Genomic analyses of primary liver cancer samples reveal a complex mutational landscape with vast intertumor and intratumor heterogeneity. Different primary liver tumors and subclones within each ...tumor display striking molecular and biological variations. Consequently, tumor molecular heterogeneity contributes to drug resistance and tumor relapse following therapy, which poses a substantial obstruction to improving outcomes of patients with liver cancer. There is an urgent need to the compositional and functional understanding of tumor heterogeneity. In this review, we summarize genomic and non-genomic diversities, which include stemness and microenvironmental causes of the functional heterogeneity of the primary liver cancer ecosystem. We discuss the importance and intricacy of intratumor heterogeneity in the context of cancer cell evolution. We also discuss methodologies applicable to determine intratumor heterogeneity and highlight the best-fit patient-derived in vivo and in vitro models to recapture the functional heterogeneity of primary liver cancer with the aim to improve future therapeutic strategies.
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By selecting constituent polyelectrolytes and controlling conditions of their deposition, the resulting polyelectrolyte multilayers can be designed as surface coatings with controlled ...adhesive properties with respect to viruses. Charge and hydrophilicity of the polyelectrolyte multilayers govern virus adhesion.
Four surfaces of different charges and hydrophobicities were designed using a layer-by-layer assembly of poly(styrene-4-sulfonate) and poly(dimethyl diallyl ammonium chloride). Contact angle measurements gave an estimate of MS2 hydrophilicity in terms of free energy of interfacial interaction in water. Experimental results on MS2 adhesion obtained using quartz crystal microbalance with dissipation monitoring were compared with predictions by the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory.
MS2 deposition onto polyelectrolyte multilayers occurred in two phases: an early phase defined by virus-surface interactions and a later phase with virus-virus interactions controlling deposition kinetics. Principal component analysis showed that the deposition rates in the two phases were independent one of another and that each was correlated to the depth of the secondary minimum of the corresponding XDLVO energy profile. Hydrophobic and electrostatic interactions governed the deposition process: short range hydrophilic repulsion prevented deposition into the primary minimum while electrostatic interactions defined the dependence of the deposition kinetics on the ionic strength. Different surfaces showed distinct kinetics of and capacities for MS2 deposition pointing to the potential of polyelectrolyte multilayers as easy-to-apply coatings for regulating virus adsorption, inactivating viruses via the virucidal action of cationic polyelectrolytes and reducing human exposure to viruses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising ...strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated survival defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma, where it promotes BRCA2 stability and inversely correlates with patient survival. Together, our findings identify deubiquitination as a means to regulate BRCA2 function and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors.BRCA2 is essential for the repair of DNA damage; therefore, defects in BRCA2 are associated with tumorigenesis but also with increased susceptibility to genotoxic stress. Here the authors show that USP21 regulates the ability of tumor cells to repair damaged DNA by regulating BRCA2 stability.
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•Modeling (XDLVO) and experiments (QCM-D) are used to study virus adhesion to paints.•Painted surfaces are assessed as potential reservoirs or transfer sites for viruses.•Paint ...hydrophobicity prevents moisture intrusion but promotes virus adhesion.•Hydrophobicity defines virus adhesion from solutions such as respiratory fluid.•Understanding virus-paint interactions can help design low adhesion paints.
Attachment of human adenovirus 40 (HAdV40) onto surfaces coated with three compositionally different household paints was evaluated experimentally and interpreted based on measured physicochemical properties of the paints. Polar, dispersive and electrostatic interactions between HAdV40 and the paints were predicted using the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) model. Quartz crystal microbalance (QCM-D) was used to quantify virus attachment to paints from 1 mM and 150 mM NaCl solutions, with the latter having the ionic strength of a typical respiratory fluid. Acrylic latex water-based, alkyd water-based, and alkyd oil-based paints were all determined to be highly hydrophobic (ΔGsws < - 48 mJ/m2). XDLVO modeling and preliminary QCM-D tests evaluated virus-paint interactions within and outside pH windows of favorable virus-paint electrostatic interactions. Hydrophobic and electrostatic interactions governed virus attachment while van der Waals interactions played a relatively minor role. In higher ionic strength solutions, the extent of virus attachment correlated with the free energy of virus-paint interfacial interaction, ΔGd0IF=ΔGd0AB+ΔGd0LW≅ΔGd0AB: more negative energies corresponded to higher values of the areal mass density of attached viruses. Hydrophobicity was the dominant factor in determining virus adhesion from high ionic strength solutions where electrostatic interactions were screened out. The hydrophobicity of paints, while desirable for minimizing moisture intrusion, also facilitates attachment of colloids such as viruses. The results call for new approaches to the materials design of indoor paints with enhanced resistance to virus adhesion. Paints so formulated should help reduce human exposure to viruses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•The novel hybrid nanocomposites were prepared from HPCD and alginate.•Capping of AgNPs on the nanocomposites was studied.•Biosynthesis of AgNPs was investigated by using aqueous ...extract of Jasminum subtriplinerve leaves.•Physicochemical characterizations of the nanocomposites were determined.•Recyclable catalytic activity was performed for degradation of pollutants in aqueous medium.
This study presents an efficient and facile method for the trapping of Ag+ ions on hybrid nanocomposite based on 2-hydroxypropyl-β-cyclodextrin (HPCD) and alginate (Alg) in aqueous medium through ionotropic gelation mechanism and followed by in situ assembly of silver nanoparticles (AgNPs) using aqueous extract of Jasminum subtriplinerve leaves as a reducing agent. The nanocomposite AgNPs/HPCD/Alg was characterized by UV-vis, EDX, TEM, HR-TEM analysis. The AgNPs were found to be spherical shape and uniform size with an average diameter of 13.5 nm. EDX data showed about 4.0% (w/w) of AgNPs capped on the nanocomposite HPCD/Alg. The role of HPCD and Alg in the nanocomposites was observed from FTIR and thermal studies. The stability and distribution of the nanoparticles in the aqueous solution were determined by zeta potential and DLS measurements. The nanocomposites showed excellent catalytic performance for degradation of pollutants within industrial effluents including 4-nitrophenol, methyl orange and rhodamine B.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Intratumor molecular heterogeneity of hepatocellular carcinoma is partly attributed to the presence of hepatic cancer stem cells (CSCs). Different CSC populations defined by various cell surface ...markers may contain different oncogenic drivers, posing a challenge in defining molecularly targeted therapeutics. We combined transcriptomic and functional analyses of hepatocellular carcinoma cells at the single‐cell level to assess the degree of CSC heterogeneity. We provide evidence that hepatic CSCs at the single‐cell level are phenotypically, functionally, and transcriptomically heterogeneous. We found that different CSC subpopulations contain distinct molecular signatures. Interestingly, distinct genes within different CSC subpopulations are independently associated with hepatocellular carcinoma prognosis, suggesting that a diverse hepatic CSC transcriptome affects intratumor heterogeneity and tumor progression. Conclusion: Our work provides unique perspectives into the biodiversity of CSC subpopulations, whose molecular heterogeneity further highlights their role in tumor heterogeneity, prognosis, and hepatic CSC therapy. (Hepatology 2018;68:127‐140).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hepatocellular carcinoma (HCC) is one of the most common cancers with a dismal outcome. The complicated molecular pathogenesis of HCC caused by tumor heterogeneity makes it difficult to identify ...druggable targets useful for treating HCC patients. One approach that has a potential for the improvement of patient prognosis is the identification of cancer driver genes that play a critical role in the development of HCC. Recent technological advances of high-throughput methods, such as gene expression profiles, DNA copy number alterations and somatic mutations, have expanded our understanding of the comprehensive genetic profiles of HCC. Integrative analysis of these omics profiles enables us to classify the molecular subgroups of HCC patients. As each subgroup classified according to genetic profiles has different clinical features, such as recurrence rate and prognosis, the tumor subclassification tools are useful in clinical practice. Furthermore, a global genetic analysis, including genome-wide RNAi functional screening, makes it possible to identify cancer vulnerable genes. Identification of common cancer driver genes in HCC leads to the development of an effective molecular target therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, ...metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
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KISLJ, NUK, SBMB, UL, UM, UPUK
The present study describes an eco-friendly approach for the synthesis of colloidal solution of silver and gold nanoparticles (L-AgNPs and L-AuNPs) from the aqueous extract of
Lactuca indica
leaf. ...Major parameters affecting on the formation of L-AgNPs and L-AuNPs were optimized using UV–Vis analysis at absorption maximum around 423 nm and 531 nm, respectively. The plant extract as reducing and capping agents of MNPs was demonstrated by Fourier-transform infrared (FTIR) spectroscopy. The nanoscale of metals was confirmed by Transmission electron microscopy (TEM) measurements. TEM studies revealed that L-AgNPs were mostly spherical with average size of 13.5 nm and L-AuNPs possessed multi shapes with an average size of 14.5 nm. Selected area electron diffraction (SAED) analysis and X-ray diffractometer (XRD) data confirm their crystalline structure. The nanomaterials showed efficient catalysis in the degradation of 4-nitrophenol and methyl orange.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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•The novel hybrid nanocomposite AuNPs/Lac/Alg were first prepared.•Its structure was well characterized by various analysis techniques.•Recyclable catalytic activity was performed for ...degradation of four pollutants.•The dispersion solution of nanocomposite was used for detection of Fe3+ ions.
This work presents a simply new method for in situ synthesis of gold nanoparticles (AuNPs) using the biodegradable polysaccharides. A novel composite of lactose/alginate (Lac/Alg) could be prepared easily through ionotropic gelation mechanism which can reduce in situ gold ions into AuNPs. Lactose plays a crucial role as a reducing reagent which are demonstrated by FTIR analysis. The crystalline structure of AuNPs with a mean size of 10 nm has been confirmed by analysis techniques. The nanocomposite powder possesses highly catalytic performance for degradation of contaminants including 4-nitrophenol, methyl orange, rhodamine 6 G and rhodamine B. The dispersion solution of AuNPs@Lac/Alg was used as an effective probe for highly selective detection of Fe3+ ions. The detection mechanism replies on the aggregation of nanocomposite in the presence of Fe3+ ions. LOD value was found to be 0.8 μM in a linear range of 2.0–80.0 μM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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