IGFBP3 mRNA expression in benign and malignant breast tumors

INTRODUCTION: Most previous studies have focused on evaluating the association between circulating insulin-like growth factor binding protein 3 (IGFBP-3) levels and breast cancer risk. Emerging evidence over the past few years suggests that IGFBP-3 may act directly on mammary epithelial cells. METHODS: To understand the role of IGFBP-3 in breast tumorigenesis, we investigated IGFBP3 mRNA expression levels in benign and malignant breast tumors and their adjacent normal tissues using real-time quantitative PCR. RESULTS: Cancer tissues had significantly lower IGFBP3 expression than benign tumor tissues (p < 0.001). IGFBP3 expressions in both tumor and adjacent tissues were higher in patients who had proliferative benign tumors than in those who had non-proliferative benign tumors. Among patients with benign breast disease, IGFBP3 expression in the tumor was significantly higher than that in their adjacent normal tissue. There were no apparent associations of IGFBP3 expression in cancer tissues with either overall survival or disease-free survival in a cohort of 521 patients with breast cancer. CONCLUSION: Our findings suggest that the expression level of IGFBP3 in breast tissues may be involved in breast tumorigenesis

Electronic structure of the iron-based superconductor LaOFeP

The recent discovery of superconductivity in the so-called iron-oxypnictide family of compounds has generated intense interest. The layered crystal structure with transition metal ions in planar square lattice form and the discovery of spin-density-wave order near 130 K seem to hint at a strong similarity with the copper oxide superconductors. A burning current issue is the nature of the ground state of the parent compounds. Two distinct classes of theories have been put forward depending on the underlying band structures: local moment antiferromagnetic ground state for strong coupling approach and itinerant ground state for weak coupling approach. The local moment magnetism approach stresses on-site correlations and proximity to a Mott insulating state and thus the resemblance to cuprates; while the latter approach emphasizes the itinerant electron physics and the interplay between the competing ferromagnetic and antiferromagnetic fluctuations. Such a controversy is partly due to the lack of conclusive experimental information on the electronic structures. Here we report the first angle-resolved photoemission spectroscopy (ARPES) investigation of LaOFeP (Tc = 5.9 K), the first reported iron-based superconductor. Our results favor the itinerant ground state, albeit with band renormalization. In addition, our data reveal important differences between these and copper based superconductors.Comment: 17 pages, 4 figure

Suppression of uPA and uPAR Attenuates Angiogenin Mediated Angiogenesis in Endothelial and Glioblastoma Cell Lines

In our earlier reports, we showed that downregulation of uPA and uPAR inhibited glioma tumor angiogenesis in SNB19 cells, and intraperitoneal injection of a hairpin shRNA expressing plasmid targeting uPA and uPAR inhibited angiogenesis in nude mice. The exact mechanism by which inhibition of angiogenesis takes place is not clearly understood.In the present study, we have attempted to investigate the mechanism by which uPA/uPAR downregulation by shRNA inhibits angiogenesis in endothelial and glioblastoma cell lines. uPA/uPAR downregulation by shRNA in U87 MG and U87 SPARC co-cultures with endothelial cells inhibited angiogenesis as assessed by in vitro angiogenesis assay and in vivo dorsal skin-fold chamber model in nude mice. Protein antibody array analysis of co-cultures of U87 and U87 SPARC cells with endothelial cells treated with pU2 (shRNA against uPA and uPAR) showed decreased angiogenin secretion and angiopoietin-1 as well as several other pro-angiogenic molecules. Therefore, we investigated the role of angiogenin and found that nuclear translocation, ribonucleolytic and 45S rRNA synthesis, which are all critical for angiogenic function of angiogenin, were significantly inhibited in endothelial cells transfected with uPA, uPAR and uPA/uPAR when compared with controls. Moreover, uPA and uPAR downregulation significantly inhibited the phosphorylation of Tie-2 receptor and also down regulated FKHR activation in the nucleus of endothelial cells via the GRB2/AKT/BAD pathway. Treatment of endothelial cells with ruPA increased angiogenin secretion and angiogenin expression as determined by ELISA and western blotting in a dose-dependent manner. The amino terminal fragment of uPA down regulated ruPA-induced angiogenin in endothelial cells, thereby suggesting that uPA plays a critical role in positively regulating angiogenin in glioblastoma cells.Taken together, our results suggest that uPA/uPAR downregulation suppresses angiogenesis in endothelial cells induced by glioblastoma cell lines partially by downregulation of angiogenin and by inhibition of the angiopoietin-1/AKT/FKHR pathway

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 2. Metal complexes of tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazine: Linear and nonlinear optical properties and electrochemical behavior

A series of metal complexes of tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazine, [Py8TPyzPzH2], having the general formula [Py8TPyzPzM]\ue2xH2O (M ) MgII(H2O), MnII, CoII, CuII, ZnII; x ) 3-8) were synthesized by reaction of the free-base macrocycle with the appropriate metal acetate in pyridine or dimethyl sulfoxide under mild conditions. Clathrated water and retained pyridine molecules for the MnII and CoII species are easily eliminated by heating under vacuum, the water molecules being recovered by exposure of the unsolvated macrocycles to air. Magnetic susceptibility measurements and EPR spectra of the materials in the solid state provide basic information on the spin state of the CuII, CoII, and MnII species. Colloidal solutions caused by molecular aggregation are formed in nondonor solvents (CH2Cl2, CHCl3), a moderately basic solvent (pyridine), and an acidic solvent (CH3COOH), with the extent of aggregation depending on the specific solvent and the central metal ion. UV-vis spectral monitoring of the solutions after preparation indicates that disaggregation systematically occurs as a function of time leading ultimately to the formation of clear solutions containing the monomeric form of the porphyrazine. Cyclic voltammetry and thin-layer spectroelectrochemistry show that each compound with an electroinactive metal ion undergoes four reversible one-electron reductions, leading to formation of the negatively charged species [Py8TPyzPzM]n- (n ) 1 - 4). The stepwise uptake of four electrons is consistent with a ring-centered reduction, but in the case of the cobalt complex a metal-centered (CoII f CoI) reduction occurs in the first process and only three additional reductions are observed. No oxidations are observed in pyridine or CH2Cl2 containing 0.1 M tetrabuthylammonium perchlorate (TBAP). The nonlinear optical properties (NLO) of the species [Py8TPyzPzM] (M ) 2HI, CuII, ZnII, MgII(H2O)) have also been examined with nanosecond pulses at 532 nm in dimethyl sulfoxide solution. Reverse saturable absorption is shown by all of the [Py8TPyzPzM] species, which exhibit distinct behavior depending on the nature of M and extent of aggregation

Synthesis and electrochemical investigation of covalently linked porphyrin dimers containing a beta-brominated subunit. Crystal structure of H-2[tripp-tpp(Br-8)]H-2

Ten meso-tetraphenylporphyrin-type heterodimers containing a partly or completely beta-brominated subunit were synthesized and characterized by UV-visible spectroscopy, cyclic voltammetry and spectroelectrochemistry, showing the presence of low electronic interactions between the two subunits. The investigated compounds are represented as M[(tripp-tpp(Br-4)]M and M[tripp-tpp(Br-8)]M (M = 2H, Zn, Ni, Co and Cu) where tripp-tpp(Br-4) is the tetraanion of 1-[5-(10,15,20-triphenylporphyrinyl)]-4-[10-(2,3,12,13-tetrabromoporphyrinyl)]-benzene and tripptpp(Br-8) is the tetraanion of 1-[5-(10,15,20-triphenylporphyrinyl)]-4-[10-(2,3,7,8,12,13,17,18-octabromoporphyrinyl)] -benzene. One of the synthesized dimers, H-2[tripp-tpp(Br-8)]H-2, was characterized by a single-crystal X-ray investigation. Copyright (C) 2003 Society of Porphyrins & Phthalocyanines

Synthesis and electrochemistry of 2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetrakis(3,5-dichloro-2,6-dimethoxyphenyl)porphyrin(H(2)tdcdmpp), [Co-II(tdcdmpp)] and [M(tdcdmpp)Cl] (M=Fe-III or Mn-III)

Four new highly chlorinated porphyrins, 2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetrakis(3,5-dichloro-2,6-dimethoxyphenyl)porphyrin (H(2)tdcdmpp), [Co-II(tdcdmpp)] and [M(tdcdmpp)Cl] (M = Fe-III or Mn-III) have been prepared. The free base was synthesized by chlorination of H(2)tdmpp [5,10,15,20-tetrakis(2,6-dimethoxyphenyl)porphyrin] and metallated to give the complexes following published procedures. The same transition-metal derivatives of tdmpp were also prepared and all eight synthesized compounds were electrochemically investigated in benzonitrile or pyridine containing 0.1 mol dm(-3) NBu(4)(n)ClO(4). As expected the half-wave potentials of the tdcdmpp complexes are shifted towards positive values while those for oxidation or reduction of the tdmpp species are shifted negatively as compared with E(1/2) for oxidation or reduction of tetraphenylporphyrin (tpp) complexes having the same central metal ions. The magnitude of the anodic shifts in E(1/2) for reduction with respect to pp is among the largest reported for chlorinated porphyrins and ranges between 590 and 860 mV depending upon the specific redox reaction and solvent. A smaller Delta E(1/2) of 330-400 mV is seen for oxidation of the same compounds and these values can be compared to a negligible shift in E(1/2) upon going from planar M(tpp) to distorted M(obtpp) (obtpp = 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetraphenylporphyrinate) complexes of cobalt and iron where the effect of macrocycle ruffling is known to predominate over the electronic effects of added halide substituents. This result indicates that the core distortion cannot compensate totally for the electron-withdrawing effect of the Cl substituents. The macrocyclic distortion also induces a large red shift of the UV/VIS absorption bands and this shift in lambda(max) ranges up to 40 nm for the chlorinated compounds with respect to the tdmpp complexes

Synthesis and electrochemistry of 2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetrakis(3,5-dichloro-2,6-dimethoxyphenyl)porphyrin(H(2)tdcdmpp), [Co-II(tdcdmpp)] and [M(tdcdmpp)Cl] (M=Fe-III or Mn-III)

Four new highly chlorinated porphyrins, 2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetrakis(3,5-dichloro-2,6-dimethoxyphenyl)porphyrin (H(2)tdcdmpp), [Co-II(tdcdmpp)] and [M(tdcdmpp)Cl] (M = Fe-III or Mn-III) have been prepared. The free base was synthesized by chlorination of H(2)tdmpp [5,10,15,20-tetrakis(2,6-dimethoxyphenyl)porphyrin] and metallated to give the complexes following published procedures. The same transition-metal derivatives of tdmpp were also prepared and all eight synthesized compounds were electrochemically investigated in benzonitrile or pyridine containing 0.1 mol dm(-3) NBu(4)(n)ClO(4). As expected the half-wave potentials of the tdcdmpp complexes are shifted towards positive values while those for oxidation or reduction of the tdmpp species are shifted negatively as compared with E(1/2) for oxidation or reduction of tetraphenylporphyrin (tpp) complexes having the same central metal ions. The magnitude of the anodic shifts in E(1/2) for reduction with respect to pp is among the largest reported for chlorinated porphyrins and ranges between 590 and 860 mV depending upon the specific redox reaction and solvent. A smaller Delta E(1/2) of 330-400 mV is seen for oxidation of the same compounds and these values can be compared to a negligible shift in E(1/2) upon going from planar M(tpp) to distorted M(obtpp) (obtpp = 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetraphenylporphyrinate) complexes of cobalt and iron where the effect of macrocycle ruffling is known to predominate over the electronic effects of added halide substituents. This result indicates that the core distortion cannot compensate totally for the electron-withdrawing effect of the Cl substituents. The macrocyclic distortion also induces a large red shift of the UV/VIS absorption bands and this shift in lambda(max) ranges up to 40 nm for the chlorinated compounds with respect to the tdmpp complexes

Synthesis, structure, and electrochemistry of an electron deficient mu-oxo porphyrindimer, [(TPPBr4)Fe]O-2

The synthesis and structural and electrochemical properties of an electron deficient iron mu-oxo porphyrin dimer, (mu-oxo)bis[(2,3,12,13-tetrabromo-5,10,15,20-tetraphenylporphyrinatoiron(III)), represented as [(TPPBr4)Fe]O-2, are reported. X-ray analysis indicates an FE-O-Fe angle of 177.4(5)degrees and an interplanar distance of 4.58 Angstrom between the two mean porphyrin planes. Opposite pyrrole rings on the same macrocycle are twisted by about 25 degrees relative to each other so that the porphyrin skeleton distortion is best described as a twisted saddle-shaped configuration. Electrochemical studies reveal that the highly halogenated mu-oxo dimer is stable in PhCN and undergoes four one-electron oxidations and four one-electron reductions in a total of seven steps. The singly reduced and singly oxidized forms of the dimer were characterized by thin-layer spectroelectrochemistry and ESR spectroscopy