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Epithelial–mesenchymal transition (EMT) is an essential step for tumor progression, although the mechanisms driving EMT are still not fully understood. In an effort to investigate these mechanisms, we observed that heregulin (HRG)-mediated activation of HER2, or HER2 overexpression, resulted in EMT, which is accompanied with increased expression of a known EMT regulator Slug, but not TWIST or Snail. We then investigated how HER2 induced Slug expression and found, for the first time, that there are four consensus HSF sequence-binding elements (HSEs), the binding sites for heat shock factor-1 (HSF-1), located in the Slug promoter. HSF-1 bound to and transactivated the Slug promoter independent of heat shock, leading to Slug expression in breast cancer cells. Mutation of the putative HSEs ablated Slug transcriptional activation induced by HRG or HSF-1 overexpression. Knockdown of HSF-1 expression by siRNA reduced Slug expression and HRG-induced EMT. The positive association between HSF-1 and Slug was confirmed by immunohistochemical staining of a cohort of 100 invasive breast carcinoma specimens. While investigating how HER2 activated HSF-1 independent of heat shock, we observed that HER2 activation resulted in concurrent phosphorylation of Akt and HSF-1. We then observed, also for the first time, that Akt directly interacted with HSF-1 and phosphorylated HSF-1 at S326. Inhibition of Akt using siRNA, dominant-negative Akt mutant, or small molecule inhibitors prevented HRG-induced HSF-1 activation and Slug expression. Conversely, constitutively active Akt induced HSF-1 phosphorylation and Slug expression. HSF-1 knockdown reduced the ability of Akt to induce Slug expression, indicating an essential role that HSF-1 plays in Akt-induced Slug upregulation. Altogether, our study uncovered the existence of a novel Akt-HSF-1 signaling axis that leads to Slug upregulation and EMT, and potentially contributes to progression of HER2-positive breast cancer.

ADL 8-2698 is an investigational opioid antagonist that seems not to reverse the analgesic effects of opiates. Ileus, a transient impairment of bowel motility, is a common postoperative complication that develops in virtually every patient who undergoes major abdominal surgery. 1 Ileus causes abdominal discomfort, nausea, and vomiting. More important, delayed return of gastrointestinal function and resumption of oral intake are major causes of prolonged hospitalization. 2 The pathophysiology of postoperative ileus is unclear, and there are no specific pharmacologic treatments. 1 – 4 Major causes of ileus are surgical manipulation of the bowel and stimulation of opioid receptors. 5 Activation of opioid receptors is common after surgery, not only because the stress of surgery provokes the release of endogenous opioids but . . .

We evaluated the effects of the levo ( l ) enantiomer of amphetamine sulfate on cognitive function in multiple sclerosis (MS) patients. Using a counterbalanced within-subjects design, 19 MS patients received four single-dose administrations of placebo, 15mg, 30mg, or 45 mg of l -amphetamine. Neuropsychological tests measuring processing speed and memory served as the primary outcomes. Performance on tests of processing speed were improved following the 45 mg condition and the largest effects were observed on the Symbol Digit Modalities Test, which measures visual processing speed and working memory. While episodic memory test effects were in the expected direction, the findings were not statistically significant. These preliminary findings show promise for the use of l -amphetamine for the symptomatic treatment of slowed mental processing in MS. Further placebo-controlled trials are needed to confirm these findings.

The aim of the study is to evaluate the test-retest reliability of measures of isokinetic and isometric leg strength and joint function among individuals exhibiting symptoms of mild osteoarthritis. Reliable procedures are needed to assess the effectiveness of an intervention on osteoarthritic symptoms. Test-retest reliability of two leg strength protocols was assessed using the intraclass correlation coefficient (R). Testing was completed on two occasions separated by 7 days. Eighteen subjects (9 male and 9 female; 54.1+/-11 years) completed an isokinetic testing trial, which consisted of a set of 5 maximal repetitions of the quadriceps and hamstrings at 60 deg/s followed by a set of 15 maximal contractions at 180 deg/s with a 2-min rest between sets and an isometric testing trial, which consist of 3 maximal contractions of the quadriceps for 6 s with a 30-s rest between contractions at 30, 45, and 80 degrees of knee flexion for a total of 9 isometric contractions. A 90-s rest occurred between angles. Most of the isokinetic variables showed moderate to high intraclass reliability (ICC). Two of the calculated isokinetic variables (work fatigue at 180 degrees /s for extension and for flexion) showed low intraclass reliability (ICC=0.78, resp. ICC=0.6). All calculated ICC values of the isometric variables were moderate to high. Test-retest reliability of isokinetic and isometric leg strength was high, allowing the intervention protocol to monitor changes in leg strength and joint function among those exhibiting symptoms of mild osteoarthritis.

Surveillance data indicate that handling of food by an ill worker is a cause of almost half of all restaurant-related outbreaks. The U.S. Food and Drug Administration (FDA) Food Code contains recommendations for food service establishments, including restaurants, aimed at reducing the frequency with which food workers work while ill. However, few data exist on the extent to which restaurants have implemented FDA recommendations. The Centers for Disease Control and Prevention's Environmental Health Specialists Network (EHS-Net) conducted a study on the topic of ill food workers in restaurants. We interviewed restaurant managers (n = 426) in nine EHS-Net sites. We found that many restaurant policies concerning ill food workers do not follow FDA recommendations. For example, one-third of the restaurants' policies did not specifically address the circumstances under which ill food workers should be excluded from work (i.e., not be allowed to work). We also found that, in many restaurants, managers are not actively involved in decisions about whether ill food workers should work. Additionally, almost 70% of managers said they had worked while ill; 10% said they had worked while having nausea or \"stomach flu,\" possible symptoms of foodbome illness. When asked why they had worked when ill, a third of the managers said they felt obligated to work or their strong work ethic compelled them to work. Other reasons cited were that the restaurant was understaffed or no one was available to replace them (26%), they felt that their symptoms were mild or not contagious (19%), they had special managerial responsibilities that no one else could fulfill (11%), there was non-food handling work they could do (7%), and they would not get paid if they did not work or the restaurant had no sick leave policy (5%). Data from this study can inform future research and help policy makers target interventions designed to reduce the frequency with which food workers work while ill.

Spongy textures are observed in anhydrous Group 1 mantle xenoliths (harzburgite, lherzolite and wehrlite) hosted in Tertiary alkali basaltic lavas from the Hessian Depression, Germany. These textures are developed only on clinopyroxene and spinel, and occur as rims or cross-cutting veinlets and patches showing optical continuity with the host grain. They are often associated with pools of amorphous glassy material. There is no preferential development of spongy domains against the xenolith-lava contact suggesting that the host magma did not play any significant role in their formation. Spongy clinopyroxene and spinel occur in all rock types, but, are more pervasive in wehrlite. Chemically, spongy domains of clinopyroxene and spinel are more refractory than unaffected areas, which is consistent with their formation through a partial melting event. The associated glassy material shows chemical characteristics which suggest that the melt pools are genetically related to the development of the spongy textures. The partial melting event was probably triggered by the infiltration of a low-density fluid. The fluid may have evolved from a silicate melt responsible for the metasomatic Fe-enrichment recorded in wehrlite. In this context, the more pervasive development of spongy clinopyroxene in wehrlite may be explained by a higher concentration of the evolved fluid phase at proximity to its silicate melt source. [PUBLICATION ABSTRACT]

A World Weather Research Programme (WWRP) project entitled the Science of Nowcasting Olympic Weather for Vancouver 2010 (SNOW-V10) was developed to be associated with the Vancouver 2010 Olympic and Paralympic Winter Games conducted between 12 February and 21 March 2010. The SNOW-V10 international team augmented the instrumentation associated with the Winter Games and several new numerical weather forecasting and nowcasting models were added. Both the additional observational and model data were available to the forecasters in real time. This was an excellent opportunity to demonstrate existing capability in nowcasting and to develop better techniques for short term (0–6 h) nowcasts of winter weather in complex terrain. Better techniques to forecast visibility, low cloud, wind gusts, precipitation rate and type were evaluated. The weather during the games was exceptionally variable with many periods of low visibility, low ceilings and precipitation in the form of both snow and rain. The data collected should improve our understanding of many physical phenomena such as the diabatic effects due to melting snow, wind flow around and over terrain, diurnal flow reversal in valleys associated with daytime heating, and precipitation reductions and increases due to local terrain. Many studies related to these phenomena are described in the Special Issue on SNOW-V10 for which this paper was written. Numerical weather prediction and nowcast models have been evaluated against the unique observational data set now available. It is anticipated that the data set and the knowledge learned as a result of SNOW-V10 will become a resource for other World Meteorological Organization member states who are interested in improving forecasts of winter weather.

Cytokines can initiate and perpetuate human diseases, and are among the best-validated of therapeutic targets. Cytokines can be blocked by the use of soluble receptors; however, the use of this approach for cytokines such as interleukin (IL)-1, IL-4, IL-6 and IL-13 that use multi-component receptor systems is limited because monomeric soluble receptors generally exhibit low affinity or function as agonists. We describe here a generally applicable method to create very high-affinity blockers called 'cytokine traps' consisting of fusions between the constant region of IgG and the extracellular domains of two distinct cytokine receptor components involved in binding the cytokine. Traps potently block cytokines in vitro and in vivo and represent a substantial advance in creating novel therapeutic candidates for cytokine-driven diseases.

Leptin is an adipocyte-derived cytokine that regulates food intake and body weight via interaction with its Ob receptor (ObR). Serum leptin levels are chronically elevated in obese humans, suggesting that obesity may be associated with leptin resistance and the inability to generate an adequate ObR response. Evidence suggests that transcriptional activation of target genes by STAT3 (signal transducer and activator of transcription) in the hypothalamus is a critical pathway that mediates leptin's action. Herein we report that activation of ObR induces the tyrosine phosphorylation of the tyrosine phosphatase SH2-containing phosphatase 2 (SHP-2) and demonstrate that Tyr986 within the ObR cytoplasmic domain is essential to mediate phosphorylation of SHP-2 and binding of SHP-2 to ObR. Surprisingly, mutation of Tyr986 to Phe, which abrogates SHP-2 phosphorylatlon and binding to the receptor, dramatically increases gene induction mediated by STAT3. Our findings indicate that SHP-2 is a negative regulator of STAT3-mediated gene induction after activation of ObR and raise the possibility that blocking the interaction of SHP-2 with ObR could overcome leptin resistance by boosting leptin's weight-reducing effects in obese individuals

Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of arbaclofen suggested similar benefits in ASD. We therefore evaluated arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5-21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.