72 research outputs found
Preparation and characterization of simvastatin/DMβCD complex and its pharmacokinetics in rats
Simvastatin is poorly bioavailable because it is practically insoluble in water and shows dissolution rate-limited absorption. Solubilizing effects of several β-cyclodextrin (βCD) derivatives such as HPβCD, SBEβCD and DMβCD on simvastatin in aqueous solution were investigated using the phase solubility technique. The solubility diagram of simvastatin with each βCD derivative could be classified as AL-type, indicating soluble complex formation of 1:1 stoichiometry. Among the above βCD derivatives DMβCD was found to be the ideal complexing agent for improving drug solubility. The simvastatin complex with DMβCD was prepared using the co-evaporation method and was then characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR) and in vitro dissolution. Dissolution and pharmacokinetic studies indicated that the simvastatin/DMβCD complex exhibited an increased dissolution rate, rapid absorption, and improved bioavailability in rats compared to free drug. Maximum plasma concentration (cmax) and the time to reach it (tmax) were 21.86 µg mL–1 and 1.4 h for the drug complex, 8.25 µg mL–1 and 3.0 h for free drug, respectively. Main pharmacokinetic parameters such as tmax, cmax were significantly different (p < 0.01) between the simvastatin complex and free drug. Bioavailability of the simvastatin complex relative to free drug was up to 167.0 %
Preparation and in vivo evaluation of gel-based nasal delivery system for risperidone
The aim of this study was to prepare a nasal gel of risperidone and to investigate the pharmacokinetics and relative bioavailability of the drug in rats. Compared with oral dosing, the risperidone nasal gel exhibited very fast absorption and high bioavailability. Maximal plasma concentration (cmax ) and the time to reach cmax (tmax) were 15.2 µg mL–1 and 5min for the nasal gel, 3.6 µg mL–1and 30 min for the oral drug suspension, respectively. Pharmacokinetic parameters such as tmax, cmax and AUC between oral and nasal routes were significantly different (p < 0.01). Relative bioavailability of the drug nasal preparation to the oral suspension was up to 1600.0%. Further, the in vitro effect of the risperidone nasal gel on nasal mucociliary movement was also investigated using a toad palate model. The risperidone nasal formulation showed mild ciliotoxicity, but the adverse effect was temporary and reversible
Continuous photon energy modulation in IMRT of pancreatic cancer
Purpose: To develop a novel IMRT optimization method based on the principle of photon energy synthesis that simultaneously optimizes fluence map and beamlet energy. The method was validated on pancreatic cancers to demonstrate the benefits of the additional degree of freedom of photon energy in IMRT.Methods: Previous work has demonstrated that the effect of a photon beam of known energy can be achieved by the combination of two existing energy photons in the proper ratio. It further implied that any energy photon can be synthesized. Based on this, we propose the concept of continuous beamlet energy modulation in IMRT, or IMRT-BEM. The IMRT-BEM was modeled as the simultaneous optimization of two fluence maps, one for the low energy beam and one for the high energy beam, and it was implemented in an in-house inverse planning system. The IMRT-BEM was applied on 10 pancreatic cancer cases, where the IMRT-BEM plan was compared with single-energy IMRT plans of 6 MV (IMRT-6MV) and 15 MV photons (IMRT-15MV).Results: The IMRT-BEM plan provides a noticeable reduction to the volume irradiated at the high dose level (PTV105%) for PTV, at least 24.7% (6.4 ± 6.8 vs. 31.1 ± 18.7 (p = 0.005) and 43.8 ± 19.8 (p = 0.005) for IMRT-BEM, IMRT-6MV, and IMRT-15MV respectively). For target dose coverage, there were statistically significant improvements between the IMRT-BEM plans and the other two plans in terms of CI and HI. Compared to the IMRT-6MV plan, there were significant reductions in the Dmean of the spinal cord, liver, bowel, duodenum, and stomach. The irradiation volumes of the medium dose (V20Gy, and V40Gy) for the duodenum and bowel were reduced significantly. There were no significant differences between the IMRT-BEM and IMRT-15MV plans except for the Dmean of the spinal cord and the duodenum, the V20Gy, and V40Gy for the duodenum, and the V20Gy of the stomach.Conclusion: IMRT-BEM has certain dosimetric advantages for PTV and improves OAR sparing in pancreatic cancer, and can be effectively used in radiation treatment planning, providing another degree of freedom for planners to improve treatment plan quality
A β-glucosidase hyper-production Trichoderma reesei mutant reveals a potential role of cel3D in cellulase production
Abstract
Background
The conversion of cellulose by cellulase to fermentable sugars for biomass-based products such as cellulosic biofuels, biobased fine chemicals and medicines is an environment-friendly and sustainable process, making wastes profitable and bringing economic benefits. Trichoderma reesei is the well-known major workhorse for cellulase production in industry, but the low β-glucosidase activity in T. reesei cellulase leads to inefficiency in biomass degradation and limits its industrial application. Thus, there are ongoing interests in research to develop methods to overcome this insufficiency. Moreover, although β-glucosidases have been demonstrated to influence cellulase production and participate in the regulation of cellulase production, the underlying mechanism remains unclear.
Results
The T. reesei recombinant strain TRB1 was constructed from T. reesei RUT-C30 by the T-DNA-based mutagenesis. Compared to RUT-C30, TRB1 displays a significant enhancement of extracellular β-glucosidase (BGL1) activity with 17-fold increase, a moderate increase of both the endoglucanase (EG) activity and the exoglucanase (CBH) activity, a minor improvement of the total filter paper activity, and a faster cellulase induction. This superiority of TRB1 over RUT-C30 is independent on carbon sources and improves the saccharification ability of TRB1 cellulase on pretreated corn stover. Furthermore, TRB1 shows better resistance to carbon catabolite repression than RUT-C30. Secretome characterization of TRB1 shows that the amount of CBH, EG and BGL in the supernatant of T. reesei TRB1 was indeed increased along with the enhanced activities of these three enzymes. Surprisingly, qRT-PCR and gene cloning showed that in TRB1 β-glucosidase cel3D was mutated through the random insertion by AMT and was not expressed.
Conclusions
The T. reesei recombinant strain TRB1 constructed in this study is more desirable for industrial application than the parental strain RUT-C30, showing extracellular β-glucosidase hyper production, high cellulase production within a shorter time and a better resistance to carbon catabolite repression. Disruption of β-glucosidase cel3D in TRB1 was identified, which might contribute to the superiority of TRB1 over RUT-C30 and might play a role in the cellulase production. These results laid a foundation for future investigations to further improve cellulase enzymatic efficiency and reduce cost for T. reesei cellulase production.http://deepblue.lib.umich.edu/bitstream/2027.42/134636/1/12934_2016_Article_550.pd
Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.This work was supported by NIH fellowship F32 GM106584 (AG), NIH grants R01 MH101244(A.G.), R01 CA188392 (B.P.), U01 CA194393(B.P.), R01 GM107427 (M.L.F.), R01 CA193910 (M.L.F./M.P.) and Prostate Cancer Foundation Challenge Award (M.L.F./M.P.). This study makes use of data generated by the Wellcome Trust Case Control Consortium and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium data is available on www.wtccc.org.uk. Funding for the Wellcome Trust Case Control Consortium project was provided by the Wellcome Trust under award 076113. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available online (http://www.UK10K.org). The PRACTICAL consortium was supported by the following grants: European Commission's Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative); Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), A Linneus Centre (Contract ID 70867902), Swedish Research Council (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), grants RO1CA056678, RO1CA082664 and RO1CA092579 from the US National Cancer Institute, National Institutes of Health; US National Cancer Institute (R01CA72818); support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296); NIH grants CA63464, CA54281 and CA098758; US National Cancer Institute (R01CA128813, PI: J.Y. Park); Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2–2009; DFNI-B01/28/2012); Cancer Research UK grants [C8197/A10123] and [C8197/A10865]; grant code G0500966/75466; NIHR Health Technology Assessment Programme (projects 96/20/06 and 96/20/99); Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK; The US Dept of Defense award W81XWH-04-1-0280; Australia Project Grant [390130, 1009458] and Enabling Grant [614296 to APCB]; the Prostate Cancer Foundation of Australia (Project Grant [PG7] and Research infrastructure grant [to APCB]); NIH grant R01 CA092447; Vanderbilt-Ingram Cancer Center (P30 CA68485); Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital (9N069 and X51003); Award Number P30CA042014 from the National Cancer Institute.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/0.1038/ncomms1097
Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
Although genome-wide association studies have identified over 100 risk loci that explain similar to 33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.Peer reviewe
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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa
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