THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors

Multiple myeloma (MM) is a hematological disease marked by abnormal growth of B cells in bone marrow. Inherent chromosomal instability and DNA damage are major hallmarks of MM, which implicates an aberrant DNA repair mechanism. Studies have implicated a role for CDK12 in the control of expression of DNA damage response genes. In this study, we examined the effect of a small molecule inhibitor of CDK12–THZ531 on MM cells. Treatment of MM cells with THZ531 led to heightened cell death accompanied by an extensive effect on gene expression changes. In particular, we observed downregulation of genes involved in DNA repair pathways. With this insight, we extended our study to identify synthetic lethal mechanisms that could be exploited for the treatment of MM cells. Combination of THZ531 with either DNA-PK inhibitor (KU-0060648) or PARP inhibitor (Olaparib) led to synergistic cell death. In addition, combination treatment of THZ531 with Olaparib significantly reduced tumor burden in animal models. Our findings suggest that using a CDK12 inhibitor in combination with other DNA repair inhibitors may establish an effective therapeutic regimen to benefit myeloma patients.     

Histamine H4 Receptor Agonism Induces Antitumor Effects in Human T-Cell Lymphoma

The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of the role of histamine in numerous physiological and pathological conditions, including tumor development and progression. The lymph nodes of patients with malignant lymphomas have shown to contain high levels of histamine, however, less is known regarding the expression and function of the H4R in T-cell lymphoma (TCL). In this work we demonstrate the expression of H4R isoforms (mRNA and protein) in three human aggressive TCL (OCI-Ly12, Karpas 299, and HuT78). Histamine and specific H4R agonists (VUF8430 and JNJ28610244) significantly reduced cell viability in a dose-dependent manner (p < 0.05). The combined treatment with the H4R antagonist (JNJ7777120, 10 µM) reversed the effects of the H4R ligands. Importantly, we screened a drug repurposing library of 433 FDA-approved compounds (1 μM) in combination with histamine (10 μM) in Hut78 cells. Histamine produced a favorable antitumor effect with 18 of these compounds, including the histone deacetylase inhibitor panobinostat. Apoptosis, proliferation, and oxidative stress studies confirmed the antitumoral effects of the combination. We conclude that the H4R is expressed in TCL, and it is involved in histamine-mediated responses.     

Properties of poly(ethylene terephthalate) prepared by high-pressure extrusion in a capillary die

The procedure of Southern and Porter has been used to prepare poly(ethylene terephthalate) segments by high-pressure extrusion in an Instron capillary rheometer at temperatures from 245° to 265°C. X-Ray measurements of crystalline orientation along the axis of long-growth segments showed that segment properties were controlled by the time-dependent crystallization of polymer melt in the rheometer reservoir. During the initial stage of extrusion, a highly oriented, translucent segment was generated by flow-induced crystallization. However, formation of the translucent morphology eventually stopped, and thereafter a poorly oriented, opaque segment was generated by solid-state extrusion. From wide- and small-angle x-ray scattering, differential scanning calorimetry, and density measurements, it was determined that the most perfect morphologies were prepared at an extrusion temperature of 265°C. In addition to having the highest degree of crystalline orientation, translucent segments extruded at 265°C have a peak melting point of 267°C and a crystallinity value of 62%. Hot-stage optical microscopy showed that the translucent segments contained axially aligned fibrous crystals whose birefringence persisted to 290°C. The exceptional thermal stability of the segments was corroborated by the results of shrinkage tests at temperatures near the melting point; even after 1 hr at 260°C, the shrinkage did not exceed 7%. The accumulated evidence suggests that the translucent segments contain an extended-chain component.     

Mechanism of cytotoxicity and cellular uptake of lipophilic inert dinuclear polypyridylruthenium(II) complexes

The accumulation, uptake mechanism, cytotoxicity, cellular localisation of—and mode of cell death induced by—dinuclear ruthenium(II) complexes ΔΔ/ΛΛ‐[{Ru(phen)₂}₂{μ‐bb_n}]⁴⁺ (Rubb_n), where phen is 1,10‐phenanthroline, bb_n is bis[4(4′‐methyl‐2,2′‐bipyridyl)]‐1,n‐alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb_n ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ‐Rubb₁₆ complex displayed the highest cytotoxicity of the series, with an IC₅₀ value of 5 μM , similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb_n bridge of the metal complex. ΔΔ‐Rubb₁₆ entered the L1210 cells by passive diffusion (with a minor contribution from protein‐mediated active transport), inducing cell death via apoptosis. Additionally, metal‐complex uptake in leukaemia cells was approximately 16‐times that observed in healthy B cells highlighting that the bb_n series of complexes may have potential as selective anticancer drugs.     

Photoelastic Measurement of High Stress Profiles in Ion-Exchanged Glass

Photoelastic fringes were directly measured to fully characterize high magnitude, steep compressive stress gradients in an ion-exchanged glass, trade named Ion-Armor™. Initially, using a thick (9.9 mm) rectangular bar and circular polariscope arrangement the overall residual stress profile in a bulk specimen was determined. However, due to the relatively large thickness of the specimen, the high density of fringes (steep stress gradient) close to the edge of the specimen became too diffused to allow an accurate count of fringe order. A thinner (0.71 mm) specimen was then used along with a polarizing light microscope to enhance the fringe contrast. This arrangement yielded approximately four isochromatic fringes, representing a maximum surface compressive stress of 984 MPa, which rapidly decreased to ~300 MPa within 25 μm depth from the strengthened surface. Also, the case-depth of the ion-exchange process was found to be 0.8 mm. Thus, the technique was able to directly capture the extremely high residual compressive stresses generated in an ion-exchanged glass. The current technique utilized for residual stress measurement is more objective and straightforward to implement than what is specified in ASTM standard C-1422, particularly for those specimens having steep stress gradients just below the strengthened surface.     

Progress toward quantitative in vivo chemical exchange saturation transfer (CEST) MRI

Chemical exchange saturation transfer (CEST) MRI provides a sensitive detection mechanism for imaging dilute labile protons, complementing the routine radiological exams. Enormous progress has been achieved in CEST MRI and image analysis, from the mathematical modeling, CEST agent design, and most importantly, increasing adoption of CEST imaging in the clinical setting. Therefore, CEST imaging represents an emerging field that involves multiple disciplines and together made a remarkable transition from the simplistic CEST-weighted MRI to quantitative CEST (qCEST) analysis. This review focuses on the recent advancements in CEST quantification techniques and findings of in vivo CEST imaging in representative disorders of ischemia, tumor, and epilepsy. In addition, limitations of current CEST methodologies are examined that should help guide future development of more sensitive and quantitative CEST imaging techniques and ultimately, facilitate their adoption in the clinical setting.     

Solvent screening for non‐aqueous extraction of Alberta oil sands

Non‐aqueous extraction of bitumen from oil sands has the potential to reduce fresh water demand of the extraction process and eliminate tailings ponds. In this study, different light hydrocarbon solvents, including aromatics, cycloalkanes, biologically derived solvents and mixtures of solvents were compared for extraction of bitumen from Alberta oil sands at room temperature and ambient pressure. The solvents are compared based on bitumen recovery, the amount of residual solvent in the extracted oil sands tailings and the content of fine solids in the extracted bitumen. The extraction experiments were carried out in a multistage process with agitation in rotary mixers and vibration sieving. The oil sands tailings were dried under ambient conditions, and their residual solvent contents were measured by a purge and trap system followed by gas chromatography. The elemental compositions of the extraction tailings were measured to calculate bitumen recovery. Supernatants from the extraction tests were centrifuged to separate and measure the contents of fine solid particles. Except for limonene and isoprene, the tested solvents showed good bitumen recoveries of around 95%. The solvent drying rates and residual solvent contents in the extracted oil sands tailings correlated to solvent vapour pressure. The contents of fine solids in the extracted bitumen (supernatant) were below 2.9% for all solvents except n‐heptane‐rich ones. Based on these findings, cyclohexane is the best candidate solvent for bitumen extraction, with 94.4% bitumen recovery, 5 mg of residual solvent per kilogram of extraction tailings and 1.4 wt% fine solids in the recovered bitumen. © 2012 Canadian Society for Chemical Engineering     

Hydrothermal catalytic production of fuels and chemicals from aquatic biomass

One of the promising avenues for biomass processing is the use of water as a reaction medium for wet or aquatic biomass. This review focuses on the hydrothermal catalytic production of fuels and chemicals from aquatic biomass. Two different regimes for conversion of aquatic biomass in hydrothermal conditions are discussed in detail. The first is hydrothermal liquefaction, and the second is hydrothermal gasification. The goals of these processes are to produce liquid‐fuel‐range hydrocarbons and methane or hydrogen, respectively. The catalytic upgrading of biocrude resulting from noncatalytic liquefaction and the stability and degradation of catalysts in high temperature water are also discussed. The review concludes with a brief discussion of the outlook for and opportunities within the field of hydrothermal catalytic valorization of biomass. Copyright © 2012 Society of Chemical Industry     

Color-tunable up-conversion emission in Y2O3:Yb3+, Er3+ nanoparticles prepared by polymer complex solution method

Abstract

Powders of Y₂O₃ co-doped with Yb³⁺ and Er³⁺ composed of well-crystallized nanoparticles (30 to 50 nm in diameter) with no adsorbed ligand species on their surface are prepared by polymer complex solution method. These powders exhibit up-conversion emission upon 978-nm excitation with a color that can be tuned from green to red by changing the Yb³⁺/Er³⁺ concentration ratio. The mechanism underlying up-conversion color changes is presented along with material structural and optical properties.

PACS

42.70.-a, 78.55.Hx, 78.60.-b