MH_dev_43

Inhibition of Q16552 REA as a pharmacological approach for Q9UKU7 . Several experimental approaches have been utilized , in order to critically examine the roles of Q16552 REA family members in intestinal inflammation . These approaches have included : ( 1 ) the use of Q16552 REA and Q96PD4 - deficient mice , ( 2 ) specific antibodies directed against Q16552 REA , ( 3 ) an Q16552 REA vaccine , ( 4 ) methods to block the Q16552 REA receptor and ( 5 ) small-molecule inhibitors of Q16552 REA . Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease ( Q9UKU7 ) , using specific strains of Q16552 REA - deficient mice . This paper will review the preclinical results using various pharmacological approaches [ specific Q16552 REA antibodies , an Q16552 REA receptor fusion protein , IL - 12 / IL - 23 p40 subunit and Q16552 REA vaccine approaches , as well as a small molecule inhibitor ( Vidofludimus ) ] to inhibit Q16552 REA in animal models of Q9UKU7 . Recent clinical results in patients with Q9UKU7 will also be discussed for DB09029 SUB ( an Q16552 REA antibody ) , Brodalumab ( an Q16552 REA receptor antibody ) and two small-molecule drugs ( Vidofludimus and DB08895 ) , which inhibit Q16552 REA as part of their overall pharmacological profiles . This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti - Q16552 REA drugs , as related to drug pharmacodynamics , Q16552 REA receptor subtypes and other pertinent factors . Finally , future pharmacological approaches of interest will be discussed , such as : ( 1 ) Retinoic acid receptor-related orphan nuclear receptor gamma t ( Rorγt ) antagonists , ( 2 ) P10276 REA ( RARα ) antagonists , ( 3 ) Pim - 1 kinase inhibitors and ( 4 ) Dual small-molecule inhibitors of NF-κB and P40763 REA , like synthetic triterpenoids .

Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 REA receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 REA receptors ( Ki = 3.4 nM ) , in addition to P28221 REA , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 REA agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 REA properties of ziprasidone in vivo using as a marker of central P08908 REA activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose-dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 REA antagonist WAY -100,635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone-induced inhibition ; the same dose of WAY -100,635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( DB01151 MEN ) , a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . DB01151 MEN ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 REA agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 REA agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .

P35367 REA antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three-way , double-blind , cross-over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : DB00341 MEN 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : DB00341 MEN affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .

8 - OH-DPAT ( P08908 REA agonist ) Attenuates 6 - Hydroxy - dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH-DPAT on 6 - OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 REA ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH-DPAT ( P08908 REA receptor agonist ; 0.25 , 0.5 and 1mg / kg , IP for 10 days ) . P04141 REA samples were collected on the tenth day of 8 - OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 REA - α , IL - 1β and P05231 REA . RESULTS : Chronic injection of 8 - OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH-DPAT . Levels of P01375 REA - α in P04141 REA increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 REA - α level of parkinsonian animals treated with 8 - OH-DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 REA decreased and increased in parkinsonian rats and in 8 - OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH-DPAT improves catalepsy in 6 - OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 REA receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .

Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A ( 2 ) in the P01375 REA - activated endothelial cells by Q9UNN8 and P25116 REA dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 REA ) - alpha up-regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 REA ) down-regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A ( 2 ) ( sPLA ( 2 ) - IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 REA and thrombin on the expression of sPLA ( 2 ) - IIA and extracellular signal-regulated kinase ( P29323 REA ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA ( 2 ) - IIA was quantitatively measured by an enzyme-linked-immunosorbent-assay following stimulation of HUVECs with either thrombin or P01375 REA in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 REA - kinase ) inhibitor LY294002 and the cholesterol-depleting drug methyl-beta-cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA ( 2 ) - IIA in HUVECs , however , P01375 REA potently induced its expression . The prior treatment of cells with P25054 REA inhibited expression of sPLA ( 2 ) - IIA through the Q9UNN8 - dependent cleavage of P25116 REA . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 REA - mediated expression of sPLA ( 2 ) - IIA through the cleavage of P25116 REA . The Q9UNN8 - dependent cleavage of P25116 REA by both P25054 REA and thrombin increased the phosphorylation of P29323 REA 1/2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 REA and thrombin against sPLA ( 2 ) - IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 REA - kinase dependent protective activity for thrombin such that its cleavage of the lipid-raft localized P25116 REA inhibits the P01375 REA - mediated expression of sPLA ( 2 ) - IIA in HUVECs .

Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first-line therapy in LDL - DB04540 ( LDL-C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL-C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein-B 100 ( apoB ) , Cholesteryl ester transport protein ( P11597 REA ) and microsomal triglyceride transfer protein ( P55157 REA ) . ApoB and P55157 REA inhibitors ( DB05528 and DB08827 MEN ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 REA and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .

Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 REA ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 REA ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 REA ) at 3 and 12 months . P10632 REA * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 REA levels ( P= 0.003 and P= 0.007 ) and were 2.2- and 2.5- fold more likely to develop P42126 REA and CND ( P= 0.039 and P= 0.041 ) , respectively . P34913 REA 55Arg , P51589 REA * 7 , P10632 REA * 1B , and P10632 REA g . 36785A allele carriers had lower EET and DHET P04141 REA levels . P10632 REA g . 25369T and P10632 REA g . 36755A allele carriers had higher EET levels . Patients with P10632 REA * 2C and P34913 REA 404del variants had worse long-term outcomes while those with P34913 REA 287Gln , P51589 REA * 7 , and P11712 REA g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .

Altered gene expression by low-dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real-time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array ( TLDA ) . We found that expression of tumor necrosis factor-α ( P01375 REA - α ) , which activates both inflammation and NF-κB-dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 REA , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion-channel genes CACNA 1 , Q12809 REA , P51787 REA and P15382 REA were down-regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion-channel function , may underlay the seemingly disparate array of arsenic-associated diseases , such as cancer , cardiovascular disease , and diabetes .

Signaling by proinflammatory cytokines : oligomerization of TRAF 2 and Q9Y4K3 REA is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain . Interleukin - 1 ( IL - 1 ) and tumor necrosis factor ( P01375 REA ) stimulate transcription factors AP - 1 and NF-kappaB through activation of the Q96HU1 kinases JNK and p38 and the O15111 REA ( IKK ) , respectively . The P01375 REA and IL - 1 signals are transduced through TRAF 2 and Q9Y4K3 REA , respectively . Overexpressed TRAF 2 or Q9Y4K3 REA activate JNK , p38 , or IKK in the absence of extracellular stimulation . By replacing the carboxy-terminal TRAF domain of TRAF 2 and Q9Y4K3 REA with repeats of the immunophilin P62942 REA , we demonstrate that their effector domains are composed of their amino-terminal Zn and RING fingers . Oligomerization of the TRAF 2 effector domain results in specific binding to Q13233 REA , a protein kinase capable of JNK , p38 , and IKK activation , and induction of P01375 REA and IL - 1 responsive genes . P01375 REA also enhances the binding of native TRAF 2 to Q13233 REA and stimulates the kinase activity of the latter . Thus , P01375 REA and IL - 1 signaling is based on oligomerization of TRAF 2 and Q9Y4K3 REA leading to activation of effector kinases .

The relationship of P04141 REA and plasma cytokine levels to cerebral white matter injury in the premature newborn . Ischemia and systemic infection are implicated in the etiology of periventricular white matter injury , a major cause of adverse motor and cognitive outcome in preterm infants . Cytokines are signaling proteins that can be produced as part of the inflammatory response to both ischemia and infection . The aim of this study was to relate cerebrospinal fluid ( P04141 REA ) concentrations of P05231 REA , P10145 REA , P22301 REA , tumor necrosis factor alpha ( P01375 REA ) , and interferon gamma ( P01579 REA ) to magnetic resonance-defined white matter injury in preterm infants . Relationships between P04141 REA and plasma cytokine concentrations were also examined . Preterm infants ( < or = 32 wk ) and more mature infants from The Royal Women ' s Hospital , Melbourne , Australia , and Christchurch Women ' s Hospital , Christchurch , New Zealand , were eligible for study if they required a clinically indicated lumbar puncture . Plasma samples were obtained in a subgroup of Christchurch infants . Preterm infants underwent advanced quantitative volumetric magnetic resonance imaging using a 1.5- Tesla scanner at term equivalent . One hundred forty-six infants were enrolled and 190 P04141 REA and 42 plasma samples obtained . There was no significant correlation between paired P04141 REA and plasma concentrations for any cytokine . In comparing plasma and P04141 REA concentrations , levels of P10145 REA were significantly higher in P04141 REA than plasma . Preterm infants with Q9BWK5 - defined cerebral white matter injury had higher levels of P05231 REA , P22301 REA , and P01375 REA in the P04141 REA than infants without such injury . Plasma cytokine concentrations may not reflect P04141 REA cytokine levels or inflammatory events within the brain . Elevated P04141 REA levels of cytokines in infants with white matter injury suggest an altered inflammatory balance .

Not all monoclonals are created equal - lessons from failed drug trials in Crohn ' s disease . The recent success of the anti-integrin antibody DB09033 can barely conceal the fact that the biologics armamentarium in Crohn ' s disease has barely evolved beyond P01375 REA blockers so far . This contrasts with other immune-related diseases considered mechanistically and genetically closely related , such as psoriasis and rheumatoid arthritis , where approved biologics target a variety of independent biological mechanisms . Several pharmacological assets that entered clinical development have proven ineffective , or less effective than originally anticipated . While blockade of Q16552 REA and its receptor via DB09029 SUB and Brodalumab , respectively , worsened Crohn ' s disease , the beneficial effect of IL -12/23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn ' s disease patients who have previously failed on P01375 REA blockers . Clinical development of the IFNγ blocker DB05111 was stopped despite demonstrating some clinical benefit , while the T cell co-stimulation blocker DB01281 did not exhibit any hint towards efficacy in Crohn ' s disease . Here I review results from these individual development programmes , and also reflect on the lack of efficacy of the P01375 REA blocker DB00005 . I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years . Finally , I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn ' s disease .

Neonatal ghrelin programs development of hypothalamic feeding circuits . A complex neural network regulates body weight and energy balance , and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases , such as obesity . The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus ( Q5SW96 ) . Here , we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice . Ghrelin blockade in neonatal mice resulted in enhanced Q5SW96 neural projections and long-term metabolic effects , including increased body weight , visceral fat , and blood glucose levels and decreased leptin sensitivity . In addition , chronic administration of ghrelin during postnatal life impaired the normal development of Q5SW96 projections and caused metabolic dysfunction . Consistent with these observations , direct exposure of postnatal Q5SW96 neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin . Moreover , chronic ghrelin exposure in neonatal mice also attenuated leptin-induced P40763 REA signaling in Q5SW96 neurons . Collectively , these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation .

Niacin reduces plasma P11597 REA levels by diminishing liver macrophage content in P11597 REA transgenic mice . The anti-dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of P11597 REA . Since liver macrophages contribute to hepatic P11597 REA expression , we investigated the role of macrophages in the P11597 REA - lowering effect of niacin in mice . In vitro studies showed that niacin does not directly attenuate P11597 REA expression in macrophages . Treatment of normolipidemic human P11597 REA transgenic mice , fed a Western-type diet with niacin for 4 weeks , significantly reduced the hepatic cholesterol concentration ( - 20 % ) , hepatic P11597 REA gene expression ( - 20 % ) , and plasma P11597 REA mass ( - 30 % ) . Concomitantly , niacin decreased the hepatic expression of P34810 REA ( - 44 % ) and P45844 REA ( - 32 % ) , both of which are specific markers for the hepatic macrophage content . The decrease in hepatic P11597 REA expression was significantly correlated with the reduction of hepatic macrophage markers . Furthermore , niacin attenuated atherogenic diet-induced inflammation in liver , as evident from decreased expression of P01375 REA ( - 43 % ) . Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic P02649 REA * 3 - Leiden . P11597 REA transgenic mice on a Western-type diet . In conclusion , niacin decreases hepatic P11597 REA expression and plasma P11597 REA mass by attenuating liver inflammation and macrophage content in response to its primary lipid-lowering effect , rather than by attenuating the macrophage P11597 REA expression level .

Microsomal transfer protein ( P55157 REA ) inhibition-a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low-density lipoprotein receptor ( LDL-R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 REA ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 REA ) , or gain-of-function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 REA ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 REA ) system have shown a high clinical potential . P55157 REA plays a critical role in the assembly / secretion of very-low-density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 REA antagonists dramatically lower LDL-cholesterol ( LDL-C ) in animals , although a reported increase of liver fat delayed their clinical development . DB08827 MEN , the best-studied P55157 REA inhibitor , reduces LDL-C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low-fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .

c-Fes tyrosine kinase binds to and activates P40763 REA after granulocyte-macrophage colony-stimulating factor stimulation . Granulocyte-macrophage colony stimulating factor ( GM - P04141 REA ) induces proliferation and maturation of myeloid progenitor cells and also activates neutrophils . In order to investigate the pleiotropic effects of GM - P04141 REA stimulation , we examined the signaling pathways of protein tyrosine kinases ( PTKs ) and signal transducers and activators of transcription ( STATs ) in GM - P04141 REA - dependent proliferation of leukemia cells . Using TF - 1 , a GM - P04141 REA - dependent human erythroleukemia cell line , we found that GM - P04141 REA enhanced DNA-binding and tyrosine phosphorylation of P40763 REA . GM - P04141 REA receptor ( GM-CSFR ) and c-Fes tyrosine kinase were also activated upon GM - P04141 REA stimulation . Furthermore , c-Fes formed a complex with P40763 REA . Experiments using a c-Fes mutant that lacked tyrosine kinase activity revealed that the activation of P40763 REA is kinase-dependent , but that the c-Fes - P40763 REA interaction is not affected by c-Fes tyrosine kinase activity . The results suggest that P40763 REA is activated by c-Fes tyrosine kinase through direct interaction during hematopoietic cell proliferation induced by GM - P04141 REA .

Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 REA ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen-presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 REA - mediated NF-ĸB signaling of DCs remain poorly defined . METHODS : Bone-marrow ( BM ) - derived DCs ( BM-DCs ) were treated with P35367 REA inverse agonists to interrupt basal P35367 REA - mediated signaling . The crosstalk of P35367 REA - mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay , NF-ĸB subunit analysis using Western blotting and P01375 REA - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 REA signaling by inverse agonists significantly inhibited P01375 REA - α and P05231 REA production of BM-DCs . P35367 REA - specific agonists were able to enhance P01375 REA - α production , but this overexpression was significantly inhibited by NF-ĸB inhibitor . The P35367 REA inverse agonist ketotifen also suppressed cellular NF-ĸB activity , suggesting crosstalk between P35367 REA and NF-ĸB signaling in DCs . After comprehensive analysis of NF-ĸB subunits , c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs , which led to inhibition of the promoter activity of P01375 REA - α . Finally , adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c-Rel controls P35367 REA - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 REA - mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation .

Forced retinoic acid receptor alpha homodimers prime mice for APL-like leukemia . P10276 REA becomes an acute promyelocytic leukemia ( APL ) oncogene by fusion with any of five translocation partners . Unlike RARalpha , the fusion proteins homodimerize , which may be central to oncogenic activation . This model was tested by replacing P29590 REA with dimerization domains from p50NFkappaB ( p50 - RARalpha ) or the rapamycin-sensitive dimerizing peptide of P62942 REA ( P13726 REA - RARalpha ) . The X-RARalpha fusions recapitulated in vitro activities of P29590 REA - RARalpha . For P13726 REA - RARalpha , these properties were rapamycin sensitive . Although in vivo the artificial fusions alone are poor initiators of leukemia , p50 - RARalpha readily cooperates with an activated mutant P32927 REA to induce APL-like disease . These results demonstrate that the dimerization interface of RARalpha fusion partners is a critical element in APL pathogenesis while pointing to other features of P29590 REA for enhancing penetrance and progression .

The low-potency , voltage-dependent Q12809 REA blocker propafenone - - molecular determinants and drug trapping . The molecular determinants of high-affinity human ether-a-go-go-related gene ( Q12809 REA ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe 656 and Tyr 652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower-affinity Q12809 REA blockers may be different . In this study , alanine-substituted Q12809 REA channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 REA channel binding site of the antiarrhythmic propafenone . DB01182 MEN ' s blockade of Q12809 REA was strongly dependent on residue Phe 656 but was insensitive or weakly sensitive to mutation of Tyr 652 , Thr 623 , Ser 624 , Val 625 , Gly 648 , or Val 659 and did not require functional inactivation . Homology models of Q12809 REA based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe 656 in the closed state ( whereas exclusive interactions between propafenone and Phe 656 are found in the open-channel model ) . These findings are supported by very slow recovery of wild-type Q12809 REA channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open-state propafenone binding-site may be formed by the Phe 656 residues alone . The binding site for propafenone ( which may involve pi-stacking interactions with two or more Phe 656 side-chains ) is either perturbed or becomes less accessible because of closed-channel gating . This provides further evidence for the existence of gating-induced changes in the spatial location of Phe 656 side chains .

Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T lymphocytes ( EBV-CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV-associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long-term persistence of transferred EBV-CTLs , precluding their use as prophylaxis . DB00864 MENMAX DB00864 MEN ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 REA ) . We have knocked down the expression of P62942 REA in EBV-CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 REA - silenced EBV-CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti-PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV-specific immune surveillance in patients at high risk of PTLD after transplantation .

Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G-protein-coupled receptors and couple to inhibitory G-proteins . Recent studies show that chronic activation of P08908 REA receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 REA receptors and SK-N-SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G-proteins and proteasomal degradation in this process . Interestingly , the small G-protein Rap and the transcription factor P35610 REA - 3 are also involved since reducing the levels of Rap 1 ( using small interfering RNA ) or P35610 REA - 3 ( using dominant negative P40763 REA ) significantly blocks P08908 REA - receptor-mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 REA - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 REA receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co-treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 REA receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long-term changes required for neurogenesis .

Circulating apoptotic proteins are increased in long-term disease-free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis-related proteins and inflammation markers are increased in long-term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 REA ) alpha , sTNF-receptor ( sTNF-R ) 1 and 2 , sFas , sFas ligand , sTNF-related apoptosis inducing ligand ( sTRAIL ) and serum P04626 REA were measured with immunoassay . High-sensitivity P02741 REA ( HS-CRP ) , fibrinogen , plasma B-type and N-terminal atrial natriuretic peptide ( NT - P01160 REA and DB04899 ) were also determined . Thirty-four patients with median 6.0 years follow-up and 12 healthy age-matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high-dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high-dose than in the standard-dose group . In conclusion , we observed increased circulating apoptotic protein levels in long-term disease-free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .

Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via down-regulation of P40763 REA - NFκB signaling . BACKGROUND / AIM : The cancer stem cell ( CSC ) model postulates the existence of a small proportion of cancer cells capable of sustaining tumor formation , self-renewal and differentiation . Signal Transducer and Activator of Transcription 3 ( P40763 REA ) signaling is known to be selectively activated in breast CSC populations . However , it is yet to be determined which molecular mechanisms regulate P40763 REA signaling in CSCs and what chemopreventive agents are effective for suppressing CSC growth . The aim of this study was to examine the potential efficacy of curcumin and epigallocatechin gallate ( EGCG ) against CSC and to uncover the molecular mechanisms of their anticancer effects . MATERIALS AND METHODS : To suppress the CSC phenotype , two breast cancer cell lines ( MDA-MB - 231 cells and MCF 7 cells transfected with P04626 REA ) were treated with curcumin ( 10 μM ) with or without EGCG ( 10 μM ) for 48 h . We used tumor-sphere formation and wound-healing assays to determine CSC phenotype . To quantify CSC populations , Fluorescence-activated cell sorting profiling was monitored . P40763 REA phosphorylation and interaction with Nuclear Factor-kB ( NFkB ) were analyzed by performing western blot and immunoprecipitation assays . RESULTS : Combined curcumin and EGCG treatment reduced the cancer stem-like Cluster of differentiation 44 ( P16070 REA ) - positive cell population . Western blot and immunoprecipitation analyses revealed that curcumin and EGCG specifically inhibited P40763 REA phosphorylation and P40763 REA - NFkB interaction was retained . CONCLUSION : This study suggests that curcumin and EGCG function as antitumor agents for suppressing breast CSCs . P40763 REA and NFκB signaling pathways could serve as targets for reducing CSCs leading to novel targeted-therapy for treating breast cancer .

Human cardiomyocyte hypertrophy induced in vitro by P40189 REA stimulation . OBJECTIVES : Recent in vivo and in vitro studies in animals have demonstrated that cytokines of the P05231 REA family are involved in cardiac hypertrophy and in protection of cardiomyocytes against apoptosis . The present study aims to analyse the capacity of human atrial cardiac cells ( i . e . , cardiomyocytes and fibroblasts ) to display the P40189 REA receptor subunit , and to evaluate its functionality . METHODS : Twenty human atrial biopsies were used for immunohistochemistry , in situ hybridisation , and western blot analysis or dissociated for isolation and primary culture of cardiac cells . RESULTS : Fibroblasts present in tissue or maintained in primary culture clearly express P40189 REA whereas the signal in cardiomyocytes is weaker . Culture of cardiac cells with a P40189 REA agonist antibody enhances atrial natriuretic peptide ( P01160 REA ) , beta myosin heavy chain ( beta-MHC ) expression in cardiomyocytes , and significantly increases the cell surface area microm ( 2 ) ) . This process could involve P40763 REA ( signal transducer and activator of transcription 3 ) phosphorylation . CONCLUSIONS : These results demonstrate that P40189 REA activation in human cardiac cells leads to cardiomyocyte hypertrophy . We discuss several hypotheses on the role of P05231 REA - type cytokines on cardiomyocyte functions .

A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 REA , P08684 REA / 5 and Q9BQB6 genes polymorphisms . DB00946 MEN is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors . DB00946 MEN metabolism is mediated by P11712 REA and CYP 3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 REA , P08684 REA and P20815 REA genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 REA * 2 and / or P11712 REA * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 REA * 1B , P20815 REA * 3 and P20815 REA * 6 polymorphisms . Among non-genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β-blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3.92 mg / week and 3.54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .

Opposing actions of extracellular signal-regulated kinase ( P29323 REA ) and signal transducer and activator of transcription 3 ( P40763 REA ) in regulating microtubule stabilization during cardiac hypertrophy . Excessive proliferation and stabilization of the microtubule ( MT ) array in cardiac myocytes can accompany pathological cardiac hypertrophy , but the molecular control of these changes remains poorly characterized . In this study , we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs , which were closely associated with P40763 REA activation . To explore the molecular signaling events contributing to control of the cardiac MT network , we stimulated cardiac myocytes with an α-adrenergic agonist phenylephrine ( PE ) , and observed increased tubulin content without changes in detyrosinated ( glu-tubulin ) stable MTs . In contrast , the hypertrophic interleukin - 6 ( P05231 REA ) family cytokines increased both the glu-tubulin content and glu-MT density . When we examined a role for P29323 REA in regulating cardiac MTs , we showed that the MEK / P29323 REA - inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents . Conversely , expression of an activated Q02750 REA mutant reduced glu-tubulin levels . Thus , P29323 REA signaling antagonizes stabilization of the cardiac MT array . In contrast , inhibiting either O60674 REA with AG490 , or P40763 REA signaling with Stattic or siRNA knockdown , blocked cytokine-stimulated increases in glu-MT density . Furthermore , the expression of a constitutively active P40763 REA mutant triggered increased glu-MT density in the absence of hypertrophic stimulation . Thus , P40763 REA activation contributes substantially to cytokine-stimulated glu-MT changes . Taken together , our results highlight the opposing actions of P40763 REA and P29323 REA pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy .

Binding of C / EBPbeta to the P02741 REA ( CRP ) promoter in Hep 3B cells is associated with transcription of CRP mRNA . Expression of the acute phase protein P02741 REA ( CRP ) is tightly regulated in hepatocytes . Although very little CRP mRNA is transcribed normally , inflammatory stimuli are followed by a dramatic increase in mRNA synthesis and accumulation . P05231 REA and IL - 1beta are believed to be the major cytokines responsible for induction of CRP and other acute phase proteins . Our previous studies , using transient transfection and EMSA experiments , implicated involvement of the transcription factors C / EBPbeta , P40763 REA , Rel p50 , and c-Rel in CRP induction . In the current study we used chromatin immunoprecipitation assays to determine the kinetics of transcription factor occupancy of these transcription factors on the endogenous CRP promoter . All of these transcription factors were found bound to the endogenous CRP promoter in the absence of cytokines , but cytokine treatment markedly increased binding of only C / EBPbeta . In addition , c-Rel and TATA box-binding protein ( P20226 REA ) appeared to occupy the promoter in parallel in the presence of cytokines . In the absence of cytokines , CRP mRNA accumulation was not measurable but began to increase by 3 h after exposure of cells to IL - 1beta plus P05231 REA , peaking at 12 h with secondary peaks at 18 and 24 h . The secondary peaks in mRNA expression paralleled the pattern of binding of c-Rel and P20226 REA to the CRP promoter . We conclude that the CRP promoter has a low level of transcription factor occupancy in the absence of cytokines and induction occurs with binding of C / EBP , and that c-Rel and P20226 REA are important for modulating CRP expression .

Effect of interferon-gamma and P01375 REA on P15941 REA mucin expression in ovarian carcinoma cell lines . In view of the potential uses of cell surface tumour associated antigens in novel anticancer treatment , a study was designed to investigate whether the biological response modifiers interferon-gamma ( P01579 REA ) and tumour necrosis factor-alpha ( P01375 REA ) could effect the expression of an epitope on the tumour associated P15941 REA epithelial mucin . Four ovarian carcinoma cell lines showing high ( OAW 42 and GG ) and low ( JAM and PE01 ) basal expression of P15941 REA were treated with 10-1000 U / mL of P01579 REA or P01375 REA for one or five days . Changes in P15941 REA expression in cells exposed to P01579 REA or P01375 REA were monitored using an ELISA technique with the monoclonal antibody O43633 REA which reacts with a core protein epitope on the P15941 REA mucin , and then corrected for the number of viable cells present . P01375 REA had little effect on P15941 REA expression , but one or five days exposure to P01579 REA significantly increased P15941 REA expression ( p < 0.01 ) in all cell lines including the two cell lines that initially showed little or no expression .

Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through P40763 REA signaling . P10275 REA ( AR ) signaling is important for prostate cancer progression . However , androgen-deprivation and / or AR targeting-based therapies often lead to resistance . Here , we demonstrate that loss of AR expression results in P40763 REA activation in prostate cancer cells . AR downregulation further leads to development of prostate cancer stem-like cells ( CSC ) , which requires P40763 REA . In human prostate tumor tissues , elevated cancer stem-like cell markers coincide with those cells exhibiting high P40763 REA activity and low AR expression . AR downregulation-induced P40763 REA activation is mediated through increased interleukin ( IL ) - 6 expression . Treating mice with soluble P05231 REA receptor fusion protein or silencing P40763 REA in tumor cells significantly reduced prostate tumor growth and CSCs . Together , these findings indicate an opposing role of AR and P40763 REA in prostate CSC development .

Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide-resistant subline , LNCaP - O43633 REA , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate-specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( DB02901 MEN ) levels in xenografted tumors were analyzed by liquid chromatography-tandem mass spectrometry . P10275 REA ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 REA did not grow in an androgen-depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 REA grew in castrated male mice , and the DB02901 MEN level in grafted LNCaP - O43633 REA tumors was 7.7- fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 REA proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 REA was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 REA , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 REA were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 REA exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 REA .

P15056 REA inhibitors suppress apoptosis through off-target inhibition of JNK signaling . DB08881 MEN and dabrafenib selectively inhibit the P15056 REA ( P15056 REA ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug-induced paradoxical P29323 REA activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX 4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib-treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK-dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 REA activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 REA inhibitors and for their use in combination therapies . DOI : http://dx.doi.org/10.7554/eLife.00969.001 .

Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 REA , Q12809 REA , Q14524 REA , P22460 REA , Q9UK17 , P15382 REA , 2 , 5 , P63252 REA , P35498 REA - 3B , P01160 REA , and P36382 REA from 192 early-onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7.6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0.1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4.1 % ; with minor allele frequency < 0.1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .

DB06589 MEN inhibits the activation of P09619 REA β-expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress P04626 REA or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 REA - transfected MDA-MB - 231 human breast carcinoma cells ( 231 - BR - P04626 REA ) . A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 REA β ) was identified around perivascular brain micrometastases . p751 - P09619 REA β ( + ) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 REA large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . DB06589 MEN treatment resulted in 70 % ( P = 0.023 ) decrease of the p751 - P09619 REA β ( + ) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .