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Objective Previous studies have reported elevated levels of interleukin-1 (IL-1) and oncostatin M (OSM) in rheumatoid joints, as well as the synergistic degradation of human articular cartilage by this cytokine combination. The present study was undertaken to investigate the ability of IL-1 and OSM to modulate gene expression of matrix metalloproteinase (MMP), ADAM, and ADAM-TS (ADAM with thrombospondin motifs) family members in human chondrocytes. Methods T/C28a4 human chondrocytes were stimulated for 2–48 hours with IL-1 and/or OSM. Total RNA was harvested, reverse transcribed, and assessed by real-time polymerase chain reaction for the expression of various MMP, ADAM, and ADAM-TS messenger RNAs (mRNA). Results were normalized to 18S ribosomal RNA. Results IL-1 and OSM synergized to markedly induce the expression of the collagenases MMP-1, MMP-8, and MMP-13 as well as MMP-3, an activator of proMMPs. Expression of mRNA for MMPs 1, 3, and 13 was induced early, whereas that of MMP-8 mRNA occurred late. Gene expression of MMP-14, an MMP that degrades collagen and activates proMMP-13, was elevated by this combination. IL-1 and OSM also synergized to induce gene expression of the aggrecanase ADAM-TS4, but not ADAM-TS5. Conclusion These data indicate that the potent cartilage-degrading properties of the combination of IL-1 and OSM are potentially mediated by a synergistic induction of the aggrecan-degrading enzyme ADAM-TS4 and the collagen-degrading enzymes MMP-1, MMP-8, MMP-13, and MMP-14, although differences in the magnitude of response and in the time course of induction were observed. A role for MMPs 3 and 14 in the activation of proMMPs may also be implicated.

L'auteur adresse ici quelques reflexions sur les modalites d'integration des NTIC a l'enseignement de la culture et de la litterature et sur le manque de recherche sur ce sujet et pose trois questions : comment la technologie peut-elle apporter un plus a l'enseignement de ces matieres ? Comment la technologie affecte les relations entre la discipline enseignee et les methodes pedagogiques ? Et quels changements vont s'operer entre les differentes disciplines.

The spontaneous recoding of visual stimuli into a phonological code to aid short-term retention has been associated with progress in learning to read (Palmer, 2000b).This study examined whether there was a comparable association with the development of writing skills.One hundred eight children (64 males) in the second year of the UK educational system (mean age 5:8 years, SD = 4 months) were recruited to the study.The children participated in tasks to assess their general cognitive abilities, reading skills, and their predominant short-term memory (STM) strategy for retaining visually presented stimuli. On the basis of their memory profile, children were classified as either engaging in verbal recoding of the stimuli (N = 31) or not (N = 77). Writing performance was indexed as alphabet transcription, spelling, and early text production skills.Children classified as verbal recoders demonstrated better spelling performance and produced more individual letters, words, and T-units in their texts than did children who persisted with a visual memory strategy. In contrast, the alphabet transcription abilities of the groups did not differ. Hierarchical regression analyses revealed that variance in text production skills was associated with STM capacity and that moreover, significant independent variance in the number of words and T-units in the children's texts was predicted by individual differences in verbal recoding abilities.The results suggest that the development of verbal recoding skills in STM may play a role in children's early progress in writing, particularly their text generation skills.

A case of acute myelogenous leukemia (AML) French-American-British (FAB)-type M5b is described, secondary to myelodysplastic syndrome (MDS), in which a primary clone containing a dup (1)(p22p36) and a subclone containing dup(1)(p22p36), dup(1)(p22p36), were identified. This is believed to be a novel mutation in AML.

Radiation therapy (RT) plays a critical role in the local-regional control of head and neck squamous cell carcinoma (HNSCC). However, the efficacy of RT in treating HNSCC is limited by severe normal tissue toxicity, predominantly mucositis. One pharmacological approach for increasing the clinical response to RT is the use of radiation response modifiers that preferentially sensitize tumor cells. Previously we demonstrated that curcumin, a natural plant polyphenol, increased the radiation sensitivity of HNSCC cells and that the observed sensitization was dependent on curcumin-mediated inhibition of thioredoxin reductase 1 (TxnRd1) a key cytosolic regulator of redox-dependent signaling. Here, we examined curcumin-induced radiation sensitization in HNSCC cell lines with differing HPV status and expressing different levels of TxnRd1, in vitro. The intrinsic radiation resistance of the HPV (-) cell lines was significantly higher than the HPV (+) cell lines used in our study. Notably, all of the HPV (-) cell lines expressed high levels of TxnRd1 and exhibited higher intrinsic resistance to RT. While curcumin was effective at increasing the radiation response of the resistant HPV (-) cell lines it had no effect on the HPV (+) cells. Based on these findings we employed an orthotopic, HPV (-) HNSCC tumor model in athymic nude mice to examine the effect of combining curcumin with fractionated RT, in vivo. The combination of curcumin feeding and fractionated RT had a significant effect on tumor doubling time and overall animal survival. We therefore propose that curcumin and RT should be considered as a first line treatment of HPV (-) HNSCC.

© 2009 American Society for Investigative Pathology. The full and final published article is available at the link below. This article has been made available through the Brunel Open Access Publishing Fund. Brk, a tyrosine kinase expressed in a majority of breast tumors, but not normal mammary tissue, promotes breast carcinoma cell proliferation. Normal epithelial cells are dependent on cell–cell or cell–matrix interactions for survival and undergo apoptosis after disruption of these interactions. Tumor cells are less sensitive to the induction of apoptosis and are predicted to have the potential to disseminate. We investigated whether Brk has further roles in breast tumor progression by relating its expression to tumor grade and demonstrating its role in the regulation of carcinoma cell survival under non-adherent conditions. Brk expression was determined by reverse transcription PCR on RNA extracted from surgical samples of human breast cancers. Breast carcinoma cell survival in suspension culture was examined when Brk protein levels were suppressed by RNA interference. Additionally, the effect of experimentally overexpressing Brk in otherwise Brk-negative breast carcinoma cells was assessed. Brk mRNA expression was notably higher in grade 3 breast tumors, as compared with lower tumor grades. In suspension culture, Brk suppression increased the rate of cell death, as compared with controls, and this cell death program exhibited characteristics of autophagy but not of apoptosis. Conversely, experimental expression of Brk in Brk-negative cells increased cell survival whereas kinase-inactive Brk did not. Therefore, Brk enhances breast carcinoma cell survival in suspension, suggesting a role for Brk in supporting breast cancer cell dissemination. Brunel Open Access Publishing Fund

The ADAMTSs (adisintegrin and metalloproteinase with thrombospondin motifs) are a group of proteases that are found both in mammals and invertebrates. Since the prototype ADAMTS-1 was first described in 1997, there has been a rapidly expanding body of literature describing this gene family and the proteins they encode. The complete human family has 19 ADAMTS genes, together with three members of a newly identified subgroup, the ADAMTSL (ADAMTS-like) proteins, which have several domains in common with the ADAMTSs. The ADAMTSs are extracellular, multidomain enzymes whose known functions include: (i) collagen processing as procollagen N-proteinase; (ii) cleavage of the matrix proteoglycans aggrecan, versican and brevican; (iii) inhibition of angiogenesis; and (iv) blood coagulation homoeostasis as the von Willebrand factor cleaving protease. Roles in organogenesis, inflammation and fertility are also apparent. Recently, some ADAMTS genes have been found to show altered expression in arthritis and various cancers. This review highlights progress in understanding the structural organization and functional roles of the ADAMTSs in normal and pathological conditions.

The adamalysin-thrombospondin (ADAMTS) proteinases are a relatively newly described branch of the metzincin family that contain metalloproteinase, disintegrin, and thrombospondin motifs. They have been implicated in various cellular events, including cleavage of proteoglycans, extracellular matrix degradation, inhibition of angiogenesis, gonadal development, and organogenesis. However, in many cases, their normal physiological roles and their potential for dysregulation in malignancy remain to be established. The expression profile of ADAMTS1–20 in human breast carcinoma was undertaken by real-time PCR using RNA isolated from malignant tumors, nonneoplastic mammary tissue, and breast cancer cell lines to identify altered regulation that may have potential pathogenetic and prognostic significance. Our studies show that seven of the ADAMTS genes (ADAMTS1, 3, 5, 8, 9, 10, and 18) are consistently down-regulated in breast carcinomas with respect to nonneoplastic mammary tissue, irrespective of the heterogeneity of the samples and the tumor type or grade (Mann-Whitney U test, P < 0.0001 for each gene). Conversely, ADAMTS4, 6, 14, and 20 are consistently up-regulated in breast carcinomas (P = 0.005, P < 0.0001, P = 0.003, and P = 0.001, respectively). ADAMTS2, 7, 12, 13, 15, 16, 17, and 19 show no significant difference between the sample types. ADAMTS1, 2, 7, 8, 10, and 12 are expressed predominantly in stromal fibroblasts. ADAMTS3, 4, 5, 6, 9, and 13–20 inclusive are expressed predominantly in myoepithelial cells; all appear to be relatively poorly expressed in luminal epithelial cells. ADAMTS15 has emerged as being an independent predictor of survival, with RNA expression levels significantly lower (P = 0.007) in grade 3 breast carcinoma compared with grade 1 and 2 breast carcinoma.

A case of three discordant cell lines in prenatal diagnosis is described, of which two were abnormal related structural abnormalities of chromosome 11. One of the abnormal cell lines was seen in all metaphases examined from direct preparations of chorionic villi, the cultured preparations showing an apparently normal male karyotype; the other abnormal cell line was seen in conjunction with a normal cell line in cultured amniocytes. Prenatal diagnosis offered solely on chorionic villus sampling would have yielded a mistakenly normal result on the basis of established criteria for distinguishing true mosaicism from confined placental mosaicism.

Objective To profile the expression of all known members of the matrix metalloproteinase (MMP), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and tissue inhibitor of metalloproteinases (TIMPs) gene families in normal cartilage and that from patients with osteoarthritis (OA). Methods Human cartilage was obtained from femoral heads at joint replacement for either osteoarthritis or following fracture to the neck of femur. Total RNA was purified and expression of genes assayed using quantitative real-time PCR. Results Several members of the above gene families were regulated in OA. Genes increasing in expression in OA were: at P

Data of this kind may occur when k laboratories make separate determinations xi of the same physical or chemical quantity, each with an estimated standard error, or when a summary is being made of the results of k replicated experiments, in each of which the difference xi between a specified pair of treatments has been observed. In practices it cannot be taken for granted that the observations xi are all estimate, of the same mean a, because personal biases or local conditions of experimentation may render this assumption false. The discussion in this paper is confined to situations in which the assumption holds.