interacts_with DB01296?
Significant pathways detection in osteoporosis based on the bibliometric network . BACKGROUND : Osteoporosis is a significant public health issue worldwide . The underlying mechanism of osteoporosis is an imbalance between bone resorption and bone formation . However , the exact pathology is still unclear , and more related genes are on demand . AIM : Here , we aim to identify the differentially expressed genes in osteoporosis patients and control . MATERIALS AND METHODS : Biblio-MetReS , a tool to reconstruct gene and protein networks from automated literature analysis , was used for identifying potential interactions among target genes . Relevant signaling pathways were also identified through pathway enrichment analysis . RESULTS : Our results showed that 56 differentially expressed genes were identified . Of them , P42224 , P02778 , O14543 , P35318 , P07996 , P04179 , and Q9H252 have been demonstrated involving in osteoporosis . Further , a bibliometric network was constructed between DEGs and other genes through the Biblio-MetReS . CONCLUSIONS : The results showed that P42224 could interact with P02778 through Toll-like receptor signaling pathway and Chemokine signaling pathway . P42224 interacted with O14543 through JAK/ P35610 pathway . Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of DB06684 , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5-HT(1A) ) receptor agonist [ Bartoszyk , G.D. , Hegenbart , R. , Ziegler , H. , 1997. P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties. Eur. J. Pharmacol. 322 , 147-153. ] , on change in affect following predator stress . DB06684 and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus-maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle . In prophylactic testing , DB06684 affected stress potentiation of startle at doses above 5 mg/kg . DB06684 increased stress elevation of startle at 10 mg/kg . Higher doses of DB06684 ( 20 and 40 mg/kg ) blocked stress potentiation of startle . In contrast , DB06684 had no effect on stress potentiation of anxiety in the plus-maze . In therapeutic testing , DB06684 increased stress elevation of startle at all doses . In contrast , therapeutic DB06684 had no effect on stress potentiation of anxiety in the plus-maze . Taken together , the data suggest a prophylactic potential for DB06684 in the treatment of changes in hypervigilance following severe stress . Stimulation of P05121 and adipokines by glucose in human adipose tissue in vitro . Adipokines such as P00747 activator inhibitor-1 ( P05121 ) , interleukin ( IL ) -8 , and tumor necrosis factor ( P01375 ) -alpha are elevated in patients with obesity , insulin resistance , and type 2 diabetes . In the present study , we investigated whether glucose affected the production of these adipokines in human adipose tissue in vitro . DB09341 ( up to 35mM ) increased secretion of P05121 ( p < 0.01 ) and P10145 ( p < 0.01 ) , but not P01375 , in a dose- and time-dependent manner . Half-maximal stimulatory concentration of glucose was about 1mM . DB01296 ( 5mM ) decreased production of P05121 ( p < 0.05 ) and P10145 ( p < 0.05 ) , indicating that the hexosamine biosynthesis pathway is not involved in the glucose-induced increment in adipokine secretion . The present data demonstrate that glucose increases P05121 and P10145 secretion . However , glucose concentrations above 5mM had no additional effects on adipokine secretion , suggesting that mechanisms other than diabetes/insulin resistance-related hyperglycemia may be involved in the observed elevation of these adipokines . Signal transducer and activator of transcription-1 ( P42224 ) , but not STAT5b , regulates P08069 gene expression in an osteosarcoma cell line . The P08069 ( IGF-IR ) exhibits potent mitogenic , antiapoptotic , and transforming activities . Previous studies have suggested that the expression of the IGF-IR gene is negatively regulated by certain cytokines , including interferon-gamma ( P01579 ) . The potential involvement of P35610 proteins in transcriptional regulation of the IGF-IR gene by P01579 was addressed by transient coexpression of vectors encoding P42224 and STAT5b , together with an IGF-IR promoter luciferase reporter , in the osteosarcoma-derived cell line Saos-2 . Physical interactions between P01579 -induced transcription factors and the IGF-IR promoter region were examined by electrophoretic mobility shift assays ( EMSA ) . The results obtained indicate that the mechanism of action of P01579 involves stimulation of P42224 which , in turn , binds P01579 activation sites ( GAS ) in the IGF-IR regulatory region , thus suppressing promoter activity . Taken together , our results suggest that the IGF-IR gene is a novel target for P42224 action and that at least part of the inhibitory effects of P42224 may involve repression of the strongly antiapoptotic IGF-IR gene . Vampire bat plasminogen activator DB04925 -alpha-1 ( desmoteplase ) : a thrombolytic drug optimized by natural selection . P00747 activators are enzymes found in all vertebrate species investigated so far . Their physiological function is the generation of localized proteolysis in the context of tissue remodeling , wound healing and neuronal plasticity . The common vampire bat ( Desmodus rotundus ) is a New World species that feeds exclusively on blood . Its saliva contains highly potent plasminogen activators , specialized in rapid lysis of fresh blood clots . Biochemical and pharmacological evidence indicates that these plasminogen activators represent a new class of thrombolytics with pharmacological and toxicological properties superior to human tissue-type plasminogen activator , the clot dissolving agent now most frequently used in medicine . A form of the enzyme produced by recombinant DNA technology is currently employed to test this hypothesis in clinical studies . P08069 targeted therapeutics : novel compounds and novel treatment strategies for cancer medicine . The insulin-like growth factor 1 receptor ( IGF-1R ) and its associated signalling system has provoked considerable interest over recent years as a novel therapeutic target in cancer . A brief outline of the IGF-1R signalling system and the rationale for its use in cancer medicine is given . This is followed by a discussion of the different possible targets within the IGF-1R system , and drugs developed to interact at each target . A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples : growth hormone releasing hormone antagonists ( e.g. JV-1-38 ) , growth hormone receptor antagonists ( e.g. pegvisomant ) , IGF-1R antibodies ( e.g. CP-751,871 , AVE1642/EM164 , DB05759 , P35240 -717454 , BIIB022 , Q99217 479 , MK-0646/h7C10 ) , and IGF-1R tyrosine kinase inhibitors ( e.g. BMS-536942 , BMS-554417 , DB00238 -AEW541 , DB00238 -ADW742 , AG1024 , potent quinolinyl-derived imidazo (1,5-a)pyrazine PQIP , picropodophyllin PPP , Nordihydroguaiaretic acid Insm-18/NDGA ) . The following tumour types are specifically discussed : lung , breast , colorectal , pancreatic , NETs , sarcoma , prostate , leukaemia , multiple myeloma . Other tumour types are mentioned briefly : squamous cell carcinoma of the head and neck , melanoma , glioblastoma , ovary , gastric and mesothelioma . Results of early stage clinical trials , involving recently patented drugs. are included where appropriate . We then outline the current understanding of toxicity related to IGF-1R targeted therapy , and finally outline areas for further research . Apolipoproteins D and E3 exert neurotrophic and synaptogenic effects in dorsal root ganglion cell cultures . Co-cultures of 3T3- Q9NUQ9 adipocytes with neurons from the rat dorsal root ganglia ( Q86YR7 ) showed enhanced neuritogenesis and synaptogenesis . Microarray analysis for upregulated genes in adipocyte/ Q86YR7 co-cultures currently points to apolipoproteins D and E ( P05090 , ApoE ) as influential proteins . We therefore tested adipocyte-secreted cholesterol and the carrier proteins P05090 and ApoE3 . DB04540 , P05090 , and ApoE3 each increased neurite outgrowth and upregulated the expression of presynaptic synaptophysin and synaptotagmin , as well as the postsynaptic density protein 95 . The neurotrophic effects of P05090 and ApoE3 were associated with an increased expression of the low-density lipoprotein receptor and apolipoprotein E receptor 2 . Simultaneous treatment with receptor-associated protein , an apolipoprotein receptor antagonist , inhibited the neurotrophic function of both apolipoproteins . The application of P05090 , ApoE3 , and cholesterol to Q86YR7 cell cultures corresponded with increased expression of the chemokine stromal cell-derived factor 1 and its receptor CXC chemokine receptor 4 ( P61073 ) . Surprisingly , the inhibition of P61073 by the antagonistic drug DB06809 decreased the apolipoprotein/cholesterol dependent neurotrophic effects . We thus assume that apolipoprotein-induced neuritogenesis in Q86YR7 cells interferes with P61073 signaling , and that adipocyte-derived apolipoproteins might be helpful in nerve repair . Attenuation of LPS-induced lung inflammation by glucosamine in rats . Acute inflammation is often observed during acute lung injury ( ALI ) and acute respiratory distress syndrome . DB01296 is known to act as an anti-inflammatory molecule . The effects of glucosamine on acute lung inflammation and its associated mechanisms remain unclear . The present study sought to address how glucosamine plays an anti-inflammatory role in acute lung inflammation in vivo and in vitro . Using the LPS intratracheal instillation-elicited rat lung inflammation model , we found that glucosamine attenuated pulmonary edema and polymorphonuclear leukocyte infiltration , as well as the production of P01375 -α , IL-1β , cytokine-induced neutrophil chemoattractant ( CINC ) -1 , macrophage inflammatory protein ( MIP ) -2 , and nitric oxide ( NO ) in the bronchoalveolar lavage fluid ( BALF ) and in the cultured medium of BALF cells . The expression of P01375 -α , IL-1β , IFN-γ , CINC-1 , MIP-2 , monocyte chemotactic protein-1 , and inducible NO synthase ( P35228 ) in LPS-inflamed lung tissue was also suppressed by glucosamine . Using the rat alveolar epithelial cell line Q401N2 , we noted that the cytokine mixture (cytomix)-regulated production and mRNA expression of CINC-1 and MIP-2 , NO production , the protein and mRNA expression of P35228 , P35228 mRNA stability , and P35228 promoter activity were all inhibited by glucosamine . Furthermore , glucosamine reduced LPS-mediated NF-κB signaling by decreasing IκB phosphorylation , p65 nuclear translocation , and NF-κB reporter activity . Overexpression of the p65 subunit restored the inhibitory action of glucosamine on cytomix-regulated NO production and P35228 expression . In conclusion , glucosamine appears to act as an anti-inflammatory molecule in LPS-induced lung inflammation , at least in part by targeting the NF-κB signaling pathway . DB01296 sulfate inhibits P01375 and P01579 -induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : DB01296 sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine-induced expression of the gene for intercellular adhesion molecule ( ICAM ) -1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE-19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT-PCR ) . The activation and nuclear translocation of the nuclear factors NF-kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time- and dose-dependent manner in ARPE-19 cells . GS effectively downregulated the P01375 - or P01579 -induced expression of P05362 in the protein and mRNA level in a dose-dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 -stimulated ARPE-19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE-19 cell stimulated with P01375 or P01579 through blockade of NF-kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye . Modulation of cytokine production and enhancement of cell viability by Q9NYK1 and Q9NR96 ligands during anthrax infection of macrophages . Inhalation of Bacillus anthracis , a bioterrorism agent , results in a high mortality rate despite appropriate antibiotic therapy . Macrophages appear to be a key factor in B. anthracis pathogenesis . The burst of pro-inflammatory cytokines from macrophages could be a major cause of death in anthrax . However , preactivation of Toll-like receptors ( TLRs ) could modify the host response . TLR ligands stimulate the release of activating cytokines but may also down-modulate the subsequent deleterious cytokine response to pathogens . We developed a cell culture model to measure macrophage responses to B. anthracis spores and bacilli . We found that germination from spores to bacilli produced a substantial stimulus for the secretion of the cytokines P05231 , P01375 , P22301 , and IL-12 p40 . Our studies showed that pretreatment of mouse macrophages with the Q9NR96 ligand DB05463 , or the Q9NYK1 ligands R-848 and IT-37 , results in a substantial decrease in the subsequent secretion of P05231 and P01375 in response to B. anthracis infection of macrophages . Furthermore , the Q9NYK1 and Q9NR96 ligands significantly decreased anthrax-induced cytotoxicity in the macrophages . These findings suggest that TLR ligands may contribute to the enhancement of innate immunity in B. anthracis infection by suppressing potentially deleterious pro-inflammatory cytokine responses and by improving macrophage viability . 8-OH-DPAT ( P08908 agonist ) Attenuates 6-Hydroxy- dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE(S) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6-OHDA ( 8 μg/2 μl/rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8-OH-DPAT ( P08908 receptor agonist ; 0.25 , 0.5 and 1mg/kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8-OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 -α , IL-1β and P05231 . RESULTS : Chronic injection of 8-OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg/kg of 8-OH-DPAT . Levels of P01375 -α in P04141 increased three weeks after 6-OHDA injection while there was a significant decrease in P01375 -α level of parkinsonian animals treated with 8-OH-DPAT ( 1 mg/kg , IP for 10 days ) . IL-1β and P05231 decreased and increased in parkinsonian rats and in 8-OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8-OH-DPAT improves catalepsy in 6-OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines . Epigenetic mechanism involved in the HBV/HCV-related hepatocellular carcinoma tumorigenesis . Hepatitis B virus ( HBV ) and hepatitis C virus ( HCV ) infection were known to be risk factors for HCC , they were suspected to promote its development by eliciting epigenetic changes . However , the precise gene targets and underlying mechanisms have not been elucidated . Epigenetic regulation of gene expression has emerged as a fundamental aspect of cancer development and progression . The molecular mechanisms of carcinogenesis in hepatocellular carcinoma involve a complex interplay of both genetic and epigenetic factors . DNA methylation , post-translational modifications of histone proteins , chromatin remodeling , and noncoding RNAs are four major types of mechanistic layers in the field of epigenetics . HBV infection could affect methylation on p16(INK4A) , P09211 , CDH1( P12830 ) , RASSF1A , P38936 ( P38936 /CIP1) genes , which may play important roles in the development of HCC . HCV infection was related to aberrant methylation on O15524 , Gadd45β , P16455 , P42224 and P25054 . Other epigenetic alterations included histone proteins , chromatin remodeling , and noncoding RNAs were described in literature . Uncovering the epigenetic alterations of HBV/HCV-induced HCC carcinogenesis could highlight a new strategy for deciphering the mechanism of HCC tumorigenesis and development , as well as a potential diagnostic advantage . P03372 1 ( P03372 ; ERα ) , not Q92731 ( ERβ ) , modulates estrogen-induced sex reversal in the American alligator , a species with temperature-dependent sex determination . All crocodilians and many turtles exhibit temperature-dependent sex determination where the temperature of the incubated egg , during a thermo-sensitive period ( P07996 ) , determines the sex of the offspring . DB00286 play a critical role in sex determination in crocodilians and turtles , as it likely does in most nonmammalian vertebrates . Indeed , administration of estrogens during the P07996 induces male to female sex reversal at a male-producing temperature ( MPT ) . However , it is not clear how estrogens override the influence of temperature during sex determination in these species . Most vertebrates have 2 forms of nuclear estrogen receptor ( P03372 ) : P03372 ( ERα ) and Q92731 ( ERβ ) . However , there is no direct evidence concerning which P03372 is involved in sex determination , because a specific agonist or antagonist for each P03372 has not been tested in nonmammalian species . We identified specific pharmaceutical agonists for each P03372 using an in vitro transactivation assay employing American alligator P03372 and Q92731 ; these were 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol ( PPT ) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol ( WAY 200070 ) , respectively . Alligator eggs were exposed to PPT or WAY 200070 at a MPT just before the P07996 , and their sex was examined at the last stage of embryonic development . Estradiol-17β and PPT , but not WAY 200070 , induced sex reversal at a MPT . PPT-exposed embryos exposed to the highest dose ( 5.0 μg/g egg weight ) exhibited enlargement and advanced differentiation of the Müllerian duct . These results indicate that P03372 is likely the principal P03372 involved in sex reversal as well as embryonic Müllerian duct survival and growth in American alligators . Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells . Human diets contain sterol oxidation products that can induce cytotoxic effects , mainly caused by cholesterol oxides . However , phytosterol oxides effects have been less extensively investigated . This study evaluates the production of inflammatory biomarkers ( IL-1β , P10145 , P22301 , TNFα ) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism ( Q9UHC9 , Q9H222 /8 , HMGCoA , ACAT ) produced by 7-ketosterols ( stigmasterol/cholesterol ) in Caco-2 cells . These effects were linked to intracellular signaling pathways by using several inhibitors . Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol . In non-pre-treated cells , only efflux transporters were down-regulated by 7-ketosterols , showing a greater influence upon Q9H222 expression . Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation ; however , the energetic metabolism inhibition reduced Q9UHC9 expression only in 7-ketocholesterol-incubated cells . In non-pre-treated cells , HMG- DB01992 was up-regulated by both 7-ketosterols . However , exposure to inhibitors down-regulated the expression levels , mainly in 7-ketocholesterol-incubated cells . While ACAT expression values in non-pre-treated cells were unchanged , exposure to inhibitors caused down-regulation of mRNA levels . These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i , which also could mediate HMGCoA activity in POPs metabolism . However , energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization . Current therapy for patients with sitosterolemia -- effect of ezetimibe on plant sterol metabolism . Sitosterolemia is a rare , autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations , caused by mutations in the adenosine triphosphate-bind-ing cassette ( DB01048 ) transporter Q9H222 or Q9H221 genes . Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol , cause premature atherosclerosis and massive xanthomas . Hitherto known treatments for sitosterolemia , including a low-sterol diet , bile-salt binding resins , ileal bypass surgery and low density lipoprotein ( LDL ) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels , subsequently developing premature atherosclerotic cardiovascular diseases . DB00973 , an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 ( Q9UHC9 ) , has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia . DB00973 also reduces the gastrointestinal absorption of plant sterols , thereby also lowering the serum concentrations of plant sterols . This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia . In the current review , we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease , one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis . DB00973 administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3 % and 48.9 % , respectively , in the two patients , demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy . Effects of vandetanib on lung adenocarcinoma cells harboring epidermal growth factor receptor T790M mutation in vivo . DB05294 is a novel multitarget tyrosine kinase inhibitor ( TKI ) that inhibits vascular endothelial growth factor receptor-2 ( P35968 ) , with additional inhibition of epidermal growth factor receptor ( P00533 ) and rearranged during transfection receptor signaling , which has shown promising results in clinical trials for advanced non-small cell lung cancer . However , the mechanisms of acquired resistance to vandetanib remain unclear . Therefore , we established in vitro vandetanib-resistant PC-9/VanR cells from PC-9 , a vandetanib-sensitive lung adenocarcinoma cell line , by chronic exposure to this agent . PC-9/VanR cells were 50-fold more resistant to vandetanib than PC-9 cells in vitro . Compared with PC-9 cells , PC-9/VanR cells showed emergence of an P00533 T790M mutation , moderately elevated MET amplification , and similar P35968 inhibition by vandetanib . Note that phospho-MET in PC-9/VanR was suppressed following P00533 inhibition by an irreversible P00533 -TKI , indicating that MET signaling of PC-9/VanR was dependent on P00533 signaling and that MET amplification was not the primary mechanism of resistance to vandetanib . In contrast to the in vitro experiment , vandetanib effectively inhibited the growth of PC-9/VanR tumors in an in vivo xenograft model through the antiangiogenesis effects of P35968 inhibition . In conclusion , the multitarget TKI vandetanib induced or selected for the P00533 T790M mutation as observed previously with highly selective P00533 -TKIs . However , vandetanib retained significant efficacy in vivo against xenografts harboring the T790M mutation , providing a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of P00533 T790M mutations limits the effectiveness of highly selective P00533 -TKIs . P21912 mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma . Cyclophosphamide-dacarbazine-vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma ( P25189 ) ; however , dacarbazine is the only recognized active drug in neuroendocrine tumours . We investigated the therapeutic benefit of temozolomide ( DB00853 ) , an oral alternative to dacarbazine , in patients with P25189 . This is a retrospective study of consecutive patients with documented progressive P25189 . We examined the correlation between DB00139 dehydrogenase B ( P21912 ) mutation and O(6)-methylguanine-DNA methyltransferase ( P16455 ) promoter methylation and P16455 expression in the French nation-wide independent cohort of 190 pheochromocytomas or paragangliomas ( PP ) . Progression-free survival ( PFS ) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point . Fifteen consecutive patients with P25189 were enrolled ; ten ( 67 % ) carried a mutation in P21912 . The mean dose intensity of DB00853 was 172 mg/m(2) /d for 5 days every 28 days . Median PFS was 13.3 months after a median follow-up of 35 months . There were five partial responses ( 33 % ) , seven stable ( 47 % ) and three progressive diseases ( 20 % ) . Grade 3 toxicities were lymphopenia in two patients and hypertension in one . Partial responses were observed only in patients with mutation in P21912 . P16455 immunohistochemistry was negative in tumour samples from four patients who responded to treatment . P21912 germline mutation was associated with hypermethylation of the P16455 promoter and low expression of P16455 in 190 samples of the French nation-wide independent cohort . This study demonstrates that DB00853 is an effective antitumour agent in patients with P21912 -related P25189 . The silencing of P16455 expression as a consequence of P16455 promoter hypermethylation in P21912 -mutated tumours may explain this finding . P40763 signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription-3 ( P40763 ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell-cell contact initiates P40763 activation . Using a panel of HNSCC cell lines , Ca(+2)-dependent cell-cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 -Y705 and P42224 -Y701 . This intercellular adhesion-induced P40763 activation was mediated by JAK and Src signaling and partially by P00533 signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 -Y705 at nascent P12830 cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion-mediated P35610 activation in monolayer and cell aggregate cultures required functional P12830 . These results indicate that , in HNSCC cells , cadherin-mediated intercellular adhesion induces P35610 signaling that may modulate cell survival and resistance to apoptosis during tumor progression . Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells . Transforming growth factor-beta ( TGF-beta ) plays a crucial role in vascular development and homeostasis by regulating many transcriptional targets . P36897 ( P36897 ) is a P36897 expressed in various TGF-beta-responsive cells . In contrast , P37023 functions as a P36897 in endothelial cells , and is responsible for human hereditary hemorrhagic telangiectasia ( DB04865 ) type II . P36897 and P37023 mediate TGF-beta signals through distinct Smad proteins , i.e. , Q15796 / P84022 and Q15797 / Q99717 , respectively . To identify target genes of P37023 and P36897 in endothelial cells , we conducted oligonucleotide microarray analysis . Human umbilical vein endothelial cells ( HUVEC ) were infected with recombinant adenoviruses carrying a constitutively active form of P37023 or P36897 . P36897 inhibited the proliferation , network formation , and tube formation of HUVEC and induced their apoptosis , whereas P37023 did not exhibit significant effects on HUVEC in vitro . mRNAs were extracted from HUVEC and used for hybridization of oligonucleotide arrays representing approximately 7,000 human genes . Northern blot and quantitative real-time polymerase chain reaction ( PCR ) analyses were also performed for some of these genes , confirming the validity of this microarray analysis . We found that P37023 specifically upregulated O43541 , O15105 , Id1 , Id2 , endoglin , P42224 , and interleukin 1 receptor-like 1 . P36897 , in contrast , upregulated P49763 , SM22alpha , connexin 37 , betaIG-H3 , and Q14766 . P37023 downregulated Q15797 , P61073 , P20827 , and plakoglobin , whereas P36897 downregulated claudin 5 and integrin beta(5) . These results revealed some new targets of TGF-beta in endothelial cells , and differences in transcriptional regulation patterns between P37023 and P36897 .