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  • 1
    Publication Date: 2018-10-02
    Description: High-grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We have developed potent synthetic analogues of a class of compounds known as phyllanthusmins, inspired by natural products isolated from Phyllanthus poilanei Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines in vitro and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its cytotoxic effects by inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition may be required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly inhibited the growth of cancer cell lines in hollow fibers, as well as reduced tumor burden in a xenograft model. We demonstrate that PHY34 acts as a late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single agent against HGSOC in vivo . This class of compounds holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating ovarian cancer. Mol Cancer Ther; 17(10); 2123–35. ©2018 AACR .
    Print ISSN: 1535-7163
    Electronic ISSN: 1538-8514
    Topics: Medicine
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  • 2
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The matrix differential calculus is applied for the first time to a quantum chemical problem via new matrix derivations of integral formulas and gradients for Hamiltonian matrix elements in a basis of correlated Gaussian functions. Requisite mathematical background material on Kronecker products, Hadamard products, the vec and vech operators, linear structures, and matrix differential calculus is presented. New matrix forms for the kinetic and potential energy operators are presented. Integrals for overlap, kinetic energy, and potential energy matrix elements are derived in matrix form using matrix calculus. The gradient of the energy functional with respect to the correlated Gaussian exponent matrices is derived. Burdensome summation notation is entirely replaced with a compact matrix notation that is both theoretically and computationally insightful. © 1996 John Wiley & Sons, Inc.
    Additional Material: 1 Tab.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0020-7608
    Keywords: Chemistry ; Theoretical, Physical and Computational Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: New formulas in the basis of explicitly correlated Gaussian basis functions, derived in a previous article using powerful matrix calculus, are implemented and applied to find variational upper bounds for nonrelativistic ground states of 4He, ∞He, Ps2, 9Be, and ∞Be. Analytic gradients of the energy are included to speed optimization of the exponential variational parameters. Five different nonlinear optimization subroutines (algorithms) are compared: TN, truncated Newton; DUMING, quasi-Newton; DUMIDH, modified Newton; DUMCGG, conjugate gradient; and POWELL, direction set (nongradient). The new analytic gradient formulas are found to significantly accelerate optimizations that require gradients. We found that the truncated Newton algorithm out-performs the other optimizers for the selected test cases. Computer timings and energy bounds are reported. © 1997 John Wiley & Sons, Inc.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Formulas are derived for the density matrices belonging to an n-particle wave function built on the basis of single-center explicitly correlated Gaussian basis functions. An explicit formula for the first-order density matrix, P(r1, r′1), is obtained for computing the probability distribution P(r1, r1). Other formulas are derived for matrix elements of the first-order density operator P on a basis of single-particle Gaussian orbitals so that natural orbitals (NOs) can be expressed in such a basis. The method is illustrated for the case of the ground state of the helium atom using the 16-term (geminal) wave function by Singer and Longstaff (E = -2.90233 au) and a set of even-tempered Gaussian orbitals. The resulting natural orbitals compare favorably with natural orbitals from Cl expansions. The method is also applied to our 20 term (trimal) wave function for the ground state of dipositronium (E = -0.51560 au). Analysis is made in this case for pair correlation functions of both the electron-electron and the positron-electron pairs; results include the radial distributions of these pairs and their relative angular momentum. © 1996 John Wiley & Sons, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 0935-6304
    Keywords: Comprehensive gas chromatography ; cryogenic modulation ; semi-volatile aromatics ; thermal sweeper ; peak widths ; peak asymmetries ; Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: ---The two current technologies for achieving comprehensive gas chromatography (GC×GC) - the thermal sweeper and the cryogenic modulator - are compared in an interlaboratory study using a multicomponent semi-volatile aromatic compound sample. The same column set (phases, film thickness, dimensions of columns) and conditions of oven temperature program were used. Carrier gas flow settings however were different for the data reported here. The thermal sweeper has a longer overall length due to the extra ca. 30 cm length of narrow bore tubing used for the modulator/accumulator section. Data reveal that the two methods behave in an analogous manner in respect of delivering GC×GC results, with key peak parameters of peak widths and symmetry measures showing good correlation. Retention time dissimilarity on the first dimension columns in the two systems arises from different flow rates used, however the second column retention is similar, and this is due to the resulting different elution temperatures that peaks elute on the first dimension in each system. Overall, the two approaches to GC×GC appear to produce equivalent results within the scope of the application studied. Each system does have its experimental limitations; the thermal sweeper has what may be called a ‘thick film effect’, where at high temperature it can be difficult to sufficiently trap the migrating bands in the accumulator column, and the pulsing of solutes in the cryogenic system may suffer from a ‘thick wall effect’ if a column with too thick a wall dimension is used at low oven temperature.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1052-9306
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A method is described for the micro-identification of both mono- and diesters of 12-deoxyphorbol based upon a combination of thin-layer chromatography and mass spectrometry. The technique may be used on as little as 5 ml of fresh plant latex. Nine thin-layer systems are described, six of which are adsorption systems based on silica gel or alumina as adsorbent, and three are partition systems using diethyleneglycol as stationary phase. The migration by means of thin-layer chromatography is dependent upon the chain length of the C-13 esterifying acid and on the presence or absence of a free primary hydroxyl group at C-20. By means of mass spectrometry it was possible to confirm the identity of the esterifying moiety at both the C-13 and C-20 positions of 12-deoxy-4βOH-phorbol.
    Additional Material: 4 Tab.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1617-4623
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary A 1.35 Md DNA HindIII fragment containing part of the arom gene cluster or cluster gene of Aspergillus nidulans encoding biosynthetic dehydroquinase (5-dehydroquinate hydrolyase) has been cloned in plasmid pBR322 on the basis of functional expression in Escherichia coli. The fungal fragment on pBR322, designated pHK29, complements a corresponding E. coli dehydroquinase structural gene (aroD) mutation. pHK29 contains one BamHI, HpaII, PstI, SmaI, XhoI and surprisingly, one HindIII site since pHK29 hybrid Aspergillus DNA is a HindIII fragment itself. The biosynthetic dehydroquinase activity extracted from E. coli strains, containing pHK29, had properties similar to those of the enzyme activity from Aspergillus. The protein specified by pHK29 appears to be 80 Kd. No increase of dehydroquinase activity was found in polynucleotide phosphorylase deficient strains (pnp) of E. coli.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1617-4623
    Keywords: Filamentous fungi ; Gene regulation ; Nitrate assimilation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The regulation of the expression of the A. nidulans niiA and niaD genes (encoding nitrite reductase and nitrate reductase activities, respectively) was investigated by Northern blotting. It was demonstrated that expression of the niiA and niaD genes is controlled at the level of mRNA accumulation and that mutations within the nirA and areA regulatory genes, as well as certain mutations within niaD itself or cnxE (for its molybdenum cofactor), markedly affect niiA and niaD transcript levels.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1617-4623
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Ammonium regulation of L-glutamate transport is annuled when L-glutamate is the sole or main carbon source. This shows that ammonium regulation mechanisms are not operative where the substrate of the ammonium repressible system can be used as a carbon as well as a nitrogen source. There is rapid loss of NADP L-glutamate dehydrogenase when glucose is replaced by L-glutamate as a carbon source. This suggests that NADP L-glutamate dehydrogenase may be subject to carbon as well as nitrogen control.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1617-4623
    Keywords: Penicillium chrysogenum ; Nitrate reductase ; niaD mutants ; Nitrate assimilation ; Fungal transformation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary A heterologous gene mediated transformation system based on niaD, the structural gene encoding nitrate reductase, has been developed for Penicillium chrysogenum. Transformation frequencies of up to 20 transformants per microgram DNA were obtained using the Aspergillus nidulans gene and 9 transformants per microgram using the A. niger gene. Vector constructs carrying the A. nidulans ans-1 sequence and the A. niger niaD gene did not show increased transformation frequencies. Southern blot hybridisation analysis demonstrated that vector sequences had integrated into the recipient genome. The control of heterologous niaD gene expression generally agreed with that found in the wild-type strain, that is, induction by nitrate and repression in the presence of ammonium.
    Type of Medium: Electronic Resource
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