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Background:The FOLFOXIRI regimen produces a high rate of radiological and histopathological responses. Bevacizumab added to chemotherapy showed an improvement in pathological response and necrosis of colorectal liver metastases (CLMs). FOLFOXIRI plus bevacizumab produced promising early clinical results and is under investigation in several randomised trials, although no data are currently available on its effects on response of CLMs and on liver toxicities.Methods:Starting from 499 patients enrolled in first-line phase II/III trials, we selected on the basis of tissue sample availability 18 patients treated with FOLFOXIRI/XELOXIRI and 24 patients treated with FOLFOXIRI plus bevacizumab who underwent secondary resection of CLMs. The 28 untreated patients who underwent primary resection of CLMs were included as control group. Responses of CLMs and chemotherapy-induced toxicities were assessed.Results:Among the patients, 63% of those treated with FOLFOXIRI plus bevacizumab, as compared with 28% of those treated with only FOLFOXIRI/XELOXIRI, showed a histopathological response (P=0.033). In the two groups, 52% and 12.5%, respectively, showed necrosis 50% (P=0.017). The incidence of liver toxicities was not significantly increased in patients treated with FOLFOXIRI plus bevacizumab.Conclusion:The addition of bevacizumab to FOLFOXIRI produces high rates of pathologic responses and necrosis of CLM without increasing liver toxicity. [ABSTRACT FROM AUTHOR]

NRAS mutations occur in 3-5% of colorectal cancer. Differently from KRAS and BRAF mutations, the role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer (mCRC) has been investigated to a lesser extent. A retrospective series suggested the role of NRAS mutations as predictors of resistance to anti-EGFR monoclonal antibodies (MoAbs) in chemo-refractory patients with mCRC. In our study, KRAS codons 12, 13, 61 and BRAF codon 600 mutational status were evaluated in mCRCs referred to our Institution from 2009 to 2012. NRAS codons 12, 13 and 61 mutational status was analyzed in KRAS/BRAF wt patients. We collected pathological and clinical features in the overall population and outcome data in a subset of NRAS mutated chemo-refractory patients treated with anti-EGFR MoAbs in advanced lines. NRAS was mutated in 47/786 (6%) mCRCs. NRAS and KRAS mutated tumors did not show significant differences in terms of clinical and pathological characteristics, except for a lower prevalence of mucinous histology (p = 0.012) and lung metastases (p = 0.012) among NRAS mutated tumors. In the uni- and multivariate model, NRAS mutations were associated with shorter overall survival (OS) compared to all wt patients (median OS 25.6 vs 42.7 months; univ: HR = 1.91, 95% CI 1.39-3.86, p = 0.0013; multiv: HR = 1.75, 95% CI 1.1.3-2.72, p = 0.013). None of the chemo-refractory NRAS mutated patients evaluable for response to anti-EGFRs achieved response. In conclusion, NRAS mutations have a relevant incidence in patients with mCRC and showed an association with specific clinical and pathological features. NRAS mutations affect mCRC patients' prognosis and predict lack of response to anti-EGFRs., (© 2014 UICC.)

A chemical genetics approach has been applied in the screening of yeast deletants strains with a pool of morpholine-derived compounds in order to identify candidate small molecules able to produce phenotypic effects on yeast cells. The analysis of the effects of structurally diverse molecules towards cell growth rate in both exponential and stationary phases provides a tool to select candidate compounds for subsequent assays to identify new chemical entities as chemical probes for drug discovery.

Transcription of the light strand of Xenopus laevis mitochondrial DNA initiates at two promoters located approximately 350 to 450 nucleotides upstream from the 5' ends of major D-loop DNA strands. Small RNAs within this region have been mapped by blot hybridization, primer extension and S1 nuclease protection methods. The results reveal that the large majority of RNAs within this region have 3' termini located at a sequence element, designated CSB 2, that is conserved in sequence and position in Xenopus, mouse, rat and human mtDNA. However, the X. laevis CSB 2 appears to be a site of RNA processing only, since RNA-to-DNA transitions are not detectable at this site. RNAs containing sequences downstream of CSB 2 are extremely rare. A significant fraction of these RNAs are processed by cleavage at a site just upstream of the most predominant 5' ends of D-loop DNAs. We suggest that RNA processing at this site may play a role in priming mtDNA replication.