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Determines whether ubiquitin conjugation is necessary for the degradation of oxidized proteins in intact cells. Inhibition of degradation by proteasome inhibitors; Rates of oxidized protein degradation by cell lysates; Presence of adenosine triphosphate; Tendency of a protein to be ubiquitinylated.

A significant body of evidence supports a key role for free radicals in causing cumulative damage to cellular macromolecules, thereby contributing to senescence/aging, and a number of age-related disorders. Proteins are recognized as major targets for oxidative damage (in addition to DNA and lipids) and the accumulation of oxidized proteins has been reported for many experimental aging models, as measured by several markers for protein oxidation. In young and healthy individuals, moderately oxidized soluble cell proteins are selectively and rapidly degraded by the proteasome. However, severely oxidized, cross-linked proteins are poor substrates for degradation and actually inhibit the proteasome. Considerable evidence now indicates that proteasome activity declines during aging, as the protease is progressively inhibited by binding to ever increasing levels of oxidized and cross-linked protein aggregates. Cellular aging probably involves both an increase in the generation of reactive oxygen species and a progressive decline in proteasome activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually contribute to cellular dysfunction and senescence. [Copyright &y& Elsevier]

Background & Aims Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ≥2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid (25 mg), and 21% had a response to placebo (P <.01). We performed a secondary analysis of data from this trial to identify clinical parameters associated with a histologic response. Methods We used a logistic regression model with a stepwise selection procedure to identify baseline and early on-treatment factors associated with a histologic response at 72 weeks. Baseline demographics, liver histology, medical history, concomitant medications, cardiometabolic parameters, and serum biochemistry, as well as the changes over the course of the trial (at weeks 12 and 24), were evaluated as potential predictors of a histologic response. The model was cross-validated by a jackknife method, and performance was evaluated with the area under the receiver operating characteristic curve. Results The logistic regression model found that obeticholic acid treatment, baseline NAS > 5, baseline triglyceride level ≤ 154 mg/dL, baseline international normalized ratio ≤ 1, baseline aspartate aminotransferase level ≤ 49 U/L, and a decrease in alanine aminotransferase level at week 24 by 17 U/L or more, to be significantly associated with histologic response (area under the receiver operating characteristic curve, 0.83; 95% confidence interval, 0.77–0.89; P <.0001). Conclusions In a secondary analysis of data from a clinical trial of obeticholic acid in patients with NASH, we identified routine clinical and laboratory parameters during the first 24 weeks of treatment (such as baseline NAS, triglyceride levels, and a decrease in alanine aminotransferase level) to significantly associate with histologic markers of response. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study. Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study. Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable. Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. NCT02548351 Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy. [Display omitted] • Reduced ALT, AST, GGT, FIB-4, and FibroTest scores were seen with OCA vs. placebo. • Reduced liver stiffness by VCTE was observed in OCA vs. placebo arms at Month 18. • NIT changes in OCA treatment arms were associated with shifts in fibrosis stage. • The antifibrotic effect of OCA might be measurable with commonly used NITs. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors and their receptor (IGF-1R) have been implicated in cancer pathophysiology. We demonstrate that IGF-1R is universally expressed in various hematologic (multiple myeloma, lymphoma, leukemia) and solid tumor (breast, prostate, lung, colon, thyroid, renal, adrenal cancer, retinoblastoma, and sarcoma) cells. Specific IGF-1R inhibition with neutralizing antibody, antagonistic peptide, or the selective kinase inhibitor NVP-ADW742 has in vitro activity against diverse tumor cell types (particularly multiple myeloma), even those resistant to conventional therapies, and triggers pleiotropic antiproliferative/proapoptotic molecular sequelae, delineated by global transcriptional and proteomic profiling. NVP-ADW742 monotherapy or its combination with cytotoxic chemotherapy had significant antitumor activity in an orthotopic xenograft MM model, providing in vivo proof of principle for therapeutic use of selective IGF-1R inhibitors in cancer. [Copyright &y& Elsevier]

Nonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH. The Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety. REGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis and ≥1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25 mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events. REGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes. ClinicalTrials.gov with the identifier NCT02548351. [ABSTRACT FROM AUTHOR]