No abstract

A general and efficient three-step procedure for the highly regioselective synthesis of 1-methyl-1H-imidazoles possessing electron-rich, electron-neutral and/or electron-deficient aryl moieties at their 4- and 5-position is described. The first step involves the Pd-catalyzed direct C-5 arylation of commercially available 1-methyl-1H-imidazole with aryl bromides and the second and third step of the sequence involve the selective C-4 bromination of the resulting 5-aryl-1-methyl-1H-imidazoles with NBS followed by a PdCl2(dppf)-catalyzed Suzuki-type reaction between 5-aryl-4-bromo-1-methyl-1H-imidazoles and arylboronic acids under phase-transfer conditions. Two so prepared 4,5-diaryl-1-methyl-1H-imidazoles, which can be regarded as Z-restricted analogues of naturally-occurring combretastatin A-4 (CA-4), have proven to be highly cytotoxic against a variety of human tumor cell lines and one of these derivatives has been shown to be more cytotoxic than CA-4 and all of the imidazole derivatives investigated in the literature so far

Background: Short-term studies have reported that the fecal immunochemical test (FIT) is less accurate in detecting proximal than distal colorectal neoplasia.Objective: To assess the long-term detection rates for advanced adenoma and colorectal cancer (CRC), according to anatomical location.Design: Retrospective study.Setting: Population-based, organized screening program in the Veneto region of Italy.Participants: Persons aged 50 to 69 years who completed 6 rounds of FIT screening.Measurements: At each screening round, the detection rates for advanced adenoma and cancer, as well as the proportional interval cancer rate (PICR), were calculated by anatomical location (proximal colon, distal colon, or rectum).Results: Between 2002 and 2014, a total of 123 347 participants had 441 647 FITs. The numbers of advanced adenomas and cancer cases detected, respectively, were 1704 and 200 in the proximal colon, 3703 and 324 in the distal colon, and 1220 and 209 in the rectum. Although the detection rate for proximal colon cancer declined only from the first to the second screening round (0.63 to 0.36 per 1000 screenees), the rate for both distal colon and rectal cancer steadily decreased across 6 rounds (distal colon, 1.65 in the first round to 0.17 in the sixth; rectum, 0.82 in the first round to 0.17 in the sixth). Similar trends were found for advanced adenoma (proximal colon, 5.32 in the first round to 4.22 in the sixth; distal colon, 15.2 in the first round to 5.02 in the sixth). Overall, 150 cases of interval cancer were diagnosed. The PICR was higher in the proximal colon (25.2% [95% CI, 19.9% to 31.5%]) than the distal colon (6.0% [CI, 3.9% to 8.9%]) or rectum (9.9% [CI, 6.9% to 13.7%]).Limitations: Participants with irregular attendance were censored. Those who had a false-positive result on a previous FIT but negative colonoscopy results were included in subsequent rounds. Conclusion:This FIT-based, multiple-round, long-term screening program had a negligible reduction in detection rates for neoplastic lesions in the proximal versus the distal colon after the first round. This was related to a higher PICR in the proximal colon and suboptimal efficacy in preventing the age-related proximal shifting of CRC.

Serum j and k free light chain levels are markers of plasma cell proliferation, and their measurements have been included in recent guidelines by the International Myeloma Working Group for the management of patients with plasma cellular dyscrasias. Five in vitro diagnostic methods for the immunochemical quantification of serum free light chains (FLC) are available, three based on polyclonal antibodies (Freelite V R , The Binding Site; FLC ELISA j and k, Sebia; human j and k FLC, Diazyme Laboratories) and two on monoclonal antibodies (N Latex FLC, Siemens Healthineers; Seralite V R , Sebia). Several studies have shown that these methods cannot be used interchangeably for the follow-up of patients because measured j and k FLC concentrations may differ significantly, especially at high levels. Because no international reference material for the measurement of FLC is available, it is not possible to establish which method is the most accurate. For this reason, knowledge about the analytical and diagnostic performances of the assays used is important. The aim of this review is to describe the main analytical features of the j and k FLC assays and how they may influence the clinical use of these parameters.

Neuroblastoma (NB) is the most common extracranial solid tumor in children, accounting for about 8% of childhood cancers. Despite aggressive treatment, patients suffering from high-risk NB have very poor 5-year overall survival rate, due to relapsed and/or treatment-resistant tumors. A further increase in therapeutic dose intensity is not feasible, because it will lead to prohibitive short-term and long-term toxicities. New approaches with targeted therapies may improve efficacy and decrease toxicity. The use of drug delivery systems allows site specific delivery of higher payload of active agents associated with lower systemic toxicity compared to the use of conventional (“free”) drugs. The possibility of imparting selectivity to the carriers to the cancer foci through the use of a targeting moiety (e.g., a peptide or an antibody) further enhances drug efficacy and safety. We have recently developed two strategies for increasing local concentration of anti-cancer agents, such as CpG-containing oligonucleotides, small interfering RNAs, and chemotherapeutics in NB. For doing that, we have used the monoclonal antibody anti-disialoganglioside (GD2), able to specifically recognize the NB tumor and the peptides containing NGR and CPRECES motifs, that selectively bind to the aminopeptidase N-expressing endothelial and the aminopeptidase A-expressing perivascular tumor cells, respectively. The review will focus on the use of tumor- and tumor vasculature-targeted nanocarriers to improve tumor targeting, uptake, and penetration of drugs in preclinical models of human NB.