interacts_with DB00072?
[ Natriuretic peptides as novel growth factor of growth plate cartilage ] . Recently evidence has accumulated that natriuretic peptides ( NPs ) are important regulator of endochondral ossification . Three peptides , P01160 , DB04899 and P09543 constitute the NPs family . cGMP production through two particulate guanylate cyclases is involved in their signal transduction . P01160 and DB04899 have high affinity for P16066 and P09543 for P20594 . Third receptor , called clearance receptor ( P17342 ) is involved in NPs clearance . Mice that overexpress DB04899 or P09543 and mice deficient in P17342 exhibited marked body elongation , whereas mice deficient in P09543 showed dwarfism . P09543 enhanced longitudinal growth in organ-cultured long bones , and stimulated the differentiation of osteoblast and cartilage lineage cells . Dwarfism was observed in mice deficient in Q13237 which lies downstream to cGMP . Since three genetically body-elongated mice were proven to have mutations in P17342 , it is possible that P09543 / P20594 /cGK II pathway is related to some clinical disorders . P09543 is also expected to have therapeutic application to diseases with dwarfism . Ras-transfection up-regulated HaCaT cell migration : inhibition by Marimastat . Cell migration is an essential process in physiological and pathological conditions such as wound healing and tumor invasion . This phenomenon involves cell adhesion on the extracellular matrix mediated by integrins , and cell detachment promoted in part by metalloproteinases ( MMPs ) . In the present study , the migration of two HaCaT-ras clones ( metastatic or not ) , was compared with HaCaT cells , and normal human primary cultured keratinocytes . Using colloidal gold migration assay , the migration index on type I and type IV collagen was similar for primary cultured keratinocytes and HaCaT , whereas it was markedly higher for the HaCaT-ras clones . High motility of ras-transfected cells was confirmed from an in vitro wound healing assay . It was not correlated with changes in integrin expression or related to a different adhesion on extracellular matrix . The Marismastat ( DB00786 ) , a MMP inhibitor , inhibited in a dose-dependent effect the migration in both assays , demonstrating the important role of MMPs in the migration process . Under our experimental conditions , P03956 activity was not detected in HaCaT and P14780 activity was secreted by these cells only after their stimulation by P01133 . Here , P08253 was the major gelatinolytic activity secreted by all the cells and its secretion was markedly higher for HaCaT-nis clones compared with HaCaT . In addition , Western blotting results confirmed a higher expression of P08253 associated with a lower expression of P16035 in HaCaT-ras compared with HaCaT . These results suggest that Ha-ras oncogene could be a stimulating factor of migration and might modified the balance between P08253 and P16035 in keratinocyte cell lines . DB05812 acetate : a promising drug for the treatment of castration-resistant prostate cancer . DB05812 acetate ( CB7630 ) , a pregnenolone analog , is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis , P05093 , and blocks the synthesis of androgens in the testes , adrenal glands and prostate without causing adrenal insufficiency . In clinical studies , abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer . The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily . Side effects are minimal and mostly associated with secondary mineralocorticoid excess , owing to a compensatory increase in upstream steroids , such as deoxycorticosterone and corticosterone . These include hypertension , hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist , such as eplerenone , or low-dose corticosteroids . Currently , abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive . A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis . Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours . BACKGROUND : Malignant tumours of the salivary glands ( MSGT ) are rare and pleomorphic entities . Patients with advanced disease may benefit from targeted therapy ; however , specific targets for optimising and personalising treatments are yet to be identified . DESIGN : Immunohistochemistry for C- P10721 , P00533 , P04626 , P15941 , phospho- P42345 , androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival . High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology . RESULTS : Several therapy leads were identified , including high levels of P04626 and androgen receptors in salivary duct carcinomas , C- P10721 in myoepithelial carcinomas and P00533 in mucoepidermoid carcinomas . Recurrent mutations involving downstream elements of the P00533 pathway were found in P01112 , notably in tumours with a myoepithelial component , and in other key oncogenes ( P01116 / P01111 /PI3KCA/ P15056 /MAP2K ) . On the other hand , < 1 % of samples had P00533 or P04626 mutations . CONCLUSION : Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads . Genotyping results suggest activation downstream of P00533 in 18 of the 107 samples that could be associated with low efficacy of P00533 inhibitors . Other molecules , such as PI3K/MEK or P42345 inhibitors , may have anti-tumour activity in this subgroup . The high mutation rate in P01112 highlights a novel key oncogenic event in MSGT . Circulating apoptotic proteins are increased in long-term disease-free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis-related proteins and inflammation markers are increased in long-term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF-receptor ( sTNF-R ) 1 and 2 , sFas , sFas ligand , sTNF-related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High-sensitivity P02741 ( HS-CRP ) , fibrinogen , plasma B-type and N-terminal atrial natriuretic peptide ( NT- P01160 and DB04899 ) were also determined . Thirty-four patients with median 6.0 years follow-up and 12 healthy age-matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg/m(2) ) , cyclophosphamide ( FEC ) ( n=14 ) or four cycles FEC followed by myeloablation with high-dose carboplatin , cyclophosphamide , thiotepa ( n=20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high-dose than in the standard-dose group . In conclusion , we observed increased circulating apoptotic protein levels in long-term disease-free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study . 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 . Effects of an Engineered Anti- P04626 Antibody chA21 on Invasion of Human Ovarian Carcinoma Cell In Vitro . OBJECTIVE : HER-2 plays an important role in the development and progression of ovarian carcinoma . A number of monoclonal antibodies ( MAbs ) and engineered antibody fragments ( such as scFvs ) against the subdomain II or IV of HER-2 extracellular domain ( O95905 ) have been developed . We investigated the effect of chA21 , an engineered anti-HER-2 antibody that bind primarily to subdomain I , on ovarian carcinoma cell invasion in vitro , and explored its possible mechanisms . METHODS : Growth inhibition of SK-OV-3 cells was assessed using a Methyl thiazolyl tetrazolium ( MTT ) assay . The invasion ability of SK-OV-3 was determined by a Transwell invasion assay . The expression of matrix metalloproteinase-2 ( P08253 ) and its tissue inhibitors ( P16035 ) was detected by immunocytochemical staining , and the expression of p38 and the phosphorylation of p38 were assayed by both immunocytochemistry and Western blot . RESULTS : After treatment with chA21 , the invasion of human ovarian cancer SK-OV-3 cells was inhibited in dose- and time-dependent manners . Simultaneously the expression of p38 , phospho-p38 , P08253 and the P08253 / P16035 ratio decreased , while P16035 expression increased . Additionally , the decrease in phospho-p38 was much greater than that of p38 . CONCLUSION : chA21 may inhibit SK-OV-3 cell invasion via the signal transduction pathway involving P08253 , P16035 , p38 and the activation of p38MAPK . 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 . 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 . Influence of CHIEF pathway genes on gene expression : a pathway approach to functionality . BACKGROUND : Candidate pathway approaches in disease association studies often utilize a tagSNP approach to capture genetic variation . In this paper we assess gene expression patterns with SNPs in genes in the CHIEF pathway to help determine their potential functionality . METHODS : Quantitative real-time RT-PCR was run to determine gene expression of 13 genes in normal colon tissue samples from 82 individuals . TagSNP genotype data were obtained from a GoldenGate Illumina multiplex bead array platform . Age , sex , and genetic ancestry adjusted general linear models were used to estimate beta coefficients and p values . RESULTS : Genetic variation in P42345 ( 1 SNP ) , P19838 ( 4 SNPs ) , Q9UGJ0 ( 3 SNPs ) , and P49815 ( 1 SNP ) significantly influenced their expression . After adjustment for multiple comparisons several associations between pathway genes and expression of other genes were significant . These included P31749 rs1130214 associated with expression of PDK1 ; NFκB1 rs13117745 and rs4648110 with Q15831 expression ; Q9UGJ0 rs6965771 with expression of NFκB1 , P42336 , and Q9UBS0 ; P23443 rs80711475 with Q15831 expression ; Q15831 rs741765 with P42336 and Q9UGJ0 expression ; and P49815 rs3087631 with P31749 , IkBκB , NFκB1 , PDK1 , P42336 , Q9UGJ0 , and P60484 expression . The higher levels of differential expression were noted for P49815 rs3087631 ( percent difference ranges from 108 % to 198 % across genes ) . Many of these SNPs and genes also were associated with colon and rectal cancer risk . CONCLUSIONS : Our results suggest that pathway genes may regulate expression of other genes in the pathway . The convergence of these genes in several biological pathways involved in cancer further supports their importance to the carcinogenic process . Metronomic chemotherapy dosing-schedules with estramustine and temozolomide act synergistically with anti- P35968 antibody to cause inhibition of human umbilical venous endothelial cell growth . The effects of ' metronomic ' or extended chemotherapy dosing schedules ( ECS ) are mediated through poorly understood anti-angiogenic mechanisms . ECS combined with biological anti-angiogenic agents have produced promising pre-clinical results . MATERIALS AND METHODS : We have expanded the list of agents with an in vitro ECS profile to include the methylating agent temozolomide ( DB00853 ) and the anti-mitotic agent estramustine ( Estracyt ) . These agents were also combined with a specific anti-angiogenic inhibitor DB06101 and a non-specific agent with anti-angiogenic properties , Compound 5h . The in vitro HUVEC ECS model system was optimised and cell proliferation assays undertaken . RESULTS : As a single agent , estramustine inhibited endothelial cell proliferation with an IC50 of 4.5 microM and was active at 10-33 % of the maximum tolerated dose ( MTD ) from clinical schedules , whilst temozolomide had IC50 of 6.6 microM and was active at 1-6 % of MTD . In combination , significant synergy was seen with DB06101 in combination with either drug , whilst modest additive effects were observed with Compound 5h . None of the combinations resulted in significant cytotoxicity or apoptosis . DISCUSSION : The results show that ECS of temozolomide and estramustine can be significantly enhanced when combined with specific anti-angiogenic inhibitors in an in vitro HUVEC system . 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 . Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP-PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 , P05556 , P31327 , P07225 , P55259 , Q9UJ96 , Q08499 , Q8N743 , and Q14642 . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 , P05556 , P31327 , P07225 and Q14642 were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 , but there was no significant correlation between loss of P60484 and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes . Reverse-phase protein array for prediction of patients at low risk of developing bone metastasis from breast cancer . BACKGROUND : A biomarker that predicts bone metastasis based on a protein laboratory assay has not been demonstrated . Reverse-phase protein array ( RPPA ) enables quantification of total and phosphorylated proteins , providing information about their functional status . The aim of this study was to identify bone-metastasis-related markers in patients with primary breast cancer using RPPA analysis . PATIENTS AND METHODS : Tumor samples were obtained from 169 patients with primary invasive breast carcinoma who underwent surgery . The patients were categorized by whether they developed breast cancer bone metastasis ( BCBM ) during follow-up . Clinical characteristics and protein expression by RPPA were compared and verified by leave-one-out cross-validation . RESULTS : Lymph node status ( p = .023 ) and expression level of 22 proteins by RPPA were significantly correlated with BCBM in logistic regression analysis . These variables were used to build a logistic regression model . After filtering the variables through a stepwise algorithm , the final model , consisting of 8 proteins and lymph node status , had sensitivity of 30.0 % , specificity of 90.5 % , positive predictive value of 30.0 % , and negative predictive value of 90.5 % in the cross-validation . Most of the identified proteins were associated with cell cycle or signal transduction ( P24941 , P38936 , Rb1 , Src , phosphorylated-ribosomal S6 kinase , P04626 , Q9H165 , and P35749 ) . CONCLUSION : Our validated model , in which the primary tumor is tested with RPPA , can predict patients who are at low risk of developing BCBM and thus who likely would not benefit from receiving a bisphosphonate in the adjuvant setting . Clinical trials excluding these patients have the potential to clarify the benefit of bisphosphonates in the adjuvant setting . Solution structure and backbone dynamics of the catalytic domain of matrix metalloproteinase-2 complexed with a hydroxamic acid inhibitor . P08253 is a member of the matrix metalloproteinase family that has been implicated in tumor cell metastasis and angiogenesis . Here , we describe the solution structure of a catalytic domain of P08253 complexed with a hydroxamic acid inhibitor ( DB01630 ) , determined by three-dimensional heteronuclear NMR spectroscopy . The catalytic domain , designated MMP-2C , has a short peptide linker replacing the internal fibronectin-domain insertion and is enzymatically active . Distance geometry-simulated annealing calculations yielded 14 converged structures with atomic root-mean-square deviations ( r.m.s.d. ) of 1.02 and 1.62 A from the mean coordinate positions for the backbone and for all heavy atoms , respectively , when 11 residues at the N-terminus are excluded . The structure has the same global fold as observed for other MMP catalytic domains and is similar to previously solved crystal structures of P08253 . Differences observed between the solution and the crystal structures , near the bottom of the S1 ' specificity loop , appear to be induced by the large inhibitor present in the solution structure . The MMP-2C solution structure is compared with P22894 crystal structure bound to the same inhibitor to highlight the differences especially in the S1 ' specificity loop . The finding provides a structural explanation for the selectivity between P08253 and P22894 that is achieved by large inhibitors . Gastrointestinal stromal tumors ( GISTs ) : focus on histopathological diagnosis and biomolecular features . Gastrointestinal stromal tumors ( GISTs ) are mesenchymal tumors of the gastrointestinal tract that are believed to originate from a neoplastic transformation of the intestinal pacemaker cells ( interstitial cells of Cajal ) normally found in the bowel wall or their precursors . Although the microscopic features have been known for a long time , the defining characteristic of GIST is the presence of the cell-surface antigen CD117 ( P10721 ) , which is demonstrated by immunohistochemistry . P10721 , which is a growth factor transmembrane receptor , is the product of the proto-oncogene c-kit ( chromosome 4 ) . Surgical removal remains the only curative treatment for patients with GISTs . Tumor size , mitotic index , anatomic location , tumor rupture and disease-free interval are the classic characteristics used to predict the clinical course of patients who undergo complete gross resection . Most GISTs express constitutively activated mutant isoforms of P10721 or kinase platelet-derived growth factor receptor alpha ( P16234 ) that are potential therapeutic targets for imatinib mesylate . Imatinib mesylate is a rationally designed , molecularly specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer and which has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant GISTs . More recently DB01268 , a new P10721 / P16234 kinase inhibitor , has been tested in patients with GIST resistant to imatinib , with promising results . Genetic polymorphisms of P03372 , Q92731 , P05093 , and P11511 and the risk of breast cancer : a case control study from North India . Estrogen is a key driver of breast cancer and genes involved in its signaling and biosynthesis are crucial in breast cancer progression . In this study , we investigated the role of estrogen signaling and synthesis related genes polymorphism in susceptibility to breast cancer risk in North India population in a case-control approach . We examined the association of single nucleotide polymorphism ( SNP ) in estrogen receptors , P03372 ( rs2234693 ) and Q92731 ( rs2987983 ) ; estrogen biosynthesis enzymes , P05093 ( rs743572 ) ; and aromatase , P11511 ( rs700519 ) with breast cancer risk . Cases ( n = 360 ) were matched to controls ( n = 360 ) by age , sex , ethnicity , and geographical location . Results provided evidence that all the genetic variants were significantly associated with breast cancer risk among North Indian women . Furthermore , on performing stratified analysis between breast cancer risk and different clinicopathological characteristics , we observed strong associations for menopausal status , estrogen receptor ( ER ) , progesterone receptor ( PR ) , human epidermal growth factor receptor 2 ( P04626 ) status , clinical stage , and histological grade . Our results suggest that these genes could be used as molecular markers to assess breast cancer susceptibility and predicting prognosis in North India population . Inhibition of cyclin-dependent kinases , GSK-3beta and CK1 by hymenialdisine , a marine sponge constituent . BACKGROUND : Over 2000 protein kinases regulate cellular functions . Screening for inhibitors of some of these kinases has already yielded some potent and selective compounds with promising potential for the treatment of human diseases . RESULTS : The marine sponge constituent hymenialdisine is a potent inhibitor of cyclin-dependent kinases , glycogen synthase kinase-3beta and casein kinase 1 . DB02950 competes with DB00171 for binding to these kinases . A P24941 -hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83 residues of P24941 , as observed with other inhibitors . DB02950 inhibits Q00535 /p35 in vivo as demonstrated by the lack of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical neurons , and also inhibits GSK-3 in vivo as shown by the inhibition of P46821 phosphorylation . DB02950 also blocks the in vivo phosphorylation of the microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3 and Q00535 /p35 in Alzheimer 's disease ( cross-reacting with Alzheimer's-specific AT100 antibodies ) . CONCLUSIONS : The natural product hymenialdisine is a new kinase inhibitor with promising potential applications for treating neurodegenerative disorders . 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 . Molecular determinants of trastuzumab efficacy : What is their clinical relevance ? DB00072 -containing therapy is a standard of care for human epidermal growth factor receptor-2 ( P04626 ) -positive breast cancer . In pre-clinical models , a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro . These include expression of the truncated P04626 receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3-kinase ( P42336 ) , loss of phosphatase and tensin homolog ( P60484 ) , activation of other downstream signal transducers , prevention of cell cycle arrest , increased signaling through alternative ( HER or non-HER ) tyrosine kinase receptors , and resistance to antibody-dependent cellular cytotoxicity . However , the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear . Here , we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in P04626 -positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy . We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small , retrospective studies , many of which have yielded conflicting findings . Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials , particularly relating to activation of the phosphatidylinositol 3-kinase pathway , but none is sufficiently strong to form a basis for patient selection . This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab . In the absence of novel , validated biomarkers of efficacy , trastuzumab eligibility should continue to be based on evaluation of P04626 status according to standard methods .