAM-induced apoptosis in C6 glioma cells. Our results demonstrated that TAM induced apoptosis of C6 glioma cells in a dose-dependent manner. The activation of AKT significantly decreased in a time-dependent manner in response to TAM treatment, JNK was transiently activated, and subsequently decreased activation and kept stable level, whereas ERK evidenced sustained activations in response to the drug treatment. The inhibition of PI3K/Akt and JNK both accelerated and enhanced TAM-induced apoptosis and ERK inhibition apparently exerted negative effect on apoptosis. We also observed that PI3K/Akt had intimate association with JNK and ERK activation in TAM-induced apoptosis. These findings may provide strategies for the molecularly targeted therapy in malignant gliomas.

Activated PKCalpha/ERK1/2 signaling inhibits tamoxifen-induced apoptosis in C6 cells.

Data have shown that tamoxifen (TAM) can be used to treat not only breast cancer with positive estrogen receptor (ER), but also negative ER including human glioma. However, the molecular mechanism of this drug against different kinds of cancers remains to be elucidated. In this study, we provided the evidence that PKCalpha-ERK1/2 signaling pathway plays a negative role in TAM-induced C6 cell apoptosis, and a combined utilization of TAM with inhibitors of PKCalpha or ERK1/2 could enhance the effectiveness of TAM on inhibiting tumor growth.

Transcriptional signature of an adult brain tumor in Drosophila.

BACKGROUND: Mutations and gene expression alterations in brain tumors have been extensively investigated, however the causes of brain tumorigenesis are largely unknown. Animal models are necessary to correlate altered transcriptional activity and tumor phenotype and to better understand how these alterations cause malignant growth. In order to gain insights into the in vivo transcriptional activity associated with a brain tumor, we carried out genome-wide microarray expression analyses of an adult brain tumor in Drosophila caused by homozygous mutation in the tumor suppressor gene brain tumor (brat). RESULTS: Two independent genome-wide gene expression studies using two different oligonucleotide microarray platforms were used to compare the transcriptome of adult wildtype flies with mutants displaying the adult bratk06028 mutant brain tumor. Cross-validation and stringent statistical criteria identified a core transcriptional signature of brat(k06028) neoplastic tissue. We find significant expression level changes for 321 annotated genes associated with the adult neoplastic brat(k06028) tissue indicating elevated and aberrant metabolic and cell cycle activity, upregulation of the basal transcriptional machinery, as well as elevated and aberrant activity of ribosome synthesis and translation control. One fifth of these genes show homology to known mammalian genes involved in cancer formation. CONCLUSION: Our results identify for the first time the genome-wide transcriptional alterations associated with an adult brain tumor in Drosophila and reveal insights into the possible mechanisms of tumor formation caused by homozygous mutation of the translational repressor brat.