Clinical Pharmacology & Therapeutics (2003) 73, P29–P29; doi:

Background/Aims TPMT*3A, the most common TPMT variant allozyme in Caucasians, has 2 alterations in amino acid sequence, resulting in striking decreases in TPMT protein levels as a result of rapid degradation. “Protein quality control” involves a dynamic balance among protein folding, degradation and aggregation with aggresome formation. We set out to test the hypothesis that, the presence of the proteasome inhibitor MG132, TPMT*3A can form aggresomes in cultured cells. Methods/Results TPMT*3A was highly ubiquinated and associated with hsp90 after transient expression in COS‐1 cells. In the presence of MG132, aggresomes formed in cells transfected with TPMT*3A, and ubiquinated TPMT*3A redistributed from the cytosol into the pellet ‐ compatible with aggresome formation. The aggresomes contained vimentin, dynein, γ‐tubulin, ubiquitin, hsp70, hsp90 and the deacetylating enzyme HDAC6 that co‐localized with TPMT*3A. Aggresome formation could be blocked by the microtubule destabilizing agent, vinblastine. Treatment with the HDAC inhibitor scriptaid inhibited aggresome formation and resulted in TPMT*3A microaggregate formation. Conclusions These results suggest that aggresome formation is one mechanism by which nonsynonymous cSNPs can alter function for proteins of pharmacogenetic importance such as TPMT. Clinical Pharmacology & Therapeutics (2005) 77, P95–P95; doi:

Clinical Pharmacology & Therapeutics (2003) 73, P77–P77; doi:

Objectives: Coronary atherosclerotic heart (CAD) is the world's biggest killers during the past decade, and has become a global public health problem that seriously threatens human health. However, annual economic burden of CAD in China is not well studied. This study aims to evaluate the annual economic burden including direct and indirect cost of CAD from societal perspective in China. Methods: A disease burden model was developed to calculate the number of treated CAD patients stratified by different subtypes and the economic burden on CAD patients in China. The data for model inputs were retrieved from literature review, real word data from sites and in-depth interviews with clinical experts. Key clinical expert confirmed the validity of the data. Two -step model method and human capital method were used to assess the economic burden of CAD. Results: Total 14.60 million CAD patients received treatment in 2018, including 12.34 million out-patients and 3.73 million inpatients. The average total annual cost was CNY 228.59 billion (15662 per treated patient). The majority (68.5%) is the direct medical cost, followed by the indirect cost accounting for 22%. In terms of direct medical costs related to hospital visits, outpatient's cost was lower than inpatient's (CNY 48.30 vs CNY 82.10 billion), and the burden of patients with myocardial infarction (MI) is the highest and the patients with stable angina pectoris had lightest burden (CNY 68.28 and 13.24 billion). Outpatient's cost was higher than inpatient's in terms of indirect cost (CNY 40.36 vs CNY10.61 billion), and the patients with MI and unstable angina had higher burden. Conclusions: The CAD was a chronic disease with a large number of patients, bringing greater economic risks to patients and society. Chronic disease management and lifestyle intervention need to be strengthened to reduce the incidence of CAD.

only, eight had received ipilimumab, two had received pembrolizumab, and two had received atezolizumab. Eighteen patients had received more than 1 ICI agent, and eleven of those patients had received two agents simultaneously. There were a total of 84 hypofractionated RT courses, 24 conventional RT courses, 19 brain radiosurgeries, and 1 brachytherapy treatment. The median duration of the ICI treatment was 3.43 months (mean 4.97 months). The median follow-up period was 6.5 months. Treatment-related adverse events of different grades were reported in 56 patients (90%). The most common adverse events were fatigue (53%), nausea and vomiting (27%), and rash/pruritus (23%). Grade 3 treatmentrelated adverse events occurred in 16% of patients. The most common grade 3 event was dyspnea/pneumonitis (4 patients, 6%) followed by various hematologic toxicities and fatigue (2 patients for each, 3%). Other grade 3 toxicities included anti-phospholipid syndrome, colitis, nausea and vomiting, hyperglycemia, elevated liver enzymes, and diarrhea. No treatment-related grade 4 or 5 toxicities were observed. The most common reason for treatment discontinuation was disease progression. Treatmentrelated adverse events leading to treatment discontinuation occurred in 8 patients (13%). At the time of the last follow-up, 16 out of 62 patients continued to receive ICI, 30 patients were alive, 27 patients had died, and 5 has been lost to follow-up. The most common cause of death was disease progression. Conclusion: The combination of ICI with RT is well tolerated without any apparent increase in grade 3 irAEs reported with ICI treatment alone. The prospective evaluation of the safety and efficacy of the regimen is required before its routine application to the clinic.