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Spontaneous preterm birth (SPB) can't be predicted accurately nowadays. We aim to investigate the value of serum amyloid A(SAA) and interleukin-6(IL-6) for forecasting the risk of SPB.A total of 302 pregnant women who completed delivery in our hospital from January 2019 to December 2021 were included. According to gestational days, they were divided into the case group (28-33The levels of SAA and IL-6 in the case group were higher than those in the control group(P 0.05), and the most practical value of SAA and IL-6 access SPB risk were 17.35 mg/L, 112.41 pg/mL respectively. The area under the ROC curve of diagnosis to predict SPB were 0.8849, 0.8664.The assessment of SPB risk by SAA and IL-6 bearscertain clinical value, which could assist clinicians in recognizing and evaluating the potential dangers of SPB.

We aimed to estimate the effects of indoor and outdoor temperature on wintertime blood pressure (BP) among peri-urban Beijing adults.We enrolled 1279 adults (ages: 40-89 years) and conducted measurements in two winter campaigns in 2018-2019 and 2019-2020. Study staff traveled to participant homes to administer a questionnaire and measure brachial and central BP. Indoor temperature was measured in the 5 min prior to BP measurement. Outdoor temperature was estimated from regional meteorological stations. We used multivariable mixed-effects regression models to estimate the within-individual and between-individual effects of indoor and outdoor temperatures on BP.Indoor and outdoor temperatures ranged from 0.0 to 28 °C and -14.3 to 6.4 °C, respectively. In adjusted models, a 1 °C increase in indoor temperature was associated with decreased SBP [-0.4 mmHg, 95% confidence interval (CI): -0.7 to -0.1 (between-individual; brachial and central BP); -0.5 mmHg, 95% CI: -0.8 to -0.2 (within-individual, brachial BP); -0.4 mmHg, 95% CI: -0.7 to -0.2 (within-individual, central BP)], DBP [-0.2 mmHg, 95% CI:-0.4 to -0.03 (between-individual); -0.3 mmHg, 95% CI: -0.5 to -0.04 (within-individual)], and within-individual pulse pressure [-0.2 mmHg, 95% CI: -0.4 to -0.04 (central); -0.3 mmHg, 95% CI: -0.4 to -0.1 (brachial)]. Between-individual SBP estimates were larger among participants with hypertension. There was no evidence of an effect of outdoor temperature on BP.Our results support previous findings of inverse associations between indoor temperature and BP but contrast with prior evidence of an inverse relationship with outdoor temperature. Wintertime home heating may be a population-wide intervention strategy for high BP and cardiovascular disease in China.

The Chinese government implemented a national household energy transition program that replaced residential coal heating stoves with electricity-powered heat pumps for space heating in northern China. As part of a baseline assessment of the program, this study investigated variability in personal air pollution exposures within villages and between villages and evaluated exposure patterns by sociodemographic factors. We randomly recruited 446 participants in 50 villages in four districts in rural Beijing and measured 24 h personal exposures to fine particulate matter (PM

As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. By multiplexing mass spectrometry fingerprints from two independent nanostructured matrixes through machine learning for highly sensitive detection and high throughput analysis, we report a laser desorption/ionization (LDI) mass spectrometry-based liquid biopsy for pan-cancer screening and classification. The Multiplexed Nanomaterial-Assisted LDI for Cancer Identification (MNALCI) is applied in 1,183 individuals that include 233 healthy controls and 950 patients with liver, lung, pancreatic, colorectal, gastric, thyroid cancers from two independent cohorts. MNALCI demonstrates 93% sensitivity at 91% specificity for distinguishing cancers from healthy controls in the internal validation cohort, and 84% sensitivity at 84% specificity in the external validation cohort, with up to eight metabolite biomarkers identified. In addition, across those six different cancers, the overall accuracy for identifying the tumor tissue of origin is 92% in the internal validation cohort and 85% in the external validation cohort. The excellent accuracy and minimum sample consumption make the high throughput assay a promising solution for non-invasive cancer diagnosis., As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. Here, the authors report a machine learning model using mass spectrometry-based liquid biopsy data for pan-cancer screening and classification.

Diabetic nephropathy (DN) is still on the rise worldwide, and millions of patients have to be treated through dialysis or transplant because of kidney failure caused by DN. Recent reports have highlighted circRNAs in the treatment of DN. Herein, we aimed to investigate the mechanism by which high glucose‐induced exo‐circ_0125310 promotes diabetic nephropathy progression. circ_0125310 is highly expressed in diabetic nephropathy and exosomes isolated from high glucose‐induced mesangial cells (MCs). High glucose‐induced exosomes promote the proliferation and fibrosis of MCs. However, results showed that the effects of exosomes on MCs can be reversed by the knockdown of circ_0125310. miR‐422a, which targets IGF1R, was the direct target of circ_0125310. circ_0125310 regulated IGF1R/p38 axis by sponging miR‐422a. Exo‐circ_0125310 increased the luciferase activity of the WT‐IGF1R reporter in the dual‐luciferase reporter gene assays and upregulated the expression level of IGF1R and p38. Finally, in vivo research indicated that the overexpression of circ_0125310 promoted the diabetic nephropathy progression. Above results demonstrated that the high glucose‐induced exo‐circ_0125310 promoted cell proliferation and fibrosis in diabetic nephropathy via sponging miR‐422a and targeting the IGF1R/p38 axis.

Overexpression of survivin is frequently observed in human malignancies and is associated with poor prognosis. The present study found that survivin is highly expressed in nasopharyngeal carcinoma (NPC) tumor tissues. Depleting survivin with shRNA inhibited cell viability, colony formation, and in vivo tumorigenesis of NPC cells. With a natural product screening, we identified Butein as a potential anti-tumor compound for NPC by reducing survivin protein level. Butein shortened the half-life of survivin and enhanced ubiquitination-mediated degradation. The mechanism study showed that Butein promoted the interaction between survivin and E3 ligase Fbxl7, and the knockdown of Fbxl7 compromised Butein-induced survivin ubiquitination. Butein suppressed the Akt-Wee1-CDK1 signaling and decreased survivin Thr34 phosphorylation, facilitating E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Moreover, Butein exhibited a strong in vivo anti-tumor activity, as the tumor volume of Butein-treated xenografts was reduced significantly. Butein alone or combined with cisplatin (CDDP) overcame chemoresistance in NPC xenograft tumors. Overall, our data indicate that Butein is a promising anti-tumor agent for NPC treatment.

Background Cancer cell membrane-camouflaged nanotechnology for metal complex can enhance its biocompatibility and extend the effective circulation time in body. The ruthenium polypyridyl complex (RuPOP) has extensive antitumor activity, but it still has disadvantages such as poor biocompatibility, lack of targeting, and being easily metabolized by the organism. Cancer cell membranes retain a large number of surface antigens and tumor adhesion molecules CD47, which can be used to camouflage the metal complex and give it tumor homing ability and high biocompatibility. Results Therefore, this study provides an electrostatic adsorption method, which uses the electrostatic interaction of positive and negative charges between RuPOP and cell membranes to construct a cancer cell membrane-camouflaged nano-platform (RuPOP@CM). Interestingly, RuPOP@CM maintains the expression of surface antigens and tumor adhesion molecules, which can inhibit the phagocytosis of macrophage, reduce the clearance rate of RuPOP, and increase effective circulation time, thus enhancing the accumulation in tumor sites. Besides, RuPOP@CM can enhance the activity of cellular immune response and promote the production of inflammatory cytokines including TNF-α, IL-12 and IL-6, which is of great significance in treatment of tumor. On the other hand, RuPOP@MCM can produce intracellular ROS overproduction, thereby accelerating the apoptosis and cell cycle arrest of tumor cells to play an excellent antitumor effect in vitro and in vivo. Conclusion In brief, engineering cancer cell membrane-camouflaged metal complex is a potential strategy to improve its biocompatibility, biological safety and antitumor effects.

Salivary adenoid cystic carcinoma (SACC) is a malignant tumor, which is characterized by a higher incidence of distant metastasis. The aim of this study was to investigate the role and mechanism of protein kinase D1 (PKD1) in regulating the epithelial-mesenchymal transition (EMT) and promotes the metastasis in SACC. We analyzed the expression of PKD1 in 40 SACC patients and different metastatic potential cell lines. Then, we investigated whether the migration and growth of SACC were regulated by PKD1 using shRNA interference or inhibition of kinase active in vitro cell. Moreover, the mechanism by which PKD1 regulates the stability of Snail protein was determined. Finally, nude mice were used to testify the function of PKD1 via tail vein injection. PKD1 was correlated with metastasis and poor prognosis of SACC patients. PKD1 inhibition attenuated proliferation, migration, invasion, and EMT of SACC cells. Conversely, kinase active PKD1 could induce EMT and promoted cell migration in human HSG cell. Furthermore, downregulation of PKD1 regulated Snail via phosphorylation at Ser-11 on Snail protein and promotion of proteasome-mediated degradation, and reduced lung metastasis in vivo. Our results suggest that PKD1 induces the EMT and promotes the metastasis, which illustrate that PKD1 may be a potential prognostic biomarker and serve as a potential therapeutic target for SACC patients.

BACKGROUND: Oral squamous cell carcinoma (OSCC) usually originates from oral potentially malignant disorders (OPMD), such as oral leukoplakia (OLK) and oral lichen planus (OLP). Identifying biomarkers for the early diagnosis and evaluation of malignant transformation in OPMD could improve the survival rate of OSCC patients. OBJECTIVE: The present study aimed to screen for potential salivary biomarkers for evaluating the malignant transformation of OPMD. METHODS: Salivary proteases from OLK and OSCC patients or healthy donors and proteases in cultural medium from DOK and Cal-27 cells were detected with a human protease array kit. The concentrations of the salivary Kallikrein 5 (KLK5) and urokinase-type plasminogen activator (uPA) proteases were measured by ELISA. Receiver operating characteristics (ROC) to determine the potential value of these proteases in clinical diagnosis were calculated using SPSS software. Immunohistochemistry was used to detect the KLK5 and uPA expression in the oral organizations. RESULTS: The salivary protease spectrum was different among patients with OLK and OSCC and healthy donors. KLK5 and uPA levels in saliva tended to increase as the disease progressed (healthy < OPMD [OLK and OLP] < OSCC). ROC curves showed the optimum diagnostic cutoffs for KLK5 as a biomarker for OLK, OLP, and OSCC were 5.97, 6.03, and 9.45 pg/mL, respectively, while the cutoffs for uPA were 17.19, 17.26, and 20.96 pg/mL. Their combined analysis showed a higher sensitivity for the differential diagnosis of disease. Furthermore, higher levels of KLK5 and uPA were observed in OSCC tissues than in OLK and OLP. CONCLUSIONS: Salivary KLK5 and uPA are potential biomarkers for evaluating OLK and OLP malignant transformation and early diagnosis of OSCC.

Objectives Air pollution can lead to many cardiovascular and respiratory diseases, but the impact of air pollution on pulmonary embolism is still uncertain. We conducted a meta-analysis to assess the relationship between air pollution and pulmonary embolism. Content We searched PubMed, EMBASE, Web of Science, and the Cochran Library for citations on air pollutants (carbon monoxide, sulfur dioxide, nitrogen dioxide, ozone and particulate matter) and pulmonary embolism. A total of nine citations met the inclusion criteria. There is no evidence of bias. CO, SO2, PM10 and PM2.5 had no significant effect on the occurrence of pulmonary embolism. NO2 and O3 can increase the risk of pulmonary embolism to a small extent. Summary This meta-analysis suggests that some air pollutants are associated with an increased risk of pulmonary embolism. Outlook Reducing air pollution and improving air quality can effectively reduce the risk of pulmonary embolism.

Background MicroRNAs (miRNAs) are involved in the regulation of both the innate and adaptive immune response to Cryptosporidium parvum infection. We previously reported that C. parvum upregulated miR‑942‑5p expression in HCT‑8 cells via TLR2/TLR4‑NF‑κB signaling. In the present study, the role of miRNA-942-5p in the regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated HCT-8 cell apoptosis induced by C. parvum was investigated. Methods Quantitative real-time polymerase chain reaction, western blotting, flow cytometry, and immunofluorescence were used for analysis. Results Forced expression of miRNA-942-5p resulted in decreased apoptosis and an increased C. parvum burden in HCT-8 cells. The opposite results were observed using the suppressed expression of miRNA-942-5p. The miRNA-942-5p led to the translational suppression of IFI27 gene through targeting the 3’-untranslated region of the IFI27 gene. Moreover, overexpression of the IFI27 gene produced a high apoptotic ratio and low C. parvum burden. In contrast, a low apoptotic ratio and a high C. parvum burden were observed following downregulation of the IFI27 gene. Both miR-942-5p and the IFI27 gene influenced TRAIL and caspase-8 expression induced by C. parvum in HCT-8 cells. Moreover, TRAIL promoted HCT-8 cell apoptosis in a concentration-dependent manner. Conclusions These data suggested that C. parvum induced the downregulation of IFI27 via relief of miR-942-5p-mediated translational suppression. IFI27 downregulation was affected the burden of C. parvum by regulating HCT-8 cell apoptosis through TRAIL-dependent pathways. Future studies should determine the mechanisms by which C. parvum infection increases miR-942-5p expression and the role of miR-942-5p in hosts' anti-C. parvum immunity in vivo. Graphical Abstract

Background Cryptosporidium species are zoonotic protozoans that are important causes of diarrhoeal disease in both humans and animals. Non-coding RNAs (ncRNAs) play an important role in the innate immune defense against Cryptosporidium infection, but the underlying molecular mechanisms in the interaction between human ileocecal adenocarcinoma (HCT-8) cells and Cryptosporidium species have not been entirely revealed. Methods The expression profiles of messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) in the early phase of infection of HCT-8 cells with Cryptosporidium parvum and at 3 and 12 h post infection were analyzed using the RNA-sequencing technique. The biological functions of differentially expressed RNAs (dif-RNAs) were discovered through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The targeting relationships between three ncRNAs and mRNAs were analyzed using bioinformatics methods, followed by building a competing endogenous RNA (ceRNA) regulatory network centered on miRNAs. Results After strictly filtering the raw data, our analysis revealed 393 dif-lncRNAs, 69 dif-miRNAs and 115 dif-mRNAs at 3 hpi, and 450 dif-lncRNAs, 129 dif-miRNAs, 117 dif-mRNAs and one dif-circRNA at 12 hpi. Of these, 94 dif-lncRNAs, 24 dif-miRNAs and 22 dif-mRNAs were detected at both post-infection time points. Eleven dif-lncRNAs, seven dif-miRNAs, eight dif-mRNAs and one circRNA were randomly selected and confirmed using the quantitative real-time PCR. Bioinformatics analyses showed that the dif-mRNAs were significantly enriched in nutritional absorption, metabolic processes and metabolism-related pathways, while the dif-lncRNAs were mainly involved in the pathways related to the infection and pathogenicity of C. parvum (e.g. tight junction protein) and immune-related pathways (e.g. cell adhesion molecules). In contrast, dif-miRNAs and dif-circRNA were significantly enriched in apoptosis and apoptosis-related pathways. Among the downregulated RNAs, the miRNAs has-miR-324-3p and hsa-miR-3127-5p appear to be crucial miRNAs which could negatively regulate circRNA, lncRNA and mRNA. Conclusions The whole transcriptome profiles of HCT-8 cells infected with C. parvum were obtained in this study. The results of the GO and KEGG pathway analyses suggest significant roles for these dif-RNAs during the course of C. parvum infection. A ceRNA regulation network containing miRNA at its center was constructed for the first time, with hsa-miR-324-3p and hsa-miR-3127-5p being the crucial miRNAs. These findings provide novel insights into the responses of human intestinal epithelial cells to C. parvum infection. Graphical Abstract

Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the

Chronic kidney disease is a global health problem and eventually develops into an end-stage renal disease (ESRD). It is now widely believed that renal tubulointerstitial fibrosis (TIF) plays an important role in the progression of ESRD. Renal tubular epithelial-mesenchymal transition (EMT) is an important cause of TIF. Studies have shown that FGF2 is highly expressed in fibrotic renal tissue, although the mechanism remains unclear. We found that FGF2 can activate STAT3 and induce EMT in renal tubular epithelial cells. STAT3, an important transcription factor, was predicted by the JASPAR biological database to bind to the promoter region of YAP1. In this study, STAT3 was shown to promote the expression of the downstream target gene YAP1 through transcription, promote EMT of renal tubular epithelial cells, and mediate the occurrence of renal TIF. This study provides a theoretical basis for the involvement of the FGF2/STAT3/YAP1 signaling pathway in the process of renal interstitial fibrosis and provides a potential target for the treatment of renal fibrosis.

Amebiasis is a disease caused by the protozoan parasite Entamoeba histolytica, which mainly shows symptoms of acute diarrhea, dysentery, amebic colitis, and amebic liver abscesses. As the fourth leading parasitic cause of human mortality, E. histolytica mainly infect children in developing countries, transmitted by food and water contamination. In the majority of infected individuals, Entamoeba sp. asymptomatically colonizes the large intestine and self-limiting, while in others, the parasite breaches the mucosal epithelial barrier to cause amebic colitis and can disseminate to soft organs to cause abscesses. Metronidazole (MTZ) is the recommended and most widely used drug for treating the invasive amebiasis. No amebiasis vaccine has been approved for human clinical trials to date, but many recent vaccine development studies hold promise. For the prevention and control of amebiasis, improvement of water purification systems and hygiene practices could decrease disease incidence. In this review, we focus on the epidemiology, transmission, clinical signs, pathogenesis, diagnosis, treatment, prevention and control of the zoonotic amebiasis.

Despite novel therapeutic options, many people with type 2 diabetes (T2D) do not achieve their HbA1c targets. Given the progressive nature of T2D, many individuals not controlled with oral therapy will require advancement to injectable therapy using either a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA), recently recommended as a first option, or traditionally a basal insulin. However, premix insulins remain frequently used, either as initial injectable therapy or as intensification from basal insulin. Premix insulin injections can potentially provide significant glycaemic improvements to basal insulin but at the expense of increased hypoglycaemia and weight gain and the need for multiple daily doses, which may affect treatment adherence. Real‐world evidence suggests that glycaemic control often remains suboptimal with premix insulins. Fixed‐ratio combinations (FRCs) of basal insulin and GLP‐1 RAs provide a novel alternative to premix insulin for therapy intensification. While no direct comparisons between premix insulins and FRCs are available, results from meta‐analyses suggest that FRCs may offer better HbA1c reductions, a lower risk of hypoglycaemia and less weight gain compared with premix insulin in a simplified treatment regimen. A head‐to‐head trial of T2D treatment intensification with premix insulin and a FRC of basal insulin plus a GLP‐1 RA is currently in progress, which should help to clarify the outcomes for each treatment option. This review discusses the unmet needs of people with T2D treated with premix insulin and provides evidence supporting FRCs of basal insulin and GLP‐1 RAs as an alternative treatment option.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progression and worse prognosis. Our previous study found that HES1 was overexpressed and promoted invasion in TNBC. However, the role of HES1 in modulating BCSC stemness of TNBC remains unclear. Here, we found that HES1 upregulates Slug both in transcriptional level and in protein level. HES1 also has a positive correlation with Slug expression in 150 TNBC patient samples. TNBC patients with high HES1 and Slug levels show worse prognosis in both progression-free survival and overall survival analyses. Survival analyses indicate that the effects of HES1 on survival prognosis may depend on Slug. Furthermore, we reveal that HES1 is a novel transcriptional activator for Slug through acting directly on its promoter. Meanwhile, HES1 knockdown reduces BCSC self-renewal, BCSC population, and cancer cell proliferation in TNBC, whereas overexpression of Slug restores the oncogenic function of HES1, both in vitro and in vivo, suggesting that HES1 performs its oncogenic role through upregulating Slug. Taken together, HES1 promotes BCSC stemness properties via targeting Slug, highlighting that HES1 might be a novel candidate for BCSC stemness regulation in TNBC and providing new clues for identifying promising prognostic biomarkers and therapeutic targets of TNBC.

Tumor microenvironment is a complex ecosystem composed of tumor extracellular matrix, fibroblasts, blood vessels, and immune cells, promoting tumor development by secreting various growth factors, hydrolase, and inflammatory factors. Tumor-associated macrophages (TAMs) constitute the largest number of immune cells in the TME, and they have a "double-edged sword" effect on tumor growth, invasion, metastasis, angiogenesis, and immunosuppression. Under the regulation of different cytokines in the TME, the bidirectional TAMs can switch their phenotypes between tumoricidal M1-like and pro-tumorigenic M2-like macrophages. TAM polarization suggests that scientists can use this property to design drugs targeting this regulation as a promising immunotherapy strategy to enhance tumor therapy efficiency. In this review, we summarize a brief introduction of TAMs and their implications for tumorigenesis. Next, we review recent advances in designing various functionalized nanomedicines and their applications in nanomedicine-based cancer therapies that target TAMs by killing them, inhibiting macrophage recruitment, and repolarizing them from pro-tumorigenic M2-like to tumoricidal M1-like macrophages. Simultaneously, the regulation of nanomedicines on the signaling pathways accounting for these effects is also summarized. This review will not only provide background scientific information for the understanding of TAMs and their roles in cancer treatment but also help scientists design nanomedicines based on tumor TAMs, which can help achieve better clinical treatment outcomes for tumors.

Background Necrotizing enterocolitis (NEC) is a disastrous gastrointestinal disease of newborns, and the mortality rate of infants with NEC is approximately 20%-30%. The exploration of pathogenic targets of NEC will be conducive to timely diagnosis of NEC. Methods The whole transcriptome RNA sequencing was performed on NEC samples to reveal the expression of lncRNAs, circRNAs, miRNAs and mRNAs. Using differential expression analysis, cross analysis, target prediction, enrichment analysis, the pathogenic ceRNA network and target was found. Results Preliminarily, 281 DEmRNAs, 21 DEmiRNAs, 253 DElncRNAs and 207 DEcircRNAs were identified in NEC samples compared with controls. After target prediction and cross analyses, a key ceRNA regulatory network was built including 2 lncRNAs, 4 circRNAs, 2 miRNAs and 20 mRNAs. These 20 mRNAs were significantly enriched in many carbohydrate metabolism related pathways. After cross analysis of hypoxia-, carbohydrate metabolism-related genes, and 20 core genes, one gene HK2 was finally obtained. Dendritic cells activated were significantly differentially infiltrated and negatively correlated with HK2 expression in NEC samples. Conclusions The promising pathogenic hypoxia-related gene HK2 has been firstly identified in NEC, which might also involve in the carbohydrate metabolism in NEC.

Background The aim of this work was to screen and validate biomarkers of ovarian cancer-initiating cells to detect the mechanisms of recurrence of epithelial ovarian cancer (EOC). Methods Stably labelled the amino acid in side population (SP) cells of epithelial ovarian cancer which were rich in cancer-initiating cells and non-SP cells with isotope in culture and differentially expressed cellular membrane proteins in SP cells were identified through proteomics technology. The new candidate biomarker was screened and validated through RT-PCR and western blot. Both in cell lines and primary EOC, cancer-initiating biofunctions of CDC50A positive cells were validated. Moreover, the characteristics of mesenchymal transition (EMT) was also detected and the correlation between the biomarker and clinical prognosis was observed. Results Through proteomics technology, candidate protein CDC50A was screened, and its significantly differential expression in SP cells was validated. CDC50A-positive cells from cell lines and primary ovarian cancer tissues were validated to show characteristics of cancer-initiating cells both in vitro and in vivo, including sphere-forming, self-renewal, differentiation, tumor metastasis and tumorigenicity in mice. The relationship between CDC50A-positive cells from primary tissues and tumour metastasis was confirmed based on their mesenchymal transition characteristics. Among 16 high-grade ovarian serous cancer patients, a high ratio of CDC50A-positive cells in primary tumours was correlated with a shorter platinum-free interval (p = 0.031, HR 0.260, 95% CI 0.77 ~ 0.885). Conclusion CDC50A could be used to screen ovarian cancer-initiating cells and might be a new target to resolve tumour development in EOC patients.

Background Prostate cancer (PCa) is known to be suitable for hypofractionated radiotherapy due to the very low α/β ratio (about 1.5–3 Gy). However, several randomized controlled trials have not shown the superiority of hypofractionated radiotherapy over conventionally fractionated radiotherapy. Besides, in vivo and in vitro experimental results show that the linear-quadratic (LQ) model may not be appropriate for hypofractionated radiotherapy, and we guess it may be due to the influence of fractionation schedules on the α/β ratio. Therefore, this study attempted to estimate the α/β ratio in different fractionation schedules and evaluate the applicability of the LQ model in hypofractionated radiotherapy. Methods The maximum likelihood principle in mathematical statistics was used to fit the parameters: α and β values in the tumor control probability (TCP) formula derived from the LQ model. In addition, the fitting results were substituted into the original TCP formula to calculate 5-year biochemical relapse-free survival for further verification. Results Information necessary for fitting could be extracted from a total of 23,281 PCa patients. A total of 16,442 PCa patients were grouped according to fractionation schedules. We found that, for patients who received conventionally fractionated radiotherapy, moderately hypofractionated radiotherapy, and stereotactic body radiotherapy, the average α/β ratios were 1.78 Gy (95% CI 1.59–1.98), 3.46 Gy (95% CI 3.27–3.65), and 4.24 Gy (95% CI 4.10–4.39), respectively. Hence, the calculated α/β ratios for PCa tended to become higher when the dose per fraction increased. Among all PCa patients, 14,641 could be grouped according to the risks of PCa in patients receiving radiotherapy with different fractionation schedules. The results showed that as the risk increased, the k (natural logarithm of an effective target cell number) and α values decreased, indicating that the number of effective target cells decreased and the radioresistance increased. Conclusions The LQ model appeared to be inappropriate for high doses per fraction owing to α/β ratios tending to become higher when the dose per fraction increased. Therefore, to convert the conventionally fractionated radiation doses to equivalent high doses per fraction using the standard LQ model, a higher α/β ratio should be used for calculation.

Purpose We identified the risk predictors related to prostate cancer (PCa) metastasis using contemporary data in a community setting. Then, we assessed the performance of indications for bone imaging recommended from the NCCN, AUA and EAU guidelines. Methods Using the Surveillance, Epidemiology, and End Results database (2010–2015), we collected clinicopathological information from PCa patients. The associated risk factors found by multivariate analyses were used to establish forest plots and nomograms for distant metastasis (DM) and bone(s)-only metastasis (BM). We next evaluated the NCCN, AUA and EAU guidelines indications for the discovery of certain subgroups of patients who should receive bone imaging. Results A total of 120,136 patients were eligible for analysis, of which 96.7% had no metastasis. The odds ratios of positive DM and BM results were 13.90 times and 15.87 times higher in patients with a histologic grade group (GG) 5 than in the reference group. The concordance index of the nomograms based on race, age, T/N stage, PSA, GG, percentage of positive scores for predicting DM and BM was 0.942 and 0.928, respectively. Performance of the NCCN, AUA and EAU guidelines was high and relatively similar in terms of sensitivity (93.2–96.9%) and negative predictive value (99.8–99.9%). NCCN guidelines had the highest accuracy, specificity and positive likelihood ratio, while negative likelihood ratio was lowest in AUA guideline. Conclusion Histologic GG 5 was the foremost factor for DM and BM. NCCN-based recommendations may be more rational in clinical practice. Nomograms predicting metastasis demonstrate high accuracy.

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF, pegfilgrastim) is a long-acting derivative of recombinant human granulocyte colony-stimulating factor with limited renal clearance and a longer half-life. It is used for the prevention of febrile neutropenia, owing to its capacity to promote neutrophil recovery. In this study, the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of 2 formulations of PEG-rhG-CSF were evaluated in healthy Chinese subjects. Twenty-four male subjects who received a single dose of subcutaneous PEG-rhG-CSF 100 µg/kg were randomized to either treatment A (3 mg/mL) or treatment B (1 mg/mL). Noncompartmental pharmacokinetic parameters of PEG-rhG-CSF were derived from serum concentration-time data. In addition, absolute neutrophil count (ANC) as a pharmacodynamic maker, immunogenicity through antidrug antibody testing, and safety were evaluated. The mean area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-t ) and the mean maximum concentration (Cmax ) of PEG-rhG-CSF after treatment A were 5070 ng·h/mL and 125 ng/mL, respectively; these values were comparable to those measured after treatment B (5340 ng·h/mL and 123 ng/mL, respectively). The mean value of area under the △ANC (baseline-adjusted ANC)-time curve and the maximum △ANC values were 4380 × 109 h/L and 33.1 × 109 /L, respectively, in the treatment A group, and 5170 × 109 h/L and 38.6 × 109 /L, respectively, in the treatment B group. The pharmacokinetic and pharmacodynamic profiles were similar for the 2 PEG-rhG-CSF formulations following a single dose of 100 µg/kg. The safety and immunogenicity profiles were also similar, with no significant differences. The dose adjustment of PEG-rhG-CSF was not considered necessary for formulation transformation.

Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR–dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.

Objective: Previous studies have reported an association between iron deficiency (ID) and increased thyroid peroxidase antibody (TPO-Ab) during early pregnancy. The objective of this study was to explore the relationship between ID and thyroid dysfunction, as well as thyroid autoantibodies, during the second trimester of pregnancy. Methods: A total of 1,592 pregnant women (13 to 28 weeks gestation) were enrolled in this cross-sectional study. According to serum ferritin (SF) concentrations, they were divided into ID (SF 4.0 mIU/L and free thyroxine [FT4] within the reference range) and thyroid autoimmunity. Results: The prevalence of ID was 23.43% (373/1,592). Compared with the non-ID group, the ID group had lower FT4 levels (13.94 pmol/L [8.91 to 29.82 pmol/L] versus 14.63 pmol/L [8.22 to 47.24 pmol/L]; P

Purpose This study aims to identify predictive local recurrence risk factors and site-specific local recurrence pattern of upper tract urothelial carcinoma (UTUC) with different primary tumor locations. Methods Three hundred and eighty-nine UTUC patients with radical nephroureterectomy were included in this study. Univariate and multivariate Cox proportional hazards regressions were performed to measure the risk of local recurrence. We also mapped the position of local recurrence sites stratified by primary tumor locations. Results A total of 73 patients (18.7%) developed local recurrence within a median follow-up of 41 months (range, 3-80 months). For patients with local recurrence, the median interval of local recurrence was 9 months. Ureter tumor, multifocality, T stage, G grade, lymph node metastasis (LNM), lymph node dissection (LND), and lymph vascular invasion (LVI) were all significantly associated with increased local recurrence by univariable analyses (P < 0.05). Only multifocality, T3–4, G3, and LNM remained independent predictors of increased local recurrence by multivariable analyses. Adjuvant radiotherapy could reduce the local recurrence (HR = 0.177; 95% CI 0.064-0.493, P = 0.001). Patients with local recurrence had poorer cancer-specific survival (4-year cancer-specific survival rate 36 ± 7.5% vs 88.4 ± 2.2%, P = 0.000). We evaluated local recurrence pattern stratified by tumor locations. Para-aortic lymph node region was the most common recurrence area for all the patients. Left-sided UTUC had more than 70% recurrent lymph nodes in the left para-aortic region (LPA). For right-sided UTUC patients, recurrent para-aortic lymph nodes distributed in the LPA (33.3%), aortocaval (AC) (41.5%), and right paracaval (RPC) (25.2%) regions. Recurrence in the internal and external iliac regions was only found in the distal ureter group (P < 0.05). Renal pelvic fossa recurrence was only found in renal pelvic tumor (22.2%, P = 0.007). The ureter tumor bed recurrence rate was higher for ureter patients (P = 0.001). Conclusions Multifocality, T3–4, G3, and LNM are predictors of higher local recurrence rate of UTUC. Adjuvant radiotherapy can reduce local recurrence rate. Local recurrence patterns are different according to primary tumor locations.

Renalase is a novel enzyme that can regulate blood pressure by degrading circulating catecholamines. We aimed to evaluate the possible effect of rs2296545, rs2576178 and rs10887800 polymorphisms of the

Atherosclerosis is one of the most common clinical cardiovascular disorders. Accumulating evidence indicates that lncRNAs exert critical functions in atherosclerosis; however, their functional roles and regulatory mechanisms remain unclear. In this study, we induced atherosclerotic plaques in three rabbit carotid arteries through an atherogenic diet and balloon injury; three age-matched rabbits were fed normal chow and served as controls. We thoroughly investigated the RNA (mRNA, lncRNA and miRNA) expression profiles in atherosclerotic rabbit carotid models with deep RNA sequencing. We identified several significantly differentially expressed RNAs. The corresponding lncRNA-miRNA-mRNA network was constructed, and the significantly dysregulated network was selected. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that the mRNAs in the network were involved in leukocyte activation, cell proliferation, cell adhesion molecules and cytokine-cytokine receptor interaction. After rigorous screening, we obtained a differentially expressed lncRNA-miRNA-mRNA interaction network associated with atherosclerosis. In the network, XLOC_054118 and XLOC_030217 upregulate the CHI3L1, SOAT, CTSB and CAPG genes by competitively binding to the miRNA ocu-miR-96-5p. XLOC_062719 and XLOC_063297 upregulate CTSS, CTSB and EDNRA genes by competitively binding to the miRNA ocu-miR-185-5p.

Purpose Our purpose was to compare toxicity and biochemical control in postprostatectomy patients treated with conventional (66 Gy) or dose-intensified (72 Gy) radiation therapy. Methods and Materials Patients who had stage pT3-4, positive surgical margins, or rising prostate-specific antigen ≥ 0.2 ng/mL after radical prostatectomy were randomly assigned to receive either 66 Gy in 33 fractions or 72 Gy in 36 fractions. A primary endpoint was to assess the difference in biochemical progression-free survival (bPFS) between these 2 cohorts, and secondary endpoints were to assess differences in genitourinary (GU), gastrointestinal (GI), and hematologic toxicities between these 2 cohorts. bPFS was estimated by the Kaplan–Meier method and toxicities were compared using the χ2 test. Results Between September 2011 and November 2016, 144 patients were enrolled: 71 patients to the 66 Gy cohort and 73 patients to the 72 Gy cohort. The median follow-up time was 48.5 months (range, 14-79 months). There was no difference in 4-year bPFS between the 66 Gy and 72 Gy cohorts (75.9% vs 82.6%; P = .299). However, in patients with a higher Gleason score (8-10), the 72 Gy cohort had statistically significant improvement in bPFS compared with the 66 Gy cohort (79.7% vs 55.7%; P = .049). Toxicity analysis showed no difference in ≥2 acute or late GI or GU toxicities between these 2 cohorts. A total of 48 patients were scored as urinary incontinence before radiation therapy, of which 39 (81.3%) reported incontinence recovery or stable at 1-year follow-up, and only 9 (18.8%) patients reported worsening. There was no difference between the 2 cohorts in urinary incontinence either at baseline or at 1-year follow-up. Conclusions Dose escalation (72 Gy) demonstrated no improvement in 4-year bPFS compared with the 66 Gy regimen. However, the dose escalation was not associated with greater acute or late GU or GI toxicities and did not increase urinary incontinence.

BackgroundNecrotizing enterocolitis (NEC) is the leading cause of death among preterm infants born at MethodsOur prospective multicenter, double-blinded, randomized, controlled trial will include infants born at n = 1549) will receive at least two feeds of fresh human milk (i.e., within 4 h of expression) per day from the time of enrollment until 32 weeks’ corrected age or discharge to home. Infants in the control group (n = 1549) will receive previously frozen human milk following the current standard protocols. Following informed consent, enrolled infants will be randomly allocated to the control or fresh human milk groups. The primary outcome is the composite outcome mortality or NEC ≥ stage 2 at 32 weeks’ corrected age, and the secondary outcomes are mortality, NEC ≥ stage 2, NEC needing surgery, late-onset sepsis, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), weight gain, change in weight, increase in length, increase in head circumference, time to full enteral feeds, and finally, the number and type of critical incident reports, including feeding errors.DiscussionOur double-blinded, randomized, controlled trial aims to examine whether fresh human milk can improve infant outcomes. The results of this study will impact both Chinese and international medical practice and feeding policy for preterm infants. In addition, data from our study will inform changes in health policy in NICUs across China, such that mothers are encouraged to enter the NICU and express fresh milk for their infants.Trial registrationChinese Clinical Trial Registry; #ChiCTR1900020577; registered January 1, 2019;http://www.chictr.org.cn/showprojen.aspx?proj=34276

Epilepsy is a nervous system disease caused by abnormal discharge of brain neurons, which is characterized by recurrent seizures. The factors that induce epilepsy include genetic and environmental factors. Genetic factors are important pathogenic factors of epilepsy, such as epilepsy caused by protocadherin-19 (PCDH-19) mutation, which is an X-linked genetic disease. It is more common in female heterozygotes, which are caused by mutations in the PCDH-19 gene. Epilepsy caused by environmental factors is mainly caused by brain injury, which is commonly caused by brain tumors, brain surgery, or trauma to the brain. In addition, the pathogenesis of epilepsy is closely related to abnormalities in some signaling pathways. The Wnt/β-catenin signaling pathway is considered a new target for the treatment of epilepsy. This review summarizes these factors inducing epilepsy and the research hypotheses regarding the pathogenesis of epilepsy. The focus of this review centers on cadherins and the pathogenesis of epilepsy. We analyzed the pathogenesis of epilepsy induced by N-cadherin and PCDH-19 in the cadherin family members. Finally, we expect that in the future, new breakthroughs will be made in the study of the pathogenesis and mechanism of epilepsy at the cellular and molecular levels.

A recent study has shown that upper tract urothelial carcinoma (UTUC) patients with high-risk factors have a high local recurrence rate. The purpose of this work was to investigate the benefit of adjuvant radiotherapy (ART) for patients with high recurrence factors.Four hundred twenty-four UTUC patients who received radical nephroureterectomy (RNU) in our hospital between 2010 and 2018 were reviewed. The significance of factors on cancer-specific survival (CSS) and recurrence-free survival (RFS) were assessed using Cox multivariate analysis. In patients with high recurrence factors, propensity score matching was used to adjust the confounding factors for ART.The median follow-up time was 40 (range 3-77) months. Multivariate analysis showed that multifocal tumor, G3, pT3/4 stage and positive lymph node (N+) were independent predictors for worse RFS. Multifocal tumor and pT3/4 stage were independent predictors of worse CSS in UTUC after surgery. A total of 286 patients with these high recurrence factors were identified: 192 (67.1%) patients received RNU only, and 94 (32.9%) patients received ART. Overall, ART did not improve CSS (ART 86.1% vs. RNU 78.5%.; P = 0.11). After propensity score matching, ART significantly improved the CSS of patients with high recurrence factors. The 3-year CSS was 73.1% in patients treated with RNU alone vs. 86.1% in patients treated with ART (P = 0.016).Results of our study demonstrated benefit of adjuvant radiotherapy in cancer specific survival in UTUC patients with high recurrence factors(multifocal tumor ,pT3/4,G3 and positive lymph node).

Met proto-oncogene (MET) amplification and tyrosine-protein kinase Met (c-Met) overexpression confer gefitinib resistance in non-small cell lung cancer (NSCLC). The natural product Licochalcone A (Lico A) exhibits a broad range of inhibitory effects against various tumors. However, the effects of Lico A on c-Met signaling and gefitinib resistance in NSCLC remain unclear. In the present study, Lico A efficiently overcame gefitinib-acquired resistance in NSCLC cells by suppressing c-Met signaling. Lico A decreased cell viability and colony formation dose-dependently and impaired in vivo tumorigenesis of gefitinib-resistant HCC827 and PC-9 cells. Furthermore, Lico A induced intrinsic apoptosis and upregulated the protein expression levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3. Lico A promoted the interaction between c-Met and E3 ligase c-Casitas B-lineage lymphoma (Cbl), which enhanced c-Cbl-mediated c-Met ubiquitination and degradation. Depletion of c-Cbl compromised Lico A-induced c-Met ubiquitination and its inhibitory efficacy in gefitinib-resistant NSCLC cells. Taken together, the results suggest that Lico A is a promising antitumor agent that might be used to overcome c-Met overexpression-mediated gefitinib resistance in NSCLC cells.

To evaluate the effectiveness and safety of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) undergoing complex percutaneous coronary intervention (PCI).It remains inconclusive whether ticagrelor is superior to clopidogrel in ACS patients undergoing complex PCI in real-world practice.Based on an all-comers PCI registry, we compared the long-term effectiveness and safety between ticagrelor and clopidogrel in ACS patients undergoing complex PCI, defined as PCI procedures for complex lesions including bifurcation, chronic total occlusion, ostial, tortuous, calcific, diffused, thrombus-containing, and restenotic lesions. The primary ischemic outcome was a composite of cardiac death, myocardial infarction, or stroke. The safety outcome comprised Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 bleeding. Propensity score matching (PSM) was performed to reduce bias.Among ACS patients who underwent complex PCI, 4373 (35.2%) and 8065 (64.8%) received dual antiplatelet therapy based on ticagrelor and clopidogrel, respectively. The incidences of composite ischemic events (before PSM: 1.74% vs. 2.84%; after PSM: 1.50% vs. 2.65%; p 0.01 for both) and all-cause death (before PSM: 1.23% vs. 2.12%, p 0.01; after PSM: 1.09% vs. 1.81%, p = 0.02) were significantly lower in the ticagrelor-treated than in the clopidogrel-treated group. There was no significant difference in BARC types 2, 3, and 5 bleeding between groups.Whilst the risk of major bleeding was comparable between the two drugs, ticagrelor was associated with a significantly lower risk of ischemic events than clopidogrel in ACS patients undergoing complex PCI.

Primary aldosteronism (PA) is a common form of secondary hypertension. Adrenal venous sampling (AVS) is the gold standard for subtyping PA. This study aimed to determine whether there is a difference between immunoassays and liquid chromatography-mass spectrometry (LC-MS/MS) methods for measuring cortisol levels that affect the judgement of AVS.This was a retrospective study.Included 72 patients who were diagnosed with PA and had undergone AVS.Patients were grouped according to whether they received adrenocorticotropic hormone (ACTH) stimulation during AVS, and the cortisol results were measured using immunoassay and LC-MS/MS.There were 48 patients in the without ACTH stimulation group and 24 in the post-ACTH stimulation group during AVS (bilateral adrenal vein cannulation success rate, 56.25% vs. 83.33%). ACTH stimulation was beneficial for increasing the success rate of AVS (p .001). Immunoassays were linearly correlated with LC-MS/MS when cortisol concentrations were1750 nmol/L (r = .959, p .001). When cortisol concentrations were17,500 nmol/L, no correlation was found between the two methods (p = .093). The two methods were consistent for the detection of cortisol for evaluating the success of cannulation for AVS. Five percent of patients showed discordant lateralization of aldosterone production according to the cortisol LC-MS/MS and immunoassay results in the without ACTH group, and 15% showed discordant lateralization in the post-ACTH group.The immunoassay method can be used to determine whether cannulation is successful. The final decision for lateralization may be more appropriate based on LC-MS/MS results.

Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival. Of the ubiquitination system components, E3 ubiquitin ligases and deubiquitinases have the most prominent roles in modulating tumor metastasis. This review will briefly summarize the observations and underlying mechanisms of multiple E3 ubiquitin ligases and deubiquitinases to regulate tumor metastasis. Further, we will discuss the relationship and importance between ubiquitination components and tumor progression.

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease, and the diagnosis is quite difficult due to the unavailability of reliable clinical markers. This study aimed to investigate the fecal metabolites in PsA by comparison with rheumatoid arthritis (RA), and to identify potential diagnostic biomarkers for PsA. The metabolic profiles of the fecal samples from 27 PsA and 29 RA patients and also 36 healthy controls (HCs) were performed on ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). And differentially altered metabolites were screened and assessed using multivariate analysis for exploring the potential biomarkers of PsA. The results showed that 154 fecal metabolites were significantly altered in PsA patients when compared with HCs, and 45 metabolites were different when compared with RA patients. A total of 14 common differential metabolites could be defined as candidate biomarkers. Furthermore, a support vector machines (SVM) model was performed to distinguish PsA from RA patients and HCs, and 5 fecal metabolites, namely, α/β-turmerone, glycerol 1-hexadecanoate, dihydrosphingosine, pantothenic acid and glutamine, were determined as biomarkers for PsA. Through the metabolic pathways analysis, we found that the abnormality of amino acid metabolism, bile acid metabolism and lipid metabolism might contribute to the occurrence and development of PsA. In summary, our research provided ideas for the early diagnosis and treatment of PsA by identifying fecal biomarkers and analyzing metabolic pathways.

Plasmid DNA transfection of mammalian cells is widely used in biomedical research and genetic drug delivery, but low transfection efficiency, especially in the context of the primary cells, limits its application. To improve the efficiency of plasmid transfection, a fully integrated self-powered electrical stimulation cell culture dish (SESD) has been developed to provide self-powered electrical stimulation (ES) of adherent cells, significantly improving the efficiency of plasmid transfection into mammalian cells and cell survival by the standard lipofectamine transfection method. Mechanistically, ES can safely increase the intracellular calcium concentration by opening calcium-ion channels, leading to a higher efficiency of plasmid transfection. Therefore, SESD has the potential to become an effective platform for high-efficiency plasmid DNA transfection in biomedical research and drug delivery.

As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists.

The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.

Particulate matter (PM) has been considered to be closely related to human health, especially fine particulate matter. However, whether PM mass concentration alone is a good indicator for health impact remains a challenging question. In this study, emissions from residential coal combustion (RCC), one of the important PM sources in northern China, were tested to examine the relationship between the emission factors of particle-generated reactive oxygen species (ROS) (EF

Key Points Question What are the care practices and outcomes for very preterm infants in Chinese neonatal intensive care units? Findings In this cohort study of 9552 very preterm infants from 57 tertiary neonatal intensive care units throughout China in 2019, 86% received complete care, among whom 95% survived and 57% survived without major morbidities. Only 76% of the infants received antenatal corticosteroids, and 12% of the infants received delivery room continuous positive airway pressure. Meaning The findings of this study suggest that survival and survival without major morbidity of very preterm infants in Chinese neonatal intensive care units remain lower than in high-income countries and clinical quality improvement as well as systems and health services reorganization are needed to improve outcomes., Importance The Chinese Neonatal Network was established in 2018 and maintains a standardized national clinical database of very preterm or very low-birth-weight infants in tertiary neonatal intensive care units (NICUs) throughout China. National-level data on outcomes and care practices of very preterm infants (VPIs) in China are lacking. Objective To assess the care practices in NICUs and outcomes among VPIs in China. Design, Setting, and Participants A cohort study was conducted comprising 57 tertiary hospitals from 25 provinces throughout China. All infants with gestational age (GA) less than 32 weeks who were admitted to the 57 NICUs between January 1 and December 31, 2019, were included. Main Outcomes and Measures Care practices, morbidities, and survival were the primary outcomes of the study. Major morbidities included bronchopulmonary dysplasia, severe intraventricular hemorrhage (grade ≥3) and/or periventricular leukomalacia, necrotizing enterocolitis (stage ≥2), sepsis, and severe retinopathy of prematurity (stage ≥3). Results A total of 9552 VPIs were included, with mean (SD) GA of 29.5 (1.7) weeks and mean (SD) birth weight of 1321 (321) g; 5404 infants (56.6%) were male. Antenatal corticosteroids were used in 75.6% (6505 of 8601) of VPIs, and 54.8% (5211 of 9503)were born through cesarean delivery. In the delivery room, 12.1% of VPIs received continuous positive airway pressure and 26.7% (2378 or 8923) were intubated. Surfactant was prescribed for 52.7% of the infants, and postnatal dexamethasone was prescribed to 9.5% (636 of 6675) of the infants. A total of 85.5% (8171) of the infants received complete care, and 14.5% (1381) were discharged against medical advice. The incidences of the major morbidities were bronchopulmonary dysplasia, 29.2% (2379 of 8148); severe intraventricular hemorrhage and/or periventricular leukomalacia, 10.4% (745 of 7189); necrotizing enterocolitis, 4.9% (403 of 8171 ); sepsis, 9.4% (764 of 8171); and severe retinopathy of prematurity, 4.3% (296 of 6851) among infants who received complete care. Among VPIs with complete care, 95.4% (7792 of 8171) survived: 65.6% (155 of 236) at 25 weeks’ or less GA, 89.0% (880 of 988) at 26 to 27 weeks’ GA, 94.9% (2635 of 2755)at 28 to 29 weeks’ GA, and 98.3% (4122 of 4192) at 30 to 31 weeks’ GA. Only 57.2% (4677 of 8171) of infants survived without major morbidity: 10.5% (25 of 236) at 25 weeks’ or less GA, 26.8% (48 of 179) at 26 to 27 weeks’ GA, 51.1% (1409 of 2755) at 28 to 29 weeks’ GA, and 69.3% (2904 of 4192) at 30 to 31 weeks’ GA. Among all infants admitted, the survival rate was 87.6% (8370 of 9552)and survival without major morbidities was 51.8% (4947 of 9552). Conclusions and Relevance The findings of this study suggest that survival and survival without major morbidity of VPIs in Chinese NICUs have improved but remain lower than in high-income countries. Comprehensive and targeted quality improvement efforts are needed to provide complete care for all VPIs, optimize obstetrical and neonatal care practices, and improve outcomes., This cohort study evaluates the care practices used for as well as the survival and major morbidities among very preterm infants hospitalized in neonatal intensive care units in China.

Discovery of effective chemical sensitizers to synergize with natural killer cells immunotherapy is urgently desired to overcome its unsatisfactory efficacy in clinic. Herein, we design a series of ruthenium (Ru) polypyridyl complex to systematically explore their potentials in facilitating NK cells treatment. Intriguingly, the chemical structure greatly determines the activity of Ru complexes, while only RuPOP effectively regulates the immuno-suppressors and target proteins within tumor cells. This unique property contributes to its good capability in enhancing the sensitivity of MDA-MB-231 cells to NK cells from cancer patients. Furthermore, besides directly damaging tumor cells, RuPOP pretreatment together with NK cells can also induce robust ROS generation, activate multiple apoptosis-related receptors like TNF-R1, DR5, Fas and maximize the interactions between NK and tumor cells via up-regulating NKG2D and its multiple ligands to trigger caspase 3-dependent apoptosis. Moreover, the combination treatment exhibits high in vivo therapeutic efficacy against breast tumor through boosting the infiltration of NK cells and reducing the protumoral capability of myeloid-derived suppressor cells (MDSC). This study sheds lights for designing metal complexes to potentiate NK cells immunotherapy with clear action mechanisms and provides important information for developing more effective adoptive cell transfer therapy in clinic.

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was −1.02% (−1.11, −0.93) in the dorzagliatin group and −0.36% (−0.45, −0.26) in the placebo group (estimated treatment difference, −0.66%; 95% CI: −0.79, −0.53; P NCT03141073).

Objective To provide national-level antibiotic use data from Chinese neonatal intensive care units to inform future antimicrobial stewardship using a large contemporary cohort of preterm infants in China. Study design This retrospective cohort study enrolled all infants less than 340/7 weeks of gestation admitted to 25 tertiary neonatal intensive care units across China between May 1, 2015, and April 30, 2018. The antibiotic use rate (AUR) was defined as the number of days an infant was prescribed with 1 or more antibiotics divided by the total length of hospital stay. Results Among 24 597 eligible infants, 21 736 (88.4%) infants received antibiotics. The median AUR was 441 per 1000 patient-days (IQR, 242-692 per 1000 patient-days). The median duration of each antibiotic course was 9 days (IQR, 6-14 days). Overall, 64.6% infants received broad-spectrum antibiotics, with a median broad-spectrum AUR of 250 per 1000 patient-days (IQR, 0-500 per 1000 patient-days), accounting for 70.7% of all antibiotic use days. Overall, 68.7% of all antibiotic use occurred among infants without infection-related morbidities, with a median duration of 8 days (IQR, 6-13 days) for each course. Only 22.9% episodes of culture-negative sepsis were prescribed with antibiotics for 7 or fewer days, and 34.7% were treated with antibiotics for more than 14 days. For early antibiotic use, the median duration of antibiotic therapy within 7 days after birth was 7 days (IQR, 4-7 days). Conclusions A high AUR among infants without infections, prolonged antibiotic durations, and excessive use of broad-spectrum antibiotics were the main problems of antibiotic use in Chinese neonatal intensive care units and should be high-impact focuses for future stewardship interventions.

Prognostic significance of heart rate (HR) in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. To evaluate the association of HR and beta-blocker use with all-cause mortality and the optimal HR range in patients with HFpEF and sinus rhythm (SR). During a follow-up of 2.7 years (IQR 1.2–4.1 years), the 330 patients with median age 73 (IQR 64–79) years, 52.1% men, were included. HFpEF was defined as patients with EF ≥ 50%. The outcome measure was all-cause mortality. In total, 96 (29.1%) of patients with HFpEF and SR died. A linear tendency between HR and mortality was observed in SR. Compared to the reference strata HR ≤ 60 bpm, HR increment was associated with progressively increased risk in mortality (Chi-square = 13.90, Log rank P = 0.001) by Kaplan–Meier analyses. Univariate Cox regression showed that in SR, compared with that in HR 61–80 bpm, the unadjusted hazard ratios for mortality were 0.41 (95% CI 0.23–0.74, P = 0.003) in HR ≤ 60 bpm, 1.38 (95% CI 0.85–2.24, P = 0.189) in HR > 80 bpm. Multivariate Cox regression showed that compared with that in HR 61–80 bpm, the adjusted hazard ratios for mortality were 0.37 (95% CI 0.19–0.75, P = 0.005) in HR ≤ 60 bpm, 0.96 (95% CI 0.52–1.74, P = 0.899) in HR > 80 bpm. Univariate Cox regression showed that the unadjusted hazard ratios for mortality were 0.52 (95% CI 0.33–0.84, P = 0.003) in patients with beta-blocker as compared patients without beta-blocker. Multivariate Cox regression showed that the adjusted hazard ratios for mortality were 0.48 (95% CI 0.26–0.87, P = 0.016) in patients with beta-blocker as compared patients without beta-blocker. HR is independently associated with increased all-cause mortality in SR and a lower HR (≤ 60 bpm) is favorable for better outcome in HFpEF patients with SR. Beta-blocker use is associated with reduced mortality and a lower HR is associated with reduced mortality in HFpEF patients with SR.

Background Berberine (BBR), a natural compound extracted from Chinese herb, has been shown to effectively attenuate nonalcoholic fatty liver disease (NAFLD) in clinic. However, the mechanism underlying the effect of BBR is not fully understood. Stearyl-coenzyme A desaturase 1 (SCD1) mediates lipid metabolism in liver. Therefore, we hypothesized that SCD1 mediated the beneficial effect of BBR on NAFLD. Methods The expression of SCD1 was measured in the liver of NAFLD patients and ob/ob mice. The effect of BBR on NAFLD was evaluated in C57BL/6 J mice on high fat diet (HFD). The effect of BBR was also investigated in HepG2 and AML12 cells exposed to high glucose and palmitic acid. Oil red O staining was performed to detect triglyceride (TG) level. Quantitative real-time polymerase chain reaction and Western blot were used to detect the messenger ribonucleic acid (mRNA) and protein expression of target genes. The activity of SCD1 promoter was measured by dual-luciferase reporter assay. Results The expression of SCD1 was increased in the liver of NAFLD patients and ob/ob mice. BBR reduced hepatic TG accumulation and decreased the expressions of hepatic SCD1 and other TG synthesis related genes both in vivo and in vitro. Knockdown of SCD1 expression mimicked the effect of BBR decreasing TG level in steatotic hepatocytes, whereas overexpression of SCD1 attenuated the effect of BBR. Mechanistically, BBR promoted the phosphorylation of AMP-activated protein kinase (AMPK) and sterol regulatory element-binding protein-1c (SREBP-1c) in HepG2 cells and the liver of HFD-fed mice. Activation of the AMPK-SREBP-1c pathway and sterol regulatory element (SRE) motif in SCD1 promoter (-920/-550) was responsible for the BBR-induced suppression of SCD1. Conclusion BBR reduces liver TG synthesis and attenuates hepatic steatosis through the activation of AMPK-SREBP-1c-SCD1 pathway.

Background This study aimed to examine the performance of the four risk of malignancy index (RMI) in discriminating borderline ovarian tumors (BOTs) and benign ovarian masses in daily clinical practice. Methods A total of 162 women with BOTs and 379 women with benign ovarian tumors diagnosed at the Second Affiliated Hospital of Harbin Medical University from January 2012 to December 2016 were enrolled in this retrospective study. Also, we classified these patients into serous borderline ovarian tumor (SBOT) and mucinous borderline ovarian tumor (MBOT) subgroup. Preoperative ultrasound findings, cancer antigen 125 (CA125) and menopausal status were reviewed. The area under the curve (AUC) of receiver operator characteristic curves (ROC) and performance indices of RMI I, RMI II, RMI III and RMI IV were calculated and compared for discrimination between benign ovarian tumors and BOTs. Results RMI I had the highest AUC (0.825, 95% CI: 0.790–0.856) among the four RMIs in BOTs group. Similar results were found in SBOT (0.839, 95% CI: 0.804–0.871) and MBOT (0.791, 95% CI: 0.749–0.829) subgroups. RMI I had the highest specificity among the BOTs group (87.6, 95% CI: 83.9–90.7%), SBOT (87.6, 95% CI: 83.9–90.7%) and MBOT group (87.6, 95% CI: 83.9–90.7%). RMI II scored the highest overall in terms of sensitivity among the BOTs group (69.75, 95% CI: 62.1–76.7%), SBOT (74.34, 95% CI: 65.3–82.1%) and MBOT (59.18, 95% CI: 44.2–73.0%) group. Conclusion Compared to other RMIs, RMI I was the best-performed method for differentiation of BOTs from benign ovarian tumors. At the same time, RMI I also performed best in the discrimination SBOT from benign ovarian tumors.

Aims/Introduction Diabetes prevalence in China has increased, but the trend in gestational diabetes mellitus prevalence is unclear. The objective of the present study was to examine the prevalence of gestational diabetes in Xiamen, China, and its association with maternal risk factors. Materials and Methods This linked‐database cohort study used the Medical Birth Registry of Xiamen. Between 1 March 2011 and 30 March 2018, 78,572 women who were diagnosed with gestational diabetes mellitus (GDM) were enrolled in the study. Maternal factors associated with the prevalence of GDM were examined using multivariate logistic regression. Results A total of 13,738 (17.6%) pregnant women were diagnosed with GDM according to the International Association of Diabetes and Pregnancy Study Groups criteria. GDM prevalence ranged from 15.5% (2012) to 19.9% (2017). Increasing age was associated with GDM; women aged >40 years versus those aged >25 years had an adjusted odds ratio (OR) of 5.91 (95% confidence interval [CI] 4.202–8.314). A positive correlation was observed between weight and GDM risk; obese women versus normal‐weight women had an adjusted OR of 2.508 (95% CI 2.253–2.792). Family history of diabetes and hypertension were more commonly observed among women with GDM. Multivariate analysis showed that family history of diabetes (OR 1.101, 90% CI 1.028–1.180), weight gain during early pregnancy (OR 1.087, 90% CI 1.052–1.124) and systolic blood pressure (OR 1.015, 90% CI 1.011–1.020) were risk factors associated with GDM incidence. Conclusions GDM affects 17.6% of all pregnant women in Xiamen. Age and maternal obesity were major contributors to GDM. The trend of GDM risk remained stable during the study.