Dual-Prodrug-Based Hyaluronic Acid Nanoplatform Provides Cascade-Boosted Drug Delivery for Oxidative Stress-Enhanced Chemotherapy.

Insufficient drug accumulation in tumors severely limits the antitumor efficiency of hyaluronic acid (HA) nanomedicine in solid tumors due to superficial penetration depth, low cell uptake, and nonspecific drug release. Hence, we constructed a dual NO prodrug (alkynyl-JSK) and doxorubicin prodrug (cis-DOX)-conjugated HA nanoparticle (HA-DOX-JSK NPs), which achieved cascade-boosted drug delivery efficiency based on a relay strategy of NO-mediated deep tumor penetration─HA target CD44 tumor cell uptake─tumor microenvironment (TME)-responsive drug release. The nanoparticle demonstrated sustained and locoregionally GSH/GST-triggered NO release and GSH/pH-responsive DOX release in the tumor. The released NO first mediated collagen degradation, causing deep tumor penetration of nanoparticles in the dense extracellular matrix. Immediately, HA was relayed to enhance CD44-targeted tumor cell uptake, and then, the nanoparticles were finally triggered by specific TME to release DOX and NO in the deep tumor. Relying on the relayed delivery strategy, a significant improvement of DOX accumulation in tumors was realized. Moreover, NO depleted GSH-induced intracellular reactive oxygen species, enhancing DOX chemotherapy. Based on this strategy, the tumor inhibition rate in breast cancer was up to 87.8% in vivo. The relay drug-delivery HA system would greatly cascade-boost drug accumulation in deep tumors for efficient solid tumor therapy.

Near Infrared-Triggered Nitric Oxide-Release Nanovesicles with Mild-Photothermal Antibacterial and Immunomodulation for Healing MRSA-Infected Diabetic Wounds.

Bacterial infection-induced excessive inflammation is a major obstacle in diabetic wound healing. Nitric oxide (NO) exhibits significant antibacterial activity but is extremely deficient in diabetes. Hence, a near-infrared (NIR)-triggered NO release system is constructed through codelivery of polyarginine (PArg) and gold nanorods (Au) in an NIR-activatable methylene blue (MB) polypeptide-assembled nanovesicle (Au/PEL-PBA-MB/PArg). Upon NIR irradiation, the quenched MB in the nanovesicles is photoactivated to generate more reactive oxygen species (ROS) to oxidize PArg and release NO in an on-demand controlled manner. With the specific bacterial capture of phenylboronic acid (PBA), NO elevated membrane permeability and boosted bacterial vulnerability in the photothermal therapy (PTT) of the Au nanorods, which is displayed by superior mild PTT antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) at temperatures < 49.7 °C in vitro. Moreover, in vivo, the antibacterial nanovesicles greatly suppressed the burst of MRSA-induced excessive inflammation, NO relayed immunomodulated macrophage polarization from M1 to M2, and the excessive inflammatory phase is successfully transferred to the repair phase. In cooperation with angiogenesis by NO, tissue regeneration is accelerated in MRSA-infected diabetic wounds. Therefore, nanoplatform has considerable potential for accelerating the healing of infected diabetic wounds.

Toward Reliable Symptom Coding in Electronic Health Records for Symptom Assessment and Research: Identification and Categorization of International Classification of Diseases, Ninth Revision, Clinical Modification Symptom Codes.

To date, symptom documentation has mostly relied on clinical notes in electronic health records or patient-reported outcomes using disease-specific symptom inventories. To provide a common and precise language for symptom recording, assessment, and research, a comprehensive list of symptom codes is needed. The International Classification of Diseases, Ninth Revision or its clinical modification ( International Classification of Diseases, Ninth Revision, Clinical Modification ) has a range of codes designated for symptoms, but it does not contain codes for all possible symptoms, and not all codes in that range are symptom related. This study aimed to identify and categorize the first list of International Classification of Diseases, Ninth Revision, Clinical Modification symptom codes for a general population and demonstrate their use to characterize symptoms of patients with type 2 diabetes mellitus in the Cerner database. A list of potential symptom codes was automatically extracted from the Unified Medical Language System Metathesaurus. Two clinical experts in symptom science and diabetes manually reviewed this list to identify and categorize codes as symptoms. A total of 1888 International Classification of Diseases, Ninth Revision, Clinical Modification symptom codes were identified and categorized into 65 categories. The symptom characterization using the newly obtained symptom codes and categories was found to be more reasonable than that using the previous symptom codes and categories on the same Cerner diabetes cohort.

Association Between Adherence to 24-Hour Movement Guidelines and Noncommunicable Disease Risk in Chinese Adults: Prospective Cohort Study.

BACKGROUND: The increasing annual global deaths are attributable to noncommunicable chronic diseases (NCDs). Adhering to healthy lifestyle behaviors is associated with lower NCD risk, particularly among individuals with ample movement, enough sleep, and reduced sedentariness. Nevertheless, there are only few prospective assessments on the association of interactions between daily activities with NCD prevention, while the associations between adhering to Canadian 24-Hour Movement Guidelines (24HGs) for adults and NCD risks are still unknown. Compared to the general population, obese and overweight populations are at a higher risk of developing NCDs. Currently, it is unclear whether the health benefits of adhering to 24HGs differ between the general population and the obese population. OBJECTIVE: This study explores prospective associations between adherence to 24HGs and NCD risks by weight status among overweight and obese adults in China. METHODS: This decadal study consists of 9227 adults aged 35 years and older without any major NCDs at enrolment in the China Health and Nutrition Survey (2004-2011) and followed up until 2015. The exposure of interest was the overall score of compliance with 24HGs measured by participants' self-report, wherein 1 point was assigned for compliance to each component, resulting in an aggregated score ranging from 0 to 3. The primary outcome was the first occurrence of major NCDs (high blood pressure, stroke, diabetes, cancer, and acute myocardial infarction). Log-binomial regression models were used to evaluate the associations. RESULTS: : Overall, 4315 males and 4912 females, with 25,175 person-years of follow-up, were included in our analyses. The average baseline age was 50.21 (SD 11.04) years. Among the overweight and obese groups, those adhering to 1 (risk ratio [RR] 0.37, 95% CI 0.19-0.74; P=.004), 2 (RR 0.37, 95% CI 0.19-0.72; P=.003), and 3 (RR 0.32, 95% CI 0.14-0.73; P=.006) recommendations of 24HGs had a significantly lower NCD risk than those not adhering to any of the activity guidelines. Among the normal or underweight groups, those adhering to 1 (RR 0.49, 95% CI 0.27-0.96; P=.03) and 3 (RR 0.40, 95% CI 0.17-0.94; P=.03) components had a significantly lower NCD risk than those not adhering to any of the activity guidelines. CONCLUSIONS: In this prospective study, we found that active adherence to recommendations of 24HGs was associated with lower risks of NCDs, especially among overweight and obese participants. Additionally, overweight and obese individuals who met at least 1 component of 24HGs were at a significantly lower risk for NCDs, but this protective effect was not found among individuals in the normal and underweight groups. Individuals with excess body weight who tend to be more susceptible to health risks may gain greater health benefits than the general population by adhering to the recommendations of 24HGs.

The Disease and Economic Burdens of Esophageal Cancer in China from 2013 to 2030: Dynamic Cohort Modeling Study.

BACKGROUND: Esophageal cancer (EC) is the sixth leading cause of tumor-related deaths worldwide. Estimates of the EC burden are necessary and could offer evidence-based suggestions for local cancer control. OBJECTIVE: The aim of this study was to predict the disease burden of EC in China through the estimation of disability-adjusted life years (DALYs) and direct medical expenditure by sex from 2013 to 2030. METHODS: A dynamic cohort Markov model was developed to simulate EC prevalence, DALYs, and direct medical expenditure by sex. Input data were collected from the China Statistical Yearbooks, Statistical Report of China Children's Development, World Population Prospects 2019, and published papers. The JoinPoint Regression Program was used to calculate the average annual percentage change (AAPC) of DALY rates, whereas the average annual growth rate (AAGR) was applied to analyze the changing direct medical expenditure trend over time. RESULTS: From 2013 to 2030, the predicted EC prevalence is projected to increase from 61.0 to 64.5 per 100,000 people, with annual EC cases increasing by 11.5% (from 835,600 to 931,800). The DALYs will increase by 21.3% (from 30,034,000 to 36,444,000), and the years of life lost (YLL) will account for over 90% of the DALYs. The DALY rates per 100,000 people will increase from 219.2 to 252.3; however, there was a difference between sexes, with an increase from 302.9 to 384.3 in males and a decline from 131.2 to 115.9 in females. The AAPC was 0.8% (95% CI 0.8% to 0.9%), 1.4% (95% CI 1.3% to 1.5%), and -0.7% (95% CI -0.8% to -0.7%) for both sexes, males, and females, respectively. The direct medical expenditure will increase by 128.7% (from US $33.4 to US $76.4 billion), with an AAGR of 5.0%. The direct medical expenditure is 2-3 times higher in males than in females. CONCLUSIONS: EC still causes severe disease and economic burdens. YLL are responsible for the majority of DALYs, which highlights an urgent need to establish a beneficial policy to reduce the EC burden.

Cost-utility analysis of imrecoxib compared with celecoxib for patients with osteoarthritis.

BACKGROUND: The objective of this study is to compare the long-term cost-utility of imrecoxib and celecoxib for patients with osteoarthritis (OA) from the perspective of the Chinese healthcare system. METHODS: An economic model was built based on the model from the National Institute for Health and Care Excellence (NICE). The simulation was carried out initially for 100 cycles of 3 months each, starting with 10,000 patients. A discount rate of 5% was applied both for cost and utility. Quality-adjusted life years (QALYs) were adopted as the utility indicator, and real-world data from the hospital information systems of 170 hospitals was collected to indicate cost. The relative incidence rates of adverse events (AEs) with imrecoxib and celecoxib were collected from randomized controlled trials. Sensitivity analysis was performed to validate the robustness of the model. RESULTS: In the base case analysis (6-month treatment duration, 55 years old and above), imrecoxib was the more cost-effective option compared to celecoxib, with an incremental cost-effectiveness ratio (ICER) of $3,041.14. This finding remained unchanged after varying the treatment duration and the age of the patients. The main drivers of the results were the relative incidence of myocardial infarction (MI), the cost of imrecoxib, and the utility of OA patients without any AEs. Probability sensitivity analysis (PSA) showed that there was a 59.02% probability of imrecoxib as the more cost-effective option, with a threshold of $30,000. CONCLUSIONS: Although there were uncertainties, imrecoxib was the more cost-effective option compared to celecoxib, with a definite possibility. Due to the limitations of the original model and this study, the results of this study should be adopted with caution.

Roles of cell fusion between mesenchymal stromal/stem cells and malignant cells in tumor growth and metastasis.

Invasion and metastasis are the basic characteristics and important markers of malignant tumors, which are also the main cause of death in cancer patients. Epithelial-mesenchymal transition (EMT) is recognized as the first step of tumor invasion and metastasis. Many studies have demonstrated that cell fusion is a common phenomenon and plays a critical role in cancer development and progression. At present, cancer stem cell fusion has been considered as a new mechanism of cancer metastasis. Mesenchymal stromal/stem cell (MSC) is a kind of adult stem cells with high self-renewal ability and multidifferentiation potential, which is used as a very promising fusogenic candidate in the tumor microenvironment and has a crucial role in cancer progression. Many research results have shown that MSCs are involved in the regulation of tumor growth and metastasis through cell fusion. However, the role of cell fusion between MSCs and malignant cells in tumor growth and metastasis is still controversial. Several studies have demonstrated that MSCs can enhance malignant characteristics, promoting tumor growth and metastasis by fusing with malignant cells, while other conflicting reports believe that MSCs can reduce tumorigenicity upon fusion with malignant cells. In this review, we summarize the recent research on cell fusion events between MSCs and malignant cells in tumor growth and metastasis. The elucidation of the molecular mechanisms between MSC fusion and tumor metastasis may provide an effective strategy for tumor biotherapy.

Modeling the Cost-effectiveness of Esophageal Cancer Screening in China.

BACKGROUND: This study aimed to examine the cost-effectiveness of one-time standard endoscopic screening with Lugol's iodine staining for esophageal cancer (EC) in China. METHODS: A Markov decision analysis model with eleven states was built. Individuals aged 40 to 69 years were classified into six age groups in five-year intervals. Three different strategies were adopted for each cohort: (1) no screening; (2) one-time endoscopic screening with Lugol's iodine staining with an annual follow-up for low-grade intraepithelial neoplasia (LGIN); and (3) one-time endoscopic screening with Lugol's iodine staining without follow-up. Quality-adjusted life-years (QALYs) indicated the effectiveness of the model. The incremental cost-effectiveness ratio (ICER) was used as the evaluation indicator. Sensitivity analysis was performed to assess the robustness of the model. RESULTS: One-time screening with follow-up was the undominated strategy for individuals aged 40-44 and 45-49 years, which saved USD 10,942.57 and USD 6611.73 per QALY gained compared to nonscreening strategy. For those aged 50-69 years, the nonscreening scenarios were undominated. One-time screening without follow-up was the extended dominated strategy. Compared to screening strategies without follow-up, all the screening strategies with follow-up were more cost-effective, with the ICER increasing from 299.57 USD/QALY for individuals aged 40-44 years to 1617.72 USD/QALY for individuals aged 65-69 years. Probabilistic sensitivity analysis (PSA) supported the results of the base case analysis. CONCLUSIONS: One-time EC screening with follow-up targeting individuals aged 40-49 years was the most cost-effective strategy.

The contribution ratio of various characteristic tea compounds in antioxidant capacity by DPPH assay.

Tea is a worldwide health beneficial beverage for its antioxidant ability. 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay is a common method to measure the antioxidant capacity of tea compounds, yet the contribution ratio of various characteristic tea compounds is still unclear. high-performance liquid chromatography (HPLC) was used to examine the content of polyphenol compounds in 24 tea samples from four tea categories (green tea, white tea, oolong tea, and black tea). Based on the results of DPPH and HPLC, contribution ratio of each tea compound was analyzed by the Pearson correlation analysis and the partial least squares regression (PLSR). The Pearson correlation analysis showed that the order of correlation between the area of 13 peaks and the antioxidant ability of tea samples was x8 > x6 > x3 > x13 > x10 > x7 > x2 > x5 > x11 > x9 > x4 > x12 > x1; the regression equation fit by PLSR was Y = 47.258 - 0.760x1 + 0.287x2 - 1.484x3 - 0.569x4 + 0.674x5 + 2.257x6 + 1.698x7 + 1.389x8 - 0.188x9 + 0.467x10 + 0.297x11 + 1.314x12 + 0.963x13. We identified nine common peaks by reference standard substances: the x3 was gallic acid (GA), x4 was theobromine, x5 was catechuic acid (CA), x6 was epigallocatechin (EGC), x8 was epigallocatechin gallate (EGCG), x9 was caffeine, x10 was epicatechin (EC), x12 was epicatechin gallate (ECG), and x13 was gallocatechin gallate (GCG). Based on the study of spectrum-effect correlation, we obtain a better understanding of the antioxidant activity of complex tea polyphenols component. PRACTICAL APPLICATIONS: Identify the contribution of specific chemical compound to antioxidant activity by the coefficients in PLSR equation and provide a deeper insight into the joint effect of multiple ingredients of tea. Further, we can infer the DPPH free radical scavenging ability of a new kind of tea by the PLSR equation without chemical detection.

Potential gains in health-adjusted life expectancy from reducing four main non-communicable diseases among Chinese elderly.

BACKGROUND: To estimate the potential gains in health-adjusted life expectancy (HALE) after hypothetical elimination of four non-communicable diseases (NCDs) among Chinese elderly from 1990 to 2016, including cardiovascular diseases (CVD), cancers, chronic respiratory diseases (CRD) and diabetes mellitus (DM). METHODS: Based on data from Global Burden of Disease 2016, we generated life table by gender using Sullivan method to calculate HALE. Disease-deleted method was used to calculate cause-elimination HALE, after hypothetical elimination of specific diseases. RESULTS: From 1990 to 2016, HALE increased for all age groups. After hypothetic eliminating the four main NCDs, potential gain in HALE by CVD, DM and cancers increased while by CRD decreased from 1990 to 2016 for both genders. Among four main NCDs, potential gain in HALE after eliminating CVD was largest and increased most for both genders. Although elimination of DM led to the smallest gain in HALE, the increasing speed of gain in HALE by DM was faster than that by CVD and cancers from 1990 to 2016. CONCLUSIONS: This study highlights the potential gains in HALE of NCDs among Chinese elderly from 1990 to 2016. HALE of Chinese elderly could further increase from the reduction of NCDs. Control measures and targeted prevention should be carried out.

The novel arsenical darinaparsin is transported by cystine importing systems.

Darinaparsin (Dar; ZIO-101; S-dimethylarsino-glutathione) is a promising novel organic arsenical currently undergoing clinical studies in various malignancies. Dar consists of dimethylarsenic conjugated to glutathione (GSH). Dar induces more intracellular arsenic accumulation and more cell death than the FDA-approved arsenic trioxide (ATO) in vitro, but exhibits less systemic toxicity. Here, we propose a mechanism for Dar import that might explain these characteristics. Structural analysis of Dar suggests a putative breakdown product: dimethylarsino-cysteine (DMAC). We show that DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, cell cycle arrest, and cell death. We found that inhibition of γ-glutamyl-transpeptidase (γ-GT) protects human acute promyelocytic leukemia cells (NB4) from Dar, but not from DMAC, suggesting a role for γ-GT in the processing of Dar. Overall, our data support a model where Dar, a GSH S-conjugate, is processed at the cell surface by γ-GT, leading to formation of DMAC, which is imported via xCT, xAG, or potentially other cystine/cysteine importing systems. Further, we propose that Dar induces its own import via increased xCT expression. These mechanisms may explain the enhanced toxicity of Dar toward cancer cells compared with ATO.

Facile dimethylarsenic exchange and pyramidal inversion in its cysteine and glutathione adducts.

Rapid thiolate exchange of dimethylarsonium, Me2As(+), is observed between two different thiolate species in solution. NMR is used to characterize the equilibrium constants for interthiol transfer as well the rapid intra molecular conformational dynamics which leads to the coalescence of diastereotopic methyl resonances. These rapid exchange kinetics have important consequences of arsenic's toxicity and pharmacology.