Publications by authors named "Andrew N Billin"
Article Synopsis
- - Clinical trials for metabolic dysfunction-associated steatohepatitis (MASH) need accurate histologic scoring to assess participants and outcomes, but varying interpretations have affected results.
- - The AI-based tool AIM-MASH showed strong consistency and agreement with expert pathologists in scoring MASH histology, achieving accuracy comparable to that of average pathologists.
- - AIM-MASH demonstrated a strong ability to predict patient outcomes, correlating well with pathologist scores and noninvasive biomarkers, indicating it could enhance the efficiency and reliability of clinical trials for MASH.
Article Synopsis
- This phase 1b study assessed the safety and effectiveness of cilofexor, a drug targeting farnesoid X receptors, in patients with compensated cirrhosis caused by primary sclerosing cholangitis over 12 weeks.
- Patients received increasing doses of cilofexor, and while most reported side effects like pruritus and fatigue, there were no serious adverse events.
- Results showed significant improvements in liver function markers, indicating that cilofexor may help manage cholestasis in these patients.
Article Synopsis
- Clinical trials for nonalcoholic steatohepatitis (NASH) rely on consistent histologic scoring, but variability in these interpretations has affected trial results.* -
- An AI tool called AIM-NASH was developed to provide standardized scoring for NASH histology, showing strong correlation with expert consensus scores and improving predictive accuracy for patient outcomes.* -
- In a retrospective analysis, AIM-NASH helped meet previously unmet pathological endpoints in the ATLAS trial, suggesting it could reduce variability in scoring and enhance the assessment of treatment responses in clinical trials.*
Article Synopsis
- * The study involved participants with varying degrees of hepatic impairment and healthy controls, revealing that cilofexor's concentration in the blood was significantly higher in those with more severe impairment compared to those with normal liver function.
- * Although cilofexor was generally well tolerated with mild side effects, proper dosing and caution are necessary for patients with moderate or severe hepatic impairment, while those with mild impairment may not need dosage adjustments.
Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate.
View Article and Find Full Text PDFCilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated.
View Article and Find Full Text PDFBiomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
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- Pruritus, or itching, is common in liver diseases, especially those involving cholestasis, and the study examines serum IL-31 as a potential biomarker linked to this symptom in various liver conditions.
- Results showed that patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) had higher baseline IL-31 levels compared to those with non-alcoholic steatohepatitis (NASH) and healthy individuals, and IL-31 correlated with pruritus severity.
- The findings suggest that IL-31 levels could be influenced by treatment with the FXR agonist cilofexor, potentially offering therapeutic insights for managing itching in liver disease patients.
Article Synopsis
- Bile acids, particularly the deoxycholate (DCA), play a significant role in the worsening of Non-Alcoholic Fatty Liver Disease (NAFLD) and their levels increase with disease severity and fibrosis.
- A detailed study involving various microbiome analyses found that certain bile acids derived from DCA were linked to increased disease activity, suggesting a biological mechanism underlying these changes.
- The findings highlight the importance of bile acids and related gut microbiota in NAFLD progression, paving the way for potential biomarkers and therapeutic approaches for conditions like Non-Alcoholic Steatohepatitis (NASH).
Background & Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH.
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- Tirabrutinib is an irreversible, small-molecule BTK inhibitor approved in Japan for treating B-cell malignancies and is under investigation for inflammatory diseases.
- A pharmacokinetic/pharmacodynamic (PK/PD) model was created to inform dose selection based on clinical data from two phase I studies, which effectively predicted drug behavior in the body.
- The model suggested a minimum daily dose of 40 mg to achieve over 90% BTK occupancy, and a positive correlation was found between increased BTK occupancy duration and enhanced treatment efficacy for rheumatoid arthritis.
Article Synopsis
- Primary sclerosing cholangitis (PSC) is a condition that leads to progressive liver damage, and researchers analyzed RNA from liver tissues of 74 PSC patients to explore relationships between gene expression and clinical outcomes, independent of fibrosis levels.
- * To isolate the impact of fibrosis on gene expression, a computational method was used, revealing that certain gene patterns could predict the timing of PSC-related clinical events.
- * The analysis identified two distinct patient groups with differing risks of events despite having similar fibrosis stages, emphasizing pathways related to eIF2 signaling and the unfolded protein response as potential areas for further investigation.
Background And Aims: We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH).
Approach And Results: In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks.
Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double-blind, placebo-controlled study, we tested the safety and efficacy of cilofexor (formerly GS-9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large-duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks.
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- The authors of the original article identified a mistake regarding the data and materials availability section.
- This discrepancy was noted on page 12 of the article.
- The authors are bringing attention to this issue after the article's publication.
Article Synopsis
- The study investigates how prolyl hydroxylase inhibitors, which stabilize hypoxia-inducible factors (HIFs), can enhance skeletal muscle repair after injury in both mice and humans, potentially countering issues like fibrosis and fatty tissue buildup.* -
- In mouse experiments, the inhibitor GSK1120360A significantly improved muscle recovery post-injury, working through myeloid HIF1α and iNOS activity rather than EPO modulation.* -
- Tests in healthy human volunteers showed that the inhibitor daprodustat reduced muscle damage markers after exercise, but did not improve functional recovery, indicating some similarities and differences in response between species.*
Skeletal muscle stem cell (MuSC) function declines with age and contributes to impaired muscle regeneration in older individuals. Acting through AMPK/p27, we have identified a pathway regulating the balance between autophagy, apoptosis, and senescence in aged MuSCs. While p27 is implicated in MuSC aging, its precise role and molecular mechanism have not been elucidated.
View Article and Find Full Text PDFIsolation of Skeletal Muscle Stem Cells for Phenotypic Screens for Modulators of Proliferation.
Methods Mol Biol
February 2019
Article Synopsis
- Adult skeletal muscle has stem cells called muscle stem cells (MuSCs) or satellite cells, which are essential for repairing muscle after injury.
- Aging leads to a reduced ability of these satellite cells to multiply and repair muscle, contributing to slower recovery and muscle loss in older adults.
- The text discusses various methods for isolating these satellite cells from mice and humans, enabling research to test small molecules that regulate their growth and development.
Recent high-profile studies report GDF11 to be a key circulating 'anti-aging' factor. However, a screen of extracellular proteins attempting to identify factors with 'anti-aging' phenotypes in aged murine skeletal muscle satellite cells did not identify GDF11 activity. We have been unable to confirm the reported activity of GDF11, similar to other laboratories offering conflicting data and describe our attempts to do so in this short take.
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- Satellite cells are specialized stem cells in adult muscles that help generate new muscle tissue after injury, but their regenerative ability decreases with age.
- Research found that certain compounds, specifically 2,4-diaminopyrimidines, can boost the proliferation of these satellite cells and enhance muscle repair in mouse models.
- The study aims to identify the molecular targets responsible for this increased proliferation, paving the way for developing new therapies for muscle repair and regeneration.
Article Synopsis
- NAD+ is a crucial cofactor for metabolic reactions and regulates important cellular functions like gene expression and DNA repair.
- Levels of NAD+ in cells are tightly controlled and can change quickly in response to diet and environment.
- Studies show that blocking the CD38 enzyme can increase NAD+ levels, improve metabolic health, and enhance exercise performance in mice fed high-fat diets.
Rhabdomyosarcoma: current challenges and their implications for developing therapies.
Cold Spring Harb Perspect Med
November 2014
Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation.
View Article and Find Full Text PDFSatellite cells are the chief contributor to skeletal muscle growth and regeneration. The study of mouse satellite cells has accelerated in recent years due to technical advancements in the isolation of these cells. The study of human satellite cells has lagged and thus little is known about how the biology of mouse and human satellite cells compare.
View Article and Find Full Text PDFWe have identified integrin beta 6 (Itgb6) as a transcript highly enriched in skeletal muscle. This finding is unexpected because Itgb6 is typically associated with epithelial expression domains in normal tissue. Further we find that ITGB6 protein expression in muscle is post-transcriptionally regulated.
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