Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms.

Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and noncoding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth, and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis

CFA-1: The first chiral metal-organic framework containing Kuratowski-type secondary building units

[EN] The novel homochiral metal-organic framework CFA-1 (Coordination Framework Augsburg-1), [Zn-5(OAc) 4(bibta)(3)], containing the achiral linker {H-2-bibta = 1H, 1' H-5,5'-bibenzo[d][1,2,3] triazole}, has been synthesised. The reaction of H-2-bibta and Zn(OAc)(2)center dot 2H(2)O in N-methylformamide (NMF) (90 degrees C, 3 d) yields CFA-1 as trigonal prismatic single crystals. CFA-1 serves as a convenient precursor for the synthesis of isostructural frameworks with redox-active metal centres, which is demonstrated by the postsynthetic exchange of Zn2+ by Co2+ ions. The framework is robust to solvent removal and has been structurally characterized by synchrotron single-crystal X-ray diffraction and solid state NMR measurements (C-13 MAS-and H-1 MAS-NMR at 10 kHz). Results from MAS-NMR and IR spectroscopy studies are corroborated by cluster and periodic DFT calculations performed on CFA-1 cluster fragments.Financial support by the DFG (Priority Program SPP 1362 "Porous Metal-organic Frameworks") is gratefully acknowledged. G. Sastre thanks the Spanish government for the provision of the programme "Severo Ochoa" (project SEV 2012 0267), and SGAI-CSIC for computing time. The authors are grateful to Dr U. Mueller for support during single crystals measurements and the Helmholtz Centre, Berlin for financing the travel costs to BESSY II. The authors are grateful to J. Jelic (Dept. of Chemistry, TU Munich) for performing DFT calculations on CFA-1 structure models employing periodic boundary conditions.Schmieder, P.; Denysenko, D.; Grzywa, M.; Baumgaertner, B.; Senkovska, I.; Kaskel, S.; Sastre Navarro, GI.... (2013). CFA-1: The first chiral metal-organic framework containing Kuratowski-type secondary building units. Dalton Transactions. 42(30):10786-10797. https://doi.org/10.1039/C3DT50787DS10786107974230Yaghi, O. M., Li, H., Davis, C., Richardson, D., & Groy, T. L. (1998). Synthetic Strategies, Structure Patterns, and Emerging Properties in the Chemistry of Modular Porous Solids†. Accounts of Chemical Research, 31(8), 474-484. doi:10.1021/ar970151fEddaoudi, M., Moler, D. B., Li, H., Chen, B., Reineke, T. M., O’Keeffe, M., & Yaghi, O. M. (2001). Modular Chemistry:  Secondary Building Units as a Basis for the Design of Highly Porous and Robust Metal−Organic Carboxylate Frameworks. Accounts of Chemical Research, 34(4), 319-330. doi:10.1021/ar000034bKitagawa, S., Kitaura, R., & Noro, S. (2004). Functional Porous Coordination Polymers. Angewandte Chemie International Edition, 43(18), 2334-2375. doi:10.1002/anie.200300610James, S. L. (2003). Metal-organic frameworks. Chemical Society Reviews, 32(5), 276. doi:10.1039/b200393gFérey, G. (2008). Hybrid porous solids: past, present, future. Chem. Soc. Rev., 37(1), 191-214. doi:10.1039/b618320bCzaja, A. U., Trukhan, N., & Müller, U. (2009). Industrial applications of metal–organic frameworks. Chemical Society Reviews, 38(5), 1284. doi:10.1039/b804680hMa, L., Abney, C., & Lin, W. (2009). Enantioselective catalysis with homochiral metal–organic frameworks. Chemical Society Reviews, 38(5), 1248. doi:10.1039/b807083kFarrusseng, D., Aguado, S., & Pinel, C. (2009). Metall-organische Gerüste für die Katalyse. Angewandte Chemie, 121(41), 7638-7649. doi:10.1002/ange.200806063Kuppler, R. J., Timmons, D. J., Fang, Q.-R., Li, J.-R., Makal, T. A., Young, M. D., … Zhou, H.-C. (2009). Potential applications of metal-organic frameworks. Coordination Chemistry Reviews, 253(23-24), 3042-3066. doi:10.1016/j.ccr.2009.05.019Seo, J. S., Whang, D., Lee, H., Jun, S. I., Oh, J., Jeon, Y. J., & Kim, K. (2000). A homochiral metal–organic porous material for enantioselective separation and catalysis. Nature, 404(6781), 982-986. doi:10.1038/35010088Evans, O. R., Ngo, H. L., & Lin, W. (2001). Chiral Porous Solids Based on Lamellar Lanthanide Phosphonates. Journal of the American Chemical Society, 123(42), 10395-10396. doi:10.1021/ja0163772Lin, W. (2005). Homochiral porous metal-organic frameworks: Why and how? Journal of Solid State Chemistry, 178(8), 2486-2490. doi:10.1016/j.jssc.2005.06.013Wu, C.-D., Hu, A., Zhang, L., & Lin, W. (2005). A Homochiral Porous Metal−Organic Framework for Highly Enantioselective Heterogeneous Asymmetric Catalysis. Journal of the American Chemical Society, 127(25), 8940-8941. doi:10.1021/ja052431tMa, L., & Lin, W. (2008). Chirality-Controlled and Solvent-Templated Catenation Isomerism in Metal−Organic Frameworks. Journal of the American Chemical Society, 130(42), 13834-13835. doi:10.1021/ja804944rKepert, C. J., Prior, T. J., & Rosseinsky, M. J. (2000). A Versatile Family of Interconvertible Microporous Chiral Molecular Frameworks:  The First Example of Ligand Control of Network Chirality. Journal of the American Chemical Society, 122(21), 5158-5168. doi:10.1021/ja993814sBradshaw, D., Prior, T. J., Cussen, E. J., Claridge, J. B., & Rosseinsky, M. J. (2004). Permanent Microporosity and Enantioselective Sorption in a Chiral Open Framework. Journal of the American Chemical Society, 126(19), 6106-6114. doi:10.1021/ja0316420Ezuhara, T., Endo, K., & Aoyama, Y. (1999). Helical Coordination Polymers from Achiral Components in Crystals. Homochiral Crystallization, Homochiral Helix Winding in the Solid State, and Chirality Control by Seeding. Journal of the American Chemical Society, 121(14), 3279-3283. doi:10.1021/ja9819918Biswas, S., Tonigold, M., & Volkmer, D. (2008). Homo- and Heteropentanuclear Coordination Compounds withTdSymmetry - the Solid State Structures of [MZn4(L)4(L′)6] (M = CoIIor Zn; L = chloride or acac; L′ = 1,2,3-benzotriazolate). Zeitschrift für anorganische und allgemeine Chemie, 634(14), 2532-2538. doi:10.1002/zaac.200800296Biswas, S., Tonigold, M., Speldrich, M., Kögerler, P., Weil, M., & Volkmer, D. (2010). Syntheses and Magnetostructural Investigations on Kuratowski-Type Homo- and Heteropentanuclear Coordination Compounds [MZn4Cl4(L)6] (MII= Zn, Fe, Co, Ni, or Cu; L = 5,6-Dimethyl-1,2,3-benzotriazolate) Represented by the NonplanarK3,3Graph. Inorganic Chemistry, 49(16), 7424-7434. doi:10.1021/ic100749kLiu, Y.-Y., Grzywa, M., Tonigold, M., Sastre, G., Schüttrigkeit, T., Leeson, N. S., & Volkmer, D. (2011). Photophysical properties of Kuratowski-type coordination compounds [MIIZn4Cl4(Me2bta)6] (MII = Zn or Ru) featuring long-lived excited electronic states. Dalton Transactions, 40(22), 5926. doi:10.1039/c0dt01750gDenysenko, D., Grzywa, M., Tonigold, M., Streppel, B., Krkljus, I., Hirscher, M., … Volkmer, D. (2011). Elucidating Gating Effects for Hydrogen Sorption in MFU-4-Type Triazolate-Based Metal-Organic Frameworks Featuring Different Pore Sizes. Chemistry - A European Journal, 17(6), 1837-1848. doi:10.1002/chem.201001872Marshall, J. H. (1978). Preparation and characterization of tetrakis(2,4-pentanedionato)hexakis(benzotriazolato)pentacopper(II). Inorganic Chemistry, 17(12), 3711-3713. doi:10.1021/ic50190a081Himes, V. L., Mighell, A. D., & Siedle, A. R. (1981). Synthesis and structure of Cu5(BTA)6(t-C4H9NC)4, a mixed-valent copper-nitrogen cluster containing eta3-benzotriazolate. Journal of the American Chemical Society, 103(1), 211-212. doi:10.1021/ja00391a049Kokoszka, G. F., Baranowski, J., Goldstein, C., Orsini, J., Mighell, A. D., Himes, V. L., & Siedle, A. R. (1983). Two-dimensional dynamical Jahn-Teller effects in a mixed-valence benzotriazolato copper cluster, Cu5(BTA)6(RNC)4. Journal of the American Chemical Society, 105(17), 5627-5633. doi:10.1021/ja00355a017Handley, J., Collison, D., Garner, C. D., Helliwell, M., Docherty, R., Lawson, J. R., & Tasker, P. A. (1993). Hexakis(benzotriazolato)tetrakis(2,4-pentanedionato)pentacopper(II): A Model for Corrosion Inhibition. Angewandte Chemie International Edition in English, 32(7), 1036-1038. doi:10.1002/anie.199310361Bakalbassis, E. G., Diamantopoulou, E., Perlepes, S. P., Raptopoulou, C. P., Tangoulis, V., Terzis, A., & Zafiropoulos, T. F. (1995). Benzotriazolate-mediated assembly of the discrete asymmetric pentanuclear nickel complex [Ni5(OH)(bta)5(acac)4(H2O)4](Hbta = benzotriazole, Hacac = pentane-2,4-dione). Journal of the Chemical Society, Chemical Communications, (13), 1347. doi:10.1039/c39950001347Tangoulis, V., Raptopoulou, C. P., Terzis, A., Bakalbassis, E. G., Diamantopoulou, E., & Perlepes, S. P. (1998). Polynuclear Nickel(II) Complexes:  Preparation, Characterization, Magnetic Properties, and Quantum-Chemical Study of [Ni5(OH)(Rbta)5(acac)4(H2O)4] (RbtaH = Benzotriazole and 5,6-Dimethylbenzotriazole). Inorganic Chemistry, 37(13), 3142-3153. doi:10.1021/ic9714091Murrie, M., Collison, D., Garner, C. D., Helliwell, M., Tasker, P. A., & Turner, S. S. (1998). Synthesis structure magnetic properties of [Cu5(bta)6L4] (bta=benzotriazolate;L=β-diketonate) Clusters. Polyhedron, 17(17), 3031-3043. doi:10.1016/s0277-5387(98)00161-2Tangoulis, V., Diamantopoulou, E., Bakalbassisc, E. G., Raptopouloua, C. P., Terzisa, A., & Perlepes, S. P. (1999). The Case of Symmetry-Dependent Ground-State Spin Value in Ni(II) Clusters of High-Nuclearity. Crystal Structure and Magnetic Properties of a Pentanuclear and a Nonanuclear Ni(II) Clusters. Molecular Crystals and Liquid Crystals Science and Technology. Section A. Molecular Crystals and Liquid Crystals, 335(1), 463-472. doi:10.1080/10587259908028888WANG, J. (2002). Synthesis and structure of Cu5(BTA)6(TTA)4?5DMF, a cop-per-nitrogen cluster containing ?3-benzotriazolate. Chinese Science Bulletin, 47(11), 890. doi:10.1360/02tb9199Yuan, Y.-X., Wei, P.-J., Qin, W., Zhang, Y., Yao, J.-L., & Gu, R.-A. (2007). Combined Studies on the Surface Coordination Chemistry of Benzotriazole at the Copper Electrode by Direct Electrochemical Synthesis and Surface-Enhanced Raman Spectroscopy. European Journal of Inorganic Chemistry, 2007(31), 4980-4987. doi:10.1002/ejic.200700436Biswas, S., Grzywa, M., Nayek, H. P., Dehnen, S., Senkovska, I., Kaskel, S., & Volkmer, D. (2009). A cubic coordination framework constructed from benzobistriazolate ligands and zinc ions having selective gas sorption properties. Dalton Transactions, (33), 6487. doi:10.1039/b904280fKaminsky, W. (2005). WinXMorph: a computer program to draw crystal morphology, growth sectors and cross sections with export files in VRML V2.0 utf8-virtual reality format. Journal of Applied Crystallography, 38(3), 566-567. doi:10.1107/s0021889805012148Kaminsky, W. (2007). From CIF to virtual morphology using theWinXMorphprogram. Journal of Applied Crystallography, 40(2), 382-385. doi:10.1107/s0021889807003986Spek, A. L. (2003). Single-crystal structure validation with the programPLATON. Journal of Applied Crystallography, 36(1), 7-13. doi:10.1107/s0021889802022112Momma, K., & Izumi, F. (2011). VESTA 3for three-dimensional visualization of crystal, volumetric and morphology data. Journal of Applied Crystallography, 44(6), 1272-1276. doi:10.1107/s0021889811038970Tarini, M., Cignoni, P., & Montani, C. (2006). Ambient Occlusion and Edge Cueing for Enhancing Real Time Molecular Visualization. IEEE Transactions on Visualization and Computer Graphics, 12(5), 1237-1244. doi:10.1109/tvcg.2006.115Denysenko, D., Werner, T., Grzywa, M., Puls, A., Hagen, V., Eickerling, G., … Volkmer, D. (2012). Reversible gas-phase redox processes catalyzed by Co-exchanged MFU-4l(arge). Chem. Commun., 48(9), 1236-1238. doi:10.1039/c2cc16235kBertini, I., Ciampolini, M., & Sacconi, L. (1971). POLARIZED SPECTRA OF THE TRIGONAL BIPYRAMIDAL CoNP3Br CHROMOPHORE. Journal of Coordination Chemistry, 1(1), 73-74. doi:10.1080/00958977108070746Bertini, I., Gatteschi, D., & Scozzafava, A. (1975). Ligand field interpretation of high-spin trigonal-bipyramidal cobalt(II) complexes. Inorganic Chemistry, 14(4), 812-815. doi:10.1021/ic50146a024Massiot, D., Fayon, F., Capron, M., King, I., Le Calvé, S., Alonso, B., … Hoatson, G. (2001). Modelling one- and two-dimensional solid-state NMR spectra. Magnetic Resonance in Chemistry, 40(1), 70-76. doi:10.1002/mrc.984Boese, A. D., & Handy, N. C. (2001). A new parametrization of exchange–correlation generalized gradient approximation functionals. The Journal of Chemical Physics, 114(13), 5497-5503. doi:10.1063/1.1347371Weigend, F., & Ahlrichs, R. (2005). Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. Physical Chemistry Chemical Physics, 7(18), 3297. doi:10.1039/b508541aSchäfer, A., Huber, C., & Ahlrichs, R. (1994). Fully optimized contracted Gaussian basis sets of triple zeta valence quality for atoms Li to Kr. The Journal of Chemical Physics, 100(8), 5829-5835. doi:10.1063/1.467146Eichkorn, K., Weigend, F., Treutler, O., & Ahlrichs, R. (1997). Auxiliary basis sets for main row atoms and transition metals and their use to approximate Coulomb potentials. Theoretical Chemistry Accounts: Theory, Computation, and Modeling (Theoretica Chimica Acta), 97(1-4), 119-124. doi:10.1007/s002140050244Weigend, F., Furche, F., & Ahlrichs, R. (2003). Gaussian basis sets of quadruple zeta valence quality for atoms H–Kr. The Journal of Chemical Physics, 119(24), 12753-12762. doi:10.1063/1.1627293Andrae, D., H�u�ermann, U., Dolg, M., Stoll, H., & Preu�, H. (1990). Energy-adjustedab initio pseudopotentials for the second and third row transition elements. Theoretica Chimica Acta, 77(2), 123-141. doi:10.1007/bf01114537Blum, V., Gehrke, R., Hanke, F., Havu, P., Havu, V., Ren, X., … Scheffler, M. (2009). Ab initio molecular simulations with numeric atom-centered orbitals. Computer Physics Communications, 180(11), 2175-2196. doi:10.1016/j.cpc.2009.06.022Perdew, J. P., Burke, K., & Ernzerhof, M. (1996). Generalized Gradient Approximation Made Simple. Physical Review Letters, 77(18), 3865-3868. doi:10.1103/physrevlett.77.3865Tkatchenko, A., & Scheffler, M. (2009). Accurate Molecular Van Der Waals Interactions from Ground-State Electron Density and Free-Atom Reference Data. Physical Review Letters, 102(7). doi:10.1103/physrevlett.102.073005Clark, S. J., Segall, M. D., Pickard, C. J., Hasnip, P. J., Probert, M. I. J., Refson, K., & Payne, M. C. (2005). First principles methods using CASTEP. Zeitschrift für Kristallographie - Crystalline Materials, 220(5/6). doi:10.1524/zkri.220.5.567.65075Yates, J. R., Pickard, C. J., & Mauri, F. (2007). Calculation of NMR chemical shifts for extended systems using ultrasoft pseudopotentials. Physical Review B, 76(2). doi:10.1103/physrevb.76.024401Barone, V., Crescenzi, O., & Improta, R. (2002). Computation of Spectroscopic Parameters in vacuo and in Condensed Phases by Methods based on the Density Functional Theory. Quantitative Structure-Activity Relationships, 21(2), 105-118. doi:10.1002/1521-3838(200207)21:23.0.co;2-vRavikovitch, P. I., & Neimark, A. V. (2001). Characterization of nanoporous materials from adsorption and desorption isotherms. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 187-188, 11-21. doi:10.1016/s0927-7757(01)00614-8Jagiello, J., & Thommes, M. (2004). Comparison of DFT characterization methods based on N2, Ar, CO2, and H2 adsorption applied to carbons with various pore size distributions. Carbon, 42(7), 1227-1232. doi:10.1016/j.carbon.2004.01.022Bennett, A. E., Rienstra, C. M., Auger, M., Lakshmi, K. V., & Griffin, R. G. (1995). Heteronuclear decoupling in rotating solids. The Journal of Chemical Physics, 103(16), 6951-6958. doi:10.1063/1.470372Kabsch, W. (1988). Automatic indexing of rotation diffraction patterns. Journal of Applied Crystallography, 21(1), 67-72. doi:10.1107/s0021889887009737Sheldrick, G. M. (2007). A short history ofSHELX. Acta Crystallographica Section A Foundations of Crystallography, 64(1), 112-122. doi:10.1107/s010876730704393