interacts_with DB09048?
Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 ) to increase the synaptic concentrations of serotonin . Beta-site amyloid precursor protein cleaving enzyme-1 ( P56817 -1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer 's disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 -1 and P31645 . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4.2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran- P31645 ' interaction and ' levomilnacipran- P56817 ' interaction were found to be -7.47 and -8.25 kcal/mol , respectively . DB08918 was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 during ' levomilnacipran- P31645 ' interaction . In the case of ' levomilnacipran- P56817 ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 -1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 and P56817 -1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 -1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial . Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization-activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f-channel isoforms expressed in the human atrium ( O60741 , 2 and 4 ) , Q9Y3Q4 mRNA levels measured by RT-PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( +85 % for Q9Y3Q4 ) ; concurrently , miR-1 expression was significantly reduced . In patch-clamped atrial myocytes , current-specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( -60 to -80 mV ) ; accordingly , a 10-mV rightward shift of the activation curve occurred ( P < 0.01 ) . β-Adrenergic and Q13639 receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 -mediated effect was significantly reduced ( P < 0.02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain-of-function of If , which may contribute to enhanced atrial ectopy . Role of DB05875 signaling in enhanced nociceptive sensitization and local cytokine production after incision . Substance P ( SP ) signaling facilitates nociceptive sensitization in various inflammatory and chronic pain models and we postulated that SP signaling might also contribute to the development of post-incisional hyperalgesia . These studies used mice with a deletion of the pre-protachykinin A gene ( ppt-A(-/-) ) which codes for SP to determine the role of SP signaling in post-incisional pain and in the increased cytokine and nerve growth factor ( P01138 ) expression observed in the incised skin . SP deficient ppt-A(-/-) mice displayed reduced mechanical allodynia and heat hyperalgesia compared to the wild-type ( wt ) mice at all post-incision time points , despite similar baseline values ( p < 0.001 ) . Furthermore , the P25103 antagonist LY303870 attenuated mechanical allodynia produced by incision in the wt mice ( p < 0.001 ) . Incision also up-regulated P05231 , P01375 and KC levels but not IL-1beta after 2h in the wt mice skin . However , ppt-A(-/-) mice had more skin P01138 levels 2h post-incision . Subcutaneous hind paw SP injection produced acute and transient elevations of IL-1beta , P05231 , and KC but modest elevations in P01375 levels in the wt mice . Systemic LY303870 reversed the SP-induced elevations of these cytokines . Hind paw injection of P05231 and P01138 dose dependently produced less mechanical allodynia in the ppt-A(-/-) compared to wt mice . Additionally , SP produced mechanical allodynia in a dose-dependent fashion in wt mice . Therefore , SP supports nociceptive sensitization after hind paw incision and potentially participates directly in modulating the intensity of inflammatory response in peri-incisional tissue . Substance P induces rapid and transient membrane blebbing in U373MG cells in a P38936 -activated kinase-dependent manner . U373MG astrocytoma cells endogenously express the full-length neurokinin 1 receptor ( P25103 ) . Substance P ( SP ) , the natural ligand for P25103 , triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK293- P25103 cells . In both cell lines , the SP-induced morphological changes are Gq-independent , and they require the Rho , Rho-associated coiled-coil kinase ( ROCK ) signaling pathway . Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs . DB01394 , a tubulin polymerization inhibitor , blocked SP-induced blebbing in U373MG but not in HEK293- P25103 cells . Although P38936 -activated kinase ( PAK ) is expressed in both cell lines , SP induced rapid phosphorylation of PAK in U373MG , but failed to phosphorylate PAK in HEK293- P25103 cells . The cell-permeable Rho inhibitor P01024 transferase inhibited SP-induced PAK phosphorylation , but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation , suggesting that Rho activates PAK in a ROCK-independent manner . Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK293- P25103 cells . Q8N0V5 V ( Mgat5 ) -mediated N-glycosylation negatively regulates Th1 cytokine production by T cells . The differentiation of naive P01730 (+) T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity , allergy , and tumor immune surveillance . We previously demonstrated that beta1,6GlcNAc-branched complex-type ( Q8N0V5 V ( Mgat5 ) ) N-glycans on TCR are bound to galectins , an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse . Mgat5(-/-) mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis . In this study we examined the role of beta1,6GlcNAc N-glycan expression in Th1/Th2 cytokine production and differentiation . beta1,6GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle . DB00075 -activated splenocytes and naive T cells from Mgat5(-/-) mice produce more P01579 and less P05112 compared with wild-type cells , the latter resulting in the loss of P05112 -dependent down-regulation of IL-4Ralpha . DB02034 , an inhibitor of Q16706 , blocked beta1,6GlcNAc N-glycan expression and caused a similar increase in P01579 production by T cells from humans and mice , but no additional enhancement in Mgat5(-/-) T cells . Mgat5 deficiency did not alter P01579 / P05112 production by polarized Th1 cells , but caused an approximately 10-fold increase in P01579 production by polarized Th2 cells . These data indicate that negative regulation of TCR signaling by beta1,6GlcNAc N-glycans promotes development of Th2 over Th1 responses , enhances polarization of Th2 cells , and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat5(-/-) mice . Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects . OBJECTIVE : The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug-metabolizing enzymes , transporters , or receptors . The aim of this study was to identify genetic markers predictive of pharmacokinetics , pharmacodynamics , and adverse effects of olanzapine . METHODS : Sixty-three healthy volunteers receiving a single 5-mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine . All genetic variants were analyzed by PharmaChip , but P14416 Taq1A polymorphism was determined by real-time polymerase chain reaction . Olanzapine was measured using high-performance liquid chromatography combined with tandem mass spectrometry . The relationship of gender and polymorphisms with olanzapine pharmacokinetics , the change in prolactin levels , and the incidence of adverse effects were evaluated by multiple regression analysis . RESULTS : The pharmacokinetics of olanzapine was influenced by polymorphisms in P20815 , P21266 , and Q13224 . P01236 levels were affected by gender and polymorphisms in P14416 and 5- P28223 . Polymorphisms in P11712 , P51580 , P22309 , P08183 , and 5- P28223 were related to some adverse effects of olanzapine . CONCLUSIONS : Several polymorphisms can explain differences in the pharmacokinetics , pharmacodynamics , and safety of olanzapine in healthy subjects . Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established . 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 . Functional identification of NR2 subunits contributing to DB01221 receptors on DB05875 receptor-expressing dorsal horn neurons . DB01221 receptors are important elements in pain signaling in the spinal cord dorsal horn . They are heterotetramers typically composed of two Q9UHB4 and two of four NR2 subunits : Q12879 -2D . Mice lacking specific NR2 subunits show deficits in pain transmission yet subunit location in the spinal cord remains unclear . We have combined electrophysiological and pharmacological approaches to investigate the composition of functional DB01221 receptors expressed by lamina I , DB05875 receptor-expressing ( P25103 + ) neurons , as well as P25103 - neurons . Under low Mg2+ conditions ( 100 microM ) , the conductance of DB01221 receptors at -90 mV ( g ( -90 mV ) ) with Q12879 or Q13224 subunits ( Q12879 /B ) is low compared to conductance measured at the membrane potential where the inward current is maximal or maximal inward current ( MIC ) ( ratio of approximately 0.07 calculated from Kuner and Schoepfer , 1996 ) . For Q14957 or O15399 subunits ( Q14957 /D ) , the ratio is higher ( ratio approximately 0.4 ) . P25103 + and P25103 - neurons express DB01221 receptors that give ratios approximately 0.28 and 0.16 , respectively , suggesting both types of subunits are present in both populations of neurons , with P25103 + neurons expressing a higher percentage of Q14957 /D type DB01221 receptors . This was confirmed using EAB318 , an Q12879 /B preferring antagonist , and UBP141 , a mildly selective Q14957 /D antagonist to increase and decrease the g ( -90 mV ) /g(MIC) ratios in both subpopulations of neurons . 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 . Distribution of polyamines and their biosynthetic enzymes in intestinal adaptation . P11926 ( ODC ) and the polyamines have been shown to be important for growth processes in the intestinal mucosa . The highest activity of ODC is found in the differentiated , nonproliferating villus-tip cells rather than in the rapidly proliferating undifferentiated crypt cells . During poststarvation refeeding and lactation , we now show that increases in ODC activity paralleled the time course of mucosal hyperplasia and thymidine incorporation . Increases in ODC ( threefold ) were similar in villus and crypt cells , and the villus-crypt gradient of decreasing ODC activity ( 40:1 ) was maintained . The activity of the other polyamine biosynthetic enzyme , S-adenosylmethionine decarboxylase ( P18827 ) , was highest in the crypt cells in the basal state and increased throughout the entire villus-crypt axis during refeeding and lactation , preserving a villus-crypt gradient opposite to that of ODC . During hyperplasia , all three polyamines increased . DB01917 was highest in the villus-tip cells , paralleling ODC activity , whereas spermidine and spermine were highest in the crypt cells and paralleled the distribution of P18827 activity . Thus P18827 activity and spermidine and spermine content may play a more important role than ODC and putrescine in regulation of intestinal mucosal proliferation . It is also possible that the threefold increases in the low levels of ODC in the crypt cells are adequate to trigger cell proliferation , whereas the higher ODC levels in villus cells may represent an association with the differentiation of the enterocytes . DB08810 protects against ethanol-induced gastric mucosal injury in rats : role of 5-hydroxytryptamine , prostaglandins and sulfhydryl compounds . This study was designed to determine the gastroprotective properties of cinitapride ( CNT ) , a novel prokinetic benzamide derivative agonist of Q13639 and 5-HT1 receptors and 5-HT2 antagonist , on mucosal injury produced by 50 % ( v/v ) ethanol . Results were compared with those for 5-hydroxytryptamine ( 5-HT : 10 mg kg-1 ) . The possible involvements of gastric mucus secretion , endogenous prostaglandins ( PGs ) and sulfhydryl compounds ( SH ) in the protection mediated by CNT were also examined . Intraperitoneal administration of CNT ( 0.50 and 1 mg kg-1 ) , 30 min before ethanol , significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus . CNT ( 1 mg kg-1 ) also produced a significant increase in gastric mucosal levels of DB00917 , but did not induce any significant changes in SH values . On the contrary , pretreatment with 5-HT worsened ethanol-induced erosions , however , did not affect gastric mucus secretion , glycoprotein content or DB00917 levels , although the non-protein SH fraction was significantly decreased . The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism . We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved . Effect of matrine on the expression of DB05875 receptor and inflammatory cytokines production in human skin keratinocytes and fibroblasts . Matrine is a kind of alkaloid found in certain Sophora plants , which has been extensively used in China for the treatment of viral hepatitis , cancer , cardiac diseases and skin diseases ( such as atopic dermatitis and eczema ) . It also has been confirmed that DB05875 ( SP ) and its receptor ( neurokinin-1 receptor , P25103 ) are involved in the pathogenesis of inflammatory skin disorders . So the present study was designed to investigate the effect of matrine on the expression of P25103 and cytokines production induced by SP in HaCaT cells ( a human epidermal keratinocyte cell line ) and dermal fibroblasts . In addition , cell viability was also evaluated . The results showed that matrine inhibited the expression of P25103 in HaCaT cells and fibroblasts . SP induced the production of interleukin ( IL ) -1beta , P10145 , interferon ( IFN ) -gamma , and monocyte chemotactic protein ( MCP ) -1 in both cell types . Matrine 5-100 microg/mL had little effect on cell viability . It inhibited SP-induced IL-1beta , P10145 and P13500 production in HaCaT cells and fibroblasts , while it increased the production of P01579 in HaCaT cells . Both SP and matrine had no effect on the secretion of P05231 . These findings suggest that matrine may have potential treatment function on SP related cutaneous inflammation by inhibition of the expression of DB05875 receptor and regulation of the production of inflammatory cytokines . Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells . We have investigated the possible effect of DB05875 ( SP ) , a main mediator of neurogenic inflammation , on the growth of capillary vessels in vivo , and on the proliferation of cultured endothelial cells in vitro . Slow release preparations of SP were implanted into the avascular cornea of New Zealand White rabbits and vessel growth was monitored daily through a slit lamp stereomicroscope . SP ( 1-5 micrograms/pellet ) induced a marked neovascularization . A selective P25103 agonist [ beta-Ala4 , Sar9 , DB00134 (O2)11 ] -SP(4-11) also induced neovascularization . The addition of SP to serum-free cultured endothelial cells , isolated from bovine adrenals ( P56817 ) and from human umbilical cord veins ( HUVE ) , increased proliferation of both cell lines in a concentration-dependent manner with maximal activity at 10(-8) M ( P56817 ) and 10(-10) M ( HUVE ) . The selective P25103 agonist induced a similar proliferative action on both cell lines , while the selective P21452 agonist [ beta-Ala8 ] - P20366 (4-10) and the selective P29371 agonist [ MePhe7 ] -NKB had no significant effect . Two different SP antagonists [ D-Pro2 , D-Trp7,9 ] -SP and [ D-Pro4 , D-Trp7,9,Phe11 ] -SP ( 4-11 ) blocked the response to SP . These findings indicate that SP can directly stimulate the process of neovascularization , probably through induction of endothelial cell proliferation . This hitherto unraveled activity of SP could play a key role in the trophic action produced by activation of the efferent function of peripheral endings of primary sensory neurons . The effect of MDA and DB01454 ( " DB01454 " ) isomers in combination with pirenpirone on operant responding in mice . The behaviorally disruptive effects of the optical isomers of 1-(3,4-methylenedioxyphenyl-2-aminopropane) ( MDA ) and its N-methyl derivative ( DB01454 ) were evaluated in 27 mice trained to bar-press for a liquid food reinforcement . In addition , a second study was conducted in which mice were pretreated with either saline or the P28223 antagonist , pirenpirone , prior to the administration of either DB01454 or MDA using the same behavioral procedure . The results indicated that the behaviorally disruptive effects produced only by R(-)-MDA , but not those of S(+)-MDA , R(-)-MDA , nor of S(+)- DB01454 , were significantly attenuated by pirenpirone . These findings support previous research findings which indicate that this isomer may be producing its behaviorally disruptive effects via an action on P28223 receptors . beta-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor gamma expression and reactive oxygen species production in MCF-7 cancer cells . Although the pharmacological role of beta-carotene in the prevention and treatment of many cancer cells has received increasing attention , the molecular mechanisms underlying such chemopreventive activity are not clear . Since peroxisome proliferator-activated receptor gamma ( P37231 ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta-carotene on the P37231 -mediated pathway and its association with reactive oxygen species production in MCF-7 cells were investigated in the present study . The results demonstrated that beta-carotene significantly increased P37231 mRNA and protein levels in time-dependent manner . In addition , beta-carotene increased the cyclin-dependent kinase inhibitor P38936 ( P38936 /CIP1) expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase-2 expression . DB07863 ( GW9662 ) , an irreversible P37231 antagonist , partly attenuated the cell death caused by beta-carotene . Further , reactive oxygen species ( ROS ) production was induced by beta-carotene , resulting in mitochondrial dysfunction and cytochrome C release . DB00143 ( DB00143 ) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by beta-carotene . In total , these observations suggest that the synergistic effect of P37231 expression and ROS production may account for beta-carotene-mediated anticancer activities . DB01079 treatment for IBS : a model of indirect costs . Irritable bowel syndrome ( IBS ) has been associated with substantial time lost from work ( absenteeism ) and reduced productivity at work ( presenteeism ) , which are the indirect costs of illness . This article presents a productivity model demonstrating the indirect costs associated with IBS and the reduction in those costs for a cohort of female employees hypothetically treated with tegaserod , a new selective serotonin ( 5-hydroxytryptamine [ 5-HT ] ) type 4 ( Q13639 ) receptor agonist , which is approved by the US Food and Drug Administration for treating women with IBS-C . The model is based on economic and epidemiologic published literature and clinical trial results . In this model , tegaserod treatment resulted in 1882 dollars in avoided lost productivity per treated female employee . Considering only the benefits of decreased work loss and the costs of medical therapy , the model predicts a benefit/cost ratio of 3.75 in the base case . From an employer 's perspective , medical therapy for IBS with tegaserod is cost-effective under a series of assumptions for the treatment of women with IBS with constipation . Evaluation of cytokine production by equine alveolar macrophages exposed to lipopolysaccharide , Aspergillus fumigatus , and a suspension of hay dust . OBJECTIVE : To evaluate cytokine production by equine alveolar macrophages after exposure to lipopolysaccharide ( LPS ) , Aspergillus fumigatus , and hay dust , and determine the effect of clenbuterol on the cytokine response . ANIMALS : 6 horses . PROCEDURE : Alveolar macrophages were exposed to PBS solution ( negative control ) , LPS , hyphae and conidia of Aspergillus fumigatus ( AF ) , or a suspension of hay dust ( Q86SQ9 ) and incubated for 24 hours at 37 degrees C . Concentrations of tumor necrosis factor ( P01375 ) -alpha and interleukin ( IL ) -1beta were measured in the supernatant . The procedure was repeated with cells that were concurrently incubated with 0.5 microM clenbuterol . RESULTS : Exposure to Q86SQ9 and AF significantly increased production of P01375 by equine alveolar macrophages . The increase in P01375 produced in response to Q86SQ9 and AF was 5 and 7 times as great , respectively , as the increase measured in response to LPS . The concentration of IL-1beta in the supernatant was significantly increased after exposure of cells to AF . DB01407 was effective at inhibiting P01375 production by cells exposed to LPS , Q86SQ9 , or AF . CONCLUSIONS AND CLINICAL RELEVANCE : Increased production of P01375 and IL-1 indicated that the pro-inflammatory cytokines produced by alveolar macrophages in response to allergens may play a role in recurrent airway obstruction ( O75106 ) in horses . Equine alveolar macrophages are not only a primary pulmonary defense mechanism but may also influence the pathogenesis of equine O75106 . The beta2-adrenoceptor agonist clenbuterol , a drug that is commonly used for treatment of equine O75106 , promotes immediate bronchodilation and may also contribute to downward modulation of the inflammatory response . P04629 and Q16620 receptors facilitate follicle assembly and early follicular development in the mouse ovary . Recent studies have demonstrated that neurotrophins ( NTs ) and their NTRK tyrosine kinase receptors , thought to be exclusively required for the development of the nervous system , are also involved in controlling ovarian development . Here , we show that primordial follicle formation is decreased in the absence of nerve growth factor ( P01138 ) or its receptor P04629 , and in the absence of Q16620 , the receptor for neurotrophin-4 ( P34130 ) and brain-derived neurotrophic factor ( P23560 ) . This deficiency is not due to premature oocyte loss , because the ovaries of Ntrk1(-/-) and Ntrk2(-/-) mice do not show an increased rate of oocyte death antedating the initiation of folliculogenesis . Moreover , exposure of P01138 -deficient ovaries to P01138 rescues the defect in follicular assembly , if P04629 receptors are present , suggesting that the absence of NTs causes a delay , and not an irretrievable loss , of follicle formation . Both the number of secondary follicles and DB00094 receptor ( P23945 ) expression are diminished in Ntrk1- and Ntrk2-null ovaries , but not in ovaries lacking the common NT receptor P08138 . Transient exposure of wild-type ovaries to P34130 increases Fshr gene expression and enhances the ability of the ovary to respond to DB00094 with formation of cyclin D2 , a cell cycle protein mediating the proliferative actions of DB00094 in the ovary . These results indicate that both P04629 and Q16620 receptors are necessary for the timely assembly of primordial follicles and for sustaining early follicular development . They also suggest that a mechanism by which Q16620 receptors facilitate subsequent follicle development is by inducing the formation of functional P23945 . Standard- and high-dose etoposide , ifosfamide , carboplatin , and epirubicin in 107 patients with non-small-cell lung cancer : a mature follow-up report . BACKGROUND : We conducted a phase I-II trial to assess the activity of standard-dose ( P18827 ) and high-dose chemotherapy ( HDC ) with etoposide , ifosfamide , cis/carboplatin , and epirubicin ( P01282 -E , VIC-E ) in 107 patients with limited-stage ( LS , stage I-IIIB ) and extensive stage ( ES , stage IV ) non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS : Updated results of a previously published trial are presented . RESULTS : Response rates and survival after P01282 -E were comparable to those of other standard-dose combination chemotherapies in NSCLC . Treatment-related mortality ( TRM ) in P18827 was 3 % in LS-NSCLC , and 8 % in ES-NSCLC . TRM was 4 % in patients selected for HDC by response rate and performance score . Five-year survival in LS-NSCLC was 12 % after P18827 , and 18 % after HDC ; it was 0 % for both treatment protocols in ES-NSCLC . CONCLUSIONS : The activity of P01282 -E P18827 and VIC-E HDC is not superior to that of established protocols in the treatment of NSCLC . In view of the toxicity and TRM associated with this protocol , less aggressive regimens should be preferred for most patients . Whether selected patients with chemosensitive disease could benefit from P01282 -E P18827 and/or VIC-E HDC in an adjuvant or neo-adjuvant setting could not be determined within the scope of this study . [ 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 .