interacts_with DB00007?
Luteinizing Hormone-Releasing Hormone ( P01148 ) -I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo . The objective of this study was to determine the effects of an luteinizing hormone-releasing hormone ( P01148 ) -I antagonist , DB00050 , on human multiple myeloma ( MM ) cells and to elucidate the mechanisms of action . We showed that P01148 -I and P22888 -I genes were expressed in MM cell lines and primary MM cells . Treatment with DB00050 inhibited growth and colony-forming ability of myeloma cells , including cell lines resistant to arsenic trioxide , bortezomib , or lenalidomide . DB00050 induced apoptosis in myeloma cells including primary myeloma cells . In addition , DB00050 inhibited the growth of human myeloma cells xenografted into mice without any apparent side effects . DB00050 downregulated the nuclear factor-kappa B ( NF-κB ) pathway activity and the expression of cytokines , including interleukin 6 , insulin-like growth factor 1 , P15692 , and stromal-derived factor 1 , important for myeloma cell growth and survival in myeloma cells and/or marrow stromal cells from myeloma patients . DB00050 decreased the phosphorylation of extracellular signal regulated kinase 1/2 and P40763 in myeloma cells , two crucial pathways for myeloma cells growth and survival . Moreover , the expression of P38936 and p53 was increased , whereas that of antiapoptotic proteins Bcl-2 and Bcl-x(L) was reduced by DB00050 . Our findings indicate that DB00050 induces cytotoxicity in myeloma cells through various mechanisms and provide a rationale for investigating DB00050 for the treatment of MM . Mutations of the Wilms tumor 1 gene ( P19544 ) in older patients with primary cytogenetically normal acute myeloid leukemia : a Cancer and Leukemia Group B study . We previously reported the adverse prognostic impact of Wilms tumor 1 gene ( P19544 ) mutations in younger adult cytogenetically normal acute myeloid leukemia ( CN-AML ) . Here , we investigated 243 older ( > or = 60 years ) primary CN-AML patients . P19544 mutated ( WT1mut ) patients ( 7 % ) had P36888 -ITD more frequently ( P < .001 ) , lower hemoglobin ( P = .01 ) , higher white blood cell count ( P = .03 ) and percentage blood blasts ( P = .03 ) , and a shorter overall survival ( P = .08 ) than P19544 wild-type ( WT1wt ) patients . Comparing older and younger WT1mut patients , they had similar pretreatment characteristics and outcome . By contrast , among WT1wt CN-AML , younger patients had a significantly better outcome . A P19544 mutation-associated gene-expression signature , reported here for the first time , included P40200 , a leukemia stem cell-specific marker , and genes involved in gene regulation ( eg , Q03164 , P29590 , and P63162 ) and in proliferative and metabolic processes ( eg , P06213 , Q9Y4H2 , and Q13131 ) , supporting the role of mutated P19544 in deregulating multiple homeostatic processes . Our results indicate that WT1mut CN-AML represents a distinct entity with poor treatment response across age groups . This study has been registered at www.clinicaltrials.gov as # NCT00900224 . Transcript and protein profiling identifies signaling , growth arrest , apoptosis , and NF-κB survival signatures following P01148 receptor activation . P01148 significantly inhibits proliferation of a proportion of cancer cell lines by activating P01148 receptor ( P30968 ) -G protein signaling . Therefore , manipulation of P30968 signaling may have an under-utilized role in treating certain breast and ovarian cancers . However , the precise signaling pathways necessary for the effect and the features of cellular responses remain poorly defined . We used transcriptomic and proteomic profiling approaches to characterize the effects of P30968 activation in sensitive cells ( HEK293- P30968 , SCL60 ) in vitro and in vivo , compared to unresponsive HEK293 . Analyses of gene expression demonstrated a dynamic response to the P01148 superagonist DB06825 . Early and mid-phase changes ( 0.5-1.0 h ) comprised mainly transcription factors . Later changes ( 8-24 h ) included a P01148 target gene , P01215 , and up- or downregulation of transcripts encoding signaling and cell division machinery . Pathway analysis identified altered MAPK and cell cycle pathways , consistent with occurrence of G(2)/M arrest and apoptosis . Nuclear factor kappa B ( NF-κB ) pathway gene transcripts were differentially expressed between control and DB06825 -treated SCL60 cultures . Reverse-phase protein and phospho-proteomic array analyses profiled responses in cultured cells and SCL60 xenografts in vivo during DB06825 anti-proliferation . Increased phosphorylated NF-κB ( p65 ) occurred in SCL60 in vitro , and p-NF-κB and IκBε were higher in treated xenografts than controls after 4 days DB06825 . NF-κB inhibition enhanced the anti-proliferative effect of DB06825 in SCL60 cultures . This study reveals details of pathways interacting with intense P30968 signaling , identifies potential anti-proliferative target genes , and implicates the NF-κB survival pathway as a node for enhancing P01148 agonist-induced anti-proliferation . DB01370 alters iron and manganese uptake and regulation of surface transferrin receptors in primary rat oligodendrocyte cultures . P02787 ( Tf ) is a major transport protein for both iron ( Fe ) and aluminum ( Al ) , as well as manganese ( Mn ) and it can mediate cellular uptake of these elements via cell surface Tf receptors . To study the effect of Al-Tf on Tf receptor regulation , primary oligodendrocyte cultures were prepared from cortices of newborn rats . The effects of Al-Tf on 54Mn and 59Fe uptake were compared to those of apo- , Fe- , or Mn-Tf ( 1.25 microM ) . To examine changes in cell surface Tf binding capacity , preincubation ( 4 h , 37 degrees C ) was performed with apo- , Al- or Fe-Tf and homologous receptor binding studies were subsequently conducted with 125I-Fe-Tf at 4 degrees C . Incubation with Al-Tf , but not with equimolar amounts of Al chloride or Al citrate , led to dose-related increases in cellular Al . Incubation with either Al- or Fe-Tf decreased 59Fe uptake , while incubation with either Al- or Mn-Tf decreased 54Mn uptake . Surface Tf receptor sites/cell were 1.05 , 0.60 and 0.46 x 10(5) after incubations with equivalent amounts of apo- , Fe- , and Al-Tf respectively . The data suggest that Al-Tf down-regulates surface Tf receptors on oligodendrocytes and can limit Fe and Mn uptake through this mechanism . A study on co-localization of DB00094 and its receptor in rat hippocampus . It has been known that DB00644 , LH and their receptors exist in hippocampal neurons . However , whether DB00094 and its receptor also exist in hippocampal neurons remained unknown yet . In situ hybridization , double-labeled immunofluorescence stain and double-labeled immunohistochemistry stain in adjacent sections were used in our research to study the distribution , co-localization of DB00094 and its receptor and co-localization of DB00094 and P30968 in rat hippocampus . The result found that pyramidal neurons from P00915 to P22748 region and granule neurons in dentate gyrus could express DB00094 and its receptor , majority of hippocampal neurons co-expressed DB00094 and its receptor , DB00094 and P30968 . These suggested that hippocampal neurons not only express DB00094 but also act as DB00094 target cells . DB00094 may regulate the function of hippocampal neurons by ways of paracrine or autocrine . At the same time , DB00644 may regulate the function of DB00094 neuron in hippocampus through P30968 . Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations . The rational development of specific inhibitors for the approximately 500 protein kinases encoded in the human genome is impeded by a poor understanding of the structural basis for the activity and selectivity of small molecules that compete for DB00171 binding . Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms , we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase P24941 . We report here that polarization and dynamic hydrogen bonding effects , so far undetected by crystallography , affect both their activity and selectivity . The effects arise from the specific solvation patterns of water molecules in the DB00171 binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactions and explain the unexpectedly high potency of certain inhibitors such as 3-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one ( DB03428 ) . The Lys89 residue in the DB00171 -binding pocket of P24941 is observed to form temporary hydrogen bonds with the three most potent inhibitors . This residue is replaced in P11802 by Thr89 , whose shorter side-chain can not form similar bonds , explaining the relative selectivity of the inhibitors for P24941 . Our results provide a generally applicable computational method for the analysis of biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors . The Lyme disease vaccine takes its toll . Vaccination with Borrelia burgdorferi outer surface protein ( Osp ) A can induce a protective response against Lyme disease and serves as a model to understand the generation of protective immune responses against the spirochete . The innate response to pathogens is activated by specific Toll-like receptors ( TLRs ) that recognize distinct pathogen-associated molecular patterns . O60603 is of particular interest for B. burgdorferi research because O60603 recognizes several pathogen-associated molecular patterns , including lipoproteins . O60603 may form heterodimers with Q9Y2C9 to identify diacylated lipoproteins , while O60603 works in concert with Q15399 to recognize triacylated lipoproteins such as OspA . We will discuss the role of Q15399 /2 in the development of responses to OspA in Q15399 -and O60603 -deficient mice , and in selected individuals that received the OspA vaccine . While > 95 % of human OspA-based Lyme disease vaccine recipients develop OspA antibodies , a very small group of individuals did not develop detectable humoral responses against OspA . We demonstrated that this hyporesponsiveness to OspA vaccination was associated with decreased cell surface expression of Q15399 . Moreover , Q15399 - and O60603 -deficient mice did not develop significant levels of OspA antibodies following vaccination with OspA , providing a correlation with human hyporesponsiveness to OspA . These data suggest that defects in the Q15399 /2 signaling pathway are associated with an impaired ability to generate antibodies following immunization with DB00045 . Chronic delivery of a thrombospondin-1 mimetic decreases skeletal muscle capillarity in mice . Angiogenesis is an essential process for normal skeletal muscle function . There is a growing body of evidence suggesting that thrombospondin-1 ( P07996 -1 ) , a potent antiangiogenic protein in tumorigenesis , is an important regulator of both physiological and pathological skeletal muscle angiogenesis . We tested the hypothesis that chronic exposure to a P07996 -1 mimetic ( DB05434 ) , which targets the P16671 P07996 -1 receptor , would decrease skeletal muscle capillarity as well as alter the balance between positive and negative angiogenic proteins under basal conditions . Osmotic minipumps with either DB05434 or vehicle ( 5 % dextrose ) were implanted subcutaneously in the subscapular region of C57/BL6 mice for 14 days . When compared to the vehicle treated mice , the DB05434 group had a 20 % decrease in capillarity in the superficial region of the gastrocnemius ( GA ) , 11 % decrease in the plantaris ( Q02083 ) , and a 35 % decrease in the soleus ( SOL ) . DB05434 also decreased muscle protein expression of vascular endothelial growth factor ( P15692 ) in both the GA ( -140 % ) and SOL ( -62 % ) ; however there was no change in P15692 in the Q02083 . Serum P15692 was not altered in DB05434 treated animals . Endogenous P07996 -1 protein expression in all muscles remained unaltered . Tunnel staining revealed no difference in muscle apoptosis between DB05434 and vehicle treated groups . These data provide evidence that the anti-angiogenic effects of P07996 -1 are mediated , at least in part , via the P16671 receptor . It also suggests that under physiologic conditions the P07996 -1/ P16671 axis plays a role in regulating basal skeletal muscle microvessel density . Comparison of lipopeptide-based immunocontraceptive vaccines containing different lipid groups . We have previously shown that incorporating the lipid moiety dipalmitoyl-S-glyceryl cysteine ( Pam2Cys ) into peptide structures effectively adjuvants otherwise weak immunogens . In this study lipopeptides based on luteinising hormone releasing hormone ( P01148 ) as a B cell epitope , [ B ] , were synthesised in tandem with a 17-residue T-helper epitope , [ T ] , derived from the fusion protein of the morbillivirus canine distemper virus . In this way vaccine candidates with the structure [ T ] -[B] were produced . These peptides were then lipidated with different diacylated moieties . The acyl moieties used were : palmitic acid ( C16 ) to give Pam2Cys , stearic acid ( C18 ) to give Ste2Cys , lauric acid ( C12 ) to give Lau2Cys and DB04519 ( Q99618 ) to give Oct2Cys . We compared the immunogenicities of these simple lipopeptides in BALB/c mice by measuring their ability to induce anti- P01148 antibodies and found that immunogenicity was dependent on the length of the alkane chains of the incorporated lipid moieties with the hierarchy C16=C18 > C12 > Q99618 . The antibody levels elicited by the lipopeptides also correlated with their ability to inhibit the reproductive capability of female mice in fertility trials . Furthermore , the C16 lipopeptide was the most effective in activating dendritic cells , measured by up regulation of surface MHC Class II molecules , and also in activating NF-kappaB in a Toll-like receptor-2 ( O60603 ) -dependent manner . Effects of phenacetin and its metabolite p-phenetidine on P23219 and P35354 activities and expression in vitro . The present study was aimed to test the possible cyclooxygenase ( P36551 ) -1/ P35354 selectivity of the old analgesic drug phenacetin and its metabolite p-phenetidine , which exhibits high renal toxicity . DB00316 ( acetaminophen ) , the main metabolite of phenacetin with low renal toxicity , and indomethacin were selected as reference compounds . Collagen-stimulated platelet thromboxane B2 ( TxB2 ) production and phorbol 12-myristate-13-acetate ( PMA ) -induced neutrophil prostaglandin E2 ( DB00917 ) synthesis were used as indicators for P23219 and P35354 activity , respectively . DB03783 was even less potent than paracetamol to reduce the production of both TxB2 and DB00917 , and no clear preference for either of the P36551 -enzymes was seen . P-phenetidine was a more potent inhibitor , already at nanomolar level , of the synthesis of these prostanoids than indomethacin and showed some preference to P35354 inhibition . Somewhat higher , micromolar , concentrations of p-phenetidine also reduced P35354 expression in neutrophils . We suggest that the very potent inhibitory activity of p-phenetidine on DB00917 synthesis combined with the reduction of P35354 expression could explain the renal papillary necrosis in phenacetin kidney . DB00644 1 directly affects corpora lutea lifespan in Mediterranean buffalo ( Bubalus bubalis ) during diestrus : presence and in vitro effects on enzymatic and hormonal activities . The expression of gonadotropin-releasing hormone ( P01148 ) receptor ( P30968 ) and the direct role of P01148 on corpora lutea function were studied in Mediterranean buffalo during diestrus . Immunohistochemistry evidenced at early , mid , and late luteal stages the presence of P30968 only in large luteal cells and P01148 in both small and large luteal cells . Real-time PCR revealed P30968 and P01148 mRNA at the three luteal stages , with lowest values in late corpora lutea . In vitro corpora lutea progesterone production was greater in mid stages and lesser in late luteal phases , whereas prostaglandin F2 alpha ( PGF2alpha ) increased from early to late stages , and DB00917 was greater in the earlier-luteal phase . Cyclooxygenase 1 ( prostaglandin-endoperoxide synthase 1 ; P23219 ) activity did not change during diestrus , whereas P35354 increased from early to late stages , and DB00917 -9-ketoreductase ( DB00917 -9-K ) was greater in late corpora lutea . P23219 activity was greater than P35354 in early corpora lutea and lesser in late luteal phase . In corpora lutea cultured in vitro , the P01148 analog ( buserelin ) reduced progesterone secretion and increased PGF2alpha secretion as well as P35354 and DB00917 -9-K activities at mid and late stages . DB00917 release and P23219 activity were increased by buserelin only in late corpora lutea . These results suggest that P01148 is expressed in all luteal cells of buffalo , whereas P30968 is only expressed in large luteal phase . Additionally , P01148 directly down-regulates corpora lutea progesterone release , with the concomitant increases of PGF2alpha production and P35354 and DB00917 -9-K enzymatic activities . Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole-cell patch-clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin-releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . DB00007 ( 10(-9)-10(-7) M ) , a specific DB00644 analog , concentration-dependently elicited a long-lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 -induced synaptic potentiation was blocked by 1 microM [ Acetyl-3,4-dehydro-Pro1,D-p-F-Phe2,D-Trp3,6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 -induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H-7 ) . The results suggest a long-term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes . P05019 stimulates human intestinal smooth muscle cell growth by regulation of P55008 phase cell cycle proteins . Autocrine production of insulin-like growth factor-I ( P05019 ) regulates growth of human intestinal muscle cells by activation of distinct phosphatidylinositol 3-kinase ( P19957 -kinase ) -dependent and P27361 /2-dependent pathways . The aim of the present study was to determine the mechanisms by which P05019 regulates the G(1) phase of the cell cycle and muscle cell proliferation . Incubation of quiescent cells with P05019 stimulated time-dependent cell cycle progression measured by using fluorescence-activated cell sorting analysis and by incorporation of [(3)H]thymidine . Studies using a microarray-based approach were used initially to identify genes expressed in human intestinal muscle encoding proteins known to participate in the G(1) phase of the cell cycle that were regulated by P05019 . Incubation of muscle cells for 24 h with P05019 elicited greater than fivefold increase in the expression of cyclin D1 and greater than twofold increase in retinoblastoma protein ( Rb1 ) . P05019 elicited a time-dependent increase in cyclin D1 protein levels mediated jointly by P27361 /2-dependent and P19957 -kinase-dependent mechanisms . Increase in cyclin D1 levels was accompanied by a time-dependent increase in cyclin D1-dependent cyclin-dependent kinase-4 ( P11802 ) activity . P05019 also elicited a rapid time-dependent increase in Rb-(Ser807/811) phosphorylation , the specific target of the cyclin D(1)-dependent P11802 kinase , and a slower increase in total Rb protein levels . We conclude that P05019 stimulates G(1) phase progression , DNA synthesis , and cell proliferation of human intestinal smooth muscle cells . Effects of P05019 on proliferation are mediated jointly by P27361 /2-dependent and P19957 -kinase-dependent pathways that regulate cyclin D1 levels , P11802 activity , and Rb activity . DB00644 agonists reduce the migratory and the invasive behavior of androgen-independent prostate cancer cells by interfering with the activity of P05019 . Androgen-independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior . We have previously shown that DB00644 agonists exert a direct and specific inhibitory action on the proliferation of androgen-independent prostate cancer cells ( DU 145 ) . These compounds mainly act by interfering with the mitogenic activity of growth factors , such as the insulin-like growth factor-I ( P05019 ) . The present experiments were performed to clarify whether DB00644 agonists might also affect the migratory and the invasive behavior of androgen-independent prostate cancer cells and to define their mechanism of action . First we showed that the DB00644 agonist DB00007 reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane . Experiments were then performed to clarify whether the DB00644 agonist might act by interfering with the pro-metastatic activity of P05019 . We found that , in androgen-independent prostate cancer cells , DB00007 : a ) interferes with the P05019 system ( receptor protein expression and tyrosine-phosphorylation ) ; b ) abrogates the P05019 -induced phosphorylation of Akt ( a kinase previously shown by us to mediate the pro-metastatic activity of P05019 in prostate cancer cells ) ; c ) counteracts the migration and the invasive activity of the cells stimulated by P05019 ; d ) abolishes the effects of P05019 on cell morphology , on actin cytoskeleton organization and on alphavbeta3 integrin expression/cellular localization . These data indicate that DB00644 agonists , in addition to their well known antiproliferative effect , can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen-independent prostate cancer cells , expressing the P30968 . DB00644 agonists act by interfering with the pro-metastatic activity of the growth factor P05019 . The bovine 5' AMPK gene family : mapping and single nucleotide polymorphism detection . The DB00131 -activated protein kinase ( AMPK ) family is an ancient stress response system whose primary function is regulation of cellular DB00171 . Activation of AMPK , which is instigated by environmental and nutritional stresses , initiates energy-conserving measures that protect the cell by inhibition and phosphorylation of key enzymes in energy-consuming biochemical pathways . The seven genes that comprise the bovine AMPK family were mapped in cattle by using a radiation hybrid panel . The seven genes mapped to six different cattle chromosomes , each with a LOD score greater than 10.0 . Q13131 mapped to BTA 20 , P54646 and O43741 to BTA 3 , Q9Y478 to BTA 17 , P54619 to BTA 5 , Q9UGJ0 to BTA 4 , and Q9UGI9 to BTA 2 . Five of the seven genes mapped to regions expected from human/cattle comparative maps . O43741 and Q9UGI9 , however , have not been mapped in humans . We predict these genes to be located on HSA 1 and 2 , respectively . Additionally , one synonymous and one non-synonymous single nucleotide polymorphism ( SNP ) were detected in Q9UGI9 in Bos taurus cattle . In an effort to determine ancestral origins , various herds of mixed breed cattle as well as other ruminant species were characterized for sequence variation in this region of Q9UGI9 . Owing to the physiological importance of this gene family , we believe that its individual genes are candidate genes for conferring resistance to diseases in cattle . Physiological and enzymatic properties of the ram epididymal soluble form of germinal angiotensin I-converting enzyme . The 94-kDa ram epididymal fluid form of the sperm membrane-derived germinal angiotensin I-converting enzyme ( P12821 ) was purified by chromatography , and some of its enzymatic properties were studied . For the artificial substrate furanacryloyl-L-phenylalanylglycylglycine ( FAPGG ) , the enzyme exhibited a Michaelis constant ( K(m) ) of 0.18 mM and a V(max) of 34 micromoles/ ( min x mg ) and for hippuryl-L-histidyl-L-leucine a K(m) of 2.65 mM and a V(max) of 163 micromoles/ ( min x mg ) under the defined standard conditions ( 300 mM NaCl and 50 mM DB03754 ; pH 7.5 and 8.3 , respectively ) . The FAPGG hydrolysis was decreased by 82.5 % and 67.5 % by DB00974 and dithioerythritol , respectively , and was totally inhibited by specific P12821 inhibitors such as captopril , P- DB00142 - DB00150 -Pro- DB00125 -Pro- DB00142 - DB00167 -Pro-Pro , and lisinopril . Optimum activity for FAPGG was with pH 6.0 , 50 mM chloride , and 500 microM zinc . Under the various conditions tested , bradykinin , angiotensin ( Ang ) I , Ang II , and P01148 were competitors for FAPGG . Bradykinin and angiotensin I were the best competitors . The enzyme cleaved Ang I into Ang II , and the optimal conditions were with pH 7.5 and 300 mM chloride . The relationship between the carboxypeptidase activity in seminal plasma and the prediction of fertility of young rams was also studied . These results indicated a correlation between sperm concentration and P12821 activity in semen but showed no statistically significant correlation between such activity and fertility of the animal . Finally , we tested the role of P12821 in fertilization ; no difference in the in vitro fertilization rate was observed in the presence of 10(-4) M captopril . Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide : molecular basis of isozyme-drug discrimination . P22748 ( CAIV ) is a membrane-associated enzyme anchored to plasma membrane surfaces by a phosphatidylinositol glycan linkage . We have determined the 2.8-angstroms resolution crystal structure of a truncated , soluble form of recombinant murine CAIV . We have also determined the structure of its complex with a drug used for glaucoma therapy , the sulfonamide inhibitor brinzolamide ( DB01194 ) . The overall structure of murine CAIV is generally similar to that of human CAIV ; however , some local structural differences are found in the active site resulting from amino acid sequence differences in the " 130 's segment " and the residue-63 loop ( these may affect the nearby catalytic proton shuttle , DB00117 -64 ) . Similar to human CAIV , the C-terminus of murine CAIV is surrounded by a substantial electropositive surface potential that may stabilize the interaction with the phospholipid membrane . Binding interactions observed for brinzolamide rationalize the generally weaker affinity of inhibitors used in glaucoma therapy toward CAIV compared with CAII . P00797 -angiotensin system modulation : the weight of evidence . Modulation of the renin-angiotensin system is considered to be the most complete way to manage high-risk patients including those with hypertension . P12821 ( P12821 ) inhibitors are effective at reducing the morbidity and mortality of patients with overt clinical heart failure , asymptomatic left ventricular dysfunction , and uncomplicated myocardial infarction . Furthermore , recent trials like the Heart Outcomes Prevention Evaluations ( HOPE ) study and the EUropean trial on Reduction Of cardiac events with DB00790 in stable coronary Artery disease ( EUROPA ) support extending the use of P12821 inhibitors to the routine/first-line treatment of patients with an increased global cardiovascular risk . Although some investigators have seen the development of angiotensin II receptor blockers ( ARBs ) as a more effective and tolerable way of reproducing the benefits of P12821 inhibition , there remain important concerns regarding the distinct pharmacologic profiles and modes of action of these two classes of drugs . Careful evaluation of data from recent large-scale studies revealed that , unlike P12821 inhibitors , ARBs are either neutral or may actually increase rates of myocardial infarction despite similar levels of blood pressure reduction . The fact that this effect is most apparent when ARBs are compared with placebo in the absence of concomitant P12821 inhibitors suggests that differential effects on the angiotensin II type 2 ( AT(2) ) receptors may be important . Other important pharmacologic differences are also known to be present and may be of direct relevance . The weight of available evidence therefore supports the use of appropriate P12821 inhibitor regimens , although not ARBs , in the treatment of global cardiovascular risk . Use of plasma somatomedin-C/insulin-like growth factor I measurements to monitor the response to nutritional repletion in malnourished patients . Changes in plasma somatomedia-C/insulin-like growth factor I ( Sm-C/ P05019 ) concentrations are a sensitive indicator of the anabolic response of normal human volunteers to alterations in nutritional intake . To determine if measurement of this peptide could be used to monitor the response to nutritional repletion in malnourished patients , six patients were studied while receiving nutritional support for periods of 10-16 days . Plasma Sm-C/ P05019 increased from a mean basal level of 0.67 +/- 0.15 U/ml ( +/-1 SD ) to a peak of 1.80 +/- 0.44 U/ml on day 10 , then declined to a concentration of 1.28 +/- 0.49 U/ml by day 16 . All patients entered positive nitrogen balance by day 2 and nitrogen accretion continued throughout the study . Changes in serum concentrations of prealbumin , transferrin , and retinol-binding protein were compared to changes in Sm-C/ P05019 during nutritional support . P02766 increased to a posttreatment mean of 121 +/- 23 % of control by the end of the study ( p greater than 0.05 , NS ) . Likewise , there was minimal change in retinol-binding protein , a peak value of 118 +/- 21 % of control being reached by day 12 of treatment ( p greater than 0.05 , NS ) . P02787 also showed minimal change , increasing to a mean value of 110 % +/- 13 % of control by day 12 ( p greater than 0.05 , NS ) . Measurement of plasma Sm-C/ P05019 concentrations appears to be a much more sensitive index of acute directional changes in nutritional status than other plasma proteins commonly used to monitor nutritional responses . The increase of Sm-C/ P05019 correlated temporally with entry into positive nitrogen balance. ( ABSTRACT TRUNCATED AT 250 WORDS ) Twisting immune responses for allogeneic stem cell therapy . Stem cell-derived tissues and organs have the potential to change modern clinical science . However , rejection of allogeneic grafts by the host 's immune system is an issue which needs to be addressed before embryonic stem cell-derived cells or tissues can be used as medicines . Mismatches in human leukocyte class I antigens and minor histocompatibility antigens are the central factors that are responsible for various graft-versus-host diseases . Traditional strategies usually involve suppressing the whole immune systems with drugs . There are many side effects associated with these methods . Here , we discuss an emerging strategy for manipulating the central immune tolerance by naturally " introducing " donor antigens to a host so a recipient can acquire tolerance specifically to the donor cells or tissues . This strategy has two distinct stages . The first stage restores the thymic function of adult patients with sex steroid inhibitory drugs ( P01148 -A ) , keratinocyte growth factor ( KGF ) , interleukin 7 ( P13232 ) and P07333 -like tyrosine kinase 3 ( P36888 ) . The second stage introduces hematopoietic stem cells and their downstream progenitors to the restored thymus by direct injection . Hematopoietic stem cells are used to introduce donor antigens because they have priority access to the thymus . We also review several clinical cases to explain this new strategy .