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As the most prevalent primary CNS tumor, glioma is characterized by high mortality and morbidity. This research aims to investigate glioma-associated microRNAs (miRNAs) and their target mRNAs, as well as to explore their biological functions in gliomas. The Gene Expression Omnibus (GEO) database was applied to acquire the GSE112264 miRNA microarray dataset and the GSE15824 mRNA dataset. We selected samples from the GSE112264 dataset and the GSE15824 to identify differently expressed miRNAs (DE-miRNAs) as well as differentially expressed mRNAs (DEGs), respectively. Next, the intersections of mRNA and target mRNAs of miRNA were selected, and we constructed miRNA-mRNA regulation networks. These DEGs were selected for Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses by conducting the package clusterProfiler. After conducting Cytoscape software, a protein-protein interaction (PPI) network was created. Next, survival analysis of the miR-423-3p was confirmed by conducting TCGA database. Subsequently, Quantitative real-time PCR (qRT-PCR) was conducted to verify miR-423-3p's expression. Finally, miR-423-3p's biological functions of in effecting the cell proliferative, migratory, and invasive capabilities of glioma were investigated by performing Cell Counting Kit-8 (CCK-8) and Transwell assays. Our analysis elucidated a novel miRNA-mRNA regulatory network related to glioma carcinogenesis, which may be considered as future therapeutic biomarkers for glioma.

Cardiovascular diseases (CVDs) have become the leading cause of death in China. CVDs are mainly caused by multiple well-known modifiable risk factors that are affected by socioeconomic and environmental determinants, lifestyle and behavioral choices, and familial and genetic predispositions. With more risk factors proved to be associated with CVD occurrence, the concept "pan-risk factor" is proposed in this review to indicate all discovered and yet-to-be-discovered CVD risk factors for comprehensive primary prevention of CVD. Recognizing more factors and their roles in CVD development and progression is the first step in reducing the ever-increasing burden of CVD. This review is an overview of the pan-risk factor whose associations with CVD outcomes have been established. Along with the accumulation of scientific evidence, an increasing number of risk factors will be discovered and included in the list of pan-risk factors.在中国，心血管疾病(CVD)已成为主要的死亡原因。心血管疾病主要是由多种众所周知的可改变的危险因素引起，这些危险因素受社会经济和环境因素, 生活方式, 行为选择以及家庭和遗传易感性的影响。随着越来越多的危险因素被证实与心血管疾病的发生有关，本文提出了“泛危险因素”的概念和术语，指所有已发现和尚未发现的心血管疾病危险因素，用于心血管疾病的一级预防。认识到更多的因素及其在心血管疾病进展中的作用，是减轻日益加重的心血管疾病负担的第一步。这篇综述是对“泛危险因素”的概述，这些因素与心血管疾病预后的关系已经确定。随着科学证据的积累，越来越多的风险因素会被发现，并被列入“泛危险因素”的名单中。.

Background Antiviral therapy should reduce the recurrence of hepatitis B virus‐related hepatocellular carcinoma (HBV‐related HCC) after surgical resection. However, there is little research on whether various antiviral drugs have different prognostic effects in patients with HBV‐related HCC after curative liver resection. The present study compared the effects of nucleotide analog (NtA) and nucleoside analog (NsA) antiviral therapies after surgical resection on the prognosis of HBV‐related HCC. Methods A total of 1303 patients with HBV‐related HCC who received curative hepatectomy at five institutes between April 2014 and April 2019 were retrospectively enrolled and analyzed. Propensity matching analysis was used to compare the outcomes of HCC patients given NsA versus NtA therapy. Subgroup analysis of patients treated with entecavir (ETV) and tenofovir disoproxil fumarate (TDF) was also performed. Results Among 1303 patients, 759 (58.2%) patients developed recurrence, and 460 (35.3%) patients died. Multivariable analyses revealed that NtA therapy significantly decreased the risk of HCC recurrence (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51–0.80; p, The aim of this study was to investigate the effect of antiviral drug on the prognosis of hepatitis B virus‐related hepatocellular carcinoma (HCC) after curative hepatectomy. We found that nucleotide analog treatment, rather than nucleoside analog treatment, significantly reduced HCC recurrence and improved overall survival after curative hepatic resection.

ObjectiveTo investigate the risk factors of cognitive frailty in elderly patients with chronic kidney disease (CKD), and to establish an artificial neural network (ANN) model.DesignA cross-sectional design.SettingTwo tertiary hospitals in southern China.Participants425 elderly patients aged ≥60 years with CKD.MethodsData were collected via questionnaire investigation, anthropometric measurements, laboratory tests and electronic medical records. The 425 samples were randomly divided into a training set, test set and validation set at a ratio of 5:3:2. Variables were screened by univariate and multivariate logistic regression analyses, then an ANN model was constructed. The accuracy, specificity, sensitivity, receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the predictive power of the model.ResultsBarthel Index (BI) score, albumin, education level, 15-item Geriatric Depression Scale score and Social Support Rating Scale score were the factors influencing the occurrence of cognitive frailty (pConclusionThe ANN model constructed in this study has good predictive ability, and can provide a reference tool for clinical nursing staff in the early prediction of cognitive frailty in a high-risk population.

Background Immune checkpoint inhibitors (ICIs) has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate immune related adverse events (irAEs) in patients. Some studies have shown that there is a close relationship between the occurrence of irAEs and prognosis. In present study, we have attempted to establish whether the occurrence of irAEs after the use of anti PD-1 antibodies is associated with treatment efficacy in people with advanced gastric cancer (AGC). Methods This study included patients treated with the anti-PD-1 antibodies for AGC patients at The Fourth Hospital of Hebei Medical University. IrAEs were identified clinically and graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS). The analysis was performed to determine the association between irAEs and clinical outcomes. Result Of the 74 AGC patients in our study, 24 developed irAEs. The DCR of the irAE displayed a trend better than that of non-irAE group but without statistical difference (41.70% VS 6.0%, p = 0.118). Median PFS in the irAE group was superior to that in the non-irAE group (176 days VS 94 days, p = 0.001). Median OS also showed this trend of difference at borderline statistical level (292 days VS 239 days, p = 0.057). Multivariate analysis also demonstrated irAE (HR = 0.269, 95%CI: 0.088 to 0.822, p = 0.021) were associated independently with the better prognosis for AGC patients. Conclusion In advanced gastric cancer treated with anti PD-1 antibodies, the occourence of irAEs might contribute to the improved prognosis.

BackgroundNumerous observational studies have shown that liver enzymes correlated with diabetes mellitus (DM) risk significantly, but limited studies showed whether different obesity subgroups present the same correlation. Our objective was to evaluate the association of liver enzymes with DM risk in different obesity subgroups based on a middle-aged Chinese population.MethodsWe conducted a population-based cross-sectional study and surveyed 9,916 people aged 40 years and above. A two-slope linear regression model was used to analyze the cutoff points of obesity in DM risk. Restricted cubic splines were used to analyze the correlation between liver enzymes and DM risk in different obesity categories. The odds ratios and 95% confidence intervals (CIs) were calculated using the logistic regression model.ResultsThe cutoff points of body mass index (BMI) and waist circumference were 30.55 kg/m2 and 98.99 cm for DM risk, respectively. The serum gamma-glutamyl transferase (GGT) concentration was positively correlated with DM risk in the subgroups with waist circumference 2 [OR = 1.04, 95% CI (1.03–1.05)], and BMI ≥30.55 kg/m2 [OR = 1.18, 95% CI (1.04–1.39)], but not in the subgroup with waist circumference ≥98.99 cm. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations have no significant correlation with the risk of diabetes in all groups.ConclusionThe results showed that serum GGT concentration was correlated with DM risk but not with AST or ALT in the middle-aged population. However, the correlation disappeared when waist circumference was over 98.99 cm, and serum GGT concentration had a limited value for DM risk in waist circumference over 98.99 cm.

Pyroptosis is a new type of pro-inflammatory programmed cell death identified over the last few years and has since attracted researchers' attention. Current research demonstrates that pyroptosis's primary process is dependent on caspase-1 protein and gasdermin D protein and is accompanied by the release of inflammatory substances. However, the specific mechanisms and physiological or pathophysiological processes involved in pyroptosis are unclear. Presently, research on the occurrence, development, and treatment of various diseases associated with pyroptosis is of significant value. Pyroptosis has been implicated in the pathogenesis of atherosclerosis. For instance, numerous studies have revealed that pyroptosis is involved in the development and progression of atherosclerosis, and it is closely associated with pyroptosis of three essential cells (vascular endothelial cells, macrophages, and vascular smooth muscle cells) in atherosclerosis. The advancement of research on pyroptosis is anticipated to give insights into its application as a potential method for treating diseases. This article mainly reviews the relationship between pyroptosis and associated mechanisms factors that cause pyroptosis and the relationship between pyroptosis and various diseases, especially atherosclerosis.

The European Union (EU) Emissions Trading System is the most important means for the EU to achieve carbon neutrality, but it has been severely affected by the outbreak of COVID-19 in Europe, and carbon price have fluctuated sharply. Research on the driving factors of carbon price during this period will help maintain the stability of the carbon emissions trading market and promote the realization of carbon neutrality. This study selected the EU carbon allowance futures price as the research object and applied the Bai-Perron structural break test to analyze the factors that influences carbon price fluctuations using the Johansen cointegration technique and the Newey-West regression estimation. Studies have shown that the outbreak of COVID-19 and the "€750 billion green recovery plan" both had a significant impact on EU carbon price. Carbon price has also undergone significant structural changes. Under the influence of these two factors, the relationship between the level of economic development and carbon price displayed a short-term negative correlation. At the same time, oil price and interbank dismantling rates were also important factors affecting carbon price, while the impact of the clean development mechanism on carbon price was not significant. The study confirmed the effectiveness of the EU's "green recovery plan" in stabilizing the carbon market during the COVID-19 pandemic and will provide a reference for the formulation of economic recovery policies of countries around the world.

Long non-coding RNA activated by DNA damage (lnc-NORAD) modulates inflammation, lipid level, and atherosclerosis in various cardiovascular diseases. This study intended to investigate the dysregulated expression of lnc-NORAD, and its linkage with clinical characteristics, inflammatory cytokines, and accumulating major adverse cardiovascular events (MACE) in coronary heart disease (CHD) patients.Totally, 160 CHD patients, 30 disease controls (DCs), and 30 healthy controls (HCs) were included. The reverse transcription-quantitative polymerase chain reaction was used to detect lnc-NORAD expression in peripheral blood mononuclear cell samples from all participants. Enzyme-linked immunosorbent assay was applied to detect proinflammatory cytokines and adhesion molecules in CHD patients. Then, MACE was recorded during a median follow-up of 12 (range: 1.0-27.0) months.Lnc-NORAD was highest in CHD patients, followed by DCs, and lowest in HCs (p 0.001). In CHD patients, lnc-NORAD was positively linked with Gensini score (p = 0.001). Meanwhile, lnc-NORAD was positively linked to C-reactive protein (p = 0.023), tumor necrosis factor-alpha (p = 0.016), interleukin (IL)-6 (p = 0.003), IL-8 (P = 0.018), and IL-17A (p = 0.029). No relation of lnc-NORAD with vascular cell adhesion molecule-1 (p = 0.094) and intercellular adhesion molecule-1 (p = 0.060) was found. Furthermore, lnc-NORAD was positively related to total cholesterol (p = 0.014) and low-density lipoprotein cholesterol (p = 0.004), whereas lnc-NORAD was not linked to triglyceride (p = 0.103) and high-density lipoprotein cholesterol (p = 0.533). However, lnc-NORAD (high vs. low), and its higher quartiles were both not linked to accumulating MACE rate (p 0.05).Increased lnc-NORAD is linked with aggravated stenosis degree, inflammation status, and blood lipid in CHD patients. However, further validation is required.

Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase Pin1, whose overexpression in CAFs has not been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective Pin1 inhibition in CAFs on pancreatic cancer, here we formulate a DNA-barcoded micellular system (DMS) encapsulating the Pin1 inhibitor AG17724. DMS functionalized with CAF-targeting anti-FAP-α antibodies (antiCAFs-DMS) can selectively inhibit Pin1 in CAFs, leading to efficacious but transient tumor growth inhibition. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to obtain a bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT inhibits tumor growth in subcutaneous and orthotopic pancreatic cancer models.

Fluoropyrimidine plus platinum (FP) and taxanes plus platinum (TP) are standard treatments for esophageal cancer (EC). This systematic review and meta-analysis aim to explore the difference in the therapeutic effect and toxicity of FP and TP regimens in EC patients. PubMed, Embase, and Cochrane were fully searched and analyzed to find relevant articles on EC patients treated with FP and TP regimens up to 22 March 2022. Thirty-one studies, with a total of 3432 participants, were included in this review. The primary outcomes showed that the prognosis and therapeutic efficacy of TP groups were better than those of FP groups for the EC patients treated with definitive chemoradiotherapy treatment (3-year OS: RR: 1.25, 95% CI: 1.08–1.44, p = 0.003; 3-year PFS: RR: 1.43, 95% CI: 1.17–1.75, p = 0.0006; ORR: RR: 1.17, 95% CI: 1.06–1.29, p = 0.001). However, TP therapy was significantly correlated with a higher incidence of leukopenia and thrombocytopenia (p < 0.05). In the preoperative neoadjuvant chemoradiotherapy group, these two groups had a similar survival time (p > 0.05). The FP regimen corresponded to a higher incidence of thrombocytopenia, while the TP regimen was associated with an increased incidence of febrile leukopenia (p < 0.05). Therefore, TP regimens could generate both superior clinical response and survival benefits when compared with FP regimens in EC patients undergoing definitive chemoradiotherapy.

Objective: This study aimed to explore the association between the risk of newly diagnosed type 2 diabetes and galectin-3 and adiponectin and to investigate whether their joint action shows a favorable diabetes assessment performance. Methods: We conducted a community-based study in 135 newly diagnosed patients with type 2 diabetes and 270 age- and sex-matched nondiabetic patients. Odds ratios and 95% confidence intervals were determined using logistic regression analysis. Receiver operating characteristic curve, decision curve analysis and calibration plot were used to explore their efficacy and clinical utility for models. Results: High quartiles of galectin-3/adiponectin (quartile 4 vs 1: OR 2.43 [95% CIs: 1.21–5.00]) showed the strongest correlation with an increased risk of type 2 diabetes in the total population, which was consistent in the older population (age≥50 years old) in adjustment models. The combination + lipids + galectin-3/adiponectin model (AUC = 0.72 [95% CIs: 0.66-0.77]) displayed better diabetes assessment performance than the other two models. Conclusions: High galectin-3 and low adiponectin levels were associated with the high risk of diabetes, and their joint action was a superior promising factor for evaluating diabetes risk. The diabetes discriminative strength of galectin-3/adiponectin was better in the older population than the younger.

The automatic diagnosis of various retinal diseases based on fundus images is important in supporting clinical decision-making. Convolutional neural networks (CNNs) have achieved remarkable results in such tasks. However, their high expression ability possibly leads to overfitting. Therefore, data augmentation (DA) techniques have been proposed to prevent overfitting while enriching datasets. Recent CNN architectures with more parameters render traditional DA techniques insufficient. In this study, we proposed a new DA strategy based on multimodal fusion (DAMF) which could integrate the standard DA method, data disrupting method, data mixing method, and autoadjustment method to enhance the image data in the training dataset to create new training images. In addition, we fused the results of the classifier by voting on the basis of DAMF, which further improved the generalization ability of the model. The experimental results showed that the optimal DA mode could be matched to the image dataset through our DA strategy. We evaluated DAMF on the iChallenge-PM dataset. At last, we compared training results between 12 DAMF processed datasets and the original training dataset. Compared with the original dataset, the optimal DAMF achieved an accuracy increase of 2.85% on iChallenge-PM.

Maternal immune activation (MIA) induced by lipopolysaccharides or polyinosinic:polycytidylic acid injections can induce behavioral abnormalities in adult mouse offspring. Here, we used the soluble tachyzoite antigen from Toxoplasma gondii, a parasite that infects approximately two billion people, to induce MIA in mice. The adult male offspring showed autism-relevant behaviors and abnormal brain microstructure, along with a pro-inflammatory T-cell immune profile in the periphery and upregulation of interleukin-6 in brain astrocytes. We show that adoptive transfer of regulatory T (Treg) cells largely reversed these MIA-induced phenotypes. Notably, pathogen-activated maternal Treg cells showed greater rescue efficacy than those from control donors. Single-cell RNA sequencing identified and characterized a unique group of pathogen-activated Treg cells that constitute 32.6% of the pathogen-activated maternal Treg population. Our study establishes a new preclinical parasite-mimicking MIA model and suggests therapeutic potential of adoptive Treg cell transfer in neuropsychiatric disorders associated with immune alterations.

Background Thrombocytopenia was reported both detrimental and advantageous to hepatocellular carcinoma (HCC). However, there is little evidence showing clearly the clinical value of preoperative thrombocytopenia on the surgical outcome of patients with small HCC. This retrospective study aimed at elucidating the correlation between preoperative thrombocytopenia and surgical outcome of small HCC patients within Milan criteria treated with liver resection. Methods Data of hepatitis B virus (HBV)-related small HCC patients were retrospectively analyzed, and we performed the propensity score matching (PSM) analysis to overcome the imbalance of clinicopathological features. Patients enrolled were subsequently categorized into two groups according to preoperative platelet counts: thrombocytopenia group and non-thrombocytopenia group. Survival outcomes of the patients in both groups were described with the Kaplan-Meier method, and the difference was compared with a log-rank test. Cox regression analysis was applied to identify the risk factors of surgical outcome. Results After PSM, the estimated 1-, 3-, and 5-year overall survival (OS) rates for small HCC patients in the thrombocytopenia group were 94.5%, 77.0%, and 57.6%, and 95.0%, 79.6%, and 68.0%, respectively, for small HCC patients in the non-thrombocytopenia group (P = 0.042). And the 1-, 3-, and 5-year estimated recurrence-free survival (RFS) rates for small HCC patients in the thrombocytopenia group were 70.4%, 51.0%, and 42.1%, and 83.8%, 63.7%, and 46.7%, respectively, for small HCC patients in the non-thrombocytopenia group (P = 0.035). Multivariate analysis indicated preoperative thrombocytopenia was a significant prognosticator of poor RFS (hazard ratio (HR) = 1.388, 95% confidence interval (CI) 1.028~1.874, P = 0.033). Conclusion Preoperative thrombocytopenia had an undesirable impact on the recurrence of small HCC patients treated with liver resection.

Rationale: Congenital biliary atresia (BA) is a destructive obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. However, the cause of BA is largely unknown. Methods: We explored the cell junctions and polarity complexes in early biopsy BA livers by immunofluorescence staining and western blot. Cdc42, as a key cell junction and polarity regulator, was found dramatically decreased in BA livers. Therefore, in order to investigate the role of Cdc42 in BA development, we constructed liver-specific and tamoxifen induced cholangiocyte-specific Cdc42 deleted transgenic mice. We further evaluated the role of bile acid in aggravating biliary damage in Cdc42 insufficient mouse liver. Results: We found a dramatic defect in the assembly of cell junctions and polarity complexes in both cholangiocytes and hepatocytes in BA livers. This defect was characterized by the disordered location of cell junction proteins, including ZO1, β-catenin, E-cadherin and claudin-3. Cdc42 and its active form, Cdc42-GTP, which serves as a small Rho GTPase to orchestrate the assembly of polarity complexes with Par6/Par3/αPKC, were substantially reduced in BA livers. Selective Cdc42 deficiency in fetal mouse cholangiocytes resulted in histological changes similar to those found in human BA livers, including obstruction in both the intra- and extrahepatic bile ducts, epithelial atrophy, and the disruption of cell junction and polarity complexes. A reduction in bile acids notably improved the histology and serological indices in Cdc42-mutant mice. Conclusion: Our results illustrate that BA is closely correlated with the impaired assembly of cell junction and polarity complexes in liver cells, which is likely caused by Cdc42 insufficiency and aggravated by bile acid corrosion.

The diagnosis and treatment of rheumatic valvular heart disease (RVHD) require substantial improvements. Studies found that circular RNAs (circRNAs) are involved in the progression of cardiovascular diseases. We screened target hsa_circ_0003748 by circRNA microarrays uploaded to a database. We used fluorescence in situ hybridization to determine the cellular location of hsa_circ_0003748. A dual-luciferase reporter gene assay revealed that has_circ_0003748 might bind the miRNA miR-577. In hVIC cells (an RVHD cell line), Cell Counting Kit-8, Transwell, and flow cytometry assays measured proliferation, migration, and cell cycle and apoptosis, respectively. We found that hsa_circ_0003748 was localized in the cytoplasm; hsa_circ_0003748 promoted the proliferation and migration of hVIC cells, arrested the cell cycle in the G2/M phase, and inhibited apoptosis. These phenomena may result from hsa_circ_0003748 promoting RVHD after sponging miR-577. Bioinformatic analysis revealed that hsa_circ_0003748 might affect RVHD progression by affecting transcription and the MAPK signaling pathway, the Ras signaling pathway, the cAMP signaling pathway, the Rap1 signaling pathway, and other signaling pathways.

To identify differentially expressed lncRNA, miRNA, and mRNA during the pathogenesis of gout, explore the ceRNA network regulatory mechanism of gout, and seek potential therapeutic targets.First, gout-related chips were retrieved by GEO database. Then, the analysis of differentially expressed lncRNAs and mRNAs was conducted by R language and other software. Besides, miRNA and its regulated mRNA were predicted based on public databases, the intersection of differentially expressed mRNA and predicated mRNA was taken, and the lncRNA-miRNA-mRNA regulatory relationships were obtained to construct the ceRNA regulatory network. Subsequently, hub genes were screened by the STRING database and Cytoscape software. Then the DAVID database was used to illustrate the gene functions and related pathways of hub genes and to mine key ceRNA networks.Three hundred and eighty-eight lncRNAs and 758 mRNAs were identified with significant differential expression in gout patient, which regulates hub genes in the ceRNA network, such as JUN, FOS, PTGS2, NR4A2, and TNFAIP3. In the ceRNA network, lncRNA competes with mRNA for miRNA, thus affecting the IL-17 signaling pathway, TNF signaling pathway, Oxytocin signaling pathway, and NF-κB signaling pathway through regulating the cell's response to chemical stress. The research indicates that five miRNAs (miR-429, miR-137, miR-139-5p, miR-217, miR-23b-3p) and five lncRNAs (SNHG1, FAM182A, SPAG5-AS1, HNF1A-AS1, UCA1) play an important role in the formation and development of gout.The interaction in the ceRNA network can affect the formation and development of gout by regulating the body's inflammatory response as well as proliferation, differentiation, and apoptosis of chondrocytes and osteoclasts. The identification of potential therapeutic targets and signaling pathways through ceRNA network can provide a reference for further research on the pathogenesis of gout.

Substantial evidence now exists to support that formation of DNA G-quadruplexes (G4s) is coupled to altered gene expression. However, approaches that allow us to probe G4s in living cells without perturbing their folding dynamics are required to understand their biological roles in greater detail. Herein, we report a G4-specific fluorescent probe (SiR-PyPDS) that enables single-molecule and real-time detection of individual G4 structures in living cells. Live-cell single-molecule fluorescence imaging of G4s was carried out under conditions that use low concentrations of SiR-PyPDS (20 nM) to provide informative measurements representative of the population of G4s in living cells, without globally perturbing G4 formation and dynamics. Single-molecule fluorescence imaging and time-dependent chemical trapping of unfolded G4s in living cells reveal that G4s fluctuate between folded and unfolded states. We also demonstrate that G4 formation in live cells is cell-cycle-dependent and disrupted by chemical inhibition of transcription and replication. Our observations provide robust evidence in support of dynamic G4 formation in living cells. Visualization of endogenous G-quadruplexes (G4s) in living cells by fluorescence microscopy has been hampered by the high concentrations of G4-binding probes required, which can artificially induce additional G4 formation. Now, a G4-specific fluorescent probe (SiR-PyPDS) has been developed that enables single-molecule and real-time detection of individual G4 structures in living cells without perturbing G4 formation and dynamics.

Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with poor prognosis and high incidence. The clinical data analysis of liver hepatocellular carcinoma samples downloaded from The Cancer Genome Atlas reveals that the THO Complex 1 (THOC1) is remarkable upregulated in HCC and associated with poor prognosis. However, the underlying mechanism remains to be elucidated. We hypothesize that THOC1 can promote the proliferation of HCC. The present study aims to identify THOC1 as the target for HCC treatment and broaden our sights into therapeutic strategy for this disease. Methods Quantitative RT-PCR, Western blot, immunofluorescence and immunohistochemistry were used to measure gene and protein expression. Colony formation and cell cycle analysis were performed to evaluate the proliferation. The gene set enrichment analysis were performed to identify the function which THOC1 was involved in. The effects of THOC1 on the malignant phenotypes of hepatocellular cells were examined in vitro and in vivo. Results The gene set enrichment analysis reveals that THOC1 can promote the proliferation and G2/M cell cycle transition of HCC. Similarly, experimental results demonstrate that THOC1 promotes HCC cell proliferation and cell cycle progression. The knockdown of THOC1 leads to R-loop formation and DNA damage and confers sensitivity to cisplatin. In addition, in vivo data demonstrate that THOC1 can enhance tumorigenesis by increasing tumor cell proliferation. Furthermore, virtual screening predicts that THOC1 as a direct target of luteolin. Luteolin can induce DNA damage and suppress the proliferation of HCC by targeting THOC1. Furthermore, the inhibition of THOC1 activity by luteolin enhances the chemosensitivity of HCC tumor cells to cisplatin. Conclusions THOC1 was identified as a predictive biomarker vital for HCC-targeted treatments and improvement of clinical prognosis. Luteolin combined with cisplatin can effectively suppress HCC tumor growth, indicating a potential and effective therapeutic strategy that uses luteolin in combination with conventional cytotoxic agents for HCC treatment.

Background/Aims: Colorectal cancer (CRC) is the third most common malignant tumour worldwide and the second leading cause of cancer-related deaths. Commonly, 5'-aminolevulinic acid synthase1 (ALAS1) is the rate-limiting enzyme for haem biosynthesis. Recent studies have shown that ALAS1 is involved in a number of cellular functions and has significant effects on non-small cell lung cancer (NSCLC). However, current concepts of disease pathogenesis fail to fully explain the role of ALAS1 expression and biological functions in CRC. Materials and Methods: A total of 67 paired tumour tissues and adjacent colorectal tissues were used to detect ALAS1 levels and further analyse the correlation between ALAS1 expression levels and clinical features. Using HCT116 cell lines, we studied the impact of ALAS1 on biological function by knocking down or inhibiting ALAS1. Results: We found an increase in the levels of ALAS1 in cancer tissues compared to adjacent colorectal tissues. The increase in ALAS1 expression was closely related to the invasion depth, N staging and tumour size of CRC patients. The proliferation and metastasis of CRC cells could be inhibited by suppressing ALAS1. Conclusions: The abnormal expression of ALAS1 is closely related to the proliferation and metastasis of CRC cells, suggesting that ALAS1 may be a novel therapeutic target for the treatment of CRC.

This study explores the athlete’s health status evaluation system based on an edge computing model and large-scale multimedia health data analysis in order to improve the assessment effect of athletes’ current health state. In addition to that, this research builds a wireless signal propagation model in edge areas using bicubic polynomial interpolation, improves the accuracy of DEM data by using bicubic polynomial interpolation, and digitally represents the sports field by utilizing DEM data. In addition to that, the model and DEM data are utilized in this paper to realize the site selection process for base station networking. The experimental analysis demonstrates that the athletes’ health status evaluation system suggested in this research, which is based on the edge computing model and the large-scale multimedia health data analysis, has a good effect on the assessment of athletes’ health.

PurposeThe association between primary aldosteronism (PA) and lower bone mineral density (BMD) has raised a concern, but the contributing factors remain unclear. We aim to explore the risk factors for lower BMD in PA patients.MethodsWe analyzed and compared the data of 60 PA patients with 60 matched essential hypertension (EH) patients. BMD, bone metabolites, and several oxidative stress and inflammation indicators—including C-reactive protein (CRP), superoxide dismutase (SOD), total bilirubin (TBIL), mean platelet volume (MPV), etc.—were assessed and compared in PA and EH patients. Bivariate correlation analysis and multivariate linear regression analysis were performed to explore the factors associated with BMD in PA patients.ResultsThe BMD measured by quantitative computed tomography in PA patients was lower than that in EH patients (141.9 ± 34.0 vs. 158.9 ± 55.9 g/cm3, p = 0.047), especially in patients less than 50 years old. BMD was independently negatively associated with age (standardized β = -0.581, p < 0.001), serum phosphorus (standardized β = -0.203, p = 0.008), urinary calcium excretion (standardized β = -0.185, p = 0.031), and MPV (standardized β = -0.172, p = 0.043) and positively associated with SOD (standardized β = 0.205, p = 0.011) and TBIL (standardized β = 0.212, p = 0.015).ConclusionsThe PA patients showed a lower BMD than the EH patients, which was associated with age, serum phosphorus, urinary calcium excretion, MPV, SOD, and TBIL. These variables might be potential markers for the assessment of bone loss and efficacy of treatments in PA patients.

Background Previous studies have reported the surgical resection (SR) and radiofrequency ablation (RFA) could achieve comparable recurrence-to-death survival (RTDS). However, the impact of primary tumor burden on RTDS of patients with recurrent hepatocellular carcinoma (HCC) following SR or RFA has not been clarified. Methods From January 2009 to March 2015, 171 patients who underwent initial hepatectomy and second curative treatments in West China Hospital were retrospectively analyzed. Survival analysis was performed by the Kaplan–Meier method. Risk factors were identified using the Cox proportional hazard model. Results At initial hepatectomy, 96 patients (56.1%) were diagnosed with HCC within the Milan criteria (MC), and 75 patients (43.9%) were HCC beyond the MC. The clinicopathological features and re-treatment methods of recurrent HCC were similar between patients with primary HCC within or beyond the MC. Patients with primary HCC within the MC had longer recurrence time (31.4 ± 24.2 months vs. 20.2 ± 16 months, P 400 ng/mL at the time of recurrence were associated with RTDS. Conclusions The primary tumor burden had no impact on RTDS, but had an impact on recurrence time. The recurrence time had an impact on RTDS and might be a good index to reflect the biology of recurrent HCC.

Oxidative damage-induced mitochondrial dysfunction may activate muscle catabolism and autophagy pathways to initiate muscle weakening in idiopathic inflammatory myopathies (IIMs). In this study, Single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) and mitochondrial DNA (mtDNA) copy number were assessed and their association with the risk of polymyositis and dermatomyositis (PM/DM) was evaluated. Excessive D-loop SNPs (8.779 ± 1.912 vs. 7.972 ± 1.903, p = 0.004) correlated positively with mtDNA copy number (0.602 ± 0.457 vs. 0.300 ± 0.118, p p = 0.047) and 16519C (p = 0.043) were significantly higher in the patients with PM/DM. Subsequent analysis showed that reactive oxygen species (ROS) generation was increased in PM/DM patients compared with that in the controls (18,477.756 ± 13,574.916 vs. 14,484.191 ± 5703.097, p = 0.012). Further analysis showed that the PM/DM risk-related allele 16304C was significantly associated with lower IL-4 levels (p = 0.021), while 16519C had a trend to be associated with higher IL-2 expression (p = 0.064). The allele 16519C was associated with a positive antinuclear antibody (ANA) status in PM/DM patients (p = 0.011). Our findings suggest that mitochondrial D-loop SNPs could be potential biomarkers for PM/DM risk and these SNPs associated with cytokine expression may be involved in the development of PM/DM. Further, mtDNA copy number-mediated mitochondrial dysfunction may precede the onset of PM/DM.

Background: Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. MS pathogenesis is closely related to the environment, genetic, and immune system, but the underlying interactions have not been clearly elucidated. This study aims to unveil the genetic basis and immune landscape of MS pathogenesis with bioinformatics.Methods:Gene matrix wasretrieved from the gene expression database NCBI GEO. Then, bioinformatics was used to standardize the samples and obtain differentially expressed genes (DEGs). The protein-protein interaction network was constructed with DEGs on the STRING website. Cytohubbaplug-in and MCODE plug-in were used to mine hub genes. Meanwhile, the CIBERSORTX algorithm was used to explore the characteristics of immune cellinfiltration in MS brain tissues. Spearman correlation analysis was performed between genes and immune cells, and the correlation between genes and different types of brain tissues was also analyzed using the WGCNA method.Results:A total of 90 samples from 2 datasetswere included, and 882 DEGs and 10 hub genes closely related to MS were extracted. Functional enrichment analysis suggested the roleof immune response in MS. Besides,CIBERSORTX algorithm results showed that MS brain tissuescontained a variety of infiltrating immune cells. Correlation analysis suggested that the hub genes were highly relevant to chronic active white matter lesions.Certain hub genes played a role in the activation of immune cells such as macrophages and natural killer cells.Conclusions: Our study shall provideguidance for the further study of the genetic basis and immune infiltration mechanism of MS.

Alzheimer's disease (AD) is an age-related degenerative change of the central nervous system, the cause of which remains unclear. Recent studies have found that brain inflammation caused by microbial infections may be one of the etiologies of AD, and antibiotics as novel treatments may be beneficial for delaying the development of AD. Several prospective studies have investigated the effects of different antibiotics on Alzheimer's disease. However, no systematic review or meta-analysis has evaluated the benefits and safety of antibiotics in AD patients.This study will analyze randomized controlled trials and observational studies published from database inception to December 31, 2022, and included direct or indirect evidence. Studies will be retrieved by searching PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Clinical Trials, CNKI, and Wan Fang databases. The outcomes of this study included the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog), Montreal Cognitive Assessment (MoCA), Standardized Mini-Mental State Examination (SMMSE), Clinical Dementia Rating (CDR), Frontal Functioning Scale (FAB), Dysfunctional Behavior Rating Instrument (DBRI), Activities of Daily Living (ADLs) Index, and Geriatric Depression Scale (GDS). The risk of bias will be assessed using the Cochrane risk-of-bias assessment instrument for randomized controlled trials. A random-effect/fixed-effects model will be used to summarize the estimates of the mean difference/risk ratio using a 95% confidence interval.This study will analyze the benefits and safety of antibiotics in patients with AD.The results of this analysis will provide evidence to evaluate the benefits and safety of antibiotics in the treatment of AD.

Nicotine, one of the main ingredients of cigarettes, promotes activation of pancreatic stellate cells(PSCs) and exacerbates pancreatic fibrosis in previous studies. Here we focus on the inner relationship between mitochondrial oxidative stress and mitochondrial dynamics to explore the possible mechanism. Primary human PSCs were stimulated by nicotine. The effect of nicotine on oxidative stress and mitochondrial dynamics was analyzed by reactive oxygen species (ROS) assay, quantitative real-time PCR, and western blotting. Mitochondrial morphology was observed. Antioxidant and small interfering RNA transfection were applied to explore the interrelationship between oxidative stress and mitochondrial dynamics, as well as its effect on PSCs activation. Nicotine exposure significantly increased Intracellular and mitochondrial ROS of hPSCs and promoted mitochondrial fission by upregulating dynamin-related protein 1(DRP1). Knockdown Drp1 reversed mitochondrial fragmentation and hPSCs activation that promoted by nicotine, but fail to alleviate oxidative stress. A mitochondrial-targeted antioxidant could reverse all the above changes. Our finding suggests that mitochondria oxidative stress mediated nicotine-promoted activation of PSCs by inducing Drp1-mediated mitochondrial fission, provides a new perspective on the possible mechanism by which nicotine affects PSCs, and reveals a potential therapeutic strategy.

Background To establish the digital diagnostic templates by cluster analysis based on a set of cephalometric films and evaluate the outcome of the different treatment methods in the patients affiliated to the same cephalometric morphology template (CMT). These templates could be used for the automatic diagnosis of dentofacial deformities and prediction of treatment outcomes in the future. Methods In this study, we assessed the coordinates of 60 different landmarks on the cephalograms of 2249 patients (14.35 ± 4.99 years, range from 7 to 62) with dentofacial deformities. The cephalometric data were subjected to dentist for clustering without a priori pattern definitions to generate biologically informative CMTs. Three templates were selected to evaluate the treatment outcome of patients affiliated to the same CMT. Results The cluster analysis yielded 21 distinct groups. The total discriminant accuracy was 89.1%, while the cross-validation accuracy was 85.0%, showing that the clusters were robust. All CMTs were automatically created and drawn using a computer, based on the average coordinates of each cluster. Individuals affiliated to the same CMT showed similar dentofacial features. We also evaluated differences in the outcomes of patients affiliated to the same CMT. Conclusions Our results demonstrated the utility of clustering methods for grouping dentofacial deformities with similar dentofacial features. Clustering methods can be used to evaluate the differences in the outcomes of patients affiliated to the same CMT, which has good clinical application value.

Funder: Welcome Trust (209441/Z/17/Z), DNA–protein interactions regulate critical biological processes. Identifying proteins that bind to specific, functional genomic loci is essential to understand the underlying regulatory mechanisms on a molecular level. Here we describe a co-binding-mediated protein profiling (CMPP) strategy to investigate the interactome of DNA G-quadruplexes (G4s) in native chromatin. CMPP involves cell-permeable, functionalized G4-ligand probes that bind endogenous G4s and subsequently crosslink to co-binding G4-interacting proteins in situ. We first showed the robustness of CMPP by proximity labelling of a G4 binding protein in vitro. Employing this approach in live cells, we then identified hundreds of putative G4-interacting proteins from various functional classes. Next, we confirmed a high G4-binding affinity and selectivity for several newly discovered G4 interactors in vitro, and we validated direct G4 interactions for a functionally important candidate in cellular chromatin using an independent approach. Our studies provide a chemical strategy to map protein interactions of specific nucleic acid features in living cells.

BACKGROUND Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) biomarkers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity. METHODS We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients. RESULTS Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients. CONCLUSIONS Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for noninvasive UC detection and surveillance.

Background: Intrahepatic cholangiocarcinoma (ICC) is characterized by a highly aggressive nature and a dismal outcome. FOXA2 is an archetypal transcription factor involved in cholangiocyte proliferation. Results: FOXA2 expression was negatively correlated with tumor stage (p = 0.024). Univariate and multivariate analyses showed that low FoxA2 expression was associated with tumor relapse and survival. At 20 weeks after TAA administration, FoxA2-/- mice displayed significant manifestations of neoplasia, while WT mice did not. RNA sequencing analysis showed that the expression of genes in the MAPK signaling pathway was significantly higher in FoxA2-/- mice. IHC and Western blot results showed that p-ERK1/2, CREB1 and RAS were highly expressed in FoxA2-/- mice. Furthermore, using in vitro experiments with siRNA, we found that low expression of FoxA2 could exacerbate the metastatic potential of ICC. The expression of p-ERK1/2 and RAS, which are key mediators of the MAPK signaling pathway, was significantly increased. Conclusion: Low FOXA2 expression negatively affected the prognosis of patients with ICC. Loss of FoxA2 expression could promote intrahepatic bile duct neoplasia partly via activation of the MAPK signaling pathway. Materials and methods: In all, the data of 85 patients with ICC were retrospectively collected and analyzed. TAA was used to induce ICC in FoxA2-/- mice and WT mice. RNA-sequencing analysis was used to identify the expression of different genes.

Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial–mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC. Significance: These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.

Background The epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear. Methods The expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected. TRPM7was knockdown by shRNA in Ovarian cancer cell lines to examine calcium [Ca2+]i, EMT markers and PI3K/AKT markers. Various cellular assays, such as invasion and migration, were performed in vitro, and further confirmed in vivo. Results TRPM7 expression is negatively correlated with E-cadherin, but positively with N-cadherin, Vimentin and Twist expression in ovarian cancer samples. TRPM7 depletion inhibited the migration and invasion in SKOV3 and OVCAR3 cells. In addition, TRPM7 silencing decreased the lung metastasis of SKOV3 tumors and prolonged the survival of tumor-bearing mice. Similar to that of TRPM7 silencing, treatment with MK886, a potent 5-lipoxygenase inhibitor to reduce TRPM7 expression, and/or BAPTA-AM, an intracellular calcium chelator, significantly mitigated the Epidermal growth factor (EGF) or Insulin-like growth factors (IGF)-stimulated migration, invasion, and the EMT in ovarian cancer cells by decreasing the levels of intracellular calcium [Ca2+]i. Furthermore, treatment with LY2904002, a PI3K inhibitor, also inhibited the migration, invasion, and treatment with both LY2904002 and BAPTA-AM further enhanced their inhibition in ovarian cancer cells. Moreover, treatment with BAPTA-AM mitigated the IGF-stimulated migration, invasion, particularly in TRPM7-silenced ovarian cancer cells. Finally, TRPM7 silencing attenuated the PI3K/AKT activation, which was enhanced by BAPTA-AM, MK886 or LY2904002 treatment in ovarian cancer cells. Conclusions TRPM7 silencing inhibited the EMT and metastasis of ovarian cancer by attenuating the calcium-related PI3k/AKT activation. Our findings suggest that TRPM7 may be a therapeutic target for intervention of ovarian cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1061-y) contains supplementary material, which is available to authorized users.

Rationale: The role of SLUG in epithelial-mesenchymal transition during tumor progression has been thoroughly studied, but its precise regulation remains poorly explored. Methods: The affinity purification, mass spectrometry and CO-IP were performed to identify the interaction between SLUG and ubiquitin-specific protease 5 (USP5). Cycloheximide chase assays and deubiquitination assays confirmed that the effect of USP5 on the deubiquitin of SLUG. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional regulation of E-cadherin by SLUG effected by USP5. EMT related markers was detected by western blotting and immunofluorescence. Molecular docking, SPR sensor (biacore) and co-location were detected to prove Formononetin targets USP5. Bioinformatics analysis was used to study the relation of USP5 and SLUG to malignancy degree of HCC. Cell migration, invasion in HCC cells and xenografts model in nude mouse were conducted to detect the promotion of USP5 and the inhibition of Formononetin on EMT. Results: USP5 interacts with and stabilizes SLUG to regulate its abundance through USP5 deubiquitination activities in epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC). USP5 is highly expressed and positively correlated with SLUG expression in HCC with high malignancy. Knockdown of USP5 inhibits SLUG deubiquitination and inhibits HCC cells proliferation, metastasis, and invasion, while overexpression of USP5 promotes SLUG stability and EMT in vitro and in vivo. Through virtual screening, we found that Formononetin exhibits excellent binding to USP5. Moreover, Formononetin inhibits deubiquitinating activities of USP5 to SLUG and consequently impedes the EMT and malignant progression of HCC. Conclusion: Our findings reveal that USP5 serve as a potential target for tumor intervention and provide a preliminary antitumor therapy for inhibit EMT by targeting USP5 or its interaction with SLUG in HCC.

Background Follow-up study of coronavirus disease 2019 (COVID-19) survivors has rarely been reported. We aimed to investigate longitudinal changes in the characteristics of COVID-19 survivors after discharge. Methods A total of 594 COVID-19 survivors discharged from Tongji Hospital in Wuhan from February 10 to April 30, 2020 were included and followed up until May 17, 2021. Laboratory and radiological findings, pulmonary function tests, electrocardiogram, symptoms and signs were analyzed. Results 257 (51.2%) patients had at least one symptom at 3 months post-discharge, which decreased to 169 (40.0%) and 138 (28.4%) at 6-month and 12-month visit respectively. During follow-up period, insomnia, chest tightness, and fatigue were the most prevalent symptoms. Most laboratory parameters returned to normal, whereas increased incidence of abnormal liver and renal function and cardiovascular injury was evidenced after discharge. Fibrous stripes (213; 42.4%), pleural thickening and adhesions (188; 37.5%) and enlarged lymph nodes (120; 23.9%) were the most common radiographical findings at 3 months post-discharge. The abnormalities of pulmonary function included obstructive, restrictive, and mixed, which were 5.5%, 4.0%, 0.9% at 6 months post, and 1.9%, 4.7%, 0.2% at 12 months. Electrocardiogram abnormalities occurred in 256 (51.0%) patients at 3 months post-discharge, including arrhythmia, ST-T change and conduction block, which increased to 258 (61.1%) cases at 6-month visit and were maintained at high frequency (242;49.8%) at 12-month visit. Conclusions Physiological, laboratory, radiological, or electrocardiogram abnormalities, particularly those related to renal, cardiovascular, and liver functions are common in patients who recovered from coronavirus disease 2019 (COVID-19) up to 12 months post-discharge.

Dynamic changes of the peripheral T cell receptor (TCR) and soluble receptors and ligands (sRLs) have the potential to be used as biomarkers to monitor the evolution of the immune system in tumor patients undergoing immunotherapy. These functional biomarkers could be used to predict immune response to treatment with immune checkpoint inhibitors (ICIs) and to provide high-value information on the immune function status of cancer patients, thereby helping physicians to make effective clinical decisions. We collected paired pre- and post-treatment peripheral blood samples from 31 solid tumor patients treated with ICIs. TCR and sRL status were investigated using next-generation sequencing and magnetic bead panels. We found that the diversity of the dominant TCR clone at baseline was correlated with durable clinical benefit in patients receiving single-agent treatment. The D50 index, the diversity from the cumulative 50% of the total complementary determinant region 3, was obtained during treatment. A significant difference in progression-free survival was demonstrated between the D50 high and D50 low groups. This result was validated in an independent cohort. A signature including soluble immune checkpoint proteins (sICPs) was identified. Upregulation of the signature during treatment was correlated with durable clinical benefit. All these results indicate that a novel biomarker based on peripheral TCR and sICPs has the potential to be used in prognostic prediction and for rapid determination of therapeutic outcomes in patients treated with immune checkpoint inhibitors.

Differentiating Vertebral Compression Fractures (VCFs) associated with trauma and osteoporosis (benign VCFs) or those caused by metastatic cancer (malignant VCFs) are critically important for treatment decisions. So far, automatic VCFs diagnosis is solved in a two-step manner, i.e. first identify VCFs and then classify it into benign or malignant. In this paper, we explore to model VCFs diagnosis as a three-class classification problem, i.e. normal vertebrae, benign VCFs, and malignant VCFs. However, VCFs recognition and classification require very different features, and both tasks are characterized by high intra-class variation and high inter-class similarity. Moreover, the dataset is extremely class-imbalanced. To address the above challenges, we propose a novel Two-Stream Compare and Contrast Network (TSCCN) for VCFs diagnosis. This network consists of two streams, a recognition stream which learns to identify VCFs through comparing and contrasting between adjacent vertebra, and a classification stream which compares and contrasts between intra-class and inter-class to learn features for fine-grained classification. The two streams are integrated via a learnable weight control module which adaptively sets their contribution. The TSCCN is evaluated on a dataset consisting of 239 VCFs patients and achieves the average sensitivity and specificity of 92.56\% and 96.29\%, respectively., Comment: submitted to TMI

Background Chronic renal failure (CRF) referred to chronic progressive renal parenchymal damage caused by various causes, with metabolite retention and imbalance of water, electrolyte, and acid‐base balance as the main clinical manifestations. Secondary hyperparathyroidism (sHPT) was a common complication in maintenance hemodialysis patients with CRF. Nuclear factor IB (NFIB) was a newly found tumor suppressor gene in various cancers. The present study aimed to illustrate the role of NFIB in sHPT clinical diagnosis and treatment response. Methods A retrospective, case‐control study, including 189 patients with sHPT and 106 CRF patients without sHPT, compared with 95 controls. Serum NFIB and 1,25(OH)2D3 levels were measured by RT‐qPCR and ELISAs, respectively. ROC analysis was conducted to verify the diagnostic value of NFIB in sHPT. Spearman's correlation analysis was conducted to verify the association between NFIB and bone mineral density (BMD) scores. After 6 months of treatment, the variance of NFIB and 1,25(OH)2D3 in different groups was recorded. Results The expression of NFIB was significantly lower in serum samples from sHPT and non‐sHPT CRF patients, compared to controls. Clinicopathological information verified sHPT was associated with NFIB, parathyroid hormone (PTH), serum calcium, serum phosphorus, time of dialysis, and serum 1,25(OH)2D3 levels. Spearman's correlation analysis illustrated the positive correlation between NFIB levels and BMD scores. At receiver operator characteristic (ROC) curve analysis, the cutoff of 1.6508 for NFIB was able to identify patients with sHPT from healthy controls; meanwhile, NFIB could also discriminate sHPT among CRF patients as well (cutoff = 1.4741). Furthermore, we found that during 6 months of treatment, NFIB levels were gradually increased, while PTH and serum P levels were decreased. Conclusions Serum NFIB was a highly accurate tool to identify sHPT from healthy controls and CRF patients. Due to its simplicity, specificity, and sensitivity, this candidate can be proposed as a first‐line examination in the diagnostic workup in sHPT., The expression of nuclear factor IB (NFIB) was significantly lower in serum samples from secondary hyperparathyroidism (sHPT) and non‐sHPT chronic renal failure (CRF) patients, compared to controls. Clinicopathological information verified sHPT was associated with NFIB, parathyroid hormone (PTH), serum calcium, serum phosphorus, time of dialysis, and serum 1,25(OH)2D3 levels. Spearman's correlation analysis illustrated the positive correlation between NFIB levels and bone mineral density (BMD) scores. At receiver operator characteristic (ROC) curve analysis, the cutoff of 1.6508 for NFIB was able to identify patients with sHPT from healthy controls; meanwhile, NFIB could also discriminate sHPT among CRF patients as well (cutoff = 1.4741). Furthermore, we found that during 6 months of treatment, NFIB levels were gradually increased, while PTH and serum P levels were decreased.

Fruit-based diets are recognized for their benefits to human health. The safety of fruit is a global concern for scientists. Fruit microbiome represents the whole microorganisms that are associated with a fruit. These microbes are either found on the surfaces (epiphytes) or in the tissues of the fruit (endophytes). The recent knowledge gained from these microbial communities is considered relevant to the field of biological control in prevention of postharvest fruit pathology. In this study, the importance of the microbiome of certain fruits and how it holds promise for solving the problems inherent in biocontrol and postharvest crop protection are summarized. Research needs on the fruit microbiome are highlighted. Data from DNA sequencing and "meta-omics" technologies very recently applied to the study of microbial communities of fruits in the postharvest context are also discussed. Various fruit parameters, management practices, and environmental conditions are the main determinants of the microbiome. Microbial communities can be classified according to their structure and function in fruit tissues. A critical mechanism of microbial biological control agents is to reshape and interact with the microbiome of the fruit. The ability to control the microbiome of any fruit is a great potential in postharvest management of fruits. Research on the fruit microbiome offers important opportunities to develop postharvest biocontrol strategies and products, as well as the health profile of the fruit.

Funder: Herchel Smith Funds, Background: Four-stranded G-quadruplexes (G4s) are DNA secondary structures in the human genome that are primarily found in active promoters associated with elevated transcription. Here, we explore the relationship between the folding of promoter G4s, transcription and chromatin state. Results: Transcriptional inhibition by DRB or by triptolide reveals that promoter G4 formation, as assessed by G4 ChIP-seq, does not depend on transcriptional activity. We then show that chromatin compaction can lead to loss of promoter G4s and is accompanied by a corresponding loss of RNA polymerase II (Pol II), thus establishing a link between G4 formation and chromatin accessibility. Furthermore, pre-treatment of cells with a G4-stabilising ligand mitigates the loss of Pol II at promoters induced by chromatin compaction. Conclusions: Overall, our findings show that G4 folding is coupled to the establishment of accessible chromatin and does not require active transcription.

The low proportion of gastric cancer (GC) patients with high HER2 expression limits the clinical application of trastuzumab, a humanized epidermal growth factor receptor 2 (HER2) antibody targeting for GC treatment. We found that Dicer was positively correlated with HER2 expression in GC tissue by immunostaining as well as induce HER2 overexpression without increasing invasiveness of GC cell. In addition, both the growth of GC referring to cell proliferation, invasion, migration and apoptosis was inhibited by Dicer overexpression. Moreover, the HER2 overexpression induced by Dicer provided more effective and additive target for trastuzumab to amplify the inhibition effect for GC cells in vitro and in vivo. Furthermore, as assessed in a subsequent experiment, calcitriol induced HER2 overexpression and amplified the inhibition effect of trastuzumab in GC cells referring to proliferation. Our finding demonstrated the calcitriol might increase indication of trastuzumab by inducing HER2 overexpression in GC patients. Dicer would be a potential target that extend the clinical indications of HER2 antibody in patients with low or negative HER2, who were not fit for HER2 antibody treatment before.

The low sensitivity of [This was a bicentric retrospective analysis of a prospective parent study (clinical trial: HS-KY-2020-826 (Huashan Hospital) and DF-2020-102 (Shanghai East Hospital)). Thirty-eight patients with gastric cancer (31 with adenocarcinoma and 7 with signet ring cell carcinoma) were included in this study. All of the participants underwent [For the detection of primary gastric cancer, the sensitivities of [In this selected cohort, [

PurposeSurgery is the major treatment option for pheochromocytoma but carries potential risks, including hemorrhage and hemodynamic instability. Even with laparoscopic adrenalectomy, intraoperative blood transfusion happens from time to time, but few studies have investigated risk factors. For the first time we develop and validate a nomogram for prediction of red blood cell transfusion in pheochromocytoma surgery.MethodsThere were 246 patients in our center and 56 patients in Peking Union Medical College Hospital, who underwent pheochromocytoma surgery, enrolled in the study. We incorporated clinical and radiological risk factors, and presented this with a nomogram. Lasso regression model was used for feature selection. Logistic regression analysis was performed to identify the odd ratios. The performance of the nomogram was assessed with respect to its discrimination, calibration and clinical usefulness.ResultsThirty-two features were reduced to five, which were phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction heart rate, tumor diameter and surgical procedure. The model showed good discrimination (C-index, 0.857; 95% CI, 0.781–0.836) and application in the validation sets also gave good discrimination (internal validation: C-index, 0.831; 95% CI, 0.750–0.822; external validation: C-index, 0.924; 95% CI, 0.766–1.000). Calibration tested with the Hosmer-Lemeshow test yielded a good agreement between prediction and observation (training P=0.358; internal validation P=0.205; external validation P=0.395). Odd ratios of phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction HR, tumor diameter and open surgery were 13.32 (95% CI, 1.48–197.38; P = 0.034), 1.04 (95% CI, 0.99–1.08; P = 0.092), 1.04 (95% CI, 1.01–1.08; P=0.006), 1.03 (95% CI, 1.02–1.06; PConclusionsThis study presents a nomogram that may be used to facilitate the prediction of red blood cell transfusion in pheochromocytoma surgery and help to do the preoperative management more efficiently.

BACKGROUND AND AIMS Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahma-related gene 1 (Brg1), an enzymatic subunit of the switch/sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently up-regulated in both HPCs and iCCA; however, its role in this correlation remains undefined. APPROACH AND RESULTS A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the β-catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/β-catenin signaling. CONCLUSIONS We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/β-catenin signaling. Our data suggest that therapies targeting Brg1-expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention., Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

The mechanism of extracellular matrix induced tumor progression is poorly understood. Based on the TCGA database and clinical tumor tissues analysis, we observed abundant type I collagen expression in tumor tissues and poor overall survival in gastric patients with high integrin β1 (ITGB1) expression. In vitro, our study found that 3D collagen culture promoted the capability of colony formation and growth in ITGB1 positive gastric cancer, whereas limited colony growth was observed in ITGB1 negative gastric cancer, suggesting the role of ITGB1 in type I collagen associated tumor progression. Mechanistically, we demonstrated that type I collagen was capable of promoting the activation of BCL9L/β-catenin signaling pathway through ITGB1, thereby contributing to the gastric cancer development. Subsequently, β-catenin signals further up-regulated the expression anti-apoptosis protein BCL2, leading to the chemo-resistance in gastric cancer cells. Blockade of β-catenin signals efficiently improved the anticancer effects of chemotherapy, providing an innovative sight for clinical gastric cancer therapy.