MH_dev_317

DB06663 MEN , a multiple somatostatin receptor subtypes ligand , reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion . Somatostatin ( SRIF ) analogs have been employed in medical therapy of non-functioning pituitary adenomas ( DB04552 ) , with contrasting results . Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor ( P15692 REA ) secretion and action , and that P15692 REA expression may be related to pituitary tumor growth . The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on P15692 REA secretion and cell proliferation in human DB04552 primary cultures . We assessed the expression of SRIF receptors ( P30872 REA - 5 ) , the in vitro effects on P15692 REA secretion , and on cell viability of SRIF and of the stable SRIF analog pasireotide ( DB06663 MEN ) , which activates P30872 REA , 2 , 3 , and 5 . Twenty-five DB04552 were examined by RT-PCR for expression of alpha-subunit , SSTR , P15692 REA , and P15692 REA receptors 1 ( P15692 REA - Q96GN5 ) and 2 ( P15692 REA - R2 ) . Primary cultures were tested with SRIF and with pasireotide . All DB04552 samples expressed alpha-sub , P15692 REA and P17948 REA and 2 , while SSTR expression pattern was highly variable . Two different groups were identified according to P15692 REA secretion inhibition by SRIF . P15692 REA secretion and cell viability were reduced by SRIF and pasireotide in the ' responder ' group , but not in the ' non-responder ' group , including DB04552 expressing P35346 REA . SRIF and pasireotide completely blocked forskolin-induced P15692 REA secretion . In addition , SRIF and pasireotide completely abrogated the promoting effects of P15692 REA on DB04552 cell viability . Our data demonstrate that pasireotide can inhibit DB04552 cell viability by inhibiting P15692 REA secretion , and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected DB04552 .

Comparison of the anti-inflammatory and therapeutic actions of P37231 REA agonists rosiglitazone and troglitazone in experimental colitis . Non-specific inflammatory bowel diseases , including ulcerative colitis and Crohn ` s disease , are chronic non-infectious diseases that showed an increase in prevalence in recent years , particularly in the developed countries . The effective methods of their treatment and prevention of recurrences are currently under investigation . One type of therapy that can prevent the inflammatory recurrence in the gastrointestinal tract is the Q07869 REA - γ agonists thiazolidinediones . Numerous studies available in literature have confirmed the beneficial effects of thiazolidinediones ( glitazones ) , namely rosiglitazone and troglitazone in the gut . The objective of the present study was to compare the possible effects of rosiglitazone 10 mg / kg b . w . or 30 mg / kg b . w . and troglitazone 30 mg / kg b . w . on experimental colitis induced by administration of 1.5 % dextran sodium sulphate ( DSS ) administered in drinking water to rats . Specimens collected from the large intestine were microscopically evaluated , and concentrations of Th1 - dependent ( P60568 REA , P27352 REA ) and Th2 - dependent ( P05112 REA , P22301 REA ) cytokines were determined in the serum and intestinal homogenates . Both rosiglitazone and troglitazone have demonstrated significant anti-inflammatory properties . This observation was confirmed by histopathological and immunoenzymatic tests . The therapeutic efficacy of rosiglitazone was dose-dependent . DB00197 MEN resulted in significantly stronger enhancement of anti-inflammatory cytokine expression than rosiglitazone and comparable downregulation of pro-inflammatory cytokine expression compared to rosiglitazone used in a higher dose .

miR -17-5 p targets the p300 / CBP-associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells . BACKGROUND : P10275 REA ( AR ) signalling is critical to the initiation and progression of prostate cancer ( PCa ) . Transcriptional activity of AR involves chromatin recruitment of co-activators , including the p300 / CBP-associated factor ( Q92831 REA ) . Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease . Whether miRNAs regulate Q92831 REA expression in PCa cells to regulate AR transcriptional activity is still unclear . METHODS : Expression of Q92831 REA was investigated in several PCa cell lines by qRT-PCR , Western blot , and immunocytochemistry . The effects of Q92831 REA expression on AR-regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation , reporter gene construct analysis , and MTS assay . Targeting of Q92831 REA by miR -17-5 p was evaluated using the luciferase reporter assay . RESULTS : Q92831 REA was upregulated in several PCa cell lines . Upregulation of Q92831 REA promoted AR transcriptional activation and cell growth in cultured PCa cells . Expression of Q92831 REA in PCa cells was associated with the downregulation of miR -17-5 p . Targeting of the 3 ' - untranslated region of Q92831 REA mRNA by miR -17-5 p caused translational suppression and RNA degradation , and , consequently , modulation of AR transcriptional activity in PCa cells . CONCLUSIONS : Q92831 REA is upregulated in cultured PCa cells , and upregulation of Q92831 REA is associated with the downregulation of miR -17-5 p . Targeting of Q92831 REA by miR -17-5 p modulates AR transcriptional activity and cell growth in cultured PCa cells .

Contribution of the 37 - kDa laminin receptor precursor in the anti-metastatic P08118 - derived peptide DB04985 MEN cell surface binding . PURPOSE : DB04985 MEN is an anti-metastatic synthetic peptide with promising therapeutic efficacy against hormone-refractory prostate cancer . The characterization of the DB04985 MEN peptide cell surface binding / internalization mechanisms and of the receptors involved remained to be explored . RESULTS : [ ( 14 ) C ] DB04985 MEN cell surface binding assays showed rapid and transient kinetic profile , that was inhibited by RGD peptides , laminin , hyaluronan , and type-I collagen . RGD peptides were however unable to inhibit DB04985 MEN intracellular uptake . Far-Western ligand binding studies enabled the identification of the 37 - kDa laminin receptor precursor ( P08865 REA ) as a potential ligand for DB04985 MEN . Overexpression of the recombinant P08865 REA indeed led to an increase in DB04985 MEN binding but unexpectedly not to its uptake . CONCLUSIONS : Our data support the implication of laminin receptors in cell surface binding and in transducing DB04985 MEN anti-metastatic effects , and provide a rational for targeting cancers that express high levels of such laminin receptors .

Role of the androgen receptor axis in prostate cancer . P10275 REA ( AR ) is expressed in nearly all prostate cancers , including treatment-refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand-independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 REA ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 REA causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 REA and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 REA - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 REA , but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 REA and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .

P10275 REA gene mutations in 46 , XY females with germ cell tumours . We present clinical findings and molecular characterization in two patients previously diagnosed as 46 , XY female gonadal dysgenesis with germ cell tumour . Both patients showed a female general phenotype with unambiguously female external genitalia and primary amenorrhoea compatible with complete androgen insensitivity syndrome . The first patient , at the age of 31 years , developed a dysgerminoma measuring 8 x 13 x 10 cm in one abdominal testis . Genetic analysis revealed a single nucleotide substitution on exon 4 in the hormone-binding domain of the androgen receptor ( AR ) gene , resulting in a change of codon 681 GAG ( glutamic acid ) to P29372 REA ( lysine ) . The second patient , at the age of 17 years , developed a dysgerminoma measuring 12 x 10 x 7 cm in one abdominal testis and gonadoblastoma in the other testis . Genetic analysis showed a point mutation on exon 3 in the DNA-binding domain of the AR gene resulting in a change of codon 607 P01215 REA ( arginine ) to CAA ( glutamine ) . Arg 607 - Gln and Arg 608 - Lys point mutations in the DNA-binding domain of the AR gene have been associated with male breast cancer in partial androgen insensitivity syndrome . A codon 607 mutation in the DNA-binding domain of the AR gene in our patient 2 is associated with early development of germ cell tumour . We suggest regular molecular genetic analysis of the AR gene in 46 , XY females with germ cell tumour and androgen insensitivity syndrome to detect differences in the specific regions of AR gene involved in early progression toward oncogenesis of the dysgenetic gonads .

P10275 REA as a therapeutic target . Androgens function as sex hormone primarily via activation of a single androgen receptor ( AR , or P10275 REA ) . AR is an important therapeutic target for the treatment of diseases such as hypogonadism and prostate cancer . AR ligands of different chemical structures and / or pharmacological properties are widely used for these therapeutic applications , and all of the AR ligands currently available for therapy modulate AR function via direct binding to the ligand-binding pocket ( P18428 REA ) of the receptor . In the past ten years , our understanding of AR structure and molecular mechanism of action has progressed extensively , which has encouraged the rapid development of newer generation of AR ligands , particularly tissue-selective AR ligands . With improved tissue selectivity , future generations of AR ligands are expected to greatly expand the therapeutic applications of this class of drugs . This review will provide an overview of the common therapeutic applications of currently available AR ligands , and discussion of the major challenges as well as novel therapeutic strategies proposed for future drug development .

Discovery and role of methylidene imidazolone , a highly electrophilic prosthetic group . The elimination of ammonia from alpha-amino acids is a chemically difficult process . While the non-acidic beta-proton has to be abstracted , the much more acidic ammonium protons must remain untouched to maintain the leaving group ability of this positively charged group . DB00117 MEN and phenylalanine ammonia-lyases ( P42357 REA and Q9P2V4 ) possess a catalytically essential electrophilic group which has been believed to be dehydroalanine for 30 years . Recently , the X-ray structure of P42357 REA has been solved . The electron density was not consistent with dehydroalanine but showed the presence of methylidene imidazolone ( Q9NP71 ) instead . The high electrophilicity of this prosthetic group as well as the geometry at the active site support a previously proposed mechanism involving a Friedel-Crafts-type attack at the aromatic ring of the substrate . Further biochemical evidence for this unprecedented electrophile-assisted ammonia elimination is also presented . Although no X-ray structure of Q9P2V4 has been published as yet , spectrophotometrical evidence for the presence of Q9NP71 has been provided . Finally , a chemical model for the Q9P2V4 reaction is described .

Changes of thyroid hormone levels and related gene expression in zebrafish on early life stage exposure to triadimefon . In this study , zebrafish was exposed to triadimefon . Thyroid hormones levels and the expression of related genes in the hypothalamic-pituitary-thyroid ( Q9HD23 ) axis , including thyroid-stimulating hormone ( P01222 REA ) , deiodinases ( dio 1 and dio 2 ) and the thyroid hormone receptor ( thraa and thrb ) were evaluated . After triadimefon exposure , increased DB00451 MEN can be explained by increased thyroid-stimulating hormone ( P01222 REA ) . The conversion of DB00451 MEN to DB00279 ( deiodinase type I-dio 1 ) was decreased , which reduced the DB00279 level . P10828 REA ( thrb ) mRNA levels were significantly down-regulated , possibly as a response to the decreased DB00279 levels . The overall results indicated that triadimefon exposure could alter gene expression in the Q9HD23 axis and that mechanisms of disruption of thyroid status by triadimefon could occur at several steps in the synthesis , regulation , and action of thyroid hormones .

P10275 REA YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF 164 in the motor neuron degeneration . X-linked spinal and bulbar muscular atrophy ( SBMA ) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration . SBMA is caused by polyglutamine repeat expansions in the androgen receptor ( AR ) . To determine the basis of AR polyglutamine neurotoxicity , we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells . The AR100 transgenic mice developed a late-onset , gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration , indicating striking recapitulation of the human disease . We then tested the hypothesis that polyglutamine-expanded AR interferes with CREB binding protein ( CBP ) - mediated transcription of vascular endothelial growth factor ( P15692 REA ) and observed altered CBP-AR binding and P15692 REA reduction in AR100 mice . We found that mutant AR-induced death of motor neuron-like cells could be rescued by P15692 REA . Our results suggest that SBMA motor neuronopathy involves altered expression of P15692 REA , consistent with a role for P15692 REA as a neurotrophic / survival factor in motor neuron disease .

DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 REA expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin-dependent kinase 4 expression , and increased P38936 REA expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .

Sp1 is required for the early response of alpha 2 ( I ) collagen to transforming growth factor-beta 1 . It is currently debated whether P05412 REA or Sp1 is the factor that mediates transforming growth factor beta 1 ( TGF-beta ) stimulation of the human alpha 2 ( I ) collagen ( P08123 REA ) gene by binding to an upstream promoter element ( TbRE ) . The present study was designed to resolve this controversy by correlating expression of P08123 REA , P05412 REA , and Sp1 in the same cell line and under different experimental conditions . The results strongly indicate that Sp1 is required for the immediate early response of P08123 REA to TGF-beta and P05412 REA is not . The Sp1 inhibitor mithramycin blocked stimulation of alpha 2 ( I ) collagen mRNA accumulation by TGF-beta , whereas the P05412 REA inhibitor curcumin had no effect . Furthermore , antibodies against Jun-B and c-Jun failed to identify immunologically related proteins in the TbRE-bound complex , irrespective of whether they were purified from untreated or TGF-beta-treated cells . P05412 REA did bind to the TbRE probe in vitro , but only in the absence of the upstream Sp1 recognition sequence . Based on this finding and DNA transfection results , we conclude that the P05412 REA sequence of the TbRE represents a cryptic site used under experimental conditions that either eliminate the more favorable Sp1 binding site or force the balance toward the less probable . Finally , a combination of cell transfections and DNA-binding assays excluded that P08123 REA transactivation involves the retinoblastoma gene product ( P06400 REA ) , an activator of Sp1 , the P06400 REA - related protein P28749 REA , an inhibitor of Sp1 , or the Sp1 - related repressor , Sp3 .

Xaliproden ( SR57746A ) induces P08908 REA receptor-mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half-life . In the present study , we investigated the mechanism of action of a non-peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 REA agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 REA and P28482 REA isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 REA adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden-induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden-induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 REA antagonist , pindobind , and pertussis toxin abolished the Xaliproden-induced P29323 REA stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein-coupled receptor , P08908 REA . These results demonstrate clearly that the non-peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin-sensitive mechanism involving P08908 REA receptors , P38936 REA Ras and MEK - 1 and by PKC and Akt pathways .

Mapping of the regulatory subunits RI beta and RII beta of DB02527 MEN - dependent protein kinase genes on human chromosome 7 . The genes encoding the regulatory subunits RI beta ( locus P31321 REA ) and RII beta ( locus P31323 REA ) of human DB02527 MEN - dependent protein kinase have been mapped in the basic CEPH ( Centre d'Etude du Polymorphisme Humain ) family panel of 40 families to chromosome 7p and 7q , respectively , using the enzymes HindIII and BanII recognizing the corresponding restriction fragment length polymorphisms ( RFLPs ) . Previous data from the CEPH database and our present RFLP data were used to construct a six-point local framework map including P31321 REA and a seven-point framework map including P31323 REA . The analysis placed P31321 REA as the most distal of the hitherto mapped 7p marker loci and resulted in an unequivocal order of pter - P31321 REA - D7S21 - D7S108 - D7S17 - D7S149 - D7S62 - cen , with a significantly higher rate of male than female recombination between P31321 REA and D7S21 . The 7q regulatory gene locus , P31323 REA , could also be placed in an unambigous order with regard to the existing CEPH database 7q marker loci , the resulting order being cen-D 7S371 - ( P08123 REA , D7S79 ) - P31323 REA - MET-D 7S87 + + + - TCRB-qter . Furthermore , in situ hybridization to metaphase chromosomes physically mapped P31323 REA to band q22 on chromosome 7 .

The use of microcalorimetry and HPLC for the determination of degradation kinetics and thermodynamic parameters of DB00790 MEN Erbumine in aqueous solutions . DB00790 MEN Erbumine ( O15534 REA ) is one of the newly used angiotensin-converting enzyme inhibitors ( P12821 REA inhibitors ) and is used for the treatment of patients with hypertension and symptomatic heart failure . It has two main degradation pathways , i . e . the degradation by hydrolysis and the degradation by cyclization . An isothermal heat conduction microcalorimetry ( MC ) and high pressure liquid chromatography ( HPLC ) were used for the characterization of aqueous solutions of O15534 REA and its stability properties . The rates of heat evolved during degradation of perindopril were measured by MC as a function of temperature and pH and from these data rate constant and change in enthalpy of the reactions were determined . With the HPLC method the concentration of perindopril and its degradation products were measured as a function of time in aqueous solutions of different pH that were stored at different temperatures . We demonstrated that reactions of degradation of perindopril at observed conditions follow the first order kinetics . The Arrhenius equation for each pH was determined . At pH 6.8 only one degradation pathway is present , i . e . the degradation by hydrolysis . Degradation constants for this pathway calculated from MC data are in good agreement with those obtained from HPLC . MC as a non-specific technique was shown to be useful in studies of O15534 REA when one reaction was present in the sample and also when more chemical and physical processes were simultaneously running .

Release of mediators of systemic inflammatory response syndrome in the course of a severe delayed hemolytic transfusion reaction caused by anti-D . BACKGROUND : In vitro studies suggest that mediators of systemic inflammatory response syndrome are generated in the course of hemolytic transfusion reactions . Evidence for the in vivo significance of these findings is given by the present clinical and laboratory analysis of a severe delayed hemolytic transfusion reaction ( P10275 REA ) . CASE REPORT : A 67 - year-old patient ( blood group O , D-negative ) with a negative pretransfusion antibody screen received a massive transfusion because of arterial bleeding ( Day 1 ) . The transfusion of group O , D-positive red cell concentrates was unavoidable because of limited supplies . At Day 10 , the patient developed a P10275 REA with symptoms of septic-toxic syndrome and signs of hemolysis ; he received an exchange transfusion . Serologic markers , as well as proinflammatory and anti-inflammatory mediators , were monitored at the onset of the P10275 REA and during the exchange transfusion . RESULTS : At Day 10 , the direct antiglobulin test was positive ; anti-D was present , most likely as the result of an anamnestic immune response . Interleukin ( IL ) - 1 was not detectable ; all other mediators monitored were elevated : IL - 1 receptor antagonist , tumor necrosis factor , P05231 REA , P10145 REA , P22301 REA , neopterin , elastase , C3a - desArg , P02741 REA , and fibrinogen . Most of the values declined during the exchange transfusion , which was followed by an improvement of the clinical presentation . CONCLUSIONS : Mediators of systemic inflammatory response syndrome were released in the course of a P10275 REA caused by anti-D . Severe clinical symptoms could be treated successfully by exchange transfusion .

P01308 REA signaling in fatty acid and fat synthesis : a transcriptional perspective . Transcription of enzymes involved in FA and TAG synthesis is coordinately induced in lipogenic tissues by feeding and insulin treatment . The three major transcription factors involved are P22415 REA , SREBP - 1c , and LXRα . New insights into the insulin-signaling pathway ( s ) that control ( s ) lipogenic gene transcription via these factors have recently been revealed . Dephosphorylation / activation of DNA-PK by P50391 REA causes phosphorylation of P22415 REA that in turn recruits Q92831 REA to be acetylated for transcriptional activation . SREBP - 1c can be induced by mTORC 1 , bifurcating lipogenesis from AKT-activated gluconeogenesis . LXRα may serve as a glucose sensor and , along with Q9NP71 , may activate lipogenic genes in the fed state . Dysregulation of FA and TAG metabolism often contributes to metabolic diseases such as obesity , diabetes , and cardiovascular diseases . Transcription factors and signaling molecules involved in transcriptional activation of FA and TAG synthesis represent attractive targets for the prevention and treatment of metabolic diseases .

The role of tumor suppressor dysregulation in prostate cancer progression . P10275 REA activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 REA ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 REA and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 REA and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 REA and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 REA and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .

P05231 REA - receptor polymorphisms rs12083537 , rs2228145 , and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis . DB06273 MENMAX DB06273 MEN ( TCZ ) , a monoclonal antibody targeting the human interleukin - 6 - receptor ( IL - 6R ) , is indicated for the treatment of rheumatoid arthritis ( RA ) . We examined whether three P08887 REA single-nucleotide polymorphisms rs12083537 , rs2228145 ( formerly rs8192284 ) , and rs4329505 with previously reported functional effects were associated with clinical response to TCZ in a retrospective study cohort consisting of 79 RA patients . Three months after initiation of TCZ therapy , changes in swollen joint count ( SJC ) and , subordinately , tender joint count ( TJC ) , serum-CRP , DAS 28 - CRP , and EULAR-response were tested for association with the P08887 REA - haplotype or genotype . The major allele ( A ) of rs12083537 and the minor allele ( C ) of rs4329505 were associated with a poor SJC response ( P= 0.02 and 0.02 , respectively ) . Moreover , the AAC-haplotype ( for rs12083537 , rs2228145 , and rs4329505 , respectively ) was associated with a poor SJC response ( P= 0.00004 ) and , with borderline significance , EULAR-response ( P= 0.05 ) . These data suggest that genetic variation in P08887 REA may aid in predicting TCZ therapy outcome in RA patients .

P10275 REA rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 SUB , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .

Mutations in the circadian gene O15516 REA in colorectal cancer . The circadian clock regulates daily variations in physiologic processes . O15516 REA acts as a regulator in the circadian apparatus controlling the expression of other clock genes , including O15534 REA . Clock genes have been implicated in cancer-related functions ; in this work , we investigated O15516 REA as a possible target of somatic mutations in microsatellite unstable colorectal cancers . Combining microarray gene expression data and public gene sequence information , we identified O15516 REA as 1 of 790 putative novel microsatellite instability ( MSI ) target genes . A total of 101 MSI colorectal carcinomas ( CRC ) were sequenced for a coding microsatellite in O15516 REA . The effect of restoring O15516 REA expression was studied in LS180 cells lacking wild-type O15516 REA by stably expressing Q86UG4 - O15516 REA or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry . Putative novel O15516 REA target genes were searched by using ChIP-seq . O15516 REA mutations occurred in 53 % of MSI CRCs . Restoring O15516 REA expression in cells with biallelic O15516 REA inactivation resulted in protection against UV-induced apoptosis and decreased G ( 2 ) - M arrest in response to ionizing radiation . Using ChIP-Seq , novel O15516 REA - binding elements were identified near DNA damage genes P38936 REA , Q14596 , P38398 REA , and Q92878 REA . O15516 REA is shown to be mutated in cancer , and altered response to DNA damage provides one plausible mechanism of tumorigenesis .

Comparative modeling of the N-terminal domain of the 67kDa laminin-binding protein : implications for putative ribosomal function . P17931 REA / p40 ( P08865 REA ) precursor appears to be involved in two seemingly unrelated activities-cell adhesion and ribosomal biogenesis . Analysis of primary structure revealed a two-domain organization of the P08865 REA . The N-terminal portion of P18428 REA is similar to the S2 family of prokaryotic ribosomal proteins , while the C-terminus is unique for Metazoa and is involved in extraribosomal functions . To gain insight into putative ribosomal functions of P18428 REA we performed comparative modeling of the N-terminal domain using crystal structures of S2p from Thermus thermophilus . The P18428 REA model assumes an alpha-beta sandwich fold similar to that of S2 . Modeling revealed the loss of a significant portion of ribosomal RNA ( rRNA ) interaction domain , lack of conservation of many residues involved in interactions with rRNA , and a major shift in surface charge distribution ( compared to the S2 protein ) . The overall stability of the fold argues against a proposed transmembrane domain in the central part of the protein . Partial overlap in S2 and laminin-binding domains suggests that ribosomal and surface receptor functions would be mutually exclusive . The possible biological role of P08865 REA bifunctionality is discussed .

Opioid and non-opioid DB01221 MEN - mediated predator-induced analgesia in mice and the effects of parasitic infection . The present study examined the nociceptive responses ( 50 degrees C , hot-plate ) of uninfected and subclinically parasitized male mice exposed to the odor of a predator , an ecologically relevant threatening stimulus . In uninfected mice a 15 - min exposure to 2 - propylthietane , the major component of weasel odor , induced a naloxone-reversible opioid analgesia . A 30 - s exposure elicited a shorter duration and lower amplitude ' non-opioid ' analgesia that was insensitive to naloxone , partially sensitive to either the serotonin - 1A ( P08908 REA ) agonist , 8 - OH-DPAT , or the GABAA antagonist , bicuculline , and blocked by the competitive N-methyl-D-aspartate ( DB01221 MEN ) antagonist , NPC 12626 . In contrast , mice chronically ( 25 days ) and subclinically infected with the murine nematode , Heligmosomoides polygyrus , failed to show a significant non-opioid analgesia and displayed a markedly lower level of opioid analgesia than uninfected mice . These results suggest that DB01221 MEN receptor mechanisms are potently associated with the expression of the analgesia arising from exposure to the naturally aversive stimulus of predator odor . These findings also demonstrate that parasites , and likely other subchronic infections , can have a significant impact on the display of opioid and non-opioid stress-induced analgesia arising from exposure to the ethologically relevant stimulus of predator odor .

Serum free thyrotropin subunit in congenital isolated thyrotropin deficiency . In two patients with congenital isolated thyrotropin ( DB00024 ) deficiency , serum DB00024 determined by a sensitive immunoradiometric assay ( IRMA ) was consistently undetectable . The basal levels of serum free P01215 REA subunit ( P01215 REA ) determined by a specific radioimmunoassay ( RIA ) were elevated in the hypothyroid state , and decreased to the undectable level during displacement therapy with thyroid hormone . The serum free P01215 REA significantly increased following intravenous administration of thyrotropin releasing hormone ( TRH ) . Serum free P01222 REA subunit ( P01222 REA ) was undectable . These findings suggest that DB00024 deficiency in this disease is not due to absence of thyrotroph in the pituitary gland or deficiency of P01215 REA , but to abnormalities of the P01222 REA gene .