Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer.

OBJECTIVES: Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults. MATERIALS AND METHODS: This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs. RESULTS: Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs. CONCLUSION: Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.

Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity.

Importance: Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective: To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, Setting, and Participants: This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures: Ibrutinib treatment for cancer control. Main Outcomes and Measures: The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and Relevance: In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2.

BACKGROUND: Targeting helper T cells, especially Th17 cells, has become a plausible therapy for many autoimmune diseases. METHODS: Using an in vitro culture system, we screened an epigenetics compound library for inhibitors of IFN-γ and IL-17 expression in murine Th1 and Th17 cultures. FINDINGS: This identified IOX1 as an effective suppressor of IL-17 expression in both murine and human CD4+ T cells. Furthermore, we found that IOX1 suppresses Il17a expression directly by targeting TET2 activity on its promoter in Th17 cells. Using established pre-clinical models of intraocular inflammation, treatment with IOX1 in vivo reduced the migration/infiltration of Th17 cells into the site of inflammation and tissue damage. INTERPRETATION: These results provide evidence of the strong potential for IOX1 as a viable therapy for inflammatory diseases, in particular of the eye. FUNDING: This study was supported by the National Key Research and Development Program of China 2021YFA1101200 (2021YFA1101204) to LW and XW; the National Natural Science Foundation of China 81900844 to XH and 82171041 to LW; the China Postdoctoral Science Foundation 2021M700776 and the Scientific Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine 20221373 to YZ; and the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, UK (DAC, LPS, PJPL, MS, ADD and RWJL). The views expressed are those of the authors and not necessarily those of the NIHR or the UK's Department of Health and Social Care.

Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC, accounting for 90% of primary liver cancer) was the sixth most common cancer in the world and the third leading cause of cancer death in 2020. The number of new HCC patients in China accounted for nearly half of that in the world. HCC was of occult and complex onset, with poor prognosis. Clinically, at least 15% of patients with HCC had strong side effects of interventional therapy (IT) and have poor sensitivity to chemotherapy and targeted therapy. Traditional Chinese medicine (TCM), as a multi-target adjuvant therapy, had been shown to play an active anti-tumor role in many previous studies. This review systematically summarized the role of TCM combined with clinically commonly used drugs for the treatment of HCC (including mitomycin C, cyclophosphamide, doxorubicin, 5-fluorouracil, sorafenib, etc.) in the past basic research, and summarized the efficacy of TCM combined with surgery, IT and conventional therapy (CT) in clinical research. It was found that TCM, as an adjuvant treatment, played many roles in the treatment of HCC, including enhancing the tumor inhibition, reducing toxic and side effects, improving chemosensitivity and prolonging survival time of patients. This review summarized the advantages of integrated traditional Chinese and modern medicine in the treatment of HCC and provides a theoretical basis for clinical research.

Mesoscale evaluation of oil submerging and floating processes during marine oil spill response: Effects of dispersant on submerging stability and the associated mechanism.

The migration of oil spills in marine environment is still not clear, especially the key processes of submerging and floating, which is an important concern for effective disposal of oil spills. In mesoscale wave tank (32 m × 0.8 m × 2 m), this study has evaluated the characteristics of oil submergence based on oil concentration and oil droplet size. The concept of effective submergence is put forward for the first time, utilized to analyze the effects of dispersant on submerging stability and associated mechanisms. The results indicate dispersants increase submerged oil concentration and promote homogeneous distribution and vertical penetration. Of concern is that dispersants increase the proportion of small oil droplets (2.5-70 µm), prolonging the residence time of oil droplets in water by delaying the floating process. Dispersants sharply reduce oil droplets size (VMD<44 µm) thus decreasing the coalescence probability. These contribute to better submerging stability. By contrast, the submerged oil, formed as oil patches, oil streamers, and large oil droplets (VMD>170 µm) when without dispersant, will float and reattach to oil slicks more quickly due to their large volume. These findings help to clarify spilled oil behaviors and provide a new idea for the research on oil submergence.

Species composition and overall diversity are significantly correlated between the tongue coating and gastric fluid microbiomes in gastritis patients.

BACKGROUND: In traditional Chinese medicine, it is believed that the "tongue coating is produced by fumigation of stomach gas", and that tongue coating can reflect the health status of humans, especially stomach health. Therefore, studying the relationship between the microbiome of the tongue coating and the gastric fluid is of great significance for understanding the biological basis of tongue diagnosis. METHODS: This paper detected the microbiomes of the tongue coating and the gastric fluid in 35 gastritis patients using metagenomic sequencing technology, systematically constructed the microbial atlas of tongue coating and gastric juice, and first described the similar characteristics between the two sites. RESULTS: There was a significant correlation between tongue coating and gastric juice in terms of microbial species composition and overall diversity. In terms of species composition, it was found that the two sites were dominated by five phyla, namely, Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria and Proteobacteria, and that most of the gastric microbial species could be detected from the patient's own tongue coating. In terms of overall diversity, a significant correlation was found between the alpha diversity of the tongue coating microbiome and the gastric juice microbiome. Furthermore, in terms of abundance, 4 classes, 2 orders, 4 families, 18 genera and 46 species were found to significantly correlate between the tongue coating and the gastric fluid. CONCLUSIONS: The results provide microbiome-based scientific evidence for tongue diagnosis, and offer a new perspective for understanding the biological basis of tongue diagnosis.

Protective Effects of the Wenfei Buqi Tongluo Formula on the Inflammation in Idiopathic Pulmonary Fibrosis through Inhibiting the TLR4/MyD88/NF-κB Pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and poor prognosis. The prognostic signatures related to conventional therapy response remain limited. The Wenfei Buqi Tongluo (WBT) formula, a traditional Chinese medicine (TCM) formula, has been widely utilized to treat respiratory diseases in China, which is particularly effective in promoting inflammatory absorption. In this study, we aim to explore the mechanism of the WBT formula in the inhibition of inflammatory response during IPF, based on network pharmacology and in vivo experiments. METHODS: Network pharmacology was applied to predict the changes of biological processes and potential pathways for the WBT formula against IPF. Histopathological changes, inflammatory factors (IL-6, IL-1ß, and TNF-α), and the proteins of the TLR4/MyD88/NF-κB pathway in bleomycin- (BLM-) induced mice model were examined by hematoxylin-eosin (H&E), Masson or immunohistochemistry staining, Western blot, and enzyme-linked immunosorbent assay analysis. RESULTS: A total of 163 possible components and 167 potential targets between the WBT formula and IPF were obtained. The enrichments of network pharmacology showed that inflammation response, TNF, and NF-κB pathways were involved in the treatment of WBT against IPF. The in vivo experiments indicated that the WBT formula could ameliorate inflammatory exudation and collagen deposition at a histopathology level in the BLM-induced mice model. The levels of IL-6, IL-1ß, and TNF-α were reduced after the WBT formula treatment. Moreover, the expressions of phosphorylated-NF-κB p65, TLR4, and MyD88 were significantly downregulated by the WBT formula, compared with the BLM-induced group. CONCLUSION: These results indicated that the WBT formula can suppress BLM-induced IPF in a mouse model by inhibiting the inflammation via the TLR4/MyD88/NF-κB pathway. This study provides a new insight into the molecular mechanisms of the WBT formula in the application at the clinic.

Deep Sequencing, Nested PCR, and Denaturing Gradient Gel Electrophoresis Reveal a Wider Distribution of Chinese Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycetes), in Native Soil Types.

Ophiocordyceps sinensis appears as stroma emerging from underground sclerotium enclosed by the skeleton of Thitarodes moth larvae. However, the actual distribution of the fungus in soil still remains unclarified. In this study, 40 soil samples were used for detection of O. sinensis to confirm its distribution in native habitats using denaturing gradient gel electrophoresis, nested internal transcribed spacer (ITS) PCR, and 454 pyrosequencing methods. The soil samples included six types: Os, where both stromata and host moth larvae were found; NL, representing no signs of stromata, but where moth larvae were found; NOs, where neither stroma nor moth larvae were found; BS, with bare soil without the presence of stroma of O. sinensis or moth larvae; AF, from soil surrounding the stroma; and MP, soil particles firmly wrapping the sclerotium of O. sinensis. Of 40 samples tested, 36 showed positive detection of O. sinensis by at least one of the three detection methods, with positive detection in all six sample types at all five sites. The results showed that traces of O. sinensis can be detected in locations with no macroscopically visible evidence of the fungus or its host and at least 100 m away from such locations.

Screening druggable targets and predicting therapeutic drugs for COVID-19 via integrated bioinformatics analysis.

BACKGROUND: Since the outbreak of coronavirus disease 2019 (COVID-19) in China, numerous research institutions have invested in the development of anti-COVID-19 vaccines and screening for efficacious drugs to manage the virus. OBJECTIVE: To explore the potential targets and therapeutic drugs for the prevention and treatment of COVID-19 through data mining and bioinformatics. METHODS: We integrated and profoundly analyzed 10 drugs previously assessed to have promising therapeutic potential in COVID-19 management, and have been recommended for clinical trials. To explore the mechanisms by which these drugs may be involved in the treatment of COVID-19, gene-drug interactions were identified using the DGIdb database after which functional enrichment analysis, protein-protein interaction (PPI) network, and miRNA-gene network construction were performed. We adopted the DGIdb database to explore the candidate drugs for COVID-19. RESULTS: A total of 43 genes associated with the 10 potential COVID-19 drugs were identified. Function enrichment analysis revealed that these genes were mainly enriched in response to other invasions, toll-like receptor pathways, and they play positive roles in the production of cytokines such as IL-6, IL-8, and INF-ß. TNF, TLR3, TLR7, TLR9, and CXCL10 were identified as crucial genes in COVID-19. Through the DGIdb database, we predicted 87 molecules as promising druggable molecules for managing COVID-19. CONCLUSIONS: Findings from this work may provide new insights into COVID-19 mechanisms and treatments. Further, the already identified candidate drugs may improve the efficiency of pharmaceutical treatment in this rapidly evolving global situation.

Targeting neuroinflammation: The therapeutic potential of ω-3 PUFAs in substance abuse.

Substance abuse is a chronic relapsing disorder that results in serious health and socioeconomic issues worldwide. Addictive drugs induce long-lasting morphologic and functional changes in brain circuits and account for the formation of compulsive drug-seeking and drug-taking behaviors. Yet, there remains a lack of reliable therapy. In recent years, accumulating evidence indicated that neuroinflammation was implicated in the development of drug addiction. Findings from both our and other laboratories suggest that ω-3 polyunsaturated fatty acids (PUFAs) are effective in treating neuroinflammation-related mental diseases, and indicate that they could exert positive effects in treating drug addiction. Thus, in the present review, we summarized and evaluated recently published articles reporting the neuroinflammation mechanism in drug addiction and the immune regulatory ability of ω-3 PUFAs. We also sought to identify some of the challenges ahead in the translation of ω-3 PUFAs into addiction treatment.

[Electroacupuncture at "Ganshu" (BL18) and "Yanglingquan" (GB34) alleviates hepatic ischemia-reperfusion injury by inhibiting translocation and release of high mobility group protein 1 in rats].

OBJECTIVE: To explore the protective effect of electroacupuncture (EA) on hepatic ischemia-reperfusion injury (HIRI) and the expression of high mobility group protein 1 (HMGB1) in liver tissues in rats. METHODS: A total of 40 male SD rats were randomly divided into 4 groups, namely sham control, HIRI model, "Ganshu"(BL18) -"Yanglingquan"(GB34) and non-acupoint group, with 10 rats in each group. The HIRI model was induced by blocking the arteries, veins and bile ducts supplying the middle and left lobes of the liver for 1 h, and reperfusion for 4 h to induce an area of about 70% HIRI. EA was applied to bila-teral BL18 and GB34, or non-acupoints about 6-8 mm to the bilateral BL18 for 30 min before modeling. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were measured by using an automatic biochemical analyzer. Serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and HMGB1 levels were assayed by ELISA. Hematoxylin - eosin (H.E.) staining was used to observe histopathological changes of the liver tissue by using tissue injury scaling (0-3 scores). The expression of HMGB1 protein in liver tissues was detected by immunohistochemical staining, Western blot and PCR, separately. RESULTS: Following modeling and compared with the sham group, the levels of serum ALT, AST, TNF-α, IL-6, and HMGB1 contents, the number of HMGB1 immunoreaction (IR)-positive cells, and HMGB1 protein and mRNA were significantly increased (P＜0.01). After the treatment, the contents of serum ALT, AST, TNF-α, IL-6, and HMGB1, liver HMGB1 IR-positive cells, protein and mRNA were considerably down-regulated in the BL18-GB34 group (P<0.05), rather than in the non-acupoint group (P>0.05) in contrast to the model group. H.E. stain showed a higher liver injury score in the model group than in the sham group (P<0.01), and a lower liver injury score in the BL18-GB34 group (not the non-acupoint group) relevant to the model group (P<0.05). CONCLUSION: EA of BL18 and GB34 points has a protective effect on ischemic liver injury in rats with HIRI, which may be associated with its functions in inhibiting the migration and release of HMGB1 from the nucleus to the cytoplasm and in down-regulating the expression of inflammatory factors.

Withdrawing mycophenolate mofetil in treating a young kidney transplant recipient with COVID-19: A case report.

RATIONALE: Coronavirus disease 2019 (COVID-19) is a novel infectious disease and became a global issue. Treatment of COVID-19 especially in solid organ transplant recipients is empirical and controversial, especially the adjustment of the immunosuppressants. PATIENT CONCERNS: A 29-year-old kidney transplant recipient with the symptoms of COVID-19 pneumonia. DIAGNOSES: COVID-19 pneumonia after kidney transplantation. INTERVENTIONS: He was treated with modified immunosuppressants (unchanged dose of tacrolimus and oral corticosteroids while discontinuing mycophenolate mofetil (MMF)), antibiotics, interferon α-2b inhalation and traditional Chinese medicine. OUTCOMES: He recovered from COVID-19 pneumonia after 29 days of hospitalization. And the renal function (measured as blood urea nitrogen, serum creatinine, and urine protein) returned to normal. LESSONS: In certain group of COVID-19 (e.g., mild to moderate cases, young patients without comorbidities), a reduction instead of an overall withdrawal of immunosuppressant in kidney transplant recipients is feasible.

Physicochemical properties and health risk assessment of polycyclic aromatic hydrocarbons of fragrant rapeseed oils in China.

BACKGROUND: Fragrant rapeseed oil is a type of hot-pressed oil in China. In this study, physicochemical properties, oxidative stability index (OSI), tocopherols, sterols, and polycyclic aromatic hydrocarbons (PAHs) in fragrant rapeseed oils were evaluated. Additionally, the cancer risk assessment pertaining to PAHs in fragrant rapeseed oil was investigated. RESULTS: Acid values (0.64-2.68 mg potassium hydroxide per gram), peroxide values (1.58-4.86 mmol kg-1 ), and color values (R = 2.6-5.8, Y = 35) of fragrant rapeseed oils were all within codex limits. Tocopherols and sterols ranged from 559.5 to 783.7 mg kg-1 and 4412.6 to 7859.8 mg kg-1 respectively. The OSI (110 °C) was between 4.8 and 15.9 h, with an average value of 10.8 h. Mean values of benzo[a]pyrene and PAH4 (chrysene, benz[a]anthracene, benzo[b]fluroranthene, and benzo[a]pyrene) were 2.32 µg kg-1 and 8.21 µg kg-1 respectively. The 95% dietary exposure of benzo[a]pyrene equivalent (BaPeq) contents from PAH4 were 0.3474 ng kg-1 day-1 , 0.3942 ng kg-1 day-1 , 1.8293 ng kg-1 day-1 , and 0.4294 ng kg-1 day-1 for male children, adolescents, adults, and seniors respectively. For females, these values were 0.3443 ng kg-1 day-1 , 0.3228 ng kg-1 day-1 , 1.8697 ng kg-1 day-1 , and 0.4084 ng kg-1 day-1 , respectively. Moreover, incremental lifetime cancer risk values at the cumulative probabilities of 91.3% and 91.6% for male adults and female adults respectively were higher than 1 × 10-5 . CONCLUSION: The results imply that the potential risk of cancer with PAHs in fragrant rapeseed oil should be a concern, especially for the health of adults. Fragrant rapeseed oil is still a product subject to contamination by PAHs. Limits for PAH4 of fragrant rapeseed oil should be included in Chinese regulations to improve safety. © 2020 Society of Chemical Industry.

Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC.

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. Sorafenib treatment activates SSP by inducing PHGDH expression. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that inactivation of PHGDH paralyzes the SSP and reduce the production of αKG, serine, and NADPH. Concomitantly, inactivation of PHGDH elevates ROS level and induces HCC apoptosis upon Sorafenib treatment. More strikingly, treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC growth in vivo. Similar findings are also obtained in other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC.

Metastatic Adrenocortical Carcinoma: a Single Institutional Experience.

Adrenocortical carcinoma (ACC) is a rare malignancy with limited data to guide the management of metastatic disease. The optimal treatment strategies and outcomes of patients with metastatic ACC remain areas of active interest. We retrospectively reviewed patients with ACC who were treated with systemic therapy between January 1997 and October 2016 at The Ohio State University Comprehensive Cancer Center. Kaplan-Meier and Cox proportional hazards regression models were used for survival analysis. We identified 65 patients diagnosed with ACC during the given time period, and 36 patients received systemic therapy for distant metastatic disease. Median age at diagnosis was 50 (range 28-87). Median overall survival (OS) from time of diagnosis of ACC was 27 months (95% CI 19.6-39.3), and median OS from time of systemic treatment for metastatic disease was 18.7 months (95% CI 9.3-26.0). Clinical characteristics at time of initiation of systemic therapy were assessed, and presence of bone metastases (p = 0.66), ascites (p = 0.19), lung metastases (p = 0.12), liver metastases (p = 0.47), as well as hormonal activity of tumor (p = 0.19), were not prognostic for survival. Six patients with liver metastases treated with systemic therapy who received liver-directed therapy with either transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) had longer survival than those who did not (p = 0.011). Our data expands the knowledge of clinical characteristics and outcomes of patients with ACC and suggests a possible role for incorporating liver-directed therapies for patients with hepatic metastases.

Inhibition of Experimental Age-Related Macular Degeneration by ZQMT in Mice.

BACKGROUND: Age-related macular degeneration (AMD) is a progressive and irreversible eye disease. The anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of neovascular AMD. However, the expense for such treatment is quite high. METHODS: We used a traditional Chinese medicine ZQMT as an alternative therapeutic regimen for AMD. We employed two in vivo animal models mimicking dry and wet AMD respectively to assess the therapeutic efficacy of ZQMT on treating AMD-related retinopathy. AMD-related retinopathy in Crb1rd8 mice was evaluated from week 1 to 8 by fundus photography. Laser-induced choroidal neovascularization (CNV) was evaluated by fluorescein angiography and histopathology. RESULTS: ZQMT increased CX3CR1 expression in murine CD4+ T cells either cultured in vitro or directly isolated from animals treated with ZQMT. We also performed both in vitro and in vivo studies to confirm that ZQMT has no apparent toxic effects. ZQMT alleviated AMD-related retinopathy in both Crb1rd8 and CNV models. Depletion of CCL2 and CX3CR1 in Crb1rd8 mice abolished the efficacy of ZQMT, suggesting that CCL2 and/or CX3CR1 may underlie the mechanisms of ZQMT in treating AMD-related retinopathy in mice. CONCLUSION: In summary, our study supports the protective roles of a traditional Chinese medicine ZQMT in AMD.

Panax Quinquefolium Saponins Attenuate Myocardial Dysfunction Induced by Chronic Ischemia.

BACKGROUND/AIMS: Previous studies in rat models of myocardial ischemia showed that Panax quinquefolium saponins (PQS) could attenuate ischemic/reperfusion injury, increase vessel density and improve cardiac function. In the current study, we examined whether PQS could attenuate myocardial dysfunction in a swine model of chronic myocardial ischemia (CMI). METHODS: CMI was established in Bama mini-pigs by placing amroid constrictor on the left anterior descending artery (LAD). Starting from 2 months after the surgery, pigs randomly received PQS (30 mg/kg/day), atorvastatin (1.5 mg/kg/day), or no drug for one month (n=6). A group of pigs receiving sham surgery was included as an additional control. Glucose utilization was assessed with positron emission tomography-computer tomography (PET-CT). Cardiac function was assessed with echocardiography. Myocyte size, nuclear density, and arteriolar density were examined in tissue section obtained from the ischemia area. Potential molecular targets of PQS were identified using proteomic analysis with isobaric tags for relative and absolute quantitation (iTARQ) and network pharmacology. RESULTS: In comparison to the sham controls, pigs implanted with ameroid constrictor had decreased ventricular wall motion, left ventricular ejection fraction (LVEF), and glucose utilization. PQS significantly increased cardiac function and glucose utilization. Arteriole density and myocyte nuclear density were increased. Myocyte diameter was decreased. PQS also attenuated the CMI-induced change of protein expression profile. The effects of atorvastatin were generally similar to that of PQS. However, PQS attenuated the reduction of left ventricular systolic WT induced by CMI more robustly than atorvastatin. CONCLUSION: The results from the current study supports the use of PQS in patients with coronary artery disease.

Overexpression of NRK1 ameliorates diet- and age-induced hepatic steatosis and insulin resistance.

NAD+ is a co-enzyme in redox reactions and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Dietary supplementation of NAD+ precursors nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we sought to identify the roles of nicotinamide riboside kinase 1 (NRK1) plays in regulating hepatic NAD+ biosynthesis and lipid metabolism. Using adenovirus mediated gene transduction to overexpress or knockdown NRK1 in mouse liver, we have demonstrated that NRK1 is critical for maintaining hepatic NAD+ levels and triglyceride content. We have further shown that the hepatic expression of Nmrk1 mRNA is significantly decreased either in mice treated with high-fat diet or in aged mice. However, adenoviral delivery of NRK1 in these diet- and age-induced mice elevates hepatic NAD+ levels, reduces hepatic steatosis, and improves glucose tolerance and insulin sensitivity. Our results provide important insights in targeting NRK1 for treating hepatic steatosis.

Analysing a Chinese Regional Integrated Healthcare Organisation Reform Failure using a Complex Adaptive System Approach.

INTRODUCTION: China's organised health system has remained outdated for decades. Current health systems in many less market-oriented countries still adhere to traditional administrative-based directives and linear planning. Furthermore, they neglect the responsiveness and feedback of institutions and professionals, which often results in reform failure in integrated care. Complex adaptive system theory (CAS) provides a new perspective and methodology for analysing the health system and policy implementation. METHODS: We observed the typical case of Qianjiang's Integrated Health Organization Reform (IHO) for 2 years to analyse integrated care reforms using CAS theory. Via questionnaires and interviews, we observed 32 medical institutions and 344 professionals. We compared their cooperative behaviours from both organisational and inter-professional levels between 2013 and 2015, and further investigated potential reasons for why medical institutions and professionals did not form an effective IHO. We discovered how interested parties in the policy implementation process influenced reform outcome, and by theoretical induction, proposed a new semi-organised system and corresponding policy analysis flowchart that potentially suits the actual realisation of CAS. RESULTS: The reform did not achieve its desired effect. The Qianjiang IHO was loosely integrated rather than closely integrated, and the cooperation levels between organisations and professionals were low. This disappointing result was due to low mutual trust among IHO members, with the main contributing factors being insufficient financial incentives and the lack of a common vision. DISCUSSION AND CONCLUSIONS: The traditional organised health system is old-fashioned. Rather than being completely organised or adaptive, the health system is currently more similar to a semi-organised system. Medical institutions and professionals operate in a middle ground between complete adherence to administrative orders from state-run health systems and completely adapting to the market. Thus, decision-making, implementation and analysis of health policies should also be updated according to this current standing. The simplest way to manage this new system is to abandon linear top-down orders and patiently wait for an explicit picture of IHO mechanisms to be revealed after complete and spontaneous negotiation between IHO allies is reached. In the meantime, bottom-up feedback from members should be paid attention to, and common benefits and fluid information flow should be prioritised in building a successful IHO.

CSH guidelines for the diagnosis and treatment of drug-induced liver injury.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.