Acetylation Enhances the Anticancer Activity and Oral Bioavailability of 5-Demethyltangeretin.

A kind of hydroxylated polymethoxyflavone (PMFs) existing in the citrus genus, 5-Demethyltangeretin (5-DTAN), has been reported to possess several bioactivities in vitro and in vivo. The aim of this study was to investigate whether acetylation could enhance the anticancer activity and oral bioavailability of 5-DTAN. PC-3 human prostate cancer cells were treated with tangeretin (TAN), 5-DTAN, and 5-acetylated TAN (5-ATAN), and the results showed that the cytotoxic effect 5-ATAN (IC50 value of 5.1 µM) on the cell viability of PC-3 cells was stronger than that of TAN (IC50 value of 17.2 µM) and 5-DTAN (IC50 value of 11.8 µM). Compared to 5-DTAN, 5-ATAN treatment caused a more pronounced DNA ladder, increased the sub-G1 phase population, and induced G2/M phase arrest in the cell cycle of PC-3 cells. We also found that 5-ATAN triggered the activation of caspase-3 and the progression of the intrinsic mitochondrial pathway in PC-3 cells, suggesting the induction of apoptosis. In a cell wound healing test, 5-ATAN dose-dependently reduced the cell migration, and the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was decreased after 48 h of 5-ATAN treatment. Moreover, oral administration of 5-ATAN showed a significantly stronger inhibitory effect on tumor size and tumor weight in tumor-bearing nude mice than those of vehicle or the 5-DTAN group (p < 0.05). Furthermore, pharmacokinetic results showed that single-dose oral administration of 5-ATAN exhibited a higher maximum concentration (Cmax) and area under the curve (AUC) of 5-DTAN in plasma than that of 5-DTAN. More extensive distribution of 5-DTAN to most tissues of mice was also observed in mice treated with 5-ATAN for 7 days. In conclusion, acetylation strongly enhances the anticancer activity and oral bioavailability of 5-DTAN and could be a promising strategy to promote the potential bioactivities of natural products.

Immunological evaluation of an inactivated SARS-CoV-2 vaccine in rhesus macaques.

Because of the relatively limited understanding of coronavirus disease 2019 (COVID-19) pathogenesis, immunological analysis for vaccine development is needed. Mice and macaques were immunized with an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine prepared by two inactivators. Various immunological indexes were tested, and viral challenges were performed on day 7 or 150 after booster immunization in monkeys. This inactivated SARS-CoV-2 vaccine was produced by sequential inactivation with formaldehyde followed by propiolactone. The various antibody responses and specific T cell responses to different viral antigens elicited in immunized animals were maintained for longer than 150 days. This comprehensive immune response could effectively protect vaccinated macaques by inhibiting viral replication in macaques and substantially alleviating immunopathological damage, and no clinical manifestation of immunopathogenicity was observed in immunized individuals during viral challenge. This candidate inactivated vaccine was identified as being effective against SARS-CoV-2 challenge in rhesus macaques.

A novel hierarchical machine learning model for hospital-acquired venous thromboembolism risk assessment among multiple-departments.

Venous thromboembolism (VTE) is a common vascular disease and potentially fatal complication during hospitalization, and so the early identification of VTE risk is of significant importance. Compared with traditional scale assessments, machine learning methods provide new opportunities for precise early warning of VTE from clinical medical records. This research aimed to propose a two-stage hierarchical machine learning model for VTE risk prediction in patients from multiple departments. First, we built a machine learning prediction model that covered the entire hospital, based on all cohorts and common risk factors. Then, we took the prediction output of the first stage as an initial assessment score and then built specific models for each department. Over the duration of the study, a total of 9213 inpatients, including 1165 VTE-positive samples, were collected from four departments, which were split into developing and test datasets. The proposed model achieved an AUC of 0.879 in the department of oncology, which outperformed the first-stage model (0.730) and the department model (0.787). This was attributed to the fully usage of both the large sample size at the hospital level and variable abundance at the department level. Experimental results show that our model could effectively improve the prediction of hospital-acquired VTE risk before image diagnosis and provide decision support for further nursing and medical intervention.

[Study on the prevalence of loss to follow-up and risk factors among human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients in Baoshan city, Yunnan province].

OBJECTIVE: To determine the prevalence of loss to follow-up (PLF) and risk factors among human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients from 1989 to 2012 in Baoshan city, Yunnan province. METHODS: The epidemic and follow-up databases of HIV/AIDS patients by the end of 2012 were downloaded from "the history card downloading site" of HIV/AIDS database in China Information System for Disease Control and Prevention and obtained the related data of patients from 1989 to 2012 who had local residence in Baoshan city. These data included demographic characteristics (genders, age at the time of HIV testing positive, and occupation, marital status, and education levels, et al), transmission routes, and disease staging, antiretroviral therapy (ART), and sources of samples, the first CD4(+)T cell counts, and status of follow-up, et al. Descriptive epidemiological study was used to describe the general characteristics of loss to follow-up. Multivariable Cox regression was used for determining risk factors associated with loss to follow-up. RESULTS: A total of 3 295 eligible HIV/AIDS patients from 1989 to 2012 were included. The accumulative study person-year was 11 416.59 years, 222 HIV/AIDS patients were lost to follow-up, and the PLF was 0.019 4/ person years (py). The highest PLF was 0.052 8/py in 2008, the lowest was 0.006 2/py in 2012. The lost patients included 56.76% (126/222) males and 43.24% (96/222) females, the PLFs were 0.020 4/py, 0.018 3/py, respectively. Baoshan city, other cities in Yunnan province, and other provinces, foreign nationality as the family register reached 53.60% (119/222) , 28.83% (64/222) , and 5.86% (13/222) , 11.71% (26/222) , respectively, and their PLFs were 0.012 5/py, 0.046 3/py, and 0.053 6/py, 0.095 6/py, respectively. Receiving ART and not receiving ART occupied 6.76% (15/222) , 93.24% (207/222) , respectively, and the PLFs were 0.001 9/py, 0.0588/py. AIDS and HIV staging standed at 8.11% (18/222) , 91.89% (204/222) , respectively, and the PLFs were 0.003 3, 0.034 5/py. The first CD4(+)T cell counts < 200, 200-350, and > 350 cells /ml accounted for 4.95% (11/222) , 73.87% (164/222) , 21.17% (47/222) , respectively, and the PLFs were 0.004 8/py, 0.024 0/py, 0.020 3/py. The results of multivariable Cox regression showed the risks of loss to follow-up (RLFs) of family register as other cities in Yunnan province (HR = 3.11, 95%CI:2.28-4.25) , other provinces (HR = 2.55, 95%CI:1.42-4.56) , and foreign nationality (HR = 2.12, 95%CI:1.35-3.33) higher than that of Baoshan city, respectively. The RLFs of not receiving ART (HR = 20.83, 95%CI:11.74-36.96) and HIV staging (HR = 3.61, 95%CI:1.82-7.16) were higher than those of receiving ART and AIDS staging, respectively, moreover, the RFLs of the first CD4(+)T cell counts between 200-350 cells/ml (HR = 0.35, 95%CI:0.15-0.82) and the first CD4(+)T cell counts > 350 cells/ml (HR = 0.29, 95%CI:0.12-0.72) were less than that of first CD4(+)T cell counts < 200 cells /ml, respectively. The RLF of transmission route as injecting drug (HR = 0.60, 95%CI:0.41-0.88) was less than that of heterosexual contact. CONCLUSION: Overall, the prevalence of loss to follow-up among HIV/AIDS patients shows a downward trend, moreover, patients of outsiders, heterosexual contact, HIV staging, baseline CD4(+)T cell counts < 200 cells/ml are at higher risk of loss to follow-up.

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema.

Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca(2+), and PKCε; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1(+) and AQP4(+), we show that transfected CRFR1(+) contributes to edema via transfected AQP4(+). In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.