Search

We have generated novel conditionally replicative adenoviruses (CRAds) targeted to melanoma cells. In these adenoviruses, the E4 region (AdΔ24TyrE4) or both E1 and E4 regions (Ad2xTyr) were controlled by a synthetic tyrosinase enhancer/promoter (Tyr2E/P) specific for melanocytes. The properties of these CRAds were compared with wild-type adenovirus (Adwt) and our previous CRAd with a targeted E1A CRII mutation (AdTyrΔ24) in submerged cultures of melanoma cells and nonmelanoma control cells. We showed that AdΔ24TyrE4 had a cell type selectivity similar to AdTyrΔ24 but had a distinct block in viral reproduction in nonmelanoma cells and that Ad2xTyr had an augmented selectivity for melanoma cells. These viruses were additionally tested in organotypic cultures of melanoma cell lines, primary human keratinocytes (PHKs), or mixed cell populations. Unexpectedly, the CRAds exhibited somewhat different cell type selectivity profiles in these cultures relative to those observed in submerged cultures, demonstrating the importance of multiple assay systems. Specifically, AdTyrΔ24 and Ad2xTyr were selective for melanoma cells, whereas AdΔ24TyrE4 exhibited no selectivity, similar to Adwt. AdTyrΔ24 and Ad2xTyr were strongly attenuated in their ability to lyse PHKs in organotypic cultures. Furthermore, Ad2xTyr had a superior melanoma selectivity in organotypic cultures of cocultivated melanoma cells and PHKs. The enhanced selectivity for melanoma cells exhibited by Ad2xTyr provides a window of opportunity for therapeutic application. These studies also demonstrate that organotypic cultures derived from mixtures of tumor and normal cells represent a promising new model for analysis of CRAd specificity and toxicity.

Supplementary Figure 1 from Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression

Supplementary Figure 2 from Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression

Supplementary Figure Legends 1-2 from Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression

A straightforward synthesis of multifunctional mesoporous polymer nanomaterials suitable for the removal of contaminants and CO2 capture is reported.

IL-mediated ultrafast ambient temperature living cationic polymerization of styrene (St), yielding well-defined PSt and polystyrene-b-poly(isobutyl vinyl ether) diblock copolymers with acceptable dispersity values (Đ ≤ 1.21) is reported.

We report a multi-stimuli (pH/thermo/redox) responsive (PCysMAM-b-PDMAEMA-b-PB-b-PDMAEMA-b-PCysMAM) pentablock copolymer biohybrid which exhibits antifouling property and contaminant removal capability.

Rising atmospheric CO2 levels and water pollution have necessitated new research towards the development of novel CO2 capture materials and innovative methods for waste water treatment. Herein, we demonstrate a facile fabrication strategy to prepare novel template-shape replicated nitrogen-rich mesoporous carbon nanospheres (NMCN) with high surface area, pore volume and ordered pore geometry via in situ co-condensation, surface-confined atom transfer radical polymerization (SC-ATRP) and post-polymerization modification. NMCN exhibited efficient CO2 capture ability (up to 4.93 mmol g-1) at ambient temperature and contaminant removal capability from waste water. This work may open a new direction for the design of novel porous carbon materials for CO2 capture and other emerging applications.

Reliable preclinical models are needed for screening new cancer drugs. Thus, we developed an improved 3D tumor organoid model termed “organoid raft cultures” (ORCs). Development of ORCs involved culturing tumors ex vivo on collagen beds (boats) with grid supports to maintain their morphological structure. The ORCs were developed from patient-derived xenografts (PDXs) of colon cancers excised from immune-deficient mice (NOD/SCID/IL2Rgammanull). We utilized these new models to evaluate the efficacy of an investigational drug, Navitoclax (ABT-263). We tested the efficacy of ABT-263, an inhibitor of BCL-2 family proteins, in these ORCs derived from a PDX that showed high expression of antiapoptotic BCL2 family proteins (BCL-2, BCL-XL, and BCL-W). Hematoxylin and eosin staining evaluation of PDXs and corresponding ORCs indicated the retention of morphological and other histological integrity of ORCs. ORCs treated with ABT-263 showed decreased expression of antiapoptotic proteins (BCL2, BCL-XL and BCL-W) and increased proapoptotic proteins (BAX and PUMA), with concomitant activation of caspase 3. These studies support the usefulness of the ORCs, developed from PDXs, as an alternative to PDXs and as faster screening models.

Unique alternating copolymers based on vinyl acetate (VAc) and

International audience; Well-defined fluoropolymers exhibit unique properties such as excellent oil and water repellency, satisfactory thermal stability, a low refractive index, and low surface energy. The origin of these properties is attributed to the presence of a strong electronegative and low polarizable fluorine atom in the backbone of such polymers, which leads to a strong C–F bond (with a high bond dissociation energy of 485 kJ mol–1). Because of these features, these polymers have found applications as functional coatings, thermoplastics, biomedical items, separators, and binders for Li ion batteries, fuel cell membranes, piezoelectric devices, high-quality wires and cables, and so forth. Usually, fluoropolymers are synthesized by the conventional radical (co)polymerization of fluoroalkenes, which leads to the production of (co)polymers with an ill-defined end group, uncontrolled molar mass, and high dispersity values. In the last two decades, significant developments of various reversible deactivation radical polymerization (RDRP) techniques have helped the design of macromolecular architectures (including block, graft, star, and dendrimers) on demand. However, for relevant new applications, well-defined fluoropolymers with controlled macromolecular architectures (e.g., block copolymers as thermoplastic elastomers and electroactive polymers or graft copolymers for fuel cell membranes) are required.Several RDRP methods, developed in the last two decades, have paved the way for the synthesis of (co)polymers with well-defined molar mass, dispersity, chain end-functionality, and macromolecular architectures. Some of these RDRP techniques have been successfully employed for the synthesis of well-defined fluorinated copolymers. These techniques include iodine-transfer polymerization (ITP), reversible addition–fragmentation chain-transfer (RAFT) polymerization, organometallic-mediated radical polymerization (OMRP), and, to a lesser extent, nitroxide-mediated polymerization (NMP). Impressive control of the molar mass parameters of the fluoropolymers synthesized via these techniques also encouraged the researchers to combine these techniques with other postpolymerization strategies, leading to innovative novel polymeric materials.Thus, synthesized well-defined fluoropolymers exhibited a unique combination of properties (such as excellent weather resistance, high thermal/chemical/aging resistance, morphological versatility, and a low dielectric constant/flammability/refractive index). These led to the application of such developed materials in various high-technology applications such as high-performance elastomers, coatings for marine antifouling applications, fluorinated surfactants, fuel cell membranes, and gel polymer electrolytes for Li ion batteries.Newer advances in the field of polymer synthesis techniques are the need of the hour in order to synthesize more advanced fluorinated materials which may change the use of such polymers in engineering and biomedical fields in the current century. However, it should be kept in mind that success in this regard shall heavily depend on a deeper understanding of the polymerization process and structure–activity relationships.

A simple and inexpensive method for ultrafast and recyclable photoRDRP (in the absence of any conventional photoinitiators or dye sensitizers) in ionic liquid is developed, yielding low dispersity poly(glycidyl methacrylate) and well-defined amphiphilic poly(glycidyl methacrylate)-b-poly(poly(ethylene glycol)methacrylate) diblock copolymers thereof. The copolymer's stimuli response has been assessed against pH and temperature changes. The absence of polymerization in the absence of light enables temporal control and paves the way for potential application in the area where precise spatiotemporal “on/off” control and resolution are desirable. DFT calculations rationalize the underlying mechanism of the polymerization.

Magnetically separable and reusable Ni–Co alloy nanoparticles were employed to achieve ambient temperature reversible deactivation radical polymerization (RDRP) of methyl acrylate (MA), for the first time, yielding well-defined PMA (at least up to 124 500 g mol−1) with a low dispersity (Đ ≤ 1.20). The controlled polymerization character of RDRP of MA was confirmed from the linear semilogarithmic plot exhibiting pseudo first order kinetics, a linear increase of the molecular weight of the polymer with monomer conversion maintaining low Đ and the synthesis of PMAs of varying molecular weights from 2200 to 124 500 g mol−1 with low Đ. In addition, linear PMA-Br was used as a macroinitiator for the synthesis of several well-defined PMA-b-poly(M) block copolymers (where “M” stands for (2-dimethylamino)ethyl methacrylate (DMAEMA), tert-butyl methylacrylate (TBMA) and 2,2,3,3,4,4,5,5-octafluoropentyl acrylate (OFPA)), with acceptable Đs (≤ 1.24), demonstrating the high chain-end fidelity of the macroinitiator. The synthesized PMA-b-PDMAEMA demonstrated dual pH- and thermo-responsive properties. Upon hydrolysis, the synthesized PMA-b-PTBMA leads to the formation of unprecedented carboxylic acid-functionalized PMA derivatives. PMA-b-POFPA copolymers with varying OFPA mol% in the copolymer led to polymers with tunable surface hydrophobicity, as revealed by the water contact angle measurements.

Recyclable Ni–Co alloy nanoparticle catalyzed synthesis of well-defined poly(methyl methacrylate) (PMMA, up to 129 500 g mol−1) with low dispersity (Đ = 1.30) via a reversible deactivation radical polymerization technique is reported. The combined advantages of easier catalyst preparation and handling, predictability, simple recovery and reusability up to multiple cycles without a notable decrease in the control over the polymerization make the process an ideal methodology for the synthesis of tailored polymers.

A novel dual pH/thermoresponsive amphiphilic poly(histidine methacrylamide)-block-hydroxyl-terminated polybutadiene-block-poly(histidine methacrylamide) (PHisMAM-b-PB-b-PHisMAM) triblock copolymer biohybrid, composed of hydrophobic PB and ampholytic PHisMAM segments, is developed via direct switching from living anionic polymerization to recyclable nanoparticle catalyst-mediated reversible-deactivation radical polymerization (RDRP). The transformation involved in situ postpolymerization modification of living polybutadiene-based carbanionic species, end-capped with ethylene oxide, into dihydroxyl-terminated polybutadiene and a subsequent reaction with 2-bromo-2-methylpropionyl bromide resulting in a telechelic ATRP macroinitiator (Br-PB-Br). Br-PB-Br was used to mediate RDRP of an l-histidine-derived monomer, HisMAM, yielding a series of PHisMAM-b-PB-b-PHisMAM triblock copolymers. The copolymer's stimuli response was assessed against pH and temperature changes. The copolymer is capable of switching among its zwitterionic, anionic, and cationic forms and exhibited unique antifouling properties in its zwitterionic form. These novel triblock copolymers are expected to be show promising potential in biomedical applications.

A new multi-stimuli responsive tryptophan-based styryl homopolymer exhibiting dual upper critical solution temperature (UCST)- and lower critical solution temperature (LCST)-type thermosensitivities under different conditions is presented. The monomer 4-vinylbenzyl N-[(tert-butoxy)carbonyl]-L-tryptophan (Boc-TrpVBz) is prepared by a simple substitution reaction followed by its subsequent RAFT polymerization to produce the poly(Boc-TrpVBz) homopolymer. Poly(Boc-TrpVBz) is not soluble in water, but is soluble in different organic solvents (such as DMSO, DMF and MeOH). An interesting upper critical solution temperature (UCST)-type turbid-to-transparent phase transition is detected for poly(Boc-TrpVBz) in mixed solvents containing any of these three solvents and a minimum percentage of water. The UCST-type cloud point is found to increase upon increasing the percentage of added water and the molecular weight of poly(Boc-TrpVBz). Furthermore, poly(Boc-TrpVBz) is soluble in water at above pH 7.5 and exhibits a lower critical solution temperature (LCST)-type transparent-to-turbid transition upon addition of tetrabutylammonium halide salts with a large organic cation. The LCST-type cloud point is variable with respect to the salt concentration and the nature of the halide ion. The deprotection of the Boc moiety of poly(Boc-TrpVBz) produces zwitterionic poly(TrpVBz) containing –NH2 and –COOH groups, which exhibits dual pH- and thermo-responsiveness in aqueous solution below pH 2. In the cases of UCST- and LCST-type transitions, the turbidity is caused by the formation of spherical polymer aggregates as observed via TEM and FESEM.

A novel triple stimuli sensitive block copolymer is prepared by magnetically separable and reusable (up to multiple cycles) Ni-Co alloy nanoparticles mediated reversible deactivation radical polymerization (RDRP) at 25 °C, that responds to changes in temperature, pH, and light. Design of this block copolymer constitutes a temperature-sensitive N-isopropylacrylamide (NIPAM), an acid-sensitive lysine methacrylamide (LysMAM), and a light responsive umbelliferone (UMB) end group. The stimuli response, in response to one stimulus as well as combinations of stimuli, has been evaluated. Responsiveness to light allows the construction of self-healing materials. Density functional theory calculations rationalize the underlying mechanism of the polymerization.

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3' untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

An overview on fluorinated olefin-based architectures prepared by reversible deactivation radical polymerization (RDRP) techniques and their applications is presented. Controlled syntheses of well-defined fluoropolymers are discussed as a route to prepare tailored macromolecules of various architectures, such as homopolymers, block copolymers (BCPs), graft copolymers, and star/miktoarms. Primary examples of different strategies of synthesis include (a) Iodine Transfer Polymerization (ITP), (b) Reversible Addition-Fragmentation Chain Transfer/Macromolecular Design via the Interchange of Xanthates (RAFT/MADIX) polymerization, (c) Atom Transfer Radical Polymerization (ATRP), (d) Nitroxide Mediated Polymerization (NMP), (e) Organometallic-Mediated Radical Polymerization (OMRP) and (f) Others systems (based on tellurium, cobalt and other complexes). Synthesis of BCPs and graft copolymers of vinylidene fluoride (VDF), chlorotrifluoroethylene (CTFE) and other fluorinated monomers are also discussed, as along with those synthesized via Copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry). Phase behavior and self-assembly of the fluorinated block copolymers are also reported. Special attention is devoted to the applications of fluoropolymer architectures in producing thermoplastic elastomers, medical tactile sensors, fuel cells membranes, functional coatings, electroactive polymers (e.g. piezoelectric/ferroelectric/dielectric devices and actuators), high energy storage capacitors, surfactants and composites.

International audience