A filter for compensation of the angular dependence of LiF: Mg,Ti(TLD-100) for beta radiation

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Functional Genomics Screening Utilizing Mutant Mouse Embryonic Stem Cells Identifies Novel Radiation-Response Genes

<div><p>Elucidating the genetic determinants of radiation response is crucial to optimizing and individualizing radiotherapy for cancer patients. In order to identify genes that are involved in enhanced sensitivity or resistance to radiation, a library of stable mutant murine embryonic stem cells (ESCs), each with a defined mutation, was screened for cell viability and gene expression in response to radiation exposure. We focused on a cancer-relevant subset of over 500 mutant ESC lines. We identified 13 genes; 7 genes that have been previously implicated in radiation response and 6 other genes that have never been implicated in radiation response. After screening, proteomic analysis showed enrichment for genes involved in cellular component disassembly (e.g. Dstn and Pex14) and regulation of growth (e.g. Adnp2, Epc1, and Ing4). Overall, the best targets with the highest potential for sensitizing cancer cells to radiation were <i>Dstn</i> and <i>Map2k6</i>, and the best targets for enhancing resistance to radiation were <i>Iqgap</i> and <i>Vcan</i>. Hence, we provide compelling evidence that screening mutant ESCs is a powerful approach to identify genes that alter radiation response. Ultimately, this knowledge can be used to define genetic variants or therapeutic targets that will enhance clinical therapy.</p></div

Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity

Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies that seek to optimize both the drug and drug carrier together in a concerted effort remain uncommon yet may be powerful. In this work, two block polymers and one dimeric prodrug molecule were designed to be coassembled into degradable, functional nanocarriers, where the chemistry of each component was defined to accomplish important tasks. The result is a poly­(ethylene glycol) (PEG)-protected redox-responsive dimeric paclitaxel (diPTX)-loaded cationic poly­(d-glucose carbonate) micelle (diPTX@CPGC). These nanostructures showed tunable sizes and surface charges and displayed controlled PTX drug release profiles in the presence of reducing agents, such as glutathione (GSH) and dithiothreitol (DTT), thereby resulting in significant selectivity for killing cancer cells over healthy cells. Compared to free PTX and diPTX, diPTX@CPGC exhibited improved tumor penetration and significant inhibition of tumor cell growth toward osteosarcoma (OS) lung metastases with minimal side effects both in vitro and in vivo, indicating the promise of diPTX@CPGC as optimized anticancer therapeutic agents for treatment of OS lung metastases

Cell growth as a function of time for wild type (WT) and (A) Dpagt1-mutant ESCs, (B) Klf8-mutant ESCs, (C) Dstn-mutant ESCs, (D) Iqgap1-mutant ESCs, (E) Map2k6-mutant ESCs, (F) Vcan-mutant ESCs, (G) Rbpms-mutant ESCs.

<p>Cells were irradiated with a dose of 2-Gy just before incubation using x-rays. Error bars indicate SEM.</p

Evaluation of hits for GO enrichment.

<p>Evaluation of hits for GO enrichment.</p

Cytotoxicity assay performance.

<p>Estimate of Dead cell relative light units (RLU), Live cell RLU, and % Viability for all clones at 0-Gy, 0.5-Gy and 4-Gy irradiation. While dead cell RLUs do not show statistically significant changes, changes in live cell RLUs and % Viability at 4-Gy are statistically significant indicating that as a whole, clones show fewer live cells and decreased viability at 4-Gy, presumably due to cell cycle arrest and decreased cell division.</p

Selected radiation response genes.

<p>Selected radiation response genes.</p

Validation assays.

<p>(A) Change in % viability over time for selected clones. (B) Change in gene expression over time for selected clones. (C) Change in % viability due to radiation dose for selected clones. (D) Change in gene expression due to radiation dose for selected clones. Error bars indicate SEM.</p