Deficiencies were found in the management of sick children by CHWs, although care was not consistently poor. Key reasons for the deficiencies appear to be guideline complexity and inadequate clinical supervision; other possible causes are discussed.

Human WWOX gene encodes a proapoptotic WW domaincontaining oxidoreductase WOX1 (also named WWOX, FOR2 or WWOXv1). Apoptotic and stress stimuli activate WOX1 via Tyr33 phosphorylation and nuclear translocation. WOX1 possesses a tetrad NSYK motif in the Cterminal short-chain alcohol dehydrogenase/reductase (SDR) domain, which may bind estrogen and androgen. Here, we determined that 17b-estradiol (E 2 ) activated WOX1, p53 and ERK in COS7 fibroblasts, primary lung epithelial cells, and androgen receptor (AR)-negative prostate DU145 cells, but not in estrogen receptor (ER)-positive breast MCF7 cells. Androgen also activated WOX1 in the AR-negative DU145 cells. These observations suggest that sex hormone-mediated Tyr33 phosphorylation and nuclear translocation of WOX1 is independent of ER and AR. Stress stimuli increase physical binding of p53 with WOX1 in vivo. We determined here that E 2 increased the formation of p53/WOX1 complex and their nuclear translocation in COS7 cells; however, nuclear translocation of this complex could not occur in MCF7 cells. By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2). In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis. These Tyr33-phosphorylated proteins are mostly located in the mitochondria without translocating to the nuclei, which is comparable to those findings in cultured breast cancer cells. Together, sex steroid hormone-induced activation of WOX1 and WOX2 is independent of ER and AR, and this activation positively correlates with cancerous progression of prostate and breast to a premetastatic state.

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Huntington's disease (HD) is one of eight established triplet repeat neurodegenerative disorders, which are collectively caused by the genetic expansion of polyglutamine repeats. While the mechanism(s) by which polyglutamine expansion causes neurodegeneration in each of these disorders is being intensely investigated, the underlying cause of polyglutamine toxicity has not been fully elucidated. A number of studies have focused on the potential role of protein aggregation and disruption of the proteasome proteolytic pathway in polyglutamine-mediated neurodegeneration. However, at present it is not clear whether polyglutamine-mediated protein aggregation is sufficient to induce cell death, nor has it been clearly determined whether proteasome inhibition precedes, coincides, or occurs as the result of the formation of polyglutamine-associated protein aggregation. To address these important components of polyglutamine toxicity, in the present study we utilized neural SH-SY5Y cells stably transfected with polyglutamine-green fluorescent protein constructs to examine the effects of polyglutamine expansion on protein aggregation, proteasome activity, and neural cell survival. Data from the present study demonstrate that polyglutamine expansion does not dramatically impair proteasome activity or elevate protein aggregate formation under basal conditions, but does significantly impair the ability of the proteasome to respond to stress, and increases stress-induced protein aggregation following stress, all in the absence of neural cell death.

Embryo growth is inversely correlated with hyperosmolar stress-induced stress-activated protein kinase/jun kinase (SAPK/JNK) induction. To examine whether stress has similar effects in stem cells derived from the embryo, the authors test trophoblast stem cells. The stress response of human placental and mouse trophoblast stem cell lines are tested here. Peak phosphorylated SAPK/JNK was induced by 400 mM sorbitol at 0.5 hours. At this dose, there is an SAPK/JNK-dependent decrease in mitogenic, phosphorylated cMyc at 0.5 hours preceding an SAPK/JNK-dependent decrease in cell cycle entrance at 24 hours. At 0.5 hours, SAPK/JNK decreases terminal deoxynucleotidyltransferase dUTP nick end labeling/apoptosis at sorbitol doses from 50 mM to 400 mM and induces phosphorylated cJun prior to an SAPK/JNK-dependent, approximate 8-fold increase in apoptosis by 24 hours at 400 mM. SAPK/JNK phosphorylation peaked at 0.5 to 4 hours and largely subsided by 12 hours. Thus, total SAPK/JNK exists before stress and mediates rapid, homeostatic molecular responses that become biologic consequences after phosphorylated SAPK/JNK ends. This suggests continuity in the homeostatic mechanisms and functions of SAPK/JNK in placental lineage cells during implantation, in which SAPK/JNK is completely responsible for cell cycle arrest and largely responsible for apoptosis.

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