Design, Synthesis, and Evaluation of Glucose Transporter Inhibitor-SN38 Conjugates for Targeting Colorectal Cancer.

Irinotecan (1), a prodrug of SN38 (2) approved by the US Food and Drug Administration for treating colorectal cancer, lacks specificity and causes many side effects. To increase the selectivity and therapeutic efficacy of this drug, we designed and synthesized conjugates of SN38 and glucose transporter inhibitors (phlorizin (5) or phloretin (6)), which could be hydrolyzed by glutathione or cathepsin to release SN38 in the tumor microenvironment, as a proof of concept. These conjugates (8, 9, and 10) displayed better antitumor efficacy with lower systemic exposure to SN38 in an orthotopic colorectal cancer mouse model compared with irinotecan at the same dosage. Further, no major adverse effects of the conjugates were observed during treatment. Biodistribution studies showed that conjugate 10 could induce higher concentrations of free SN38 in tumor tissues than irinotecan at the same dosage. Thus, the developed conjugates exhibit potential for treating colorectal cancer.

Evaluating the comparative efficiency of medical centers in Taiwan: a dynamic data envelopment analysis application.

BACKGROUND: People in Taiwan enjoy comprehensive National Health Insurance coverage. However, under the global budget constraint, hospitals encounter enormous challenges. This study was designed to examine Taiwan medical centers' efficiency and factors that influence it. METHODS: We obtained data from open sources of government routine publications and hospitals disclosed by law to the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan. The dynamic data envelopment analysis (DDEA) model was adopted to estimate all medical centers' efficiencies during 2015-2018. Beta regression models were used to model the efficiency level obtained from the DDEA model. We applied an input-oriented approach under both the constant returns-to-scale (CRS) and variable returns-to-scale (VRS) assumptions to estimate efficiency. RESULTS: The findings indicated that 68.4% (13 of 19) of medical centers were inefficient according to scale efficiency. The mean efficiency scores of all medical centers during 2015-2018 under the CRS, VRS, and Scale were 0.85, 0.930, and 0.95,respectively. Regression results showed that an increase in the population less than 14 years of age, assets, nurse-patient ratio and bed occupancy rate could increase medical centers' efficiency. The rate of emergency return within 3-day and patient self-pay revenues were associated significantly with reduced hospital efficiency (p < 0.05). The result also showed that the foundation owns medical center has the highest efficiency than other ownership hospitals. CONCLUSIONS: The study results provide information for hospital managers to consider ways they could adjust available resources to achieve high efficiency.

Evaluating the Operational Efficiency and Quality of Tertiary Hospitals in Taiwan: The Application of the EBITDA Indicator to the DEA Method and TOBIT Regression.

This study estimates the efficiency of 19 tertiary hospitals in Taiwan using a two-stage analysis of Data Envelopment Analysis (DEA) and TOBIT regression. It is a retrospective panel-data study and includes all the tertiary hospitals in Taiwan. The data were sourced from open information hospitals legally required to disclose to the National Health Insurance (NHI) Administration, Ministry of Health and Welfare. The variables, including five inputs (total hospital beds, total physicians, gross equipment, fixed assets net value, the rate of emergency transfer in-patient stay over 48 h) and six outputs (surplus or deficit of appropriation, length of stay, the total relative value units [RVUs] for outpatient services, total RVUs for inpatient services, self-pay income, modified EBITDA) were adopted into the Charnes, Cooper and Rhodes (CCR) and Banker, Charnes and Cooper (BCC) model. In the CCR model, the technical efficiency (TE) from 2015-2018 increases annually, and the average efficiency of all tertiary hospitals is 96.0%. In the BCC model, the highest pure technical efficiency (PTE) was in 2018 and the average efficiency of all medical centers is 99.1%. The average scale efficiency of all medical centers was 96.8% in the BBC model, meaning investment can be reduced by 3.2% and the current production level can be maintained with a fixed return to scale. Correlation coefficient analysis shows that all variables are correlated positively; the highest was the number of beds and the number of days in hospital (r = 0.988). The results show that TE in the CCR model was similar to PTE in the BCC model in four years. The difference analysis shows that more hospitals must improve regarding surplus or deficit of appropriation, modified EBITDA, and self-pay income. TOBIT regression reveals that the higher the bed-occupancy rate and turnover rate of fixed assets, the higher the TE; and the higher number of hospital beds per 100,000 people and turnover rate of fixed assets, the higher the PTE. DEA and TOBIT regression are used to analyze the other factors that affect medical center efficiency, and different categories of hospitals are chosen to assess whether different years or different types of medical centers affect operational performance. This study provides reference values for the improvable directions of relevant large hospitals' inefficiency decision-making units through reference group analysis and slack variable analysis.

Further Insights on Structural Modifications of Muramyl Dipeptides to Study the Human NOD2 Stimulating Activity.

A series of muramyl dipeptide (MDP) analogues with structural modifications at the C4 position of MurNAc and on the d-iso-glutamine (isoGln) residue of the peptide part were synthesized. The C4-diversification of MurNAc was conveniently achieved by using CuAAC click strategy to conjugate an azido muramyl dipeptide precursor with structurally diverse alkynes. d-Glutamic acid (Glu), replaced with isoGln, was applied for the structural diversity through esterification or amidation of the carboxylic acid. In total, 26 MDP analogues were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, MDP derivatives with an ester moiety are found to be more potent than reference compound MDP itself or MDP analogues containing an amide moiety. Among the varied lengths of the alkyl chain in ester derivatives, the MDP analogue bearing the d-glutamate dodecyl (C12) ester moiety showed the best NOD2 stimulation potency.