This paper reports a polydimethylsiloxane microfluidic model system that can develop an array of nearly identical human microtissues with interconnected vascular networks. The microfluidic system ...design is based on an analogy with an electric circuit, applying resistive circuit concepts to design pressure dividers in serially-connected microtissue chambers. A long microchannel (550, 620 and 775 mm) creates a resistive circuit with a large hydraulic resistance. Two media reservoirs with a large cross-sectional area and of different heights are connected to the entrance and exit of the long microchannel to serve as a pressure source, and create a near constant pressure drop along the long microchannel. Microtissue chambers (0.12 μl) serve as a two-terminal resistive component with an input impedance >50-fold larger than the long microchannel. Connecting each microtissue chamber to two different positions along the long microchannel creates a series of pressure dividers. Each microtissue chamber enables a controlled pressure drop of a segment of the microchannel without altering the hydrodynamic behaviour of the microchannel. The result is a controlled and predictable microphysiological environment within the microchamber. Interstitial flow, a mechanical cue for stimulating vasculogenesis, was verified by finite element simulation and experiments. The simplicity of this design enabled the development of multiple microtissue arrays (5, 12, and 30 microtissues) by co-culturing endothelial cells, stromal cells, and fibrin within the microchambers over two and three week periods. This methodology enables the culturing of a large array of microtissues with interconnected vascular networks for biological studies and applications such as drug development.
Shell cross-linked micelles (SCMs) containing acid sites in the shell and base sites in the core are prepared from amphiphilic poly(2-oxazoline) triblock copolymers. The materials are utilized as ...two-chamber nanoreactors for a prototypical acid–base bifunctional tandem deacetalization–nitroaldol reaction. The acid and base sites are localized in different regions of the micelle, allowing the two steps in the reaction sequence to largely proceed in separate compartments, akin to the compartmentalization that occurs in biological systems.
The three strongest prognostic determinants in operable breast cancer used in routine clinical practice are lymph node (LN) stage, primary tumor size, and histologic grade. However, grade is not ...included in the recent revision of the TNM staging system of breast cancer as its value is questioned in certain settings.
This study is based on a large and well-characterized consecutive series of operable breast cancer (2,219 cases), treated according to standard protocols in a single institution, with a long-term follow-up (median, 111 months) to assess the prognostic value of routine assessment of histologic grade using Nottingham histologic grading system.
Histologic grade is strongly associated with both breast cancer-specific survival (BCSS) and disease-free survival (DFS) in the whole series as well as in different subgroups based on tumor size (pT1a, pT1b, pT1c, and pT2) and LN stages (pN0 and pN1 and pN2). Differences in survival were also noted between different individual grades (1, 2, and 3). Multivariate analyses showed that histologic grade is an independent predictor of both BCSS and DFS in operable breast cancer as a whole as well as in all studied subgroups.
Histologic grade, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive breast cancer and should be incorporated in breast cancer staging systems.
The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation of DNA replication
. Increased ...levels of cyclin D promote cell division by activating cyclin-dependent kinases 4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclin D-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer
. However, the mechanisms that regulate levels of cyclin D are incompletely understood
. Here we show that autophagy and beclin 1 regulator 1 (AMBRA1) is the main regulator of the degradation of cyclin D. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclin D in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a substrate receptor for the cullin 4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclin D, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.
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•Furfural hydrogenation was investigated utilizing non-precious mixed metal oxides (Ni-Co-Al and Ni-Mg-Al).•Furfuryl alcohol selectivity of ∼80% was achieved for all catalysts tested, ...but 1.1Ni-0.8Co-Al had the highest TOF (1690h−1).•XAS, XPS, and STEM suggested the formation of bimetallic nanoparticles of Ni and Co after reduction.
The hydrogenation of furfural is investigated over various reduced nickel mixed metal oxides derived from layered double hydroxides (LDHs) containing Ni-Mg-Al and Ni-Co-Al. Upon reduction, relatively large Ni(0) domains develop in the Ni-Mg-Al catalysts, whereas in the Ni-Co-Al catalysts smaller metal particles of Ni(0) and Co(0), potentially as alloys, are formed, as evidenced by XAS, XPS, STEM and EELS. All the reduced Ni catalysts display similar selectivities towards major hydrogenation products (furfuryl alcohol and tetrahydrofurfuryl alcohol), though the side products varied with the catalyst composition. The 1.1Ni-0.8Co-Al catalyst showed the greatest activity per titrated site when compared to the other catalysts, with promising activity compared to related catalysts in the literature. The use of base metal catalysts for hydrogenation of furanic compounds may be a promising alternative to the well-studied precious metal catalysts for making biomass-derived chemicals if catalyst selectivity can be improved in future work by alloying or tuning metal-oxide support interactions
Parent and amine-functionalized analogues of metal–organic frameworks (MOFs), UiO-66(Zr), MIL-125(Ti), and MIL-101(Cr), were evaluated for their hydrogen sulfide (H2S) adsorption efficacy and ...post-exposure acid gas stability. Adsorption experiments were conducted through fixed-bed breakthrough studies utilizing multicomponent 1% H2S/99% CH4 and 1% H2S/10% CO2/89% CH4 natural gas simulant mixtures. Instability of MIL-101(Cr) materials after H2S exposure was discovered through powder X-ray diffraction and porosity measurements following adsorbent pelletization, whereas other materials retained their characteristic properties. Linker-based amine functionalities increased H2S breakthrough times and saturation capacities from their parent MOF analogues. Competitive CO2 adsorption effects were mitigated in mesoporous MIL-101(Cr) and MIL-101–NH2(Cr), in comparison to microporous UiO-66(Zr) and MIL-125(Ti) frameworks. This result suggests that the installation of H2S binding sites in large-pore MOFs could potentially enhance H2S selectivity. In situ Fourier transform infrared measurements in 10% CO2 and 5000 ppm H2S environments suggest that framework hydroxyl and amine moieties serve as H2S physisorption sites. Results from this study elucidate design strategies and stability considerations for engineering MOFs in sour gas purification applications.
Abstract
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, ...combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing
TGFBR2
promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of
CDKN2A/CDKN2B
deletion breakpoints reveals homozygous
MTAP
deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.
Studies on aminopolymer/oxide composite materials for direct CO2 capture from air have often focused on the prototypical poly(ethylenimine) (PEI) as the aminopolymer. However, it is known that PEI ...will oxidatively degrade at elevated temperatures. This degradation has been ascribed to the presence of secondary amines, which, when oxidized, lose their CO2 capture capacity. Here, we demonstrate the use of small molecule poly(propylenimine) (PPI) in linear and dendritic architectures supported in silica as adsorbent materials for direct CO2 capture from air. Regardless of amine loading or aminopolymer architecture, the PPI-based sorbents are found to be more efficient for CO2 capture than PEI-based sorbents. Moreover, PPI is found to be more resistant to oxidative degradation than PEI, even while containing secondary amines, as supported by FTIR, NMR, and ESI-MS studies. These results suggest that PPI-based CO2 sorbents may allow for longer sorbent working lifetimes due to an increased tolerance to sorbent regeneration conditions and suggest that the presence of secondary amines may not mean that all aminopolymers will oxidatively degrade.
Sterically hindered amine solutions have been studied extensively for CO2 capture via absorption due to their high theoretical amine efficiencies (1 CO2/N) and weak amine–CO2 species formed. More ...recently, extensive research has been undertaken on amine-based solids in adsorptive CO2 separations. However, very limited work exists that describes the behavior of sterically hindered amines on solid supports for acid gas separations. To this end, the sterically hindered aminopolymer, poly(2,2-dimethylenimine), is synthesized and incorporated into the pores of mesoporous silica, SBA-15. The CO2 adsorption performance of the hindered polymer/silica composite is compared with unhindered aminopolymer/silica composites under dry and humid conditions using in-situ Fourier-transform infrared spectroscopy and fixed bed breakthrough analysis. The hindered polymer sorbents had lower amine efficiencies when compared with unhindered polymer sorbents under both dry and humid conditions. The addition of poly(ethylene glycol) helps alleviate some of the limitations associated with the hindered aminopolymer/silica composites, improving the CO2 adsorption performance under the conditions studied. The experiments suggest that these hindered polymer sorbents are less effective at CO2 capture than their unhindered polymer counterparts due to the poor molecular mobility and hydrophobicity of the polymer chains.
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