interacts_with DB09048?
[ Role of neurokinin-1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin-1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague-Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0.1 ml/kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT-PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r=0.83 , P < 0.01 ) and LCP ( r=0.79 , P < 0.01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury . Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association . Localized Epidermal Cysts as a Radiation Recall Phenomenon in a Melanoma Patient Treated with Radiotherapy and the P15056 Inhibitor DB08881 . P15056 inhibitors are broadly used for metastatic melanoma with P15056 mutations . Their use results in various cutaneous side effects , such as the development of keratoacanthomas and squamous cell carcinomas . We report a patient with metastatic melanoma treated with vemurafenib who developed dozens of histologically confirmed epidermal cysts within 2 months after initiation of vemurafenib administration . The cystic lesions were observed only in the localized area where a large exophytic melanoma tumor mass had been previously irradiated . Localized epidermal cysts may constitute an unusual radiation recall reaction in patients treated with P15056 inhibitors . Evaluation of degarelix in the management of prostate cancer . Medical castration using gonadotropin-releasing hormone ( DB00644 ) receptor agonists currently provides the mainstay of androgen deprivation therapy for prostate cancer . Although effective , these agents only reduce testosterone levels after a delay of 14 to 21 days ; they also cause an initial surge in testosterone that can stimulate the cancer and lead to exacerbation of symptoms ( " clinical flare " ) in patients with advanced disease . Phase III trial data for the recently approved P30968 blocker , degarelix , demonstrated that it is as effective and well tolerated as DB00644 agonists . However , it has a pharmacological profile more closely matching orchiectomy , with an immediate onset of action and faster testosterone and PSA suppression , without a testosterone surge or microsurges following repeated injections . As a consequence , with this DB00644 blocker , there is no risk of clinical flare and no need for concomitant antiandrogen flare protection . DB06699 therefore provides a useful addition to the hormonal armamentarium for prostate cancer and offers a valuable new treatment option for patients with hormone-sensitive advanced disease . Here , we review key preclinical and clinical data for degarelix , and look at patient-focused perspectives in the management of prostate cancer . Diphtheria toxin mutant CRM197 possesses weak P13639 -ADP-ribosyl activity that potentiates its anti-tumorigenic activity . CRM197 , a mutated diphtheria toxin ( DT ) , has long been recognized to be a non-toxic protein . Based on its non-toxic feature , this protein has been utilized for various purposes , including as an inhibitor of heparin-binding P01133 -like growth factor ( HB- P01133 ) and as an immunological adjuvant for vaccination . Here we show evidence that CRM197 has a weak toxicity . This toxicity was observed in cells over-expressing the DT receptor/proHB- P01133 , but not in parental cells , indicating that the toxicity was mediated through DT receptor . CRM197 did not show any toxicity toward DT-resistant cells , which have a mutation in elongation factor 2 , and a cell-free assay revealed the existence of weak P13639 -ADP ribosylation activity in fragment A of CRM197 . Thus , the present study indicates a requirement for specific care in the use of CRM197 at a high dosage , although the toxicity of CRM197 is about 10(6) times less than that of wild-type DT . We found that a monoclonal antibody to DT inhibited CRM197 toxicity , but did not affect the inhibitory activity of CRM197 toward HB- P01133 -induced mitogenic activity . CRM197 strongly inhibits tumour growth in nude mice . The anti-DT monoclonal antibody administered with CRM197 reduced the anti- tumourigenic effect of CRM197 , indicating that the toxicity of CRM197 potentiates its anti- tumourigenic effect . Hypothalamic-pituitary-adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A . Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats . Hyperactivity of the hypothalamic-pituitary-adrenal ( Q9Y251 ) axis is one of the most consistent biological findings in anxiety- and depression-related disorders . The Q9Y251 axis is reported to be susceptible to developmental reprogramming . The present study focused on Q9Y251 reactivity in postnatal day ( P01160 ) 80 male rats exposed perinatally to environmental-dose Q03001 . When female breeders were orally administered 2 μg/(kg.day) Q03001 from gestation day 10 to lactation day 7 , their offspring ( P01160 80 Q03001 -exposed rats ) showed obvious anxiety/depression-like behaviors . Notably , significant increase in serum corticosterone and adrenocorticotropin , and corticotropin-releasing hormone mRNA were detected in Q03001 -exposed rats before or after the mild stressor . Additionally , the level of glucocorticoid receptor mRNA in the hippocampus , but not the hypothalamus , was decreased in Q03001 -exposed rats . The levels of hippocampal mineralocorticoid receptor mRNA , neuronal nitric oxide synthase and phosphorylated DB02527 response element binding protein were increased in Q03001 -exposed rats . In addition , the testosterone level was in Q03001 -exposed rats . The results indicate that reprogramming-induced hyperactivity of the Q9Y251 axis is an important link between perinatal Q03001 exposure and persistent potentiation in anxiety and depression . Characterization of the interaction of ingenol 3-angelate with protein kinase C . DB05013 ( I3A ) is one of the active ingredients in Euphorbia peplus , which has been used in traditional medicine . Here , we report the initial characterization of I3A as a protein kinase C ( PKC ) ligand . I3A bound to P17252 in the presence of phosphatidylserine with high affinity ; however , under these assay conditions , little PKC isoform selectivity was observed . PKC isoforms did show different sensitivity and selectivity for down-regulation by I3A and phorbol 12-myristate 13-acetate ( PMA ) in WEHI-231 , Q9BPY8 -92 , and Colo-205 cells . In all of the three cell types , I3A inhibited cell proliferation with somewhat lower potency than did PMA . In intact CHO- P04264 cells , I3A was able to translocate different green fluorescent protein-tagged PKC isoforms , visualized by confocal microscopy , with equal or higher potency than PMA . PKC-delta in particular showed a different pattern of translocation in response to I3A and PMA . I3A induced a higher level of secretion of the inflammatory cytokine interleukin 6 compared with PMA in the WEHI-231 cells and displayed a marked biphasic dose-response curve for the induction . I3A was unable to cause the same extent of association of the C1b domain of PKC-delta with lipids , compared with PMA or the physiological regulator diacylglycerol , and was able to partially block the association induced by these agents , measured by surface plasmon resonance . The in vitro kinase activity of P17252 induced by I3A was lower than that induced by PMA . The novel pattern of behavior of I3A makes it of great interest for further evaluation . DB00183 infusions in patients with panic disorder . II. Neuroendocrinology . Cholecystokinin ( CCK ) has well-documented anxiogenic effects in animals and normal people , and panicogenic effects in patients with panic disorder , but little is known about its neuroendocrine profile . We examined neuroendocrine responses to intravenous infusions of pentagastrin , a selective P32239 agonist , in 10 patients with panic disorder and 10 normal control subjects . DB00183 potently activated the hypothalamic-pituitary-adrenal ( Q9Y251 ) axis , but did not release growth hormone or any of several vasoactive peptides ( neurokinin A , DB05875 , vasoactive intestinal peptide ) . The Q9Y251 axis response was unrelated to increases in symptoms . Panic patients did not differ from controls in neuroendocrine responses to the CCK agonist . Differential sensitivity to novelty stress accounted for the only patient-control differences in neuroendocrine profiles . The data suggest that CCK may help modulate normal Q9Y251 axis activity , but its anxiogenic effects are unrelated to its stimulatory effects on the Q9Y251 axis . DB00183 provides a safe and readily available probe for further study of CCK receptor systems in humans . The role of the spinal opioid receptor like1 receptor , the P25103 , and cyclooxygenase-2 in maintaining postoperative pain in the rat . Postoperative incident pain is not easily treated with opioids . Mechanical hyperalgesia induced by skin incision in rats is one of the animal models of postoperative incident pain . It is thought that mechanical hyperalgesia is maintained by the sensitization of spinal dorsal horn neurons . The P25103 , the opioid receptor like1 ( P41146 ) receptor , and cyclooxygenase ( P36551 ) -2 reportedly are involved in the development of spinal sensitization . In this study , we clarified the role of the P25103 , the P41146 receptor , and P35354 in the maintenance of mechanical hyperalgesia induced by skin incision . A 1-cm longitudinal incision was made through skin and fascia of the plantar aspect of the right foot in the rat . Four hours after the skin incision , significant mechanical hyperalgesia developed . An P41146 receptor agonist ( nociceptin ) , P25103 antagonists ( CP-96,345 and FK888 ) , and P35354 inhibitors ( NS398 and JTE522 ) were administered intrathecally 4 h after the skin incision . An P41146 receptor agonist and P25103 antagonists , but not P35354 inhibitors , significantly attenuated the level of mechanical hyperalgesia induced by the skin incision . These findings suggest that the spinal P41146 receptor and the P25103 play an important role in maintaining the mechanical hyperalgesia induced by skin incision . IMPLICATIONS : Intrathecal injection of an P25103 antagonist and an P41146 receptor agonist may be effective for the treatment of postoperative incident pain . Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague-Dawley rats were used . DB04630 ( 200 microg/day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0.02 mEq/day ) , and the experimental group was supplied with a higher sodium diet ( 2. /day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real-time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape . DB00125 -induced insulin release is decreased and glucagon increased in parallel with islet NO production . DB00435 ( NO ) produced by islet constitutive NO synthase ( P29474 ) is a putative modulator of islet hormone secretion . We show here for the first time that the release of insulin induced by L-arginine or L-homoarginine is inhibited and that of glucagon stimulated in parallel with the rate of islet NO production . It was found that L-homoarginine was approximately 25-30 % less potent than L-arginine as an insulin secretagogue but equally potent as a glucagon secretagogue . Biochemical determination of islet P29474 activity revealed that the NO production with L-homoarginine as substrate was only approximately 40 % of that of L-arginine . Selective inhibition of islet P29474 potentiated insulin release during amino acid stimulation . Moreover , inhibition of P29474 suppressed glucagon release , more so with L-arginine than with L-homoarginine as secretagogue , reflecting the relative rates of their NO production . In K+-depolarized islets , inhibition of P29474 enhanced the insulin response to L-arginine by 50 % and that to L-homoarginine by 23 % , largely corresponding to their relative NO production . The intracellular NO donor hydroxylamine dose dependently inhibited insulin but increased glucagon secretion in K+-depolarized and amino acid-stimulated islets . We conclude that both amino acids have a dual action on insulin release , since their stimulatory effects are reduced in parallel with the rates of their NO production . Furthermore , the greater NO production induced by L-arginine relative to L-homoarginine corresponds to NO-mediated increases in glucagon release . These NO effects are mainly exerted independently of membrane depolarization events . Efficacy and safety of repeated dosing of netupitant , a neurokinin-1 receptor antagonist , in treating overactive bladder . AIM : NK-1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks . Oral delivery of P01160 -1186 Q05397 inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models . Tumor metastasis is a leading cause of cancer-related death . Focal adhesion kinase ( Q05397 ) is a cytoplasmic tyrosine kinase recruited to integrin-mediated matrix attachment sites where Q05397 activity is implicated in the control of cell survival , migration , and invasion . Although genetic studies support the importance of Q05397 activity in promoting tumor progression , it remains unclear whether pharmacological Q05397 inhibition prevents tumor metastasis . Here , we show that the Q05397 inhibitor P01160 -1186 blocks Q05397 DB00135 -397 phosphorylation in vivo and exhibits anti-tumor efficacy in orthotopic breast carcinoma mouse tumor models . P01160 -1186 ( 100 mg/kg intraperitoneal , i.p. ) showed promising pharmacokinetics ( PK ) and inhibited tumor Q05397 DB00135 -397 phosphorylation for 12 hours . Oral administration of 150 mg/kg P01160 -1186 gave a more sustained PK profile verses i.p. , and when given twice daily , P01160 -1186 significantly inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lungs . Moreover , low-level 0.5 mg/ml P01160 -1186 ad libitum administration in drinking water prevented oncogenic P01116 - and P15056 -stimulated MDA-MB-231 breast carcinoma tumor growth and metastasis with inhibition of tumoral Q05397 and p130Cas phosphorylation . Although P01160 -1186 was not cytotoxic to cells in adherent culture , tumors from animals receiving P01160 -1186 exhibited increased TUNEL staining , decreased leukocyte infiltrate and reduced tumor-associated splenomegaly . In vitro , P01160 -1186 reduced tumor necrosis factor-a triggered interleukin-6 cytokine expression , indicating that Q05397 inhibition may impact tumor progression via effects on both tumor and stromal cells . As oral administration of P01160 -1186 also decreased experimental tumor metastasis , P01160 -1186 may therefore be useful clinically to curb breast tumor progression . Saccharomyces cerevisiae elongation factor 2 . Mutagenesis of the histidine precursor of diphthamide yields a functional protein that is resistant to diphtheria toxin . Protein synthesis elongation factor 2 ( P13639 ) is the target of the ADP-ribosylating activity of diphtheria toxin which is responsible for cell killing . DB03223 , an unique post-translationally modified histidine residue , is both required for and the site of this ADP-ribosylation . Although present in the P13639 of all eukaryotes and archaebacteria , the function of diphthamide is unknown . Here we describe the site-specific mutagenesis of the histidine precursor of diphthamide , histidine 699 , in yeast P13639 . Plasmid-borne EFT was randomly mutagenized at the histidine 699 codon , and the technique of plasmid shuffling was utilized to select strains that were maintained by the mutant EFT . These mutants were screened for diphtheria toxin resistance . Sequence analysis of the EFT in 49 toxin-resistant isolates showed that histidine 699 had been replaced by 1 of 4 amino acids : asparagine , glutamine , leucine , or methionine . All 11 of the possible codons corresponding to these 4 amino acids were found . The growth rates of cells sustained by the mutant forms of P13639 were slightly slower than those of isogenic wild-type cells . We conclude that despite its strict conservation and universal post-translational modification , the histidine precursor of diphthamide is not essential to the function of yeast P13639 in protein synthesis . Regulation of P28074 protein and β subunits of mammalian proteasome by constitutively activated signal transducer and activator of transcription 3 ( P40763 ) : potential role in bortezomib-mediated anticancer therapy . The ubiquitin-proteasome system facilitates the degradation of ubiquitin-tagged proteins and performs a regulatory role in cells . Elevated proteasome activity and subunit expression are found in several cancers . However , the inherent molecular mechanisms responsible for increased proteasome function in cancers remain unclear despite the well investigated and defined role of the mammalian proteasome . This study was initiated to elucidate the mechanisms involved in the regulation of β subunits of the mammalian proteasome . Suppression of P40763 tyrosine phosphorylation coordinately decreased the mRNA and protein levels of the β subunits of the 20 S core complex in DU145 cells . Notably , P28074 , a molecular target of bortezomib , was shown to be a target of P40763 . Knockdown of P40763 decreased P28074 protein . Inhibition of phospho- P40763 substantially reduced P28074 protein levels in cells expressing constitutively active- P40763 . Accumulation of activated P40763 resulted in the induction of P28074 promoter and protein levels . In addition , a direct correlation was observed between the endogenous levels of P28074 and constitutively active P40763 . P28074 and P40763 protein levels remained unaltered following the inhibition of proteasome activity . The P01133 -induced concerted increase of β subunits was blocked by inhibition of the P01133 receptor or P40763 but not by the PI3K/AKT or MEK/ P29323 pathways . Decreased proteasome activities were due to reduced protein levels of catalytic subunits of the proteasome in P40763 -inhibited cells . Combined treatments with bortezomib and inhibitor of P40763 abrogated proteasome activity and enhanced cellular apoptosis . Overall , we demonstrate that aberrant activation of P40763 regulates the expression of β subunits , in particular P28074 , and the catalytic activity of the proteasome . Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib-selected variants of Jurkat T cell lymphoblastic lymphoma/leukemia line . To study the mechanism of acquired resistance to bortezomib , a new antitumor drug that is the first therapeutic proteasome inhibitor , we established a series of bortezomib-resistant T lymphoblastic lymphoma/leukemia cell lines , designated the JurkatBs , from the parental Jurkat line via repeated drug selection . There were no significant differences in the growth curves or colony formation between the JurkatB cells and parental Jurkat cells . The effects of bortezomib on cytotoxicity , cell cycle arrest , and induction of apoptosis were decreased in JurkatB cells compared with parental Jurkat cells . A mutation in the proteasome beta5 subunit ( P28074 ) gene ( G322A ) , which encodes an amino acid change from Ala to DB00156 at polypeptide position 108 , was detected by sequencing full-length cDNA clones and direct polymerase chain reaction products of the P28074 gene . DB00188 caused less inhibition of chymotrypsin-like activity in resistant cells . When the G322A mutant P28074 was retrovirally introduced into parental Jurkat cells , it conferred bortezomib resistance to these cells , resulting in decreased cytotoxicity , apoptosis , and inhibition of chymotrypsin-like activity . The predicted structure of A108T-mutated P28074 shows a conformational change that suggests decreased affinity to bortezomib . In short , the G322A mutation of the P28074 gene is a novel mechanism for bortezomib resistance . Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways . White adipose tissue is intimately involved in the regulation of immunity and inflammation . We reported that human mesenteric preadipocytes express the DB05875 ( SP ) -mediated neurokinin-1 receptor ( P25103 ) , which signals proinflammatory responses . Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism(s) . Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery . Proliferative and antiapoptotic responses were delineated in 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium ( MTS ) , bromodeoxyuridine ( BrdU ) , caspase-3 , and TUNEL assays , as well as Western immunoanalysis . SP ( 10(-7) M ) increased MTS and proliferation ( BrdU ) and time dependently ( 15-30 min ) induced Akt , P01133 receptor , IGF receptor , integrin alphaVbeta3 , phosphatidylinositol 3-kinase , and PKC-theta phosphorylation . Furthermore , pharmacological antagonism of Akt and PKC-theta activation significantly attenuated SP-induced preadipocyte proliferation . Exposure of preadipocytes to the proapoptotic P48023 ( P48023 , 100 microM ) resulted in nuclear DNA fragmentation ( TUNEL assay ) , as well as increased cleaved poly ( ADP-ribose ) polymerase , cleaved caspase-7 , and caspase-3 expression . Cotreatment with SP almost completely abolished these responses in a P25103 -dependent fashion . SP ( 10(-7) M ) also time dependently stimulated expression 4E binding protein 1 and phosphorylation of P08133 S6 kinase , which increased protein translation efficiency . SP increases preadipocyte viability , reduces apoptosis , and stimulates proliferation , possibly via cell cycle upregulation and increased protein translation efficiency . SP-induced proliferative and antiapoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn 's disease . Ontogeny of gene expression in the gonadotroph of the developing female rat . During the infantile period of the female rat ( 8-21 postnatal days [ P01160 ] of age ) , there is a dramatic increase in plasma DB00094 , which is thought to be important in initiating ovarian activity and , perhaps , the onset of puberty . To begin to understand the regulation of this DB00094 surge , we determined the ontogenetic development of LHbeta , FSHbeta , and P30968 ( P30968 ) mRNA levels in the pituitary gland throughout the infantile period of the female rat . Steady-state mRNA levels were determined by an external standard quantitative reverse transcriptase polymerase chain reaction assay . FSHbeta and P30968 mRNA levels increased to peak on P01160 12 ( p < 0.03 ) . LHbeta mRNA levels remained relatively constant until rising on P01160 18 . A DB00644 antagonist ( 10-100 microg/animal ) was administered daily from P01160 8-11 or P01160 11-13 , and animals were killed on P01160 12 or P01160 14 , respectively . FSHbeta , LHbeta , and P30968 mRNAs were not affected by DB00644 antagonist treatment . Plasma DB00094 was selectively reduced in the first group , whereas both plasma LH and DB00094 were suppressed in the second group . These data indicate that gene expression of LHbeta , FSHbeta , and P30968 are differentially regulated in the infantile female rat pituitary . DB00644 is involved in regulating the secretion of DB00094 and LH during the infantile period but not in regulating FSHbeta , LHbeta , or P30968 mRNA gene expression . P01160 -induced decrease of iron regulatory protein activity is independent of P09601 induction . Atrial natriuretic peptide ( P01160 ) -preconditioned livers are protected from ischemia-reperfusion injury . P01160 -treated organs show increased expression of heme oxygenase ( HO ) -1 . Because P09601 liberates bound iron , the aim of our study was to determine whether P01160 affects iron regulatory protein ( P09544 ) activity and , thus , the levels of ferritin . Rat livers were perfused with Krebs-Henseleit buffer [ +/- P01160 , 8-bromo-cGMP ( 8-Br-cGMP ) , and tin protoporphyrin , 20 min ] , stored in University of Wisconsin solution ( 4 degrees C , 24 h ) , and reperfused ( 120 min ) . P09544 activity was assessed by gel-shift assays , and ferritin , P09544 phosphorylation , and PKC localization were assessed by Western blot . Control livers displayed decreased P09544 activity at the end of ischemia but no change in ferritin content during ischemia and reperfusion . P01160 -pretreated livers showed reduced P09544 activity , an effect mimicked by 8-Br-cGMP . Ferritin levels were increased in P01160 -pretreated organs . Simultaneous perfusion of livers with P01160 and tin protoporphyrin did not reduce P01160 -induced action , arguing against a role for P09601 in changes in P09544 activity . P01160 and 8-Br-cGMP decreased membrane localization of P17252 and PKC-epsilon , but this modulation of PKC seems unrelated to inhibition of P09544 binding . This work shows the cGMP-mediated attenuation of P09544 binding activity by P01160 , which results in increased hepatic ferritin levels . This change in IRPs is independent of P01160 -induced P09601 and reduced PKC activation . DB08439 impairs early tendon repair but improves later remodeling . BACKGROUND : P35354 inhibitors inhibit bone repair . HYPOTHESIS : Cyclooxygenase inhibitors might also have a negative effect on early tendon repair , although a positive effect on late tendon repair previously has been shown . STUDY DESIGN : Controlled laboratory study . METHODS : Achilles tendon transection was performed on 80 rats . Sixty rats were given daily intramuscular injections of either parecoxib ( 6.4 mg/kg body weight ) or saline for the first 5 days after surgery and sacrificed either at 8 or 14 days . The remaining 20 rats were given intramuscular parecoxib or saline injections from day 6 until sacrifice at 14 days . RESULTS : At 8 days , early parecoxib treatment caused a 27 % decrease in force at failure ( P = .007 ) , a 25 % decrease in maximum stress ( P = .01 ) , and a 31 % decrease in energy uptake ( P = .05 ) . Stiffness and transverse area were not significantly affected . At 14 days , early parecoxib treatment caused a decrease in stiffness ( P = .004 ) . In contrast to early treatment , late parecoxib treatment caused a 16 % decrease in cross-sectional area ( P = .03 ) and a 29 % increase in maximum stress ( P = .04 ) . CONCLUSIONS : During early tendon repair , a cyclooxygenase-2 inhibitor had a detrimental effect . During remodelling , however , inflammation appears to have a negative influence , and cyclooxygenase-2 inhibitors might be of value . CLINICAL RELEVANCE : The results suggest that cyclooxygenase-2 inhibitors should be used with care in the early period after tendon injury . A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors . P10721 or alpha-platelet-derived growth factor receptor ( alpha- P09619 ) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors ( GIST ) . Despite excellent responses to imatinib mesylate ( IM ) , patients are relapsing . We developed an IM-resistant GIST cell line ( GIST-R ) from the IM-sensitive GIST882 cell line ( GIST-S ) by growing these cells in IM . Gene expression profiling ( GEP ) of GIST-S , GIST-R cells and two IM resistant GIST patients demonstrated that P10721 is downregulated implying a major role in IM resistance . Instead , GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - P30530 - in a ' kinase switch ' . Further , the two IM resistant GIST patients express P30530 and not c-Kit , seen by immunohistochemistry ( IHC ) . Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to P30530 . In GIST-R , P30530 is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation . The kinase switch is associated with a morphological change from spindle to epithelioid . Molecular modeling of the kinase domain of mutant c-Kit ( V654A ) and P30530 showed no binding to IM but efficient binding to DB05216 , a novel c-Kit/ P30530 kinase inhibitor . DB05216 synergizes with docetaxel ( taxotere ) and is cytotoxic to GIST cells .