Abstract
Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; ...however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active b-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABCþ/Sox2þ population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3458. doi:1538-7445.AM2012-3458
Abstract
Ionizing radiation (IR) is a critical component in the treatments of breast cancer patients with all stages of the disease and a gold standard modality in patients with multiple brain ...metastasis, demonstrating improved overall survival (OS) in recent meta-analysis. However, the problem of recurrent or persistent disease exists due to tumor radio-resistance, and the development of distant metastasis after IR has presented a major obstacle to treatment. We investigated which molecule could be targeted for radio-sensitization. We found that c-Met over-expression and activation of downstream-signaling were induced in response to IR in a panel of human breast cancer cells by q-PCR, FACS, and Western blot analysis. The radio-sensitizing effect of c-Met silencing in vitro showed that increased c-Met activity is required for radio-resistance. In addition, c-Met inhibition combined with IR showed synergistic antitumor response including improved tumor regression and lengthened overall survival in breast cancer orthotopic and experimental brain metastasis xenograft models. Our preclinical findings establish a basis for a novel strategy to target the HGF/c-Met pathway with radiation when treating primary and brain metastatic breast cancer and possibly other c-Met pathway dependent cancers.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3460. doi:1538-7445.AM2012-3460
Tumor-tropic properties of neural stem cells (NSCs) provide a novel approach with which to deliver targeting therapeutic genes to brain tumors. Previously, we developed a therapeutic strategy against ...metastatic brain tumors using a human NSC line (F3) expressing cytosine deaminase (F3.CD). F3.CD converts systemically administered 5-fluorocytosine (5-FC), a blood-brain barrier permeable nontoxic prodrug, into the anticancer agent 5-fluorouracil (5-FU). In this study, we potentiated a therapeutic strategy of treatment with nucleosides in order to chemically facilitate the endogenous conversion of 5-FU to its toxic metabolite 5-FU ribonucleoside (5-FUR). In vitro, 5-FUR showed superior cytotoxic activity against MDA-MB-435 cancer cells when compared to 5-FU. Although adenosine had little cytotoxic activity, the addition of adenosine significantly potentiated the in vitro cytotoxicity of 5-FU. When MDA-MB-435 cells were co-cultured with F3.CD cells, F3.CD cells and 5-FC inhibited the growth of MDA-MB-435 cells more significantly in the presence of adenosine. Facilitated 5-FUR production by F3.CD was confirmed by an HPLC analysis of the conditioned media derived from F3.CD cells treated with 5-FC and adenosine. In vivo systemic adenosine treatment also significantly potentiated the therapeutic effects of F3.CD cells and 5-FC in an MDA-MB-435 metastatic brain tumor model. Simple adenosine addition improved the antitumor activity of the NSCs carrying the therapeutic gene. Our results demonstrated an increased therapeutic potential, and thereby, clinical applicability of NSC-based gene therapy.
Although benfotiamine has various beneficial anti-diabetic effects, the detailed mechanisms underlying the impact of this compound on the insulin signaling pathway are still unclear. In the present ...study, we evaluated the effects of benfotiamine on the hepatic insulin signaling pathway in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a type 2 diabetes mellitus model. OLETF rats treated with benfotiamine showed decreased body weight gain and reduced adipose tissue weight. In addition, blood glucose levels were lower in OLETF rats treated with benfotiamine. Following treatment with benfotiamine, the levels of Akt phosphorylation (S473/T308) in the OLETF groups increased significantly compared to the OLETF control group so that they were almost identical to the levels observed in the control group. Moreover, benfotiamine restored the phosphorylation levels of both glycogen synthase kinase (GSK)-$3{\alpha}/{\beta}$ (S21, S9) and glycogen synthase (GS; S641) in OLETF rats to nearly the same levels observed in the control group. Overall, these results suggest that benfotiamine can potentially attenuate type 2 diabetes mellitus in OLETF rats by restoring insulin sensitivity through upregulation of Akt phosphorylation and activation of two downstream signaling molecules, GSK-$3{\alpha}/{\beta}$ and GS, thereby reducing blood glucose levels through glycogen synthesis.
The kiwi (Actinidia deliciosa) is well known to contain anti-oxidants. In this study, we investigated the anti-oxidant effects of kiwi extract on carbon tetrachloride ($CCl_4$) induced liver injury ...in BALB/c mice. The radical scavenging effect of 80% methanol extract of Halla-Gold kiwi was observed. For the animal study, mice were randomly divided into four groups: normal group, $CCl_4$-induced model group, kiwi extract administered group, and silymarin treated group. The kiwi extract was provided daily for 10 days. At the 24 h after last administration, $CCl_4$ was injected. The kiwi extract showed strong inhibitory effect of DPPH radicals and superoxide scavenging. In animal study, administration of $CCl_4$ resulted in significantly elevated plasma levels of ALT and AST but they decreased in kiwi-extract pretreated group. Anti-oxidant enzymes such as GSH-px and GSH-rd were restored in the kiwi extract treatment group. Histopathological degeneration was also prevented in the kiwi extract treated group compared with of the control group, which exhibited $CCl_4$-induced hepatotoxicity. On the basis of the obtained results, it can be concluded that kiwi extract showed protective effects, not only as anti-oxidant effects, but also in the protection of hepatotoxicity in $CCl_4$-intoxicated mice.
•Advanced water purification is essential for sustainable future.•The latest trends in MOFs for the adsorptive removal of emerging PPCPs.•MOFs play an important role as advanced adsorbents for ...PPCPs.•The optimized MOFs by various synthetic strategies can remedy water pollution issues.
Water is essential for the sustainability of mankind. Due to the scarcity of water resources, access to fresh drinking water has been an important global agenda for governments and private sectors. Unfortunately, a significant amount of pharmaceuticals and personal care products (PPCPs) are released into the environment, where these pollutants pose serious health risks for humans and other living organisms. Conventional water treatment processes are ineffective for such low-level pollutants. Metal-organic frameworks (MOFs), emerging as a new class of porous materials, are alternative and non-conventional adsorbents affording high porosity and impressive structural tunability. In this review, we focus on the latest advances in MOF research, especially for the adsorptive removal of PPCPs. Especially, the correlation between the structural property of MOFs and PPCP adsorption was analyzed to suggest a designable MOF platform. The structural properties such as functionality, aperture and cage size, flexibility and defect, and surface area of the MOFs could be considered to adsorb a variety of PPCPs efficiently.
Highly VM-Scalable SSD in Cloud Storage Systems Lee, Wonyoung; Kang, Mincheol; Kim, Soontae
IEEE transactions on computer-aided design of integrated circuits and systems,
01/2024, Letnik:
43, Številka:
1
Journal Article
Recenzirano
Solid-state drives (SSDs) are widely used in cloud storage. As the capacity of an SSD has been increasing, it has become common for many virtual machines (VMs) to share a single SSD to maximize ...resource utilization. However, this sharing can degrade the efficiency of internal operations, such as garbage collection, resulting in increased latencies. Existing literature in this field has mostly focused on inter-device isolation considering the storage device as a black-box entity or presumed an SSD to be shared by up to only eight VMs. In this study, we first analyze a realistic SSD usage environment in cloud systems and identify that block-level data isolation (BDI) should be guaranteed to efficiently scale up the number of VMs in an SSD with minimum latency increases. However, previous schemes cannot work efficiently with BDI when the SSD is shared by dozens of VMs. Based on this analysis, we propose an SSD internal resource management scheme in a cloud environment, called highly VM-scalable SSD (VMS). VMS dynamically partitions physical resources and allocates them to VMs, while the VMs share global buffer blocks to lower latency during abrupt fluctuations of write I/O intensities. Our experimental results show up to 29% of latency reduction. VMS exhibits reduced latencies even in the experiment with 64 VMs, where existing schemes do not function normally.
Identifying optimal synthesis conditions for metal–organic frameworks (MOFs) is a major challenge that can serve as a bottleneck for new materials discovery and development. A trial-and-error ...approach that relies on a chemist’s intuition and knowledge has limitations in efficiency due to the large MOF synthesis space. To this end, 46,701 MOFs were data mined using our in-house developed code to extract their synthesis information from 28,565 MOF papers. The joint machine-learning/rule-based algorithm yields an average F1 score of 90.3% across different synthesis parameters (i.e., metal precursors, organic precursors, solvents, temperature, time, and composition). From this data set, a positive-unlabeled learning algorithm was developed to predict the synthesis of a given MOF material using synthesis conditions as inputs, and this algorithm successfully predicted successful synthesis in 83.1% of the synthesized data in the test set. Finally, our model correctly predicted three amorphous MOFs (with their representative experimental synthesis conditions) as having low synthesizability scores, while the counterpart crystalline MOFs showed high synthesizability scores. Our results show that big data extracted from the texts of MOF papers can be used to rationally predict synthesis conditions for these materials, which can accelerate the speed in which new MOFs are synthesized.
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