MH_dev_217

DB05651 MEN , a novel isotype-selective histone deacetylase inhibitor , has broad spectrum antitumor activity in vitro and in vivo . Nonselective inhibitors of human histone deacetylases ( HDAC ) are known to have antitumor activity in mice in vivo , and several of them are under clinical investigation . The first of these , DB02546 ( DB02546 ) , has been approved for treatment of cutaneous T-cell lymphoma . Questions remain concerning which HDAC isotype ( s ) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor . We have developed an isotype-selective HDAC inhibitor , DB05651 MEN , which potently targets human Q13547 REA but also has inhibitory activity against Q92769 REA , O15379 REA , and Q96DB2 in vitro . In intact cells , DB05651 MEN inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal . DB05651 MEN induced hyperacetylation of histones , selectively induced apoptosis , and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner . DB05651 MEN exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro , and HDAC inhibitory activity was required for these effects . In vivo , DB05651 MEN significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors . Our findings suggest that the isotype-selective HDAC inhibition by DB05651 MEN is sufficient for antitumor activity in vivo and that further clinical investigation is warranted .

Genetic determinants of diabetes are similarly associated with other immune-mediated diseases . PURPOSE OF REVIEW : I discuss the increasing number of genes discovered to exert pleiotropic action on susceptibility to diabetes and simultaneously to other immune-mediated diseases . While a genetic correlation between type 1 diabetes and autoimmunity is not surprising , the mechanism of a relationship to other conditions such as atopy is less obvious . The recent wave of genome-wide association studies offers confirmation of previously recognized risk loci , but also novel loci that also are likely to act via multiple pathogenetic pathways . I will review this material more in a genetical than an immunological way . RECENT FINDINGS : Identification of Q9BYX4 , an RNA helicase involved in the innate immune response to viral infection as a risk factor for type 1 diabetes and rheumatoid arthritis . Confirmation of the roles of P16410 REA and Q9Y2R2 REA as general immune function modulators with a nonlinear dose-response effect on autoimmunity , and confirmation of the role of P01589 REA , which may act via a regulatory T cell subset on immune disease risk . Expansion of the role of P37231 REA in immunity . SUMMARY : The wave of genome-wide association studies already experienced in the last 2 years has solidified what we thought we knew and added a list of genes in new pathways . The association of Q9BYX4 with type 1 diabetes may offer a real window into early events in the development of that disease .

Muscle KATP channels : recent insights to energy sensing and myoprotection . DB00171 MEN - sensitive potassium ( K ( DB00171 MEN ) ) channels are present in the surface and internal membranes of cardiac , skeletal , and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity . In so doing , they can play an important role in the control of contractility , particularly when cellular energetics are compromised , protecting the tissue against calcium overload and fiber damage , but the cost of this protection may be enhanced arrhythmic activity . Generated as complexes of Kir 6.1 or Kir 6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits , Q09428 REA or SUR 2 , the differential assembly of K ( DB00171 MEN ) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation , and hence to the tissue-specific pharmacological control of contractility . The last 10 years have provided insights into the regulation and role of muscle K ( DB00171 MEN ) channels , in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified . As yet , few human diseases have been correlated with altered muscle K ( DB00171 MEN ) activity , but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types .

Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 REA or Q09428 REA genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long-term follow-up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 REA , Q14654 REA , or Q09428 REA genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow-up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 REA and Q09428 REA genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .

Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 MEN - binding cassette transporters ( ABCs ) in one of the most drug-resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical-pathologic characteristics and P01116 REA mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real-time polymerase chain reaction with a relative standard curve . P01116 REA mutations in exon 2 were assessed by high-resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical-pathologic characteristics . P01116 REA mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up-regulation of P21439 REA , O95342 REA , P33527 REA , O15438 REA , O15440 REA , Q5T3U5 REA , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up-regulation of O95477 REA , Q8IZY2 , and P45844 REA implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down-regulation of Q99758 REA , O95255 REA , P13569 REA , and Q09428 REA suggests a possible role of stem cells in the development and progression of PDAC .

Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification . P37231 REA ( PPARgamma ) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism , adipocyte differentiation , and tumor suppression and proliferation . To understand the role of PPARgamma in tumorigenesis , transgenic mice were generated with mammary gland-directed expression of the dominant-negative transgene Pax 8P PARgamma . Transgenic mice were phenotypically indistinguishable from wild-type ( WT ) mice , but mammary epithelial cells expressed a greater percentage of CD29 ( hi ) / P25063 REA ( neg ) , CK5 ( + ) , and double-positive CK14 / CK18 cells . These changes correlated with reduced P60484 REA and increased Ras and extracellular signal-regulated kinase ( P29323 REA ) and AKT activation . Although spontaneous tumorigenesis did not occur , transgenic animals were highly susceptible to progestin / 7,12- dimethylbenz ( a ) anthracene-induced mammary carcinogenesis , which in contrast to WT mice resulted in a high tumor multiplicity and , most importantly , in the appearance of predominantly estrogen receptor alpha-positive ( ER ( + ) ) ductal adenocarcinomas . Tumors expressed a similar P60484 REA ( lo ) / pERK ( hi ) / pAKT ( hi ) phenotype as mammary epithelium and exhibited high activation of estrogen response element-dependent reporter gene activity . Tumorigenesis in MMTV-Pax 8P PARgamma mice was insensitive to the chemopreventive effect of a PPARgamma agonist but was profoundly inhibited by the ER antagonist fulvestrant . These results reveal important new insights into the previously unrecognized role of PPARgamma in the specification of mammary lineage and the development of ER ( + ) tumors .

Pharmacogenetics and future strategies in treating hyperglycaemia in diabetes . This review focuses on current evidence for pharmacogenetics for the 3 commonly used drug classes in treating diabetes : metformin , sulphonylureas and thiazolidinediones . Currently , metformin pharmacogenetics is focussing on drug transport with the recent finding that variation in O75051 REA transporters might affect metformin response . An aetiological approach has identified monogenic patients with diabetes due to TCF 1 mutations who are particularly sensitive to the hypoglycaemic effects of sulphonylureas , and Q14654 REA or Q09428 REA mutations in which sulphonylureas can be used in place of insulin treatment . In Type 2 diabetes sulphonylurea response has been shown to be associated with variants Q9NQB0 associated with type 2 diabetes risk . For thiazolidinediones , focus has been on PPARgamma variants although with no consistent result . Genome wide association studies offer great potential to unravel what genetic factors influence response and side effects of diabetes therapies . Large numbers of well phenotyped patients for response and side effect as well as similarly sized similarly phenotyped replication cohorts are required . Establishing such cohorts is a priority in diabetes pharmacogenetics research .

[ In vitro comparison of podophyllotoxin analogues ; etoposide , teniposide and NK 611 using human lung cancer cell lines ] . In an attempt to predict the antitumor activity of a new podophyllotoxin analogue , NK 611 , in the treatment of lung cancer , we compared the drug with etoposide and teniposide using four human small cell lung cancer ( SCLC ) cell lines , SBC - 2 , - 3 , - 4 , - 7 , and two non-small cell lung cancer cell lines , O95477 REA , EBC - 1 . In terms of the fifty percent tumor growth inhibitory concentration ( IC 50 ) determined by MTT assay , teniposide was most potent among the drugs . The degree of cross-resistance of each drug was investigated using an etoposide-resistant SCLC subline ( SBC - 3 / DB00609 ) , an adriamycin-resistant subline ( SBC - 3 / P35318 REA 100 ) , and a cisplatin-resistant subline ( SBC - 3 / DB00515 ) . As for relative resistant ( the ratio of IC 50 for resistant subline to that for the parent subline ) , NK 611 was least cross-resistant to etoposide , adriamycin , and cisplatin among drugs tested . These results indicate that NK 611 may play a role in a salvage chemotherapy for patients with resistant SCLC .

DB09302 MEN : Q8NBP7 inhibitor for LDL cholesterol reduction . The proof of concept that proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) inhibition affects cholesterol levels was first established after the demonstration that Q8NBP7 loss-of-function mutations result in a significant drop in circulating LDL cholesterol levels . Subsequent studies revealed that Q8NBP7 binds the epidermal growth factor precursor homology domain-A on the surface LDL Receptor ( P01130 REA ) and directs P01130 REA and Q8NBP7 for lysosomal degradation . DB09302 MEN ( also known as SAR 236553 / REGN 727 ) is a monoclonal antibody that binds circulating Q8NBP7 and blocks its interactions with surface P01130 REA . DB09302 MEN clinical trials with different doses on different administration schedules were shown to significantly reduce LDL cholesterol both as a mono-therapy and in combination with statins or ezetimibe . Although there is great potential for anti - Q8NBP7 therapies in the management of cholesterol metabolism , there is no clear evidence yet that blocking Q8NBP7 reduces cardiovascular disease outcome . This is being investigated in ongoing Phase III clinical trials with alirocumab .

Synthesis and evaluation of ( S ) - 2 - ( 2 - [ 18F ] fluoroethoxy ) - 4 - ( [ 3 - methyl - 1 - ( 2 - piperidin - 1 - yl-phenyl ) - butyl-carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography ( PET ) . 18F - labeled non-sulfonylurea hypoglycemic agent ( S ) - 2 - ( 2 - [ ( 18 ) F ] fluoroethoxy ) - 4 - ( ( 3 - methyl - 1 - ( 2 - piperidin - 1 - yl-phenyl ) - butylcarbamoyl ) - methyl ) - benzoic acid ( [ ( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea-receptor ( Q09428 REA ) ligand repaglinide , was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [ ( 18 ) F ] DB00912 SUB could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 - [ ( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50-60 GBq / micromol . Labeling was conducted by exchanging the ethoxy-moiety into a 2 - [ ( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non-radioactive ( 19 ) F-compound for binding to the human Q09428 REA isoform was assessed . [ ( 19 ) F ] DB00912 SUB induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1.03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [ ( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0.12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [ ( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .

P01308 REA action on H292 bronchial carcinoma cells as compared to normal bronchial epithelial cells . DB00030 MENMAX DB00030 MEN may contribute to bronchial carcinoma due to P08069 REA activation by high local concentrations . Therefore , effects of insulin and P05019 REA on human bronchial carcinoma cells ( H292 ) and normal bronchial epithelium cells ( P02100 REA ) were studied . TGF-β was included since it also influences carcinoma progression . H292 and P02100 REA cells expressed both the insulin receptor and the P08069 REA ; in H292 cells an additional , shorter , splicing variant ( IR-A ) of the insulin receptor was present . P06213 REA expression was around four to five times higher in H292 than in P02100 REA cells at mRNA and protein levels . P01308 REA and TGF-β exerted contrary actions on proliferation and gene expression in H292 cells . Genes regulated by insulin , P05019 REA , and TGF-β were linked to inflammation , cell adhesion , muscle contraction and differentiation . P01308 REA and P05019 REA also suppressed DNA repair genes . EC ( 50 ) for insulin-induced proliferation was around 5 nM in H292 and around 30 nM P02100 REA cells . The EC ( 50 ) values for gene expression ranged from 9 to 90 nM in both cell types , dependent on the gene studied . In H292 cells , the proliferative response was much stronger if TGF-β was present . In P02100 REA cells this interaction of insulin and TGF-β was not observed , and changes in gene expression were mostly lower by at least 10 - fold as compared to H292 . All in all , the insulin effects in H292 were generally much stronger than in P02100 REA cells and - with regard to proliferation - occurred at lower concentrations . Thus , insulin will hardly induce cancer from normal bronchial cells but may favour progression of pre-existing tumours .

Differential actions of vasopeptidase inhibition versus angiotensin-converting enzyme inhibition on diuretic therapy in experimental congestive heart failure . BACKGROUND : DB00886 MEN ( OMA ) , a vasopeptidase inhibitor , simultaneously inhibits angiotensin-converting enzyme ( P12821 REA ) and neutral endopeptidase , which degrades vasodilatory factors ( eg , P35318 REA ) and natriuretic peptides . Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides , we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than P12821 REA inhibition plus diuretic ( ACEI + D ) in congestive heart failure . METHODS AND RESULTS : We compared the actions of OMA alone and with diuretic ( OMA + D ) to ACEI + D in a model of pacing-induced congestive heart failure . OMA + D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI + D . Glomerular filtration rate was lower with ACEI + D than with either OMA group . Plasma renin activity and aldosterone immediately increased with ACEI + D , whereas OMA + D resulted in higher plasma renin activity and a delayed increase in aldosterone . OMA alone did not increase plasma renin activity and aldosterone , but resulted in a sustained increase in plasma adrenomedullin , with higher urinary atrial natriuretic peptide , adrenomedullin , and cGMP excretions than with ACEI + D . CONCLUSIONS : Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI + D . There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI + D and OMA + D . Thus , OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI + D that can be explained by potentiation of natriuretic peptides .

P08183 REA , Q9UNQ0 , and P60484 REA determine the response of glioblastoma to temozolomide and ABT - 888 therapy . PURPOSE : Little is known about the optimal clinical use of ABT - 888 ( veliparib ) for treatment of glioblastoma . ABT - 888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma , because it may synergize with the standard-of-care temozolomide ( DB00853 ) . We have elucidated important factors controlling ABT - 888 efficacy in glioblastoma . EXPERIMENTAL DESIGN : We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type ( WT ) and Abcb 1 / Abcg 2 - deficient ( KO ) recipients . RESULTS : ABT - 888 / DB00853 is not efficacious against p53 ;p 16 ( Ink 4a ) / p19 ( Arf ); K-Ras ( v12 ); LucR allografts in wild-type recipients , indicating inherent resistance . Abcb 1 / Abcg 2 mediated efflux of ABT - 888 at the blood-brain barrier ( BBB ) causes a 5 - fold reduction of ABT - 888 brain penetration ( P < 0.0001 ) that was fully reversible by elacridar . Efficacy studies in WT and KO recipients and / or concomitant elacridar demonstrate that Abcb 1 / Abcg 2 at the BBB and in tumor cells impair DB00853 / ABT - 888 combination treatment efficacy . DB04881 MEN also markedly improved DB00853 / ABT - 888 combination treatment in the spontaneous p53 ;p 16 ( Ink 4a ) / p19 ( Arf ); K-Ras ( v12 ); LucR glioblastoma model . Importantly , ABT - 888 does enhance DB00853 efficacy in Pten deficient glioblastoma allografts and spontaneous tumors , even in Abcb 1 / Abcg 2 proficient wild-type mice . Loss of P60484 REA occurs frequently in glioblastoma ( 36 % ) and in silico analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival ( 310 days vs . 620 days , n = 117 ) . CONCLUSIONS : The potential of ABT - 888 in glioblastoma can best be demonstrated in patients with P60484 REA null tumors . Therefore , clinical trials with ABT - 888 should evaluate these patients as a separate group . Importantly , inhibition of P08183 REA and Q9UNQ0 ( by elacridar ) may improve the efficacy of DB00853 / ABT - 888 therapy in all glioblastoma patients .

Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome-wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 REA and Q14654 REA / Q09428 REA ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta-Analysis Gene-set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta-analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 ( - 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta-analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 ( - 4 ) , after removing known loci ) , highlighting new associations for follow-up ( P33121 REA , P19838 REA , P11168 REA , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .

Q13547 REA contributes to cell cycle and apoptosis . Histone deacetylases ( HDACs ) are generally thought to play important roles in human disease . However , little information is available concerning the specific functions of individual HDACs . We previously reported on transgenic mice that expressed human Q13547 REA and experienced steatosis and nuclear pleomorphism in their hepatic tissues . To find out if the over-expression of Q13547 REA contributes to the expression of genes related to the cell cycle , apoptosis , and lipid metabolism that eventually contribute to the pathological changes in the livers of the transgenic mice , the expression profiles of the related genes in liver tissues were determined by reverse transcription-polymerase chain reaction ( RT-PCR ) and Western blot analysis . The activated human Q13547 REA significantly induced the expression levels of mRNA for p53 , P37231 REA and Bak and reduced the P38936 REA expression level compared with the levels in control littermates . However , the protein levels of p53 and P37231 REA were significantly decreased . In conclusion , our results indicate that Q13547 REA can regulate gene expression at the mRNA and protein levels independently and that this may be a potential cytopathic factor for hepatic tissue in transgenic mice that over-express Q13547 REA .

DB00074 MEN induction in patients receiving tacrolimus-based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine-based immunosuppression . However , its clinical utility in patients receiving tacrolimus-based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC - P01589 REA ) , 100 received basiliximab and delayed tacrolimus ( dTAC - P01589 REA ) , and 132 patients received tacrolimus without basiliximab ( TAC-No ) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC - P01589 REA compared to TAC-IL - 2RA and TAC-No Groups ( 33 vs . 14.9 vs . 14.3 % , p < 0.001 ) . Inferior creatinine clearance was observed in dTAC - P01589 REA Group compared to TAC - P01589 REA and TAC-No Groups at months 1 ( 41.6 vs . 49.9 vs . 44.8 mL / min , p = 0.004 ) , 3 ( 49.8 vs . 57.2 vs . 53.5 mL / min , p = 0.017 ) , and 6 ( 53.1 vs . 61.8 vs . 57.0 mL / min , p = 0.001 ) . Patients who received basiliximab ( TAC - P01589 REA and dTAC - P01589 REA Groups ) had lower incidence of posttransplant diabetes ( 24 vs . 18 vs . 39.3 % , p = 0.009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction .

Mixed modeling of meta-analysis P-values ( MixMAP ) suggests multiple novel gene loci for low density lipoprotein cholesterol . Informing missing heritability for complex disease will likely require leveraging information across multiple SNPs within a gene region simultaneously to characterize gene and locus-level contributions to disease phenotypes . To this aim , we introduce a novel strategy , termed Mixed modeling of Meta-Analysis P-values ( MixMAP ) , that draws on a principled statistical modeling framework and the vast array of summary data now available from genetic association studies , to test formally for locus level association . The primary inputs to this approach are : ( a ) single SNP level p-values for tests of association ; and ( b ) the mapping of SNPs to genomic regions . The output of MixMAP is comprised of locus level estimates and tests of association . In application of MixMAP to summary data from the Global Lipids Gene Consortium , we suggest twelve new loci ( Q16512 REA , P02751 REA , P22309 REA , P37231 REA , DMDGH , Q03181 REA , Q00534 REA , Q7Z7G8 , Q05329 REA , Q9UQC2 , P02749 REA and O15118 REA ) for low-density lipoprotein cholesterol ( LDL-C ) , a causal risk factor for cardiovascular disease and we also demonstrate the potential utility of MixMAP in small data settings . Overall , MixMAP offers novel and complementary information as compared to SNP-based analysis approaches and is straightforward to implement with existing open-source statistical software tools .

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 .

Vitamin D analogues . The plethora of actions attributed to 1,25 ( OH ) 2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases , immune dysfunction , endocrine disorders , and metabolic bone disease . However , the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases . New vitamin D analogues are under development that display greater specificity , in most cases , by retaining the therapeutic properties of 1,25 ( OH ) 2D3 , but with lower calcemic activity . Two analogues have been approved for use in patients : calcipotriol ( DB02300 from Leo Pharmaceuticals , Copenhagen , Denmark ) for the treatment of psoriasis ; and 19 - nor -1,25 ( OH ) 2D2 ( DB00910 MEN from Abbott Laboratories , Abbott Park , IL ) for secondary hyperparathyroidism . Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis , and for immunosuppression . The selectivity of the analogues can be attributed to the combined interactions with four proteins : the vitamin D receptor ( P11473 REA ) , the serum vitamin D binding protein ( DBP ) , the vitamin D - 24 - hydroxylase and to a newly described membrane receptor . Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22 - oxacalcitriol ( O75051 REA ) , which is being tested for secondary hyperparathyroidism . However , the low calcemic activity of other analogues , including 19 - nor -1,25 ( OH ) 2D2 , involves other , as yet undefined , mechanisms . Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders .

UMD ( Universal mutation database ) : a generic software to build and analyze locus-specific databases . The human genome is thought to contain about 80,000 genes and presently only 3,000 are known to be implicated in genetic diseases . In the near future , the entire sequence of the human genome will be available and the development of new methods for point mutation detection will lead to a huge increase in the identification of genes and their mutations associated with genetic diseases as well as cancers , which is growing in frequency in industrial states . The collection of these mutations will be critical for researchers and clinicians to establish genotype / phenotype correlations . Other fields such as molecular epidemiology will also be developed using these new data . Consequently , the future lies not in simple repositories of locus-specific mutations but in dynamic databases linked to various computerized tools for their analysis and that can be directly queried on-line . To meet this goal , we devised a generic software called UMD ( Universal Mutation Database ) . It was developed as a generic software to create locus-specific databases ( LSDBs ) with the 4 ( th ) Dimension ( R ) package from ACI . This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data . Thanks to the flexible structure of the UMD software , it has been successfully adapted to nine genes either involved in cancer ( P25054 REA , P04637 REA , P06400 REA , O00255 REA , Q09428 REA , P40337 REA , and P19544 ) or in genetic diseases ( P35555 REA and P01130 REA ) . Four new LSDBs are under construction ( P49748 REA , P11310 REA , KIR 6 , and P29400 REA ) . Finally , the data can be transferred to core databases .