Search

Your search keyword '"Lim, Sharlene"' showing total 25 results
Start Over Author "Lim, Sharlene"
25 results on '"Lim, Sharlene"'

1. SAT-438 Utility of SomaSignalTM panels for drug response and monitoring disease progression in patients with advanced fibrosis due to non-alcoholic steatohepatitis

Author

Kowdley, Kris, Zhu, Kaiyi, Xu, Jun, Melehani, Jason, Boyette, Lisa, Watkins, Timothy R, Lim, Sharlene, Malkov, Vlad, Billin, Andrew, Noureddin, Mazen, and Loomba, Rohit

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Good Health and Well Being, Clinical Sciences, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences
Published
2023

3. Utility of SomaSignalTM panels for drug response and monitoring disease progression in patients with advanced fibrosis due to non-alcoholic steatohepatitis

Author

Kowdley, Kris, primary, Zhu, Kaiyi, additional, Xu, Jun, additional, Melehani, Jason, additional, Boyette, Lisa, additional, Watkins, Timothy R., additional, Lim, Sharlene, additional, Malkov, Vlad, additional, Billin, Andrew, additional, Noureddin, Mazen, additional, and Loomba, Rohit, additional

Published
2023
Full Text
View/download PDF

4. Modulation of Survival Motor Neuron Pre-mRNA Splicing by Inhibition of Alternative 3′ Splice Site Pairing*

Author

Lim, Sharlene R and Hertel, Klemens J

Subjects
Spinal Muscular Atrophy, Genetics, Neurodegenerative, Rare Diseases, Neurosciences, Pediatric, Alleles, Base Sequence, Cell Line, Cyclic AMP Response Element-Binding Protein, Dose-Response Relationship, Drug, Exons, Humans, Introns, Models, Genetic, Molecular Sequence Data, Nerve Tissue Proteins, Oligonucleotides, Antisense, Protein Biosynthesis, RNA Splicing, RNA, Messenger, RNA-Binding Proteins, SMN Complex Proteins, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, Time Factors, Tumor Cells, Cultured, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology
Abstract

Spinal muscular atrophy is caused by the loss of functional survival motor neuron (SMN1) alleles. A translationally silent nucleotide transition in the duplicated copy of the gene (SMN2) leads to exon 7 skipping and expression of a nonfunctional gene product. It has been suggested that differential SMN2 splicing is caused by the disruption of an exonic splicing enhancer. Here we show that the single nucleotide difference reduces the intrinsic strength of the 3' splice site of exon 7 2-fold, whereas the strength of the 5' splice site of the exon 7 is not affected. Thus, a decrease in splice site strength is magnified in the context of competing exons. These data suggest that lower levels of exon 7 definition not only reduce intron 6 removal but, more importantly, increase the efficiency of the competing exon 7 skipping pathway. Antisense oligonucleotides were tested to modulate exon 7 inclusion, which contains the authentic translation stop codon. Oligonucleotides directed toward the 3' splice site of exon 8 were shown to alter SMN2 splicing in favor of exon 7 inclusion. These results suggest that antisense oligonucleotides could be used as a therapeutic strategy to counteract the progression of SMA.

Published
2001

5. A 24‐Week , Phase IIa , Randomized, Double‐blind, Placebo‐controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis ( NOVESA )

Author

Khanna, Dinesh, primary, Denton, Christopher P., additional, Furst, Daniel E., additional, Mayes, Maureen D., additional, Matucci‐Cerinic, Marco, additional, Smith, Vanessa, additional, de Vries, Dick, additional, Ford, Paul, additional, Bauer, Yasmina, additional, Randall, Matthew J., additional, Ebrahimpoor, Mitra, additional, Kupcsik, Laszlo, additional, Stiers, Pieter‐Jan, additional, Deberdt, Liesbeth, additional, Prasad, Niyati, additional, Lim, Sharlene, additional, Pujuguet, Philippe, additional, and Ahmed, Sohail, additional

Published
2023
Full Text
View/download PDF

9. IDL-2965: a selective, highly potent, clinical-stage integrin antagonist for treatment of non-alcoholic steatohepatitis

Author

Kossen, Karl, primary, Schaefer, Caralee, additional, Lim, Sharlene, additional, Michener, Marshall, additional, Griggs, Dave, additional, Ruminski, Peter, additional, Radhakrishnan, Ramachandran, additional, Rubino, Christopher, additional, Marmon, Tonya, additional, Gershman, Ari, additional, Hanning, Roxann, additional, Jones, Renee, additional, Kamau-Kelley, Watiri, additional, and Seiwert, Scott, additional

Published
2020
Full Text
View/download PDF

11. Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease

Author

Rajagopalan, Ravi, primary, Pan, Lin, additional, Schaefer, Caralee, additional, Nicholas, John, additional, Lim, Sharlene, additional, Misialek, Shawn, additional, Stevens, Sarah, additional, Hooi, Lisa, additional, Aleskovski, Natalia, additional, Ruhrmund, Donald, additional, Kossen, Karl, additional, Huang, Lea, additional, Yap, Sophia, additional, Beigelman, Leonid, additional, Serebryany, Vladimir, additional, Liu, Jyanwei, additional, Sastry, Srikonda, additional, Seiwert, Scott, additional, and Buckman, Brad, additional

Published
2017
Full Text
View/download PDF

13. Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

Author

Lim, Sharlene R., primary, Qin, Xiaoli, additional, Susser, Simone, additional, Nicholas, John B., additional, Lange, Christian, additional, Herrmann, Eva, additional, Hong, Jin, additional, Arfsten, Ann, additional, Hooi, Lisa, additional, Bradford, Williamson, additional, Nájera, Isabel, additional, Smith, Patrick, additional, Zeuzem, Stefan, additional, Kossen, Karl, additional, Sarrazin, Christophe, additional, and Seiwert, Scott D., additional

Published
2012
Full Text
View/download PDF

15. Sequence and Phenotypic Analysis for Resistance Monitoring in Hepatitis C Virus Drug Development: Recommendations From the HCV DRAG

Author

Kwong, Ann D., primary, Najera, Isabel, additional, Bechtel, Jill, additional, Bowden, Scott, additional, Fitzgibbon, Joseph, additional, Harrington, Patrick, additional, Kempf, Dale, additional, Kieffer, Tara L., additional, Koletzki, Diana, additional, Kukolj, George, additional, Lim, Sharlene, additional, Pilot–Matias, Tami, additional, Lin, Kai, additional, Mani, Nina, additional, Mo, Hongmei, additional, O'Rear, Jules, additional, Otto, Michael, additional, Parkin, Neil, additional, Pawlotsky, Jean–Michel, additional, Petropoulos, Chris, additional, Picchio, Gaston, additional, Ralston, Robert, additional, Reeves, Jacqueline D., additional, Schooley, Robert T., additional, Seiwert, Scott, additional, Standring, David, additional, Stuyver, Lieven, additional, Sullivan, James, additional, and Miller, Veronica, additional

Published
2011
Full Text
View/download PDF

16. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)

Author

Seiwert, Scott D., primary, Andrews, Steven W., additional, Jiang, Yutong, additional, Serebryany, Vladimir, additional, Tan, Hua, additional, Kossen, Karl, additional, Rajagopalan, P. T. Ravi, additional, Misialek, Shawn, additional, Stevens, Sarah K., additional, Stoycheva, Antitsa, additional, Hong, Jin, additional, Lim, Sharlene R., additional, Qin, Xiaoli, additional, Rieger, Robert, additional, Condroski, Kevin R., additional, Zhang, Hailong, additional, Do, Mary Geck, additional, Lemieux, Christine, additional, Hingorani, Gary P., additional, Hartley, Dylan P., additional, Josey, John A., additional, Pan, Lin, additional, Beigelman, Leonid, additional, and Blatt, Lawrence M., additional

Published
2008
Full Text
View/download PDF

23. Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

Author

Lim, Sharlene R., Qin, Xiaoli, Susser, Simone, Nicholas, John B., Lange, Christian, Herrmann, Eva, Hong, Jin, Arfsten, Ann, Hooi, Lisa, Bradford, Williamson, Nájera, Isabel, Smith, Patrick, Zeuzem, Stefan, Kossen, Karl, Sarrazin, Christophe, and Seiwert, Scott D.

Abstract

ABSTRACTDanoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor that promotes multi-log10reductions in HCV RNA when administered as a 14-day monotherapy to patients with genotype 1 chronic HCV. Of these patients, 14/37 experienced a continuous decline in HCV RNA, 13/37 a plateau, and 10/37 a rebound. The rebound and continuous-decline groups experienced similar median declines in HCV RNA through day 7, but their results diverged notably at day 14. Plateau group patients experienced a lesser, but sustained, median HCV RNA decline. Baseline danoprevir susceptibility was similar across response groups but was reduced significantly at day 14 in the rebound group. Viral rebound in genotype 1b was uncommon (found in 2/23 patients). Population-based sequence analysis of NS3 and NS4A identified treatment-emergent substitutions at four amino acid positions in the protease domain of NS3 (positions 71, 155, 168, and 170), but only two (155 and 168) were in close proximity to the danoprevir binding site and carried substitutions that impacted danoprevir potency. R155K was the predominant route to reduced danoprevir susceptibility and was observed in virus isolated from all 10 rebound, 2/13 plateau, and 1/14 continuous-decline patients. Virus in one rebound patient additionally carried partial R155Q and D168E substitutions. Treatment-emergent substitutions in plateau patients were less frequently observed and more variable. Single-rebound patients carried virus with R155Q, D168V, or D168T. Clonal sequence analysis and drug susceptibility testing indicated that only a single patient displayed multiple resistance pathways. These data indicate the ascendant importance of R155K for viral escape during danoprevir treatment and may have implications for the clinical use of this agent.

Published
2011
Full Text
View/download PDF

24. Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease

Author

Rajagopalan, Ravi, Pan, Lin, Schaefer, Caralee, Nicholas, John, Lim, Sharlene, Misialek, Shawn, Stevens, Sarah, Hooi, Lisa, Aleskovski, Natalia, Ruhrmund, Donald, Kossen, Karl, Huang, Lea, Yap, Sophia, Beigelman, Leonid, Serebryany, Vladimir, Liu, Jyanwei, Sastry, Srikonda, Seiwert, Scott, and Buckman, Brad

Abstract

AbstractThe current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitrodisplayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection.

Published
2016
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results