Identification of CDK1, PBK, and CHEK1 as an Oncogenic Signature in Glioblastoma: A Bioinformatics Approach to Repurpose Dapagliflozin as a Therapeutic Agent

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells\u27 presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle\u27s main regulatory proteins. Herein, we identified and validated the biomarker and predictive properties of a chemoradio-resistant oncogenic signature in GBM comprising CDK1, PBK, and CHEK1 through our comprehensive in silico analysis. We found that CDK1/PBK/CHEK1 overexpression drives the cell cycle, subsequently promoting GBM tumor progression. In addition, our Kaplan-Meier survival estimates validated the poor patient survival associated with an overexpression of these genes in GBM. We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib

Metrology Camera System of Prime Focus Spectrograph for Subaru Telescope

The Prime Focus Spectrograph (PFS) is a new optical/near-infrared multi-fiber spectrograph designed for the prime focus of the 8.2m Subaru telescope. PFS will cover a 1.3 degree diameter field with 2394 fibers to complement the imaging capabilities of Hyper SuprimeCam. To retain high throughput, the final positioning accuracy between the fibers and observing targets of PFS is required to be less than 10um. The metrology camera system (MCS) serves as the optical encoder of the fiber motors for the configuring of fibers. MCS provides the fiber positions within a 5um error over the 45 cm focal plane. The information from MCS will be fed into the fiber positioner control system for the closed loop control. MCS will be located at the Cassegrain focus of Subaru telescope in order to to cover the whole focal plane with one 50M pixel Canon CMOS camera. It is a 380mm Schmidt type telescope which generates a uniform spot size with a 10 micron FWHM across the field for reasonable sampling of PSF. Carbon fiber tubes are used to provide a stable structure over the operating conditions without focus adjustments. The CMOS sensor can be read in 0.8s to reduce the overhead for the fiber configuration. The positions of all fibers can be obtained within 0.5s after the readout of the frame. This enables the overall fiber configuration to be less than 2 minutes. MCS will be installed inside a standard Subaru Cassgrain Box. All components that generate heat are located inside a glycol cooled cabinet to reduce the possible image motion due to heat. The optics and camera for MCS have been delivered and tested. The mechanical parts and supporting structure are ready as of spring 2016. The integration of MCS will start in the summer of 2016.Comment: 11 pages, 15 figures. SPIE proceeding. arXiv admin note: text overlap with arXiv:1408.287

Assessing Computational Amino Acid β-Turn Propensities with a Phage-Displayed Combinatorial Library and Directed Evolution

SummaryStructure propensities of amino acids are important determinants in guiding proteins' local and global structure formation. We constructed a phage display library—a hexa-HIS tag upstream of a CXXC (X stands for any of the 20 natural amino acids) motif appending N-terminal to the minor capsid protein pIII of M13KE filamentous phage—and developed a novel directed-evolution procedure to select for amino acid sequences forming increasingly stable β-turns in the disulfide-bridged CXXC motif. The sequences that emerged from the directed-evolution cycles were in good agreement with type II β-turn propensities derived from surveys of known protein structures, in particular, Pro-Gly forming a type II β-turn. The agreement strongly supported the notion that β-turn formation plays an active role in initiating local structure folding in proteins

Paeoniae alba Radix Promotes Peripheral Nerve Regeneration

The present study provides in vitro and in vivo evaluation of Paeoniae alba Radix (PR) on peripheral nerve regeneration. In the in vitro study, we found the PR caused a marked enhancement of the nerve growth factor-mediated neurite outgrowth from PC12 cells as well as their expression of growth associated protein 43 and synapsin I. In the in vivo study, silicone rubber chambers filled with the PR water extract were used to bridge a 10-mm sciatic nerve defect in rats. At the conclusion of 8 weeks, regenerated nerves in the PR groups, especially at 1.25 mg ml−1 had a higher rate of successful regeneration across the wide gap, relatively larger mean values of total nerve area, myelinated axon count and blood vessel number, and a significantly larger nerve conductive velocity compared to the control group (P  <  .05). These results suggest that the PR extract can be a potential nerve growth-promoting factor, being salutary in aiding the growth of injured peripheral nerve

In-Silico Analysis of TMEM2 as a Pancreatic Adenocarcinoma and Cancer-Associated Fibroblast Biomarker, and Functional Characterization of NSC777201, for Targeted Drug Development

Pancreatic adenocarcinoma (PAAD), known as one of the deadliest cancers, is characterized by a complex tumor microenvironment, primarily comprised of cancer-associated fibroblasts (CAFs) in the extracellular matrix. These CAFs significantly alter the matrix by interacting with hyaluronic acid (HA) and the enzyme hyaluronidase, which degrades HA - an essential process for cancer progression and spread. Despite the critical role of this interaction, the specific functions of CAFs and hyaluronidase in PAAD development are not fully understood. Our study investigates this interaction and assesses NSC777201, a new anti-cancer compound targeting hyaluronidase. This research utilized computational methods to analyze gene expression data from the Gene Expression Omnibus (GEO) database, specifically GSE172096, comparing gene expression profiles of cancer-associated and normal fibroblasts. We conducted in-house sequencing of pancreatic cancer cells treated with NSC777201 to identify differentially expressed genes (DEGs) and performed functional enrichment and pathway analysis. The identified DEGs were further validated using the TCGA-PAAD and Human Protein Atlas (HPA) databases for their diagnostic, prognostic, and survival implications, accompanied by Ingenuity Pathway Analysis (IPA) and molecular docking of NSC777201, in-vitro, and preclinical in-vivo validations. The result revealed 416 DEGs associated with CAFs and 570 DEGs related to NSC777201 treatment, with nine overlapping DEGs. A key finding was the transmembrane protein TMEM2, which strongly correlated with FAP, a CAF marker, and was associated with higher-risk groups in PAAD. NSC777201 treatment showed inhibition of TMEM2, validated by rescue assay, indicating the importance of targeting TMEM2. Further analyses, including IPA, demonstrated that NSC777201 regulates CAF cell senescence, enhancing its therapeutic potential. Both in-vitro and in-vivo studies confirmed the inhibitory effect of NSC777201 on TMEM2 expression, reinforcing its role in targeting PAAD. Therefore, TMEM2 has been identified as a theragnostic biomarker in PAAD, influenced by CAF activity and HA accumulation. NSC777201 exhibits significant potential in targeting and potentially reversing critical processes in PAAD progression, demonstrating its efficacy as a promising therapeutic agent