Harmine Ameliorates Cognitive Impairment by Inhibiting NLRP3 Inflammasome Activation and Enhancing the BDNF/TrkB Signaling Pathway in STZ-Induced Diabetic Rats

Diabetes mellitus (DM) is considered a risk factor for cognitive dysfunction. Harmine not only effectively improves the symptoms of DM but also provides neuroprotective effects in central nervous system diseases. However, whether harmine has an effect on diabetes-induced cognitive dysfunction and the underlying mechanisms remain unknown. In this study, the learning and memory abilities of rats were evaluated by the Morris water maze test. Changes in the nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway were determined in both streptozotocin (STZ)-induced diabetic rats and high glucose (HG)-treated SH-SY5Y cells by western blotting and histochemistry. Herein, we found that harmine administration significantly ameliorated learning and memory impairment in diabetic rats. Further study showed that harmine inhibited NLRP3 inflammasome activation, as demonstrated by reduced NLRP3, ASC, cleaved caspase-1, IL-1β, and IL-18 levels, in the cortex of harmine-treated rats with DM. Harmine was observed to have similar beneficial effects in HG-treated neuronal cells. Moreover, we found that harmine treatment enhanced BDNF and phosphorylated TrkB levels in both the cortex of STZ-induced diabetic rats and HG-treated cells. These data indicate that harmine mitigates cognitive impairment by inhibiting NLRP3 inflammasome activation and enhancing the BDNF/TrkB signaling pathway. Thus, our findings suggest that harmine is a potential therapeutic drug for diabetes-induced cognitive dysfunction

Detection of Brucellae in peripheral blood mononuclear cells for monitoring therapeutic efficacy of brucellosis infection.

BACKGROUND: Brucellosis is one of the most severe widespread zoonoses caused by the Gram-negative bacterium Brucella species. The diagnosis and clinical assessment of human brucellosis are very important for the management of patients, while there is a lack of effective methods to detect Brucellae. Classical culture of Brucella species is time consuming and often fails. A simple and sensitive assay is needed for diagnosis of Brucella infection and monitoring of treatment in man. METHODS: Blood samples and peripheral blood mononuclear cells (PBMCs) were collected from 154 patients hospitalized for brucellosis. Brucella antibodies were detected by Rose Bengal Plate Test (RBPT), Standard Tube Agglutination Test (SAT) and enzyme-linked immunosorbent assay (ELISA). Intracellular Brucellae were detected by blood culture and immunofluorescence staining (IFS). RESULTS: Among 154 brucellosis patients, 59.7% (92/154) were antibody reactive by RBPT, 81.8% (126/154) by SAT and 95.5% (147/154) by ELISA, respectively. Only 3.2% (5/154) of patient blood samples resulted in positive Brucella culture, while 68.8% (106/154) carried IFS detectable Brucella antigens in PBMCs. Gender (P = 0.01) but not age (P > 0.05) was a significant risk factor. The frequency of intracellular Brucella antigens was similar between patients receiving different treatment regimens (P > 0.05). However, a significant decrease of intracellular Brucellae was observed only in patients with acute brucellosis after the third course of treatment (P < 0.05), suggesting that current regimens to treat chronic brucellosis were not effective. CONCLUSIONS: IFS appears a sensitive assay for detection of Brucella antigens in PBMCs and could be used for diagnosis and therapeutic monitoring of brucellosis in clinical practice

Pemetrexed plus Platinum as the First-Line Treatment Option for Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

To compare the efficacy and toxicities of pemetrexed plus platinum with other platinum regimens in patients with previously untreated advanced non-small cell lung cancer (NSCLC). Methods: A meta-analysis was performed using trials identified through PubMed, EMBASE, and Cochrane databases. Two investigators independently assessed the quality of the trials and extracted data. The outcomes included overall survival (OS), progression-free survival (PFS), response rate (RR), and different types of toxicity. Hazard ratios (HRs), odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled using RevMan software. Results: Four trials involving 2,518 patients with previously untreated advanced NSCLC met the inclusion criteria. Pemetrexed plus platinum chemotherapy (PPC) improved survival compared with other platinum-based regimens (PBR) in patients with advanced NSCLC (HR = 0.91, 95% CI: 0.83–1.00, p = 0.04), especially in those with non-squamous histology (HR = 0.87, 95% CI: 0.77–0.98, p = 0.02). No statistically significant improvement in either PFS or RR was found in PPC group as compared with PBR group (HR = 1.03, 95% CI: 0.94–1.13, p = 0.57; OR = 1.15, 95% CI: 0.95–1.39, p = 0.15, respectively). Compared with PBR, PPC led to less grade 3–4 neutropenia and leukopenia but more grade 3–4 nausea. However, hematological toxicity analysis revealed significant heterogeneities. Conclusion: Our results suggest that PPC in the first-line setting leads to a significant survival advantage with acceptable toxicities for advanced NSCLC patients, especially those with non-squamous histology, as compared with other PRB. PPC could be considered as the first-line treatment option for advanced NSCLC patients, especially those with non-squamous histology

Making tradeoffs for environmental protection and policy design

There are always painful tradeoffs in environmental problems. In the current period, the tradeoff. has to be made between consuming environmental goods and "dirty" goods. Since many pollutants accumulate in nature and cause long time problems, the current period's decision also has important impacts on future generations. This yields another tradeoff. between control of the pollution flow and cleanup of the pollution stock in the future. For a local government, tradeoffs between strict environmental policies and local economic prosperity are also concerns. This thesis analyzes the tradeoffs made by households, firms and government under different policy regimes. Chapter 2 considers assigning tradable permits to households that are suffering from pollution generated by firms. The households can sell a limited number of permits to polluters according to personal preferences for environmental goods and "dirty" goods. It is shown that, the market transaction between households and polluters can achieve the efficient pollution level. Chapter 3 considers a case in which the stock pollution is reversible with capital investment. In a natural resource extraction model with externalities of heavy metal pollution in the surrounding farmland, the firms tradeoff. between controlling the pollution flow and abating the pollution stock, as well as the firms extraction decisions are analyzed. Chapter 4 derives the optimal environmental bond required by a local government as a financial assurance for inducing firms to do pollution abatement. A local government needs to make tradeoffs between charging a large amount of bond and encouraging local economic prosperity. For a local government, the optimal bond amount does not necessarily cover the worst-case scenario. This thesis contributes to environmental policy design by considering the interests of different parties

Clinical development of chimeric antigen receptor-T cell therapy for hematological malignancies

Abstract. Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development. Chimeric antigen receptor (CAR)-T cell therapy is the most widely applied cellular therapy. Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017, five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies. Moreover, clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing. Both China and the United States have contributed significantly to the development of clinical trials. However, CAR-T cell therapy has many limitations such as a high relapse rate, adverse side effects, and restricted availability. Various methods are being implemented in clinical trials to address these issues, some of which have demonstrated promising breakthroughs. This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy

Advances in targeted therapy and immunotherapy for esophageal cancer

Abstract. Esophageal cancer (EC) is one of the most common aggressive malignant tumors in the digestive system with a severe epidemiological situation and poor prognosis. The early diagnostic rate of EC is low, and most EC patients are diagnosed at an advanced stage. Multiple multimodality treatments have gradually evolved into the main treatment for advanced EC, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. And the emergence of targeted therapy and immunotherapy has greatly improved the survival of EC patients. This review highlights the latest advances in targeted therapy and immunotherapy for EC, discusses the efficacy and safety of relevant drugs, summarizes related important clinical trials, and tries to provide references for therapeutic strategy of EC

Identifying and Predicting the Credit Risk of Small and Medium-Sized Enterprises in Sustainable Supply Chain Finance: Evidence from China

COVID-19 has created a strong demand for supply chain finance (SCF) for small and medium-sized enterprises (SMEs). However, the rapid development of SCF leads to more complex credit risks. How to effectively discriminate and manage SMEs to reduce credit risk has become one of the most critical issues in SCF. In addition, sustainable SCF (SSCF) has received increasing attention, and credit risk management is important to achieve SSCF. Therefore, it is significant to identify the key factors influencing the credit risk of SMEs and construct a prediction model to promote SSCF. This study uses the lasso-logistic model to identify factors influencing the credit risk of SMEs and to predict the credit risk of SMEs. The empirical results show that (i) the key factors influencing SMEs’ credit risk include six variables—the matching degree of order data, ratio of contract enforcement, number of contract defaults, degree of business concentration, and number of administrative penalties; and (ii) the lasso-logistic model can identify the key factors influencing credit risk and have a better prediction performance. Moreover, transaction credit and reputation supervision significantly influence the credit risk of SMEs

Study on mass transfer property of oxygen molecules and kinetic regimes of pressured pulverized coal combustion

The effects of pressure on diffusion of oxygen molecules during the coal combustion could not be ignored. The compressibility factor of real oxygen is investigated to evaluate the deviation between real and ideal oxygen, and obtain the mean free path of real oxygen. Comparing the Knudsen pore diameter with the minimum pore diameter, it is found that with the increase of pressure, Knudsen diffusion cannot exist at low pressure and may delay to occur at higher temperature. When pressure exceeds 3.5 MPa, no Knudsen diffusion occurs within the whole temperature range of our research. Comparing the diffusion rate at 1 MPa with the burning rate, one can conclude that the combustion mainly take place on the internal and external surfaces, and the reaction is controlled by the chemical kinetics below 1400 K. When themperature is between 1400 K and 1600 K, the reaction is controlled by both the diffusion and the chemical kinetics. When the temperature is more than 1600 K, the combustion primarily happens on the external surfaces and is controlled by the diffusion