Switching the Photochromic Activity of Acenaphthylene Derivatives through a Tandem Nucleophile-Promoted Addition Reaction.

New acenaphthylene-based dithienylethenes have been prepared. Surprisingly they did not show photochromism. However, they readily underwent a tandem addition of a nucleophile and an electrophile, leading to a small library of dearomatized colourless analogues, which, on the contrary, were endowed with photochromic activity.

Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome.

Background: In patients with Lynch syndrome, germline mutations in DNA mismatch repair (MMR) genes cause a high risk of developing a broad spectrum of cancers. To date, the management of patients with Lynch syndrome has represented a major challenge because of large variations in age at cancer onset. Several factors, including genetic anticipation, have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown.

Breakpoint determination of 15 large deletions in Peutz-Jeghers subjects.

The Peutz-Jeghers Syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers. STK11/LKB1 (hereafter named STK11) germline mutations account for the large majority of PJS cases whereas large deletions account for about 30% of the cases. We report here the first thorough molecular characterization of 15 large deletions identified in a cohort of 51 clinically well-characterized PJS patients.

A highly convergent synthesis of tricyclic N-heterocycles coupling an Ugi reaction with a tandem S(N)2'-Heck double cyclization.

A small library of natural product-like compounds has been assembled by coupling an Ugi multicomponent reaction with two postcondensation transformations, carried out in one-pot fashion: a S(N)2' cyclization followed by an intramolecular Heck reaction.

Optimized synthesis of phosphatidylserine.

The synthesis of phosphatidyl serine containing saturated fatty acids was thoroughly studied and optimized in order to establish a protocol amenable to large-scale synthesis. The key step was a one-pot multicomponent reaction involving an O-benzyl phosphorodiamidite, protected serine and diacylglycerol, followed by in situ oxidation of the resulting phosphite. In order to replace expensive and poorly stable tetrazole, a screening of substitutes was carried out and imidazolium chloride was selected as the best suited one.

The Italian external quality control program for familial adenomatous polyposis of the colon: five years of experience.

Familial adenomatous polyposis is a rare autosomal dominant inherited disease (incidence, 1/8000). More than 90% of families affected by familial adenomatous polyposis have a mutation in the tumor suppressor gene adenomatous polyposis coli (APC). Mutations in this gene are characterized by 100% penetrance, although there is a variation in phenotypic expression of the disease.

Multicomponent synthesis of dihydrobenzoxazepinones, bearing four diversity points, as potential α-helix mimics.

A very short convergent synthesis of dihydrobenzoxazepinones, bearing four diverse diversity points, based on coupling the Ugi reaction with a Mitsunobu cyclization, was developed. These compounds are potential α-helix mimics, where three of the four appendages are expected to imitate the residues in i, i + 4 and i + 7 positions. A library of 22 compounds bearing lipophilic substituents, designed to interact with the hydrophobic cleft of anti-apoptotic protein Bcl-xL, was synthesized.

Isocyanides and arylacetic acids: synthesis and reactivity of 3-aryl-2-acyloxyacrylamides, an example of serendipity-oriented synthesis.

Research progress is often promoted by unexpected results that open the way to new scenarios. In this communication, an unprecedented condensation of arylacetic acids and isocyanides and the unusual base-mediated rearrangement of the resulting products to give two novel classes of polysubstituted pyrrolones and pyrrolidinediones are reported.

Effects of VEGF on phenotypic severity in children with hereditary hemorrhagic telangiectasia.

The purpose of this study was to estimate vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 serum levels in children with hereditary hemorrhagic telangiectasia (HHT) type 1 and type 2 and to correlate them to the presence of arteriovenous malformations (AVMs). High VEGF levels were initially found in an infant who had been hospitalized with intestinal bleeding and suspected HHT. This case led to the evaluation of VEGF and TGF-beta1 by standard enzyme-linked immunosorbent assay in 13 children with HHT and familiarity.

Influence of some detoxification enzyme polymorphisms on cytogenetic biomarkers between individuals exposed to very low doses of 1,3-butadiene.

Objective: To evaluate the variation of some biomarkers related to the level of enzymatic activity dependent on the different polymorphisms.

Methods: We studied 27 butadiene-exposed workers and 37 controls using different biomarkers of the genotoxic effect. The genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism-polymerase chain reaction techniques; the subjects were assigned to a specific group based on the microsomal epoxide hydrolase (mEH) activity predicted by their genotype (low, intermediate, high).

De novo balanced chromosome rearrangements in prenatal diagnosis.

Objective: We surveyed the datasheets of 29 laboratories concerning prenatal diagnosis of de novo apparently balanced chromosome rearrangements to assess the involvement of specific chromosomes, the breakpoints distribution and the impact on the pregnancy outcome.

Method: By means of a questionnaire, data on 269.371 analyses performed from 1983 to 2006 on amniotic fluid, chorionic villus and fetal blood samples were collected.

Noncolonic cancer stem cells in bone marrow of colorectal cancer patients.

Objective: To investigate whether preoperative noncolonic cancer stem cells in bone marrow (BM) of R0 colorectal cancer (CRC) patients are cancer cells and impact on liver metastases (LM) rates.

Method: Prospective data on continuous CRC patients were collected from five centres. Bone marrow aspirates, taken at laparotomy, were sent to a single lab.

A novel intramolecular Ugi reaction with 7-azabicyclo[2.2.1]heptane derivatives followed by post-condensation acylations: a new entry to azanorbornyl peptidomimetics.

beta-amino acids have been employed in the past as bifunctional building blocks in intramolecular Ugi multicomponent reactions to yield beta-lactam derivatives. By using 7-azabicyclo[2.2.

Multicomponent synthesis of benzoxazinones via tandem Ugi/Mitsunobu reactions: an unexpected cine-substitution.

A short (2 steps) synthesis of diverse benzoxazinones by coupling the Ugi multicomponent reaction with an intramolecular Mitsunobu substitution is reported. The cyclization step proceeds via an unexpected cine substitution.

The Italian external quality assessment scheme in classical cytogenetics: four years of activity.

Background: The Italian external quality assessment scheme in classical cytogenetics was started in 2001 as an activity funded by the National Health System and coordinated by the Italian Public Institute of Health.

Objectives: The aim of our work is to present data from the first 4 years of activity, 2001-2004.

Methods: Italian cytogenetics public laboratories were enrolled on a voluntary basis, and this nationwide program covered prenatal, postnatal and oncological diagnosis.

Synthesis and DNA-cleaving activity of lactenediynes conjugated with DNA-complexing moieties.

Lactenediynes are compounds characterized by the fusion of a beta-lactam with a cyclodeca-3-ene-1,5-diyne. In this work the most promising members of this family have been activated by attaching a carbalkoxy or a carbamoyl group to the azetidinone nitrogen, and conjugated to various DNA-complexing moieties, either acting by intercalation or through groove binding. These conjugated artificial enediynes have been demonstrated to possess in vitro ability to produce single and double strand cleavage of plasmid DNA.

Hereditary haemorrhagic telangiectasia: a rare disease as a model for the study of human atherosclerosis.

Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler-Weber syndrome is an autosomal dominant disease characterized by local angiodysplasia affecting different organism districts. From a clinical viewpoint, HHT patients suffer from epistaxis, mucocutaneous telangiectases and arteriovenous malformations in various organs. Mutations in two known genes (ENG and ALK1) account for the majority of HHT patients.

Polyfunctionalized pyrrolidines by Ugi multicomponent reaction followed by palladium-mediated SN2' cyclizations.

A 4-component Ugi reaction with a suitable isocyanide, followed by a novel secondary transformation involving a Pd(II)-mediated (R5 = H) or a Pd(0)-mediated (R5 = CO2Me) SN2' cyclization to give highly functionalized N-acyl-2-vinylpyrrolidines, is reported. The overall yields are usually good and in most cases the Pd(0)-catalyzed reaction gave the final product in almost quantitative yield.

Porous silicon surfaces: a candidate substrate for reverse protein arrays in cancer biomarker detection.

This paper introduces a new substrate for reverse-phase protein microarray applications based on macroporous silicon. A key feature of the microarray substrate is the vastly surface enlarging properties of the porous silicon, which simultaneously offers highly confined microarray spots. The proof of principle of the reverse array concept was demonstrated in the detection of different levels of cyclin E, a possible cancer biomarker candidate which regulates G1-S transition and correlates with poor prognosis in different types of human cancers.

Multicomponent reactions in solid-phase synthesis.

Multicomponent reactions are a powerful tool in combinatorial chemistry and diversity-oriented synthesis for the assembly of collections of complex molecules in a highly straightforward and efficient manner. Additional advantages in terms of isolation and purification can be obtained by performing these condensations on a polymeric support or with the aid of solid-supported reagents, scavengers or catalysts. This review covers research published in this area during the last two years and provides a perspective of future directions.

Novel splice isoforms of STRADalpha differentially affect LKB1 activity, complex assembly and subcellular localization.

STRADalpha is a pseudokinase that forms a heterotrimeric complex with the scaffolding protein MO25 and the tumor suppressor serine threonine protein kinase LKB1. Mutations in the LKB1 gene are responsible for the Peutz-Jeghers Syndrome (PJS) characterized by a predisposition to hamartomatous polyps and hyperpigmentation of the buccal mucosa. Mutations in LKB1 have also been observed in some sporadic tumours unrelated to PJS.

SCE frequency measurement could be useful in the prenatal diagnosis of Roberts syndrome.

In a previously published article (Resta et al., 2006) on Robert's syndrome in prenatal diagnosis, a case of a 36-year-old woman and her 36-year-old, nonconsanguineous husband were presented. Our findings suggest the existence of nonsense mediated decay (NMD) variability which could account for the varying severity reported in carriers of identical mutations.

Molecular and clinical characteristics in 46 families affected with Peutz-Jeghers syndrome.

Germline mutations of the tumor suppressor gene LKB1/STK11 are responsible for the Peutz-Jeghers syndrome (PJS), an autosomal-dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyps, and an increased risk of associated malignancies. In this study, we assessed the presence of pathogenic mutations in the LKB1/STK11 gene in 46 unrelated PJS families, and also carried genotype-phenotype correlation in regard of the development of cancer in 170 PJS patients belonging to these families. All LKB1/STK11 variants detected with single-strand conformational polymorphism were confirmed by direct sequencing, and those without LKB1/STK11 mutation were further submitted to Southern blot analysis for detection of deletions/rearrangements.

Ugi multicomponent reaction followed by an intramolecular nucleophilic substitution: convergent multicomponent synthesis of 1-sulfonyl 1,4-diazepan-5-ones and of their benzo-fused derivatives.

A short, two-step approach to the synthesis of diazepane or diazocane systems, based on a Ugi multicomponent reaction followed by a subsequent intramolecular SN2 reaction was studied. 1-sulfonyl tetrahydrobenzo[e]-1,4-diazepin-1-ones 1 were obtained in very high yield through a Ugi multicomponent reaction followed by Mitsunobu cyclization. On the other hand, aliphatic 1-sulfonyl 1,4-diazepan-5-ones 2 could be obtained employing different cyclization conditions (sulfuryl diimidazole).

Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC.

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by inactivating mutations of DNA mismatch repair genes. Large genomic rearrangements in these genes have been increasingly recognized as important causes of HNPCC. Using multiplex ligation-dependent probe amplification, we identified three MSH2 deletions in Italian patients with HNPCC (proband A: exons 1-3, proband M: exon 8, and proband C: exons 1-6).