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The main pathophysiological abnormalities in type 2 diabetes (T2D) include pancreatic β-cell dysfunction and insulin resistance. Due to hyperglycemia, patients receive long-term treatment. However, side effects and drug tolerance usually lead to treatment failure. GuaLouQuMaiWan (GLQMW), a common traditional Chinese medicine (TCM) prescription, has positive effects on controlling blood sugar and improving quality of life, but the mechanism is still unclear. To decipher their molecular mechanisms, we used a novel computational systems pharmacology-based approach consisting of bioinformatics analysis, network pharmacology, and drug similarity comparison. We divided the participants into nondisease (ND), impaired glucose tolerance (IGT), and type 2 diabetes groups according to the WHO’s recommendations for diabetes. By analyzing the gene expression profile of the ND-IGT-T2D (ND to IGT to T2D) process, we found that the function of downregulated genes in the whole process was mainly related to insulin secretion, while the upregulated genes were related to inflammation. Furthermore, other genes in the ND-IGT (ND to IGT) process are mainly related to inflammation and lipid metabolic disorders. We speculate that 17 genes with a consistent trend may play a key role in the process of ND-IGT-T2D. We further performed target prediction for 50 compounds in GLQMW that met the screening criteria and intersected the differentially expressed genes of the T2D process with the compounds of GLQMW; a total of 18 proteins proved potential targets for GLQMW. Among these, RBP4 is considerably related to insulin resistance. GO/KEGG enrichment analyses of the target genes of GLQMW showed enrichment in inflammation- and T2D therapy-related pathways. Based on the RDKit tool and the DrugBank database, we speculate that (-)-taxifolin, dialoside A_qt, spinasterol, isofucosterol, and 11,14-eicosadienoic acid can be used as potential drugs for T2D via molecular docking and drug similarity comparison.

Aim. The aim of this study is to evaluate the impact of Chinese native culture education based on Chinese native culture on the intercultural competence of undergraduate nursing students. Method. A quasi-experimental design with pretest and posttest was used. We recruited nursing students from 4 classes of the School of Nursing in our hospital in 2016 as research subjects. Undergraduate nursing students ( n = 79 ) who completed one semester of education in indigenous Chinese culture completed a demographic questionnaire and the transcultural self-efficacy tool (TSET). Chinese native culture education is the topics related to nursing, consistent with the culture of Chinese patients under the background of Chinese native culture, including the dietary habits, taboos, religions, values, particularly Chinese medicine, and specific diseases. The control group ( n = 91 ) was students who did not participate in Chinese native culture education and completed the instrument during the same time frame. Result. Students who participated in Chinese native cultural education significantly improved their transcultural self-efficacy in three dimensions: cognition, emotion, and practice. Compared with the control group, the students in the cultural education group had higher change scores in three sizes of transcultural self-efficacy. Conclusion. When strengthening cultural education for undergraduate nursing students, adding content related to Chinese native culture can improve their transcultural self-efficacy and meet the growing cultural needs of patients.

To evaluate the impact of hypertension on the clinical outcome of COVID-19 patients aged 60 years old and older.This single-center retrospective cohort study enrolled consecutive COVID-19 patients aged 60 years old and older, who were admitted to Liyuan Hospital from January 1, 2020 to April 25, 2020. All included patients were divided into two groups: hypertension and nonhypertension group. The baseline demographic characteristics, laboratory test results, chest computed tomography (CT) images and clinical outcomes were collected and analyzed. The prognostic value of hypertension was determined using binary logistic regression.Among the 232 patients included in the analysis, 105 (45.3%) patients had comorbid hypertension. Compared to the nonhypertension group, patients in the hypertension group had higher neutrophil-to-lymphocyte ratios, red cell distribution widths, lactate dehydrogenase, high-sensitivity C-reactive protein, D-dimer and severity of lung lesion, and lower lymphocyte counts (all P0.05). Furthermore, the hypertension group had a higher proportion of intensive care unit admissions [24 (22.9%) vs. 14 (11.0%), P=0.02) and deaths [16 (15.2%) vs. 3 (2.4%), P0.001] and a significantly lower probability of survival (P0.001) than the nonhypertension group. Hypertension (OR: 4.540, 95% CI: 1.203-17.129, P=0.026) was independently correlated with all-cause in-hospital death in elderly patients with COVID-19.The elderly COVID-19 patients with hypertension tend to have worse conditions at baseline than those without hypertension. Hypertension may be an independent prognostic factor of poor clinical outcome in elderly COVID-19 patients.

Abstract: Inflammation, as a complex immunopathological process, is the organism's natural defense response against harmful, foreign, and destructive immune or non-immune factors. It is the main pathological form of various diseases, such as tumors, neurodegenerative diseases, periodontitis, alcoholic steatohepatitis, asthma, and other diseases. The P2X7 receptor (P2X7R) is widely distributed in vivo and up-regulated in various inflammatory pathological states. Studies have shown that milder chronic inflammation is related to a deficiency or inhibition of P2X7R, which is an indispensable part of the pro-inflammatory mechanism in vivo. P2X7R, a unique subtype of seven purinergic P2X receptors, is an ATP-gated non-selective cationic channel. P2X7R will promote the influx of Ca2+ and the outflow of K+ after being stimulated. The influx of Ca2+ is essential for activating the body's innate immune response and inducing the production of inflammatory factors. This paper reviews the regulation of P2X7R in inflammation from the perspectives of innate immunity and adaptive immunity.

Craniofacial tissue defects caused by trauma, developmental malformation, or surgery are critical issues of high incidence, which are harmful to physical and psychological health. Transplantation of engineered tissues or biomaterials is a potential method to repair defects and regenerate the craniofacial tissues. Revascularization is essential to ensure the survival and regeneration of the grafts. Since microvessels play a critical role in blood circulation and substance exchange, the pre-establishment of the microvascular network in transplants provides a technical basis for the successful regeneration of the tissue defect. In this study, we reviewed the recent development of strategies and applications of prevascularization in tissue engineering and regeneration of craniofacial tissues. We focused on the cellular foundation of the

Quercetin is the main dietary flavonoid with a wide range of pharmacological activities. However, the poor gastrointestinal absorption and low bioavailability of quercetin curtail its clinical applications.We performed a systematic research on the quercetin drug delivery system in PubMed, Web of Science, SciFinder, Google Scholar, Chinese National Knowledge Infrastructure database, and summarized it reasonably.The bioavailability of quercetin can be improved through the application of delivery systems technologies, such as microparticle delivery systems, solid dispersions, encapsulation, phospholipid complexes, and hydrogels. Quercetin delivery systems have been demonstrated to exhibit stronger antibacterial, anti-oxidant, anti-inflammatory, anti-cancer, and other pharmacological effects in vitro and in vivo animal experiments, promoting the development and optimization of quercetin delivery systems for clinical applications.

OBJECTIVE To investigate a previously uncharacterized function of Sijunzi Decoction (SJZD) in inhibition of gastric cancer stem cells (GCSCs). METHODS MKN74 and MKN45, two CD44 positive gastric cancer cell lines with stem cell properties were used. The cells were divided into 2 groups. Treatment group was treated with SJZD (1-5 mg/mL) for indicated time (48 h-14 days). The control group was treated with equal volume of phosphate buffered saline. Cell Counting Assay Kit-8 were used to measure cell viability. Spheroid colony formation and GCSCs marker expression were performed to determine GCSCs stemness. Cell fractionation and chromatin immunoprecipitation assays were used to assess the distribution and DNA-binding activity of β-catenin after SJZD treatment, respectively. RESULTS SJZD treatment repressed cell growth and induced apoptosis in MKN74 and MKN45 cell lines (P

Pulp loss is accompanied by the functional impairment of defense, sensory, and nutrition supply. The approach based on endogenous stem cells is a potential strategy for pulp regeneration. However, endogenous stem cell sources, exogenous regenerative signals, and neovascularization are major difficulties for pulp regeneration based on endogenous stem cells. Therefore, the purpose of our research is to seek an effective cytokines delivery strategy and bioactive materials to reestablish an ideal regenerative microenvironment for pulp regeneration. In in vitro study, we investigated the effects of Wnt3a, transforming growth factor-beta 1, and bone morphogenetic protein 7 (BMP7) on human dental pulp stem cells (h-DPSCs) and human umbilical vein endothelial cells. 2D and 3D culture systems based on collagen gel, matrigel, and gelatin methacryloyl were fabricated to evaluate the morphology and viability of h-DPSCs. In in vivo study, an ectopic nude mouse model and an in situ beagle dog model were established to investigate the possibility of pulp regeneration by implanting collagen gel loading BMP7. We concluded that BMP7 promoted the migration and odontogenic differentiation of h-DPSCs and vessel formation. Collagen gel maintained the cell adhesion, cell spreading, and cell viability of h-DPSCs in 2D or 3D culture. The transplantation of collagen gel loading BMP7 induced vascularized pulp-like tissue regeneration in vivo. The injectable approach based on collagen gel loading BMP7 might exert promising therapeutic application in endogenous pulp regeneration.

BackgroundIn the Checkmate9ER trial, first-line treatment with nivolumab combined with cabozantinib (NI + CA) has shown efficacy for advanced renal cell carcinoma. This study aims to evaluate the impact of the health and economic outcomes of NI + CA in China.MethodsClinical efficacy data were derived from pivotal phase III CheckMate 9ER trial. A three-state partitioned survival model was established based on disease progression. Progression-free survival and overall survival of NI + CA vs. sunitinib were fitted with log-logistic and log-normal distributions, respectively. Mixture cure, non-mixture cure, and Royston/Parmar spline models were used to evaluate model robustness. The results derived the computational cost from the Chinese healthcare system perspective. The primary outcomes were quality-adjusted life-years (QALYs), total cost in US dollars, as well as incremental cost-effectiveness ratios (ICERs) at the willingness-to-pay threshold in China. One-way and probabilistic sensitivity analysis were also used to assess the robustness of the model.ResultsIn the base-case analysis result, 0.86 additional QALYs could be obtained in the NI+CA (3.84 QALYs) versus the sunitinib strategy (2.97 QALYs). The ICER of NI+CA compared with the sunitinib strategy was US$292,945 per QALY. The ICER value in the NI+CA strategy was higher than the Chinese willingness-to-pay threshold of US$38,024 per QALY. Although NI+CA can improve long-term patient survival significantly over sunitinib in the treatment of advanced renal cell carcinoma, it is unlikely to be cost-effective due to high cost. The results of the one-way sensitivity analysis showed that drug cost, health utility value at the stage of disease progression, and subsequent treatment proportion had a greater impact on the stability of ICER values.ConclusionsNivolumab combined with cabozantinib can prolong the life of patients with advanced renal cell carcinoma and improve their quality of life, but there is a corresponding increase in medical cost. The NI + CA strategy is unlikely to be considered cost-effective in the treatment of advanced RCC from the perspective of Chinese healthcare system.

As global aging accelerates, the prevention and treatment of age-related bone diseases are becoming a critical issue. In the process of senescence, bone marrow mesenchymal stem cells (BMSCs) gradually lose the capability of self-renewal and functional differentiation, resulting in impairment of bone tissue regeneration and disorder of bone tissue homeostasis. Alteration in epigenetic modification is an essential factor of BMSC dysfunction during aging. Its transferability and reversibility provide the possibility to combat BMSC aging by reversing age-related modifications. Emerging evidence demonstrates that epigenetic therapy based on aberrant epigenetic modifications could alleviate the senescence and dysfunction of stem cells. This review summarizes potential therapeutic targets for BMSC aging, introduces some potential approaches to alleviating BMSC aging, and analyzes its prospect in the clinical application of age-related bone diseases.

Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that although the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and β-galactosidase activities, suggesting that lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together, this study discloses a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. Since serpinB2 levels can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions. This article has an associated First Person interview with the first author of the paper.

Introduction Several teaching methods have been used in clinical nursing teaching to increase quality and efficiency, but disagreements over their effects persist. This study will evaluate the effects of five teaching methods in clinical nursing on nursing students’ knowledge, skill scores, learning satisfaction, and patients’ satisfaction. Methods We will conduct searches in PubMed, Embase, Web of Science, The Cochrane Library, China National Knowledge Infrastructure Database (CNKI), China Biological literature database (CBM), Wanfang Database, and China Science and Technology Journal Database (CSTJ) up to April 2022. Relevant randomized controlled trials meeting the eligibility criteria will be included. And the study selection and data extraction will be independently screened for eligibility by two authors. The quality of evidence will be evaluated using the Cochrane risk of bias tool. Pairwise meta-analysis and network meta-analysis (NMA) will be conducted using Rev Man, Stata, and R software. Statistical analyses including homogeneity tests, sensitivity analysis, transitivity tests, consistency tests, and publication bias will be completed. Ethics and dissemination No formal research ethics approval is required. The results will be disseminated to a peer-reviewed journal for publication. Protocol registration number INPLASY2021120040.

Background Experiencing internship shapes nursing students’ professional commitment and aggravates its changes. However, few studies have been investigated how this changes empirically. Objectives The aims of this study are to investigate (a) what are the changes of professional commitment of nursing students before and after the internship? (b) Which of multiple independent variables is the strongest predictor? Methods A longitudinal study was conducted with 996 senior undergraduate nursing students (ready to enter clinical practice) in the China universities. The survey was conducted in the spring of 2015 and autumn of 2016. The data were collected by a paper-and-pencil questionnaire. The instruments used included Professional Commitment Scale and Perceived Stress Scale. Analysis of paired t-test and linear regression analysis were performed on the data. Results Nursing students showed lower professional commitment (2.79 ± 0.36) than they were (2.92 ± 0.36) before internship. Socio-demographic variables, pre-internship professional commitment and stress perceived during internship predicted 40.1% of the variance in the post-internship commitment. Discussion These data summarize the nursing students’ professional commitment changes and the main influential factors that contribute to post-internship professional commitment of undergraduate nursing student. The findings are timely, which indicate that senior nursing students’ professional commitment can be increased by enhancing pre-internship commitment and reducing students’ stress levels during internship.

RNF40 (OMIM: 607700) is a really interesting new gene (RING) finger E3 ubiquitin ligase containing multiple coiled-coil domains and a C-terminal RING finger motif, which engage in protein–DNA and protein–protein interactions. RNF40 encodes a polypeptide of 1001 amino acids with a predicted molecular mass of 113,678 Da. RNF40 and its paralog RNF20 form a stable heterodimer complex that can monoubiquitylate histone H2B at lysine 120 as well as other nonhistone proteins. Cancer is a major public health problem and the second leading cause of death. Through its protein ubiquitylation activity, RNF40 acts as a tumor suppressor or oncogene to play major epigenetic roles in cancer development, progression, and metastasis, highlighting the essential function of RNF40 and the importance of studying it. In this review, we summarize current knowledge about RNF40 gene structure and the role of RNF40 in histone H2B monoubiquitylation, DNA damage repair, apoptosis, cancer development, and metastasis. We also underscore challenges in applying this information to cancer prognosis and prevention and highlight the urgent need for additional investigations of RNF40 as a potential target for cancer therapeutics.

The 2019 novel coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a major challenge threatening the global healthcare system. Respiratory virus infection is the most common cause of asthma attacks, and thus COVID-19 may contribute to an increase in asthma exacerbations. However, the mechanisms of COVID-19/asthma comorbidity remain unclear.The "Limma" package or "DESeq2" package was used to screen differentially expressed genes (DEGs). Alveolar lavage fluid datasets of COVID-19 and asthma were obtained from the GEO and GSV database. A series of analyses of common host factors for COVID-19 and asthma were conducted, including PPI network construction, module analysis, enrichment analysis, inference of the upstream pathway activity of host factors, tissue-specific analysis and drug candidate prediction. Finally, the key host factors were verified in the GSE152418 and GSE164805 datasets.192 overlapping host factors were obtained by analyzing the intersection of asthma and COVID-19. FN1, UBA52, EEF1A1, ITGB1, XPO1, NPM1, EGR1, EIF4E, SRSF1, CCR5, PXN, IRF8 and DDX5 as host factors were tightly connected in the PPI network. Module analysis identified five modules with different biological functions and pathways. According to the degree values ranking in the PPI network, EEF1A1, EGR1, UBA52, DDX5 and IRF8 were considered as the key cohost factors for COVID-19 and asthma. The HThis study constructed a network of common host factors between asthma and COVID-19 and predicted several drugs with therapeutic potential. Therefore, this study is likely to provide a reference for the management and treatment for COVID-19/asthma comorbidity.

Ring finger protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, is an emerging tumor suppressor, but its underlying mechanism remains largely elusive. To address this issue, we used Affymetrix GeneChip Human Transcriptome Array 2.0 to profile gene expression in MDA-MB-231 cells stably expressing empty vector pCDH and Flag-RNF144A, and found that 128 genes were differentially expressed between pCDH- and RNF144A-expressing cells with fold change over 1.5. We further demonstrated that RNF144A negatively regulated the protein and mRNA levels of glial maturation factor γ (GMFG). Mechanistical investigations revealed that transcription factor YY1 transcriptionally activated GMFG expression, and RNF144A interacted with YY1 and promoted its ubiquitination-dependent degradation, thus blocking YY1-induced GMFG expression. Functional rescue assays showed that ectopic expression of RNF144A suppressed the proliferative, migratory, and invasive potential of breast cancer cells, and the noted effects were partially restored by re-expression of GMFG in RNF144A-overexpressing breast cancer cells. Collectively, these findings reveal that RNF144A negatively regulates GMFG expression by targeting YY1 for proteasomal degradation, thus inhibiting the proliferation, migration, and invasion of breast cancer cells.

Rehabilitation intervention which refers to the functional training by caregivers with the aid of specialized nursing techniques and the progressive promotion of patients’ training initiative, with the purpose of improving mobility and quality of life, is of great significance. The purpose of the study was to investigate the effect of the rehabilitation intervention-centered targeted nursing model on the cardiac function recovery and negative emotions in patients with acute myocardial infarction (AMI). A total of 120 AMI patients admitted to our hospital between January 2019 and January 2020 were selected as the study subjects and randomly divided into group A (n = 60) and group B (n = 60), in which the group B patients received routine nursing combined with rehabilitation intervention, while based on the treatment in group B, the patients in group A underwent rehabilitation intervention-centered targeted nursing model. Then, the cardiac function indexes, negative emotion score, levels of risk factors for heart failure, complication rate (CR), and the quality of life (QOL) of the patients were compared between the two groups. The cardiac function indexes of the patients after nursing in group A were significantly better than those in group B ( P < 0.001 ); the negative emotion scores of the patients after nursing in group A were significantly lower than those in group B ( P < 0.001 ); the levels of risk factors for heart failure of the patients after nursing in group A were significantly lower than those in group B ( P < 0.001 ); the CR of the patients in group A at 15 d and 30 d after admission was significantly lower than that in group B ( P < 0.05 ); the QOL scores of the patients after nursing in group A were significantly higher than those in group B ( P < 0.001 ). Rehabilitation intervention-centered targeted nursing model can optimize cardiac function, weaken the levels of risk factors for heart failure, reduce the incidence of complications, improve psychological conditions, and enhance the quality of life in AMI patients, which is worthy of application and promotion in clinical practice.

Chuanxiong Rhizoma, the dried rhizome of Ligusticum chuanxiong Hort., is a commonly used drug for promoting blood circulation and dissipating congestion. Tetramethylpyrazine (TMP), the main active ingredient of Ligusticum chuanxiong, has significant antioxidant, anti-inflammatory, and vascular protective effects. However, the protective properties and underlying mechanisms of TMP against endothelial injury-induced insufficient angiogenesis and thrombosis have not been elucidated. Therefore, we aimed to explore the protective effects of TMP on endothelial injury and its antithrombotic effects and study the mechanism. In vitro experiments showed that TMP could alleviate hydrogen peroxide– (H2O2–) induced endothelial injury of human umbilical vein endothelial cells (HUVECs) and the protective mechanism might be related to the regulation of MAPK signaling pathway, and its antioxidative and antiapoptotic effects. In vivo experiments showed that TMP restored PTK787-induced damage to intersegmental vessels (ISVs) in Tg(fli-1: EGFP)y1 transgenic (Flik) zebrafish larvae. Similarly, adrenalin hydrochloride– (AH–) induced reactive oxygen species (ROS) production and thrombosis in AB strain zebrafish were inhibited by TMP. RT-qPCR assay proved that TMP could inhibit the expression of fga, fgb, fgg, f7, and von Willebrand factor (vWF) mRNA to exert an antithrombotic effect. Our findings suggest that TMP can contribute to endothelial injury protection and antithrombosis by modulating MAPK signaling and attenuating oxidative stress and antiapoptosis.

Background: Very-low-birth-weight (VLBW) infants have a high risk of postdischarge growth retardation (GR). Continued GR might exert negative long-term effects on their health. This study examined the prevalence and the risk factors for postdischarge GR among VLBW infants in Taiwan. Methods: Nationwide data from the Taiwan Premature Infant Follow-up Network between 2007 and 2011 were analyzed. Infants with a gestational age (GA)

BackgroundComorbidity is the phenomenon of two or more diseases occurring simultaneously not by random chance and presents great challenges to accurate diagnosis and treatment. As an effort toward better understanding the genetic causes of comorbidity, in this work, we have developed a computational method to predict comorbid diseases. Two diseases sharing common genes tend to increase their comorbidity. Previous work shows that after mapping the associated genes onto the human interactome the distance between the two disease modules (subgraphs) is correlated with comorbidity.MethodsTo fully incorporate structural characteristics of interactome as features into prediction of comorbidity, our method embeds the human interactome into a high dimensional geometric space with weights assigned to the network edges and uses the projection onto different dimension to “fingerprint” disease modules. A supervised machine learning classifier is then trained to discriminate comorbid diseases versus non-comorbid diseases.ResultsIn cross-validation using a benchmark dataset of more than 10,000 disease pairs, we report that our model achieves remarkable performance of ROC score = 0.90 for comorbidity threshold at relative risk RR = 0 and 0.76 for comorbidity threshold at RR = 1, and significantly outperforms the previous method and the interactome generated by annotated data. To further incorporate prior knowledge pathways association with diseases, we weight the protein-protein interaction network edges according to their frequency of occurring in those pathways in such a way that edges with higher frequency will more likely be selected in the minimum spanning tree for geometric embedding. Such weighted embedding is shown to lead to further improvement of comorbid disease prediction.ConclusionThe work demonstrates that embedding the two-dimension planar graph of human interactome into a high dimensional geometric space allows for characterizing and capturing disease modules (subgraphs formed by the disease associated genes) from multiple perspectives, and hence provides enriched features for a supervised classifier to discriminate comorbid disease pairs from non-comorbid disease pairs more accurately than based on simply the module separation.

Background. Hyperplasia of mammary glands (HMG) is the breast disease with the highest clinical incidence. Many traditional Chinese medicine (TCM) doctors suggest that the treatment of HMG should be based on the left and right breast pain difference. However, these views are based on case reports, and an objective basis has not been established for treatment according to left-side and right-side differences. Methods. We enrolled 150 patients who met the clinical diagnostic criteria of HMG. The incidence bias was determined according to the score difference between bilateral breast pain and mass in patients with HMG. A left group, right group, and bilateral group were included, and TCM constitution was investigated in each group. Blood biochemical indicators were measured for 120 fasting patients. We conducted a network pharmacology study of the key herb qingpi and chenpi, which are used by TCM doctors to treat different lateral HMG. Results. In patients with biased onset of HMG, the results showed that the frequency and constitution score of stagnant blood in the L group were higher than those of the R group, and the frequency and constitution score of phlegm-dampness in the R group were higher than those of the L group. Both the L and R groups had high proportion of stagnant Qi. The results indicated that the concentration of coagulation factor VIII (FVIII) was higher in the L group than that in the R group, and the concentration of lipoprotein a (Lp-α) was higher in the R group than that in the L group. The results showed that sinensetin and neohesperidin contained in qingpi might interfere with platelet activation, thrombogenesis, prolactin signaling pathway, and atherosclerosis process, in removing “blood stasis” and eventually treating the left-leaning group of HMG patients. Sitosterol and citromitin contained in chenpi could regulate lipid metabolism by interfering with regulation of lipolysis in adipocytes, salivary secretion, estrogen signaling pathway, and thyroid hormone signaling pathway. Chenpi could eliminate “phlegm turbidity” and treat HMG patients in the right-leaning group. Conclusions. We preliminarily confirmed that the clinical pathogenesis of HMG is not a left-right equilibrium and TCM constitution, coagulation function, and lipid metabolism may be used as the objective basis for the difference between the left and right in HMG pathogenesis. For left-sided HMG patients, the doctor can consider qingpi, herb of activating blood and removing stasis, to treat HMG. However, for right-sided HMG, we think doctors should apply herb of activating Qi and eliminating phlegm, such as chenpi.

Triple-negative breast cancer (TNBC) is a highly lethal disease due to aggressive clinical phenotype and the lack of validated therapeutic targets. Our recent quantitative proteomic analysis of 90 cases of TNBC tissues and 72 cases of matched adjacent normal tissues revealed that the expression levels of BPTF-associated protein of 18 KDa (BAP18), a component of the MLL1 and NURF chromatin complexes, were upregulated in TNBC tissues relative to normal tissues. However, the biological function and the underlying mechanism of BAP18 in TNBC progression remain unexplored. Here, we report that BAP18 promoted TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung colonization in vivo. Mechanistic investigations revealed that S100 calcium-binding protein A9 (S100A9), a member of the S100 protein family that is frequently upregulated in breast tumors and acts as an oncogenic driver in breast cancer progression, was a downstream target gene of BAP18. BAP18 was recruited to histone H3 trimethylation at lysine 4 (H3K4me3)-marked promoter of S100A9 and enhanced its promoter activities. Notably, knockdown of BAP18 by short hairpin RNA in TNBC cells suppressed xenograft tumor growth in mice, the noted effect was partially reverted by re-expression of S100A9 in BAP18-depleted cells. Taken together, these results suggest that BAP18 promotes TNBC progression through, at least in part, transcriptional activation of oncogene S100A9, and represents a potential therapeutic target for TNBC.

ObjectiveThis study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.Study designRetrospective discovery and longitudinal confirmation.SettingMaternity units from two US hospitals.ParticipantsSix previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.Outcome measuresBiomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.ResultsOur discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks’ gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.ConclusionsOur study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

Background To estimate the prevalence of elevated blood glucose level (EBG, including type 2 diabetes mellitus and impaired fasting glucose), and its association with non-valvular atrial fibrillation (NVAF) in Guangzhou, China. Methods The population-based follow-up Guangzhou Heart Study collected baseline data from July 2015 to August 2017 among 12,013 permanent residents aged > 35 from 4 Guangzhou districts. Two streets (Dadong and Baiyun) in the Yuexiu District, and one street (Xiaoguwei) and two towns (Xinzao and Nancun) in the Panyu District were chosen as representative of urban and rural areas, respectively. Each participant completed a comprehensive questionnaire, and underwent physical examination, blood sample collection for laboratory testing, electrocardiography, and other evaluations. Multivariable logistic regression analyses were used to estimate the independent association between hyperglycemia and NVAF prevalence. Results The prevalence of EBG in overall study population was 29.9%. Compared with residents without EBG, the odds ratio (OR) for AF among residents with EBG was significantly higher (1.94, 95% confidence interval [CI]: 1.40–2.70, P P = 0.007), and driven by women (OR = 1.80, 95% CI: 1.12–2.91, P = 0.016). Conclusions In Guangzhou, China, prevalence of EBG is high among residents aged > 35 years and associated with a multivariate adjusted increase in prevalence of NVAF overall and in women.

Background Growing evidence indicates that high phosphoserine phosphatase (PSPH) expression is associated with tumor prognosis in many types of cancers. However, the role of PSPH in non-small cell lung cancer (NSCLC) is unclear. The purpose of this study was to investigate the clinical significance of PSPH in NSCLC. Methods One hundred forty-three patients with histologically confirmed NSCLC who underwent surgery were included. Quantitative real-time PCR and Western blot were used to assess PSPH expression in paired tumor and corresponding adjacent non-tumorous tissues. The role of PSPH in invasion and cell growth was investigated in vitro. Results Compared to adjacent normal lung tissues, PSPH messenger RNA and protein levels were significantly higher in NSCLC tissues, and the PSPH expression level was positively related to clinical stage, metastasis, and recurrence. High PSPH expression was predictive of poor overall survival. A549 cells transfected with small interfering-PSPH showed inhibited cell migration, invasion, and proliferation. We further demonstrated that PSPH might promote the invasive capabilities of NSCLC cells through the AKT/AMPK signaling pathway. Conclusion Our results indicate that PSPH may act as a putative oncogene in NSCLC, and may be a vital molecular marker for the metastasis and proliferation of NSCLC cells by regulating the AKT/AMPK signaling pathway.

Epidermal growth factor receptor (EGFR) mutations are associated with leptomeningeal metastases (LM) of nonsmall cell lung cancer and sensitivity to tyrosine kinase inhibitor (TKI) treatment. Owing to the difficulty of obtaining carcinomatous meningeal tissue for analysis, cerebrospinal fluid (CSF) might be an alternative.To investigate the EGFR mutation detection in the CSF of lung adenocarcinoma patients with LM.Twenty-five lung adenocarcinoma patients with LM diagnosed by CSF cytology were retrospectively evaluated. The results of EGFR mutation detection in CSF, the treatment plan, and clinical outcome information were recorded.Nineteen patients had a known EGFR status in their primary tumors. Twenty patients received EGFR mutation analysis in CSF after LM diagnosis and 14 of them with a known EGFR mutation status of both primary tumors and CSF. Ten (71.4%) had the same EGFR gene status. In primary tumors, no T790M mutations were detected, whereas in CSF, 2 L858R cases and 1 19del case had T790M mutations at the same time. The detection rate of T790M mutations in CSF was 18.1% (2 of 11) in all cases with EGFR-sensitive mutations in the primary lesion.EGFR mutation detection in CSF of lung adenocarcinoma patients with LM might be an alternative when leptomeningeal biopsy cannot be applied and may help to guide TKI treatments.

Quercetin is the major representative of the flavonoid subgroup of flavones, with good pharmacological activities for the treatment of liver diseases, including liver steatosis, fatty hepatitis, liver fibrosis, and liver cancer. It can significantly influence the development of liver diseases via multiple targets and multiple pathways via antifat accumulation, anti-inflammatory, and antioxidant activity, as well as the inhibition of cellular apoptosis and proliferation. Despite extensive research on understanding the mechanism of quercetin in the treatment of liver diseases, there are still no targeted therapies available. Thus, we have comprehensively searched and summarized the different targets of quercetin in different stages of liver diseases and concluded that quercetin inhibited inflammation of the liver mainly through NF-κB/TLR/NLRP3, reduced PI3K/Nrf2-mediated oxidative stress, mTOR activation in autophagy, and inhibited the expression of apoptotic factors associated with the development of liver diseases. In addition, quercetin showed different mechanisms of action at different stages of liver diseases, including the regulation of PPAR, UCP, and PLIN2-related factors via brown fat activation in liver steatosis. The compound inhibited stromal ECM deposition at the liver fibrosis stage, affecting TGF1β, endoplasmic reticulum stress (ERs), and apoptosis. While at the final liver cancer stage, inhibiting cancer cell proliferation and spread via the hTERT, MEK1/ERK1/2, Notch, and Wnt/β-catenin-related signaling pathways. In conclusion, quercetin is an effective liver protectant. We hope to explore the pathogenesis of quercetin in different stages of liver diseases through the review, so as to provide more accurate targets and theoretical basis for further research of quercetin in the treatment of liver diseases.

Background: Vascular endothelial growth factor (VEGF) is a supergene family derived from a platelet growth factor. It plays a pivotal role in regulating angiogenesis and lymphangiogenesis. sFlt-1 is a soluble antagonist of VEGF with an essential effect of maintaining the balance of vascular growth. Recently, sFlt-1 has emerged as a new marker for early diagnosis and disease surveillance of angiogenesis-related diseases. However, few comprehensive reviews focus on the relationship between sFlt-1 and related diseases despite that many results have yielded. Methods: In this review, we analyzed the relationship between sFlt-1 and angiogenesis-related diseases by searching PubMed, Web of Science, and other databases, and summarized our current understanding of the role of sFlt-1 in angiogenesis-related diseases. Results: sFlt-1 is associated with pre-eclampsia, perinatal cardiomyopathy, diabetic nephropathy, hypertension, tumor, atherosclerosis, and other diseases. The mechanisms of sFlt-1 that regulate those diseases are mainly associated with the bioavailability of VEGF and vascular endothelial cell integrity. Conclusion: From the summary article, sFlt-1 is a double regulator in angiogenesis-related diseases; too much or too little may cause different diseases. Therefore, maintaining the stability of sFlt-1 content in the body is essential to control the development of related diseases.

Background. Solute carrier family 12 member 5 (SLC12A5) has been reported to play an oncogenic role in certain malignancies. Its prognostic roles and immune mechanisms of action in human cancers, however, remain largely unknown. Methods. Data derived from TCGA, GEPIA, and TIMER databases were utilized to delve into the expressing patterns, prognostic values, clinical significances, and tumor immunity of SLC12A5 in tumors. Additionally, the association of SLC12A5 expressions with tumor mutation burden (TMB), methyltransferases, and mismatch repairs (MMRs) was also analyzed. Results. Herein, we observed that SLC12A5 was significantly overexpressed in various malignancies, and SLC12A5 levels correlated with overall survival, disease-specific survival, and tumor stage of certain cancers. Furthermore, we noticed that SLC12A5 was distinctly associated with methyltransferases, mismatch repair proteins, TMB, and MSI in human cancers. Conclusions. SLC12A5 may act as a potential prognostic and immunological biomarker and therapeutic target for human cancers.

Thrombus is considered to be the pathological source of morbidity and mortality of cardiovascular disease and thrombotic complications, while oxidative stress is regarded as an important factor in vascular endothelial injury and thrombus formation. Therefore, antioxidative stress and maintaining the normal function of vascular endothelial cells are greatly significant in regulating vascular tension and maintaining a nonthrombotic environment. Leonurine (LEO) is a unique alkaloid isolated from Leonurus japonicus Houtt (a traditional Chinese medicine (TCM)), which has shown a good effect on promoting blood circulation and removing blood stasis. In this study, we explored the protective effect and action mechanism of LEO on human umbilical vein endothelial cells (HUVECs) after damage by hydrogen peroxide (H2O2). The protective effects of LEO on H2O2-induced HUVECs were determined by measuring the cell viability, cell migration, tube formation, and oxidative biomarkers. The underlying mechanism of antioxidation of LEO was investigated by RT-qPCR and western blotting. Our results showed that LEO treatment promoted cell viability; remarkably downregulated the intracellular generation of reactive oxygen species (ROS), malondialdehyde (MDA) production, and lactate dehydrogenase (LDH); and upregulated the nitric oxide (NO) and superoxide dismutase (SOD) activity in H2O2-induced HUVECs. At the same time, LEO treatment significantly promoted the phosphorylation level of angiogenic protein PI3K, Akt, and eNOS and the expression level of survival factor Bcl2 and decreased the expression level of death factor Bax and caspase3. In conclusion, our findings suggested that LEO can ameliorate the oxidative stress damage and insufficient angiogenesis of HUVECs induced by H2O2 through activating the PI3K/Akt-eNOS signaling pathway.

Deep caries, trauma, and severe periodontitis result in pulpitis, pulp necrosis, and eventually pulp loss. However, no clinical therapy can regenerate lost pulp. A novel pulp regeneration strategy for clinical application is urgently needed. Signaling transduction plays an essential role in regulating the regenerative potentials of dental stem cells. Cytokines or growth factors, such as stromal cell-derived factor (SDF), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), vascular endothelial growth factor (VEGF), WNT, can promote the migration, proliferation, odontogenic differentiation, pro-angiogenesis, and pro-neurogenesis potentials of dental stem cells respectively. Using the methods of signaling modulation including growth factors delivery, genetic modification, and physical stimulation has been applied in multiple preclinical studies of pulp regeneration based on cell transplantation or cell homing. Transplanting dental stem cells and growth factors encapsulated into scaffold regenerated vascularized pulp-like tissue in the root canal. Also, injecting a flowable scaffold only with chemokines recruited endogenous stem/progenitor cells for pulp regeneration. Notably, dental pulp regeneration has gradually developed into the clinical phase. These findings enlightened us on a novel strategy for structural and functional pulp regeneration through elaborate modulation of signaling transduction spatially and temporally via clinically applicable growth factors delivery. But challenges, such as the adverse effects of unphysiological signaling activation, the controlled drug release system, and the safety of gene modulation, are necessary to be tested in future works for promoting the clinical translation of pulp regeneration.

Background: Mesenchymal stem cells-conditioned medium (MSC-CM) provides a promising cell-free therapy for Alzheimer’s disease (AD) mainly due to the paracrine of MSCs, but the precise mechanisms remain unclear. Studies suggests that mitochondrial dysfunction precedes the accumulation of amyloid-β plaques and neurofibrillary tangles, and involves in the onset and development of AD. Objective: In the present study, we evaluated the protective effects and explored the related-mitochondrial mechanisms of human umbilical cord derived MSC-CM (hucMSC-CM) in an AD model in vitro. Methods: To this end, an AD cellular model was firstly established by okadaic acid (OA)-treated SH-SY5Y cells, and then treated by hucMSC-CM to assess the oxidative stress, mitochondrial function, apoptosis, AD-related genes, and signaling pathways. Results: hucMSC-CM significantly deceased tau phosphorylated at Thr181 (p181-tau) level, which was increased in AD. hucMSC-CM also alleviated intracellular and mitochondrial oxidative stress in OA-treated SH-SY5Y cells. In addition, hucMSC-CM suppressed apoptosis and improved mitochondrial function in OA-treated SH-SY5Y cells. Flow cytometric analysis indicated that hucMSC-CM exerted the protective effects relying on or partly extracellular vesicle (EV) mitochondrial transfer from hucMSCs to OA-treated SH-SY5Y cells. Moreover, RNA sequencing data further demonstrated that hucMSC-CM regulated many AD-related genes, signaling pathways and mitochondrial function. Conclusion: These results indicated that MSC-CM or MSC-EVs containing abundant mitochondria may provide a novel potential therapeutic approach for AD.

This article aims to explore the underlying molecular mechanisms and prognosis‐related genes in pancreatic cancer metastasis. Pancreatic cancer metastasis‐related gene chip data were downloaded from GENE EXPRESSION OMNIBUS(GEO)database. Differentially expressed genes were screened after R‐package pre‐treatment. Functional annotations and related signalling pathways were analysed using DAVID software. GEPIA (Gene Expression Profiling Interactive Analysis) was used to perform prognostic analysis, and differential genes associated with prognosis were screened and validated using data from GEO. We screened 40 healthy patients, 40 primary pancreatic cancer and 40 metastatic pancreatic cancer patients, collected serum, designed primers and used qPCR to test the expression of prognosis‐related genes in each group. 109 differentially expressed genes related with pancreatic cancer metastasis were screened, of which 49 were up‐regulated and 60 were down‐regulated. Functional annotation and pathway analysis revealed differentially expressed genes were mainly concentrated in protein activation cascade, extracellular matrix construction, decomposition, etc In the biological process, it is mainly involved in signalling pathways such as PPAR, PI3K‐Akt and ECM receptor interaction. Prognostic analysis showed the expression levels of four genes were significantly correlated with the overall survival time of patients with pancreatic cancer, namely SCG5, CRYBA2, CPE and CHGB. qPCR experiments showed the expression of these four genes was decreased in both the primary pancreatic cancer group and the metastatic pancreatic cancer group, and the latter was more significantly reduced. Pancreatic cancer metastasis is closely related to the activation of PPAR pathway, PI3K‐Akt pathway and ECM receptor interaction. SCG5, CRYBA2, CPE and CHGB genes are associated with the prognosis of pancreatic cancer, and their low expression suggests a poor prognosis.

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer. Significance: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors. See related commentary by Koleilat and Kwong, p. 1094. This article is highlighted in the In This Issue feature, p. 1079

Objective To perform a meta-analysis to quantitatively assess functional magnetic resonance imaging (MRI) in the diagnosis of locally recurrent prostate cancer. Materials and methods A comprehensive search of the PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted from January 1, 1995 to December 31, 2016. Diagnostic accuracy was quantitatively pooled for all studies by using hierarchical logistic regression modeling, including bivariate modeling and hierarchical summary receiver operating characteristic (HSROC) curves (AUCs). The Z test was used to determine whether adding functional MRI to T2-weighted imaging (T2WI) results in significantly increased diagnostic sensitivity and specificity. Results Meta-analysis of 13 studies involving 826 patients who underwent radical prostatectomy showed a pooled sensitivity and specificity of 91%, and the AUC was 0.96. Meta-analysis of 7 studies involving 329 patients who underwent radiotherapy showed a pooled sensitivity of 80% and specificity of 81%, and the AUC was 0.88. Meta-analysis of 11 studies reporting 1669 sextant biopsies from patients who underwent radiotherapy showed a pooled sensitivity of 54% and specificity of 91%, and the AUC was 0.85. Sensitivity after radiotherapy was significantly higher when diffusion-weighted MRI data were combined with T2WI than when only T2WI results were used. This was true when meta-analysis was performed on a per-patient basis (p = 0.027) or per sextant biopsy (p = 0.046). A similar result was found when 1H-magnetic resonance spectroscopy (1H-MRS) data were combined with T2WI and sextant biopsy was the unit of analysis (p = 0.036). Conclusion Functional MRI data may not strengthen the ability of T2WI to detect locally recurrent prostate cancer in patients who have undergone radical prostatectomy. By contrast, diffusion-weight MRI and 1H-MRS data may improve the sensitivity of T2WI for patients who have undergone radiotherapy.

Background and Aims Esophageal stricture is a common adverse event after endoscopic submucosal dissection (ESD) when it involves the entire circumference of the esophagus. We aimed to assess the effectiveness and safety of endoscopic transplantation of autologous esophageal mucosa in preventing stricture formation after circumferential ESD. Methods Nine patients who underwent circumferential ESD for early esophageal cancer were enrolled. After the patients underwent ESD, autologous esophageal mucosal patches were attached to the ulcer surface by using hemoclips and were then fixed with a covered metal mesh stent. The stent was removed 7 days after the procedure. The patients were followed up with endoscopy at scheduled times. Results Epithelialization occurred within a median of 7.1 days, with a graft survival rate of 96.5%. Strictures occurred at a mean of 24.7 days (range 18-34 days) after the procedure. The median number of endoscopic balloon dilatation sessions was 2.7 (range 0-6). Conclusions Transplantation of autologous esophageal mucosa could be a safe way of relieving the severity of esophageal stricture after circumferential ESD.

The number of people with dementia is increasing rapidly worldwide. Developing strategies to improve quality of life for those with dementia is crucial and is receiving more attention. Natural environments are known for their healing effects on most people. This pilot study aimed to understand the benefits that natural environments, such as gardens, can provide for people with dementia. In total, 42 staff members in nine dementia care facilities were recruited as participants in this study and answered a semistructured questionnaire. One-way analysis of variance with repeated measures and the Mann–Whitney U test were used to compare the effects of garden visits on evaluated characteristics and the differences in evaluated characteristics between free garden use and unfree garden use groups. Data from open-ended questions underwent text analysis to obtain the principal beliefs of the participants. The staff members reported that garden visits had positive effects on mood, social interaction, depression, and agitation in people with dementia because of the multisensory, gentle stimuli of the natural environment. Of the evaluated cognitive characteristics, attention and orientation to time were improved the most after residents with dementia had spent time in a garden. Additionally, staff members in the free garden use group scored the effects of garden visits on the mood, long-term memory, language abilities, spatial ability, aggression, and agitation of patients with dementia as significantly higher than staff members in the unfree garden use group. Recommendations for future studies are discussed.

Background and purpose We hypothesized that a plan’s robustness to anatomical changes can be improved by optimizing with multiple CT scans of a patient. The purpose of this study was to determine whether an intensity modulated proton therapy (IMPT) plan could be developed to meet dose criteria on both planning and adaptive CT plans. Material and methods Eight lung cancer patients who underwent adaptive IMPT were retrospectively selected. Each patient had two CTs: a primary planning CT (PCT) and an adaptive planning CT (ACT), and IMPT plans associated with the scans. PCT and ACT were then used in combination to optimize one plan (MCT plan). The doses to the target and organs at risk from the PCT plan, ACT plan, P-ACT plan (PCT plan calculated on ACT data), and MCT plans calculated on both CTs were compared. Results The MCT plan maintained the D 95% on both CTs (mean, 65.99 Gy on PCT and 66.02 Gy on ACT). Target dose coverage on ACT was significantly better with the MCT plan than with the P-ACT plan ( p = 0.01). MCT plans had slightly higher lung V 20 (0.6%, p = 0.02) than did PCT plans. The various plans showed no statistically significant difference in heart and spinal cord dose. Conclusions The results of this study indicate that an IMPT plan can meet the dose criteria on both PCT and ACT, and that MCT optimization can improve the plan’s robustness to anatomical change.

Lipoprotein lipase (LPL) is a rate-limiting enzyme that catalyzes hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins including chylomicrons (CM), low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). A variety of parenchymal cells can synthesize and secrete LPL. Recent studies have demonstrated that complicated processes are involved in LPL biosynthesis, secretion and transport. The enzyme activity of LPL is regulated by many factors, such as apolipoproteins, angiopoietins, hormones and miRNAs. In this article, we also reviewed the roles of LPL in atherosclerosis, coronary heart disease, cerebrovascular accident, Alzheimer disease and chronic lymphocytic leukemia. LPL in different tissues exerts differential physiological functions. The role of LPL in atherosclerosis is still controversial as reported in the literature. Here, we focused on the properties of LPL derived from macrophages, endothelial cells and smooth muscle cells in the vascular wall. We also explore the existence of crosstalk between LPL and those cells when the molecule mainly plays a proatherogenic role. This review will provide insightful knowledge of LPL and open new therapeutic perspectives.

Background Protein-protein interaction (PPI) prediction remains a central task in systems biology to achieve a better and holistic understanding of cellular and intracellular processes. Recently, an increasing number of computational methods have shifted from pair-wise prediction to network level prediction. Many of the existing network level methods predict PPIs under the assumption that the training network should be connected. However, this assumption greatly affects the prediction power and limits the application area because the current golden standard PPI networks are usually very sparse and disconnected. Therefore, how to effectively predict PPIs based on a training network that is sparse and disconnected remains a challenge. Results In this work, we developed a novel PPI prediction method based on deep learning neural network and regularized Laplacian kernel. We use a neural network with an autoencoder-like architecture to implicitly simulate the evolutionary processes of a PPI network. Neurons of the output layer correspond to proteins and are labeled with values (1 for interaction and 0 for otherwise) from the adjacency matrix of a sparse disconnected training PPI network. Unlike autoencoder, neurons at the input layer are given all zero input, reflecting an assumption of no a priori knowledge about PPIs, and hidden layers of smaller sizes mimic ancient interactome at different times during evolution. After the training step, an evolved PPI network whose rows are outputs of the neural network can be obtained. We then predict PPIs by applying the regularized Laplacian kernel to the transition matrix that is built upon the evolved PPI network. The results from cross-validation experiments show that the PPI prediction accuracies for yeast data and human data measured as AUC are increased by up to 8.4 and 14.9% respectively, as compared to the baseline. Moreover, the evolved PPI network can also help us leverage complementary information from the disconnected training network and multiple heterogeneous data sources. Tested by the yeast data with six heterogeneous feature kernels, the results show our method can further improve the prediction performance by up to 2%, which is very close to an upper bound that is obtained by an Approximate Bayesian Computation based sampling method. Conclusions The proposed evolution deep neural network, coupled with regularized Laplacian kernel, is an effective tool in completing sparse and disconnected PPI networks and in facilitating integration of heterogeneous data sources.

Background Atherosclerosis is a chronic vascular inflammatory disease with complex pathogenesis. Its serious consequence is insufficient blood supply to heart and brain, which eventually leads to myocardial ischemia, infarction and stroke. Hydroxysafflor yellow A (HSYA), a single chalcone glycoside compound with a variety of pharmacological effects, which has shown a potential biological activity for prevention and treatment of atherosclerosis. Purpose The main purpose of this review is to comprehensively elucidate the mechanism of HSYA on atherosclerosis and its risk factors (hyperlipidemia, hypertension and diabetes mellitus). Method The literatures on HSYA in the treatment of atherosclerosis and its risk factors were searched in PubMed, Google Scholar, China National Knowledge Infrastructure, including in vitro (cell), in vivo (animal) and clinical (human) studies, and summarized reasonably. Results HSYA is a promising natural product for treating atherosclerosis. It can suppress foam cell formation, vascular endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, and platelet activation. The mechanisms are achieved by regulating the reverse cholesterol transport process, fatty acid synthesis, oxidative stress, PI3K/Akt/mTOR, NLRP3 inflammasome, TNFR1/NF-κB, NO-cGMP, Bax/Bcl-2, MAPKs, CDK/CyclinD and TLR4/Rac1/Akt signaling pathways. Besides, HSYA is devoted to lowering blood lipids, regulating ion channels, reducing vascular inflammation, and protecting pancreatic beta cells, which is conducive to reducing the harm of independent risk factors of atherosclerosis. Conclusions HSYA exhibits the preventive and therapeutic effects on atherosclerosis and its risk factors in vivo and in vitro, which is relevant to multiple mechanisms. The clinical trials of HSYA need to be further investigated to provide a solid foundation for its clinical application.

Objective Randomized clinical trials and published meta-analyses assessing the clinical effectiveness of Chinese herbal medicine (CHM) on the treatment of stable chronic obstructive pulmonary disease (COPD) yielded inconsistent results in terms of disease outcomes, in which the design of placebo-controlled studies can contribute to the heterogeneity. This study aimed to evaluate the efficacy and safety of CHM compared to placebo on the treatment of stable COPD, to provide robust evidence for the use of CHM in COPD. Methods Nine electronic databases were searched from inception to October 1, 2019 to identify placebo controlled randomized trials of CHM for the treatment of stable COPD and studies in English or Chinese were included. The primary outcomes were symptom score (CAT score), quality of life (SGRQ) and frequency of acute exacerbations. The secondary outcomes included lung function, clinical total effective rate and adverse events. The selection of studies, data extraction and coding and assessment of risk of bias of the included studies were conducted by two reviewers independently. Mean difference (MD) was used to analyze continuous variable and relative risk ratio (RR) for dichotomous data. Results A total of eleven studies involving 1223 patients were included. While maintaining routine western pharmacotherapies (WP), CHM had significant advantage over the treatment of placebo in improving CAT score (MD -3.93; 95 %CI -6.01 to -1.85) and SGRQ score (MD -6.20; 95 %CI -10.13 to -2.28), reducing the frequency of acute exacerbations (MD -0.78; 95 %CI -1.40 to -0.16) and improving clinical effective rate (RR 1.29; 95 %CI 1.14 to 1.45), but had no significant effect on improving FEV1%pred (MD 8.18; 95 %CI -4.22 to 20.58). High heterogeneity was found for the changes in exacerbation frequency and FEV1%pred. No serious adverse events related to CHM were reported. Conclusions This meta-analysis of placebo-controlled RCTs demonstrated that the use of CHM in addition to WP could alleviate clinical symptoms, improve quality of life and clinical efficiency and reduce the frequency of exacerbations, which could be an alternative approach for treatment adjustment of COPD. CHM was a relatively safe treatment. These findings need to be verified in future with high-quality clinical trials.

Immune activation and inflammation are closely associated with the development of depression. Pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has exhibited antidepressant-like effects in a couple of studies. However, the underlying mechanisms are far from being fully elucidated. The study aimed to investigate the effects of PIO on depression-like behaviors induced by lipopolysaccharide (LPS) and to explore the possible underlying mechanisms. The results showed that PIO pretreatment attenuated the depression-like behaviors in mice challenged with intracerebroventricular (i.c.v.) LPS administration. Moreover, Western blot analysis revealed the effects of PIO on inhibiting activation of the nuclear factor kappa B/interleukin 6/signal transducer and activator of transcription 3 (NF-κB/IL-6/STAT3) pathway, improving down-regulation of the cAMP response-element-binding protein/brain derived neurotrophic factor (CREB/BDNF) pathway, as well as regulating disturbed expression of proteins involved in central serotonergic neurotransmission following LPS administration. The beneficial effects of PIO, at both the behavioral and molecular level, were significantly inhibited by the PPAR-γ specific antagonist GW9662. In summary, our data reveals for the first time that the modulation of the NF-κB/IL-6/STAT3 and CREB/BDNF pathways, as well as the potential impact on central serotonergic neurotransmission, may be involved in the PPAR-γ-dependent effects of PIO on depression-like behaviors induced by LPS. Additionally, our findings may provide a novel therapeutic target for the treatment of depression-like behaviors in patients with inflammatory status.

Previous work has suggested that ceria nanoparticles (CNPs) have regenerative antioxidant properties, which have motivated researchers to consider CNPs as therapeutic agents for treating a number of diseases, including cancer. Recent studies have shown CNPs to be toxic to cancer cells, to inhibit invasion and sensitize cancer cells to radiotherapy. In addition, several hydrophilic polymers have been used to coat the CNP surface in order to enhance its properties of extensive biocompatibility and systemic nontoxicity to normal cells and tissues. However, the results of previous studies were based on high CNP doses (10 μg/mL or more), and these doses may cause serious side effects in clinical applications. The impact of low CNP doses on tumor cells remains unknown. In this study, we report experiments indicating that CNPs‐AL‐ polyethylene glycol (PEG)600, a type of surface‐modified CNP that is more stable and less toxic than traditional CNPs could promote proliferation of hepatoma cells in a dose‐dependent manner. In addition, further research showed that a low dose (0.01 μg/mL) of CNPs‐AL‐PEG600 could reduce hepatoma cell apoptosis and activate AKT/ERK signaling pathways. These results may provide information that is important for using CNPs‐AL‐PEG600 as a therapeutic agent in clinical cancer treatments.

A failure of bone marrow mesenchymal stem cells (BM-MSCs) to adhere to hematopoietic cells is an essential cause of the progression of chronic myelogenous leukemia and is also a cause of failure of bone marrow (BM) transplantation, but the exact mechanisms of this have not been fully elucidated. Recent studies have indicated that microRNAs (miRNAs) are contained in leukemia-derived exosomes and are involved in modulating the BM microenvironment. In this study, we found that K562 cell-derived exosomes transfer miR-711 to BM-MSCs and suppress the adhesive function of BM-MSCs. Using qRT-PCR, we also confirmed a significantly higher level of miR-711 in exosomes derived from K562 cells than in exosomes derived from parental cells. The BM-MSCs co-cultured with exosomes derived from K562 cells showed a lower adhesion rate than did controls. We further demonstrated that exosomal transfer of miR-711 induced decreased adhesive abilities by inhibiting expression of adhesion molecule CD44 in BM-MSCs. In conclusion, our study reveals that K562 cell-derived exosomal miR-711 can be transferred to BM-MSCs and weaken adhesive abilities by silencing the expression of the adhesion molecule CD44.

The randomized controlled trials( RCTs) about modified Sanzi Yangqin Decoction in the treatment of patients with exacerbation of chronic obstructive pulmonary disease( AECOPD) were collected from 7 databases( PubMed,CNKI,etc.) till December25,2018 from their inception. All the studies searched were strictly evaluated and independently screened by two researchers according to the inclusion and exclusion criteria,and the methodological quality of included studies was evaluated. In order to systematically review the efficacy and safety of modified Sanzi Yangqin Decoction for treating AECOPD,the Meta-analysis and trial sequential analysis were conducted by using Stata/SE 14. 0 and TSA 0. 9. 5. 10 Beta,respectively. A total of 22 RCTs involving 2 012 patients were included. The results of Meta-analysis suggested that: as compared with the control group,the clinical symptoms in AECOPD patients were improved( RR = 1. 19,95%CI[1. 15,1. 24],P = 0); the pulmonary functions including forced expiratory volume in one second( FEV_1)( SMD= 0. 96,95%CI[0. 39,1. 52],P= 0. 001),the percentage of forced expiratory volume in one second( FEV_1%)( SMD =0. 80,95%CI[0. 20,1. 41],P = 0. 009),forced vital capacity( FVC)( SMD = 0. 69,95% CI[0. 06,1. 31],P = 0. 032),first seconds breathing volume percentage of forced vital capacity( FEV_1/FVC) were improved( SMD = 0. 81,95%CI[0. 64,0. 97],P = 0);the arterial oxygen partial pressure( PaO_2) was improved( SMD= 0. 87,95%CI[0. 41,1. 32],P= 0); the arterial partial pressure of carbon dioxide( PaCO_2) was decreased( SMD =-0. 91,95%CI[-1. 33,-0. 49],P = 0) in the trial group. In addition,the incidence of adverse reactions in the experimental group was low,and there were no serious adverse events. The trial sequential analysis( TSA) showed that the studies included in the improvement of clinical efficacy had passed the conventional and TSA threshold at the same time,further confirming the efficacy of trial group. This research showed that,conventional Western medicine treatment,combined with modified Sanzi Yangqin Decoction in treating acute exacerbation patients with chronic obstructive pulmonary disease could improve the clinical efficiency and pulmonary functions,improve the PaO_2,decrease the PaCO_2,with a high safety. However,the quality of existing research is low,requiring more high quality clinical trials for further validation.

This study aims to evaluate the diagnostic accuracy and clinical application value of multi-slice spiral CT (MSCT) enhanced scans combined with multiplanar reformations (MPRs) images compared with postoperative pathological results in preoperative T staging of rectal cancer. One hundred sixty-eight consecutive patients with rectal cancer were admitted in our hospital between January 2013 and October 2018. Conventional MSCT plain scans, multi-phase dynamic contrast-enhanced scans, and MPRs were performed in all patients before surgical operation. The preoperative T staging of the rectal cancer lesions was evaluated using MSCT enhanced scans combined with MPRs, which was verified by postoperative pathological results. The diagnostic accuracy of MSCT enhanced scans combined with MPRs in evaluating T staging of the rectal cancer lesions were analyzed by χ2 test and Kappa test. Compared with postoperative pathology, T staging using MSCT enhanced scans combined with MPRs had overall accuracy of 85.7%. Consistency between MSCT enhanced scans combined with MPRs and postoperative pathological staging was effective for T staging (Kappa = 0.658, χ2 = 4.200, P = .122). Conventional MSCT enhanced scans combined with MPRs are simple and feasible. It is consistent with the pathological diagnosis of evaluating T staging in the rectal cancer lesions. It can provide reliable imaging evidence for the preoperative evaluation of primary rectal cancer, especially in patients with magnetic resonance imaging (MRI) contraindications, or in grass-roots hospitals due to lack of MRI equipment.

OBJECTIVE: To study the expression of high-mobility group box 1 (HMGB1) in neonates with sepsis and its role in the pathogenesis of neonatal sepsis. METHODS: A total of 62 neonates with sepsis were enrolled as the sepsis group, 66 neonates with local infection were enrolled as the local infection group, and 70 healthy neonates were enrolled as the healthy control group. Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-17 (IL-17), interleukin-23 (IL-23), C-reactive protein (CRP) and procalcitonin (PCT) were measured. The mRNA expression of HMGB1, Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) and the protein expression of TLR4 and NF-κB in peripheral blood mononuclear cells (PBMCs) were also measured. PBMCs from healthy neonates were divided into 4 groups:control, HMGB1 treatment, HMGB1+TAK-242 (a TLR4 inhibitor) treatment and HMGB1+PDTC (an NF-κB inhibitor) treatment, and the mRNA expression of TLR4, NF-κB and IL-8 and the protein expression of TLR4 and NF-κB were measured. PBMCs from healthy neonates were divided into another 3 groups:control, LPS treatment and LPS+glycyrrhizin (an HMGB1 inhibitor) treatment, and the mRNA expression of HMGB1, TLR4, NF-κB and IL-8 and the protein expression of TLR4 and NF-κB were measured. RESULTS: Compared with the local infection and healthy control groups, the sepsis group had significantly higher serum levels of IL-6, IL-8, IL-17, IL-23, CRP and PCT (P < 0.05), as well as significantly higher mRNA expression of HMGB1, TLR4 and NF-κB and protein expression of TLR4 and NF-κB in PBMCs (P < 0.05). HMGB1 significantly induced the mRNA and protein expression of TLR4 and NF-κB in PBMCs (P < 0.05). TAK-242 inhibited the mRNA and protein expression of TLR4 and NF-κB and mRNA expression of IL-8 (P < 0.05). PDTC inhibited the mRNA and protein expression of NF-κB and the mRNA expression of IL-8 (P < 0.05). LPS significantly induced the mRNA expression of HMGB1 and the mRNA and protein expression of TLR4 and NF-κB and then stimulated the mRNA expression of IL-8 (P < 0.05). Glycyrrhizin inhibited the mRNA expression of HMGB1 and the mRNA and protein expression of TLR4 and NF-κB and then reduced the mRNA expression of IL-8 (P < 0.05). CONCLUSIONS: HMGB1 plays an important role in the pathogenesis of neonatal sepsis by activating the TLR4/NF-κB signaling pathway and inducing the secretion of inflammatory factors including IL-8. The HMGB1 blocker glycyrrhizin can inhibit activation of the TLR4/NF-κB signaling pathway and the secretion of inflammatory factors.