3,099 research outputs found
[2-(Piperidin-1-yl)ethylamine]dithiocyanatozinc(II)
In the mononuclear title compound, [Zn(NCS)2(C7H16N2)], the ZnII atom is four-coordinated by two N atoms of the chelating 2-(piperidin-1-yl)ethylamine ligand and two N atoms from two thiocyanate ligands in a distorted tetrahedral geometry. In the crystal structure, molecules are linked through intermolecular N—H⋯S hydrogen bonds, forming chains along the b axis
Activation of PI3K/AKT and MAPK Pathway through a PDGFRβ-Dependent Feedback Loop Is Involved in Rapamycin Resistance in Hepatocellular Carcinoma
Background: Rapamycin is an attractive approach for the treatment and prevention of HCC recurrence after liver transplantation. However, the objective response rates of rapamycin achieved with single-agent therapy were modest, supporting that rapamycin resistance is a frequently observed characteristic of many cancers. Some studies have been devoted to understanding the mechanisms of rapamycin resistance, however, the mechanisms are cell-type-dependent and studies on rapamycin resistance in HCC are extremely limited. Methodology/Principal Findings: The anti-tumor sensitivity of rapamycin was modest in vitro and in vivo. In both human and rat HCC cells, rapamycin up-regulated the expression and phosphorylation of PDGFRb in a time and dose-dependent manner as assessed by RT-PCR and western blot analysis. Using siRNA mediated knockdown of PDGFRb, we confirmed that subsequent activation of AKT and ERK was PDGFRb-dependent and compromised the anti-tumor activity of rapamycin. Then, blockade of this PDGFRb-dependent feedback loop by sorafenib enhanced the anti-tumor sensitivity of rapamycin in vitro and in an immunocompetent orthotopic rat model of HCC. Conclusions: Activation of PI3K/AKT and MAPK pathway through a PDGFRb-dependent feedback loop compromises the anti-tumor activity of rapamycin in HCC, and blockade of this feedback loop by sorafenib is an attractive approach t
Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma
Background & Aims:
Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer. Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression. We aim to investigate its ITH in hope of helping develop new therapeutic strategies.
Methods:
We obtained 69 spatially distinct regions from 6 operable ICCs. Patient-derived primary cancer cells (PDPCs) were established for each region, followed by whole-exome sequencing(WES) and multi-level validation.
Results:
We observed widespread ITH for both somatic mutations and clonal architecture, shaped by multiple mechanisms, like clonal “illusion”, parallel evolution and chromosome instability. A median of 60.3% mutations were heterogeneous mutations, among which 85% of the driver mutations located on the branches of tumor phylogenetic trees. Many truncal and clonal driver mutations occurred in tumor-suppressor genes, such as TP53, SMARCB1 and PBRM1 that involved in DNA repair and chromatin-remodeling. Genome doubling occurred in most cases (5/6) after the accumulation of truncal mutations and was shared by all intratumoral subregions. In all cases, ongoing chromosomal instability is evident throughout the evolutionary trajectory of ICC. The recurrence of ICC1239 provided evidence to support the polyclonal metastatic seeding in ICC. The change of mutation landscape and internal diversity among subclones during metastasis, such as the loss of chemoresistance mediator, may be used for new treatment strategy. Targeted therapy against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be developed in 5/6 patients.
Conclusions:
Integrated investigations of spatial ITH and clonal evolution may provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ICC.
Lay summary:
We applied multiregional whole exome sequencing to investigate the evolution trajectory of ICC. The results revealed that many fuels, such as parallel evolution and chromosome instability, may participate and promote the branch diversity of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors, we found some clues of polyclonal metastatic seeding, indicating that symbiotic communities of multiple clones existed and were maintained during metastasis. More realistically, some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, can be promising treatment targets for ICC patients
Nanostructured luminescently labeled nucleic acids
Important and emerging trends at the interface of luminescence, nucleic acids and nanotechnology
are: (i) the conventional luminescence labeling of nucleic acid nanostructures (e.g. DNA tetrahedron);
(ii) the labeling of bulk nucleic acids (e.g. single‐stranded DNA, double‐stranded DNA) with
nanostructured luminescent labels (e.g. copper nanoclusters); and (iii) the labeling of nucleic acid
nanostructures (e.g. origami DNA) with nanostructured luminescent labels (e.g. silver
nanoclusters). This review surveys recent advances in these three different approaches to the
generation of nanostructured luminescently labeled nucleic acids, and includes both direct and
indirect labeling methods
Emergence of scale-free close-knit friendship structure in online social networks
Despite the structural properties of online social networks have attracted
much attention, the properties of the close-knit friendship structures remain
an important question. Here, we mainly focus on how these mesoscale structures
are affected by the local and global structural properties. Analyzing the data
of four large-scale online social networks reveals several common structural
properties. It is found that not only the local structures given by the
indegree, outdegree, and reciprocal degree distributions follow a similar
scaling behavior, the mesoscale structures represented by the distributions of
close-knit friendship structures also exhibit a similar scaling law. The degree
correlation is very weak over a wide range of the degrees. We propose a simple
directed network model that captures the observed properties. The model
incorporates two mechanisms: reciprocation and preferential attachment. Through
rate equation analysis of our model, the local-scale and mesoscale structural
properties are derived. In the local-scale, the same scaling behavior of
indegree and outdegree distributions stems from indegree and outdegree of nodes
both growing as the same function of the introduction time, and the reciprocal
degree distribution also shows the same power-law due to the linear
relationship between the reciprocal degree and in/outdegree of nodes. In the
mesoscale, the distributions of four closed triples representing close-knit
friendship structures are found to exhibit identical power-laws, a behavior
attributed to the negligible degree correlations. Intriguingly, all the
power-law exponents of the distributions in the local-scale and mesoscale
depend only on one global parameter -- the mean in/outdegree, while both the
mean in/outdegree and the reciprocity together determine the ratio of the
reciprocal degree of a node to its in/outdegree.Comment: 48 pages, 34 figure
Low Level of Low-Density Lipoprotein Receptor-Related Protein 1 Predicts an Unfavorable Prognosis of Hepatocellular Carcinoma after Curative Resection
BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC). METHODS: LRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP), the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP) 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens. RESULTS: Low LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set. CONCLUSIONS: LRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy
Profiling of the Tetraspanin CD151 Web and Conspiracy of CD151/Integrin β1 Complex in the Progression of Hepatocellular Carcinoma
Tetraspanin CD151 has been implicated in metastasis through forming complexes with different molecular partners. In this study, we mapped tetraspanin web proteins centered on CD151, in order to explore the role of CD151 complexes in the progression of hepatocellular carcinoma (HCC). Immunoprecipitation was used to isolate tetraspanin complexes from HCCLM3 cells using a CD151 antibody, and associated proteins were identified by mass spectrometry. The interaction of CD151 and its molecular partners, and their roles in invasiveness and metastasis of HCC cells were assayed through disruption of the CD151 network. Finally, the clinical implication of CD151 complexes in HCC patients was also examined. In this study, we identified 58 proteins, characterized the tetraspanin CD151 web, and chose integrin β1 as a main partner to further investigate. When the CD151/integrin β1 complex in HCC cells was disrupted, migration, invasiveness, secretion of matrix metalloproteinase 9, and metastasis were markedly influenced. However, both CD151 and integrin β1 expression were untouched. HCC patients with high expression of CD151/integrin β1 complex had the poorest prognosis of the whole cohort of patients. Together, our data show that CD151 acts as an important player in the progression of HCC in an integrin β1-dependent manner
Expression of CD82 in Human Trophoblast and Its Role in Trophoblast Invasion
BACKGROUND: Well-controlled trophoblast invasion at maternal-fetal interface is a critical event for the normal development of placenta. CD82 is a member of transmembrane 4 superfamily, which showed important role in inhibiting tumor cell invasion and migration. We surmised that CD82 are participates in trophoblast differentiation during placenta development. METHODOLOGY/PRINCIPAL FINDINGS: CD82 was found to be strongly expressed in human first trimester placental villous and extravillous trophoblast cells as well as in trophoblast cell lines. To investigate whether CD82 plays a role in trophoblast invasion and migration, we further utilized human villous explants culture model on matrigel and invasion/migration assay of trophoblast cell line HTR8/SVneo. CD82 siRNA significantly promoted outgrowth of villous explants in vitro (P<0.01), as well as invasion and migration of HTR8/SVneo cells (P<0.05), whereas the trophoblast proliferation was not affected. The enhanced effect of CD82 siRNA on invasion and migration of trophoblast cells was found associated with increased gelatinolytic activities of matrix metalloproteinase MMP9 while over-expression of CD82 markedly decreased trphoblast cell invasion and migration as well as MMP9 activities. CONCLUSIONS/SIGNIFICANCE: These findings suggest that CD82 is an important negative regulator at maternal-fetal interface during early pregnancy, inhibiting human trophoblast invasion and migration
Determining the neurotransmitter concentration profile at active synapses
Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission
- …