\n\nConclusion-Activation of the EP3 receptor raises baseline blood pressure and contributes to Ang II dependent hypertension a least partially via enhancing Ca2+ sensitivity and 432 intracellular calcium concentration in vascular smooth muscle cells. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension. (Arterioscler Thromb Vasc Biol. 2012;32:3024-3032.)”
“SPIN90 is a key regulator of actin cytoskeletal organization. Using the BioGRID(beta) database (General Repository for Interaction Datasets), we identified IRSp53 as a binding partner of SPIN90, and confirmed the in vivo formation of a SPIN90-IRSp53 complex

mediated through direct association of the proline-rich domain (PRD) of

SPIN90 with the SH3 domain of IRSp53. SPIN90 and IRSp53 positively cooperated to mediate Rac ERK inhibitor ic50 activation, PXD101 and co-expression of SPIN90 and IRSp53 in COS-7 cells led to the complex formation of SPIN90-IRSp53 in the leading edge of cells. PDGF treatment induced strong colocalization of SPIN90 and IRSp53 at membrane protrusions. Within such PDGF-induced protrusions, knockdown of SPIN90 protein using siRNA significantly reduced lamellipodia-like protrusions as well as localization of IRSp53 at those sites. Finally, competitive inhibition of SPIN90-IRSp53 binding by SPIN90 PRD dramatically reduced ruffle formation, further suggesting that SPIN90 plays a key role in the formation of the membrane protrusions associated with cell motility. (C) 2009 Elsevier Inc. All rights reserved.”
“Most centres in Europe have not introduced

a rapid response team (RRT), partly because of concerns that data from other health-care systems may not be relevant. We tested whether patient characteristics and outcomes for deteriorating patients differ between two health-care systems separated by distance and culture.\n\nWe obtained data from 3,063 RRT calls: 815 calls at Karolinska University Hospital (Sweden) and Evofosfamide 2,248 calls at Austin Hospital (Australia) and compared demographic and clinical data, as well as outcomes for patients reviewed by a RRT.\n\nAt Karolinska, 46.9% of patients were female compared with 45.1% at Austin. Mean age was 66.5 years versus 69.4 years. The unit of admission was surgical/medical in 49.1%/50.9% versus 48.8%/51.1% of patients, respectively. Overall, 56.7% versus 55.8% of the calls were out-of-hours (1700-0800 hours). There was a predominance of respiratory triggers at both centres and the “worried” criterion was frequently used in both hospitals (17.2% versus 14.4%) as a trigger for RRT activation. Overall, 30-day mortality was 27.7% versus 29.4% and allocation of Limitations of Medical Treatment (LOMT) orders was 34.2% versus 30.8%. The allocation of LOMT orders was influenced by the RRT in 14.4% versus 12.6% of cases.

In contrast, PTN was found to be downregulated in injured DRG of SD rats, the most sensitive strain in behavioural studies. These changes in PTN were not paralleled by concomitant modifications of MK gene expression. The 3 results demonstrate previously unidentified differences between PTN and MK patterns of expression. Furthermore, the data suggest that upregulation of PTN, but not MK, could play an important role in the recovery from CCI.”
“There are increasing reports of geminivirus mixed infections of field plant hosts. These mixed infections have been suggested to result in recombinations, emergence Autophagy inhibitor price of new viruses and new disease epidemics. We previously reported the

occurrence of mixed infection between African cassava mosaic virus (ACMV) and East African cassava mosaic Cameroon virus (EACMCV) resulting in severe symptoms in cassava fields AZD1208 supplier in Cameroon.

Here, we show that reassortment of DNA-A and DNA-B components of ACMV and EACMCV does not form viable recombinants. However, in the presence of both components of either virus, the DNA-A component of the other virus replicated and spread in the absence of its DNA-B component. This result suggests that failure of ACMV and EACMCV to form viable recombinants is due to the inability of each DNA-A component to trans-replicate the heterologous DNA-B component. This study also shows that ACMV DNA-A induces a resistance to ACMV and EACMCV as indicated by absence or late symptom development. Moreover, this resistance enabled plants to recover from severe symptoms caused by EACMCV in Nicotiana benthamiana, suggesting that the resistance induced is not specific to ACMV and is consistent with the phenomenon of cross-protection between related viruses. (C) 2011 Elsevier B.V. All rights reserved.”
“Adiponectin is a protein hormone secreted entirely by abdominal fat tissue. It exhibits various biological activities. The present study was performed to evaluate the effects of metformin

alone or in combination with adiponectin MCC950 Immunology & Inflammation inhibitor on blood glucose, TG (triglyceride), CHOL (Total cholesterol), LDL (Low density lipoprotein) and HDL (High density lipoprotein) levels in mice and also to evaluate the anti-ulcerogenic activity of adiponectin against ethanol induced gastric mucosal injury in rats. Three groups of mice were gavaged with 1% volume/body weight high fat-sucrose. Metformin at a dosage of 250 mg/kg was added to the feed and a dosage of 2.5 mg/kg adiponectin was injected intraperitoneally (i.p). Blood glucose was measured at one hour intervals for five hours. Blood concentrations of TG, CHOL, LDL and HDL were also measured at the end of the fifth hour of the experiment. On the other hand, four groups of adult healthy rats were i.p. injected with distilled water, omeprazole 20 mg/kg, 2.

It is an important cause of acute-on-chronic liver failure in endemic areas. Chronic HEV infection and progressive disease has been reported in recipients of solid organ transplants, haematological malignancies, HIV patients and those on haemodialysis. Clearance of HEV may occur after reducing immunosuppressive therapy, especially those targeting T-cells, in about one third of cases. Antiviral therapy should be considered

for patients for whom immunosuppressive therapy 3 cannot be reduced and for those who do not achieve viral clearance after reducing immunosuppression. For the patients with severe infection, fulminant hepatic failure and acute-on-chronic infection, ribavirin monotherapy should be considered to expedite the viral clearance and recovery. Although ribavirin therapy is contraindicated in pregnancy owing

to teratogenicity, the risks of untreated HEV AZD1208 to the mother and fetus are high and treatment may be offered. A twelve-week course of pegylated interferon, ribavirin or a combination of the two agents leads to viral clearance in about two-thirds of patients with chronic hepatitis E. Three-to twelve-month treatment with pegylated interferon clears virus in liver transplant recipients and patients on haemodialysis. In kidney and heart transplant patients where interferon may lead to organ rejection, ribavirin may be given.”
“Physiological click here responses to stress are controlled by expression of a large number of genes, many of which are regulated by microRNAs. Since most banana cultivars are salt-sensitive, improved understanding of genetic regulation of salt induced stress responses in banana can support future crop management and improvement Roscovitine cost in the face of increasing soil salinity related to irrigation and climate change. In this study we focused on determining miRNA

and their targets that respond to NaCl exposure and used transcriptome sequencing of RNA and small RNA from control and NaCl-treated banana roots to assemble a cultivar-specific reference transcriptome and identify orthologous and Musa-specific miRNA responding to salinity. We observed that, banana roots responded to salinity stress with changes in expression for a large number of genes (9.5% of 31,390 expressed unigenes) and reduction in levels of many miRNA, including several novel miRNA and banana-specific miRNA-target pairs. Banana roots expressed a unique set of orthologous and Musa-specific miRNAs of which 59 respond to salt stress in a dose-dependent manner. Gene expression patterns of miRNA compared with those of their predicted mRNA targets indicated that a majority of the differentially expressed miRNAs were down-regulated in response to increased salinity, allowing increased expression of targets involved in diverse biological processes including stress signaling, stress defence, transport, cellular homeostasis, metabolism and other stress-related functions.

Thus, chronic exposure of skin to UVB irradiation leads to histological changes consistent with aging, such as wrinkling, abnormal pigmentation, and loss of elasticity. We investigated the protective effect of the standardized green

tea seed extract (GSE) on UVB-induced skin photoaging in hairless mice. MATERIALS/METHODS: Skin photoaging was induced by UVB irradiation on the back of Skh-1 hairless mice three times per week and UVB irradiation was performed for 10 weeks. Mice were divided into six groups; normal control, UVB irradiated control group, positive control (UVB + dietary supplement of vitamin C 100 ZD1839 manufacturer mg/kg), GSE 10 mg/kg (UVB + dietary supplement of GSE 10 mg/kg), GSE 100 mg/kg (UVB + dietary supplement of GSE 100 mg/kg), and GSE 200 mg/kg (UVB + dietary supplement of GSE 200 mg/kg). RESULTS: The dietary supplement GSE attenuated UVB irradiation-induced wrinkle formation and the decrease in density of dermal collagen fiber. In addition, results of the antioxidant BIX 01294 nmr analysis showed that GSE induced a significant increase in antioxidant enzyme activity compared with the UVB irradiation control group. Dietary supplementation with GSE 200 mg/kg resulted in a significant decrease in expression of MMP-1, MMP-3, and MMP-9 and an increase in expression of TIMP and type-1 collagen.

CONCLUSIONS: Findings of this study suggest CHIR-99021 price that dietary supplement GSE could be useful in attenuation of UVB irradiation-induced skin photoaging and wrinkle formation due to regulation of antioxidant defense systems and MMPs expression.”
“123 Background and Purpose An immature vascular phenotype in diabetes mellitus may cause more severe vascular damage and poorer functional outcomes after stroke, and it would be feasible to repair damaged functional vessels using endothelial progenitor cell (EPC) transplantation. However, high glucose induces p38 mitogen-activated protein kinase activation, which can accelerate the senescence

and apoptosis of EPCs. The aim of this study was to investigate the combined effects of EPC transplantation and p38 mitogen-activated protein kinase inhibitor administration on diabetic stroke outcomes. Methods Bone marrow-derived EPCs were injected intra-arterially into db/db mice after ischemic stroke induction. RWJ 67657 (RWJ), a p38 mitogen-activated protein kinase inhibitor, was administered orally for 7 consecutive days, with the first dose given 30 minutes before stroke induction. Functional outcome was determined at days 0, 1, 7, 14, and 21. Angiogenesis, neurogenesis, infarct volume, and Western blotting assays were performed on day 7, and white matter remodeling was determined on day 14. Results Neither EPC transplantation nor RWJ administration alone significantly improved diabetic stroke outcome although RWJ displayed a potent anti-inflammatory effect.

Inevitably, due to increased survival and associated resource issues, opportunities for follow-up and support will be reduced. We delivered and evaluated an intervention which supported the transition from cancer patient to cancer survivor, for breast cancer patients being discharged to primary care. Methods: We delivered and evaluated a pilot of a patient-centred group intervention ‘Preparing Patients for Discharge’, aimed at reducing distress. Between January and September 2008,

172 participants were recruited and 74 (43%) expressed an interest in participating in the intervention; 32 of 74 took part, and participated in its evaluation using a semi-structured evaluation questionnaire, standardized measures [Hospital Anxiety NSC23766 supplier and Depression Scale (HADS) and Clinical Outcomes SCH727965 mouse for Routine Evaluation (CORE)] and independent qualitative interviews. Results: The qualitative analysis of questionnaire data indicated key 4 factors were 1) shared experience, 2) support and reassurance, and 3) positive views about cancer and being discharged. The interview data revealed that the intervention enabled participants to: share

experiences, focus on emotional needs, and have open discussions about recurrence, while increasing confidence in being discharged and using alternative support services. However, no significant differences were found in pre-post-interventions scores of HADS and CORE. Conclusions: Providing a structured group selleck intervention approach for breast cancer patients offers an early opportunity to support cancer survivors and facilitate and encourage self-management. (C) 2013 Elsevier Ltd. All rights reserved.”
“Background/Aims: Rapid hepatic recurrence is sometimes experienced after gastric or pancreatobiliary cancer surgery. The aim of this study was to investigate the risk factors for the timing of hepatic recurrence.\n\nMethodology: The medical records of 20 patients who had hepatic

recurrence after either a gastrectomy for gastric cancer (11 patients) or a pancreatoduodenectomy for pancreatobiliary cancer (9 patients) between 2002 and 2007 were retrospectively reviewed. The cumulative recurrence rate of liver metastasis was calculated using the Kaplan-Meier method, and 14 possible factors affecting the rapid hepatic recurrence were analyzed by univariate and multivariate analyses.\n\nResults: The median time for the hepatic recurrence after the operation was 4.9 months (range 1 to 20.4 months). Among 1.4 factors, only postoperative infectious complications significantly accelerated the hepatic recurrence based on a univariate analysis (p=0.049). Two more factors, gastric cancer and preoperative tumor marker elevation, had a tendency to affect the rapid recurrence, but did not show statistical significance (both p=0.06). A multivariate analysis revealed that postoperative infectious complications (p=0.005) and gastric cancer (p=0.04) were significant and independent factors.

“
“The lacrimal gland (LG) and superficial

gland of the third eyelid (SGTE) belong to accessory organs of the eye. The aim of the present studies was to evaluate the histological, histochemical and fine structure of the LG and SGTE obtained from 3 adult females and 2 adult males of alpaca (Vicugna pacos). The LG was situated in the dorsolateral angle of the orbit between the dorsal rectus and the lateral rectus muscles. The SGTE was located between the medial rectus muscle, the ventral rectus muscle and was partially covered by the ventral oblique muscle of the eyeball. There were no effect of gender on the morphometry of examined LG and SGTE. The third eyelid resembles an anchor in shape. During 3 histological BMN-673 Navitoclax and ultrastructural analyses using light and transmission electron microscopy, it was established that the LG and SGTE are tubulo-acinar glands with mucoserous characters. The LG contains either lymphocytes or plasma cells, while SGTE had rare plasma cells and numerous lymphocytes in connective

tissue. The cartilage of the third eyelid was composed of hyaline tissue. Numerous aggregations of lymphocytes as lymph nodules in bulbar surface of the third eyelid were observed. The LG and SGTE secretory cells exhibited a similar ultrastructure appearance in electron microscopic examination, with secretory cells tightly filled with intracytoplasmatic secretory granules and numerous clusters of mucus of different sizes which were observed in the peripheral cells compartment.”
“The main goal of this paper is to present the rovibrational energies and spectroscopic constants of the Cl-2 molecular system in the relativistic states , A’:(1)2 (u) , A:(1)1 (u) , and . More

precisely, we have evaluated the Cl-2 omega (e) , omega (e) x (e) , omega (e) y (e) , alpha (e) , gamma (e) and B (e) rovibrational spectroscopic constants using two different procedures. The first was obtained by combining the rovibrational energies, calculated through solving Schrodinger’s nuclear equation and the diatomic rovibrational energy equation. The second was obtained by using the Dunham method. The calculated properties are in good agreement with available experimental data.”
“Cytoskeleton assembly is instrumental https://www.selleckchem.com/products/poziotinib-hm781-36b.html in the regulation of biological functions by physical forces. In a number of key cellular processes, actin filaments elongated by formins such as mDia are subject to mechanical tension, yet how mechanical forces modulate the assembly of actin filaments is an open question. Here, using the viscous drag of a microfluidic flow, we apply calibrated piconewton pulling forces to individual actin filaments that are being elongated at their barbed end by surface-anchored mDia1 proteins. We show that mDia1 is mechanosensitive and that the elongation rate of filaments is increased up to two-fold by the application of a pulling force.

The lowest dose of CLON injected into the

MnR decreased the total risk assessment (TRA) frequency, an ethological parameter of anxiolytic-like effect, but did not change feeding behavior. The 3 highest dose of CLON injected into the MnR increased the TRA frequency, an anxiogenic-like effect. Similar result was observed after CLON injected into the Pn and mRt at the highest dose. In addition, clonidine at the highest dose caused hyperphagy accompanied by a reduction in the latency to start eating and an increase in feeding frequency when injected into the MnR but not in the Pn or mRt. These data indicate that MnR alpha(2)-adrenergic receptors participate in the control of anxiety-like and feeding behaviors, probably decreasing the facilitatory influence on MnR serotonergic neurons. The present results Selleckchem AG-881 suggest that

these behaviors involve independent neural pathways. (C) 2010 Elsevier B.V. All rights reserved.”
“Cold shock domain proteins (CSPs) are highly conserved from bacteria to higher plants and animals. Bacterial cold shock proteins function as RNA chaperones by destabilizing RNA secondary structures and promoting translation as an adaptative mechanism to low temperature stress. In animals, cold shock domain proteins exhibit broad functions related to growth and development. In order to understand better the function of CSPs in planta, detailed analyses were performed for Arabidopsis GW4869 manufacturer thaliana CSPs (AtCSPs) on the transcript and protein levels using an extensive series of tissue harvested throughout developmental stages within the entire life cycle of Arabidopsis. On both the transcript and protein levels, AtCSPs were enriched in shoot apical meristems and siliques. Although all AtCSPs exhibited similar expression patterns, AtCSP2 was the most abundantly expressed gene. In situ hybridization analyses were also used to confirm HM781-36B that AtCSP2 and AtCSP4 transcripts accumulate in developing embryos and shoot apices. AtCSPs

transcripts were also induced during a controlled floral induction study. In vivo ChIP analysis confirmed that an embryo expressed MADS box transcription factor, AGL15, interacts within two AtCSP promoter regions and alters the respective patterns of AtCSP transcription. Comparative analysis of AtCSP gene expression between Landsberg and Columbia ecotypes confirmed a 1000-fold reduction of AtCSP4 gene expression in the Landsberg background. Analysis of the AtCSP4 genomic locus identified multiple polymorphisms in putative regulatory cis-elements between the two ecotypes. Collectively, these data support the hypothesis that AtCSPs are involved in the transition to flowering and silique development in Arabidopsis.”
“Background Despite early repair, patients with aortic coarctation (CoA) continue to have a reduced life expectancy due to the development of late complications.

The hollow-site-stacked interfaces, in which Ti atoms locate on the hollow site of interfacial C atoms (cases III and IV), are more thermodynamically stable with larger work of adhesion, and interfacial fracture toughness. The center-site-stacked (cases I and II) and top-site-stacked (cases V and VI) interfaces have a decreasing interface adhesion as the order. The electronic Captisol nmr structure of hollow-site-stacked interface (case IV) gives the evidence that atomic bonding exists between interfacial C, Si, and Ti atoms, and the C-Ti bonds exhibit more covalent

features than Si-Ti. The tilt direction of Ti atoms, namely the stacking style of Ti, has a subtle and secondary effect on the interface stability. (C) 2013 American Institute of Physics. [http://0-dx.doi.org.brum.beds.ac.uk/10.1063/1.4775496]“
“Kiaa1867 (human Kirre, hKirre) has a critical role in brain development and/or maintenance of the glomerular slit diaphragm in kidneys. Murine homolog of this Saracatinib gene, mKirre expressed in OP9 and AFT024 cells could support hematopoietic stem cells/hematopoietic progenitor cells (HSC/HPC) expansion in vitro. HKirre is also expressed in human FBMOB-hTERT

cell line and fetal liver fibroblast-like cells but its function has remained unclear. In this paper, we cloned a hKirre gene from human fetal liver fibroblast-like cells and established a stably overexpressing hKirre-AFT024 cell line. Resultant cells could promote self-renewal and ex vivo expansion of HSCs/HPCs significantly higher than AFT024-control cells transformed with mock plasmid. The Expanded human umbilical cord blood (hUCB) CD34(+) cells retained the capacity of multipotent differentiation as long as 8 weeks and successfully repopulated the bone marrow of sublethally irradiated NOD/SCID mice, which demonstrated the expansion of long-term primitive transplantable HSCs/HPCs. Importantly, hkirre could upregulate the expressions of Wnt-5A, BMP4, and SDF-1 and downregulate TGF-beta with other hematopoietic growth factors. By SDS-PAGE and Western Blot see more analysis, a similar to 89 kDa protein in total lysate of AFT024-hKirre was identified. Supernatants from AFT024-hkirre could also support

CD34(+)CD38(-) cells expansion. These results demonstrated that the AFT024-hKirre cells have the ability to efficiently expand HSCs/HPCs.”
“Smokeless tobacco use in the form of the betel quid is common in the Western Pacific Region, and yet few studies have determined the nicotine delivery of this habit. During a validation substudy, we randomly sampled 201 adults from a rural province of Cambodia and determined nonparametric (bootstrapped) confidence intervals (CIs) for salivary cotinine levels in tobacco users. We found that cotinine levels for daily betel quid use among women (95% CI = 218.6-350.0 ng/mL) were (1) similar to the levels for daily cigarette smoking in men (95% CI = 240.2-317.1 ng/mL) and (2) significantly higher than the levels for daily cigarette smoking in women (95% CI = 71.

1-h plasma D-xylose levels were measured in 48 untreated patients, 41 treated patients and 41 healthy controls. 4-h urine D-xylose excretion was measured in 47 untreated patients, 51 treated patients and 42 healthy controls. 100 mg of (13)C-D-xylose and 5 g of D-xylose were dissolved in 250 ml tap water and given orally. (13)CO(2) was measured in breath every 30 min for 4 h. Blood was sampled after 1 h, and urine collected after 4 h. Results. Test sensitivity/specificity for celiac disease was 88%/84% with the (13)C-D-xylose breath test, 65%/71% with the 1-h plasma D-xylose test, and 55%/74% with the 4-h urine D-xylose excretion test. Breath test results improved

significantly in the treated celiac group compared to untreated patients, but were not normalized compared AICAR PI3K/Akt/mTOR inhibitor to healthy controls. No difference was found between 1-h plasma D-xylose levels and CYT387 in vitro 4-h urinary D-xylose excretion in treated celiac patients and healthy controls. Conclusions. The (13)C-D-xylose breath test was superior to D-xylose testing in plasma and urine for assessment of small intestinal malabsorption with considerably higher sensitivity and specificity for untreated celiac disease.”
“Background: Schistosomiasis mansoni is a debilitating and sometimes fatal disease. Accurate diagnosis plays a key role in patient

management and infection control. However, currently available parasitological methods are laborious and lack sensitivity. The selection of target antigen candidates has turned out to be a promising tool

for the development of more sensitive diagnostic methods. In our previous investigations, the use of crude antigens led to false-positive results. Recently, focus has been given to highly purified Schistosoma mansoni antigens, especially to circulating antigens.\n\nMethod: Thus, our main goal was to test different types of circulating cathodic antigen glycoprotein (CCA), as “crude antigen,” the protein chain of recombinant CCA and two individual peptides. These schistosome proteins/peptides were PLX3397 tested in a new diagnostic method employing immunomagnetic separation based on the improvement of antigen-antibody binding.\n\nPrincipal Findings: Use of recombinant CCA as a diagnostic antigen allowed us to develop a diagnostic assay with high sensitivity and specificity with no false-negative results. Interestingly, the “crude antigen” worked as a good marker for control of cure after praziquantel treatment.\n\nConclusions/Significance: Our new diagnostic method was superior to enzyme-linked immunosorbent assay in diagnosing low endemicity patients.”
“BACKGROUND & AIMS: Gastric ischemia is infrequently reported in the medical literature and under-recognized clinically and histopathologically. Various medical terms are used to describe gastric ischemia. We define and review the pathogenesis, diagnosis, and management of gastric ischemia.\n\nMETHODS: We describe 6 cases of gastric ischemia.

\n\nMethods Using a deterministic approach, we merged EMS data from the North Carolina Pre-hospital Medical Information System (PreMIS) with data from the Reperfusion

BTSA1 of Acute Myocardial Infarction in Carolina Emergency Departments-Emergency Response (RACE-ER) Project. Our sample included all patients with STEMI from June 2008 to October 2010 who arrived by EMS and who had primary percutaneous coronary intervention (PCI). Prehospital system delays were compared using both RACE-ER and PreMIS to examine agreement between the 2 data sources.\n\nResults Overall, 8,680 patients with STEMI in RACE-ER arrived at a PCI hospital by EMS; 21 RACE-ER hospitals and 178 corresponding EMS agencies across the state were represented. Of these, 6,010 (69%) patients were successfully linked with PreMIS. Linked and notlinked patients were similar. Overall, 2,696 patients were treated with PCI only and were taken directly to a PCI-capable hospital by EMS; 1,750 were transferred from a non-PCI facility. For those being transported directly to a PCI center, 53% reached the 90-minute target guideline goal. For those transferred from a non-PCI facility, 24% reached the 120-minute target goal for primary

PCI.\n\nConclusions We successfully linked prehospital EMS data with inhospital clinical data. With this linked STEMI cohort, less than half of patients reach goals set by guidelines. Such a data source could be used for future research selleck inhibitor and quality improvement WZB117 interventions. (Am Heart J 2013;165:363-70.)”
“Binding of urokinase-type plasminogen activator (uPA) to its receptor, uPAR, in estrogen receptor-alpha (ER alpha) expressing breast cancer cells, transiently activates ERK downstream of FAK, Src family kinases, and H-Ras. Herein, we show that when uPAR is over-expressed, in two separate ER alpha-positive breast cancer cell lines, ERK activation occurs autonomously of uPA and is sustained. Autonomous ERK activation

by OAR requires H-Ras and Rac1. A mutated form of uPAR, which does not bind vitronectin (uPAR-W32A), failed to induce autonomous ERK activation. Expression of human uPAR or mouse uPAR but not uPAR-W32A in MCF-7 cells provided a selection advantage when these cells were deprived of estrogen in cell culture for two weeks. Similarly, MCF-7 cells that express mouse uPAR formed xenografts in SOD mice that survived and increased in volume in the absence of estrogen supplementation, probably reflecting the pro-survival activity of phospho-ERK. Autonomous uPAR signaling to ERK was 123 sensitive to the EGFR tyrosine kinase inhibitors, Erlotinib and Gefitinib. The transition in uPAR signaling from uPA-dependent and transient to autonomous and sustained is reminiscent of the transformation in ErbB2/HER2 signaling observed when this gene is amplified in breast cancer. uPAR over-expression may provide a pathway for escape of breast cancer cells from ER alpha-targeting therapeutics. (C) 2012 Elsevier Inc. All rights reserved.