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As a new investigation for renewable energy generation, the recent three-layer solar structure is composited with three effective material usages of Al (resonator), InSb (substrate), and Ag (based). The overall wavelength of overall 2800 nm with the bandwidth order from 0.2 to 3.0 μm is 91.68%, the extracted percentage is 97.07% at 800 nm (1.41-2.21) µm, and the output is 95.02% with the 1420 nm wavelength by the bandwidth separation of 1.09 and 2.51 μm respectively. With the graphene accumulation in this absorber, the radiated output can be determined in the first visible area, the second ultraviolet region, and the near-infrared spectra respectively. The multi-step exploration of the absorbed rate in design performance, the selected materials and parameter assignments, and the analyzed parametric numbers for each layer will be included in the proposed presentation. The demonstrated solar structure can be performed at the low-temperate rate of less than 100 °C for heating processes of water or space, between 100 and 250 °C for industrial processes, and above 250 °C to release the steam for running turbines in the electricity generation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The contributed absorber design in graphene addition with the displacement of three materials for resonator design in Aluminum (Al), the middle substrate position with Titanium nitride (TiN), and the ground layer deposition by Iron (Fe) respectively. For the absorption validation highlight, the best four absorption wavelengths (µm) of 0.29, 0.58, 1, and 2 are also selected to indicate the changes in radiation outputs for every observation. With the displacement of wavelength and bandwidth configuration, the current absorber is observed at 97.32% (more than 97%) for 1.5-2.5 µm wavelength range (1000 nm bandwidth) and above 95% rate (95.38%) is displayed by the 2000 nm bandwidth due to 0.5 and 2.5 µm wavelength separation. The 2800 nm band rate demonstration by 0.2-3 µm wavelength separation verifies 92.42%. For every analysis in this work, the output radiation is shown in ultraviolet region (UV), visible spectrum (Vis), and near-infrared (NIR) area respectively. In the following distribution of the current absorber, the design development in lithography and step-by-step, parametric assignment and AM configuration, radiation analysis for each parameter changes in graph presentation and conclusion. Additionally, the ML approach is applied to reduce the time required in the study. The current solar absorber in the new design can be generated for the multi-solar purposes of water heating, lighting, ventilation, charging for electronic devices, and electric vehicle transportation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

We designed an ultra-broadband graphene absorber structure with the applied resonator design based on the Al-AlSb-Cr structure, and a thin effective layer of graphene is inserted. To develop the role of the graphene in solar absorbers, the current structure investigates above 98% for 1500 nm bandwidth and 2800 nm (overall bandwidth) for 93.68%. In this study, the procedure of the investigated design in flow chat configuration, the multi-step presentation of the developed layers, and the analysis of the used parameters will be involved. The design is optimized using machine learning algorithm. The optimized design shows good performance compared to the other system. The newly investigated graphene design can be absorbed not only in visible places but also in near-infrared energy and ultraviolet zones. The other applications of the light trapping process, photovoltaic devices, and energy harvesting can also be used., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Numerous neurological disorders share a fatal pathologic process known as glutamate excitotoxicity. Among which, ischemic stroke is the major cause of mortality and disability worldwide. For a long time, the main idea of developing anti-excitotoxic neuroprotective agents was to block glutamate receptors. Despite this, there has been little successful clinical translation to date. After decades of "neuron-centered" views, a growing number of studies have recently revealed the importance of non-neuronal cells. Glial cells, cerebral microvascular endothelial cells, blood cells, and so forth are extensively engaged in glutamate synthesis, release, reuptake, and metabolism. They also express functional glutamate receptors and can listen and respond for fast synaptic transmission. This broadens the thoughts of developing excitotoxicity antagonists. In this review, the critical contribution of non-neuronal cells in glutamate excitotoxicity during ischemic stroke will be emphasized in detail, and the latest research progress as well as corresponding therapeutic strategies will be updated at length, aiming to reconceptualize glutamate excitotoxicity in a non-neuronal perspective., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Flexible hydroelectric generators (HEGs) are promising self-powered devices that spontaneously derive electrical power from moisture. However, achieving the desired compatibility between a continuous operating voltage and superior current density remains a significant challenge. Herein, a textile-based van der Waals heterostructure is rationally designed between conductive 1T phase tungsten disulfide@carbonized silk (1T-WS 2 @CSilk) and carbon black@cotton (CB@Cotton) fabrics with an asymmetric distribution of oxygen-containing functional groups, which enhances the proton concentration gradients toward high-performance wearable HEGs. The vertically staggered 1T-WS 2 nanosheet arrays on the CSilk fabric provide abundant hydrophilic nanochannels for rapid carrier transport. Furthermore, the moisture-induced primary battery formed between the active aluminum (Al) electrode and the conductive textiles introduces the desired electric field to facilitate charge separation and compensate for the decreased streaming potential. These devices exhibit a power density of 21.6 µW cm -2 , an open-circuit voltage (V oc ) of 0.65 V sustained for over 10 000 s, and a current density of 0.17 mA cm -2 . This performance makes them capable of supplying power to commercial electronics and human respiratory monitoring. This study presents a promising strategy for the refined design of wearable electronics., (© 2024 Wiley‐VCH GmbH.)

Flexible moisture-electric generators (MEGs) capture chemical energy from atmospheric moisture for sustainable electricity, gaining attention in wearable electronics. However, challenges persist in the large-scale integration and miniaturization of MEGs for long-term, high-power output. Herein, a vertical heterogeneous phase-engineering MoS 2 nanosheet structure based silk and cotton were rationally designed and successfully applied to construct wearable MEGs for moisture-energy conversion. The prepared METs exhibit ∼0.8 V open-circuit voltage, ∼0.27 mA/cm 2 current density for >10 h, and >36.12 μW/cm 2 peak output power density, 3 orders higher than current standards. And the large-scale device realizes a current output of 0.145 A. An internal phase gradient between the 2H semiconductor MoS 2 in carbonized silks and 1T metallic MoS 2 in cotton fibers enables a phase-engineering-based heterogeneous electric double layer functioning as an equivalent parallel circuit, leading to enhanced high-power output. Owing to their facile customization for seamless adaptation to the human body, we envision exciting possibilities for these wearable METs as integrated self-power sources, enabling real-time monitoring of physiological parameters in wearable electronics.

DNA cytosine methylation plays a vital role in repressing retrotransposons, and such derepression is linked with developmental failure, tumorigenesis and aging. DNA methylation patterns are formed by precisely regulated actions of DNA methylation writers (DNA methyltransferases) and erasers (TET, ten-eleven translocation dioxygenases). However, the mechanisms underlying target-specific oxidation of 5mC by TET dioxygenases remain largely unexplored. Here we show that a large low-complexity domain (LCD), located in the catalytic part of Tet enzymes, negatively regulates the dioxygenase activity. Recombinant Tet3 lacking LCD is shown to be hyperactive in converting 5mC into oxidized species in vitro. Endogenous expression of the hyperactive Tet3 mutant in mouse oocytes results in genome-wide 5mC oxidation. Notably, the occurrence of aberrant 5mC oxidation correlates with a consequent loss of the repressive histone mark H3K9me3 at ERVK retrotransposons. The erosion of both 5mC and H3K9me3 causes ERVK derepression along with upregulation of their neighboring genes, potentially leading to the impairment of oocyte development. These findings suggest that Tet dioxygenases use an intrinsic auto-regulatory mechanism to tightly regulate their enzymatic activity, thus achieving spatiotemporal specificity of methylome reprogramming, and highlight the importance of methylome integrity for development., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Ischemic stroke is a common issue that severely affects the human health. Between the central nervous system and the enteric system, the " Gut-Brain " axis, the bidirectional connection involved in the neuro-immuno-endocrine network, is crucial for the occurrence and development of ischemic stroke. Ischemic stroke can lead to change in the gut microbiota and gastrointestinal hormones, which will then reversely affect the disease development. Traditional Chinese Medicine (TCM) has unique advantages with reference to the treatment for ischemic stroke. The latest research revealed that a significant portion of medicines and prescriptions of TCM exert their therapeutic effects by improving the gut microbiota and regulating the secretion of gastrointestinal hormones. The present review summarized the Chinese medicines that play a therapeutic role in cerebral ischemia through regulating the "Gut-Brain" axis and described the corresponding mechanisms. This study attempts to provide reference for clinical selection of Chinese medicines and helps better understand the relevant mechanisms of action., Competing Interests: Declaration of interest All authors declare that No conflict of interest exists., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Lung adenocarcinoma (LUAD) is the most common malignant tumor that seriously affects human health. Previous studies have indicated that abnormal levels of glycosylation promote progression and poor prognosis of lung cancer. Thus, the present study aimed to explore the prognostic signature related to glycosyltransferases (GTs) for LUAD., Methods: The gene expression profiles were obtained from The Cancer Genome Atlas (TCGA) database, and GTs were obtained from the GlycomeDB database. Differentially expressed GTs-related genes (DGTs) were identified using edge package and Venn diagram. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ingenuity pathway analysis (IPA) methods were used to investigate the biological processes of DGTs. Subsequently, Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct a prognostic model for LUAD. Kaplan-Meier (K-M) analysis was adopted to explore the overall survival (OS) of LUAD patients. The accuracy and specificity of the prognostic model were evaluated by receiver operating characteristic analysis (ROC). In addition, single-sample gene set enrichment analysis (ssGSEA) algorithm was used to analyze the infiltrating immune cells in the tumor environment., Results: A total of 48 DGTs were mainly enriched in the processes of glycosylation, glycoprotein biosynthetic process, glycosphingolipid biosynthesis-lacto and neolacto series, and cell-mediated immune response. Furthermore, B3GNT3, MFNG, GYLTL1B, ALG3, and GALNT13 were screened as prognostic genes to construct a risk model for LUAD, and the LUAD patients were divided into high- and low-risk groups. K-M curve suggested that patients with a high-risk score had shorter OS than those with a low-risk score. The ROC analysis demonstrated that the risk model efficiently diagnoses LUAD. Additionally, the proportion of infiltrating aDCs (p < 0.05) and Tgds (p < 0.01) was higher in the high-risk group than in the low-risk group. Spearman's correlation analysis manifested that the prognostic genes (MFNG and ALG3) were significantly correlated with infiltrating immune cells., Conclusion: In summary, this study established a novel GTs-related risk model for the prognosis of LUAD patients, providing new therapeutic targets for LUAD. However, the biological role of glycosylation-related genes in LUAD needs to be explored further., (© 2022. The Author(s).)

Phaeocystis globosa is a marine-bloom-forming haptophyte with a polymorphic life cycle alternating between free-living cells and a colonial morphotype, that produces high biomass and impacts ecological structure and function. The mechanisms of P. globosa bloom formation have been extensively studied, and various environmental factors are believed to trigger these events. However, little is known about the intrinsic biological processes that drive the bloom process, and the mechanisms underlying P. globosa bloom formation remain enigmatic. Here, we investigated a P. globosa bloom occurring along the Chinese coast and compared the proteomes of in situ P. globosa colonies from bloom and dissipation phases using a tandem mass tag (TMT)-based quantitative proteomic approach. Among the 5540 proteins identified, 191 and 109 proteins displayed higher abundances in the bloom and dissipation phases, respectively. The levels of proteins involved in photosynthesis, pigment metabolism, nitrogen metabolism, and matrix substrate biosynthesis were distinctly different between these two phases. Ambient nitrate is a key trigger of P. globosa bloom formation, while the enhanced light harvest and multiple inorganic carbon-concentrating mechanisms support the prosperousness of colonies in the bloom phase. Additionally, colonies in the bloom phase have greater carbon fixation potential, with more carbon and energy being fixed and flowing toward the colonial matrix biosynthesis. Our study revealed the key biological processes underlying P. globosa blooms and provides new insights into the mechanisms behind bloom formation.

Background: A cluster randomized controlled trial of endoscopy-based screening for esophageal cancer (EC) and gastric cancer (GC) was conducted to evaluate the efficacy and feasibility of this strategy in a non-high-incidence rural area of China. The trial design and baseline findings are presented here., Methods: A total of 33 eligible villages in Luoshan County in Henan Province were assigned randomly to the intervention or control group in a 1:1 ratio by a computer-generated randomization list. Local residents aged 40 to 69 years were enrolled from the villages. Participants in the intervention group were risk-stratified with a questionnaire, and high-risk individuals were subsequently screened by endoscopy. The primary outcomes were EC and GC mortality. The secondary outcomes comprised the detection rate, stage distribution, and the treatment rate. In this study, baseline characteristics were assessed by a questionnaire. Multivariate logistic regression analysis was performed to explore factors associated with endoscopy compliance., Results: Trial recruitment was completed in 2017, and ultimately, there were 12,475 and 11,442 participants allocated to the intervention (17 clusters) and the control group (16 clusters), respectively. We included 23,653 participants in the analysis, with 12,402 in the intervention group and 11,251 in the control group. A total of 6,286 (50.7%) participants in the intervention group were estimated as high-risk individuals, and 2,719 (43.3%) underwent endoscopy. Multivariate logistic regression analysis demonstrated that some factors including age, gender, education, personality and mental health, and upper gastrointestinal diseases or symptoms might affect endoscopy compliance. The detection rates for positive cases of EC and GC were 0.22% and 0.55%, respectively. The rates for esophageal and gastric precancerous lesions were 0.70% and 2.35%, respectively. The early detection rates for EC and GC were 50.0% and 33.3%, respectively. Additionally, the overall treatment rate for positive cases was 90.0%., Conclusions: The diagnostic yield of endoscopy-based screening for EC and GC was relatively low in a non-high-incidence rural area. The study may offer clues for the improvement of endoscopy compliance and the optimization of screening strategies for upper gastrointestinal cancer in non-high-incidence areas., Trial Registration: Chinese Clinical Trial Registry ChiCTR-EOR-16008577., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4052/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Esophageal cancer is a malignant tumor that seriously endangers human health. Compared with surgery alone, enhanced recovery after surgery (ERAS) has been widely used in clinical practice because it can improve perioperative care, minimize complications, and accelerate the recovery of esophageal cancer patients. However, there is a lack of data supporting the cost-effectiveness of ERAS., Methods: This retrospective cohort study included 968 esophageal cancer patients according to the pre-determined inclusion and exclusion criteria. Based on the Chinese expert consensus and guidelines, we improved the ERAS protocols consisting of 17 core measures. Subjects receiving >60% of the ERAS optimization measures were classified as the ERAS group, while those receiving <60% were classified as the pre-ERAS group. The demographic information, clinical and cost data of these patients were collected from the medical records. Based on the data distribution, the clinical effects and costs between the two groups were examined using the independent-sample t -test, the rank sum test, or the chi-square test. The effect of cost-effectiveness ratio calculation was measured by the disease cure rate obtained from the discharge report., Results: A total of 374 and 594 patients were included in the ERAS and pre-ERAS groups, respectively, and there were no significant differences in gender, American Society of Anesthesiologists (ASA) grade, tumor location, tumor stage, and other basic conditions between the two groups. The intraoperative blood loss, hospital stays, postoperative rehabilitation time, postoperative complications, and the number of secondary admissions within 30 days postoperatively of the ERAS group were lower than those of the pre-ERAS group (P<0.05). Compared with the pre-ERAS group, participants in the ERAS group had lower direct medical cost, direct non-medical cost, and indirect cost (P<0.05). Moreover, the cost-effectiveness ratio of the ERAS group (118,439.0 Yuan) was lower than that of the pre-ERAS group (143,369.0 Yuan) with respect to the cure rate., Conclusions: The study demonstrated that compared with pre-ERAS, the application of ERAS in esophageal cancer patients may accelerate postoperative rehabilitation, reduce the length of hospital stays and postoperative complications, and have better cost-effectiveness, highlighting the potential of ERAS to improve the quality of medical care., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4169/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: The disease burden of lung cancer is high in Henan province, China, it is out of the utmost significance to figure the current epidemic status and temporal trend of lung cancer for effective prevention and control., Methods: The qualified data was obtained from the Henan Provincial Central Cancer Registry of China, covering 30.51% of the whole population. Incidence, mortality, proportions, and cumulative rates (among patients aged 0-74 years old) of lung cancer by areas, sex and age groups were estimated. The world Segi's standard population was applied to calculate the age-standardized rate. Joinpoint regression was used to calculate annual percentage change (APC) and average annual percentage change (AAPC) to evaluate temporal trends from 2010 to 2018., Results: In 2018, there were about 55,344 new cases of lung cancer in Henan province, with the crude incidence of 50.75/100,000, the age-standardized incidence rate by world standard (Segi's) population (ASIRW) of 37.14/100,000, and the cumulative rate of 4.57%. About 41,782 people died from lung cancer in 2018, with the crude mortality rate of 38.31/100,000, the age-standardized mortality rate by world standard (Segi's) population (ASMRW) of 27.09/100,000, and the cumulative rate of 3.22%. The age-specific incidence and mortality of lung cancer increased gradually as age increased and reached the peak at the age of 85+ years. The overall ASIRW (AAPC =0.3, P=0.531) and ASMRW (AAPC =-0.2, P=0.687) remained stable from 2010 to 2018, but decreased in urban areas from 2014 to 2018 (APC for ASIRW =-4.7, P=0.023; APC for ASMRW =-5.3, P=0.012). From 2010 to 2018, the incidence rate increased in the rural population aged 75+ years old (AAPC =4.2, P=0.023)., Conclusions: The incidence and mortality rates of lung cancer significantly decreased in urban areas partly due to the Cancer Screening Program in Urban China. Nonetheless, the disease burden remains high, especially in males and elderly population. Comprehensive prevention and control programs, such as smoking cessation intervention, screening, early diagnosis and early treatment programs, need to be implemented to reduce the burden of lung cancer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4029/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Ischemic stroke is a highly disabling and potentially fatal disease. After ischemic stroke, autophagy plays a key regulatory role as an intracellular catabolic pathway for misfolded proteins and damaged organelles. Mounting evidence indicates that astrocytes are strongly linked to the occurrence and development of cerebral ischemia. In recent years, great progress has been made in the investigation of astrocyte autophagy during ischemic stroke. This article summarizes the roles and potential mechanisms of astrocyte autophagy in ischemic stroke, briefly expounds on the crosstalk of astrocyte autophagy with pathological mechanisms and its potential protective effect on neurons, and reviews astrocytic autophagy-targeted therapeutic methods for cerebral ischemia. The broader aim of the report is to provide new perspectives and strategies for the treatment of cerebral ischemia and a reference for future research on cerebral ischemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Su, Zhai, Wang, Zhang, Wang, Ma, Han, Wu, Yu, Zhao and Wang.)

Background: It is great of significance to figure the time-trend of esophageal cancer (EC) and its current status for effective prevention and control, especially in EC high risk areas. As one of world-renowned high-risk areas, the epidemiology of EC in Henan has not been recently updated. Therefore, we aimed to depict the status quo of EC and analyze its time-trend in Henan., Methods: The EC data were extracted from the Henan Provincial Cancer registry database derived from the population based cancer registry system, which covered 30.51% of the whole population in Henan and were qualified according to national and international guidelines. The incidence and mortality of EC were estimated by area (rural/urban), gender, and age groups. The age-standardized rates (ASRs) were calculated according to the Segi's population. Joinpoint regression was used to calculate annual percentage change (APC) and average annual percentage change (AAPC) to evaluate the time-trend of EC., Results: As estimated, there were 29,913 new EC cases in Henan, 2018. The crude incidence and the age-standardized incidence rate by world standard population (ASIRW) was 27.43/10 5 and 19.96/10 5 , respectively. The incidence in males and rural was 1.83 and 1.51 times higher than that in females and urban areas, respectively. Meanwhile, it was estimated that 22,688 deaths occurred in 2018. The crude mortality and the age-standardized mortality rate by world standard population (ASMRW) were 20.80/10 5 and 14.47/10 5 , respectively. Similarly, males and rural areas had higher mortality compared with females and urban areas. The age-specific incidence and mortality of EC showed significant increasing after 60-64 years group. In general, the time-trend of incidence (APC: -8.9, P<0.001) and mortality (APC: -7.6, P<0.001) of EC showed a significant decreasing trend since 2014, and downward trend were also observed in rural areas for incidence (APC: -5.2, P<0.001) and mortality (APC: -3.9, P<0.001) from 2010 to 2018., Conclusions: The EC incidence and mortality in Henan has exhibited a significant declining trend in past years. Nonetheless, the disease burden remains high, especially in males and rural areas. Therefore, the ongoing prevention and control strategies of EC should be maintained alongside the establishment of more effective strategies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4027/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: There is limited and inconsistent literature examining the relationship between food worry and mental health in the context of the COVID-19 pandemic. This study examined the association between food worry and mental health among community dwelling Canadian adults during the COVID-19 pandemic., Methods: Adults age 16 years and older completed an anonymous online questionnaire between April 1, 2020 and November 30 2020. Measures of pre-pandemic and current food worry, depression (PHQ-2), anxiety (GAD-2), and sociodemographic variables were included. Multivariable logistic regression models were used to determine the association between food worry and symptoms of depression and anxiety., Results: In total, 1605 participants were included in analyses. Worry about affording food was reported by 320 (14.78%) participants. In models adjusting for sociodemographic covariates, compared with people without food worry, participants who had food worry were 2.07 times more likely to report anxiety symptoms (aOR 2.07, 95% CI: 1.43 - 2.98, p < .001) and were 1.9 times more likely to report depressive symptoms (aOR 1.89, 95% CI: 1.39-2.57, p < .0001). Lower income, lower education, and pre-existing mental health conditions were significant predictors of symptoms of depression. Female gender, younger age, lower education, lower income, and pre-existing mental health condition were significant predictors of anxiety symptoms., Conclusion: Our study highlights the relationship between food worry and poor mental health. Policy supports such as improved income supports, clinical implications such as screening for food worry in primary care, referral to emergency food programs and support with meal planning may help mitigate mental health symptoms during the current pandemic, during future societal recovery from this pandemic and during future pandemics., (© 2022. The Author(s).)

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 cross‑sectional, 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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1003/coif). All authors report that the research was funded by Merck Serono Co. Ltd. The authors have no other conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Biomimetic mineralization based on self-assembly has made great progress, providing bottom-up strategies for the construction of new organic-inorganic hybrid materials applied in the treatment of hard tissue defects. Herein, inspired by the cooperative effects of key components in biomineralization microenvironments, a new type of biocompatible peptide scaffold based on flexibly self-assembling low-complexity protein segments (LCPSs) containing phosphate or phosphonate groups is developed. These LCPSs can retard the transformation of amorphous calcium phosphate into hydroxyapatite (HAP), leading to merged mineralization structures. Moreover, the application of phosphonated LCPS over phosphorylated LCPS can prevent hydrolysis by phosphatases that are enriched in extracellular mineralization microenvironments. After being coated on the etched tooth enamel, these LCPSs facilitate the growth of HAP to generate new enamel layers comparable to the natural layers and mitigate the adhesion of Streptococcus mutans. In addition, they can effectively stimulate the differentiation pathways of osteoblasts. These results shed light on the potential biomedical applications of two LCPSs in hard tissue repair., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The 17α-hydroxylase/17, 20-lyase deficiency (17-OHD) is a rare disease. The clinical characteristics and gene mutation of 2 late-diagnosed 17-OHD patients with testicular tumor admitted to our hospital from March 2018 to February 2019 were analyzed retrospectively. The two 17-OHD patients were female (46, XY). Laparoscopic abdominal exploration found undeveloped testicles in grey-yellow or grey-red in the groin and iliac fossa. The testicles were removed and showed malignancy in pathology study. Sequencing of the CYP17A1 gene identified c.1247G>A/c.1427T>C and c.985&#95;987delTACinsAA/c.1306G>A complex heterozygous mutations. Taking together, the possibility of 17-OHD should be considered in patients with hypertension, hypokalemia, adrenal adenomatoid hyperplasia together with 46, XY gonadal dysplasia, so as to make early diagnosis and treatment, and avoid dysplastic testicular turning to malignancy.

Dementia literacy is important for risk mitigation and preventative strategies before disease onset. The aim of our study was to investigate dementia literacy and how demographic characteristics influence these perceptions in order to provide evidence for how dementia-centered public health initiatives should structure their focus. We conducted a globally administered online survey, through Amazon Mechanical Turk (mTurk). Survey items evaluated: (1) personal perception on the preventability of dementia, and (2) risk awareness of lifestyle factors. Differences in risk scoring between the 598 respondents were compared using Kruskal-Wallis testing factored by demographic categorizations. Most of the sample demonstrated understanding that lifestyle factors contribute some risk toward dementia, though these risk scores were generally low. Differences in risk scoring varied by demographic characteristics. Women, older adults, those with non-post-secondary attainment, below average income, and White background tended to report lower risk scores. Public health education and initiatives for dementia prevention should focus on lifestyle risk factors, in addition to considering the barriers related to the demographic factors identified that may prevent populations from accessing programs and information., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Horst, Furlano, Wong, Ford, Han and Nagamatsu.)

A novel STING agonist, CDG SF , ipsilaterally modified with phosphorothioate and fluorine, was synthesized. The phosphorothioate in CDG SF might be a site for covalent conjugation. Injection of CDG SF generated an immunogenic ("hot") tumor microenvironment to suppress melanoma, more efficiently than dithio CDG. In particular, immunization with SARS-CoV-2 spike protein using CDG SF as an adjuvant elicited an exceptionally high antibody titer and a robust T cell response, overcoming the drawbacks of aluminum hydroxide. These results highlighted the therapeutic potential of CDG SF for cancer immunotherapy and the adjuvant potential of the STING agonist in the SARS-CoV-2 vaccine for the first time.

We developed a host-guest ATP responsive strategy for efficient intracellular delivery of phosphopeptides, employing a pegylated arginine clustered calix[5]arene nanocarrier system that has great capability of recognizing the phosphate moieties on peptides and penetrating the cell membrane.

Tet3 regulates the dynamic balance between 5-methylcyotsine (5mC) and 5-hydroxymethylcytosine (5hmC) in DNA during brain development and homeostasis. However, it remains unclear how its functions are modulated in a context-dependent manner during neuronal differentiation. Here, we show that cyclin-dependent kinase 5 (cdk5) phosphorylates Tet3 at the highly conserved serine 1310 and 1379 residues within its catalytic domain, changing its in vitro dioxygenase activity. Interestingly, when stably expressed in Tet1, 2, 3 triple-knockout mouse embryonic stem cells (ESCs), wild-type Tet3 induces higher level of 5hmC and concomitant expression of genes associated with neurogenesis whereas phosphor-mutant (S1310A/S1379A) Tet3 causes elevated 5hmC and expression of genes that are linked to metabolic processes. Consistent with this observation, Tet3-knockout mouse ESCs rescued with wild-type Tet3 have higher level of 5hmC at the promoter of neuron-specific gene BRN2 when compared to cells that expressed phosphor-mutant Tet3. Wild-type and phosphor-mutant Tet3 also exhibit differential binding affinity to histone variant H2A.Z. The differential 5hmC enrichment and H2A.Z occupancy at BRN2 promoter is correlated with higher gene expression and more efficient neuronal differentiation of ESCs that expressed wild-type Tet3. Taken together, our results suggest that cdk5-mediated phosphorylation of Tet3 is required for robust activation of neuronal differentiation program., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objective: To observe the effect of manual acupuncture (MA)＋ electroacupuncture (EA) on changes of neurological function and expression of monocarboxylate transporter 2(MCT2)in cerebral ischemia (CI) rats, so as to explore its mechanism underlying improvement of ischemic cerebrovascular disease., Methods: Eighty male Wistar rats were equally randomized into four groups: normal control (normal), sham operation (sham), model and acupuncture. The CI model was induced by middle cerebral artery occlusion (MCAO) with a thread embolus. Manual acupuncture stimulation (mild twisting reinforcing-reducing method) was applied to "Baihui"(GV20)and "Fengfu"(GV16) for 10 min. EA (1 mA, 2 Hz /15 Hz) was respectively applied to bilateral "Quchi" (LI11) and "Zusanli"(ST36) for 20 min, once per day for 7 days. The neurological deficit severity was evaluated according to Zea Longa's methods. The activity of lactate dehydrogenase (LDH), fructose-6-phosphate kinase (PFK) and pyruvate kinase (PK) in the peri-ischemic cortex tissue was detected by enzymatic chemistry, and the expression of MCT2 detected by immunofluorescence histochemistry, Western blot and quantitative real-time PCR, separately., Results: After CI and in comparison with the normal and sham groups, the Zea Longa's score, the fluorescence intensity and the expression level of MCT2 protein were significantly increased ( P <0.01), and the activity of LDH, PFK and PK in the peri-ischemic cortex was significantly decreased in the model group ( P <0.01). There was no significant change in the relative expression of MCT2 mRNA ( P >0.05). Following the intervention and in comparison with the model group, the Zea Longa's score was considerably decreased in the acupuncture group ( P <0.01), the activity of LDH, PFK and PK，and the expression levels of MCT2 protein and mRNA were considerably or further up-regulated in the acupuncture group ( P <0.01, P <0.05)., Conclusion: Acupuncture intervention can improve neurological function in CI rats, which is possibly related with its effects in up-regulating the expression of MCT2 and promoting the utilization of lactate in peri-ischemic cortex.

Intracellular protein delivery is of significance for cellular protein analysis and therapeutic development, but remains challenging technically. Herein, we report a general and highly potent strategy for intracellular protein delivery based on commercially available cationic lipids. In this strategy, a designed double branching poly-glutamate tag is site-specifically attached onto the C-terminal of protein cargos via expressed protein ligation (EPL), which mediates the entrapment of proteins into cationic liposomes driven by electrostatic interaction. The resultant protein-lipid complexes can enter into cytosol with a high efficiency even at the low protein concentration while maintaining protein's biological activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recent evidence suggests a link between cathepsin L (CTSL) and vascular diseases. However, its contribution to reactive oxygen species (ROS) homeostasis in the vasculature remains unknown. p66shc is a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals. In this study, we explored the relationship between CTSL and oxidative damage in vasculature and whether the oxidative damage is mediated by p66shc.Carotid arteries from aged mice (24 months old) showed a reduction in CTSL expression compared with young wild-type mice (4 months old). Local knockdown of CTSL in carotid arteries of young mice by adenoviral vector encoding the short hairpin RNA targeting CTSL leading to premature vascular aging, as shown by mitochondrial disruption, increased β-galactosidase-positive cells, reduced telomerase activity, and up-regulation of p66shc. Knockdown of CTSL decreased the expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, III, and IV, leading to increased mitochondrial ROS and hyperpolarization of the mitochondrial membrane in vitro. Furthermore, knockdown of CTSL also stimulated ROS production and senescence in vascular cells, accompanied by the up-regulation of p66shc.However, p66shc knockdown blunted the alteration in ROS production, and senescence in CTSL knockdown vascular cells. This study suggests that CTSL knockdown partially induces vascular cells damage via increased ROS production and up-regulation of p66shc.

Objective: To determine critical reference value (cut-off value) of serum pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase(NSE) in the diagnosis of small cell lung cancer(SCLC). To evaluate the clinical significance of serum levels of ProGRP and NSE in diagnosis and differential diagnosis in SCLC. Methods: Three hundred and fifty-two SCLC patients, 163 non small cell lung cancer(NSCLC)patients , 193 benign pulmonary disease patients and 140 healthy people visiting in National Cancer Hospital were analyzed retrospectively from January 2014 to July 2017.The levels of serum ProGRP and NSE of people were determined using electrochemiluminescent immunoassay respectively . Reference value ranges of the makers were determined by using the method of ROC curves. Results: In NSCLC group, benign lung disease group, healthy control group and mixed group (NSCLC+ lung benign diseases+ healthy control group) as a reference, the cut-off values were 58.3, 62.3, 57.8, 61.3 ng/L. In the diagnosis and differential diagnosis of SCLC and NSCLC, benign lung diseases, healthy controls and mixed group, AUC of ProGRP was 0.940 (0.919-0.961), 0.941 (0.921-0.960), 0.959 (0.944-0.975), 0.946 (0.928-0.963) respectively. The sensitivities of ProGRP were 86.4%, 84.9%, 86.4% and 84.7% respectively. The specificities of ProGRP were 95.7%, 96.9%, 99.3%, 98% respectively. In all groups the Youden's index of ProGRP and NSE were 0.821 vs 0.612, 0.818 vs 0.674, 0.857 vs 0.810, 0.827 vs 0.674. In healthy controls, no statistically significant difference was found between ProGRP and NSE ( P >0.05) in the diagnosis of AUC. However, in the remaining 3 groups, the ProGRP diagnosis of AUC was significantly greater than that of NSE ( P <0.01). Compared with single marker detection, the sensitivity of combined detection of ProGRP and NSE in diagnosis of SCLC increased to 95.5%, 94%, 96.6% and 94% in each group. There was no significant difference between ProGRP and ProGRP+ NSE in the diagnosis of AUC when compared with the NSCLC group and the mixed group ( P >0.05). However, when combined with a healthy control group and a benign lung disease group, the ProGRP+ NSE combination was the highest for AUC diagnosis, compared with ProGRP and NSE ( P <0.01). In the SCLC ED group serum ProGRP and NSE levels[776.33(3 103.4)ng/L, 52.14(60.59)μg/L]were higher than those in the SCLC LD group[295.59(799.65)ng/L, 23.36(22.97)μg/L], respectively (all P <0.001). The serum ProGRP levels of N0, N1, N2 and N3 in TNM staging were 113.0(343.65), 167.04(724.56), 427.42(1 388.62), 735.99(1 709.95)ng/L respectively (all P <0.001). Serum ProGRP and NSE levels were not statistically different between the sex groups and the age groups (all P >0.05). Conclusion: To establish the cut-off value of serum ProGRP is helpful for the diagnosis and differential diagnosis of SCLC.

A thioacetohydrazide functionalized pillar[5]arene was synthesized, which could further assemble into a linear supramolecular metal-organic polymer upon adding Zn 2+ . Furthermore, the obtained linear supramolecular metal-organic polymer could self-assemble to form a fluorescent supramolecular metal-organic gel at high concentration. When TBAOH was added to the viscous solution at high temperature, the obtained solution could not form a supramolecular metal-organic gel upon cooling. More importantly, when Hg 2+ ions are added to the metal-organic gel, the strong blue fluorescence is clearly quenched, and this metal-organic gel (xerogel) could effectively remove Hg 2+ from water. Simultaneously, a thin film based on the metal-organic gel was prepared, which was confirmed to be a convenient test kit for detecting Hg 2+ .

Radix Astragali (RA) with slight sweet and warm property is a significant "qi tonifying" herb; it is indicated for the syndrome of dampness stagnancy due to spleen deficiency (DSSD). The purpose of this research was to explore effects of RA and its split components on gene expression profiles related to water metabolism in rats with the DSSD syndrome for identifying components representing property and flavor of RA. The results indicated that RA and its split components, especially polysaccharides component, significantly increased the body weight and the urine volume and decreased the water load index of model rats. Our data also indicated differentially expressed genes (DEGs) related to water metabolism involved secretion, ion transport, water homeostasis, regulation of body fluid levels, and water channel activity; the expression of AQP1, AQP3, AQP4, AQP5, AQP6, and AQP8 was improved; calcium, cAMP, MAPK, PPAR, AMPK, and PI3K-Akt signaling pathway may be related to water metabolism. In general, results indicate that RA and its split components could promote water metabolism in rats with the DSSD syndrome via regulating the expression of AQPs, which reflected sweet-warm properties of RA. Effects of the polysaccharides component are better than others.

Recent studies indicated that Gene Associated with Retinoid-IFN-Induced Mortality 19 (GRIM-19), a newly discovered mitochondria-related protein, can regulate mitochondrial function and modulate cell viability possibly via interacting with STAT3 signal. In the present study we sought to test: 1) whether GRIM-19 is involved in high glucose (HG) induced altered cell metabolism in both cancer and cardiac cells, 2) whether GRIM-19/STAT3 signaling pathway plays a role in HG induced biological effects, especially whether AMPK activity could be involved. Our data showed that HG enhanced cell proliferation of both HeLa and H9C2 cells, which was closely associated with down-regulated GRIM-19 expression and increased phosphorylated STAT3 level. We showed that GRIM-19 knock-down alone in normal glucose cultured cells can also result in an increase in phosphorylated STAT3 level and enhanced proliferation capability, whereas GRIM-19 over-expression can abolished HG induced STAT3 activation and enhanced cell proliferation. Importantly, both down-regulated or over-expression of GRIM-19 increased lactate production in both HeLa and H9C2 cells. The activated STAT3 was responsible for increased cell proliferation as either AG-490, an inhibitor of JAK2, or siRNA targeting STAT3 can attenuate cell proliferation increased by HG. In addition, HG increased lactate acid levels in HeLa cells, which was also observed when GRIM-19 was genetically manipulated. However, HG did not affect the lactate levels in H9C2 cells. Of note, over-expression of GRIM-19 and silencing of STAT3 both increased lactate production in H9C2 cells. As expected, HG resulted in significant decreases in phosphorylated AMPKα levels in H9C2 cells, but not in HeLa cells. Interestingy, activation of AMPKα by metformin was associated with a reversal of the suppressed GRIM-19 expression in H9C2 cells, the fold of changes in GRIM-19 expression by metformin were much less in HeLa cells. Metformin did not affect the phosphorylated STAT3 lelvels, however, decreased its levels in H9C2, especially in the setting of HG culture. Not like HG alone which resulted in no changes in lactate acid in H9C2 cells, metformin can increase lactate acid levels in H9C2 cells. Increased lactate induced by metformin was also observed in HeLa cells.

In mammals, active DNA demethylation involves oxidation of 5-methylcytosine (5mC) into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by Tet dioxygenases and excision of these two oxidized bases by thymine DNA glycosylase (TDG). Although TDG is essential for active demethylation in embryonic stem cells and induced pluripotent stem cells, it is hardly expressed in mouse zygotes and dispensable in pronuclear DNA demethylation. To search for other factors that might contribute to demethylation in mammalian cells, we performed a functional genomics screen based on a methylated luciferase reporter assay. UNG2, one of the glycosylases known to excise uracil residues from DNA, was found to reduce DNA methylation, thus activating transcription of a methylation-silenced reporter gene when co-transfected with Tet2 into HEK293T cells. Interestingly, UNG2 could decrease 5caC from the genomic DNA and a reporter plasmid in transfected cells, like TDG. Furthermore, deficiency in Ung partially impaired DNA demethylation in mouse zygotes. Our results suggest that UNG might be involved in Tet-mediated DNA demethylation., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

The current study presents a rare case of an accessory spleen that manifested as a solid intrasplenic pseudotumor. The affected patient was previously healthy. Upon examination with computed tomography (CT), an ovoid, soft-tissue mass of ~4.1 cm in diameter was found on the upper pole of the spleen. Biochemical indices, such as blood routine and coagulation tests, and tumor marker analysis, revealed no abnormalities. Another CT scan was performed, but this failed to indicate whether the mass was benign or malignant. Therefore, the lesion was resected along with the spleen by laparoscopic surgery. The resected sample was subject to pathological examinations for final validation, and was finally diagnosed as an accessory spleen. The patient was followed up for six months with no signs of recurrence.

The membrane-associated protein, focal adhesion kinase (FAK), modulates cell-extracellular matrix interactions and also conveys prosurvival and proliferative signals. Notably, increased intraepithelial FAK levels accompany transformation of premalignant oral intraepithelial neoplasia (OIN) to oral squamous cell carcinoma (OSCC). OIN chemoprevention is a patient-centric, optimal strategy to prevent OSCC's comorbidities and mortality. The cancer chemopreventive and synthetic vitamin A derivative, fenretinide, has demonstrated protein-binding capacities, for example, mTOR- and retinol-binding protein interactions. These studies used a continuum of human oral keratinocytes (normal-HPV E6/E7-transduced-OSCC) to assess potential fenretinide-FAK drug protein interactions and functional consequences on cellular growth regulation and motility. Molecular modeling studies demonstrated that fenretinide has approximately 200-fold greater binding affinity relative to the natural ligand (ATP) at FAK's kinase domain. Fenretinide also shows intermediate binding at FAK's FERM domain and interacts at the ATP-binding site of the closest FAK analogue, PYK2. Fenretinide significantly suppressed proliferation via induction of apoptosis and G2-M cell-cycle blockade. Fenretinide-treated cells also demonstrated F-actin disruption, significant inhibition of both directed migration and invasion of a synthetic basement membrane, and decreased phosphorylation of growth-promoting kinases. A commercially available FAK inhibitor did not suppress cell invasion. Notably, although FAK's FERM domain directs cell invasion, FAK inhibitors target the kinase domain. In addition, FAK-specific siRNA-treated cells showed an intermediate cell migration capacity; data which suggest cocontribution of the established migrating-enhancing PYK2. Our data imply that fenretinide is uniquely capable of disrupting FAK's and PYK2's prosurvival and mobility-enhancing effects and further extend fenretinide's chemopreventive contributions beyond induction of apoptosis and differentiation., (©2015 American Association for Cancer Research.)

Isoquercitrin is a rare, natural ingredient with several biological activities that is a key precursor for the synthesis of enzymatically modified isoquercitrin (EMIQ). The enzymatic production of isoquercitrin from rutin catalyzed by hesperidinase is feasible; however, the bioprocess is hindered by low substrate concentration and a long reaction time. Thus, a novel biphase system consisting of [Bmim][BF4]:glycine-sodium hydroxide (pH 9) (10:90, v/v) and glyceryl triacetate (1:1, v/v) was initially established for isoquercitrin production. The biotransformation product was identified using liquid chromatography-mass spectrometry, and the bonding mechanism of the enzyme and substrate was inferred using circular dichroism spectra and kinetic parameters. The highest rutin conversion of 99.5% and isoquercitrin yield of 93.9% were obtained after 3 h. The reaction route is environmentally benign and mild, and the biphase system could be reused. The substrate concentration was increased 2.6-fold, the reaction time was reduced to three tenths the original time. The three-dimensional structure of hesperidinase was changed in the biphase system, which α-helix and random content were reduced and β-sheet content was increased. Thus, the developed biphase system can effectively strengthen the hesperidinase-catalyzed synthesis of isoquercitrin with high yield.

Objective: To observe the effect of electroacupuncture(EA) intervention on changes of neurological function and expression of cerebral cytochrome P 450 2 C 11 (CYP 2 0 11) mRNA in focal cerebral ischemia (FCI) rats, so as to explore its mechanism underlying improvement of ischemic cerebral vascular disease., Methods: Wistar rats were randomly divided into normal, model, EA and EA+ 17-ODYA (17-Octadecynoic acid, an inhibitor for the metabolism of arachidonic acid by cytochrome P 450) groups. Focal cerebral ischemia rats were induced by middle cerebral artery occlusion (MCAO) with thread embolus. EA was applied to bilateral "Neiguan"(PC 6 ) and "Quchi" (LI 11) after MCAO. Zea Longa's score and beam walking test (BWT) score of rats were used to evaluate the neurological impairment. Local cerebral blood flow (LCBF) of the pial tissue was moni- tored using Laser-Doppler Flowmetry. The expression of cerebral CYP 2 C 11 mRNA was examined by Real-time Quantitative PCR (qPCR)., Results: In comparison with the normal group, BWT score and LCBF of the model group were significantly decreased (P<0.05), and Zea Longa's score and cerebral CYP 2 C 11 mRNA expression level of the model group were significantly increased (P<0.05). While in comparison with the model group, BWT score, LCBF and cerebral CYP2 C 11 mRNA levels were considerably up-regulated and Zea Longa's score was down-regulated in the EA group (P<0.05) rather than in the EA + 17- ODYA group (P<0.05). H.E. stainshowed that the nerve impairment of the ischemic cerebral tissue including the neuronal degeneration, necrosis, apoptosis, etc. was relatively milder in the EA group., Conclusion: EA intervention can improve cerebral blood flow and up-regulate cerebral CYP 2 C 11 mRNA expression in FCI rats, which may contribute to its action in improving neu- rological impairment.

Objective: To observe the effect of electroacupuncture (EA) intervention on dynamic changes of neurological function, blood glucose and insulin levels in rats with focal cerebral ischemia (CI), so as to explore its mechanism underlying improvement of ischemic cerebral vascular disease., Methods: Male Wistar rats were randomly divided into four groups: normal, sham-operation (sham), model and EA. CI model was induced by middle cerebral artery occlusion (MCAO). The four groups were further randomized into 5 subgroups according to time-points of MCAO: 6 hour, day 1, day 3, day 7 and day 14 (8 rats/ group). EA (2 Hz/15 Hz, 1 mA) was applied to bilateral "Neiguan" (PC 6) and "Quchi" (LI 11) for 30 min, once daily for 1 day to 14 days. Neurological impairment was evaluated by Zea Longa 5-point scoring system. Local cerebral blood flow (LCBF) of the cerebral pia mater was determined using Laser Doppler Flowmetry. The levels of abdominal cavity venous blood glucose and serum insulin were measured by using a glucose meter and radioimmunoassay, respectively., Results: In comparison with the normal and sham groups, the rats' body weights and LCBF levels at time-points of day 1, 3, 7 and 14, and blood glucose and serum insulin levels at most time-points of 6 h, day 1, 3, 7 and 14 after CI were significantly decreased in the model group (P < 0.05), and neurological scores at time-points of 6 h, day 1, 3, 7 and 14 were markedly increased in the model group (P < 0.05). After EA intervention, compared with the model group, the rats' body weights at time points of day 3, 7 and 14, LCBF levels on day 7 and 14, blood glucose on day 14, and serum insulin contents at time-points of day 1, 3, 7 and 14 were considerably increased in the EA group (P < 0.05), while Zea Longa scores at time-points of day 3 and 7 were evidently decreased in the EA group (P<0.05)., Conclusion: EA intervention is effective in improving neurological function in CI rats, which is probably associated with its functions in improving cerebral blood flow, and up-regulating blood glucose and insulin levels.

The presence of the EMT (epithelial-mesenchymal transition), EndMT (endothelial-mesenchymal transition) and VM (vasculogenic mimicry) demonstrates the multidirectional extent of phenotypic plasticity in cancers. Previous findings demonstrating the crosstalk between head and neck squamous cell carcinoma (HNSCC) and vascular endothelial growth factor (VEGF) imply that HNSCC cells share some functional commonalities with endothelial cells. Our current results reveal that cultured HNSCC cells not only possess endothelial-specific markers, but also display endotheliod functional features including low density lipoprotein uptake, formation of tube-like structures on Matrigel and growth state responsiveness to VEGF and endostatin. HNSCC cell subpopulations are also highly responsive to transforming growth factor-β1 and express its auxiliary receptor, endoglin. Furthermore, the endotheliod characteristics observed in vitro recapitulate phenotypic features observed in human HNSCC tumors. Conversely, cultured normal human oral keratinocytes and intact or ulcerated human oral epithelia do not express comparable endotheliod characteristics, which imply that assumption of endotheliod features is restricted to transformed keratinocytes. In addition, this phenotypic state reciprocity facilitates HNSCC progression by increasing production of factors that are concurrently pro-proliferative and pro-angiogenic, conserving cell energy stores by LDL internalization and enhancing cell mobility. Finally, recognition of this endotheliod phenotypic transition provides a solid rationale to evaluate the antitumorigenic potential of therapeutic agents formerly regarded as exclusively angiostatic in scope., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To construct a recombinant short hairpin RNA (shRNA) expression vector targeting EZH2 gene, and to determine its effect on the proliferation of colon adenocarcinoma SW480 cells., Methods: The DNA sequence with short hairpin structure was designed according to the EZH2 cDNA sequence and cloned into PGFP-V-RS vector to construct a recombinant expression vector silencing EZH2 gene. After identification, the shRNA-expressing vector was then transfected into SW480 cells. RT-PCR and Western blot were used to detect the inhibitory effect at both mRNA and protein levels. MTT was used to detect cell viability due to the alteration of EZH2 gene activity., Results: At 48 h after transfection, the expression of EZH2 mRNA in the gene silencing group and negative control group were 0.339 ± 0.013 and 1.968 ± 0.072, respectively. The expression of EZH2 protein in the gene silencing group and negative control group were 0.229 ± 0.008 and 1.168 ± 0.053, respectively. The expression of EZH2 in the gene silencing group was significantly lower than that in the negative control group (P < 0.01, P < 0.05). At 48 and 72 h after transfection, the inhibition rate of cell growth in the gene silencing group was 30.7% and 25.9%, respectively, indicating that the cell growth was significantly inhibited in comparison with that in the blank control group (P < 0.05)., Conclusions: A recombinant shRNA expression vector targeting EZH2 gene has been successfully constructed in this study, with a significant inhibitory effect on the proliferation of SW480 cells. This lays an experimental foundation for further exploring the mechanism underlying the action of EZH2 gene on tumor biology.

Systemic delivery of fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and subtherapeutic intraoral drug levels. Local drug delivery, however, provides site-specific therapeutically relevant levels while minimizing systemic exposure. These studies evaluated the pharmacokinetic and growth-modulatory parameters of fenretinide mucoadhesive patch application on rabbit buccal mucosa. Fenretinide and blank-control patches were placed on right/left buccal mucosa, respectively, in eight rabbits (30 min, q.d., 10 days). No clinical or histological deleterious effects occurred. LC-MS/MS analyses of post-treatment samples revealed a delivery gradient with highest fenretinide levels achieved at the patch-mucosal interface (no metabolites), pharmacologically active levels in fenretinide-treated oral mucosa (mean: 5.65 μM; trace amounts of 4-oxo-4-HPR) and undetectable sera levels. Epithelial markers for cell proliferation (Ki-67), terminal differentiation (transglutaminase 1-TGase1) and glucuronidation (UDP-glucuronosyltransferase1A1-UGT1A1) exhibited fenretinide concentration-specific relationships (elevated TGase1 and UGT1A1 levels <5 μM, reduced Ki-67 indices >5 μM) relative to blank-treated epithelium. All fenretinide-treated tissues showed significantly increased intraepithelial apoptosis (TUNEL) positivity, implying activation of intersecting apoptotic and differentiation pathways. Human oral mucosal correlative studies showed substantial interdonor variations in levels of the enzyme (cytochrome P450 3A4-CYP3A4) responsible for conversion of fenretinide to its highly active metabolite, 4-oxo-4-HPR. Complementary in vitro assays in human oral keratinocytes revealed fenretinide and 4-oxo-4-HPR's preferential suppression of DNA synthesis in dysplastic as opposed to normal oral keratinocytes. Collectively, these data showed that mucoadhesive patch-mediated fenretinide delivery is a viable strategy to reintroduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials.

Objective: To observe different effects of acetoacetate extract of Radix Aconite and Radix Aconite Decoction on the energy metabolism in deficient cold model rats., Methods: Wistar rats were randomly divided into the blank control group (n=10) and the deficient cold model group (n=30). The deficient cold rat model was established using decoction consisting of gypsum, Radix Gentianae, Cortex Phellodendri, and Rhizoma Anemarrhenae. The decoction was given to rats of the deficient cold model group by gastrogavage for 5 days. Then these rats were randomly divided into the acetoacetate extract of Radix Aconite group (n=10), the Radix Aconite Decoction group (n=10), and the model group (n=10). Rats in the model model group were administered with the decoction by gastrogavage. Rats in the other two groups were administered with the acetoacetate extract of Radix Aconite or Radix Aconite Decoction by gastrogavage for 5 days. The contents of lactic acid (LA), lactate dehydrogenase (LDH), pyruvate (PA), glycogen (Gn) and activities of Na(+) -K(+) -ATPase and Ca(2+) -Mg(2+) -ATPase in the hepatic tissue were detected., Results: Compared with the blank control group, the PA content, activities of Na(+)-K(+) -ATPase and Ca(2+) -Mg(2+) -ATPase decreased in the model group. Compared with the model group, the PA content increased in the other two groups. Compared with the control group, the contents of LDH and PA, and activities of Na(+) -K(+) -ATPase increased in the the acetoacetate extract of Radix Aconite group with statistical difference (P < 0.05)., Conclusions: The febricity of acetoacetate extract of Radix Aconite was slightly higher than that of Radix Aconite Decoction, seemingly generating more energy. But the final conclusions and concrete mechanisms of action need further studies.

Objective: To investigate the clinical value of combination of human epididymis protein 4 (HE4), CA125 and the Risk of Ovarian Malignancy Algorithm (ROMA) in diagnosis of ovarian carcinoma., Methods: To detect the serum concentration of HE4 using ELISA and CA125 using ECL in patients of ovarian carcinoma group (n = 119), borderline ovarian tumor group (n = 36), benign ovarian neoplasm group (n = 96) and female healthy control group (n = 53). The ROMA based on the serum level of CA125, HE4 and a woman's menopausal status was used to calculate the predicted probability (PP) and diagnostic results of ovarian cancers., Results: The receiver operating characteristic (ROC) analysis showed the cut-off value was 67.3 pmol/L (the AUC was 0.906, the sensitivity was 80.7% and specificity was 94.6%). The serum levels of HE4 and CA125 in the ovarian carcinoma group were significantly higher than that in the borderline ovarian tumor group, benign ovarian neoplasm group and female healthy control group (P < 0.01). The serum levels of CA125 and HE4 showed statistically no significant difference between the borderline ovarian tumor group and benign ovarian neoplasm group (P > 0.05). The levels of HE4 and CA125 were reduced significantly in ovarian patients after surgery therapy (P < 0.01). The sensitivity and specificity of HE4 + CA125 combination was 92.7% and 72.5%. The ROMA that can classify patients into high and low risk groups was established as 9.3% in premenopausal and 27.3% in postmenopausal women., Conclusions: HE4 is a helpful biomarker for ovarian carcinoma diagnosis. Biomarker combination of HE4 and CA125, and applying of the ROMA are helpful to improve the accuracy in diagnosis of ovarian cancers.

Objective: Pemphigus is an autoimmune blistering disease of skin and mucous membranes. Pemphigus vulgaris (PV) is a major subtype of pemphigus, which is histologically characterized by suprabasal acantholysis. The major antigen in PV is desmosomal glycoproteins desmoglein (Dsg) 3. The autoantibodies against Dsg3 cause loss of adhesion between keratinocytes. Some PV patients also have circulating anti-Dsg1 autoantibodies. Enzyme-linked immunosorbent assays (ELISAs) with recombinant Dsg3 and Dsg1 are highly sensitive and specific for detecting anti-Dsg3 and anti-Dsg1 autoantibodies in PV patients. To evaluate the role of desmosomal glycoproteins desmoglein (Dsg3) ELISA and Dsg1 ELISA for detecting anti-Dsg3 and anti-Dsg1 autoantibodies in monitoring disease activity in Pemphigus vulgaris patients., Methods: Twenty PV patients with long-term follow-up were included. We tested their serial sera with modified Dsg3 ELISA (MESACUP Desmoglein TEST "Dsg3", Medical & Biological Laboratories Co. LTD.), Dsg1 ELISA(MESACUP Desmoglein TEST "Dsg1", Medical & Biological Laboratories Co. LTD.) and indirect immunofluorescence (IIF). Then we analyzed the correlation between Dsg3 ELISA index values, Dsg1 ELISA index values, IIF titres and disease activity scores (ABSIS) along the time course., Results: There were significant correlations between Dsg3 ELISA index values, Dsg1 ELISA index values, IIF titres and disease activity scores (both skin scores and oral scores) (P<0.01) along the time course. Significant differences of Dsg3 ELISA index values, Dsg1 ELISA index values and IIF titres between active time-point group and clinical remission time-point group were also observed (P<0.01). We found that Dsg3 ELISA index values, Dsg1 ELISA index values and IIF titres fluctuated in parallel with disease activity, and ELISA index values were superior to IIF titres., Conclusion: Dsg3 ELISA index values fluctuating in parallel with disease activity are useful to monitor disease activity, predict flares or relapses and plan the schedules for tapering the drugs.

Coronary flow velocity pattern (CFVP) recorded within 3 days of percutaneous coronary intervention (PCI) has been reported to be useful in predicting left ventricular (LV) function. The aim of this prospective study was to investigate, via transthoracic Doppler echocardiography, whether the relationship between CFVP and recovery of LV function persists. Our study group comprised 37 patients with 1st anterior-wall acute myocardial infarction who underwent successful PCI for lesions in the left anterior descending coronary artery (LAD). The CFVP in the LAD was recorded at 24-48 hours, 7 days, and 4 weeks after PCI. Myocardial contrast echocardiography was performed at 24-48 hours after PCI. The diastolic deceleration time (DDT) at each stage correlated significantly with the regional LV wall-motion score index at 6-month follow-up (r=-0.58 at 24-48 hr, -0.57 at day 7, and -0.50 at week 4; P <0.01 for all). The mean DDT increased over time. Optimal cutoff values for DDT to predict regional LV wall-motion score indices of <2.0 were 327 ms at 24-48 hours (sensitivity, 0.78; specificity, 0.64), 495 ms at day 7 (sensitivity, 0.75; specificity, 0.69), and 525 ms at week 4 (sensitivity, 0.83; specificity, 0.69). The DDT at 24-48 hours significantly correlated, better than the peak creatine kinase value, with reperfusion (r=0.68, P <0.01) as defined by myocardial contrast echocardiography. In conclusion, CFVP in the LAD can be used, within 4 weeks after PCI, to predict the recovery of regional LV function in patients with reperfused anterior-wall acute myocardial infarction.

Objective: To study the cyclodextrin inclusion complexes of Dragon's blood for improving the drug solubility and the preparation., Method: The inclusion complexes were prepared with beta-cyclodextrin, HP-beta-cyclodextrin, SBE-beta-cyclodextrin and confirmed by DTA. The activity of the inclusion complex was tested by animal experiments. Inclusion complexes tablets were prepared and the dissolution test was performed., Result: The solubility of inclusion complexes was increased to 13. 75-168. 39 times. The activity of the inclusion complex was markedly improved, and dissolution rate was 78.69%., Conclusion: The cyclodextrin inclusion complexes of Dragon's blood have a good solubility, dissolution rate and pharmacological activity.

An in vitro transformation system of carcinogen-treated Syrian hamster embryo (SHE) cell cultures represents multistep genetic and nongenetic changes that develop during the neoplastic progression of normal cells to tumor cells in vivo. During this neoplastic progression, SHE cells demonstrate an altered response to epidermal growth factor (EGF). In the present report, we examined the role of the adapter protein Gab1 (Grb2-associated binder-1) in the neoplastic progression of SHE cells. We used two asbestos-transformed SHE cell clones in different neoplastic stages: a 10W+8 clone, which is immortal and retains the ability to suppress the tumorigenicity of tumor cells in cell-cell hybrid experiments, and a 10W-1 clone, which has lost this tumor suppressor ability. 10W+8 cells expressed full-length 100-kDa Gab1 and associated 5.2-kb mRNA. Upon repeated cell passaging, 10W-1 cells showed increasing expression of a novel 87-kDa form of Gab1 as well as 4.6-kb mRNA with diminishing expression of the original 100-kDa Gab1. cDNA encoding the 87-kDa Gab1 predicts a form of Gab1 lacking the amino-terminal 103 amino acids (Gab1(Delta1-103)), which corresponds to loss of most of the pleckstrin homology (PH) domain. Gab1(Delta1-103) retains the ability to be phosphorylated in an EGF-dependent manner and to associate with the EGF receptor and SHP-2 upon EGF stimulation. The endogenous expression of Gab1(Delta1-103) in 10W-1 cells appeared closely related to EGF-dependent colony formation in soft agar. Moreover, transfection and expression of Gab1(Delta1-103), but not Gab1, in 10W+8 cells enhanced their EGF-dependent colony formation in soft agar. These results demonstrate that Gab1 is a target of carcinogen-induced transformation of SHE cells and that the expression of a Gab1 variant lacking most of the PH domain plays a specific role in the neoplastic progression of SHE cells.

The adaptor protein Grb2-associated binder-1 (Gab1) is known to bind to the SHP-2 tyrosine phosphatase on epidermal growth factor (EGF) receptor stimulation. To clarify the roles of these two proteins in EGF receptor (EGFR) signaling and determine their possible alteration during neoplastic cell progression, we studied these proteins in a Syrian hamster embryo (SHE) cell line model of neoplastic progression. Specifically, we used asbestos-transformed SHE fibroblasts: the 10W+8 clone, which is immortal but nontumorigenic; and the 10W2T clone, which is tumorigenic. Gab1 was detected, and the EGF-dependent formation of the EGFR-Gab1-SHP-2 complex was observed in 10W+8 cells. After cloning hamster Gab1 cDNA, exogenous expression of Gab1 significantly enhanced EGF-dependent mitogenic activity in 10W+8 cells. On the other hand, Gab1 was not detected in 10W2T cells, and the EGF-dependent association of SHP-2 with EGFR was also absent. Exogenous Gab1 expression in transfected 10W2T cells restored the EGF-dependent association of SHP-2 with EGFR, although it only showed a marginal effect on EGF-dependent mitogenic activity. Thus, Gab1 plays a pivotal role in the EGFR signaling pathway via the formation of the EGFR-Gab1-SHP-2 complex, and alteration in the expression and function of Gab1 is implicated in the neoplastic progression of SHE cells.

In Syrian hamster embryo (SHE) fibroblasts, epidermal growth factor receptor (EGFR) tyrosine kinase activity regulates the metabolism of endogenous linoleic acid to (13S)-hydroperoxyoctadecadienoic acid (13S)-HPODE). (13S)-HPODE stimulates EGF-dependent mitogenesis in a SHE cell phenotype, which expresses tumor suppressor genes (supB+), but was not effective in a variant that does not express these suppressor genes (supB-). In the present study, we have investigated the potential effects of this lipid metabolite on the EGFR signaling pathways in these two SHE cell lines. Treatment of quiescent SHE cells with EGF produced a rapid, transient increase in the tyrosine phosphorylation of EGFR. Dependence on EGF concentration for EGFR tyrosine phosphorylation was similar in both SHE cell lines, but a more prolonged phosphorylation was detected in the supB- variant. Incubation of supB+ cells with (13S)-HPODE and EGF increased EGFR autophosphorylation and tyrosine phosphorylation on several signaling proteins with Src homology-2 domains including GTPase-activating protein. The lipid metabolite did not significantly alter EGF-dependent tyrosine phosphorylation in the supB- variant. Tyrosine phosphorylation of mitogen-activated protein (MAP) kinase was also measured. The addition of (13S)-HPODE increased the extent and duration of MAP kinase tyrosine phosphorylation in supB+ cells but not in the supB- variant. MAP kinase activity in supB+ cells, as measured in immunoprecipitates from cells after the addition of EGF, was increased by the presence of (13S)-HPODE. The addition of (13S)-HPODE did not directly alter EGFR kinase activity or the internalization of the EGFR. However, the addition of (13S)-HPODE to supB+ cells extended the tyrosine phosphorylation of the EGFR in response to EGF. The dephosphorylation of the EGFR was measured directly, and a slower rate was observed in the supB- compared with the supB+ cells. Incubation of the supB+ cells with (13S)-HPODE attenuated the dephosphorylation of the EGFR. Thus, (13S)-HPODE stimulates EGF-dependent mitogenesis and up-regulation of EGF-dependent tyrosine phosphorylation by inhibiting the dephosphorylation of the EGFR. This study shows that a metabolite of an essential dietary fatty acid, linoleic acid, can modulate tyrosine phosphorylation and activity of key signal transduction proteins in a growth factor mitogenic pathway.