What spelling errors can tell us about the development of processes involved in children’s spelling

Introduction: Spelling is an essential foundation for reading and writing. However, many children leave school with spelling difficulties. By understanding the processes children use when they spell, we can intervene with appropriate instruction tailored to their needs. Methods: Our study aimed to identify key processes (lexical-semantic and phonological) by using a spelling assessment that distinguishes different printed letter strings/word types (regular and irregular words, and pseudowords). Misspellings in the test from 641 pupils in Reception Year to Year 6 were scored using alternatives to binary correct versus incorrect scoring systems. The measures looked at phonological plausibility, phoneme representations and letter distance. These have been used successfully in the past but not with a spelling test that distinguishes irregularly spelled words from regular words and pseudowords. Results: The findings suggest that children in primary school rely on both lexical-semantic and phonological processes to spell all types of letter string, but this varies depending on the level of spelling experience (younger Foundation/Key stage 1 and older Key stage 2). Although children in younger year groups seemed to rely more on phonics, based on the strongest correlation coefficients for all word types, with further spelling experience, lexical processes seemed to be more evident, depending on the type of word examined. Discussion: The findings have implications for the way we teach and assess spelling and could prove to be valuable for educators

What spelling errors can tell us about the development of processes involved in children's spelling

Spelling is an essential foundation for reading and writing. However, many children leave school with spelling difficulties. By understanding the processes children use when they spell, we can intervene with appropriate instruction tailored to their needs. Our study aimed to identify key processes (lexical-semantic and phonological) by using a spelling assessment that distinguishes different printed letter strings/word types (regular and irregular words, and pseudowords). Misspellings in the test from 641 pupils in Reception Year to Year 6 were scored using alternatives to binary correct versus incorrect scoring systems. The measures looked at phonological plausibility, phoneme representations and letter distance. These have been used successfully in the past but not with a spelling test that distinguishes irregularly spelled words from regular words and pseudowords. The findings suggest that children in primary school rely on both lexical-semantic and phonological processes to spell all types of letter string, but this varies depending on the level of spelling experience (younger Foundation/Key stage 1 and older Key stage 2). Although children in younger year groups seemed to rely more on phonics, based on the strongest correlation coefficients for all word types, with further spelling experience, lexical processes seemed to be more evident, depending on the type of word examined. The findings have implications for the way we teach and assess spelling and could prove to be valuable for educators

Wig-1, a novel regulator of N-Myc mRNA and N-Myc-driven tumor growth

Wig-1 is a transcriptional target of the p53 tumor suppressor and encodes an mRNA stability-regulating protein. We show here that Wig-1 knockdown causes a dramatic inhibition of N-Myc expression and triggers differentiation in neuroblastoma cells carrying amplified N-Myc. Transient Wig-1 knockdown significantly delays development of N-Myc-driven tumors in mice. We also show that N-Myc expression is induced upon moderate p53-activating stress, suggesting a role of the p53-Wig-1-N-Myc axis in promoting cell cycle re-entry upon p53-induced cell cycle arrest and DNA repair. Moreover, our findings raise possibilities for the improved treatment of poor prognosis neuroblastomas that carry amplified N-Myc

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Bak Compensated for Bax in p53-null Cells to Release Cytochrome c for the Initiation of Mitochondrial Signaling during Withanolide D-Induced Apoptosis

The goal of cancer chemotherapy to induce multi-directional apoptosis as targeting a single pathway is unable to decrease all the downstream effect arises from crosstalk. Present study reports that Withanolide D (WithaD), a steroidal lactone isolated from Withania somnifera, induced cellular apoptosis in which mitochondria and p53 were intricately involved. In MOLT-3 and HCT116p53+/+ cells, WithaD induced crosstalk between intrinsic and extrinsic signaling through Bid, whereas in K562 and HCT116p53−/− cells, only intrinsic pathway was activated where Bid remain unaltered. WithaD showed pronounced activation of p53 in cancer cells. Moreover, lowered apoptogenic effect of HCT116p53−/− over HCT116p53+/+ established a strong correlation between WithaD-mediated apoptosis and p53. WithaD induced Bax and Bak upregulation in HCT116p53+/+, whereas increase only Bak expression in HCT116p53−/− cells, which was coordinated with augmented p53 expression. p53 inhibition substantially reduced Bax level and failed to inhibit Bak upregulation in HCT116p53+/+ cells confirming p53-dependent Bax and p53-independent Bak activation. Additionally, in HCT116p53+/+ cells, combined loss of Bax and Bak (HCT116Bax−Bak−) reduced WithaD-induced apoptosis and completely blocked cytochrome c release whereas single loss of Bax or Bak (HCT116Bax−Bak+/HCT116Bax+Bak−) was only marginally effective after WithaD treatment. In HCT116p53−/− cells, though Bax translocation to mitochondria was abrogated, Bak oligomerization helped the cells to release cytochrome c even before the disruption of mitochondrial membrane potential. WithaD also showed in vitro growth-inhibitory activity against an array of p53 wild type and null cancer cells and K562 xenograft in vivo. Taken together, WithaD elicited apoptosis in malignant cells through Bax/Bak dependent pathway in p53-wild type cells, whereas Bak compensated against loss of Bax in p53-null cells

N-Myc downstream-regulated gene 2 is involved in p53-mediated apoptosis

The tumor suppressor, p53, is a transcription factor which can modulate the transcription of a number of target genes that are involved in cell-cycle arrest and apoptosis. However, the apoptotic pathway mediated by p53 is not fully understood. Here, we showed that N-Myc downstream-regulated gene 2 (NDRG2) is a new target gene that is regulated by p53. NDRG2 mRNA and protein levels can be upregulated in a p53-dependent manner. The first intron of the NDRG2 gene contains a site that binds p53 directly and mediates wild-type p53-dependent transactivation. In addition, silencing of NDRG2 attenuates p53-mediated apoptosis, whereas overexpression of NDRG2 suppresses tumor cell growth, regardless of the presence or absence of p53. Our results indicate that NDRG2 is a novel p53-inducible target that is involved in the p53-mediated apoptosis pathway

Generation of Reactive Oxygen Species by Polyenylpyrroles Derivatives Causes DNA Damage Leading to G2/M Arrest and Apoptosis in Human Oral Squamous Cell Carcinoma Cells

10.1371/journal.pone.0067603PLoS ONE86-POLN

Differential modulatory effects of GSK-3β and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis) in melanoma

<p>Abstract</p> <p>Background</p> <p>GSK-3β phosphorylates numerous substrates that govern cell survival. It phosphorylates p53, for example, and induces its nuclear export, HDM2-dependent ubiquitination, and proteasomal degradation. GSK-3β can either enhance or inhibit programmed cell death, depending on the nature of the pro-apoptotic stimulus. We previously showed that the multikinase inhibitor sorafenib activated GSK-3β and that this activation attenuated the cytotoxic effects of the drug in various BRAF-mutant melanoma cell lines. In this report, we describe the results of studies exploring the effects of GSK-3β on the cytotoxicity and antitumor activity of sorafenib combined with the HDM2 antagonist MI-319.</p> <p>Results</p> <p>MI-319 alone increased p53 levels and p53-dependent gene expression in melanoma cells but did not induce programmed cell death. Its cytotoxicity, however, was augmented in some melanoma cell lines by the addition of sorafenib. In responsive cell lines, the MI-319/sorafenib combination induced the disappearance of p53 from the nucleus, the down modulation of Bcl-2 and Bcl-x_L, the translocation of p53 to the mitochondria and that of AIF to the nuclei. These events were all GSK-3β-dependent in that they were blocked with a GSK-3β shRNA and facilitated in otherwise unresponsive melanoma cell lines by the introduction of a constitutively active form of the kinase (GSK-3β-S9A). These modulatory effects of GSK-3β on the activities of the sorafenib/MI-319 combination were the exact reverse of its effects on the activities of sorafenib alone, which induced the down modulation of Bcl-2 and Bcl-x_Land the nuclear translocation of AIF only in cells in which GSK-3β activity was either down modulated or constitutively low. In A375 xenografts, the antitumor effects of sorafenib and MI-319 were additive and associated with the down modulation of Bcl-2 and Bcl-x_L, the nuclear translocation of AIF, and increased suppression of tumor angiogenesis.</p> <p>Conclusions</p> <p>Our data demonstrate a complex partnership between GSK-3β and HDM2 in the regulation of p53 function in the nucleus and mitochondria. The data suggest that the ability of sorafenib to activate GSK-3β and alter the intracellular distribution of p53 may be exploitable as an adjunct to agents that prevent the HDM2-dependent degradation of p53 in the treatment of melanoma.</p