BackgroundThe issue of whether patients diagnosed with metastatic colorectal cancer who harbor KRAS codon 13 mutations could benefit from the addition of anti-epidermal growth factor receptor therapy remains under debate. The aim of the current study was to perform computational analysis to investigate the structural implications of the underlying mutations caused by c.38G>A (p.G13D) on protein conformation.MethodsMolecular dynamics (MD) simulations were performed to understand the plausible structural and dynamical implications caused by c.35G>A (p.G12D) and c.38G>A (p.G13D). The potential of mean force (PMF) simulations were carried out to determine the free energy profiles of the binding processes of GTP interacting with wild-type (WT) KRAS and its mutants (MT).ResultsUsing MD simulations, we observed that the root mean square deviation (RMSD) increased as a function of time for the MT c.35G>A (p.G12D) and MT c.38G>A (p.G13D) when compared with the WT. We also observed that the GTP-binding pocket in the c.35G>A (p.G12D) mutant is more open than that of the WT and the c.38G>A (p.G13D) proteins. Intriguingly, the analysis of atomic fluctuations and free energy profiles revealed that the mutation of c.35G>A (p.G12D) may induce additional fluctuations in the sensitive sites (P-loop, switch I and II regions). Such fluctuations may promote instability in these protein regions and hamper GTP binding.ConclusionsTaken together with the results obtained from MD and PMF simulations, the present findings implicate fluctuations at the sensitive sites (P-loop, switch I and II regions). Our findings revealed that KRAS mutations in codon 13 have similar behavior as KRAS WT. To gain a better insight into why patients with metastatic colorectal cancer (mCRC) and the KRAS c.38G>A (p.G13D) mutation appear to benefit from anti-EGFR therapy, the role of the KRAS c.38G>A (p.G13D) mutation in mCRC needs to be further investigated.

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To evaluate the KRAS, BRAF, EGFR, and HER2 gene status in colorectal cancer by novel techniques and evaluate whether anti-HER2 therapies could be offered in the treatment of these patients. There are conflicting data on the prevalence of BRAF mutations and EGFR and HER2 gene amplification in colorectal KRAS wild type patients. In our study we tried to evaluate these expressions and their relationship to future treatment assays. Clinical-pathological data and paraffin-embedded specimens were collected from 186 patients who underwent colorectal resections at General Yagüe Hospital in Burgos, Spain. KRAS and BRAF status was analyzed by real-time PCR in all patients. EGFR and HER2/NEU gene amplification was detected using fluorescent in situ hybridisation technique (FISH) in 38 KRAS and BRAF wild type patients. KRAS mutations were present in 48% of the colorectal cancer patients. BRAF mutations were present in 6.25% of the KRAS wild type patients. EGFR and HER2 gene amplification was observed in 5.3% and 26.3%, respectively, of KRAS and BRAF wild type colorectal cancer patients. HER2, but not EGFR gene amplification, was frequently observed in KRAS and BRAF wild type colorectal cancer patients. These data indicate that HER2 amplification could be one of the genes to be considered in the therapeutic management of colorectal cancer.

This study was designed to assess whether the effects of computer-assisted practice on visual word recognition differed for children with reading disabilities (RD) with or without aptitude-achievement discrepancy. A sample of 73 Spanish children with low reading performance was selected using the discrepancy method, based on a standard score comparison (i.e., the difference between IQ and achievement standard scores). The sample was classified into three groups: (1) a group of 14 children with dyslexia (age M = 103.85 months; SD = 8.45) who received computer-based reading practice; (2) a group of 31 "garden-variety" (GV) poor readers (age M = 107.06 months; SD = 6.75) who received the same type of instruction; and (3) a group of 28 children with low reading performance (age M = 103.33 months; SD = 9.04) who did not receive computer-assisted practice. Children were pre- and posttested in word recognition, reading comprehension, phonological awareness, and visual and phonological tasks. The results indicated that both computer-assisted intervention groups showed improved word recognition compared to the control group. Nevertheless, children with dyslexia had more difficulties than GV poor readers during computer-based word reading under conditions that required extensive phonological computation, because their performance was more affected by low-frequency words and long words. In conclusion, we did not find empirical evidence in favor of the IQ-achievement discrepancy definition of reading disability, because IQ did not differentially predict treatment outcomes.

The primary purpose of the study reported here was to explore the effects of the complexity of syllable structure and the effects of task differences in the explanation of deficit in phonological awareness (PA). A sample of 97 subjects was selected and organized into three different groups: 29 readingdisabled (RD) children, 41 normal readers matched in age with the former, and 27 younger normal readers at the same reading level as those with reading disabilities. We administered PA tasks which included items with different complexity of syllable structure. The results showed that the complexity of syllable structure had no particularly marked effect on the dyslexic children. Rather, the isolation task revealed the phonological deficit across all syllable structures.