novel insights into the genetics and pathophysiology of adrenocortical tumors

International audienceAdrenocortical tumors (ACTs) are typically unilateral and can be classified as benign adrenocortical adenomas (ACAs) or malignant adrenocortical cancers (ACCs). In rare cases, tumors may occur in both adrenal glands as micronodular hyperplasia (primary pigmented nodular adrenal dysplasia) or as macronodular hyperplasia (primary bilateral macronodular adrenal hyperplasia, PBMAH). The study of certain tumor predisposition syndromes has improved our understanding of sporadic ACTs. Most ACAs are associated with abnormalities of the cAMP signaling pathway, whereas most ACCs are linked to alterations in IGF2, TP53, or the Wnt/βcatenin pathways. Over the past year, single-nucleotide polymorphism array technology and next-generation sequencing have identified novel genetic alterations in ACTs that shed new light on the molecular mechanisms of oncogenesis. Among these are somatic mutations of PKA catalytic subunit alpha gene (PRKACA) in ACA, germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) in primary bilateral macronodular adrenal hyperplasia and somatic alterations of the E3 ubiquitin ligase gene ZNRF3 in ACC. This review focuses on the recent discoveries and their diagnostic, prognostic, and therapeutic implications

Silencing mutated β-catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options. Activating β-catenin somatic mutations are found in ACC and have been associated with a poor clinical outcome. In fact, activation of the Wnt/β-catenin signaling pathway seems to play a major role in ACC aggressiveness, and might, thus, represent a promising therapeutic target. Similar to patient tumor specimen the H295 cell line derived from an ACC harbors a natural activating β-catenin mutation. We herein assess the in vitro and in vivo effect of β-catenin inactivation using a doxycyclin (dox) inducible shRNA plasmid in H295R adrenocortical cancer cells line (clone named shβ). Following dox treatment a profound reduction in β-catenin expression was detectable in shβ clones in comparison to control clones (Ctr). Accordingly, we observed a decrease in Wnt/βcatenin-dependent luciferase reporter activity as well as a decreased expression of AXIN2 representing an endogenous β-catenin target gene. Concomitantly, β-catenin silencing resulted in a decreased cell proliferation, cell cycle alterations with cell accumulation in the G1 phase and increased apoptosis in vitro. In vivo, on established tumor xenografts in athymic nude mice, 9 days of β-catenin silencing resulted in a significant reduction of CTNNB1 and AXIN2 expression. Moreover, continous β-catenin silencing, starting 3 days after tumor cell inoculation, was associated with a complete absence of tumor growth in the shβ group while tumors were present in all animals of the control group. In summary, these experiments provide evidences that Wnt/β-catenin pathway inhibition in ACC is a promising therapeutic target

AGK Cutting Rules and Multiple Scattering in Hadronic Collisions

We discuss the AGK rules for the exchange of an arbitrary number of reggeized gluons in perturbative QCD in the high energy limit. Results include the cancellation of corrections to single jet and double jet inclusive cross sections, both for hard and soft rescattering contributions.Comment: 31 pages, latex, 20 figure

Microwave assisted synthesis of novel bis-flavone dimers as new anticancer agents

In this study we describe a microwave based click chemistry method used to prepare a family of novel bis-flavone dimers. The substituted 7-hydroxy and 4’-hydroxy flavonoids were linked through a triazole ring. The compounds were easily synthesized and purified in high yields. The bis-flavonoids were tested on different cell lines including HCT116, HepG2, MCF7 and MOLT-4. Several analogues showed to have anticancer activity with IC50 values in the range of 20-60 µM. Flavonoids are known for their anticancer properties and this method provides the basis for new medicinal structures

Multiparton interactions and production of minijets in high energy hadronic collisions

We discuss the inclusive cross section to produce two minijets with a large separation in rapidity in high energy hadronic collisions. The contribution to the inclusive cross section from the exchange of a BFKL Pomeron is compared with the contribution from the exchange of two BFKL Pomerons, which is induced by the unitarization of the semi-hard interaction. The effect of the multiple exchange is studied both as a function of the azimuthal correlation and as a function of the transverse momentum of the observed minijets.Comment: TeX file, 20 pages, 4 figures available on reques

Electrochemically Triggered Co-Conformational Switching in a [2]catenane Comprising a Non-Symmetric Calix[6]arene Wheel and a Two-Station Oriented Macrocycle

Catenanes with desymmetrized ring components can undergo co-conformational rearrangements upon external stimulation and can form the basis for the development of molecular rotary motors. We describe the design, synthesis and properties of a [2]catenane consisting of a macrocycle—the ‘track’ ring—endowed with two distinct recognition sites (a bipyridinium and an ammonium) for a calix[6]arene—the ‘shuttle’ ring. By exploiting the ability of the calixarene to thread appropriate non-symmetric axles with directional selectivity, we assembled an oriented pseudorotaxane and converted it into the corresponding oriented catenane by intramolecular ring closing metathesis. Cyclic voltammetric experiments indicate that the calixarene wheel initially surrounds the bipyridinium site, moves away from it when it is reduced, and returns in the original position upon reoxidation. A comparison with appropriate model compounds shows that the presence of the ammonium station is necessary for the calixarene to leave the reduced bipyridinium site

Dynamical chiral symmetry breaking by a magnetic field and multi-quark interactions

Catalysis of dynamical symmetry breaking by a constant magnetic field in (3+1) dimensions is considered. We use the three flavour Nambu -- Jona-Lasinio type model with 't Hooft and eight-quark interaction terms. It is shown that the multi-quark interactions introduce new additional features to this phenomenon: (a) the local minimum of the effective potential catalyzed by the constant magnetic field is smoothed out with increasing strength of the field at the characteristic scale H~10^{19} G, (b) the multi-quark forces generate independently another local minimum associated with a larger dynamical fermion mass. This state may exist even for multi-quark interactions with a subcritical set of couplings, and is globally stable with respect to a further increase of the magnetic field.Comment: 6 pages, 3 figures, added discussion and references, version to appear in Phys.Lett.

Plugging a bipyridinium axle into multichromophoric calix[6]arene wheels bearing naphthyl units at different rims

Tris-(N-phenylureido)-calix[6]arene derivatives are heteroditopic non-symmetric molecular hosts that can form pseudorotaxane complexes with 4,4'-bipyridinium-type guests. Owing to the unique structural features and recognition properties of the calix[6]arene wheel, these systems are of interest for the design and synthesis of novel molecular devices and machines. We envisaged that the incorporation of photoactive units in the calixarene skeleton could lead to the development of systems whose working modes can be governed and monitored by means of light-activated processes. Here we report on the synthesis, structural characterization, and spectroscopic, photophysical and electrochemical investigation of two calix[6]arene wheels decorated with three naphthyl groups anchored to either the upper or lower rim of the phenylureido calixarene platform. We found that the naphthyl units interact mutually and with the calixarene skeleton in a different fashion in the two compounds, which thus exhibit a markedly distinct photophysical behavior. For both hosts, the inclusion of a 4,4'-bipyridinium guest activates energy- and/or electron-transfer processes that lead to non-trivial luminescence changes

Substrate-Induced Self-Assembly of Cooperative Catalysts

Dissipative self-assembly processes in Nature rely on chemical fuels that activate proteins for assembly through the formation of a noncovalent complex. The catalytic activity of the assemblies causes fuel degradation, resulting in the formation of an assembly in a high-energy, out-of-equilibrium state. Herein, we apply this concept to a synthetic system and demonstrate that a substrate can induce the formation of vesicular assemblies, which act as cooperative catalysts for cleavage of the same substrate

Interactions of flavones and related compounds with nucleic acids.

This project focused on a group of active ingredients isolated from herbal medicines, most of them flavonoids, as a foundation for the development of new anticancer drugs. Interactions between these compounds and genomic DNA, synthetic polynucleotides, or higher order DNA isoforms (triple and quadruple helical forms) have been studied using a range of physicochemical and biological techniques. The studies demonstrated that flavonoids and isoflavonoids bind to the various nucleic acid forms with weak or moderate affinities and no significant specificity, apart from quercetin that demonstrated a differential binding for G-quadruplex structures. Rational drug design has been subsequently employed to elucidate the mode of binding and novel compounds have been synthesized in order to provide precise structure-activity related studies and result in a second generation of chemotherapeutic anticancer agents with improved properties. Interaction with DNA is thought to involve the planar ring structures. The double bond of the O in C4 in a flavone scaffold gives planarity to the molecule, and this allows the molecule to intercalate between the bases in the different nucleic acid structures. The comparison between flavone, flavanone and isoflavonoid indicates that the position of the B ring and the double bond in the C ring are important for the interactions with DNA. Introduction of nitrogen in the ring did not improve the binding but tertiary amines improved binding 100 fold. Introduction of sulfur produced two binding constants. Position 7 in the A ring of the flavones is extremely relevant for the binding to the nucleic acids, but substitutions in the B ring did not improve the binding. Methoxylation or acetoxylation in positions 5 and 7 decreased the affinity for DNA. Novel compounds were tested for their specificity against different DNA isoforms and their anticancer activity in various tumour cell lines