inhibitor11: July 2012

Tuesday, July 31, 2012

Prognostic Models to Predict Survival in Non-Small-Cell Lung Cancer Patients Treated with First-Line Paclitaxel and Carboplatin with or without Bevacizumab.

Prognostic Models to Predict Survival in Non-Small-Cell Lung Cancer Patients Treated with First-Line Paclitaxel and Carboplatin with or without Bevacizumab.

J Thorac Oncol. 2012 Jul 26;

Authors: Hoang T, Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH

Abstract
BACKGROUND:: To determine prognostic factors and build a model to predict 1-year overall survival (OS) and 6-month progression-free survival (PFS) in advanced non-small-cell lung cancer (NSCLC) patients treated with first-line paclitaxel and carboplatin with or without bevacizumab. MATERIALS AND METHODS:: We analyzed 26 pretreatment clinical variables in 850 NSCLC patients treated in the randomized Eastern Cooperative Oncology Group 4599 study. Univariate and multivariate analyses were performed to identify prognostic factors. Cox regression with 50% randomly sampled data was used to build nomograms with a prognostic score assigned to each factor. The model was validated with the remaining 50% of data. RESULTS:: Eleven poor factors for OS (hazard ratio) were as follows: skin metastasis (4.49), body mass index less than 18.5 (2.09), increased serum lactate dehydrogenase (1.74), adrenal metastasis (1.52), performance status greater than 0 (1.45), low serum albumin (1.45), men (1.39), bone metastasis (1.39), large cell/not otherwise specified histology (1.29), mediastinal nodal metastasis (1.23), and treatment without bevacizumab (1.18). Seven poor factors for PFS were as follows: skin metastasis (3.13), treatment without bevacizumab (1.52), bone metastasis (1.41), liver metastasis (1.40), low serum albumin (1.39), performance status greater than 0 (1.21), and mediastinal nodal metastasis (1.14). Based on these factors, we built and validated two nomograms predicting 1-year OS and 6-month PFS. CONCLUSION:: Using our proposed models, the probability of survival with first-line paclitaxel and carboplatin with or without bevacizumab in nonsquamous NSCLC patients can be estimated. These prognostic models provide a tool for research design and clinical decision making, such as patient stratification and therapy selection.

PMID: 22843087 [PubMed - as supplied by publisher]

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Generation of anti-Notch antibodies and their application in blocking Notch signalling in neural stem cells.

Generation of anti-Notch antibodies and their application in blocking Notch signalling in neural stem cells.

Methods. 2012 Jul 26;

Authors: Falk R, Falk A, Dyson MR, Melidoni A, Parthiban K, Young J, Roake W, McCafferty J

Abstract
Notch signalling occurs via direct cell:cell interactions and plays an important role in linking the fates of neighbouring cells. There are four different mammalian Notch receptors that can be activated by five cell surface ligands. The ability to inhibit specific Notch receptors would help identify the roles of individual family members and potentially provide a means to study and control cell differentiation. Anti-Notch antibodies in the form of single chain Fvs were generated from an antibody phage display library by selection on either the ligand binding domain or the negative regulatory region (NRR) of Notch1 and Notch2. 6 antibodies targeting the NRR of Notch1 and 4 antibodies recognising the NRR of Notch2 were found to prevent receptor activation in cell-based luciferase reporter assays. These antibodies were potent, highly specific inhibitors of individual Notch receptors and interfered with endogenous signalling in stem cell systems of both human and mouse origin. Antibody-mediated inhibition of Notch efficiently down-regulated transcription of the immediate Notch target gene hairy and enhancer of split 5 (Hes5) in both mouse and human neural stem cells and revealed a redundant regulation of Hes5 in these cells as complete down-regulation was seen only after simultaneous blocking of Notch1 and Notch2. In addition, these antibodies promoted differentiation of neural stem cells towards a neuronal fate. In contrast to the widely used small molecule ?-secretase inhibitors, which block all 4 Notch receptors (and a multitude of other signalling pathways), antibodies allow blockade of individual Notch family members in a highly specific way. Specific inhibition will allow examination of the effect of individual Notch receptors in complex differentiation schemes regulated by the co-ordinated action of multiple signalling pathways.

PMID: 22842086 [PubMed - as supplied by publisher]

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Synthesis, biological evaluation, and molecular modeling of natural and unnatural flavonoidal alkaloids, inhibitors of kinases.

Synthesis, biological evaluation, and molecular modeling of natural and unnatural flavonoidal alkaloids, inhibitors of kinases.

J Med Chem. 2012 Mar 22;55(6):2811-9

Authors: Nguyen TB, Lozach O, Surpateanu G, Wang Q, Retailleau P, Iorga BI, Meijer L, Gu�ritte F

Abstract
The screening of the ICSN chemical library on various disease-relevant protein kinases led to the identification of natural flavonoidal alkaloids of unknown configuration as potent inhibitors of the CDK1 and CDK5 kinases. We thus developed an efficient and modular synthetic strategy for their preparation and that of analogues in order to determine the absolute configuration of the active natural flavonoidal alkaloids and to provide further insights on the structure-activity relationships in this series. The structural determinants of the interaction between some flavonoidal alkaloids with specific kinases were also evaluated using molecular modeling.

PMID: 22352892 [PubMed - indexed for MEDLINE]

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Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1).

Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1).

Eur Respir J. 1996 Nov;9(11):2263-72

Authors: Hoekx JC, Hedlin G, Pedersen W, Sorva R, Hollingworth K, Efthimiou J

Abstract
The aim of this study was to compare fluticasone propionate (FP) with budesonide (BUD) at a dose of 400 microg x day(-1) in the treatment of children with asthma. Two hundred and twenty nine children with mild-to-moderate asthma, currently receiving 200-400 microg x day(-1) of inhaled corticosteroid, were randomized to receive either 400 microg x day(-1) of FP from the Diskhaler (registered trade mark of the Glaxo Group of Companies) or 400 microg x day(-1) of BUD from the Turbuhaler (registered trade mark of Astra Pharmaceuticals Ltd) for 8 weeks, in a parallel-group, double-blind, double-dummy study. Primary efficacy was assessed by measurement of daily peak expiratory flow (PEF). In addition, pulmonary function tests were performed at each clinic visit and a self-administered patient-centred questionnaire was completed by one parent of each patient at the start and end of study treatment. Mean morning PEF increased following treatment both with FP and BUD, but was significantly higher following treatment with FP during Weeks 1-4 (p=0.015) and Weeks 1-8 (p=0.019). Similar results were found for mean evening PEF and percentage predicted morning and evening PEF. Children receiving FP experienced significantly less disruption in their physical activities (i.e. sports, games) because of their asthma compared to children treated with BUD (p=0.03). Mean cortisol levels increased in both groups, but the increase was significantly higher in the FP group at 4 weeks (p=0.022). Serum and urine markers of bone formation and resorption changed very little and showed no consistent pattern of change. Fluticasone propionate at a dosage of 400 microg x day(-1) from the Diskhaler provided a more rapid and greater improvement in lung function in children with mild-to-moderate asthma than BUD 400 microg day(-1) from the Turbuhaler. Both treatments were well-tolerated, with a similar safety profile.

PMID: 8947070 [PubMed - indexed for MEDLINE]

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A phase I trial of dasatinib, a Src-family kinase Inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.

A phase I trial of dasatinib, a Src-family kinase Inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.

Clin Cancer Res. 2012 Jul 26;

Authors: Alvarez Secord A, Teoh DK, Barry WT, Yu M, Broadwater G, Havrilesky LJ, Lee PS, Berchuck A, Lancaster JM, Wenham RM

Abstract
PURPOSE: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer. EXPERIMENTAL DESIGN: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Using a "3+3" design, cohorts of 3-6 patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. RESULTS: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 years (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 patients in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3-4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 40% (3 complete responses, (15%); 5 partial responses, (25%)),10 (50%) had stable disease, and 2 were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. CONCLUSIONS: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.

PMID: 22837181 [PubMed - as supplied by publisher]

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Monday, July 30, 2012

Insulin inhalation: NN 1998.

Insulin inhalation: NN 1998.

Drugs R D. 2004;5(1):46-9

Authors:

Abstract
Aradigm Corporation has developed an inhaled form of insulin using its proprietary AERx drug delivery system. The system uses liquid insulin that is converted into an aerosol containing very small particles (1-3 micro in diameter), and an electronic device suitable for either the rapid transfer of molecules of insulin into the bloodstream or localised delivery within the lung. The AERx insulin Diabetes Management System (iDMS), AERx iDMS, instructs the user on breathing technique to achieve the best results. Aradigm Corporation and Novo Nordisk have signed an agreement to jointly develop a pulmonary delivery system for insulin [AERx iDMS, NN 1998]. Under the terms of the agreement, Novo Nordisk has exclusive rights for worldwide marketing of any products resulting from the development programme. Aradigm Corporation will initially manufacture the product covered by the agreement, and in return will receive a share of the overall gross profits from Novo Nordisk's sales. Novo Nordisk will cover all development costs incurred by Aradigm Corporation while both parties will co-fund final development of the AERx device. Both companies will explore the possibilities of the AERx platform to deliver other compounds for the regulation of blood glucose levels. Additionally, the agreement gives Novo Nordisk an option to develop the technology for delivery of agents outside the diabetes area. In April 2001, Aradigm Corporation received a milestone payment from Novo Nordisk related to the completion of certain clinical and product development stages of the AERx drug delivery system. Profil, a CRO in Germany, is cooperating with Aradigm and Novo Nordisk in the development of inhaled insulin. Aradigm and Novo Nordisk initiated a pivotal phase III study with inhaled insulin formulation in September 2002. This 24-month, 300-patient trial is evaluating inhaled insulin in comparison with insulin aspart. Both medications will be given three times daily before meals in addition to basal insulin administered once or twice daily. In 2003, the US FDA adopted new GMP guidelines requiring sterile production of inhalation products and their devices. Novo Nordisk, therefore, will need to repeat phase III studies following device optimisation. These studies may begin at the end of 2004 and will include efficacy studies for 6-12 months and safety studies for up to 2 years (Lehman Brothers, Equity research, 7 August 2003). A phase IIb, 12-week clinical trial in 107 patients with type 2 diabetes was completed in the US. This trial was designed to compare the safety and efficacy of pulmonary insulin delivered via AERx iDMS, with intensified treatment with subcutaneous insulin administered at mealtimes. The results of the study positively compared pulmonary insulin with intensified subcutaneous insulin. Aradigm Corporation has a total of 85 patents pertaining to its proprietary AERx drug delivery system. Among those granted patents, 18 patents cover pulmonary insulin formulation including the method of patient breathing technique during pulmonary delivery of insulin. This patent guides patients on how to breathe in certain defined ways to achieve an effective amount and reproducibility of blood levels of insulin.

PMID: 14725493 [PubMed - indexed for MEDLINE]

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Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.

Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.

BMJ. 2012;344:e1771

Authors: Hemmingsen B, Christensen LL, Wetterslev J, Vaag A, Gluud C, Lund SS, Almdal T

Abstract
OBJECTIVES: To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes.
DESIGN: Systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.
DATA SOURCES: The Cochrane Library, Medline, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature until March 2011. We also searched abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes Congresses, contacted relevant trial authors and pharmaceutical companies, hand searched reference lists of included trials, and searched the US Food and Drug Administration website.
REVIEW METHODS: Two authors independently screened titles and abstracts for randomised clinical trials comparing metformin and insulin versus insulin alone (with or without placebo) in patients with type 2 diabetes, older than 18 years, and with an intervention period of at least 12 weeks. We included trials irrespective of language, publication status, predefined outcomes, antidiabetic interventions used before randomisation, and reported outcomes.
RESULTS: We included 26 randomised trials with 2286 participants, of which 23 trials with 2117 participants could provide data. All trials had high risk of bias. Data were sparse for outcomes relevant to patients. Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced HbA(1c), weight gain, and insulin dose, compared with insulin alone; trial sequential analyses showed sufficient evidence for a HbA(1c) reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 U/day.
CONCLUSIONS: There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control.

PMID: 22517929 [PubMed - indexed for MEDLINE]

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Drug-Induced Atrial Fibrillation.

Drug-Induced Atrial Fibrillation.

Drugs. 2012 Jul 27;

Authors: Kaakeh Y, Overholser BR, Lopshire JC, Tisdale JE

Abstract
Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with severe consequences, including symptoms, haemodynamic instability, increased cardiovascular mortality and stroke. While other arrhythmias such as torsades de pointes and sinus bradycardia are more typically thought of as drug induced, AF may also be precipitated by drug therapy, although ascribing causality to drug-associated AF is more difficult than with other drug-induced arrhythmias. Drug-induced AF is more likely to occur in patients with risk factors and co-morbidities that commonly co-exist with AF, such as advanced age, alcohol consumption, family history of AF, hypertension, thyroid dysfunction, sleep apnoea and heart disease. New-onset AF has been associated with cardiovascular drugs such as adenosine, dobutamine and milrinone. In addition, medications such as corticosteroids, ondansetron and antineoplastic agents such as paclitaxel, mitoxantrone and doxorubicin have been reported to induce AF. Whether bisphosphonate drugs are associated with new-onset AF remains controversial and requires further study. The potential contribution of specific drug therapy should be considered when patients present with new-onset AF.

PMID: 22834678 [PubMed - as supplied by publisher]

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Drug-Induced Atrial Fibrillation.

Drug-Induced Atrial Fibrillation.

Drugs. 2012 Jul 27;

Authors: Kaakeh Y, Overholser BR, Lopshire JC, Tisdale JE

PMID: 22834678 [PubMed - as supplied by publisher]

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antigen peptide; +92 new citations

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These pubmed results were generated on 2012/07/28

PubMed, a service of the National Library of Medicine, includes over 15 million citations for biomedical articles back to the 1950's. These citations are from MEDLINE and additional life science journals. PubMed includes links to many sites providing full text articles and other related resources.

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Sunday, July 29, 2012

ATPase; +24 new citations

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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These pubmed results were generated on 2012/07/28

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[Short-acting insulin analogs--critical assessment of meta-analyses].

[Short-acting insulin analogs--critical assessment of meta-analyses].

Dtsch Med Wochenschr. 2006 Dec;131 Suppl 8:S274-9

Authors: Kunt T

Abstract
Short-acting insulin analogs have for nearly ten years been prescribed for type 1 and 2 diabetes mellitus. There is extensive scientific and practical evidence of their being better than normal insulin. For this reason these insulins have been recommended in the guidelines of most leading specialist societies. In everyday practice they are an important component of the therapeutic portfolio which can produce an improvement in insulin treatment, especially of selective cases. On the other hand, there is growing economic pressure, especially in Germany, affecting their use. However, it must be critically asserted that those meta-analyses on insulin analogs, which have been commissioned by insurance companies or governmental organisations, do not do justice to their advantage. Current meta-analyses of short-acting insulin analogs exclude decisive advantages of insulin analogs from their analyses and compare highly heterogeneous groups. They do not distinguish between differing incidences of hypoglycemia associated with different HbA1c values as well as between conventional and intensive treatment. Furthermore positive data and positive major studies are excluded, while approval studies or trials with completely different aims are cited. Short study duration is also often neglected. As a result, the International Diabetes Federation (IDF) has rejected the Cochrane Review for 2005 for methodological reasons. Also, no recommendations can be derived from the recommendations of of the Institut f�r Qualit�tssicherung und Wirtschaftlichkeit in der Medizin (IQWiG: Institute for Quality Assurance and Cost Effectiveness in Medicine). After critical assessment of meta-analyses the IDF concluded in its guidelines that insulin analogs should generally be used.

PMID: 17139586 [PubMed - indexed for MEDLINE]

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Drug-Induced Atrial Fibrillation.

Drug-Induced Atrial Fibrillation.

Drugs. 2012 Jul 27;

Authors: Kaakeh Y, Overholser BR, Lopshire JC, Tisdale JE

PMID: 22834678 [PubMed - as supplied by publisher]

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Drug-Induced Atrial Fibrillation.

Drug-Induced Atrial Fibrillation.

Drugs. 2012 Jul 27;

Authors: Kaakeh Y, Overholser BR, Lopshire JC, Tisdale JE

PMID: 22834678 [PubMed - as supplied by publisher]

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Saturday, July 28, 2012

Assessments of growth conditions on the production of cyanophycin by recombinant Escherichia coli strains expressing cyanophycin synthetase gene.

Assessments of growth conditions on the production of cyanophycin by recombinant Escherichia coli strains expressing cyanophycin synthetase gene.

Biotechnol Prog. 2012 Mar-Apr;28(2):358-63

Authors: Tseng WC, Fang TY, Cho CY, Chen PS, Tsai CS

Abstract
The synthesis of cyanophycin, a biodegradable polymer, is directed by cyanophycin synthetase. Polymerase chain reaction (PCR) cloned the gene cphA coding for cyanophycin synthetase from Synechocystis sp. PCC 6803 into pET-21b followed by transformation into two Escherichia coli hosts. The culture conditions for cyanophycin production were investigated, and the molecular weight and compositions of purified cyanophycin were analyzed. The results showed that E. coli BL21-CodonPlus(DE3)-RIL could produce 120 mg cyanophycin per gram dry cell weight in terrific medium. The purified cyanophycin consisted of insoluble and soluble forms at pH 7. The insoluble form had a higher molecular weight (20-32 kDa) than the soluble form (14-25 kDa). Both forms are composed of three major amino acids, aspartic acid, arginine, and lysine, and the insoluble form showed a higher arginine/lysine molar ratio (4.61 � 0.31) than the soluble form (0.89 � 0.05). In addition, the nitrogen sources could affect the yields of insoluble and soluble forms of cyanophycin. The medium containing additional lysine could enhance the proportion of the soluble form, but had little effect on the lysine and arginine percentages of both soluble and insoluble forms. The medium containing additional arginine slightly decreased the proportion of soluble form and altered its amino acid composition, with a minimal effect on the lysine and arginine percentages in the insoluble form.

PMID: 22252992 [PubMed - indexed for MEDLINE]

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Confirmation of the existence of two distinct genetic groups of infectious bursal disease virus in Australia.

Confirmation of the existence of two distinct genetic groups of infectious bursal disease virus in Australia.

Aust Vet J. 2002 Nov;80(11):689-94

Authors: Ignjatovic J, Sapats S

Abstract
OBJECTIVE: To characterise infectious bursal disease viruses (IBDVs) prevalent at major commercial sites throughout Australia and to compare the nucleic acid sequences of local strains of IBDV with those of characterised overseas strains.
DESIGN: Samples of bursae were collected from 20 broiler farms that belonged to different poultry companies in New South Wales (NSW), Queensland (Qld), Victoria (Vic), Westem (WA) and South Australia (SA).
METHOD: Bursae were collected from broilers between 24 and 35 days of age. Bursal tissue was homogenised and tested for the presence of IBDV antigen using four monoclonal antibodies (Mabs) which detect antigenic variation in IBDV strains. The nucleotide sequences of the hypervariable region (HVR) within the VP2 gene of IBDVs was determined and the deduced amino acid sequences compared with three vaccine strains and six previously characterised Australian IBDV strains. The deduced amino acid sequences were also compared with the published amino acid sequences of overseas strains. The phylogenetic relationships between Australian strains and overseas strains were then determined.
RESULTS: IBDV was detected in birds from 14 out of 20 farms sampled. Typing with four Mabs showed that all viruses from Vic (6) and SA (10) were antigenic variants, whereas all viruses from NSW (29), Qld (4) and WA (5) were classical-like strains. Nucleotide sequencing of one sample from each of the 14 farms on which IBDV was detected confirmed results obtained with Mabs. The amino acid sequences of all Australian viruses differed from the amino acid sequences of foreign IBDV strains. Phylogenetic analysis showed that Australian IBDV viruses belonged to two distinct genetic groups. Very virulent (vv) IBDV strains belonged to a third genetic group, and overseas classical and variant strains belonged to a fourth genetic group.
CONCLUSIONS: The results confirmed previous findings that there are two groups of IBDV strains circulating in commercial broilers in Australia. The majority are classical-like strains that are antigenically and genetically similar to vaccine strains 002/73 and V877. These classical strains were prevalent in broilers in three states, NSW, Qld and WA. The second group of strains are antigenic variants that were only found in broilers in two states, Vic and SA. All Australian IBDVs characterised to date are genetically distinct and can be differentiated from all other overseas strains. This enables identification of incursion of any exotic strain into Australian poultry, be it classical, US variant or wIBDV strains.

PMID: 12465828 [PubMed - indexed for MEDLINE]

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Development and Validation of a High-Content Screening Assay to Identify Inhibitors of Cytoplasmic Dynein-Mediated Transport of Glucocorticoid Receptor to the Nucleus.

Development and Validation of a High-Content Screening Assay to Identify Inhibitors of Cytoplasmic Dynein-Mediated Transport of Glucocorticoid Receptor to the Nucleus.

Assay Drug Dev Technol. 2012 Jul 25;

Authors: Johnston PA, Shinde SN, Hua Y, Shun TY, Lazo JS, Day BW

Abstract
Abstract Rapid ligand-induced trafficking of glucocorticoid nuclear hormone receptor (GR) from the cytoplasm to the nucleus is an extensively studied model for intracellular retrograde cargo transport employed in constructive morphogenesis and many other cellular functions. Unfortunately, potent and selective small-molecule disruptors of this process are lacking, which has restricted pharmacological investigations. We describe here the development and validation of a 384-well high-content screening (HCS) assay to identify inhibitors of the rapid ligand-induced retrograde translocation of cytoplasmic glucocorticoid nuclear hormone receptor green fluorescent fusion protein (GR-GFP) into the nuclei of 3617.4 mouse mammary adenocarcinoma cells. We selected 3617.4 cells, because they express GR-GFP under the control of a tetracycline (Tet)-repressible promoter and are exceptionally amenable to image acquisition and analysis procedures. Initially, we investigated the time-dependent expression of GR-GFP in 3617.4 cells under Tet-on and Tet-off control to determine the optimal conditions to measure dexamethasone (Dex)-induced GR-GFP nuclear translocation on the ArrayScan-VTI automated imaging platform. We then miniaturized the assay into a 384-well format and validated the performance of the GR-GFP nuclear translocation HCS assay in our 3-day assay signal window and dimethylsulfoxide validation tests. The molecular chaperone heat shock protein 90 (Hsp90) plays an essential role in the regulation of GR steroid binding affinity and ligand-induced retrograde trafficking to the nucleus. We verified that the GR-GFP HCS assay captured the concentration-dependent inhibition of GR-GFP nuclear translocation by 17-AAG, a benzoquinone ansamycin that selectively blocks the binding and hydrolysis of ATP by Hsp90. We screened the 1280 compound library of pharmacologically active compounds set in the Dex-induced GR-GFP nuclear translocation assay and used the multi-parameter HCS data to eliminate cytotoxic compounds and fluorescent outliers. We identified five qualified hits that inhibited the rapid retrograde trafficking of GR-GFP in a concentration-dependent manner: Bay 11-7085, 4-phenyl-3-furoxancarbonitrile, parthenolide, apomorphine, and 6-nitroso-1,2-benzopyrone. The data presented here demonstrate that the GR-GFP HCS assay provides an effective phenotypic screen and support the proposition that screening a larger library of diversity compounds will yield novel small-molecule probes that will enable the further exploration of intracellular retrograde transport of cargo along microtubules, a process which is essential to the morphogenesis and function of all cells.

PMID: 22830992 [PubMed - as supplied by publisher]

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Confirmation of the existence of two distinct genetic groups of infectious bursal disease virus in Australia.

Confirmation of the existence of two distinct genetic groups of infectious bursal disease virus in Australia.

Aust Vet J. 2002 Nov;80(11):689-94

Authors: Ignjatovic J, Sapats S

PMID: 12465828 [PubMed - indexed for MEDLINE]

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A complete sequence of Saccharomyces paradoxus mitochondrial genome that restores the respiration in S. cerevisiae.

A complete sequence of Saccharomyces paradoxus mitochondrial genome that restores the respiration in S. cerevisiae.

FEMS Yeast Res. 2012 Jul 25;

Authors: Proch�zka E, Franko F, Pol�kov� S, Sulo P

Abstract
We determined the complete sequence of 71,355 bp long mitochondrial genome from Saccharomyces paradoxus entirely by direct sequencing of purified mitochondrial DNA (mtDNA). This mtDNA possesses the same features as its close relative Saccharomyces cerevisiae - A+T content 85.9%, set of genes coding for the three components of cytochrome oxidase, cytochrome b, three subunits of ATPase, both ribosomal subunits, gene for ribosomal protein, rnpB gene, tRNA package (24) and yeast genetic code. Genes are interrupted by nine group I and group II introns, two of which are in positions unknown in S. cerevisiae, but recognized in Saccharomyces pastorianus. The gene products are related to S. cerevisiae and the identity of amino acid residues varies from 100% for cox2 to 83% for rps3. The remarkable differences from S. cerevisiae are (i) different gene order (translocation of trnF-trnT1-trnV-cox3-trnfM-rnpb-trnP and transposition of trnW-rns); (ii) occurrence of two unusual GI introns, (iii) eight active ori elements, (iv) reduced number of GC clusters and divergent intergenic spacers. Despite these facts, the sequenced S. paradoxus mtDNA introduced to S. cerevisiae was able to support the respiratory function to the same extent as the original mtDNAs. � 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

PMID: 22830625 [PubMed - as supplied by publisher]

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Friday, July 27, 2012

Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1).

Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1).

Eur Respir J. 1996 Nov;9(11):2263-72

Authors: Hoekx JC, Hedlin G, Pedersen W, Sorva R, Hollingworth K, Efthimiou J

PMID: 8947070 [PubMed - indexed for MEDLINE]

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Carnosic acid inhibits the growth of ER-negative human breast cancer cells and synergizes with curcumin.

Carnosic acid inhibits the growth of ER-negative human breast cancer cells and synergizes with curcumin.

Fitoterapia. 2012 Jul 21;

Authors: Einbond LS, Wu HA, Kashiwazaki R, He K, Roller M, Su T, Wang X, Goldsberry S

Abstract
BACKGROUND: Studies indicate that extracts and purified components, including carnosic acid, from the herb rosemary display significant growth inhibitory activity on a variety of cancers. Purpose: This paper examines the ability of rosemary/carnosic acid to inhibit the growth of human breast cancer cells and to synergize with curcumin. MATERIALS AND METHODS: To do this, we treated human breast cancer cells with rosemary/carnosic acid and assessed effects on cell proliferation, cell cycle distribution, gene expression patterns, activity of the purified Na/K ATPase and combinations with curcumin. RESULTS: Rosemary/carnosic acid potently inhibits proliferation of ER-negative human breast cancer cells and induces G1 cell cycle arrest. Further, carnosic acid is selective for MCF7 cells transfected for Her2, indicating that Her2 may function in its action. To reveal primary effects, we treated ER negative breast cancer cells with carnosic acid for 6h. At a low dose, 5?g/ml (15?M), carnosic acid activated the expression of 3 genes, induced through the presence of antioxidant response elements, including genes involved in glutathione biosynthesis (CYP4F3, GCLC) and transport (SLC7A11). At a higher dose, 20?g/ml, carnosic acid activated the expression of antioxidant (AKR1C2, TNXRD1, HMOX1) and apoptosis (GDF15, PHLDA1, DDIT3) genes and suppressed the expression of inhibitor of transcription (ID3) and cell cycle (CDKN2C) genes. Carnosic acid exhibits synergy with turmeric/curcumin. These compounds inhibited the activity of the purified Na-K-ATPase which may contribute to this synergy. CONCLUSION: Rosemary/carnosic acid, alone or combined with curcumin, may be useful to prevent and treat ER negative breast cancer.

PMID: 22828666 [PubMed - as supplied by publisher]

potassium channel genes

Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib.

Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib.

Blood Cancer J. 2011 Aug;1(8):e32

Authors: Kim TM, Ha SA, Kim HK, Yoo J, Kim S, Yim SH, Jung SH, Kim DW, Chung YJ, Kim JW

Abstract
The use of selective inhibitors targeting Bcr-Abl kinase is now established as a standard protocol in the treatment of chronic myelogenous leukemia; however, the acquisition of drug resistance is a major obstacle limiting the treatment efficacy. To elucidate the molecular mechanism of drug resistance, we established K562 cell line models resistant to nilotinib and imatinib. Microarray-based transcriptome profiling of resistant cells revealed that nilotinib- and imatinib-resistant cells showed the upregulation of kinase-encoding genes (AURKC, FYN, SYK, BTK and YES1). Among them, the upregulation of AURKC and FYN was observed both in nilotinib- and imatinib-resistant cells irrespective of exposure doses, while SYK, BTK and YES1 showed dose-dependent upregulation of expression. Upregulation of EGF and JAG1 oncogenes as well as genes encoding ATP-dependent drug efflux pump proteins such as ABCB1 was also observed in the resistant cells, which may confer alternative survival benefits. Functional gene set analysis revealed that molecular categories of 'ATPase activity', 'cell adhesion' or 'tyrosine kinase activity' were commonly activated in the resistant clones. Taken together, the transcriptome analysis of tyrosine kinase inhibitors (TKI)-resistant clones provides the insights into the mechanism of drug resistance, which can facilitate the development of an effective screening method as well as therapeutic intervention to deal with TKI resistance.

PMID: 22829191 [PubMed - in process]

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Confirmation of the existence of two distinct genetic groups of infectious bursal disease virus in Australia.

Confirmation of the existence of two distinct genetic groups of infectious bursal disease virus in Australia.

Aust Vet J. 2002 Nov;80(11):689-94

Authors: Ignjatovic J, Sapats S

PMID: 12465828 [PubMed - indexed for MEDLINE]

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Thursday, July 26, 2012

Structural and functional differences in barrier properties of African American, Caucasian and East Asian skin.

Structural and functional differences in barrier properties of African American, Caucasian and East Asian skin.

J Dermatol Sci. 2010 Aug;59(2):123-8

Authors: Muizzuddin N, Hellemans L, Van Overloop L, Corstjens H, Declercq L, Maes D

Abstract
BACKGROUND: Differences in structural and functional skin characteristics have been linked with ethnical background. But racial differences in skin have not been thoroughly investigated by objective methods and the data are often contradictory.
OBJECTIVES: This study was undertaken to compare skin barrier-related parameters of the stratum corneum on African American, Caucasian and East Asian skin by objective measurements.
METHODS: Baseline values of trans epidermal water loss were collected on the face. Consecutive stratum corneum D-squame tape strippings were collected on the panelist's ventral forearm and face to evaluate skin barrier strength and cohesion. Stratum corneum ceramides, maturation, measured as the transglutaminase-mediated cross-linking of stratum corneum proteins, and stratum corneum trypsin like enzyme activity were measured on the D-squame tape strippings.
RESULTS: East Asian and to some extent Caucasian skin was characterized by low maturation and relatively weak skin barrier. African American skin was characterized by low ceramide levels and high protein cohesion in the uppermost layers of the stratum corneum. These data can be interpreted in terms of the high prevalence of xerosis in black skin and increased skin sensitivity in East Asian skin.
CONCLUSION: These results demonstrate that skin properties at the level of the stratum corneum vary considerably among these ethnic groups. This contributes to an improved understanding of physiological differences between these study populations.

PMID: 20654785 [PubMed - indexed for MEDLINE]

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A human corneal endothelium equivalent constructed with acellular porcine corneal matrix.

A human corneal endothelium equivalent constructed with acellular porcine corneal matrix.

Indian J Med Res. 2012 Jun;135(6):887-94

Authors: Ju C, Gao L, Wu X, Pang K

Abstract
Background & objectives: Artificial corneal endothelium equivalents can not only be used as in vitro model for biomedical research including toxicological screening of drugs and investigation of pathological corneal endothelium conditions, but also as potential sources of grafts for corneal keratoplasty. This study was aimed to demonstrate the feasibility of constructing human corneal endothelium equivalents using human corneal endothelial cells and acellular porcine corneal matrix. Methods: Porcine corneas were decellularized with sodium dodecyl sulphate (SDS) solution. Human corneal endothelial cells B4G12 were cultured with leaching liquid extracted from the acellular porcine corneal matrix, and then cell proliferative ability was evaluated by MTT assay. B4G12 cells were transplanted to a rat corneal endothelial deficiency model to analyze their in vivo bio-safety and pump function, and then seeded and cultured on acellular porcine corneal matrix for two wk. Corneal endothelium equivalents were analyzed using HE staining, trypan blue and alizarin red S co-staining, immunofluorescence and corneal swelling assay. Results: The leaching liquid from acellular porcine corneal matrix had little influence on the proliferation ability of B4G12 cells. Animal transplantation of B4G12 cells showed that these cells had similar function to the native cells without causing a detectable immunological reaction and neoplasm in vivo. These formed a monolayer covering the surface of the acellular porcine corneal matrix. Trypan blue and alizarin red S co-staining showed that B4G12 cells were alive after two wk in organ culture and cell boundaries were clearly delineated. Proper localizations of ZO-1 and Na+/K+ ATPase were detected by immunofluorescence assay. Functional experiments were conducted to show that the Na+/K+ ATPase inhibitor ouabain could block the ionic-pumping function of this protein, leading to persistent swelling of 51.7 per cent as compared to the control. Interpretation & conclusions: Our findings showed that B4G12 cells served as a good model for native corneal endothelial cells in vivo. Corneal endothelium equivalents had properties similar to those of native corneal endothelium and could serve as a good model for in vitro study of human corneal endothelium.

PMID: 22825608 [PubMed - in process]

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Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1).

Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1).

Eur Respir J. 1996 Nov;9(11):2263-72

Authors: Hoekx JC, Hedlin G, Pedersen W, Sorva R, Hollingworth K, Efthimiou J

PMID: 8947070 [PubMed - indexed for MEDLINE]

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Lessons from the other side of the Atlantic.

Lessons from the other side of the Atlantic.

Prescrire Int. 2012 Jun;21(128):165-6

Authors:

Abstract
In the United States, bevacizumab was approved for use in combination with paclitaxel for the treatment of metastatic breast cancer on the basis of a single trial showing a beneficial impact on progression-free survival, a surrogate endpoint. The indication in breast cancer was withdrawn in 2011 when a new review of the data showed no increase in overall survival. In the European Union, bevacizumab was approved for use in combination with paclitaxel or docetaxel, again based on an improvement in progression-free survival. Following a review of clinical trials using this same endpoint, the indication for combination with paclitaxel was maintained while the indication for combination with docetaxel was withdrawn in 2011. Furthermore, bevacizumab was approved for use in combination with capecitabine on the basis of progression-free survival data.

PMID: 22822597 [PubMed - in process]

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Curcumin sensitizes chemotherapeutic drugs via modulation of PKC, telomerase, NF-kappaB and HDAC in breast cancer.

Curcumin sensitizes chemotherapeutic drugs via modulation of PKC, telomerase, NF-kappaB and HDAC in breast cancer.

Ther Deliv. 2011 Oct;2(10):1275-93

Authors: Royt M, Mukherjee S, Sarkar R, Biswas J

Abstract
BACKGROUND: Several tumor markers are overexpressed in breast cancer. Chemotherapy in breast cancer fails due to resistance to chemotherapeutic drugs. A phytochemical such as curcumin can be used in a therapeutic modality as it elicits anti-tumor effects.
METHODS: Action of curcumin on the expression of several tumor markers, such as protein kinase C, telomerase, NF-kappaB and histone deacetylase in MCF-7 (ER positive), MDA-MB-231 (ER negative), MCF- 12F (control) and also in mice mammary tumors were investigated.
RESULTS: Curcumin downregulated the expression of tumor markers both in vitro and in vivo and sensitized tumor cells to the chemotherapeutic drugs cyclophosphamide and paclitaxel.
DISCUSSION: Curcumin may be of considerable value in synergistic therapy of cancer such that the drug dose level could be minimized reducing the associated toxicity.

PMID: 22826883 [PubMed - in process]

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Wednesday, July 25, 2012

Long-term quality of life in young adults treated for oral cavity squamous cell cancer.

Long-term quality of life in young adults treated for oral cavity squamous cell cancer.

Ann Otol Rhinol Laryngol. 2012 Jun;121(6):395-401

Authors: Thomas L, Moore EJ, Olsen KD, Kasperbauer JL

Abstract
OBJECTIVES: We assessed the long-term quality of life (QOL) in patients who survived oral cavity squamous cell cancer when they were young and looked for any clinical factors that might adversely affect function and QOL.
METHODS: We performed a retrospective case series and questionnaire survey in a tertiary care center. The subjects were consecutive patients treated for oral cancers during a 25-year period, when they were 40 years of age or less. The patients completed the University of Washington Quality of Life questionnaire and the M. D. Anderson Dysphagia Inventory (MDADI). We made an overall descriptive report of swallowing and QOL measures in the study population and looked for any clinical factors associated with functional outcomes.
RESULTS: Among the 62 patients treated over the course of 25 years, 46 were alive and disease-free. Twenty-six participated. The median follow-up duration was 14.7 years (range, 3 to 27 years). Age at diagnosis and duration of follow-up did not correlate with overall QOL or health-related QOL. Seventy-seven percent rated their overall QOL as outstanding, very good, or good. The key domains affected by cancer were appearance, mood, saliva, and shoulder function. Radiotherapy significantly adversely affected the QOL. The median MDADI scores on all 4 subscales were at least 85%. Higher T-stage and radiotherapy were significantly associated with lower scores on all subscales.
CONCLUSIONS: The long-term health-related QOL in this cohort was quite good. Radiotherapy and tumor stage correlated with swallowing outcomes, and only radiotherapy seemed to adversely affect the overall QOL.

PMID: 22737962 [PubMed - indexed for MEDLINE]

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Dermatomyositis as paraneoplastic syndrome of peritoneal and ovarian relapse after long-term complete remission in patient with metastatic bilateral breast cancer.

Dermatomyositis as paraneoplastic syndrome of peritoneal and ovarian relapse after long-term complete remission in patient with metastatic bilateral breast cancer.

Coll Antropol. 2012 Mar;36(1):325-9

Authors: Murgi? J, Prpi? M, Kirac I, Camino-Varela AM, Bolanca A, Kusi? Z

Abstract
Dermatomyositis is a rare disease characterised by inflammatory muscle affection and characteristic cutaneous changes. When occuring in a patient with cancer, dermatomyositis may indicate recurrence or progression and poor outcome. Herein, the treatment of metastatic breast cancer, metastatic pattern, characteristics of long-term survivors, and link between dermatomyositis and breast cancer are discussed and the literature reviewed. We report a 57-year old female patient with metastatic bilateral breast cancer whose ovarian and peritoneal relapse after long-term remission was disclosed by occurence of paraneoplastic dermatomyositis. The patient previously had a 15-year long disease free-period after primary treatment for breast cancer before onset of pulmonary dissemination. Following antracycline-based chemotherapy, the complete remission lasting another 15 years was accomplished. Dermatomyositis had been resolved upon induction of second-line taxane-based chemotherapy. After completion of six cycles of gemcitabine and paclitaxel chemotherapy, check-up revealed further progression. The patient subsequently underwent six cycles of third-line CAP chemotherapy (cyclofosfamide, doxorubicine, cisplatin) but disease progressed and oral capecitabine chemotherapy was initiated. The patient received four cycles of capecitabine followed by further vast progression and finally expired following massive pulmonary embolism. Our case stresses the need of thorough staging and check-up when dermatomyositis arises in patients with breast cancer, regardless of previous stable long-term complete remission. Furthermore, we believe that treatment with curative intent in young patients with metastatic breast cancer, who have good performance statuses and no comorbidities is required, because it is more likely to produce long-term complete remission. However, following disease relapse a poor outcome can be expected.

PMID: 22816241 [PubMed - in process]

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Gazing into the crystal ball; the future of computer-aided drug design.

Gazing into the crystal ball; the future of computer-aided drug design.

J Comput Aided Mol Des. 2012 Jan;26(1):77-9

Authors: Martin E, Ertl P, Hunt P, Duca J, Lewis R

PMID: 22089332 [PubMed - indexed for MEDLINE]

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Structural and functional differences in barrier properties of African American, Caucasian and East Asian skin.

Structural and functional differences in barrier properties of African American, Caucasian and East Asian skin.

J Dermatol Sci. 2010 Aug;59(2):123-8

Authors: Muizzuddin N, Hellemans L, Van Overloop L, Corstjens H, Declercq L, Maes D

PMID: 20654785 [PubMed - indexed for MEDLINE]

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A human islet cell culture system for high-throughput screening.

A human islet cell culture system for high-throughput screening.

J Biomol Screen. 2012 Apr;17(4):509-18

Authors: Walpita D, Hasaka T, Spoonamore J, Vetere A, Takane KK, Fomina-Yadlin D, Fiaschi-Taesch N, Shamji A, Clemons PA, Stewart AF, Schreiber SL, Wagner BK

Abstract
A small-molecule inducer of beta-cell proliferation in human islets represents a potential regeneration strategy for treating type 1 diabetes. However, the lack of suitable human beta cell lines makes such a discovery a challenge. Here, we adapted an islet cell culture system to high-throughput screening to identify such small molecules. We prepared microtiter plates containing extracellular matrix from a human bladder carcinoma cell line. Dissociated human islets were seeded onto these plates, cultured for up to 7 days, and assessed for proliferation by simultaneous Ki67 and C-peptide immunofluorescence. Importantly, this environment preserved beta-cell physiological function, as measured by glucose-stimulated insulin secretion. Adenoviral overexpression of cdk-6 and cyclin D(1), known inducers of human beta cell proliferation, was used as a positive control in our assay. This induction was inhibited by cotreatment with rapamycin, an immunosuppressant often used in islet transplantation. We then performed a pilot screen of 1280 compounds, observing some phenotypic effects on cells. This high-throughput human islet cell culture method can be used to assess various aspects of beta-cell biology on a relatively large number of compounds.

PMID: 22156222 [PubMed - indexed for MEDLINE]

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Tuesday, July 24, 2012

ATPase; +30 new citations

30 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

ATPase

These pubmed results were generated on 2012/07/24

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Evolution of the Gynecologic Oncology Group protocols in the treatment of epithelial ovarian cancer.

Evolution of the Gynecologic Oncology Group protocols in the treatment of epithelial ovarian cancer.

Clin Obstet Gynecol. 2012 Mar;55(1):131-55

Authors: Seamon LG, Richardson DL, Copeland LJ

Abstract
This chapter reviews some of the sentinel Gynecologic Oncology Group (GOG) ovarian trials, describes their rationale, provides summary tables for reference, and is organized into early ovarian cancer (GOG 1, 7601, 7602, 95, 157, 175, 212), advanced ovarian cancer optimal (2, 25, 52, 104, 114, 158, 172, 182, 178, 212, 252), and suboptimal disease (3, 22, 47, 97, 111, 162, 182, 218, 252, 262).

PMID: 22343234 [PubMed - indexed for MEDLINE]

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Molecular cellular mechanisms of Peptide regulation of melatonin synthesis in pinealocyte culture.

Molecular cellular mechanisms of Peptide regulation of melatonin synthesis in pinealocyte culture.

Bull Exp Biol Med. 2012 Jun;153(2):255-8

Authors: Khavinson VKh, Linkova NS, Kvetnoy IM, Kvetnaia TV, Polyakova VO, Korf HW

Abstract
The effects of epithalone and vilone peptides on the synthesis of melatonin and factors involved in this process, arylalkylamine-N-acetyltransferase (AANAT) enzyme and pCREB transcription protein, were studied in rat pinealocyte culture. Epithalone stimulated AANAT and pCREB synthesis and increased melatonin level in culture medium. Simultaneous addition of norepinephrine and peptides into the culture potentiated the expression of AANAT and pCREB.

PMID: 22816096 [PubMed - in process]

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Comparison of the efficacy and safety of Consupren solution and Sandimmun Neoral solution, 50 ml in stable heart transplant patients.

Comparison of the efficacy and safety of Consupren solution and Sandimmun Neoral solution, 50 ml in stable heart transplant patients.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2002 Dec;146(2):87-90

Authors: Toman J, Spinarov� L, Krejc� J, Hude P, Kopecn� E, Kamar�d V

Abstract
Cyclosporine A (CyA) is a standard component of immunosuppressive regimen after heart transplantation in most centres. The widespread clinical use of cyclosporine-based immunosuppressive regimens since 1983 has led to significant improvements in the survival of cardiac allograft recipients due to decreased mortality from infections and rejections. (1-3) CyA has been shown to be safe and effective. Owing to its success when used after the heart transplantation the number of patients has also risen. This caused growing financial demands on health insurance companies in the Czech Republic where the immunosuppressive drugs are fully reimbursed. A prospective randomized study in 11 stable heart transplant patients was performed to compare the efficacy and safety of Consupren (IVAX-CR) a Sandimmun Neoral (Novartis) solution based immunosuppressive regimen. The results suggest that Consupren solution can be used as an alternative treatment to Sandimmun Neoral in CyA based regimen.

PMID: 12572904 [PubMed - indexed for MEDLINE]

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Monday, July 23, 2012

Evolution of the Gynecologic Oncology Group protocols in the treatment of epithelial ovarian cancer.

Evolution of the Gynecologic Oncology Group protocols in the treatment of epithelial ovarian cancer.

Clin Obstet Gynecol. 2012 Mar;55(1):131-55

Authors: Seamon LG, Richardson DL, Copeland LJ

PMID: 22343234 [PubMed - indexed for MEDLINE]

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Design of combinatorial libraries for the exploration of virtual hits from fragment space searches with LoFT.

Design of combinatorial libraries for the exploration of virtual hits from fragment space searches with LoFT.

J Chem Inf Model. 2012 Feb 27;52(2):373-9

Authors: Lessel U, Wellenzohn B, Fischer JR, Rarey M

Abstract
A case study is presented illustrating the design of a focused CDK2 library. The scaffold of the library was detected by a feature trees search in a fragment space based on reactions from combinatorial chemistry. For the design the software LoFT (Library optimizer using Feature Trees) was used. The special feature called FTMatch was applied to restrict the parts of the queries where the reagents are permitted to match. This way a 3D scoring function could be simulated. Results were compared with alternative designs by GOLD docking and ROCS 3D alignments.

PMID: 22148673 [PubMed - indexed for MEDLINE]

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Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.

Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.

BMJ. 2012;344:e1771

Authors: Hemmingsen B, Christensen LL, Wetterslev J, Vaag A, Gluud C, Lund SS, Almdal T

PMID: 22517929 [PubMed - indexed for MEDLINE]

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