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Summary: Background: It is generally recognized that there is unequal mortality in childhood central nervous system (CNS) malignancy in the United States (US), but little is known about the trends and contributors of racial/ethnic disparities in death. We assessed the trends of racial/ethnic disparities in all-cause and cause-specific death, and the contributions of tumour, treatment and socioeconomic factors to this disparity. Methods: This registry-based cohort study included children (aged ≤19 years) diagnosed with malignant CNS tumours, using data from the US population-based cancer registry in the Surveillance, Epidemiology, and End Results (SEER) Program. The clinical outcomes were all-cause and cause-specific death for each racial/ethnic group (White, Black, Hispanic, non-Hispanic Asian/Pacific Islander [API], and non-Hispanic American Indian/Alaska Native [AI/AN] children). We quantified absolute disparities using absolute rate difference in 5-year cumulative incidence of death. Cox proportion risk models were used to estimate the relative racial/ethnic disparities, and the contribution of factors to disparities in death. Findings: In this study, data from 14,510 children with malignant CNS tumours (mean [SD] age, 8.5 [5.7]; 7988 [55.1%] male) were analysed. Overall, the cumulative incidence of death from CNS tumours across four racial/ethnic groups decreased from 2001 to 2020. Black patients had the highest risk of death from all causes and CNS tumours between 2001 and 2020, with adjusted hazard ratios (HR) of 1.52 (1.38–1.68) and 1.47 (1.31–1.64), respectively. The absolute disparity in all-cause death between Hispanic and White patients increased slightly (from 8.2 percentage points [ppt] to 9.4 ppt), and the relative disparity in death from CNS tumours increased from 1.33 (1.15–1.55) in 2001–2005 to 1.78 (1.44–2.20) in 2016–2020. The absolute disparities in death from CNS tumours between Black and White patients (from 11.8 ppt to 4.3 ppt) and between API and White patients (from 10.1 ppt to 5.1 ppt) decreased from 2001–2005 to 2011–2015. Interpretation: Race/ethnicity disparities in death from CNS tumours among childhood malignant CNS tumours had reduced from 2001 to 2020, and quantifying the contribution of factors to this disparity in death could provide a basis for decreasing mortality among racial/ethnic minority patients. Funding: Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program.

Tea tree is a fluorine (F)-enriched plant, leading to much concern about the safety of drinking tea from tea tree (Camellia sinensis (L.) Kuntze). Tea tree is a perennial leaf-harvested crop, and tea production in China is generally categorized as spring tea, summer tea and autumn tea in its annual growth rounds. However, the seasonally dynamic changes of F content and accumulation in the leaves and its drinking safety are poorly understood. In this study, 85 tea varieties cultivated under the same conditions were investigated to analyze the seasonal variation of F content and it’s relationships with F accumulation, aluminum (Al), calcium (Ca) and manganese (Mn) and hazard quotient (HQ) in young leaves (one bud and two leaves, YL) and mature leaves (canopy leaves, ML). The average F contents and accumulations were 350 mg kg−1 and 203 g ha−1 in YL, and they were 2451 mg kg−1 and 2578 g ha−1 in ML, respectively, with F mainly accumulated in ML. As the growing season progresses, the F content showed a gradual increase in YL, while a decrease in ML, inferring that F may be redistributed from mature leaves to young leaves. Additionally, the F content was quite different among tea varieties which are suitable for processing oolong tea, green tea, and black tea, with higher F accumulation in oolong tea varieties than in green and black tea varieties. Moreover, F content and accumulation could be obviously affected by the geographical origin of the tea tree varieties, with significantly higher F content in the varieties from F rich fluorite belts than other regions. Furthermore, F content and accumulation showed a significant positive correlation with the content of Al and Mn (p < 0.05). Based on a daily tea consumption of 8.7 g, the HQ was investigated to show that the proportion of tea leaves with HQ

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisulam did not significantly prevent cancer progression due to metastasis and drug resistance. Therefore, it is necessary to discover new potent derivatives to explore alternative therapeutic strategies. Here, we synthesize multiple indisulam derivatives and examine their inhibitory effects on the viability and migration of gastric cancer cells. Among them, compounds SR‐3‐65 and WXM‐1‐170 exhibit better inhibitory effects on the migration of gastric cancer cells than indisulam. Mechanistically, we discover that they could attenuate the PI3K/AKT/GSK-3β/β-catenin signaling pathway and lead to the suppression of epithelial-to-mesenchymal transition (EMT)-related transcription factors. The influence of SR‐3‐65 on the migration of gastric cancer cells is blocked by the PI3K inhibitor LY294002 while SR‐3‐65 and WXM‐1‐170 reverse the effect of PI3K activator 740 Y-P on the migration of gastric cancer cells. Molecular docking and molecular dynamics simulation further confirm that PI3K is the target of SR‐3‐65. Our study unveils a novel mechanism by which SR‐3‐65 and WXM‐1‐170 inhibit the migration of gastric cancer cells. Together with the previous discovery, we reveal that subtle structural change in indisulam results in a striking switch on the molecular targets and their associated signaling pathways for the inhibition of the migration of gastric cancer cells. These findings might provide informative insights for the development of targeted therapy for gastric cancer.

Background: Gestational diabetes mellitus (GDM) is characterized by insulin resistance during pregnancy, and it is always combined with serious complications. Dendrobium mixture (DMix) is a kind of traditional Chinese medicine, and it has been proved to be an effective treatment for diabetes. However, the regulatory role of DMix in GDM remains elusive. Methods: High fat feed combined with streptozotocin injection and high glucose medium were used to establish GDM animal and cell models, respectively. The levels of blood glucose, blood lipid, and insulin were measured with commercial kits. Western blotting was used to detect protein expression. Results: DMix improved pancreas and placenta injury in GDM rats. DMix reversed the influence of GDM on the levels of SOD, MDA, and glutathione in the serum. Hyperglycemia and hyperlipidemia in GDM rats were suppressed by DMix. The activation of MAPK and inhibition of Nrf2/HO1 in GDM animal and cell models were reversed by DMix. The increase of ROS intensity, apoptosis, and inflammation factors in HG treated cells were reversed by DMix. Conclusion: This research proved that DMix improved GDM through inhibiting oxidative condition, inflammation factors, hyperglycemia and hyperlipidemia. This study might provide a novel thought for the prevention and treatment of GDM.

Natural odour compounds could be a potential alternative to synthetic herbicides. The odour compound of Periploca sepium Bunge, named 2-hydroxy-4-methoxy-benzaldehyde (HMB), is a herbicidal compound. However, its herbicidal mechanism is unclear. In this experiment, the physiological and biochemical indices, ultrastructure, and photosynthetic function of the leaves of Humulus scandens (Lour.) Merr. treated by HMB were assessed to elucidate the herbicidal mechanism. The results of physiological and biochemical indices are as follows: First, after 4 h of treatment with 2.5 and 5.0 mg/mL, the damage rates in the membrane permeation assay were 74.7% and 89.1%, respectively. Second, compared to the negative control group, multiple physiological and biochemical indices of the two treated groups were changed, including catalase content (−18.5 and −26.5 ng/mL), superoxide dismutase content (−27.4 and −56.6 ng/mL), peroxidase content (382.0 and 880.0 ng/mL), reactive oxygen species content (16.7 and 27.2 ng/mL), malondialdehyde content (8.9 and 25.2 nmol/g), and water potential values (0.2 and 0.3 MPa), except for the photosynthetic pigment contents (chlorophyll a, b, and carotene). Furthermore, the results of transmission electron microscopy showed that the organelles in the mesophyll tissue cells disappeared and severe plasmolysis led to cell atrophy after 4 h of treatment. There were fewer starch granules after 24 h of treatment, but there was no obvious abnormality in the upper and lower epidermal cells. The results of photosynthetic function showed that in the light response, the net photosynthetic rate (Pn), transpiration rate (Tr), stomatal conductance (Gs), and stomatal limitation value of the tested leaves were lower than those of the negative control group by 26.6 μmol·m−2·s−1, 7.7 mmol·m−2·s−1, 0.9 mol·m−2·s−1, and 0.2, respectively. However, the intercellular CO2 concentration (Ci) increased and was higher than the air CO2 concentration. In the CO2 response, the Pn, Tr and Gs of the tested leaves first increased and then decreased, but the Ci value continuously increased and finally reached 1727.5 μmol·mol−1. It is obvious that HMB may have inhibited the effect on the photosynthetic system of the tested leaves. Overall, HMB killed the weeds by destroying the structure and multiple physiological functions of the tested leaves.

17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) was isolated from the Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z. Wei (Papilionaceae) (MKL) roots. This study aimed to study the effects of MHBFC on cardiac hypertrophy after banding of the abdominal aorta in wild-type mice and endothelial nitric oxide synthase (eNOS) knockout mice in order to verify whether MHBFC depends on the eNOS gene in reversing cardiac hypertrophy. By observing the blood pressure, body weight, ventricular hypertrophy index, expression of B-type natriuretic peptide (BNP), myosin heavy chain beta (β-MHC), atrial natriuretic peptide (ANP), serum amyloid A SAA mRNA, level of endothelin-1 (ET-1) protein, histopathological changes of myocardial cells, and the myocardial ultrastructure, we found that MHBFC significantly ameliorated the changes in the structure of the heart and aorta, significantly decreased the blood pressure, myocardial cell cross-section area, level of ET-1 protein, and mRNA levels of BNP, β-MHC, ANP and SAA, prevented myocardial ultrastructure alterations, and relieved myocardial and perivascular fibrosis of wild-type mice. However, MHBFC could not induce any significant change in eNOS gene knockout mice. These results show that MHBFC is beneficial to protect against cardiac hypertrophy after banding of the abdominal aorta in wild-type mice, but has no such effect on eNOS gene knockout mice, which indicates that MHBFC is dependent on the existence of the eNOS gene in reversing cardiac hypertrophy.

Background: An artificial intelligence method could accelerate the clinical implementation of tumour-stroma ratio (TSR), which has prognostic relevance in colorectal cancer (CRC). We, therefore, developed a deep learning model for the fully automated TSR quantification on routine haematoxylin and eosin (HE) stained whole-slide images (WSI) and further investigated its prognostic validity for patient stratification. Methods: We trained a convolutional neural network (CNN) model using transfer learning, with its nine-class tissue classification performance evaluated in two independent test sets. Patch-level segmentation on WSI HE slides was performed using the model, with TSR subsequently derived. A discovery (N=499) and validation cohort (N=315) were used to evaluate the prognostic value of TSR for overall survival (OS). Findings: The CNN-quantified TSR was a prognostic factor, independently of other clinicopathologic characteristics, with stroma-high associated with reduced OS in the discovery (HR 1.72, 95% CI 1.24-2.37, P=0.001) and validation cohort (2.08, 1.26-3.42, 0.004). Integrating TSR into a Cox model with other risk factors showed improved prognostic capability. Interpretation: We developed a deep learning model to quantify TSR based on histologic WSI of CRC and demonstrated its prognostic validity for patient stratification for OS in two independent CRC patient cohorts. This fully automatic approach allows for the objective and standardised application while reducing pathologists' workload. Thus, it can potentially be of significant aid in clinical prognosis prediction and decision-making. Funding: National Key Research and Development Program of China, National Science Fund for Distinguished Young Scholar, and National Science Foundation for Young Scientists of China.

Background: Dai is a major Chinese ethnic minority group residing in rural areas of the southern part of Yunnan. However, no data exist on the Human Papillomavirus (HPV) prevalence and genotype distribution among Dai women. Method: A total of 793 participants (Dai = 324, Han = 251, other ethnic = 218) were included in this study. PCR was performed to detect the HPV-positive samples, and genotyping was performed with an HPV Geno-Array. Result: The overall HPV prevalence was very low among Dai women compared to the others. The prevalence of high-risk-HPV infections was significantly higher (p = 0.001) among other ethnic women (22.0%) than that among Han (13.1%) and Dai women (7.1%). The overall HPV, high-risk-HPV, single and multiple infection prevalence among rural women were 12.9%, 12.1%, 12.3%, and 0.5%, respectively. HPV-16 (5.5%) was shown to be the most prevalent genotype, followed by HPV-52 (2.6%) and HPV-58 (2.4%). Urban women had relatively higher rates of overall HPV (16.0%), high-risk-HPV (14.1%), single genotype (11.9%), and multiple genotype (4.1%) infections. In urban women, HPV-52 (3.6%) was the most prevalent genotype, followed by HPV-39 (2.7%) and HPV-16 (1.2%). In the urban area, HPV prevalence was highest in women aged 50 years). Education and smoking habit were significantly associated with HPV infection among both rural and urban area women (p

Millettia pulchra Kurz var-laxior (Dunn) Z. Wei, a wild-growing plant of the family Fabaceae is known to possess multifarious medicinal properties. 17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) is a flavonoid monomer extracted from its root, which has been used in traditional Chinese medicine, with a long history as a remedy of hypertension and cardiovascular remodeling. The present study was conducted to further investigate the regulatory mechanisms of MHBFC based on the endothelial nitric oxide synthase-nitric oxide (eNOS-NO) signaling pathway. The abdominal aorta of the male Sprague–Dawley rats was narrowed to induce cardiac remodeling, and the rats were given corresponding drugs for 6 weeks after operation. At the end of the experiment, the relevant indexes were detected. The results showed that Nω-nitro-L-arginine methyl ester (L-NAME) could increase the myocardial cell cross-section area, myocardial fibrosis, and the cardiac collagen volume fraction. The serum NO and eNOS levels and the expression of p-eNOS, p-PI3K and p-Akt protein were decreased, and myocardial microvascular endothelial cell (MMVEC) apoptosis increased. However, the above changes were reversed after treatment with MHBFC. These results indicated that MHBFC could increase eNOS protein phosphorylation by increasing PI3K and Akt protein phosphorylation, and activated the eNOS-NO signaling pathway, increased eNOS enzyme activity, catalyzed the generation of protective NO, and counteracted MMVEC apoptosis induced by cardiac remodeling, thereby protecting against myocardial damage and reversing cardiac remodeling.

This study was designed to explore baseline data about the prevalence and distribution of human papillomavirus (HPV) genotypes among Chinese women who had cervical intraepithelial lesions and cervical cancer. A total of 511 patients were recruited, and biopsy samples were collected from these patients. Polymerase chain reaction was used to detect HPV-positive samples, and the HPV GenoArray kit was used for genotyping. A total of 23 genotypes were detected, including 13 that were high risk-HPV (HR-HPV), 3 that were potential high risk-HPV (PHR-HPV) and 7 that were low risk-HPV (LR-HPV). The prevalence rates of HPV infection in Han women diagnosed with cervical intraepithelial lesions (CIN) 1, 2, and 3 and squamous cell carcinoma (SCC) were 98.30%, 97.56, 100% and 90%, respectively. The HPV-positive cases in women of other ethnicities diagnosed with CIN1, CIN2, and CIN3 and SCC were 95%, 90.91%, 88.23% and 83.33%, respectively. The most frequent genotypes in both ethnic groups were HPV-16, 52, and 58. LR-HPV was detected in SCC lesions in the non-Han ethnic group. In the Han ethnic group, the LR-HPV genotype was mostly restricted to CIN1 lesions. Furthermore, we found a high prevalence of PHR-HPV-81 in SCC lesions among Han women. Ethnic background, smoking, sex at an early age, unprotected sex, use of contraceptives, and the withdrawal method were found to be significantly associated with HPV infection. In conclusion, this study explores epidemiological data regarding the prevalence of HPV and the genotype distribution in patients with SCC and CIN lesions in Yunnan Province, China., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)