Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia.

The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD+) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD+ AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD+ AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.

How National Health Insurance Coverage Policy Affected the Use of Trastuzumab and Rituximab in China: A Bicentric Retrospective Study.

Background: Cancer is a significant health concern and is China's leading cause of mortality. Targeted therapies, such as trastuzumab and rituximab, have enhanced clinical treatment efficacy. However, their high costs burden patients and healthcare systems considerably. Patient demographic factors further influence the utilization of these expensive drugs. On September 1, 2017, China implemented the National Health Insurance Coverage (NHIC) policy, necessitating additional real-world evidence to assess its impact on patients. Methods: Data on human epidermal growth factor receptor 2-positive breast cancer and CD20-positive non-Hodgkin B-cell lymphoma patients were gathered in Jiangsu Cancer Hospital and Fujian Cancer Hospital from September 2015 to August 2019, including demographic and clinical information. All eligible patients were divided into two groups. Univariate analysis and multivariable logistic regression were used to investigate the differences between subgroups. An interrupted time-series regression was used to examine the change in trastuzumab and rituximab utilization percentages. Results: Before and after the NHIC policy, utilization of trastuzumab increased from 61.13% to 75.10%, and the increase was statistically significant. Rituximab therapy increased statistically significantly from 64.79% to 74.88%. The key factor influencing trastuzumab and rituximab use was the NHIC policy. With policy implementation, medical insurance status, occupations, and cancer disease stage affected trastuzumab and rituximab use. Conclusion: The NHIC policy is essential to the utilization of trastuzumab and rituximab, and the patient's income level and repayment abilities continue to impact the use of innovative anti-cancer drugs. Appropriate steps, such as reducing the urban-rural gap and broadening medical insurance coverage, would enable more people to access novel anti-cancer drugs.

Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase.

Human dihydroorotate dehydrogenase (hDHODH) is a promising drug target for many diseases including autoimmune diseases, cancer, and viral infection. To develop more novel and potent hDHODH inhibitors, we screened our in-house library of old drugs. We found that tiratricol (3,3',5-triiodothyroacetic acid), a thyroid hormone metabolite, has potent hDHODH inhibitory activity (IC50 : 0.754 ± 0.126 µM), and its precursor tetrac (3,3',5,5'-tetraiodothyroacetic acid) also shows a certain inhibitory activity against hDHODH (IC50 : 11.960 ± 1.453 µM). Enzyme kinetic analysis shows that tiratricol and tetrac are noncompetitive inhibitors versus CoQ0 , which is different from the positive control A771726. ThermoFMN assay, molecular docking and site-directed mutagenesis all indicate that tiratricol and tetrac interact with more key residues of hDHODH than A771726, especially some hydrophobic residues in Subsite 1. In conclusion, our experiment results indicate a potential new use for the old drug, tiratricol, and provide a novel chemical scaffold for the design of hDHODH inhibitors.

wSDTNBI: a novel network-based inference method for virtual screening.

In recent years, the rapid development of network-based methods for the prediction of drug-target interactions (DTIs) provides an opportunity for the emergence of a new type of virtual screening (VS), namely, network-based VS. Herein, we reported a novel network-based inference method named wSDTNBI. Compared with previous network-based methods that use unweighted DTI networks, wSDTNBI uses weighted DTI networks whose edge weights are correlated with binding affinities. A two-pronged approach based on weighted DTI and drug-substructure association networks was employed to calculate prediction scores. To show the practical value of wSDTNBI, we performed network-based VS on retinoid-related orphan receptor γt (RORγt), and purchased 72 compounds for experimental validation. Seven of the purchased compounds were confirmed to be novel RORγt inverse agonists by in vitro experiments, including ursonic acid and oleanonic acid with IC50 values of 10 nM and 0.28 µM, respectively. Moreover, the direct contact between ursonic acid and RORγt was confirmed using the X-ray crystal structure, and in vivo experiments demonstrated that ursonic acid and oleanonic acid have therapeutic effects on multiple sclerosis. These results indicate that wSDTNBI might be a powerful tool for network-based VS in drug discovery.

The impact of policy on availability and price of low-price medicines in public healthcare institutions: A retrospective survey in Nanjing, China.

In an effort to promote rational drug pricing and relieve the pressure of drug shortages, the Chinese government implemented a low-price medicine (LPM) policy in July 2014, and abolished price regulations for most medications in June 2015. This study examines trends in the availability and pricing of LPMs since policy implementation. Data on price and availability of 752 LPMs during 2013-2017 were obtained from the Jiangsu Institute of Medicine Information. Availability was defined as the proportion of facilities in which a medicine was in inventory during each survey period. A price index was constructed based on purchasing prices in 40 public healthcare facilities, using a standard method developed by the International Labour Organization. Mean availability fluctuated slightly but held at low levels (<15%). Levels were conspicuously lower in primary hospitals than in secondary and tertiary hospitals. Our logistic regression model showed that the essential medicine designation was the main factor facilitating availability. The overall price index remained static before implementation of the policy, while there was a marked upward trend after implementation of the policy. Further efforts are needed to improve the pharmaceutical supply system, and simultaneously curb unreasonable inflation in medicine costs.

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor γ-t (RORγt) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual RORγt/DHODH inhibitors are expected not only to reduce RORγt-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit 1, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual RORγt/DHODH inhibitors. Compound 14d stands out with IC50 values of 0.110 µM for RORγt and of 0.297 µM for DHODH. With acceptable mouse pharmacokinetic profiles, 14d exhibited remarkable in vivo anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.

Impact of the National Health Insurance Coverage Policy on the Utilisation and Accessibility of Innovative Anti-cancer Medicines in China: An Interrupted Time-Series Study.

Objective: The study aimed to evaluate the impact of the National Health Insurance Coverage (NHIC) policy on the utilisation and accessibility of innovative anti-cancer medicines in Nanjing, China. Methods: We used the adjusted World Health Organisation and Health Action International methodology to calculate the price and availability of 15 innovative anti-cancer medicines included in the National Health Insurance drug list in 20 tertiary hospitals and six secondary hospitals in Nanjing before and after NHIC policy implementation. Interrupted time-series regression was used to analyse the changes in the utilisation of the study medicines. Results: The price reduction rates of innovative anti-cancer medicines ranged between 34 and 65%. The mean availability rate was 27.44% before policy implementation and increased to 47.33% after policy implementation. The utilisation of anti-cancer medicines suddenly increased with a slope of 33.19-2,628.39 when the policy was implemented. Moreover, the usage rate of bevacizumab, bortezomib, and apatinib significantly increased (p < 0.001, p = 0.009, and p < 0.001, respectively) after policy implementation. With regard to price reduction and medical insurance reimbursement, the medicines became more affordable after policy implementation (0.06-1.90 times the per capita annual disposable income for urban patients and 0.13-4.46 times the per capita annual disposable income for rural patients). Conclusion: The NHIC policy, which was released by the central government, effectively improved the utilisation and affordability of innovative anti-cancer medicines. However, the availability of innovative anti-cancer medicines in hospitals remained low and the utilisation of innovative anti-cancer medicines was affected by some factors, including the incidence of cancer, limitation of indications within the insurance program, and the rational use of innovative anti-cancer medicines. It is necessary to improve relevant supporting policies to promote the affordability of patients. The government should speed up the process of price negotiation to include more innovative anti-cancer medicines in the medical insurance coverage, consider including both medical examinations and adjuvant chemotherapy in the medical insurance, and increase investment in health care.

Paricalcitol versus Calcitriol + Cinacalcet for the Treatment of Secondary Hyperparathyroidism in Chronic Kidney Disease in China: A Cost-Effectiveness Analysis.

Background: Chronic Kidney Disease (CKD) is a global chronic disease with increasing prevalence in recent years, particularly CKD accompanied by Secondary Hyperparathyroidism (SHPT) leads to reduced quality of life, increased mortality, a considerable economic burden for patients and society. The aim of this study was to investigate the cost-effectiveness analysis of paricalcitol vs. calcitriol + cinacalcet for CKD patients with SHPT in China in 2020. Methods: A Markov model was conducted employing data derived from published literature, clinical trials, official sources, and tertiary public hospital data in China, based on a 10-year horizon from the perspective of the healthcare system. Calcitriol + Cinacalcet was used as the reference group. CKD stage 5 (CKD-5) dialysis patients suffering from SHPT were included in the study. Effectiveness was measured in quality-adjusted life years (QALYs). The discount rate (5%) was applied to costs and effectiveness. Sensitivity analysis was performed to confirm the robustness of the findings. Results: The base case analysis demonstrated that Patients treated with paricalcitol could gain an increase in utility (0.183 QALYs) and require fewer expenditures (6925.612 yuan). One-way sensitivity analysis was performed to showed that impact factors were the price of cinacalcet, the hospitalization costs of patients with paricalcitol and calcitriol, the costs and utilities of hemodialysis and the costs of calcitriol, the costs of paricalcitol regardless of period. Probabilistic simulation analysis displayed when willingness-to-pay was ¥217113, the probability that Paricalcitol was dominant is 96.20%. Conclusion: The results showed that paricalcitol administrated to treat patients diagnosed with Secondary hyperparathyroidism in Chronic Kidney Disease, compared to calcitriol and cinacalcet, might be dominant in China.

Availability, cost and affordability of selected antibiotics and antiviral medicines against infectious diseases from 2013 to 2019 in Nanjing, China.

OBJECTIVES: As economic globalisation develops in-depth, infectious diseases that occur in a country or region no longer remains a regional issue. Antibiotics and antiviral medicines are essential medicines for the therapy of infectious diseases. This study aims to evaluate their availability, cost and affordability of AaAMs against infectious diseases in 41 public hospitals from 2013 to 2019 in Nanjing, China. METHODS: Data on the availability and price of 17 antibiotics and 6 antiviral medicines in 41 public hospitals were obtained from the Jiangsu Institute of Medicine Information. We adopted the WHO/Health Action International method to measure the availability, cost and affordability of these medicines. RESULTS: The availability of selected medicines against infectious diseases was relatively low; the median availability of originator brands was near-zero and that of lowest-priced generics during the survey period less than 50%. The total availability of medicines was poor in primary hospitals as compared to secondary and tertiary hospitals. The median daily-defined dose cost of originator brands was expensive (range from 66.11 RMB to 107.83 RMB), whereas that of lowest price generics was fairly acceptable at < 8 RMB. The affordability of most surveyed medicines was reasonable, which showed significant improvement over time, but the daily cost of a few medicines for originator brands exceeded the average daily wage. CONCLUSIONS: In general, the affordability of medicines surveyed was acceptable, while the availability was too low. There should be a great concern for improving the reserve system of anti-infective medicines in healthcare institutions. Policy should focus on improving the availability of generic drugs in hospitals and encouraging preferentially prescribed.

The Effects of County Public Hospital Reform on the Consumption and Costs of Antibiotics: Evidence from a Quasinatural Experiment in Jiangsu, China.

BACKGROUND: Overuse of antibiotics is a major driver for rapid spread of antimicrobial resistance worldwide, particularly common in China. The close linkage between hospital revenue and sales of drugs has become the key incentive for overprescription of antibiotics. Since 2009, the Chinese government implemented a series of measures to cut off the link, including removing the markup of drugs, increasing financial subsidies, and adjusting charges for medical service. OBJECTIVE: To evaluate the impacts of county public hospital reform on the consumption and costs of procured antibiotics in Jiangsu province. METHODS: A quasiexperiment design was conducted in Jiangsu province where 99 county public hospitals implemented the reform successively in different periods. Of these, 37 county public hospitals implemented the reform since January 2013, which were regarded as the intervention group, and the remaining 62 hospitals were included in the control group. A difference-in-differences (DID) analysis with generalized linear regressions was used on the procurement records of antibiotics from January 2012 to December 2013. Modified Park test was used for family distribution and Box-Cox test for log link. Placebo tests were employed to test the common-trend hypothesis of two groups. RESULTS: For the intervention group, the average volume of procured restricted antibiotics and injectable antibiotics increased by 24.12% and 2.75% while the costs increased by 19.01% and 9.09%, respectively. The average costs per DDD of restricted and injectable antibiotics were much higher than unrestricted and oral antibiotics. The DID results showed that the reform had a positive impact on the average volume (p = 0.005) and costs (p = 0.001) of nonrestricted antibiotics. In addition, the implementation of the reform was associated with a reduction in volume (p = 0.031) and costs (p = 0.043) of procured oral antibiotics. The reform also contributed to an increase in average costs per DDD of total antibiotics (p = 0.049). CONCLUSIONS: The reform is effective in reducing the consumption and costs of unrestricted and oral antibiotics, but it has failed to reduce the consumption and costs of expensive restricted and injectable antibiotics, leading to increased burden of diseases. It is critical that the health policy initiatives can deincentivize overuse of antibiotics at both hospital and individual physician's levels. The reform should enforce government financial support, improve hospital governance, optimize performance evaluation, and establish specialized management approach for antibiotic use.

Mitochondrial Fission Is Required for Blue Light-Induced Apoptosis and Mitophagy in Retinal Neuronal R28 Cells.

Light emitting diodes (LEDs) are widely used to provide illumination due to their low energy requirements and high brightness. However, the LED spectrum contains an intense blue light component which is phototoxic to the retina. Recently, it has been reported that blue light may directly impinge on mitochondrial function in retinal ganglion cells (RGCs). Mitochondria are high dynamic organelles that undergo frequent fission and fusion events. The aim of our study was to elucidate the role of mitochondrial dynamics in blue light-induced damage in retinal neuronal R28 cells. We found that exposure to blue light (450 nm, 1000 lx) for up to 12 h significantly up-regulated the expression of mitochondrial fission protein Drp1, while down-regulating the expression of mitochondrial fusion protein Mfn2 in cells. Mitochondrial fission was simultaneously stimulated by blue light irradiation. In addition, exposure to blue light increased the production of reactive oxygen species (ROS), disrupted mitochondrial membrane potential (MMP), and induced apoptosis in R28 cells. Notably, Drp1 inhibitor Mdivi-1 and Drp1 RNAi not only attenuated blue light-induced mitochondrial fission, but also alleviated blue light-induced ROS production, MMP disruption and apoptosis in cells. Compared with Mdivi-1 and Drp1 RNAi, the antioxidant N-acetyl-L-cysteine (NAC) only slightly inhibited mitochondrial fission, while significantly alleviating apoptosis after blue light exposure. Moreover, we examined markers for mitophagy, which is responsible for the clearance of dysfunctional mitochondria. It was found that blue light stimulated the conversion of LC3B-I to LC3B-II as well as the expression of PINK1 in R28 cells. Mdivi-1 or Drp1 RNAi efficiently inhibited the blue light-induced expression of PINK1 and co-localization of LC3 with mitochondria. Thus, our data suggest that mitochondrial fission is required for blue light-induced mitochondrial dysfunction and apoptosis in RGCs.

Effect of same-temperature GaN cap layer on the InGaN/GaN multiquantum well of green light-emitting diode on silicon substrate.

GaN green LED was grown on Si (111) substrate by MOCVD. To enhance the quality of InGaN/GaN MQWs, same-temperature (ST) GaN protection layers with different thickness of 8 Å, 15 Å, and 30 Å were induced after the InGaN quantum wells (QWs) layer. Results show that a relative thicker cap layer is benefit to get InGaN QWs with higher In percent at fixed well temperature and obtain better QW/QB interface. As the cap thickness increases, the indium distribution becomes homogeneous as verified by fluorescence microscope (FLM). The interface of MQWs turns to be abrupt from XRD analysis. The intensity of photoluminescence (PL) spectrum is increased and the FWHM becomes narrow.