A ceRNA circuitry involving the long noncoding RNA KLHL14-AS, PAX8, and BCL2 drives thyroid carcinogenesis

Klhl14-AS is a long noncoding RNA expressed since early specification of thyroid bud and is the most enriched gene in the mouse thyroid primordium at E10.5. Here, we studied its involvement in thyroid carcinogenesis by analyzing its expression in cancer tissues and different models of neoplastic transformation. Compared with normal thyroid tissue and cells, Klhl14-AS was significantly downregulated in human thyroid carcinoma tissue specimens, particularly the anaplastic histotype, thyroid cancer cell lines, and rodent models of thyroid cancer. Downregulating the expression of Klhl14-AS in normal thyroid cells decreased the expression of thyroid differentiation markers and cell death and increased cell viability. These effects were mediated by the binding of Klhl14-AS to two miRNAs, Mir182-5p and Mir20a-5p, which silenced Pax8 and Bcl2, both essential players of thyroid differentiation. MIR182-5p and MIR20a-5p were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on Pax8 and Bcl2 were rescued by Klhl14-AS overexpression, confirming Klhl14-AS as a ceRNA for both Pax8 and Bcl2. This work connects deregulation of differentiation with increased proliferation and survival in thyroid neoplastic cells and highlights a novel ceRNA circuitry involving key regulators of thyroid physiology. Significance: This study describes a new ceRNA with potential tumor suppression activity and helps us better understand the regulatory mechanisms during thyroid differentiation and carcinogenesis

Outcomes of pregnancies after kidney transplantation: lessons learned from CKD. A comparison of transplanted, nontransplanted chronic kidney disease patients and low-risk pregnancies: a multicenter nationwide analysis.

BACKGROUND: Kidney transplantation (KT) may restore fertility in CKD. The reasons why materno-foetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of non-transplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD and 1418 low-risk controls recruited in 2 large Italian Units, in the same period (2000-2014). The following outcomes were considered: maternal and foetal death; malformations; preterm delivery; small for gestational age baby (SGA); need for the neonatal intensive care unit (NICU); doubling of serum creatinine or increase in CKD stage. Data were analysed according to kidney diseases, renal function (staging according to CKD-EPI), hypertension, maternal age, partity, ethnicity. RESULTS: Materno-foetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. KT patients with e-GFR >90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ('progressive CKD') are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 versus 1: RR 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. CONCLUSIONS: The materno-foetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney diseas

A periodic hybrid DFT approach (including dispersion) to MgCl2-supported Ziegler-Natta catalysts-1: TiCl4 adsorption on MgCl2 crystal surfaces

The adsorption of TiCl4 on the surfaces of MgCl2 crystals has been investigated by means of state-of-the-art periodic hybrid DFT methods, as the first step of a comprehensive study aiming to elucidate the structure of the active species in industrial MgCl2-supported Ziegler-Natta catalysts for ethene and propene polymerization. A first distinctive feature of the approach was the thorough evaluation of dispersion forces, crucial because the binding of TiCl4 on MgCl2 surfaces turned out to be essentially dispersion-driven. Also important was a careful investigation of the effects of different choices on basis set and density functional (DF) on the quantitative aspects of the results; this allowed us to trace the unusually large disagreement in the previous literature and identify unambiguous trends. In particular, three full sets of calculations were run adopting the B3LYP(-D), PBE0(-D) and M06 approximations: to the best of our knowledge, the last represents the first case of M06 functional implementation in a periodic code (CRYSTAL) of widespread use. The results consistently indicated that the adsorption of TiCl4 on well-formed MgCl2 crystals under conditions relevant for catalysis can only occur on MgCl2(1 1 0) or equivalent lateral faces, whereas the interaction with MgCl2(1 0 4) - for decades claimed as the most important surface in stereoselective catalysts - is too weak for the formation of stable adducts. The implications of these findings for catalysis are discussed. (C) 2011 Elsevier Inc. All rights reserve

A periodic hybrid DFT approach (including dispersion) to MgCl2-supported Ziegler-Natta catalysts-1: TiCl4 adsorption on MgCl2 crystal surfaces

The adsorption of TiCl4 on the surfaces of MgCl2 crystals has been investigated by means of state-of-the-art periodic hybrid DFT methods, as the first step of a comprehensive study aiming to elucidate the structure of the active species in industrial MgCl2-supported Ziegler-Natta catalysts for ethene and propene polymerization. A first distinctive feature of the approach was the thorough evaluation of dispersion forces, crucial because the binding of TiCl4 on MgCl2 surfaces turned out to be essentially dispersion-driven. Also important was a careful investigation of the effects of different choices on basis set and density functional (DF) on the quantitative aspects of the results; this allowed us to trace the unusually large disagreement in the previous literature and identify unambiguous trends. In particular, three full sets of calculations were run adopting the B3LYP(-D), PBE0(-D) and M06 approximations: to the best of our knowledge, the last represents the first case of M06 functional implementation in a periodic code (CRYSTAL) of widespread use. The results consistently indicated that the adsorption of TiCl4 on well-formed MgCl2 crystals under conditions relevant for catalysis can only occur on MgCl2(1 1 0) or equivalent lateral faces, whereas the interaction with MgCl2(1 0 4) - for decades claimed as the most important surface in stereoselective catalysts - is too weak for the formation of stable adducts. The implications of these findings for catalysis are discussed. (C) 2011 Elsevier Inc. All rights reserved

Accurate experimental and theoretical enthalpies of association of TiCl4with typical Lewis bases used in heterogeneous Ziegler-Natta catalysis

Adducts of TiCl4with Lewis bases used as internal or external donors in heterogeneous Ziegler-Natta (ZN) catalysis represent a fundamental interaction contributing to the final composition of MgCl2supported ZN-catalysts. This study presents the accurate experimental evaluation, from titration calorimetry, of the formation enthalpy of TiCl4adducts with 15 Lewis bases of industrial interest. In addition, we report the accurate energies of association of TiCl4with the same Lewis bases from calculations at the DLPNO-CCSD(T) level of theory. These accurate experimental and theoretical association values are compared with selected methods based on density functional theory (DFT) in combination with popular continuum solvation models. Calculations suggest that the PBE-D3, and M06 functionals in combination with a triple-ζ plus polarization quality basis set provide the best performance when the basis set superposition error (BSSE) is not removed from the association energies. Cleaning the association energies with the BSSE with the counterpoise protocol suggests B3LYP-D3, TPSS-D3 and M06L as the best performing functionals. The introduction of solvent effects with the PCM and SMD continuum solvation models allows the DFT-based association enthalpies to be compared with the experimental values obtained from titration calorimetry. Both solvation models in combination with the PBE-D3, PBE0-D3, B3LYP-D3, TPSS-D3, M06L, and M06 functionals provide association enthalpies close to the experimental values with MUEs in the range of 10-15 kJ mol-1