Discovery of potent and selective inhibitors of procollagen C-proteinase for the treatment of fibrotic disorders

Introduction   Fibrosis is a component of many tissue pathologies leading to loss of normal tissue function, primarily due to excessive collagen deposition. Collagen is deposited following cleavage of the C- and N- terminal peptides from the pro-collagen molecule. The cleavage of the globular C-peptide by PCP reduces solubility of the fibrillar collagen molecule, resulting in deposition of insoluble collagen. Increased insoluble collagen deposition is a feature of all organ fibroses, with inhibition of this process, a key potential anti-fibrotic mechanism. The aim of this work was to discover potent and selective PCP inhibitors as experimental, topically applied, anti-fibrotic drugs for clinical evaluation.
Materials and methods   PCP was cloned from human osteosarcoma cells and enzymatic activity demonstrated using a PCP-specific peptide cleavage assay. Activities were confirmed by measuring cleavage of [³H]C-peptide from type-I pro-collagen. A cell-based fibroplasias model was employed to demonstrate compound efficacy using collagen deposition, liberated C-peptide and histological endpoints. The activities of PCP inhibitors in fibroblast and epithelial in vitro cell proliferation and migration assays, and selectivity vs. a panel of MMPs were also determined.
Discussion   In summary, we have identified and characterized potent and selective inhibitors of PCP for progression to clinical studies for investigation as a treatment paradigm for fibrotic disease.  

  Results     

72.

China’s next great leap forward          下载免费PDF全文

Katie Lewis 《Canadian Medical Association journal》2009,180(13):E112-E114

     

73.

DXA-Generated Z-Scores and T-Scores May Differ Substantially and Significantly in Young Adults     

John J. Carey  Miriam F. Delaney  Thomas E. Love  Bradford J. Richmond  Barbara A. Cromer  Paul D. Miller  Martha Manilla-McIntosh  Steven A. Lewis  Charles L. Thomas  Angelo A. Licata 《Journal of clinical densitometry》2007,10(4):11-358

Central dual-energy X-ray absorptiometry (DXA) is the gold standard for non-invasive measurement of bone mineral density (BMD). Using this value and subject demographics, DXA software calculates T-scores and Z-scores. Professional society guidelines for the management of osteoporosis are based on T-scores and Z-scores, rather than on the actual BMD value. Although one expects T-scores and Z-scores to be very similar in young men and women for any given BMD measurement, little literature exists on this issue. Our clinical experience shows that some younger adult individuals (premenopausal women and men younger than 50 yr) have larger than expected difference between their DXA T-score and Z-score. This cross-sectional study evaluates the extent of this discordance between Z-scores and T-scores in a sample of 4275 men and women aged 20–49 yr. All subjects were scanned by central DXA using equipment manufactured by GE Lunar, GE, Madison, WI, or Hologic, Inc., Bedford, MA. Significant differences between Z-scores and T-scores were seen within individuals at the lumbar spine, total hip, femoral neck, and trochanter (p value < 0.001) for both DXA systems. Although these differences were less than half a standard deviation (SD) in most instances, the magnitude of difference was substantial at times, being 1 or more SD in up to 11% of cases (range: −1.95 to +1.54 SD). The smallest differences were seen at the total hip and the largest differences were seen at the femoral neck for both technologies. This is in part because there is no single standard Z-score definition, resulting in different methods of calculation across, and even within, DXA manufacturers. Standardization of Z-score definition and method of calculation is indicated. DXA Z-scores should be interpreted with caution in men and women aged 20–50 yr.     

74.

RUSSELL TRACTION IN THE TREATMENT OF FRACTURES OF THE FEMUR: OBSERVATIONS ON ONE HUNDRED FIFTY-SIX CASES     

Lewis KM 《Annals of surgery》1941,113(2):226-244

     

75.

An alternative approach to measuring treatment persistence with antipsychotic agents among patients with schizophrenia in the Veterans Health Administration          下载免费PDF全文

Xinhua S Ren  Shirley Qian    Lewis E Kazis 《Neuropsychiatric Disease and Treatment》2007,3(2):277-284

     

76.

Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle     

Thompson  Debra A.; Janecke  Andreas R.; Lange  Jessica; Feathers  Kecia L.; Hubner  Christian A.; McHenry  Christina L.; Stockton  David W.; Rammesmayer  Gabriele; Lupski  James R.; Antinolo  Guillermo; Ayuso  Carmen; Baiget  Montserrat; Gouras  Peter; Heckenlively  John R.; den Hollander  Anneke; Jacobson  Samuel G.; Lewis  Richard A.; Sieving  Paul A.; Wissinger  Bernd; Yzer  Suzanne; Zrenner  Eberhart; Utermann  Gerd; Gal  Andreas 《Human molecular genetics》2006,15(9):1559

Human Molecular Genetics     

77.

Risk assessors need to be assessed     

P M Lewis  A R Evans  R Kulkarni    P Roberts 《British medical journal》2003,327(7423):1108-1109

     

78.

Superficial retinal refractile deposits in juxtafoveal telangiectasis   总被引：1，自引：0，他引：1  

J Moisseiev  H Lewis  E Bartov  S L Fine  R P Murphy 《American journal of ophthalmology》1990,109(5):604-605

     

79.

An innovative health care model for management of teenage pregnancy     

B D Lewis 《Journal of National Black Nurses' Association》1988,2(2):58-66

     

80.

Outcome-oriented approach to inspection of medication areas     

J P Thornton  R K Lewis 《American journal of hospital pharmacy》1990,47(2):382-384

     

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DXA-Generated Z-Scores and T-Scores May Differ Substantially and Significantly in Young Adults

Central dual-energy X-ray absorptiometry (DXA) is the gold standard for non-invasive measurement of bone mineral density (BMD). Using this value and subject demographics, DXA software calculates T-scores and Z-scores. Professional society guidelines for the management of osteoporosis are based on T-scores and Z-scores, rather than on the actual BMD value. Although one expects T-scores and Z-scores to be very similar in young men and women for any given BMD measurement, little literature exists on this issue. Our clinical experience shows that some younger adult individuals (premenopausal women and men younger than 50 yr) have larger than expected difference between their DXA T-score and Z-score. This cross-sectional study evaluates the extent of this discordance between Z-scores and T-scores in a sample of 4275 men and women aged 20–49 yr. All subjects were scanned by central DXA using equipment manufactured by GE Lunar, GE, Madison, WI, or Hologic, Inc., Bedford, MA. Significant differences between Z-scores and T-scores were seen within individuals at the lumbar spine, total hip, femoral neck, and trochanter (p value < 0.001) for both DXA systems. Although these differences were less than half a standard deviation (SD) in most instances, the magnitude of difference was substantial at times, being 1 or more SD in up to 11% of cases (range: −1.95 to +1.54 SD). The smallest differences were seen at the total hip and the largest differences were seen at the femoral neck for both technologies. This is in part because there is no single standard Z-score definition, resulting in different methods of calculation across, and even within, DXA manufacturers. Standardization of Z-score definition and method of calculation is indicated. DXA Z-scores should be interpreted with caution in men and women aged 20–50 yr.     

Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Human Molecular Genetics