MH_dev_311

P25021 REA mediated relaxation of buffalo ( Bubalus bubalus ) ureter . On the buffalo ureter , histamine did not elicit any direct effect . However , it caused concentration-dependent relaxation of the tissues precontracted by carbachol , phenylephrine , norepinephrine , KCI or BaCl 2 and also inhibited the contractile effect of carbachol . DB08805 MEN selectively antagonised the relaxation and inhibition of contractile response but mepyramine did not show this effect . Isoprenaline , dobutamine , salbutamol , verapamil and papaverine neither produced any direct effect nor relaxed the carbachol-contracted tissues ; norepinephrine and epinephrine had contractile effects . Hence , the histamine-induced relaxation was mediated through the activation of H2 receptors and not through adrenergic mechanisms or blockade of Ca ( 2 + ) - channels or inhibition of cyclic nucleotide phosphodiesterase .

Genetics of bipolar disorder . Many linkage loci and candidate genes have been reported in molecular genetic studies of bipolar disorder . However , none of these findings have been consistently replicated . Meta-analyses of linkage studies have also reported conflicting results . Among recently reported candidate genes , P23560 REA , P59103 , P31749 REA , Q12879 REA , P17861 REA , P35626 REA , Q13639 REA , O14732 REA and P14867 REA may have some importance . Study of the possible roles of epigenetics or analysis of genetic diseases , in which bipolar disorder is one of phenotypes , may also be promising . In addition to monoaminergic and intracellular signaling pathways , recent studies have revealed possible roles for mitochondrial dysfunction , for glutamatergic dysfunction and for the endoplasmic reticulum stress pathway .

Intraretinal lipid transport is dependent on high density lipoprotein-like particles and class B scavenger receptors . PURPOSE : In our companion paper we demonstrated that circulating lipoproteins enter the retina via the retinal pigment epithelium ( Q96AT9 ) and possibly Müller cells . In order to understand how these lipids are transported within the retina , expression and localization of the main proteins known to be involved in systemic lipid transport was determined . METHODS : Expression of O95477 REA , apoA 1 ( the major HDL protein ) , Q8WTV0 , SR - Q15878 REA , P16671 REA , lecithin : cholesterol acyltransferase ( P04180 REA ) , and cholesteryl ester transfer protein ( P11597 REA ) was determined by reverse transcriptase polymerase chain reaction ( RT-PCR ) and immunoblots . Localization was determined by immunohistochemistry using fresh monkey vibrotome sections and imaged by confocal microscopy . RESULTS : O95477 REA and apoA 1 were localized to the ganglion cell layer , retinal pigment epithelium ( Q96AT9 ) , and rod photoreceptor inner segments . ApoA 1 was also observed associated with rod photoreceptor outer segments , presumably localized to the interphotoreceptor matrix ( IPM ) . The scavenger receptors Q8WTV0 and SR - Q15878 REA localized mainly to the ganglion cell layer and photoreceptor outer segments ; in the latter they appear to be associated with microtubules . P04180 REA and P11597 REA localized mainly to the IPM . CONCLUSIONS : The presence and specific localization of these well-known lipid transport proteins suggest that the retina employs an internal lipid transport mechanism that involves processing and maturation of HDL-like particles .

Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers . OBJECTIVE : The purpose of this study was to explore whether non-human leukocyte antigen ( non-HLA ) genetic markers can improve type 1 diabetes ( T1D ) prediction in a prospective cohort with high-risk HLA-DR , DQ genotypes . METHODS : The Diabetes Autoimmunity Study in the Young ( DAISY ) follows prospectively for the development of T1D and islet autoimmunity ( IA ) children at increased genetic risk . A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms ( SNPs ) and one microsatellite . RESULTS : In multivariate analyses adjusting for family history and HLA - Q93038 REA / 4 genotype , Q9Y2R2 REA ( rs2476601 ) and two P57075 ( rs11203203 and rs9976767 ) SNPs were associated with development of IA [ hazard ratio ( HR )= 1.87 , 1.55 , and 1.54 , respectively , all p ≤ 0.003 ] , while Q8NEA6 and P01589 REA showed borderline association with development of IA . P01308 REA , P57075 , and Q9BYX4 were significantly associated with progression from IA to diabetes ( HR = 1.65 , 1.44 , and 1.47 , respectively , all p ≤ 0.04 ) , while Q9Y2R2 REA and IL27 showed borderline association with progression from IA to diabetes . In survival analysis , 45 % of general population DAISY children with Q9Y2R2 REA rs2476601 TT or HLA - Q93038 REA / 4 and P57075 rs11203203 AA developed diabetes by age 15 , compared with 3 % of children with all other genotypes ( p < 0.0001 ) . Addition of non-HLA markers to HLA - Q93038 REA / 4 , DQ8 did not improve diabetes prediction in first-degree relatives . CONCLUSION : Addition of Q9Y2R2 REA and P57075 SNPs to HLA-DR , DQ genotyping can improve T1D risk prediction .

P04035 REA inhibition induces IL - 1beta release through Rac 1 / PI3K / P31749 REA - dependent caspase - 1 activation . Q03426 REA deficiency ( MKD ) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis . Lipopolysaccharide-stimulated peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin - 1beta ( IL - 1beta ) because of the presence of hyperactive caspase - 1 , and this has been proposed to be the primary cause of recurring inflammation . Here we show that inhibition of P04035 REA by simvastatin treatment , mimicking MKD , results in increased IL - 1beta secretion in a Rac 1 / PI3K - dependent manner . Simvastatin treatment was found to activate protein kinase B ( P31749 REA ) / c-akt , a primary effector of PI3K , and ectopic expression of constitutively active P31749 REA was sufficient to induce IL - 1beta release . The small GTPase Rac 1 was activated by simvastatin , and this was required for both P31749 REA activation and IL - 1beta secretion . IL - 1beta release is mediated by caspase - 1 , and simvastatin treatment resulted in increased caspase - 1 activity in a Rac 1 / PI3K - dependent manner . These data suggest that , in MKD , dysregulated isoprenoid biosynthesis activates Rac 1 / PI3K / P31749 REA , resulting in caspase - 1 activation with increased IL - 1beta release . Importantly , inhibition of Rac 1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL - 1beta release . These data suggest that pharmacologic inhibition of Rac 1 could provide a novel therapeutic strategy for treatment of MKD .

DB08827 SUB . Aegerion Pharmaceuticals is developing lomitapide , a small-molecule , microsomal triglyceride transfer protein ( P55157 REA ) inhibitor , for the treatment of both familial and primary hypercholesterolemia . Oral , once-daily lomitapide will be targeted at patients resistant to P04035 REA inhibitors ( statins ) either due to abnormalities in liver function or to discontinuation because of muscle pain . An oral formulation of lomitapide is in phase III development for homozygous familial hypercholesterolemia ( hyperlipoproteinemia type IIa ) in the US , Canada , Italy , and South Africa . This review discusses the key development milestones and therapeutic trials of this drug .

What future for combination therapies ? For most patients who require lipid-lowering treatment , statin monotherapy is the appropriate treatment . However , in those patients where statin monotherapy does not produce optimal lipid levels , the combination of a statin with niacin , a bile acid sequestrant , a fibric acid derivative , a cholesterol absorption inhibitor or a fish oil preparation may provide improved control . The choice of combination therapy depends upon the patient ' s lipid profile and tolerability of the medication . Combination of a statin with niacin , a bile acid sequestrant or ezetimibe , a cholesterol absorption inhibitor , should be considered for patients with very high low-density lipoprotein cholesterol ( LDL-C ) levels , while combination with either a fibric acid derivative or a fish oil should be considered for patients with high LDL-C and high triglyceride levels . A number of new lipid-lowering agents are currently in development , including cholesteryl ester transfer protein ( P11597 REA ) inhibitors , acyl coenzyme A : cholesterol acyltransferase ( ACAT ) inhibitors , ileal bile acid transport ( Q12908 REA ) inhibitors , microsomal triglyceride transfer protein ( P55157 REA ) inhibitors and dual peroxisome proliferator-activated receptor ( Q07869 REA ) alpha and gamma agonists . Introduction of these novel therapies will provide opportunities for developing different combination strategies that may help to optimise lipid profiles in patients who are currently difficult to treat . The introduction of new combinations will require careful study to ensure that the risks of drug interactions and adverse events are minimised .

Transcriptional profiling of Francisella tularensis infected peripheral blood mononuclear cells : a predictive tool for tularemia . In this study , we analyzed temporal gene expression patterns in human peripheral blood mononuclear cells ( PBMCs ) infected with the Francisella tularensis live vaccine strain from 1 to 24 h utilizing a whole human Affymetrix gene chip . We found that a considerable number of induced genes had similar expression patterns and functions as reported previously for gene expression profiling in patients with ulceroglandular tularemia . Among the six uniquely regulated genes reported for tularemia patients as being part of the alarm signal gene cluster , five , namely caspase 1 , Q9UL46 , TAP - 1 , P32455 REA , and P30793 REA , were induced in vitro . We also detected four out of the seven potential biomarkers reported in tularemia patients , namely P98066 REA at 4 h and P42224 REA , P50591 REA , and Q8WVN6 at 16 and 24 h . These observations underscore the value of using microarray expression profiling as an in vitro tool to identify potential biomarkers for human infection and disease . Our results indicate the potential involvement of several host pathways / processes in Francisella infection , notably those involved in calcium , zinc ion binding , Q07869 REA signaling , and lipid metabolism , which further refines the current knowledge of F . tularensis infection and its effects on the human host . Ultimately , this study provides support for utilizing in vitro microarray gene expression profiling in human PBMCs to identify biomarkers of infection and predict in vivo immune responses to infectious agents .

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 SUB , 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 .

[ A genetic view of addiction ] . The genetic analyses of addictions recently converted to genome-wide association studies ( GWAS ) and thanks to national and international consortia , allowed to recruit large cohorts of patients . This approach allowed the identification of the first susceptibility gene in addiction ( tobacco ) , with genes P30532 REA , P32297 REA and P30926 REA encoding the α5 , α3 and b4 subunits involved in the formation of nicotinic receptors , explaining 14 % of the attributable risk for tobacco dependence . Variants of P00325 REA and P00326 REA genes encoding alcohol dehydrogenases enzymes have also been consistently associated , this time with alcohol dependence ( AD ) . Finally , P14416 REA and Q8NFD2 genes , involved in the dopaminergic pathway , and which were initially associated with AD , are now considered to be involved in a broader phenotype ( addiction to psychoactive substances ) including opiates . Future directions in molecular study of addiction are gene x environment interactions though the epigenetic approach . Numerous studies already investigated the methylome in addiction , including histone and microRNA modifications .

Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 REA ) cause abetalipoproteinemia ( P00519 REA ) , characterized by the absence of plasma apoB-containing lipoproteins . In this study , we characterized the effects of various P55157 REA missense mutations found in P00519 REA patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 REA ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 REA . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 REA is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 REA .

Rizatriptan in migraineurs with unilateral cranial autonomic symptoms : a double-blind trial . The objective and background is to confirm in a double-blind , placebo-controlled study the high DB00669 MEN response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms . In this randomized , double-blind , placebo-controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo ( ratio 1:1 ) and treated for a single moderate or severe migraine attack . The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h . Secondary endpoints included pain relief , no associated symptoms and sustained pain freedom or relief . Significantly more patients reported pain freedom at 2 h after taking rizatriptan ( 54 % ) than after placebo ( 8 % ) ( therapeutic gain 46 % [ 28 % ; 64 % ] ; P < 0.001 ) . Similarly , significantly more patients reported total migraine freedom at 2 h after rizatriptan ( 51 % ) than after placebo ( 8 % ) ( therapeutic gain 43 % [ 26 % ; 61 % ] ; P < 0.001 ) . Rizatriptan was also more effective than placebo on most secondary endpoints . We confirm in a placebo-controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans , probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular P28222 REA / 1D receptors . Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients .

Cutting edge : high molecular weight hyaluronan promotes the suppressive effects of P01730 REA + CD25 + regulatory T cells . DB08818 MEN is a glycosaminoglycan present in the extracellular matrix . When hyaluronan is degraded during infection and injury , low m . w . forms are generated whose interactions influence inflammation and angiogenesis . Intact high m . w . hyaluronan , conversely , conveys anti-inflammatory signals . We demonstrate that high m . w . hyaluronan enhances human P01730 REA ( + ) CD25 ( + ) regulatory T cell functional suppression of responder cell proliferation , whereas low m . w . hyaluronan does not . High m . w . hyaluronan also up-regulates the transcription factor Q9BZS1 on P01730 REA ( + ) CD25 ( + ) regulatory T cells . These effects are only seen with activated P01730 REA ( + ) CD25 ( + ) regulatory T cells and are associated with the expression of P16070 REA isomers that more highly bind high m . w . hyaluronan . At higher concentrations , high m . w . hyaluronan also has direct suppressive effects on T cells . We propose that the state of HA in the matrix environment provides contextual cues to P01730 REA ( + ) CD25 ( + ) regulatory T cells and T cells , thereby providing a link between the innate inflammatory network and the regulation of adaptive immune responses .

Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis : DB11320 H1 receptors protect and H2 receptors accelerate atherosclerosis . DB11320 is not only essential for acute inflammatory reactions , but it also participates in a chronic inflammatory disorder . We generated apolipoprotein E ( apoE ) and histamine receptors ( HHRs ) , including the major H1 and H2 receptors ( P35367 REA , P25021 REA ) double knockout mice ( DKO ) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis , in which apoE-KO and DKO mice were fed a high cholesterol diet . We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in P35367 REA / apoE-DKO mice , but in P25021 REA / apoE-DKO mice less atherosclerosis , despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice . Furthermore , the increased expressions of scavenger receptors ( SRs ) , such as SR-A , P16671 REA and lectin-like oxidized low-density lipoprotein receptor 1 ( P78380 REA ) , nuclear factor-kappa B ( NFκB ) , monocyte chemoattractant protein ( P13500 REA ) , matrix metalloproteinases ( MMPs ) or liver X receptor ( LXR ) - related inflammatory signaling factors , were consistent with the pro-atherogenic phenotype of P25021 REA / apoE-DKO mice . We hypothesize that histamine / P35367 REA and P25021 REA signaling has conflicting innate functions , inflammatory / atherogenic and anti-inflammatory / anti-atherogenic actions , and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis , independently of serum cholesterol metabolism . Specific histamine signaling blockers , in particular , P25021 REA blockers , are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis .

DB00428 - induced increase in cholesterol ester transfer protein ( P11597 REA ) and its reversal by insulin in transgenic mice expressing human P11597 REA . High plasma triacylglycerol and low high-density lipoprotein levels are risk factors for cardiovascular disease in diabetes . Plasma high-density lipoprotein levels are regulated by cholesterol ester transfer protein ( P11597 REA ) . The regulation of P11597 REA under diabetic conditions is not clear , and this is due to a lack of appropriate models . We used transgenic mice expressing human P11597 REA to study the regulation of this protein under type - 1 diabetic conditions and further investigated whether insulin reverses the effect of diabetes . Mice expressing human P11597 REA under the control of its natural flanking region and age-matched littermates not expressing this protein were made diabetic by injecting streptozotocin , and the reversal of diabetes was assessed by injecting insulin . The plasma total cholesterol , low-density lipoprotein-cholesterol , and triacylglycerol concentrations were elevated , whereas high-density lipoprotein-cholesterol concentrations were reduced after the onset of diabetes . P01308 REA injection partially recovered this effect . The plasma cholesterol ester transfer activity , P11597 REA mass , and hepatic P11597 REA mRNA abundance were significantly higher in diabetic mice that were partially restored by insulin administration . There was a strong correlation between high-density lipoprotein-cholesterol concentrations and cholesterol ester transfer activity . These results suggest that an increase in P11597 REA under diabetic conditions might be a major factor responsible for increased incidence of diabetes-induced atherosclerosis .

Low ethanol concentration alters P30532 REA RNA levels during early human development . DB00898 MENMAX DB00898 MEN use is common and consumption during pregnancy has been shown to lead to a myriad of physical and neurologic abnormalities commonly referred to as fetal alcohol spectrum disorder . Substance addiction , which includes alcohol , has been shown to involve the major nicotinic acetylcholine receptor subunit P30532 REA . Using human embryonic stem cells as a model of early human development , we show that low concentrations of ethanol ( 20mM ) can alter the expression of P30532 REA . Changes in P30532 REA expression is linked to altered GABA and DB01221 receptor expression , as well as abnormal development of the frontal cortex . These results suggest that alcohol exposure can alter early neurologic development , which may favor addiction and other developmental abnormalities in unborn children .

Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV / HAART-associated dyslipidemia : further evidence for a unique form of metabolic syndrome in HIV patients . INTRODUCTION : Plasma triglycerides ( TG ) and HDL-C are inversely related in Metabolic Syndrome ( MetS ) , due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein ( P11597 REA ) . We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug ( HAART ) - treated HIV patients . METHODS : Fasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV / HAART patients and 71 HIV-negative persons ( 31 normotriglyceridemic ( NL ) and 40 hypertriglyceridemic due to type IV hyperlipidemia ( HTG ) ) . P11597 REA mass and activity were compared in 19 NL and 87 HIV / HAART subjects . RESULTS : Among the three groups , a plot of HDL-C vs . TG gave similar slopes but significantly different y-intercepts ( 9.24 ± 0.45 , 8.16 ± 0.54 , 6.70 ± 0.65 , sqrt ( HDL-C ) for NL , HIV and HTG respectively ; P < 0.001 ) ; this difference persisted after adjusting HDL-C for TG , age , BMI , gender , glucose , P01730 REA count , viral load and HAART strata ( 7.18 ± 0.20 , 6.20 ± 0.05 and 4.55 ± 0.15 sqrt ( HDL-C ) for NL , HIV and HTG , respectively , P < 0.001 ) . P11597 REA activity was not different between NL and HIV , but P11597 REA mass was significantly higher in HIV ( 1.47 ± 0.53 compared to 0.93 ± 0.27 μg / mL , P < 0.0001 ) , hence P11597 REA specific activity was lower in HIV ( 22.67 ± 13.46 compared to 28.46 ± 8.24 nmol / μg / h , P= 0.001 ) . CONCLUSIONS : Dyslipidemic HIV / HAART patients have a distinctive HDL-C plasma concentration adjusted for TG . The weak inverse relationship between HDL-C and TG is not explained by altered total P11597 REA activity ; it could result from a non - P11597 REA - dependent mechanism or a decrease in P11597 REA function due to inhibitors of P11597 REA activity in HIV patients ' plasma .

Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development . The brain plays a prominent role in the regulation of inflammation . Immune cells are under control of the so-called cholinergic anti-inflammatory reflex , mainly acting via autonomic innervation of the spleen . Activation of this reflex inhibits the secretion of proinflammatory cytokines and may reduce the development of atherosclerosis . Therefore , the aim of this study was to evaluate the effects of selective parasympathetic ( Px ) and sympathetic ( Sx ) denervation of the spleen on inflammatory status and atherosclerotic lesion development . Female P02649 REA * 3 - Leiden . P11597 REA mice , a well-established model for human-like lipid metabolism and atherosclerosis , were fed a cholesterol-containing Western-type diet for 4 wk after which they were subdivided into three groups receiving either splenic Px , splenic Sx , or sham surgery . The mice were subsequently challenged with the same diet for an additional 15 wk . Selective Px increased leukocyte counts ( i . e . , dendritic cells , B cells , and T cells ) in the spleen and increased gene expression of proinflammatory cytokines in the liver and peritoneal leukocytes compared with Sx and sham surgery . Both Px and Sx increased circulating proinflammatory cytokines IL - 1β and P05231 REA . However , the increased proinflammatory status in denervated mice did not affect atherosclerotic lesion size or lesion composition . CONCLUSION : Predominantly selective Px of the spleen enhances the inflammatory status , which , however , does not aggravate diet-induced atherosclerotic lesion development .

Array-comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array-CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array-based comparative genomic hybridization ( array-CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 REA , TERC , P42336 REA , P10242 REA , P08183 REA , P01112 REA , GARP , P30279 REA , P07332 REA , P04626 REA , P01127 REA , and Q05066 REA . The highest frequencies of losses were detected in p44S10 , O15164 REA , P06858 REA , Q13126 REA , P35226 REA , P11161 REA , and Q13163 REA . Genomic alterations in TGFbeta 2 , cellular retinoid-binding protein 1 gene ( P09455 REA ) , P42336 REA , P28222 REA , P01112 REA , P21860 REA , and O14965 REA differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 REA , P00519 REA , and P08620 REA were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 REA immunoreactivity in primary and metastatic OSCC . Higher P08620 REA immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 REA immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .

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 SUB ) 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 .

5 - Hydroxytryptamine stimulates cyclic AMP formation in the tunica muscularis mucosae of the rat oesophagus via Q13639 REA receptors . The nature of Q13639 REA receptor coupling in the tunica muscularis mucosae of the rat oesophagus has been studied . 5 - HT and renzapride stimulated cyclic AMP formation concentration dependently , with - log EC50 values of 7.1 and 6.8 , respectively . DB04917 MEN , relative to 5 - HT , acted as a partial agonist . Tropisetron ( ICS 205 930 ) and a novel Q13639 REA antagonist , SDZ 205 557 , inhibited 5 - HT-induced cyclic AMP production competitively , with pA2 estimates of 6.7 and 7.7 , respectively . These data are consistent with the hypothesis that Q13639 REA receptors mediate relaxation of the smooth muscle cells of the tunica muscularis mucosae of rat oesophagus via activation of adenylyl cyclase .

DB00074 MEN induction in patients receiving tacrolimus-based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine-based immunosuppression . However , its clinical utility in patients receiving tacrolimus-based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC - P01589 REA ) , 100 received basiliximab and delayed tacrolimus ( dTAC - P01589 REA ) , and 132 patients received tacrolimus without basiliximab ( TAC-No ) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC - P01589 REA compared to TAC-IL - 2RA and TAC-No Groups ( 33 vs . 14.9 vs . 14.3 % , p < 0.001 ) . Inferior creatinine clearance was observed in dTAC - P01589 REA Group compared to TAC - P01589 REA and TAC-No Groups at months 1 ( 41.6 vs . 49.9 vs . 44.8 mL / min , p = 0.004 ) , 3 ( 49.8 vs . 57.2 vs . 53.5 mL / min , p = 0.017 ) , and 6 ( 53.1 vs . 61.8 vs . 57.0 mL / min , p = 0.001 ) . Patients who received basiliximab ( TAC - P01589 REA and dTAC - P01589 REA Groups ) had lower incidence of posttransplant diabetes ( 24 vs . 18 vs . 39.3 % , p = 0.009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction .

P30047 REA - dependent and - independent inhibitors of P30793 REA . P30047 REA ( P30047 REA ) mediates the feedback inhibition of P30793 REA activity by ( 6R ) - L-erythro - DB00360 ( BH4 ) through protein complex formation . Since guanine and BH4 have a common pyrimidine ring structure , we examined the inhibitory effect of guanine and its analogs on the enzyme activity . DB02377 MEN , 8 - hydroxyguanine , 8 - methylguanine , and 8 - bromoguanine inhibited the enzyme activity in a P30047 REA - dependent and pH-dependent manner and induced complex formation between P30793 REA and P30047 REA . The type of inhibition by this group is a mixed type . All these properties were shared with BH4 . In striking contrast , inhibition by DB01667 and 8 - mercaptoguanine was P30047 REA - independent and pH-independent . The type of inhibition by DB01667 and 8 - mercaptoguanine was a competitive type . The two compounds did not induce complex formation between the enzyme and P30047 REA . These results demonstrate that guanine compounds of the first group bind to the BH4 - binding site of the P30793 REA / P30047 REA complex , whereas DB01667 and 8 - mercaptoguanine bind to the active site of the enzyme . Finally , the possible implications in Lesch-Nyhan syndrome and Parkinson diseases of the inhibition of P30793 REA by guanine and 8 - hydroxyguanine are discussed .

Detection of thymidylate synthase modulators by a novel screening assay . P04818 REA ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS-specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 ' - deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 MEN ) ; to the nonpyrimidine TS-inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( DB00293 ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS-affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 REA cells with DB00544 , DB01629 , FUdR , DB00432 MEN , AG331 , AG337 , DB00293 , and methotrexate up-regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription-polymerase chain reaction . Our studies demonstrate a novel application of a TBE-dependent reporter plasmid that could be used for the high-throughput identification of potential chemotherapeutic agents that modulate TS RNA-binding activity , either directly or indirectly .

A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase . The assembly of triglyceride-rich lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein B ( apoB ) , a microsomal triglyceride transfer protein ( P55157 REA ) , and protein disulfide isomerase ( P07237 REA ) . In the P55157 REA complex , the amino-terminal region of P55157 REA ( residues 22-303 ) interacts with the amino-terminal region of apoB ( residues 1-264 ) . Here , we report the identification and characterization of a site on apoB between residues 512 and 721 , which interacts with residues 517-603 of P55157 REA . P07237 REA binds in close proximity to this apoB binding site on P55157 REA . The proximity of these binding sites on P55157 REA for P07237 REA and amino acids 512-721 of apoB was evident from studies carried out in a yeast two-hybrid system and by co-immunoprecipitation . The expression of P07237 REA with P55157 REA and apoB 16 ( residues 1-721 ) in the baculovirus expression system reduced the amount of P55157 REA co-immunoprecipitated with apoB by 73 % . The interaction of residues 512-721 of apoB with P55157 REA facilitates lipoprotein production . Mutations of apoB that markedly reduced this interaction also reduced the level of apoB-containing lipoprotein secretion .

Agents with selective estrogen receptor ( ER ) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells . Tamoxifen , a member of the selective estrogen receptor modulator ( SERM ) family , is widely used in the treatment of estrogen receptor ( ER ) - expressing breast cancer . It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells , but whether this effect is drug specific or represents a general property of SERMs is unknown . In this study , we demonstrate that tamoxifen and DB05487 MEN , a novel benzopyranone with SERM activity , induce glioma cell apoptosis in a dose - and time-dependent manner . Moreover , administration of tamoxifen and DB05487 MEN suppresses tumor growth in vivo and extends animal survival in glioma xenograft models . None of the eight glioma cell lines examined express either P03372 REA or - beta , suggesting the mechanism for tamoxifen - and DB05487 MEN - induced glioma cell apoptosis is independent of the ER signaling pathway . Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and DB05487 MEN , and not by other apoptotic stimuli , including nuclear factor ( NF ) - kappaB with its target genes IEX - 3 , P04179 REA , P05231 REA , and P10145 REA . We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis , suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity . These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway .

Surface proteins of P13671 REA / 36 cells involved in dengue virus 4 binding and entry . Dengue virus ( DENV ) is the causative agent of the most important mosquito-borne viral disease , which is endemic to over 100 countries in tropical and subtropical areas of the world . It is transmitted to humans by Aedes mosquitoes . The first step in the viral infection of host cells is virion attachment to the plasma membrane , which is mediated by specific surface molecules . There are several molecules that participate in DENV infection of mosquitoes , but only a few have been identified . In this work , we co-purified 4 proteins from P13671 REA / 36 cells using a recombinant DENV 4 E protein and identified them as 70 kDa Heat Shock and 70 kDa Heat Shock cognate proteins ( HSP 70 / HSc 70 ) , Binding immunoglobulin protein ( P11021 REA ) , P10599 REA / protein disulphide isomerase ( P07237 REA ) , and 44 kDa Endoplasmic reticulum resident protein ( Q9BS26 ) via matrix-assisted laser desorption / ionisation time of flight ( Maldi-ToF ) analysis . Using immunofluorescence and flow cytometry assays , we observed re-localisation of HSP 70 / HSc 70 and , to a lesser extent , P11021 REA to the plasma membrane under stress conditions , such as during DENV infection . By performing binding and infection assays independently , we found that all 4 proteins participate in both processes , but to differing extents : HSP 70 / HSc 70 is the most critical component , while Q9BS26 is less important . Viral infection was not inhibited when the cells were incubated with antibodies against all of the surface proteins after virus binding , which suggests that DENV entry to P13671 REA / 36 cells is mediated by these proteins at the same step and not sequentially .

DB08827 SUB : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : DB08827 SUB ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 REA ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol ( LDL-C ) by a mean of more than 50 % . DB08827 SUB is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . DB08827 SUB undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 REA substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . DB08827 SUB is contraindicated in patients with moderate-to-severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 REA inhibitors , and pregnant patients . CONCLUSION : DB08827 SUB is an oral P55157 REA inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or can not tolerate statin therapy .