MH_dev_301

Human parainfluenza virus-associated respiratory tract infection among children and genetic analysis of HPIV - 3 strains in Beijing , China . The relevance of human parainfluenza viruses ( HPIVs ) to the epidemiology of acute respiratory infections ( Q9Y4X5 REA ) in China is unclear . From May 2008 to September 2010 , 443 nasopharyngeal aspirates ( NPAs ) from hospitalized pediatric patients ( age from 1 to 93 months ) in Beijing were collected and screened for HPIVs and other common respiratory viruses by real-time RT-PCR . Sixty-two of 443 samples were positive for HPIVs with 4 positive for HPIV - 2 and 58 positive for HPIV - 3 , indicating that HPIV - 3 was the predominant virus present during the study period . A phylogenetic tree based on all the available HN ( hemagglutinin-neuraminidase ) sequences of HPIV - 3 indicated that three distinct clusters ( A , B , and C ) were circulating with some temporal and regional clustering . Cluster C was further divided into sub-clusters , C1 , P06681 REA , P01024 REA and C4 . HPIV - 3 from Beijing isolates belonged to sub-cluster P01024 REA , and were grouped with the isolates from two Provinces of China and the neighboring country of Japan . Genetic analysis based on entire HN gene revealed that the HPIV - 3 isolates from Beijing were highly similar with 97.2 % - 100 % identity at the nucleotide level and these could be divided into two closely related lineages , C3a and C3b . These findings suggested that there was co-circulation of multiple lineages of HPIV - 3 in the Beijing region during the study period . This is the first study to describe the epidemiology and molecular characterization of HPIVs in China .

DB08888 MEN for vitreoretinal diseases . P02751 REA and laminin are clinically relevant plasmin receptors in the eye . Located at the vitreoretinal interface , they are cleaved by ocriplasmin ( DB05028 , ThromboGenics , Iselin , NJ ) , a novel ophthalmic medication . A series of clinical trials to study ocriplasmin for the treatment of vitreoretinal diseases such as vitreomacular traction , macular hole , and exudative age-related macular degeneration are underway . The results are promising and may impact patient care .

DB08896 MEN ( DB08896 MEN ) : a new oral multikinase inhibitor of angiogenic , stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity . Angiogenesis , a critical driver of tumor development , is controlled by interconnected signaling pathways . Vascular endothelial growth factor receptor ( VEGFR ) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature . DB08896 MEN ( DB08896 MEN ) , a novel oral multikinase inhibitor , potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays . Furthermore , regorafenib inhibits additional angiogenic kinases ( P17948 REA / 3 , platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1 ) and the mutant oncogenic kinases P10721 REA , P07949 REA and B-RAF . The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging . DB08896 MEN administered once orally at 10 mg / kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts . In a daily ( qd ) × 4 dosing study , the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition ( TGI ) . A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd × 5 dosing at 10 and 30 mg / kg . DB08896 MEN exhibited potent dose-dependent TGI in various preclinical human xenograft models in mice , with tumor shrinkages observed in breast MDA-MB - 231 and renal 786 - O carcinoma models . Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki - 67 and phosphorylated extracellular regulated kinases 1/2 . These data demonstrate that regorafenib is a well-tolerated , orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies .

Selective inhibition of the tumor marker O60218 REA by antiinflammatory N-phenylanthranilic acids and glycyrrhetic acid . A human aldose reductase-like protein , O60218 REA in the aldo-keto reductase ( AKR ) superfamily , was recently identified as a tumor marker of several types of cancer . DB02383 MEN , an aldose reductase inhibitor ( Q9Y4X5 REA ) , is known to be the most potent inhibitor of the enzyme . In this study , we compared the inhibitory effects of other ARIs including flavonoids on O60218 REA and aldose reductase to evaluate their specificity . However , ARIs showed lower inhibitory potency for O60218 REA than for aldose reductase . In the search for potent and selective inhibitors of O60218 REA from other drugs used clinically , we found that non-steroidal antiinflammatory N-phenylanthranilic acids , diclofenac and glycyrrhetic acid competitively inhibited O60218 REA , showing K ( i ) values of 0.35- 2.9 microM and high selectivity to this enzyme ( 43-57 fold versus aldose reductase ) . Molecular docking studies of mefenamic acid and glycyrrhetic acid in the O60218 REA - nicotinamide adenine dinucleotide phosphate ( NADP ( + ) ) complex and site-directed mutagenesis of the putative binding residues suggest that the side chain of Val 301 and a hydrogen-bonding network among residues Val 301 , Gln 114 and Ser 304 are important for determining the inhibitory potency and selectivity of the non-steroidal antiinflammatory drugs . Thus , the potent and selective inhibition may be related to the cancer chemopreventive roles of the drugs , and their structural features may facilitate the design of new anti-cancer agents targeting O60218 REA .

Estrogen-astrocyte-luteinizing hormone-releasing hormone signaling : a role for transforming growth factor-beta ( 1 ) . The purpose of this study was to identify factors from astrocytes that can regulate P01148 REA neurosecretion . Exposure of P01148 REA - secreting ( GT1 - 7 ) cells to conditioned media ( CM ) from P13671 REA glial cells and hypothalamic astrocytes ( HA ) stimulated P01148 REA release . Assays of P13671 REA and HA CM revealed that transforming growth factor-beta ( 1 ) ( TGF-beta ( 1 ) ) and 3alpha - hydroxy - 5alpha - pregnane - 20 - one ( 3alpha , 5alpha - THP ) , both known P01148 REA secretagogues , were present in CM and their levels increased in parallel to the P01148 REA - releasing activity of CM . In contrast , TGF-alpha was undetectable in P13671 REA or HA CM . Ultrafiltration to remove peptides with molecular weights > 10 kDa virtually abolished the P01148 REA - releasing ability of the HA CM . Furthermore , immunoneutralization with a panspecific DB00116 - beta antibody dose-dependently attenuated the P01148 REA - releasing activity of the CM . Rat hypothalamus and GT1 - 7 cells were demonstrated to express TGF-beta receptors as well as furin , an enzyme that converts latent TGF-beta ( 1 ) to active TGF-beta ( 1 ) . P03372 REA - alpha and Q92731 REA mRNA and protein were also demonstrated in HAs by reverse transcription-polymerase chain reaction and double immunofluorescence , and treatment with 17beta - estradiol ( 17beta - E ( 2 ) ) increased both active and latent TGF-beta ( 1 ) levels in HA CM . The effect of 17beta - E ( 2 ) was completely blocked by the ER antagonist ICI 8280 . As a whole , these studies provide evidence of a previously undescribed 17beta - E ( 2 ) - TGF-beta ( 1 ) - P01148 REA signaling pathway .

Characterization of aberrant melting peaks in unlabeled probe assays . An unlabeled probe assay relies on a double-stranded DNA-binding dye to detect and verify target based on amplicon and probe melting . During the development and application of unlabeled probe assays , aberrant melting peaks are sometimes observed that may interfere with assay interpretation . In this report , we investigated the origin of aberrant melting profiles observed in an unlabeled probe assay for exon 10 of the P07949 REA gene . It was determined that incomplete 3 ' blocking of the unlabeled probe allowed polymerase-mediated probe extension resulting in extension products that generated the aberrant melting profiles . This report further examined the blocking ability of the 3 ' modifications P01024 REA spacer , amino-modified P13671 REA , phosphate , inverted dT , and single 3 ' nucleotide mismatches in unlabeled probe experiments . Although no 3 ' blocking modifications in these experiments were 100 % effective , the amino-modified P13671 REA , inverted dT , and P01024 REA spacer provided the best blocking efficiencies ( 1 % or less unblocked ) , phosphate was not as effective of a block ( up to 2 % unblocked ) , and single nucleotide mismatches should be avoided as a 3 ' blocking modification .

Expression and biological activity of O95477 REA in alveolar epithelial cells . The mechanisms used by alveolar type I pneumocytes for maintenance of the lipid homeostasis necessary to sustain these large squamous cells are unknown . The processes may involve the DB00171 - binding cassette transporter A1 ( O95477 REA ) , a transport protein shown to be crucial in apolipoprotein A-I ( apoA-I ) - mediated mobilization of cellular cholesterol and phospholipid . Immunohistochemical data demonstrated the presence of O95477 REA in lung type I and type II cells and in cultured pneumocytes . Type II cells isolated from rat lungs and cultured for 5 days in 10 % serum trans-differentiated toward cells with a type I-like phenotype which reacted with the type I cell-specific monoclonal antibody VIIIB 2 . Upon incubation of the type I-like pneumocytes with agents that up-regulate the O95477 REA gene ( 9 - cis-retinoic acid [ 9cRA ] and 22 - hydroxycholesterol [ 22 - OH , 9cRA / 22 - OH ] ) , O95477 REA protein levels were enhanced to maximum levels after 8 to 16 hours and remained elevated for 24 hours . In the presence of apoA-I and 9cRA / 22 - OH , efflux of radioactive phospholipid and cholesterol from pneumocytes was stimulated 3 - to 20 - fold , respectively , over controls . Lipid efflux was inhibited by DB01599 MEN . DB02772 density gradient analysis of the media from stimulated cells incubated with apoA-I identified heterogeneous lipid particles that isolated at a density between 1.063 and 1.210 g / ml , with low or high apoA-I content . Thus , pneumocytes with markers for the type I phenotype contained functional O95477 REA protein , released lipid to apoA-I protein , and were capable of producing particles resembling nascent high-density lipoprotein , indicating an important role for O95477 REA in the maintenance of lung lipid homeostasis .

CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin . Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier . Ubiquitin is also a natural constituent of plasma , and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties . In addition , ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo . However , its mechanism of action is unknown . Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 ( P61073 REA and CD184 ) agonist . Extracellular ubiquitin promotes intracellular Ca ( 2 + ) flux and reduces DB02527 levels through a G protein-coupled receptor that signals via a Galpha ( i / o ) protein in THP 1 cells . O00206 REA stimulation reduces ubiquitin-binding sites , which enabled identification of four Galpha ( i / o ) PCRs as ubiquitin receptor candidates . Overexpression of candidate genes in HEK 293 cells , gene silencing in THP 1 cells , competition binding , and signaling studies with the P61073 REA agonist stromal cell-derived factor - 1alpha ( chemokine ( CXC motif ) ligand 12 ) and inhibitor DB06809 MEN identify P61073 REA as a functional ubiquitin receptor . Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology , has implications for the understanding of P61073 REA - mediated events , and is expected to facilitate development of new therapeutic avenues for a variety of diseases .

DB00106 MEN and other gonadotrophin-releasing hormone antagonists in prostate cancer . Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer . DB00044 - releasing hormone ( P01148 REA ) agonists , such as buserelin , goserelin , leuprorelin and triptorelin , stimulate the pituitary ' s gonadotrophin-releasing hormone ( DB00644 ) receptor , ultimately leading to its de-sensitization and subsequent reduction of LH and testosterone levels . However , this reduction is accompanied by a well described increase or ' surge ' in LH and testosterone levels , necessitating the concomitant administration of an antiandrogen to combat the potential effects of transient acceleration in cancer activity . Two pure DB00644 antagonists have been developed , abarelix and degarelix , that are devoid of any agonist effect on the P30968 REA and consequently do not result in testosterone flare . DB00106 MEN was the first DB00644 antagonist to be developed and was approved by the USA Food and Drug Administration in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone-dependent prostate carcinoma , when rapid androgen suppression is necessary . Clinical data on both abarelix and degarelix show that they can produce rapid and sustained decreases in testosterone to castrate levels without the need for co-administration of an antiandrogen , and with a very low complication rate in the short term .

Synthesis , biological activity and HPLC validation of 1,2 , 3,4- tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( DB00382 SUB ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 REA ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1,2 , 3,4- tetrahydroacridine . The compounds P13671 REA - 2KW / HCl , P13671 REA - 4KW / HCl and P13671 REA - 3KW / HCl have four-fold higher antiacetylcholinesterase activity than DB00382 SUB . All of the acquired compounds present higher selectivity towards P22303 REA than DB00382 SUB and lower selectivity towards BuChE . In addition , a rapid , selective and stability-indicating HPLC method was developed and validated for the determination of P13671 REA - 2KW / HCl , P13671 REA - 3KW / HCl and P13671 REA - 4KW / HCl . DB00382 SUB and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3.9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8.3 mM sodium dihydrogen phosphate , 50:50 v / v ) ( overall pH 4 ) . A 1.5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 REA - 2KW / HCl , P13671 REA - 3KW / HCl and P13671 REA - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 REA - 2KW / HCl , P13671 REA - 3KW / HCl and P13671 REA - 4KW / HCl , 0.04 μg / ml and 0.12 μg / ml for DB00382 SUB , 0.42 μg / ml and 1.41 μg / ml for 4 - FBA , respectively .

Effect of currently approved carriers and adjuvants on the pre-clinical efficacy of a conjugate vaccine against oxycodone in mice and rats . Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects . The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the P13671 REA position ( 6OXY ) conjugated to the native DB05299 ( nKLH ) carrier protein . To provide an oxycodone vaccine formulation suitable for human studies , we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses , and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats . 6OXY conjugated to tetanus toxoid ( TT ) or a GMP grade KLH dimer ( dKLH ) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats , while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice . Immunization with 6OXY - TT s . c . absorbed on alum adjuvant provided similar protection to 6OXY - TT administered i . p . with Freund ' s adjuvant in rats . The toll-like receptor 4 ( O00206 REA ) agonist monophosphoryl lipid A ( MPLA ) adjuvant , alone or in combination with alum , offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY - specific antibody secreting B cells in mice vaccinated with 6OXY - nKLH or 6OXY - TT . The immunogenicity of oxycodone vaccines may be modulated by O00206 REA signaling since responses to 6OXY - nKLH in alum were decreased in O00206 REA - deficient mice . These data suggest that TT , nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species , strains and via different routes of administration , while adjuvant formulations may need to be tailored to individual immunogens or patient populations .

Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients . RATIONALE : DB00850 MENMAX DB00850 MEN , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 REA , P35462 REA , P28223 REA , and P28335 REA ) on short-term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 REA , P35462 REA , P28223 REA , and P28335 REA gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 REA and the - 697C and 23Ser alleles of P28335 REA were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0.02 , 0.01 , and 0.02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 REA and P35462 REA genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 REA and P28335 REA genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .

NFκB inhibitors induce cell death in glioblastomas . Identification of novel target pathways in glioblastoma ( GBM ) remains critical due to poor prognosis , inefficient therapies and recurrence associated with these tumors . In this work , we evaluated the role of nuclear-factor-kappa-B ( NFκB ) in the growth of GBM cells , and the potential of NFκB inhibitors as antiglioma agents . NFκB pathway was found overstimulated in GBM cell lines and in tumor specimens compared to normal astrocytes and healthy brain tissues , respectively . Treatment of a panel of established GBM cell lines ( U138MG , U87 , U373 and P13671 REA ) with pharmacological NFκB inhibitors ( BAY 117082 , parthenolide , MG132 , curcumin and arsenic trioxide ) and NFκB-p 65 siRNA markedly decreased the viability of GBMs as compared to inhibitors of other signaling pathways such as MAPKs ( P29323 REA , JNK and p38 ) , PKC , P00533 REA and PI3K / Akt . In addition , NFκB inhibitors presented a low toxicity to normal astrocytes , indicating selectivity to cancerous cells . In GBMs , mitochondrial dysfunction ( membrane depolarization , bcl-xL downregulation and cytochrome c release ) and arrest in the G2 / M phase were observed at the early steps of NFκB inhibitors treatment . These events preceded sub - P55008 detection , apoptotic body formation and caspase - 3 activation . Also , NFκB was found overstimulated in cisplatin-resistant P13671 REA cells , and treatment of GBMs with NFκB inhibitors overcame cisplatin resistance besides potentiating the effects of the chemotherapeutics , cisplatin and doxorubicin . These findings support NFκB as a potential target to cell death induction in GBMs , and that the NFκB inhibitors may be considered for in vivo testing on animal models and possibly on GBM therapy .

Gene expression profiles of DB00171 - binding cassette transporter A and C subfamilies in mouse retinal vascular endothelial cells . The purpose of this study was to quantify gene expression levels of the DB00171 - binding cassette ( DB01048 ) transporter A and C subfamilies O95477 REA - A9 , and P33527 REA - 6 / Mrp 1-6 , Q99622 / Mrp 7 in mouse retinal vascular endothelial cells ( RVEC ) using a combination of a magnetic isolation method for mouse RVEC and real-time quantitative PCR analysis . The transcript level of endothelial cell markers , such as CD31 , Tie - 2 , claudin - 5 , occludin , ABCB 1a / mdr 1a , and Q9UNQ0 , were more than 20 - fold higher than those in the non-RVEC fraction , suggesting that RVEC in the RVEC fraction are concentrated at least 20 - fold compared with those of the non-RVEC fraction . In the O95477 REA to A9 families , the transcript level of Q99758 REA and A9 in the RVEC fraction was 1.2- and 32 - fold higher than that in the non-RVEC fraction . Although Q99758 REA was expressed in both the RVEC and non-RVEC fractions , A9 is predominantly expressed in the RVEC fraction . In the P33527 REA to P13671 REA and Q99622 families , the transcript level of O15438 REA , C4 , and P13671 REA in the RVEC fraction was 27 - , 251 - , and 242 - fold higher , respectively , than that in the non-RVEC fraction , suggesting that O15438 REA , C4 , and P13671 REA are predominantly expressed in the RVEC . In conclusion , Q99758 REA , Q8IUA7 , O15438 REA , O15439 REA , and O95255 REA mRNAs are predominantly expressed at the inner blood-retina barrier ( inner BRB ) and appear to play a major role in the efflux transport of their substrates at the inner BRB .

Effect of citalopram on the desensitization of serotonin - 2A receptor-mediated calcium mobilization in rat glioma cells . 1 . The authors have investigated the effect of citalopram , an effective antidepressant drug with selective serotonin ( 5 - HT ) uptake inhibition , on P28223 REA receptor-mediated intracellular calcium ( Ca2 + ) rise in P13671 REA cultured cells . 2 . DB00215 , at concentrations of 10 and 30 mu M , did not significantly reduce the Ca2 + mobilization induced by 10 mu M 5 - HT , indicating that citalopram has little affinity for P28223 REA receptors . 3 . DB00215 did not alter a subsequent response to 5 - HT after citalopram was pre-applied to the cells . 4 . However , citalopram inhibited the desensitization of P28223 REA receptors . When the cells were pretreated with citalopram and 5 - HT , the subsequent response to 5 - HT was significantly greater than that obtained following pretreatment with 5 - HT alone . 5 . To investigate the mechanism of action of citalopram on the desensitization of P28223 REA receptors , NaF-induced cGMP generation was measured . DB00215 inhibited the generation of cGMP induced by NaF in P13671 REA cells as well as W - 7 . 6 . These results indicate that citalopram antagonized the desensitization of P28223 REA receptor-mediated Ca2 + mobilization and this antagonism may be mediated by a calmodulin-dependent pathway in P13671 REA glioma cells .

P02751 REA expression in the intervertebral disc of monkey . BACKGROUND : P02751 REA , a large dimeric plasma glycoprotein found only in vertebrates , is a core component of several extracellular matrices . Integrin receptors regulate different cell activities . P02751 REA expression patterns in intervertebral disc have not been extensively studied . The aim of this study was to evaluate the distribution of fibronectin in the different regions of the intervertebral disc , and in intervertebral discs of different levels of monkeys . METHODS : Spines of nine 3-4 year-old cynomolgus monkeys ( Macaca fascicularis ) were studied . From every spine , 5 vertebral motion segments were sectioned ( P01031 REA - P13671 REA , DB00279 - DB00451 , P02786 REA - P28907 REA , Q401N2 - Q96MH2 , Q9NP50 - Q15004 ) producing forty-five vertebral motion segments . These were bisected in the sagittal plane . Immunohistochemical studies were performed using specific antibodies to detect fibronectin . RESULTS : A positive immunoreaction for fibronectin was found in the endplates , in the peripheral annulus fibrosus , and in the longitudinal ligaments . There was no fibronectin immunoreactivity in the nucleus pulposus and in the central annular region close to the nucleus pulposus . There were no differences in immunoreactivity to fibronectin among discs of different levels and discs of different monkeys . CONCLUSIONS : P02751 REA may exert a role in the organization of the extracellular matrix of the intervertebral discs . Identifying the structural features of the intervertebral disc extracellular matrix may help to understand the mechanisms of intervertebral disc pathology .

Acerogenin A , a natural compound isolated from Acer nikoense Maxim , stimulates osteoblast differentiation through bone morphogenetic protein action . We investigated the effects of acerogenin A , a natural compound isolated from Acer nikoense Maxim , on osteoblast differentiation by using osteoblastic cells . Acerogenin A stimulated the cell proliferation of MC3T3 - E1 osteoblastic cells and RD - P13671 REA osteoblastic cells ( Runx 2 - deficient cell line ) . It also increased alkaline phosphatase activity in MC3T3 - E1 and RD - P13671 REA cells and calvarial osteoblastic cells isolated from the calvariae of newborn mice . Acerogenin A also increased the expression of mRNAs related to osteoblast differentiation , including P02818 REA , Osterix and Runx 2 in MC3T3 - E1 cells and primary osteoblasts : it also stimulated P02818 REA and Osterix mRNA expression in RD - P13671 REA cells . The acerogenin A treatment for 3days increased Bmp - 2 , Bmp - 4 , and Bmp - 7 mRNA expression levels in MC3T3 - E1 cells . Adding noggin , a BMP specific-antagonist , inhibited the acerogenin A-induced increase in the P02818 REA , Osterix and Runx 2 mRNA expression levels . These results indicated that acerogenin A stimulates osteoblast differentiation through BMP action , which is mediated by Runx 2 - dependent and Runx 2 - independent pathways .

DB05007 MEN - - a multitargeted tyrosine kinase inhibitor : results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib . INTRODUCTION : Although patients with non-small cell lung cancer ( NSCLC ) whose tumors harbor epidermal growth factor receptor ( P00533 REA ) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib , they uniformly develop resistance to these agents . The secondary P00533 REA T790M mutation is found in 50 % of patients with acquired resistance . Herein , we studied DB05007 MEN , an oral small molecule inhibitor of multiple receptor tyrosine kinases , including P00533 REA , P35968 REA , P04626 REA , and EphB 4 , in NSCLC patients known or suspected of having tumors harboring T790M . METHODS : Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥ 12 weeks of stable disease or response to erlotinib or gefitinib and / or those patients with a documented P00533 REA T790M . DB05007 MEN 300 mg was administered once daily . The primary end point was objective response rate . Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA . RESULTS : Forty-one patients were enrolled ; 33 were evaluable for efficacy . One partial response was observed ( response rate 3 % and 90 % confidence interval , 0 % to 14 % ) . Of patients whose tumors harbored T790M , 67 % ( 8/ 12 ) had progression of disease as best response compared with 14 % ( 3/21 ) of those without this mutation . Plasma samples from 40 patients were available for mutation testing , 14 ( 35 % ) of which were found to have P00533 REA mutations . CONCLUSIONS : The 3 % response rate observed did not meet the prespecified threshold to recommend further study of DB05007 MEN in patients who develop acquired resistance to erlotinib or gefitinib . Patients with T790M had a significantly worse progression-free survival .

Serial changes in serum vitamin P04264 REA , triglyceride , cholesterol , osteocalcin and 25 - hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 REA concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 REA concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non-detectable , subsequently returning to pre-operative values within 3 weeks . Serum vitamin P04264 REA tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 REA - triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 REA concentrations were similar and fell significantly after operation in both groups , returning to pre-operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 MEN status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy .

Preparation of phosphorylated starch by dry-heating in the presence of pyrophosphate and its calcium-phosphate solubilizing ability . Starch was phosphorylated through dry-heating in the presence of pyrophosphate at various conditions , and the characteristics of phosphorylated starch ( PS ) were examined . Starch phosphorylation increases as the pH increases from 3 to 6 , but diminishes at pH 7 . Increased temperatures enhance phosphorylation . Data from ( 31 ) P NMR suggests that starch phosphorylation occurs mainly at the P01024 REA - OH and P13671 REA - OH of the glucose residue . The phosphate linkage is mainly due to monostarch monophosphate . Although starch had almost no calcium phosphate-solubilising capacity , this capacity was markedly enhanced by phosphorylation . X-ray diffraction analysis indicates that the crystal structure of hydroxyapatite was not present in the calcium phosphate-PS complex .