interacts_with DB00072?
Signaling of P00533 receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo . BACKGROUND : P00533 receptor tyrosine kinases can mediate proliferation , migration , adhesion , differentiation , and survival in many types of cells and play critical roles in many malignancies . Recent reports suggest a role for P00533 signaling in proliferation and survival of neuroblastoma , a common form of pediatric cancer that often has an extremely poor outcome . METHODS : The authors examined P00533 family expression in neuroblastoma cell lines and patient samples by flow cytometry , western blot , and quantitative real time polymerase chain reaction ( Q-PCR ) . Response to P00533 inhibition was assessed in vitro by cell-cycle analysis and western blot and in vivo by serial tumor-size measurements . RESULTS : A panel of neuroblastoma cell lines and primary patient tumors expressed P00533 , HER-3 , and HER-4 , with HER-2 in some tumors . HER-4 mRNA was expressed predominantly in cleavable isoforms . Whereas P00533 inhibition with erlotinib and pan- P00533 inhibition with DB05424 inhibited P01133 -induced phosphorylation of P00533 , AKT , and P27361 /2 , only DB05424 induced growth inhibition and dose-dependent apoptosis in vitro . Both DB05424 and erlotinib treatment of neuroblastoma xenograft tumors resulted in decreased tumor growth in vivo , although DB05424 was more effective . In vivo expression of P00533 was observed predominantly in vascular endothelial cells . CONCLUSIONS : Pan- P00533 inhibition is required for P00533 -related neuroblastoma apoptosis in vitro , although P00533 contributes indirectly to tumor growth in vivo . Inhibition of P00533 in endothelial cells may be an important aspect of erlotinib 's impact on neuroblastoma growth in vivo . Our results suggest that non- P00533 P00533 family members contribute directly to neuroblastoma growth and survival , and pan- P00533 inhibition represents a potential therapeutic target for treating neuroblastoma . DB00072 has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand-induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 -driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 -FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 /TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 -FKBP . DB00072 inhibited homodimer-mediated but not heterodimer-mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth . AP1510 triggered phosphorylation of Erk1/2 but not AKT , whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc- P04626 homodimer binding , but not TGFα-induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 -overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3-kinase ) /AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab . Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor/ P04626 -positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F. Hoffmann-La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 -positive metastatic breast cancer , trastuzumab/chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . DB00072 adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer , including capecitabine ( DB01101 ; F. Hoffmann-La Roche ) , gemcitabine , and vinorelbine . DB00072 is also being investigated as part of triplet drug regimens . DB00072 has good single-agent activity in first-line therapy . This is of relevance to women with P04626 -positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible . The kinetic and physical basis of K( DB00171 ) channel gating : toward a unified molecular understanding . K( DB00171 ) channels can be formed from Kir6.2 subunits with or without Q09428 . The open-state stability of K( DB00171 ) channels can be increased or reduced by mutations throughout the Kir6.2 subunit , and is increased by application of PIP(2) to the cytoplasmic membrane . Increase of open-state stability is manifested as an increase in the channel open probability in the absence of DB00171 ( Po(zero) ) and a correlated decrease in sensitivity to inhibition by DB00171 . Single channel lifetime analyses were performed on wild-type and I154C mutant channels expressed with , and without , Q09428 . Channel kinetics include a single , invariant , open duration ; an invariant , brief , closed duration ; and longer closed events consisting of a " mixture of exponentials , " which are prolonged in DB00171 and shortened after PIP(2) treatment . The steady-state and kinetic data can not be accounted for by assuming that DB00171 binds to the channel and causes a gate to close . Rather , we show that they can be explained by models that assume the following regarding the gating behavior : 1 ) the channel undergoes DB00171 -insensitive transitions from the open state to a short closed state ( C(f) ) and to a longer-lived closed state ( C(0) ) ; 2 ) the C(0) state is destabilized in the presence of Q09428 ; and 3 ) DB00171 can access this C(0) state , stabilizing it and thereby inhibiting macroscopic currents . The effect of PIP(2) and mutations that stabilize the open state is then to shift the equilibrium of the " critical transition " from the open state to the DB00171 -accessible C(0) state toward the O state , reducing accessibility of the C(0) state , and hence reducing DB00171 sensitivity . Agents with selective estrogen receptor ( ER ) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells . Tamoxifen , a member of the selective estrogen receptor modulator ( SERM ) family , is widely used in the treatment of estrogen receptor ( ER ) -expressing breast cancer . It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells , but whether this effect is drug specific or represents a general property of SERMs is unknown . In this study , we demonstrate that tamoxifen and DB05487 , a novel benzopyranone with SERM activity , induce glioma cell apoptosis in a dose- and time-dependent manner . Moreover , administration of tamoxifen and DB05487 suppresses tumor growth in vivo and extends animal survival in glioma xenograft models . None of the eight glioma cell lines examined express either P03372 or -beta , suggesting the mechanism for tamoxifen- and DB05487 -induced glioma cell apoptosis is independent of the ER signaling pathway . Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and DB05487 , and not by other apoptotic stimuli , including nuclear factor ( NF ) -kappaB with its target genes IEX-3 , P04179 , P05231 , and P10145 . We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis , suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity . These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway . Characterization of DB05005 -B , an orally bioavailable antagonist of the P51686 chemokine receptor , for treatment of inflammatory bowel disease . The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions . Chemokine receptor 9 ( P51686 ) is a chemokine receptor known to be central for migration of immune cells into the intestine . Its only ligand , O15444 , is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation . To date , there are no reports of small-molecule antagonists targeting P51686 . We report , for the first time , the discovery of a small molecule , DB05005 -B , which is an orally bioavailable , selective , and potent antagonist of human P51686 . DB05005 -B inhibited P51686 -mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM , respectively . In the presence of 100 % human serum , DB05005 -B inhibited P51686 -mediated chemotaxis with an IC(50) of 33 nM , and the addition of α1-acid glycoprotein did not affect its potency . DB05005 -B inhibited chemotaxis of primary P51686 -expressing cells to O15444 with an IC(50) of 6.8 nM . DB05005 -B was an equipotent inhibitor of O15444 -directed chemotaxis of both splice forms of P51686 ( CCR9A and CCR9B ) with IC(50) values of 2.8 and 2.6 nM , respectively . DB05005 -B also inhibited mouse and rat P51686 -mediated chemotaxis . Inhibition of P51686 with DB05005 -B results in normalization of Crohn 's disease such as histopathology associated with the P01375 (ΔARE) mice . Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for P51686 antagonists in the treatment of intestinal inflammation . Vanadate induction of NF-kappaB involves O15111 beta and P45985 in macrophages . The present studies investigated the signaling pathways of vanadate , a vanadium ion with +5 oxidation state , to activate NF-kappaB transcription factor , a pivotal regulator of inflammatory responses . Treatment of macrophages with vanadate results in the activation of both NF-kappaB and c-Jun N-terminal kinase ( JNK ) . The activity of a recently identified cellular kinase , O15111 -beta ( IKKbeta ) , was significantly elevated concomitant with the increased degradation of P25963 and enhanced NF-kappaB activity in cells exposed to vanadate . To determine whether the IKK pathway and JNK pathway are interconnected or bifurcate upon vanadate stimulation , cells were transfected with either a kinase inactive form of IKKbeta or a kinase inactive form of P45985 ( P45985 ) . Inactive IKKbeta was able to block vanadate-induced degradation of P25963 , yet it was unable to influence the activation of JNK by vanadate . Conversely , blockage of JNK activation by transfection of a kinase-inactive form of P45985 resulted in partially inhibition of vanadate-induced P25963 degradation . Both vanadate-induced degradation of P25963 and activation of JNK were potently inhibited by pretreatment of cells with DB06151 or dimercaprol . These results demonstrate that early activation of stress kinases or change of cellular redox states plays a key role in vanadate-induced activation of NF-kappaB and JNK . Inhibition of PI3K/AKT/ P42345 pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice . Invasive pituitary adenomas ( PAs ) are often refractory to standard therapy and salvage treatment with temozolomide ( DB00853 ) . Hyperactivation of the phosphoinositide 3-kinase ( PI3K ) /AKT/mammalian target of rapamycin ( P42345 ) pathway contributes to chemotherapy resistance in many cancers . DB05241 , a novel dual-PI3K/ P42345 inhibitor , has recently shown its efficacy as a monotherapy and in combination with conventional therapeutics in many cancers . The hyperactive PI3K/AKT/ P42345 pathway frequently occurs in invasive PAs . In this study , we investigated whether DB05241 sensitizes PA cells to DB00853 in vitro and in vivo . Experiments were carried out to evaluate the effect of DB05241 and DB00853 alone or in combination on cell proliferation and apoptosis of PA cell lines ( α DB00279 -1 , GH3 , and MMQ ) in vitro as well as the tumor growth and serum GH and prolactin secretions in a GH3 xenograft tumor model of female nude mice . DB05241 and DB00853 synergistically inhibited the growth of PA cell lines and induced apoptosis . Combination of DB05241 and DB00853 synergistically inhibited tumor growth , decreased serum GH and prolactin levels , and reduced the sacrifice rate of GH3 xenograft tumor models without increased systemic side effects . In addition , DB05241 in combination with DB00853 dramatically decreased phosphorylation of AKT and P42345 as well as the expression of Bcl-2 . The increased expression of cleaved poly ( ADP-ribose ) polymerase and Bcl-2-associated X protein along with elevated caspase-3/7 activity were also observed in the combination group . Therefore , dual inhibitors of PI3K and P42345 may enhance alkylating agent-mediated cytotoxicity and provide a novel regimen in the treatment of invasive PAs . Chemotherapeutic drugs and human tumor cells cytokine network . The ability of human tumor cell lines to produce various cytokines , chemokines , angiogenic and growth factors was investigated using Luminex multiplex technology . Media conditioned by tumor cells protected tumor cells from drug-induced apoptosis and stimulated tumor cell proliferation . Antibodies neutralizing P05231 , P10145 , P13500 and P13501 blocked this stimulation . Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of P05231 , P10145 , P13500 , P13501 , BFGF , G- P04141 and P15692 . This stimulation was associated with drug-induced activation of NF-kappaB , AP-1 , P05549 , CREB , Q9BYW2 , P35610 -1 , P35610 -3 , P35610 -5 and P39905 -2 transcription factors and upregulation of P05231 , P10145 , P09038 , P04141 -3 and P13501 gene expression . Treatment of tumor cells with doxorubicin and antibodies neutralizing DB00099 , P13500 or P13501 had higher inhibitory effects than each modality used alone . These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug-mediated destruction . Clinical studies showed that antibodies neutralizing P15692 ( DB00112 / DB00112 ) or blocking P04626 /neu signaling ( Herceptin/ DB00072 ) could increase the efficacy of chemotherapy , although these beneficial effects have been limited . It is possible that drug-stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy . In addition , numerous growth factors and chemokines share angiogenic and growth-stimulating properties , and thus reduction of a single factor is insufficient to completely block tumor growth . Thus , a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy . DB00741 is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . DB00741 ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta-hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 -induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells . [ Cellular adhesion signal transduction network of tumor necrosis factor-alpha induced hepatocellular carcinoma cells ] . OBJECTIVE : To systemically explore the cellular adhesion signal transduction network of tumor necrosis factor-alpha ( P01375 -α ) -induced hepatocellular carcinoma cells with bioinformatics tools . METHODS : Published microarray dataset of P01375 -α-induced HepG2 , human transcription factor database HTRI and human protein-protein interaction database HPRD were used to construct and analyze the signal transduction network . RESULTS : In the signal transduction network , MYC and SP1 were the key nodes of signaling transduction . Several genes from the network were closely related with cellular adhesion. P00533 ( P00533 ) is a possible key gene of effectively regulating cellular adhesion during the induction of P01375 -α . CONCLUSION : P00533 is a possible key gene for P01375 -α-induced metastasis of hepatocellular carcinoma . Targeted therapy in gastric cancer . Gastric cancer is often diagnosed at an advanced stage . Although chemotherapy prolongs survival and improves quality of life , the survival of gastric cancer patients with advanced disease is short . Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis , new targeted treatment options have become available for gastric cancer patients . DB00072 , an antibody targeted to HER-2 , was shown to improve survival of advanced gastric cancer patients harboring HER-2 overexpression due to gene amplification in their tumor cells , and is currently also explored in adjuvant and neoadjuvant settings . Another agent with promising results in clinical trials is ramucirumab , an antibody targeting P35968 . No clear survival benefit , however , were experienced with agents targeting P00533 ( cetuximab , panitumumab ) , P15692 ( bevacizumab ) , or P42345 ( everolimus ) . Drugs targeting c-MET/ P14210 are currently under investigation in biomarker-selected cohorts , with promising results in early clinical trials . This review will summarize the current status of targeted treatment options in gastric cancer . C. elegans vulval development as a model system to study the cancer biology of P00533 signaling . Molecular genetic studies of C. elegans vulval development have helped to define an evolutionarily conserved signaling pathway from an P01133 -like ligand through P01133 -receptor , Ras and Q96HU1 kinase to the nucleus . Further studies have identified novel positive regulators such as Q8IVT5 -1 and Q09428 -8/ Q5T124 -2 and negative regulators such as cbl/SLI-1 . The many negative regulatory proteins might serve to prevent inappropriate signaling , and thus are analogous to tumor suppressor genes . Substance P autocrine signaling contributes to persistent P04626 activation that drives malignant progression and drug resistance in breast cancer . P00533 receptor transmodulation by heterologous G-protein-coupled receptors ( GPCR ) generates functional diversity in signal transduction . Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs . In this work , we found that the pain-associated tachykinin Substance P ( SP ) contributes to persistent transmodulation of the P00533 receptors , P00533 and P04626 , in breast cancer , acting to enhance malignancy and therapeutic resistance . SP and its high-affinity receptor P25103 were highly expressed in P04626 (+) primary breast tumors ( relative to the luminal and triple-negative subtypes ) and were overall correlated with poor prognosis factors . In breast cancer cell lines and primary cultures derived from breast cancer samples , we found that SP could activate P04626 . Conversely , RNA interference-mediated attenuation of P25103 , or its chemical inhibition , or suppression of overall GPCR-mediated signaling , all strongly decreased steady-state expression of P00533 and P04626 , establishing that their basal activity relied upon transdirectional activation by GPCR . Thus , SP exposure affected cellular responses to anti- P00533 therapies . Our work reveals an important oncogenic cooperation between P25103 and P04626 , thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored . [ DB00072 ( Herceptin ) and breast cancer : mechanisms of resistance ] . The detection of overexpression of human epidermal growth factor receptor 2 ( P04626 ) in some breast cancer tumors has led to the development of a targeted treatment that is tumor selective , effective at extending life expectancy in the patients with advanced or early breast cancers . DB00072 ( Herceptin ) , a humanized monoclonal antibody to P04626 is indicated for patients whose tumor demonstrates an amplified copy number for the P04626 oncogene and/or overexpresses the P04626 oncoprotein . Despite a high level of efficacy in combination with chemotherapy , trastuzumab as single agent has limited effectiveness ( up to 30 % response rates ) and patients who respond to trastuzumab will relapse despite continued treatment . The mechanism of trastuzumab action is not fully understood but has been related to cell cycle inhibition . As to mechanisms of resistance , little is known but many preclinical data raised different hypothesis . Thus , the co-expression of growth factor receptors ( P00533 family , DB01277 R ) , and the activation of PI3K-Akt pathway , mainly by loss of P60484 function may be responsible for the resistance phenotype . It would be interesting to identify the mechanisms of trastuzumab resistance in breast tumors in order to reverse or prevent it . The characterization of these mechanisms would also provide novel strategies for alternative treatments . Nuclear factor-kappaB enhances ErbB2-induced mammary tumorigenesis and neoangiogenesis in vivo . The ( P04626 /Neu ) ErbB2 oncogene is commonly overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in transgenic mice . Nuclear factor ( NF ) -kappaB activity is increased in both human and murine breast tumors . The immune response to mammary tumorigenesis may regulate tumor progression . The role of endogenous mammary epithelial cell NF-kappaB had not previously been determined in immune-competent animals . Furthermore , the role of the NF-kappaB components , p50 and p65 , in tumor growth was not known . Herein , the expression of a stabilized form of the NF-kappaB-inhibiting P25963 protein ( IkappaBalphaSR ) in breast tumor cell lines that express oncogenic ErbB2 inhibited DNA synthesis and growth in both two- and three-dimensional cultures . Either NF-kappaB inhibition or selective silencing of p50 or p65 led to a loss of contact-independent tumor growth in vitro . IkappaBalphaSR reversed the features of the oncogene-induced phenotype under three-dimensional growth conditions . The NF-kappaB blockade inhibited ErbB2-induced mammary tumor growth in both immune-competent and immune-deficient mice . These findings were associated with both reduced tumor microvascular density and a reduction in the amount of vascular endothelial growth factor . The expression of IkappaBalphaSR in breast cancer tumors inhibited angiogenesis . Thus , mammary epithelial cell NF-kappaB activity enhances ErbB2-mediated mammary tumorigenesis in vivo by promoting both growth and survival signaling via the promotion of tumor vasculogenesis . ICE/ P29466 inhibitors as novel anti-inflammatory drugs . In recent years , several strategies that selectively inhibit pro-inflammatory cytokines , have yielded effective protein-based therapies for inflammatory disorders , validating the therapeutic hypothesis that intervention in cytokine signalling can provide clinical benefit . However , these protein-based products must be administered by injection , a constraint associated with inconvenience , adverse effects and expense for patients , caregivers and insurers . Besides interfering with the effects of cytokines such as P01375 or IL-1beta that have already been produced , inhibition of pro-inflammatory cytokine production or signalling with low-molecular weight orally-active drugs would combine the convenience of conventional pharmaceuticals with the focused efficacy of the protein therapies . Reducing IL-1beta and Q14116 production by inhibition of IL-1beta converting enzyme ( ICE , caspase-1 ) is one promising strategy because of the key roles of these cytokines in many inflammatory diseases . DB04875 , the first orally available , potent and selective ICE inhibitor to enter clinical trials , is currently under investigation in rheumatoid arthritis . Synaptic Q12879 and Q13224 containing DB01221 receptors within the superficial dorsal horn activated following primary afferent stimulation . DB01221 receptors are important elements in pain signaling in the spinal cord dorsal horn . They are heterotetramers , typically composed of two Q05586 and two of four GluN2 subunits : Q12879 -2D . Mice lacking some of the GluN2 subunits show deficits in pain transmission yet functional synaptic localization of these receptor subtypes in the dorsal horn has not been fully resolved . In this study , we have investigated the composition of synaptic DB01221 receptors expressed in monosynaptic and polysynaptic pathways from peripheral sensory fibers to lamina I neurons in rats . We focused on DB05875 receptor-expressing ( P25103 + ) projection neurons , critical for expression of hyperalgesia and allodynia . EAB-318 and ( R ) -CPP , Q12879 /B antagonists , blocked both monosynaptic and polysynaptic DB01221 EPSCs initiated by primary afferent activation by ∼90 % . Physiological measurements exploiting the voltage dependence of monosynaptic EPSCs similarly indicated dominant expression of Q12879 /B types of synaptic DB01221 receptors . In addition , at synapses between C fibers and P25103 + neurons , DB01221 receptor activation initiated a secondary , depolarizing current . DB08954 , a Q13224 antagonist , caused modest suppression of monosynaptic DB01221 EPSC amplitudes , but had a widely variable , sometimes powerful , effect on polysynaptic responses following primary afferent stimulation when inhibitory inputs were blocked to mimic neuropathic pain . We conclude that Q13224 subunits are moderately expressed at primary afferent synapses on lamina I P25103 + neurons , but play more important roles for polysynaptic DB01221 EPSCs driven by primary afferents following disinhibition , supporting the view that the analgesic effect of the Q13224 antagonist on neuropathic pain is at least in part , within the spinal cord . Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) DB00072 ( Herceptin ) . An optimized CAR vector containing P10747 , 4-1BB , and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR(+) in CD3(+) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10(10) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X-ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon-gamma ( P01579 ) , granulocyte macrophage-colony stimulating factor ( GM- P04141 ) , tumor necrosis factor-alpha ( P01375 ) , interleukin-6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .