Astragaloside IV antagonizes the malignant progression of breast cancer induced by macrophage M2 polarization through the TGF-ß-regulated Akt/Foxo1 pathway.

BACKGROUND: Astragaloside IV (AS­IV) was used for breast cancer (BC) treatment in China from ancient times; however, the mechanism of the prevention effect of AS-IV on BC remains not entirely clear. METHODS: qRT-PCR, western blot and flow cytometry were employed to validate the expression of gene and protein expressions. CCK-8 assay, scratch assay, and transwell assay were used to assess the BC cell proliferation, migration, and invasion. Co-culture of conditional medium from macrophages and BC were performed. RESULTS: AS-IV suppressed macrophage polarized to M2 phenotype and thereby inhibited M2 macrophage-induced BC progression. The inhibitory effect of AS-IV on M2 macrophage polarization was exerted via the deactivation of the Akt/Foxo1 signaling pathway in macrophages by suppressing TGF-ß. The addition of TGF-ß or the treatment with Akt activator SC79 reversed the regulatory effect of AS-IV on M2 macrophage polarization, which increased M2 macrophage polarization-induced BC cell proliferation, migration and invasion. CONCLUSION: This present study revealed a new mechanism of AS-IV inhibited M2 macrophage polarization-induced BC progression and may provide a potential target for the treatment of BC.

Real-World Utilization, Barriers, and Factors Associated With the Targeted Treatment of Metastatic Colorectal Cancer Patients in China: A Multi-Center, Hospital-Based Survey Study.

Objectives: To explore the utilization, barriers, and factors associated with the targeted treatment of Chinese metastatic colorectal cancer (mCRC) patients. Methods: A total of 1,688 mCRC patients from 19 hospitals in 14 cities were enrolled from March 2020 to March 2021 using stratified, multistage cluster sampling. The use of targeted therapy and any barriers patients experienced were collected. Logistic regression analyses were conducted to identify the factors associated with initiating targeted treatment. Results: About 51.6% of the patients initiated targeted therapy, of whom 44.5%, 20.2%, and 35.2% started first-, second-, and third-line treatment, respectively. The most reported barriers were high medical costs and a lack of belief in the efficacy of targeted therapy. Patients treated in the general hospital, diagnosed at an older age, less educated, and who had a lower family income, no medical insurance, poor health-related quality of life, metastasis outside the liver/lung or systemic metastasis, a shorter duration of mCRC were less likely to initiate targeted therapy. Conclusion: Reduced medical costs and interventional education to improve public awareness could facilitate the use of targeted treatment for mCRC.

Manganese-based nanoadjuvants for enhancement of immune effect of DNA vaccines.

As a highly pathogenic avian influenza virus, influenza A (H5N1) has been reported to infect humans, posing a major threat to both poultry industry and public health. It is an urgent need to develop a kind of effective vaccine to prevent death and reduce the incidence rate of H5N1 avian influenza. Compared with traditional inactivated or attenuated vaccines, deoxyribonucleic (DNA) vaccines have the advantages of continuously expressing plasmid-encoded antigens and inducing humoral and cellular immunity. However, the immune effect of DNA vaccines is limited to its poor immunogenicity. Using of nanoadjuvants with DNA vaccines holds a great promise to increase the transfection efficiency and immunogenicity of DNA vaccines. In this study, we developed a nano co-delivery system with a manganese-based liposome as adjuvant for delivery of a DNA vaccine. This system has been found to protect DNA vaccine, enhance phagocytosis as well as promote activation of antigen-presenting cells (APCs) and immune cells in draining lymph nodes. In addition, the effect of this nanovaccine has been evaluated in mouse models, where it induces highly potent hemagglutination inhibitory antibody (HI) and IgG antibodies, while activating both humoral and cellular immunity in the host. Overall, this strategy opens up a new prospect for manganese nanoadjuvants in increasing the immunogenicity of DNA vaccines.

Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees.

Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.

Status and associated factors of cross-regional healthcare-seeking among patients with advanced colorectal cancer in China: a multicenter cross-sectional study.

Background: The imbalanced allocation of medical resources leads to the occurrence of cross-regional healthcare-seeking in China. Due to the low cure rate, advanced colorectal cancer (CRC) patients may seek cross-regional healthcare for high-level medical facilities. Investigating status of cross-regional healthcare-seeking and its associated factors among advanced CRC patients is important for policymakers to understand access to health services and improve the quality of oncology services. Methods: From March 2020 to March 2021, a cross­sectional, nation-wide, hospital-based, multi-center survey was conducted. Nineteen hospitals in seven regions were selected by multi-stage stratified sampling. All eligible CRC patients in the selected hospitals were invited to participate in the current study. The outcome variable, cross-regional healthcare-seeking, was defined as seeking health facilities outside the local administration policy of medical insurance. The demographics, clinical information, and medical treatment history of each eligible CRC patient in stage III or IV, were collected through the patients' self-reporting or medical records by trained interviewers. Univariate and multivariate logistic analyses were used to explore the associated factors of cross-regional healthcare-seeking. All statistical analyses were conducted using SAS 9.4. Results: A total of 4,589 individuals with advanced CRC were included. The average age of the patients was 60.1±11.6 years, and 59.5% were males. About 37.5% of the patients suffered from metastatic CRC at first diagnosis. Approximately 36.5% of the patients had sought cross-regional health care previously, and among them, 31.9% had encountered problems. The most common problems included complicated procedures (95.3%), unreimbursed expenses of outpatient service (71.0%), and reimbursement delay (59.4%). Logistic regression analysis showed that patients who completed undergraduate or above [odds ratio (OR) =1.40, 95% confidence interval (CI): 1.13-1.73], had an annual household income of more than 100,000 Chinse Yuan (CNY) (OR =1.46, 95% CI: 1.21-1.78), and had metastasis at diagnosis (OR =1.33, 95% CI: 1.18-1.51) were more likely to seek cross-regional health care. Conclusions: About one third of advanced CRC patients seek cross-regional health care, and 31.9% had encountered problems. There is a need to simplify procedures of reimbursement, optimize direct settlement system and referral mechanisms in order to improve the equality of health services.

Out-of-pocket medical expenditure and associated factors of advanced colorectal cancer in China: a multi-center cross-sectional study.

Background: Colorectal cancer (CRC) causes a substantial disease burden in China. Information on the medical expenditure of CRC patients is critical for decision-makers to allocate medical resources reasonably, however, relevant data is limited in China, especially advanced CRC. The aim of this survey was to quantify the out-of-pocket medical expenditure of advanced CRC and explore associated factors. Methods: A nation-wide, multi-center, cross-sectional survey was conducted from March 2020 to March 2021. Nineteen hospitals in seven geographical regions were selected by multi-stage stratified sampling. For each eligible CRC patient with stage III or IV disease in the selected hospitals, the socio-demographics, clinical information, and range of out-of-pocket medical expenditure data were collected based on patients' self-reporting or medical records. Multivariable logistic analysis was used to explore associated factors of medical expenditure. All statistical analyses were conducted using SAS 9.4. Results: The mean age of the 4,428 advanced CRC patients included was 59.5±11.6 years, 59.6% were male, and 80.1% of patients were in stage III or IV at the time of diagnosis. Besides, 57.2% of patients had an annual household income of less than 50,000 Chinese Yuan (CNY), 40.9% of patients had an out-of-pocket medical expenditure of 50,000-99,999 CNY. As for the affordability of medical expenditure, 33.2% could afford 50,000-99,999 CNY. Multivariate analysis showed that patients who were in the southern [odds ratio (OR): 1.63, 95% confidence interval (CI): 1.31-2.03] and southwestern (OR: 1.55, 95% CI: 1.25-1.93), were in stage III at the time of diagnosis (OR: 1.33, 95% CI: 1.13-1.57), visited three or more hospitals (OR: 1.26, 95% CI: 1.04-1.52), had sought cross-regional health care (OR: 1.60, 95% CI: 1.40-1.83), used genetic testing (OR: 1.26, 95% CI: 1.10-1.45) and targeted drugs (OR: 2.12, 95% CI: 1.79-2.51) had higher out-of-pocket medical expenditure. Conclusions: Patients with advanced CRC had a high out-of-pocket medical expenditure. It is necessary to strengthen the prevention and control of CRC to reduce the disease burden; also, it is critical to deepen the reform of the medical system, increase proportion of medical insurance reimbursement, and remove barriers to cross-regional health care.

Utilization of genetic biomarkers testing and its associated factors in advanced colorectal cancer patients in China: a nationwide multicenter clinical epidemiological study.

Background: Biomarkers are a key tool in early detection, prognostication, survival, and predicting treatment response of colorectal cancer (CRC). However, little is known about biomarker testing for CRC patients in real-life clinical practice in China. This study aimed to address the usage of biomarker testing and analyze factors related to its acceptance among Chinese patients with advanced CRC. Methods: A multicenter, cross-sectional, hospital-based clinical epidemiology study was conducted from March 2020 to March 2021. Nineteen hospitals were selected in seven geographical regions of China using stratified, multistage, nonrandomized cluster sampling. Data on demographics and clinical characteristics of each eligible CRC patient in stage III or IV diseases were recorded based on the patients' self-reporting and/or medical records. In addition, information on whether biomarker testing [RAS, BRAF, and microsatellite instability (MSI)] was performed, the results and timing for performing biomarker testing, and the reasons for refusing biomarker testing were also recorded. Univariate and multivariate logistic regression were conducted to explore the potential factors of biomarker testing. Results: A total of 4,526 patients were enrolled in the study, of whom 41.4%, 36.1%, and 28.2% underwent RAS, BRAF, and MSI testing, respectively. RAS, BRAF, and high-level MSI (MSI-high) mutation rates in Chinese patients with advanced CRC were 37.0%, 9.9%, and 8.1%, respectively. The logistic regression analysis revealed that the treating hospital, age at diagnosis, education, family income, tumor site, history of chemotherapy and radiotherapy, and metastases were dependent factors affecting the utilization of biomarker testing in advanced CRC in China (P<0.005). Conclusions: The biomarker testing rate, especially MSI testing, is less prevalent in clinical practice for patients with advanced CRC in China. Our findings may guide the formulation of biomarker testing of CRC strategies in China and other low-income countries.

A study on the willingness and influencing factors of novel coronavirus vaccination among medical personnel in North China.

AIM: To understand the awareness of the willingness to be vaccinated and influencing factors of the new coronavirus vaccine (neo-crown vaccine) among medical personnel in North China and to provide a theoretical basis and application guidelines for the feasibility of coronavirus vaccination by medical personnel to guide the public to actively be vaccinated by taking initiative and obtaining a coronavirus vaccination as soon as possible. METHODS: From April 2021 to June 2021, medical staff in North China were selected to complete an online questionnaire survey using Questionnaire Star to analyze the willingness rate to be vaccinated with the new coronavirus vaccine, and the influencing factors were analyzed using binary logistic regression. RESULTS: Among 621 respondents, 85.7% were willing to be vaccinated after the launch of the new vaccine. In the questionnaire, respondents were asked to answer questions such as "Do you think it is better to receive as few vaccines as possible at the same time?," "If I get the new coronavirus vaccine, I may have serious side effects.," "The new coronavirus vaccine is safe.," "Specifically, for the new coronavirus vaccine, do you think it is safe?," and "Specifically, for the new coronavirus vaccine, do you think it is easy to administer?." These beliefs have an important influence on the vaccination of medical staff with the new coronavirus vaccine in Northern China (OR = 1.610,95% CI: 1.055 ~ 2.456; OR = 1.715,95% CI: 1.164 ~ 2.526; OR = 0.401, 95% CI: 0.212 ~ 0.760; OR = 0.352,95% CI: 0.147 ~ 0.843; OR = 3.688,95% CI: 1.281 ~ 10.502, respectively; All P values < .05). CONCLUSIONS: Medical staff have a high willingness to be vaccinated with the new coronavirus vaccine, which plays a positive role in the publicity of the vaccine.

Luteolin inhibits FcεRΙ- and MRGPRX2-mediated mast cell activation by regulating calcium signaling pathways.

Luteolin is a flavonoid found in many fruits, vegetables, and herbs. The antiinflammatory effects of luteolin have been reported. In this study, the effect of luteolin on allergic diseases and the underlying molecular mechanism were investigated. We found that luteolin inhibits Fc epsilon RΙ (FcεRΙ)- and Mas-related G protein-coupled receptor X2 (MRGPRX2)-mediated mast cells (MCs) activation, including degranulation and release of cytokines in vitro. Moreover, luteolin reduces the degree of swelling and Evans blue exudation of mice paw in a dose-dependent manner. The concentrations of histamine, TNF-α, MCP-1, IL-8, and IL-13 in mice serum are also decreased by luteolin administration. Our study reveals that luteolin can inhibit FcεRΙ- and MRGPRX2-mediated allergic responses in vivo and in vitro, and our results discover luteolin inhibited mast cells mediated anaphylactic reaction by inhibiting the phosphorylation level of PLCγ.

Imiquimod-related dermatitis is mainly mediated by mast cell degranulation via Mas-related G-protein coupled receptor B2.

While imiquimod (IMQ) has been widely used in dermatology, its side effect manifested as dermatitis couldn't be ignored. However, the underlying mechanism has not been fully understood. Considering the clinical features of IMQ-related dermatitis similar to pseudo-allergic reaction and the presence of large numbers of mast cell in tissues treated with IMQ, the possibility that IMQ-related dermatitis mediated by mast cell-specific Mas-related G protein-coupled receptor X2 (MRGPRX2) should be addressed. To investigate the role of MRGPRX2 in vivo, MrgprB2, the mice homology of human MRGPRX2, was detected in IMQ-induced dermatitis mouse model. Histopathological changes including mast cell degranulation and footpad swelling were assayed in wild-type and MrgprB2-/- mice. The results showed that IMQ application induced dermatitis and footpad swelling with inflammatory cells infiltration plus mast cell activation in the skin of wild-type mice but reduced significantly in MrgprB2-/- mice. Further, compared to wild-type mice, serum histamine and inflammatory cytokine levels were compromised in MrgprB2-/- mice treated with IMQ, while the serum IgE level didn't change significantly. In vitro studies, levels of mediators released from murine peritoneal mast cells (MPMCs) after IMQ treatment were increased in a dose-dependent manner, which were much mild in MPMCs from MrgprB2-/- mice. Intracellular Ca2+ concentration was increased in a dose dependent manner after IMQ treatment both in MrgprB2-HEK293 and MRGPRX2-HEK293 cells. Moreover, ß-hexosaminidase released after IMQ treatment was blocked by siRNA directed at the MRGPRX2 receptor in LAD2 cells. In summary, MrgprB2 /MRGPRX2 mediate mast cell activation and participate in IMQ-related dermatitis.

Groundwater Depth Forecasting Using Configurational Entropy Spectral Analyses with the Optimal Input.

Accurate groundwater depth forecasting is particularly important for human life and sustainable groundwater management in arid and semi-arid areas. To improve the groundwater forecasting accuracy, in this paper, a hybrid groundwater depth forecasting model using configurational entropy spectral analyses (CESA) with the optimal input is constructed. An original groundwater depth series is decomposed into subseries of different frequencies using the variational mode decomposition (VMD) method. Cross-correlation analysis and Shannon entropy methods are applied to select the optimal input series for the model. The ultimate forecasted values of the groundwater depth can be obtained from the various forecasted values of the selected series with the CESA model. The applicability of the hybrid model is verified using the groundwater depth data from four monitoring wells in the Xi'an of Northwest China. The forecasting accuracy of the models was evaluated based on the average relative error (RE), root mean square error (RMSE), correlation coefficient (R) and Nash-Sutcliffe coefficient (NSE). The results indicated that comparing with the CESA and autoregressive model, the hybrid model has higher prediction performance.

Effectiveness and Safety of the Combination of the Traditional Chinese Medicine Prescription Jade Screen and Desloratadine in the Treatment of Chronic Urticaria: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The aim of this study is to systematically evaluate the clinical efficacy and safety of the traditional Chinese medicine prescription Jade Screen combined with desloratadine in the treatment of chronic urticaria. METHODS: Two researchers independently conducted literature searches. The extracted data were analyzed using Rev Man 5.2.3 software. The established retrieval time range of the various databases was up to 15 March, 2017. RESULTS: Sixteen randomized controlled trials were included in this study. The results of the meta-analysis showed that the total effective rate of using Jade Screen and desloratadine in combination to treat chronic urticaria was higher than that with desloratadine alone (P < 0.00001), while its recurrence rate (P < 0.00001) and symptom score (P = 0.006) were both significantly lower than the latter. The rate of adverse reaction in the combination group was lower than that when orally taking desloratadine alone (P = 0.74), and the serum level of total IgE in the combination group was lower than that when orally taking desloratadine alone (P = 0.82); however, the results of the rate of adverse reaction and the serum level of total IgE were insignificant. CONCLUSION: Using Jade Screen and desloratadine together to treat chronic urticaria gains a better clinical effect than using desloratadine alone.

[Effects of baicalin and other Chinese herbal monomer on androgen receptor mRNA expression in SZ95 sebocytes].

OBJECTIVE: To determine the effects of Chinese herbal monomers such as baicalin, berberine, and matrine on the androgen receptor (AR) mRNA expression in SZ95 sebocytes in vitro and to explore the possible mechanism of using traditional Chinese medicines to treat acne. METHODS: SZ95 sebocytes were cultured and then treated with berberine, baicalin, matrine, and 13-cis-retinoic acid for 24 hours. Reverse transcription polymerase chain reaction was applied to detect the changes of AR. RESULT: AR mRNA was downregulated by 13-cis-retinoic acid of 1 x 10(-5) mol/L and 1 x 10(-6) mol/L, and by baicalin of 1 x 10(-4) mol/L (P < 0.05). CONCLUSION: 13-cis-retinoic acid and baicalin may exert antiandrogenitic action by inhibiting AR mRNA expression in human sebocytes.