Hereditary nonpolyposis colorectal cancer: an approach to the selection of candidates to genetic testing based on clinical and molecular characteristics

OBJECTIVE: Identification of clinical and molecular characteristics associated with constitutional MLH1 and MSH2 mutations and definition of a stepwise strategy for the selection of colorectal cancer (CRC) patients amenable to MLH1 and MSH2 genetic testing. METHODS: 90 unrelated CRC patients were initially selected on the basis of either familial or early onset occurrence of CRC. They were screened for the presence of constitutional MLH1 and MSH2 mutations and for microsatellite instability (MSI). RESULTS: 16 pathogenetic mutations (9 MLH1 and 7 MSH2) were identified in 41% of Amsterdam hereditary nonpolyposis colorectal cancer (HNPCC) families, 5% of suspected HNPCC families, and 14% of sporadic early-onset CRC patients. The presence of the mutations correlated with MSI, with early age of onset and proximal location of the tumor, and with the presence of some extracolonic tumors of the HNPCC spectrum and/or multiple tumors in the family. CONCLUSIONS: Evaluation of clinical and molecular characteristics is useful for the identification of candidates to MLH1 and MSH2 mutational analysis and allows the application of a rational approach to genetic testing.     

Palladium-catalyzed direct heck arylation of dual pi-deficient/pi-excessive heteroaromatics. Synthesis of C-5 arylated imidazo[1,5-a]pyrazines

A general and efficient synthesis of 5-aryl imidazo[1,5- a]pyrazines by palladium-catalyzed coupling of the corresponding 8-substituted derivatives with aryl halides is described. The scope of this new reaction for the imidazo[1,5- a]pyrazine ring system was explored using three readily available 8-substituted precursors, X = NH2, NMe2, and OMe, as well as 8-aryl derivatives, X = Ar'. On the basis of these results as well as studies using a deuterated derivative, a Heck-like mechanism is proposed for this transformation.     

Nitric oxide release mediated by calix[4]hydroquinones

Calix[4]monohydroquinone has been used as a supramolecular system for the generation of NO gas. In a one-electron reduction scheme involving NO+ subsetcalix[4]monohydroquinone complex, NO is released without the presence of an external reducing agent. Free calix[4]monoquinone, thus obtained, can be reused for a new NO-releasing cycle after NaBH4-reduction to calix[4]monohydroquinone.     

Towards the improvement of the synthesis of novel 4(5)-aryl-5(4)-heteroaryl-2-thio-substituted imidazoles and their p38 MAP kinase inhibitory activity

A series of 2-alkylsulfanyl-4-(4-fluorophenyl)-5-(2-aminopyridin-4-yl)-substituted imidazoles was prepared and interaction possibilities of the 2-thioether moiety with phosphate/ribose binding pockets of p38 MAP kinase were investigated. Introduction of the alkyl/benzyl amino function at the pyridine moiety was carried out via nucleophilic substitution or via palladium catalyzed aryl-C-N-bond formation.     

Catalytic behavior of supported Pd catalysts in the selective hydrogenation of campholenic aldehyde to naturanol

Selective catalytic reduction of campholenic aldehyde to naturanol was investigated over Sn-and Fe-doped SiO₂, and Fe₂O₃-supported Pd catalysts. On Pd/SiO₂ and Pd-Sn/SiO₂ only saturated campholenic aldehyde is formed. Addition of Fe increases the C=O hydrogenation rate producing the corresponding unsaturated alcohol with a good selectivity. Also Fe₂O₃-supported catalysts were found to be more selective towards carbonyl hydrogenation. Addition of tin to Pd/Fe₂O₃ contributes to a further selectivity enhancement towards naturanol.     

Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy‐Resistant L858R/T790M/C797S Mutant

The treatment of non‐small‐cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third‐generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine‐mutated L858R/T790M/C797S EGFR.     

Magnetic nanoparticles coated with polyaniline to stabilize immobilized trypsin

It is reported the synthesis of magnetic nanoparticles via the chemical co-precipitation of Fe ³⁺ ions and their preparation by coating them with polyaniline. The electronic micrograph analysis showed that the mean diameter for the nanoparticles is ～15 nm. FTIR, powder X-ray diffraction and Mössbauer spectroscopy were used to understand the chemical, crystallographic and ⁵⁷Fe hyperfine structures for the two samples. The nanoparticles, which exhibited magnetic behavior with relatively high spontaneous magnetization at room temperature, were identified as being mainly formed by maghemite (γFe₂O₃). The coated magnetic nanoparticles (sample labeled “mPANI”) presented a real ability to bind biological molecules such as trypsin, forming the magnetic enzyme derivative (sample “mPANIG-Trypsin”). The amount of protein and specific activity of the immobilized trypsin were found to be 13±5 μg of protein/mg of mPANI (49.3 % of immobilized protein) and 24.1±0.7 U/mg of immobilized protein, respectively. After 48 days of storage at 4 ^°C, the activity of the immobilized trypsin was found to be 89 % of its initial activity. This simple, fast and low-cost procedure was revealed to be a promising way to prepare mPANI nanoparticles if technological applications addressed to covalently link biomolecules are envisaged. This route yields chemically stable derivatives, which can be easily recovered from the reaction mixture with a magnetic field and recyclable reused.     

Quantum mechanical calculations of conformationally relevant 1H and 13C NMR chemical shifts of N-, O-, and S-substituted calixarene systems

QM GIAO calculations of (13)C and (1)H chemical shift values of the ArCH(2)Ar group in N-, O-, and S-substituted calixarene systems were performed with a hybrid DFT functional MPW1PW91 and 6-31G(d,p) basis set. A good reproduction of experimental data was obtained for some representative calixarenes and for a series of simplified calixarene models. This allowed the derivation of chemical shift surfaces versus phi and chi dihedral angles. The applicability of chemical shift surfaces in the study of calixarene conformational features is illustrated.     

Encoding Individual Source Sequences for the Wiretap Channel

We consider the problem of encoding a deterministic source sequence (i.e., individual sequence) for the degraded wiretap channel by means of an encoder and decoder that can both be implemented as finite-state machines. Our first main result is a necessary condition for both reliable and secure transmission in terms of the given source sequence, the bandwidth expansion factor, the secrecy capacity, the number of states of the encoder and the number of states of the decoder. Equivalently, this necessary condition can be presented as a converse bound (i.e., a lower bound) on the smallest achievable bandwidth expansion factor. The bound is asymptotically achievable by Lempel–Ziv compression followed by good channel coding for the wiretap channel. Given that the lower bound is saturated, we also derive a lower bound on the minimum necessary rate of purely random bits needed for local randomness at the encoder in order to meet the security constraint. This bound too is achieved by the same achievability scheme. Finally, we extend the main results to the case where the legitimate decoder has access to a side information sequence, which is another individual sequence that may be related to the source sequence, and a noisy version of the side information sequence leaks to the wiretapper.