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Mounting evidence has demonstrated that a myriad of developmental signaling pathways, such as the Wnt, Notch, Hedgehog and Hippo, are frequently deregulated and play a critical role in regulating cancer stem cell (CSC) activity in human cancers, including gynecologic malignancies. In this review article, we describe an overview of various signaling pathways in human cancers. We further discuss the developmental roles how these pathways regulate CSCs from experimental evidences in gynecologic cancers. Moreover, we mention several compounds targeting CSCs in gynecologic cancers to enhance the treatment outcomes. Therefore, these signaling pathways might be the potential targets for developing targeted therapy in gynecologic cancers.

Invasion and metastasis of breast cancer cells is an important cause of death in breast cancer patients. In the tumor microenvironment, M2 polarization of macrophages can promote the invasion and metastasis of tumor cells. OVOL2 is an evolutionarily conserved transcription regulator, but its effect in macrophages has not been described previously. The aim of this study was to investigate the effects of OVOL2 on macrophage polarity and the role of these effects in the tumor metastasis. We found that overexpression of OVOL2 in macrophages significantly inhibited M2 polarization and thus inhibits breast cancer metastasis. We propose a novel mechanism in which OVOL2 inhibits M2 polarization of macrophages and thus reduces their ability to induce invasion and metastasis of breast cancer. By shedding new light on the regulation of metastasis in cancers, our study provides a new strategy for the targeted therapy of cancer.

BACKGROUND Several groups have previously developed logistic regression models for predicting delayed graft function (DGF). In this study, we used an automated machine learning (ML) modeling pipeline to generate and optimize DGF prediction models en masse. METHODS Deceased donor renal transplants at our institution from 2010 to 2018 were included. Input data consisted of 21 donor features from United Network for Organ Sharing. A training set composed of ~50%/50% split in DGF-positive and DGF-negative cases was used to generate 400 869 models. Each model was based on 1 of 7 ML algorithms (gradient boosting machine, k-nearest neighbor, logistic regression, neural network, naive Bayes, random forest, support vector machine) with various combinations of feature sets and hyperparameter values. Performance of each model was based on a separate secondary test dataset and assessed by common statistical metrics. RESULTS The best performing models were based on neural network algorithms, with the highest area under the receiver operating characteristic curve of 0.7595. This model used 10 out of the original 21 donor features, including age, height, weight, ethnicity, serum creatinine, blood urea nitrogen, hypertension history, donation after cardiac death status, cause of death, and cold ischemia time. With the same donor data, the highest area under the receiver operating characteristic curve for logistic regression models was 0.7484, using all donor features. CONCLUSIONS Our automated en masse ML modeling approach was able to rapidly generate ML models for DGF prediction. The performance of the ML models was comparable with classic logistic regression models.

BACKGROUND & AIMS Early determination of the prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is important to guide clinical management and decrease mortality. The aim of this study was to develop a new simplified prognostic score to accurately predict outcomes in patients with HBV-ACLF. METHODS Prospective clinical data from 2,409 hospitalized patients with acute deterioration of HBV-related chronic liver disease were used to develop a new prognostic score that was validated in an external group. RESULTS A total of 954 enrolled patients with HBV-ACLF were diagnosed based on the Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) criteria. Six predictive factors were significantly related to 28-day mortality and constituted a new prognostic score (=1.649×ln(international normalized ratio)+0.457×hepatic encephalopathy score+0.425×ln(neutrophil)+0.396×ln(total bilirubin)+0.576×ln(serum urea)+0.033×age). The C-indices of the new score for 28-/90-day mortality (0.826/0.809) were significantly higher than those of 4 other scores (COSSH-ACLF, 0.793/0.784; CLIF-C ACLF, 0.792/0.770; MELD, 0.731/0.727; MELD-Na, 0.730/0.726; all p

Purpose: The authors aimed to identify Notch signaling pathway gene mutations as a prognostic biomarker for bladder cancer. Methods: First, critical Notch signaling pathway genes were screened using The Cancer Genome Atlas and validation sets. Second, immune infiltration, protein–protein interaction network, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis analyses were performed. Finally, potential immunotherapy drug targets were screened using T-cell receptors, B-cell receptors and CERES scores for bladder cancer. Results: The NOTCH7 gene was identified, with a significant difference in immune infiltration level between mutant and wild type in bladder cancer, mainly related to T cells. NOTCH7 was an immunotherapy prognostic factor, and IRF1 and B2M were the potential drug targets for NOTCH7 mutation in bladder cancer. Conclusion: NOTCH7 gene mutation can be used as an immunotherapy biomarker for bladder cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive malignancy with a 5-year survival rate below 10%. Its unique genetic makeup and tumor microenvironment produce a lack of response to current treatments, including chemotherapy, radiotherapy, and immunotherapy. Recent preclinical studies have revealed that ferroptosis, an iron-dependent form of nonapoptotic cell death driven by unrestricted lipid peroxidation, may be an attractive therapeutic goal in PDAC. Understanding the dual role of ferroptotic cell death in both promoting and suppressing tumor immunity, as well as its integrated regulatory mechanisms and signaling pathways, may lead to more effective treatment designs for clinical trials of PDAC and may minimize or delay the emergence of drug resistance or side effects.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of targets genes by binding to the 3′-untranslated regions. They play vital roles in diverse biological processes, including the development of hepatic fibrosis (HF). HF is characterized by the accumulation of extracellular matrix (ECM) and hepatic stellate cells (HSCs) are considered a major cell type for producing ECM. Alteration of the HSC phenotype plays a crucial role in the HF pathological process. MiRNAs involved in various biological process, such as differentiation, apoptosis, migration, and their relevant signaling pathways, are expressed in HSCs; however, emerging evidence indicates that numerous miRNAs are abnormally expressed in activated HSCs. In this review, we summarize the categorization of miRNAs in HF and describe the relationships among them. We also discuss miRNAs recently discovered to be related to HF, and attempt to find potential miRNAs that may serve as novel biomarkers for use in HF treatment.

OBJECTIVES In addition to the association between positive fluid balance (FB) and acute kidney injury (AKI) after cardiac surgery reported by former studies, this study examined the relationship between FB and progressive AKI. DESIGN A retrospective, observational study. SETTING University teaching, grade A tertiary hospital in Shanghai, China. PARTICIPANTS Adult patients after cardiac surgery from July-December 2016. INTERVENTIONS Perioperative data relating to postoperative fluid intake and output were collected. AKI progression was defined as a worsening of AKI stage. FB was calculated as (fluid intake [L] - fluid output [L]/body weight [kg] × 100%). MEASUREMENTS AND MAIN RESULTS The study comprised 1,522 patients. The incidences of AKI and progressive AKI were 33.1% (n = 504) and 18.1% (n = 91), respectively. There was an exponential increase between 24-hour FB and AKI occurrence, and an approximate "U"-shape association between 48-hour FB and AKI progression. Multivariate logistic regression showed that 24-hour FB ≥5% was an independent risk factor for AKI incidence (odds ratio [OR] 3.976; p < 0.001) and 48-hour FB

AIM To assess the performance of the apparent diffusion coefficient (ADC) and relative ADC (rADC) to differentiate benign from malignant breast lesions using the plateau pattern of the time–intensity curve (Type II TIC), including the impact of lesions-enhancement subtypes and menopausal status of patients. MATERIALS AND METHODS Between September 2016 and December 2019, 408 patients with 169 benign and 239 malignant lesions with Type II TIC underwent magnetic resonance imaging (MRI), including diffusion-weighted imaging, with b-values of 50 and 800 s/mm2. ADC and rADC values were calculated by placing regions of interest (ROIs) on the lesion, the parenchyma of the normal breast, and the pectoralis major muscle. A receiver operating characteristic (ROC) curve was generated to compare the diagnostic performance of each parameter in distinguishing between benign and malignant breast lesions. Further classification was undertaken to study the discriminatory performance of each parameter in the different lesions enhancement subtypes (mass-like enhancement [MLE] and non-MLE [NMLE]) and menopausal status of patients (pre-menopausal and post-menopausal). RESULTS There was a significant difference in the ADC and rADC values between benign and malignant lesions. The sensitivities of lesion ADC, gland rADC, and muscle rADC were 79.29%, 77.51%, and 79.29%, respectively, with specificities of 94.56%, 82.01%, and 94.98%, respectively. The area under the ROC curve (AUC) of muscle rADC was the highest (AUC=0.92), especially in the MLE subtype (AUC=0.96), and was not affected by the menopausal status. CONCLUSION Muscle rADC and lesion ADC assessment improved the diagnostic performance of breast MRI in distinguishing between benign and malignant breast lesions with Type II TIC, especially muscle rADC in the MLE subtype.

Objectives: Rhinoviruses (RV) represent the most common aetiological agent of all acute respiratory tract infections across all age groups and a significant burden of disease among children. Recent studies have shown that RV-A and RV-C species are associated with increased disease severity. In order to better understand the potential associations between RV species and clinical features among paediatric cases, this study aimed to integrate genetic and epidemiological data using Bayesian phylogenetic methods. Methods: Potential associations between RV species and subtypes, and clinical disease severity using a matched dataset of 52 RV isolates sampled from children (< 18 years) in Sydney, Australia, between 2006 and 2009 were uncovered using epidemiological and phylogenetic methods. Results: It was found that RV-C was significantly more likely to be isolated from paediatric cases aged < 2 years compared with RV-A, although no significant differences in recorded symptoms were observed. Significant phylogenetic-trait associations between age and the VP4/VP2 capsid protein phylogeny suggest that age-specific variations in infectivity among subtypes may may be possible. Conclusion: This study adds to the growing body of epidemiological evidence concerning RV. Improving surveillance and testing for RV, including routine whole genome sequencing, may improve understanding of the varied disease outcomes of RV species and subtypes. Future studies could aim to identify specific genetic markers associated with age-specific infectivity of RV, which could inform treatment practices and public health surveillance of RV.

Objective: Radiomics, an emerging tool for medical image analysis, is potential towards precisely characterizing gastric cancer (GC). Whether using one-slice 2D annotation or whole-volume 3D annotation remains a long-time debate, especially for heterogeneous GC. We comprehensively compared 2D and 3D radiomic features' representation and discrimination capacity regarding GC, via three tasks. Methods: Four-center 539 GC patients were retrospectively enrolled and divided into the training and validation cohorts. From 2D or 3D regions of interest (ROIs) annotated by radiologists, radiomic features were extracted respectively. Feature selection and model construction procedures were customed for each combination of two modalities (2D or 3D) and three tasks. Subsequently, six machine learning models (Model_2D^LNM, Model_3D^LNM; Model_2D^LVI, Model_3D^LVI; Model_2D^pT, Model_3D^pT) were derived and evaluated to reflect modalities' performances in characterizing GC. Furthermore, we performed an auxiliary experiment to assess modalities' performances when resampling spacing is different. Results: Regarding three tasks, the yielded areas under the curve (AUCs) were: Model_2D^LNM's 0.712 (95% confidence interval, 0.613-0.811), Model_3D^LNM's 0.680 (0.584-0.775); Model_2D^LVI's 0.677 (0.595-0.761), Model_3D^LVI's 0.615 (0.528-0.703); Model_2D^pT's 0.840 (0.779-0.901), Model_3D^pT's 0.813 (0.747-0.879). Moreover, the auxiliary experiment indicated that Models_2D are statistically more advantageous than Models3D with different resampling spacings. Conclusion: Models constructed with 2D radiomic features revealed comparable performances with those constructed with 3D features in characterizing GC. Significance: Our work indicated that time-saving 2D annotation would be the better choice in GC, and provided a related reference to further radiomics-based researches., Published in IEEE Journal of Biomedical and Health Informatics

Background Patient‐derived organoid (PDO) models are highly valuable and have potentially widespread clinical applications. However, limited information is available regarding organoid models of non‐small cell lung cancer (NSCLC). This study aimed to characterize the consistency between primary tumors in NSCLC and PDOs and to explore the applications of PDOs as preclinical models to understand and predict treatment response during lung cancer. Methods Fresh tumor samples were harvested for organoid culture. Primary tumor samples and PDOs were analyzed via whole‐exome sequencing. Paired samples were subjected to immunohistochemical analysis. There were 26 antineoplastic drugs tested in the PDOs. Cell viability was assessed using the Cell Titer Glo assay 7–10 days after drug treatment. A heatmap of log‐transformed values of the half‐maximal inhibitory concentrations was generated on the basis of drug responses of PDOs through nonlinear regression (curve fit). A total of 12 patients (stages I–III) were enrolled, and 7 paired surgical tumors and PDOs were analyzed. Results PDOs retained the histological and genetic characteristics of the primary tumors. The concordance between tumors and PDOs in mutations in the top 20 NSCLC‐related genes was >80% in five patients. Sample purity was significantly and positively associated with variant allele frequency (Pearson r = 0.82, P = 0.0005) and chromosome stability. The in vitro response to drug screening with PDOs revealed high correlation with the mutation profiles in the primary tumors. Conclusions PDOs are highly credible models for detecting NSCLC and for prospective prediction of the treatment response for personalized precision medicine. Key points Lung cancer organoid models could save precious time of drug testing on patients, and accurately select anticancer drugs according to the drug sensitivity results, so as to provide a powerful supplement and verification for the gene sequencing., Lung cancer organoid models could save the precious time of drug testing on patients, and accurately select anticancer drugs according to the drug sensitivity results, so as to provide a powerful supplement and verification for the gene sequencing.

Fatty acid binding protein 5 (FABP5) has been reported to play an important role in various cancers. We found that high FABP5 expression was associated with poor histological differentiation and vascular invasion. High FABP5 expression indicated a poor prognosis. Downregulation of FABP5 suppressed cell proliferation, cell migration and invasion, and induced cell apoptosis. Bioinformatic analysis revealed that the Hippo signaling pathway was related to FABP5. We found that overexpression of yes-associated protein 1 (YAP1) could partially reverse the effect of FABP5 knockdown on growth and apoptosis. The FABP5 inhibitor SBFI-26 suppressed the proliferation and promoted the apoptosis of gastric cancer (GC) cells and interfered with the Hippo signaling pathway by inhibiting YAP1. Our data suggested that FABP5 might act as a potential target associated with the Hippo signaling pathway for GC treatment.

Aim: To investigate the effect of rs3733846 in the flanking region of miR-143/145 on susceptibility to cervical squamous cell carcinoma (CSCC). Materials & methods: We collected venous blood samples from 242 CSCC patients and 250 healthy controls. The rs3733846 polymorphism was genotyped by SnaPshot and Sanger sequencing. The expression of miR-143/145 in CSCC tissues was detected by quantitative real-time PCR. Results: The rs3733846 AG genotype was associated with a decreased risk of CSCC in genetic model (AGvs.AA: adjusted odds ratio [OR]: 0.44; 95% CI: 0.30–0.66; p < 0.001). Patients with the rs3733846 AG/GG genotypes had a reduced risk of developing poorly differential status (OR: 0.57; 95% CI: 0.33–0.98; p < 0.04) and lymph node metastasis (OR: 0.49; 95% CI: 0.26–0.92; p < 0.03). Conclusion: The rs3733846 in the flanking region of miR-143/145 was related to the susceptibility of CSCC.

Introduction The purpose of this study was to predict pathologic complete response (pCR) to neoadjuvant therapy in breast cancer using radiomics based on pretreatment staging contrast-enhanced computed tomography (CECT). Patients and Methods A total of 215 patients were retrospectively analyzed. Based on the intratumoral and peritumoral regions of CECT images, radiomic features were extracted and selected, respectively, to develop an intratumoral signature and a peritumoral signature with logistic regression in a training dataset (138 patients from November 2015 to October 2017). We also developed a clinical model with the molecular characterization of the tumor. A radiomic nomogram was further constructed by incorporating the intratumoral and peritumoral signatures with molecular characterization. The performance of the nomogram was validated in terms of discrimination, calibration, and clinical utility in an independent validation dataset (77 patients from November 2017 to December 2018). Stratified analysis was performed to develop a subtype-specific radiomic signature for each subgroup. Results Compared with the clinical model (area under the curve [AUC], 0.756), the radiomic nomogram (AUC, 0.818) achieved better performance for pCR prediction in the validation dataset with continuous net reclassification improvement of 0.787 and good calibration. Decision curve analysis suggested the nomogram was clinically useful. Subtype-specific radiomic signatures showed improved AUCs (luminal subgroup, 0.936; human epidermal growth factor receptor 2-positive subgroup, 0.825; and triple negative subgroup, 0.858) for pCR prediction. Conclusion This study has revealed a predictive value of pretreatment staging-CECT and successfully developed and validated a radiomic nomogram for individualized prediction of pCR to neoadjuvant therapy in breast cancer, which could assist clinical decision-making and improve patient outcome.

Heat shock proteins (HSPs) play essential roles in stress tolerance in insects, such as the cigarette beetle, Lasioderma serricorne, which is an important pest of stored products. However, the function of HSPs in environmental stress response in L. serricorne is poorly understood. In this study, six cDNAs encoding putative HSP70s were identified in L. serricorne (LsHSP70-1 to LsHSP70-6). The LsHSP70 proteins identified have signature motifs of insect HSP70s and exhibit high amino-acid identity with their respective orthologs from other insect species. Phylogenetic analysis showed that these LsHSP70s fall into three major clans: HSP70 in the cytosol (four genes), endoplasmic reticulum (one gene), and mitochondria (one gene). LsHSP70 genes are differentially expressed in different developmental stages. LsHSP70-4 and LsHSP70-5 are mainly expressed at the larval stage, while LsHSP70-3 shows the highest level at the pupal stage. The other genes are ubiquitously expressed. Furthermore, the expression levels of LsHSP70-1 and LsHSP70-4 are significantly upregulated upon exposure to temperatures of both 0 and 15 °C, while LsHSP70-3 is inducible at 15 °C and LsHSP70-6 at 0 °C. In addition, treatment at 0 °C causes significant downregulation of LsHSP70-2 and LsHSP70-3. Exposure to a temperature of 30 °C upregulates LsHSP70-1 expression, while 35 and 40 °C treatments result in significantly enhanced transcription of all the LsHSP70 genes. To the best of the authors’ knowledge, this is the first report on the sequence characteristics, phylogenetic relationships, and expression profiles of HSP70 genes in L. serricorne. The cold- and heat-inducible regulation of LsHSP70s suggests that these genes are related to tolerance of abnormal temperatures.

Background. Although the prognosis of low-grade glioma is better than that of glioblastoma, there are still some groups with poor prognosis. The integrated stress response contributes to the malignant progress of tumors. As there had limited research focused on the integrated stress status in LGG, it is urgent to profile and reclassify LGG based on the integrated stress response. Methods. Information of glioma patients was obtained from the Chinese Glioma Genome Atlas, The Cancer Genome Atlas, and the GSE16011 cohorts. Statistical analyses were conducted using GraphPad Prism 8 and R language. Results. We summarized and quantified four types of integrated stress responses. Relationships between these four types of stress states and the clinical characteristics were analyzed in low-grade glioma. We then reclassified the patients based on these four scores and found that cluster 2 had the worst prognosis, while cluster 1 had the best prognosis. We also established an accurate integrated stress response risk signature for predicting cluster 2. We found that immune response and suppressive immune cell components were more enriched in the high-risk group. We also profiled the genomic differences between the low- and high-risk groups, including the nonmissense mutation of driver genes and the copy number variations. Conclusion. Low-grade glioma patients were divided into three clusters based on the integrated stress status, with cluster 2 exhibiting malignant transformation trends. The signature adequately reflected the traits of cluster 2, while a high risk score indicated a worse prognosis and an enriched inhibitory immune microenvironment.

Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory element-binding transcription factor 1 (SREBP1) controls the transcription of major enzymes involved in de novo lipogenesis, including ACLY, ACACA, FASN, and SCD. Studies have shown the increased de novo lipogenesis in human hepatocellular carcinoma (HCC) samples. Multiple mechanisms, such as activation of the AKT/mechanistic target of rapamycin (mTOR) pathway, lead to high SREBP1 induction and the coordinated enhanced expression of ACLY, ACACA, FASN, and SCD genes. Subsequent functional analyses have unraveled these enzymes' critical role(s) and the related de novo lipogenesis in hepatocarcinogenesis. Importantly, targeting these molecules might be a promising strategy for HCC treatment. This paper comprehensively summarizes de novo lipogenesis rewiring in HCC and how this pathway might be therapeutically targeted.

Image-guided therapies have been on the rise in recent years as they can achieve higher accuracy and are less invasive than traditional methods. By combining augmented reality technology with image-guided therapy, more organs, and tissues can be observed by surgeons to improve surgical accuracy. In this review, 233 publications (dated from 2015 to 2020) on the design and application of augmented reality-based systems for image-guided therapy, including both research prototypes and commercial products, were considered for review. Based on their functions and applications. Sixteen studies were selected. The engineering specifications and applications were analyzed and summarized for each study. Finally, future directions and existing challenges in the field were summarized and discussed.

Background Endoscopic thyroidectomy is widely performed as it does not result in neck scar. However, there is a paucity of reports pertaining to completely endoscopic lateral neck dissection (LND). In this study, we introduce our step-wise approach for performing endoscopic selective LND via the chest–breast approach. We refer to this approach as Qin’s seven steps. Methods The Qin’s seven steps are: (1) establishment of working space range; (2) dissection of lymph nodes between the SCM and the sternohyoid muscle (level IV) and exposure of omohyoid; (3) dissection of lymph nodes at level IV; (4) dissection of lymph nodes at level III; (5) dissection of lymph nodes at carotid triangle (level III); (6) exposure of accessory nerve and dissection of lymph nodes at level II a; (7) dissection of lymph nodes at level II b. We reviewed the clinical data of 35 patients with papillary thyroid cancer (PTC) who were operated using the Qin’s seven steps. Results All 35 patients successfully underwent LND; bilateral LND was performed in 5 patients. The mean tumor size was 1.8 ± 1.0 cm; seven patients had multiple lesions. The mean number of retrieved lymph nodes in level II, III and IV were 8.8 ± 5.6, 6.1 ± 4.0 and 9.3 ± 5.1, respectively. As for complications, there were 3 cases of accessory nerve injury and 1 case of hypoglossal nerve injury. Internal jugular vein injury, cervical plexus injury and lymphatic leakage occurred in 2, 7, and 1 patients, respectively. Conclusion The Qin’s seven steps for performing endoscopic selective LND could be safely used in PTC patients with lateral lymph node metastasis. Satisfactory results were achieved in the short-term follow-up period. We recommend the use of Qin’s seven steps for PTC patients who are not desirous of neck scar.

Ischemia-reperfusion injury (IRI) has indeed been shown as a main complication of hepatectomy, liver transplantation, trauma, and hypovolemic shock. A large number of studies have confirmed that microvascular and parenchymal damage is mainly caused by reactive oxygen species (ROS), which is considered to be a major risk factor for IRI. Under normal conditions, ROS as a kind of by-product of cellular metabolism can be controlled at normal levels. However, when IRI occurs, mitochondrial oxidative phosphorylation is inhibited. In addition, oxidative respiratory chain damage leads to massive consumption of adenosine triphosphate (ATP) and large amounts of ROS. Additionally, mitochondrial dysfunction is involved in various organs and tissues in IRI. On the one hand, excessive free radicals induce mitochondrial damage, for instance, mitochondrial structure, number, function, and energy metabolism. On the other hand, the disorder of mitochondrial fusion and fission results in further reduction of the number of mitochondria so that it is not enough to clear excessive ROS, and mitochondrial structure changes to form mitochondrial membrane permeable transport pores (mPTPs), which leads to cell necrosis and apoptosis, organ failure, and metabolic dysfunction, increasing morbidity and mortality. According to the formation mechanism of IRI, various substances have been discovered or synthesized for specific targets and cell signaling pathways to inhibit or slow the damage of liver IRI to the body. Here, based on the development of this field, this review describes the role of mitochondria in liver IRI, from aspects of mitochondrial oxidative stress, mitochondrial fusion and fission, mPTP formation, and corresponding protective measures. Therefore, it may provide references for future clinical treatment and research.

Background: Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. Methods: In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients’ prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Results: Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Conclusions: These results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.

Monoclonal antibodies, antibody fragments and fusion proteins derived thereof have revolutionized the practice of medicine. Major challenges faced by the biopharmaceutical industry are however high production costs, long processing times and low productivities associated with their production in mammalian cell lines. The yeast Saccharomyces cerevisiae, a well-characterized eukaryotic cell factory possessing the capacity of post­translational modifications, has been industrially exploited as a secretion host for production of a range of products, including pharmaceuticals. However, due to the incompatible surface glycosylation, few antibody molecules have been functionally expressed in S. cerevisiae. Here, three non-glycosylated antibody fragments from human and the Camelidae family were chosen for expression in a S. cerevisiae strain (HA) previously evolved for high α-amylase secretion. These included the Fab fragment Ranibizumab (Ran), the scFv peptide Pexelizumab (Pex), and a nanobody consisting of a single V-type domain (Nan). Both secretion and biological activities of the antibody fragments were confirmed. In addition, the secretion level of each protein was compared in the wild type (LA) and two evolved strains (HA and MA) with different secretory capacities. We found that the secretion of Ran and Nan was positively correlated with the strains’ secretory capacity, while Pex was most efficiently secreted in the parental strain. To investigate the mechanisms for different secretion abilities in these selected yeast strains for the different antibody fragments, RNA-seq analysis was performed. The results showed that several bioprocesses were significantly enriched for differentially expressed genes when comparing the enriched terms between HA.Nan vs. LA.Nan and HA.Pex vs. LA.Pex, including amino acid metabolism, protein synthesis, cell cycle and others, which indicates that there are unique physiological needs for each antibody fragment secretion.

Background & aims Gain of function (GOF) mutations in the CTNNB1 gene are one of the most frequent genetic events in hepatocellular carcinoma (HCC). T-box transcription factor 3 (TBX3) is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene mediating activated β-catenin-driven HCC formation. Methods We evaluated the expression pattern of TBX3 in human HCC specimens. Tbx3 was conditionally knocked out in murine HCC models by hydrodynamic tail vein injection of Cre together with c-Met and ΔN90-β-catenin (c-Met/β-catenin) in Tbx3flox/flox mice. TBX3 was overexpressed in human HCC cell lines to investigate the functions of TBX3 in vitro. Results A bimodal expression pattern of TBX3 in human HCC samples was detected: high expression of TBX3 in GOF CTNNB1 HCC and downregulation of TBX3 in non-CTNNB1 mutant tumors. High expression of TBX3 was associated with increased differentiation and decreased expression signatures of tumor growth. Using Tbx3flox/flox mice, we found that ablation of Tbx3 significantly accelerates c-Met/β-catenin-driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/β-catenin mouse HCC was successfully prevented by overexpression of LATS2, which inhibited YAP/TAZ activity. In human HCC cell lines, overexpression of TBX3 inhibited HCC cell growth as well as YAP/TAZ activation. A negative correlation between TBX3 and YAP/TAZ target genes was observed in human HCC samples. Mechanistically, phospholipase D1 (PLD1), a known positive regulator of YAP/TAZ, was identified as a novel transcriptional target repressed by TBX3. Conclusion Our study suggests that TBX3 is induced by GOF CTNNB1 mutants and suppresses HCC growth by inactivating PLD1, thus leading to the inhibition of YAP/TAZ oncogenes. Lay summary TBX3 is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene in promoting liver cancer development. Herein, we demonstrate that TBX3 is in fact a tumor suppressor gene that restricts liver tumor growth. Strategies which increase TBX3 expression and/or activities may be effective for HCC treatment.

The purpose of this study was to employ novel tracers PET imaging approach to define the time course and intensity of myocardial repair after apoptosis and to correlate the imaging signal to immunohistochemical staining in myocardial infarction (MI). We designed novel αVβ3-targeted and radio-functionalized tracers for detection of apoptosis in H9C2 cells and myocardial tissue. MI rats were imaged with [18F]FDG, [18F]ANP-Cin or [18F]ANP-RGD2 using a small-animal PET/CT device. Rats were sacrificed, and tissue samples from viable and injured myocardial areas were sectioned for TUNEL assay and histology. The uncorrected radiochemical yield of [18F]ANP-Cin and [18F]ANP-RGD2 were 41.3 ± 5.4% and 21.17 ± 4.7%, respectively. Two tracers meet many criteria for cardiac imaging, including high stability, high binding, no toxicity, fast renal clearance and excellent biodistribution in rat models. The uptake of [18F]ANP-Cin was significantly higher on the 1st and 3rd day than the 7th or 28th day after MI induction, a timeframe associated with increased cardiomyocyte apoptosis. Higher uptake of [18F]ANP-Cin was observed in MI rats than in N-acetylcysteine (NAC)-treated rats on the 3rd days. In contrast with [18F]ANP-Cin, no hot-spots was observed with [18F]ANP-RGD2 on the 1st day and more hot-spots was observed from the 3rd day to the 7th day, then less on the 28th days in the high apoptotic site. There was no uptake of [18F]FDG in or around the apoptotic region. On the 7th day the uptake of [18F]ANP-RGD2 was higher in NAC-treated rats than MI rats. [18F]ANP-Cin and [18F]ANP-RGD2 are superior to [18F]FDG for PET/CT imaging for evaluation of cardiomyocyte apoptosis and tissue repair processes in the MI rats.

Background & aims Mothers against decapentaplegic homolog 7 (SMAD7) is an antagonist of the transforming growth factor β (TGF-β) signaling. In the present investigation, we sought to determine the relevance of SMAD7 in liver carcinogenesis using in vitro and in vivo approaches. Approach & results We found that SMAD7 is upregulated in a subset of human hepatocellular carcinoma (HCC) samples with poor prognosis. Gene set enrichment analysis (GSEA) revealed that SMAD7 expression correlates with activated YAP/NOTCH pathway and cholangiocellular signature genes in HCCs. These findings were substantiated in human HCC cell lines. In vivo, overexpression of Smad7 alone was unable to initiate HCC development, but it significantly accelerated c-Myc/MCL1 induced mouse HCC formation. Consistent with human HCC data, c-Myc/MCL1/Smad7 liver tumors exhibited an increased cholangiocellular gene expression along with Yap/Notch activation and epithelial-mesenchymal transition (EMT). Intriguingly, blocking of the Notch signaling did not affect c-Myc/MCL1/Smad7-induced hepatocarcinogenesis while preventing cholangiocellular signature expression and EMT, whereas ablation of Yap abolished c-Myc/MCL1/Smad7-driven HCC formation. In mice overexpressing a myristoylated/activated form of AKT, co-expression of SMAD7 accelerated carcinogenesis and switched the phenotype from HCC to intrahepatic cholangiocarcinoma (iCCA) lesions. In human iCCA, SMAD7 expression was robustly upregulated, especially in the most aggressive tumors and directly correlated with the levels of YAP/NOTCH targets as well as cholangiocellular and EMT markers. Conclusions The present data indicate that SMAD7 contributes to liver carcinogenesis by activating the YAP/NOTCH signaling cascade and by inducing a cholangiocellular and EMT signature.

Accumulating evidence has suggested that long noncoding RNAs (lncRNAs) exert crucial modulation roles in the biological behaviors of multiple malignancies. Nonetheless, the specific function of lncRNA LINC00284 in papillary thyroid cancer (PTC) remains not fully understood. The objective of this research was to explore the influence of LINC00284 in PTC and elucidate its potential mechanism. The Cancer Genome Atlas (TCGA), gene expression omnibus (GEO) datasets were used to analyze LINC00284 expression differences in thyroid cancer and normal samples, followed by the verification of qRT-PCR in our own PTC and adjacent non-tumor tissues. The impacts of LINC00284 on PTC cell growth were detected in vitro via CCK-8, colony formation, EdU assays, and in vivo via a xenograft tumor model. Bioinformatics analyses and biological experiments were conducted to illuminate the molecular mechanism. We found that LINC00284 expression was remarkably increased in PTC tissues and its overexpression was closely correlated with larger tumor size. In addition, silencing LINC00284 could effectively attenuate PTC cell proliferation, induce apoptosis and G1 arrest in vitro, as well as suppress tumorigenesis in mouse xenografts. Mechanistic investigations showed that LINC00284 acted as a competing endogenous RNA (ceRNA) for miR-3127-5p, thus resulting in the disinhibition of its endogenous target E2F7. In short, our findings indicated that LINC00284–miR-3127-5p–E2F7 axis exerted oncogenic properties in PTC and may offer a new promising target for the diagnosis and therapy of PTC.

Background Although programmed cell death‐ligand 1 (PD‐L1) plays a well‐known function in immune checkpoint response by interacting with programmed cell death‐1 (PD‐1), the cell‐intrinsic role of PD‐L1 in tumors is still unclear. Here, we explored the molecular regulatory mechanism of PD‐L1 in the progression and metastasis of ovarian cancer. Methods Immunohistochemistry of benign tissues and ovarian cancer samples was performed, followed by migration, invasion, and angiogenesis assays in PD‐L1‐knockdown ovarian cancer cells. Immunoprecipitation, mass spectrometry, and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD‐L1 in ovarian cancer. Results Our results showed that PD‐L1 induced angiogenesis, which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer. Mechanistically, PD‐L1 was identified to directly interact with vascular endothelial growth factor receptor‐2 (VEGFR2) and then activated the FAK/AKT pathway, which further induced angiogenesis and tumor progression, leading to poor prognosis of ovarian cancer patients. Meanwhile, PD‐L1 was found to be regulated by the oncogenic transcription factor c‐JUN at the transcriptional level, which enhanced the expression of PD‐L1 in ovarian cancer. Furthermore, we demonstrated that PD‐L1 inhibitor durvalumab, combined with the antiangiogenic drug, apatinib, could enhance the effect of anti‐angiogenesis and the inhibition of cell migration and invasion. Conclusion Our results demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, suggesting that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients., This manuscript demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, and suggested that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.

Mycobacterium tuberculosis, the pathogen that causes tuberculosis, exhibits complex host–pathogen interactions. Pattern recognition receptors and their downstream signaling pathways play crucial roles in determining the outcome of infection. In particular, the scaffold protein β-arrestin 2 mediates downstream signaling of G protein–coupled receptors. However, the role of β-arrestin 2 in conferring immunity against M. tuberculosis has not yet been explored. We found that β-arrestin 2 was upregulated in the lesioned regions of lung tissues in patients with tuberculosis. M. tuberculosis infection upregulated β-arrestin 2 expression in human macrophages, and silencing of β-arrestin 2 significantly enhanced bactericidal activity by enhancing the expression of proinflammatory cytokines such as TNF-α. β-Arrestin 2 was shown to inhibit the activation of the TLR2/ERK1/2 pathway and its transcriptional regulation activity upon M. tuberculosis infection. Furthermore, β-arrestin 2 transcriptionally regulates TNF-α by binding to CREB1. These observations revealed that the upregulation of β-arrestin 2 is critical for M. tuberculosis to escape immune surveillance through an unknown mechanism. Our research offers a novel interference modality to enhance the immune response against tuberculosis by targeting β-arrestin 2 to modulate the TLR2–β-arrestin 2–ERK1/2–CREB1–TNF-α regulatory axis.

This article uses amplitude integration of electroencephalogram integration to detect the development of the nervous system of late perform infants, and to study its changes, using a stratified randomized controlled trial method. The preform infants in the neonatal department of postnatal birth had the research object. The sample size was calculated, according to the first set of tires into small gestational age groups, and gestational age large. The subjects of each group were randomly divided into small gestational age groups, small gestational age intervention groups, large gestational age groups and large gestational age intervention groups. Two preterm children increased with age growth. The performance of the broadband and narrowband sector decreased voltage need the voltage lower bound ofa growing trend to the voltage difference becomes smaller. Oral exercise intervention is safe and effective for premature infants over 30 weeks old and can be used clinically as a neuroprotective strategy.

Single-molecule localization microscopy (SMLM) relies on the blinking behavior of a fluorophore, which is the stochastic switching between fluorescent and dark states. Blinking creates multiple localizations belonging to the same fluorophore, confounding quantitative analyses and interpretations. Here we present a method, termed distance distribution correction (DDC), to eliminate blinking-caused repeat localizations without any additional calibrations. The approach relies on obtaining the true pairwise distance distribution of different fluorophores naturally from the imaging sequence by using distances between localizations separated by a time much longer than the average fluorescence survival time. We show that, using the true pairwise distribution, we can define and maximize the likelihood, obtaining a set of localizations void of blinking artifacts. DDC results in drastic improvements in obtaining the closest estimate of the true spatial organization and number of fluorescent emitters in a wide range of applications, enabling accurate reconstruction and quantification of SMLM images. Distance distribution correction (DDC) eliminates repeat localizations caused by fluorophore blinking without the need for calibrations. Use of DDC yields accurate and quantifiable single-molecule localization microscopy data.

Autophagy, a process for self-degradation of intracellular components and dysfunctional organelles, is closely related with neurodegenerative diseases. It has been shown that cadmium (Cd) induces neurotoxicity partly by impairing autophagy. However, the underlying mechanism is not fully elucidated. In this study, we show that Cd induced expansion of autophagosomes with a concomitant abnormal expression of autophagy-related (Atg) proteins in PC12 cells and primary murine neurons. 3-MA, a classical inhibitor of autophagy, attenuated Cd-induced expansion of autophagosomes and apoptosis in the cells. Further investigation demonstrated that Cd activated JNK pathway contributing to autophagosome expansion-dependent neuronal apoptosis. This is supported by the findings that pharmacological inhibition of JNK with SP600125 or expression of dominant negative c-Jun markedly attenuated Cd-induced expansion of autophagosomes and abnormal expression of Atg proteins, as well as apoptosis in PC12 cells and/or primary neurons. Furthermore, we noticed that chelating intracellular free Ca2+ ([Ca2+]i) with BAPTA/AM profoundly blocked Cd-elicited activation of JNK pathway and consequential expansion of autophagosomes, abnormal expression of Atg proteins, and apoptosis in the neuronal cells. Similar events were also seen following prevention of [Ca2+]i elevation with EGTA or 2-APB, implying a Ca2+-dependent mechanism involved. Taken together, the results indicate that Cd impairs autophagy leading to apoptosis by Ca2+-dependent activation of JNK signaling pathway in neuronal cells. Our findings highlight that manipulation of intracellular Ca2+ level and/or JNK activity to ameliorate autophagy may be a promising intervention against Cd-induced neurotoxicity and neurodegeneration.

Paclitaxel (PTX) is a first-line chemotherapeutic drug for breast cancer, but PTX resistance often occurs in metastatic breast cancer. In addition, due to the poor targeting of chemotherapeutic drugs and the presence of the blood-brain barrier (BBB), it is hard to effectively treat brain metastatic breast cancer using paclitaxel. Thus, it is urgent to develop an effective drug delivery system for the treatment of brain metastatic breast cancer. The current study found that TWF1 gene, an epithelial-mesenchymal transition-associated gene, was overexpressed in brain metastatic breast cancer (231-BR) cells and was associated with the PTX resistance of 231-BR cells. Knockdown of TWF1 by small interference RNA (siRNA) in 231-BR cells could effectively increase the sensitivity of brain metastatic breast cancer cells to paclitaxel. Then, a liposome-based drug delivery system was developed for PTX delivery across BBB, enhancing PTX sensitivity and brain metastases targeting via BRBP1 peptide modification. The results showed that BRBP1-modified liposomes could effectively cross the BBB, specifically accumulate in brain metastases, and effectively interfere TWF1 gene expression in vitro and in vivo, and thus they enhanced proliferation inhibition, cell cycle arrest, and apoptosis induction, thereby inhibiting the formation and growth of brain metastases. In summary, our results indicated that BRBP1-modified and PTX- and TWF1 siRNA-loaded liposomes have the potential for the treatment of brain metastatic breast cancer, which lays the foundation for the development of a new targeted drug delivery system.

Introduction This retrospective study investigated the factors and the effects of different venous outflows on forearm arteriovenous graft patency. Methods The venous outflow sites included basilic, cephalic, median antecubital, and deep veins. Comparisons among multiple groups were analyzed. Findings A total of 179 patients with forearm loop arteriovenous grafts met the inclusion criteria. Of these, 72 were basilic, 48 were cephalic, 44 were median antecubital, and 15 were deep. The median observation period was 19 months. The survival rate was 84.9% at 24 months and 78.2% at 48 months. Primary, secondary, and assisted primary patency rates for all arteriovenous grafts were 48.9%, 72.4%, and 68.4% at 12 months; 13.8%, 33.9%, and 23.6% at 24 months; and 0.6%, 4.6%, and 2.3% at 48 months, respectively. Differences in primary patency were statistically significant compared with those of secondary and assisted primary patency ( P < 0.05). Primary patency rates for cephalic, median antecubital, basilic, and deep were 47.9%, 48.6%, 47.7%, and 40.0% at 12 months and 12.5%, 13.9%, 22.7%, and 0% at 24 months, respectively. Secondary patency rates for cephalic, median antecubital, basilic, and deep were 75.0%, 69.4%, 75.0%, and 73.3% at 12 months and 39.6%, 30.6%, 38.6%, and 13.3% at 24 months, respectively. There was no significant difference in primary thrombosis among basilic, cephalic, median antecubital and deep. There were no significant differences observed in primary or secondary patency rates among all the groups. Stenoses in the venous anastomosis and outflow vein were frequently observed in all types of arteriovenous grafts. Central venous stenosis was most commonly seen in deep (26.67%). On average, 1.9 interventions per patient were performed on the graft to maintain function. Conclusion Different venous outflow selections were not associated with long-term patency and the occurrence of thrombosis in hemodialysis forearm loop arteriovenous grafts.

Objective To explore the effect of locating the ulnar nerve compression sites and guiding the small incision so as to decompress the ulnar nerve in situ on the elbow by high‐frequency ultrasound before operation. Methods A retrospective analysis was conducted on 56 patients who underwent ultrasound‐assisted in situ decompression for cubital tunnel syndrome from May 2018 to August 2019. The patients' average age was 51.13 ± 7.35 years, mean duration of symptoms was 6.51 ± 1.96 months, and mean postoperative follow‐up was 6.07 ± 0.82 months. Nine patients had Dellon's stage mild, 39 had stage moderate, and eight had stage severe. Ultrasound and electromyography were completed in all patients before operation. The presence of ulnar nerve compressive lesion, the specific location, and the reason and extent of compression were determined by ultrasound. A small incision in situ surgery was given to decompress the ulnar nerve according to the pre‐defined compressive sites. Results All patients underwent in situ decompression. The compression sites around the elbow were as follows: two in the arcade of Struthers, one in the medial intermuscular septum, four in the anconeus epitrochlearis muscle, five beside the cyst of the proximal flexor carpi ulnaris (FCU), and the remaining 44 cases were all from the compression between Osborne's ligament to the two heads of the FCU. The compression localizations diagnosed by ultrasound were confirmed by operations. Preoperative ultrasound confirmed no ulnar nerve subluxation in all cases. The postoperative outcomes were satisfactory. There was no recurrence or aggravation of symptoms in this group of patients according to the modified Bishop scoring system; results showed that 43 cases were excellent, 10 were good, and three were fair. Conclusions High‐frequency ultrasound can accurately and comprehensively evaluate the ulnar nerve compression and the surrounding tissues, thus providing significant guidance for the precise minimally invasive treatment of ulnar nerve compression., The ulnar nerve became thinner at the site of Osborne's ligament in the longitudinal section. The accurate site of ulnar nerve compression could be located by high‐frequency ultrasound, that is the important foundation for the precise in situ ulnar nerve decompression.

Background and aims: Alcoholic fatty liver (AFL) is an early form of alcoholic liver disease (ALD) that usually manifests as lipid synthesis abnormalities in hepatocytes. β-arrestin2 (Arrb2) is involved in multiple biological processes. The present study aimed to explore the role of Arrb2 in the regulation of lipid metabolism in AFL and the underlying mechanism and identify potential targets for the treatment of AFL. Methods: The expression of Arrb2 was detected in liver tissues obtained from AFL patients and Gao-binge AFL model mice. In addition, we specifically knocked down Arrb2 in AFL mouse liver in vivo and used Arrb2-siRNA or pEX3-Arrb2 to silence or overexpress Arrb2 in AML-12 cells in vitro to explore the functional role and underlying regulatory mechanism of Arrb2 in AFL. Finally, we investigated whether Arrb2 could cause changes in hepatic lipid metabolites, thereby leading to dysregulation of lipid metabolism based on liquid chromatography-mass spectrometry (LC-MS) analysis. Results: Arrb2 was up-regulated in the livers of AFL patients and AFL mice. The in vivo and in vitro results confirmed that Arrb2 could induce lipid accumulation and metabolism disorders. Mechanistically, Arrb2 induced hepatic metabolism disorder via AMP-activated protein kinase (AMPK) pathway. The results of LC-MS analysis revealed that hepatic lipid metabolites with the most significant differences were primary bile acids. Conclusions: Arrb2 induces hepatic lipid metabolism disorders via AMPK pathway in AFL. On one hand, Arrb2 increases fatty acid synthesis. On the other hand, Arrb2 could increase the cholesterol synthesis, thereby leading to the up-regulation of primary bile acid levels.

Gametogenesis is one of the most extreme cellular differentiation processes that takes place in Drosophila male and female germlines. This process begins at the germline stem cell, which undergoes asymmetric cell division (ACD) to produce a self-renewed daughter that preserves its stemness and a differentiating daughter cell that undergoes epigenetic and genomic changes to eventually produce haploid gametes. Research in molecular genetics and cellular biology are beginning to take advantage of the continually advancing genomic tools to understand: (1) how germ cells are able to maintain their identity throughout the adult reproductive lifetime, and (2) undergo differentiation in a balanced manner. In this review, we focus on the epigenetic mechanisms that address these two questions through their regulation of germline-soma communication to ensure germline stem cell identity and activity.

Background: Eosinophilic esophagitis (EoE) is an immune-mediated clinicopathological condition characterized by esophageal infiltration with eosinophils resulting in chronic inflammation and stricture. Summary: The recent increase in the incidence of EoE and the characteristic presentation of symptoms with difficulty swallowing and food bolus impaction has raised key concerns of clinicians as well as researchers. EoE often presents with dysphagia, food impaction, nausea, regurgitation or vomiting, and decreased appetite. It is more common in males, affecting both adults and children. The causative manner of this condition is complex and multifactorial. Throughout recent years, researchers have made a significant contribution to understanding the pathogenesis of EoE, genetic background, natural history, work on allergy, and standardization in the evaluation of disease activity. There is relatively high prevalence of EoE among the population, emphasizing the importance of this disease. Key messages: Esophageal involvement with eosinophils may be manifested as isolated or with coexisting conditions and should be taken into consideration in the differential diagnosis. This study aimed to provide gastroenterologists with novel insights into the evaluation of esophageal involvement with eosinophils and to pay special attention to the etiological factors, coexisting clinical diseases, and complications.

Aim: To understand the pathological progress of COVID-19 and to explore the potential biomarkers. Background: The COVID-19 pandemic is ongoing. There is metabolomics research about COVID-19 indicating the rich information of metabolomics is worthy of further data mining. Methods: We applied bioinformatics technology to reanalyze the published metabolomics data of COVID-19. Results: Benzoate, β-alanine and 4-chlorobenzoic acid were first reported to be used as potential biomarkers to distinguish COVID-19 patients from healthy individuals; taurochenodeoxycholic acid 3-sulfate, glucuronate and N,N,N-trimethyl-alanylproline betaine TMAP are the top classifiers in the receiver operating characteristic curve of COVID-severe and COVID-nonsevere patients. Conclusion: These unique metabolites suggest an underlying immunoregulatory treatment strategy for COVID-19.

Objectives We examined the expression, distribution, and contribution to vasodilatation of the calcium-activated potassium (KCa) channel family in the commonly used coronary artery bypass graft internal thoracic artery (ITA) and saphenous vein (SV) to understand the role of large conductance KCa (BKCa), intermediate-conductance KCa (IKCa), and small-conductance KCa (SKCa) channel subtypes in graft dilating properties determined by endothelium-smooth muscle interaction that is essential to the postoperative performance of the graft. Methods Real-time polymerase chain reaction and western blot were employed to detect the messenger RNA and protein level of KCa channel subtypes. Distribution of KCa channel subtypes was examined by immunohistochemistry. KCa subtype-mediated vasorelaxation was studied using wire myography. Results Both ITA and SV express all KCa channel subtypes with each subtype distributed in both endothelium and smooth muscle. ITA and SV do not differ in the overall expression level of each KCa channel subtype, corresponding to comparable relaxant responses to respective subtype activators. In ITA, BKCa is more abundantly expressed in smooth muscle than in endothelium, whereas SKCa exhibits more abundance in the endothelium. In comparison, SV shows even distribution of KCa channel subtypes in the 2 layers. The BKCa subtype in the KCa family plays a significant role in vasodilatation of ITA, whereas its contribution in SV is quite limited. Conclusions KCa family is abundantly expressed in ITA and SV. There are differences between these 2 grafts in the abundance of KCa channel subtypes in the endothelium and the smooth muscle. The significance of the BKCa subtype in vasodilatation of ITA may suggest the potential of development of BKCa modulators for the prevention and treatment of ITA spasm during/after coronary artery bypass graft surgery.

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.

Background Distinguishing anorectal malignant melanoma from low rectal cancer remains challenging because of the overlap of clinical symptoms and imaging findings. We aim to investigate whether combining quantitative and qualitative magnetic resonance imaging (MRI) features could differentiate anorectal malignant melanoma from low rectal cancer. Methods Thirty-seven anorectal malignant melanoma and 98 low rectal cancer patients who underwent pre-operative rectal MRI from three hospitals were retrospectively enrolled. All patients were divided into the primary cohort (N = 84) and validation cohort (N = 51). Quantitative image analysis was performed on T1-weighted (T1WI), T2-weighted (T2WI), and contrast-enhanced T1-weighted imaging (CE-T1WI). The subjective qualitative MRI findings were evaluated by two radiologists in consensus. Multivariable analysis was performed using stepwise logistic regression. The discrimination performance was assessed by the area under the receiver operating characteristic curve (AUC) with a 95% confidence interval (CI). Results The skewness derived from T2WI (T2WI-skewness) showed the best discrimination performance among the entire quantitative image features for differentiating anorectal malignant melanoma from low rectal cancer (primary cohort: AUC = 0.852, 95% CI 0.788–0.916; validation cohort: 0.730, 0.645–0.815). Multivariable analysis indicated that T2WI-skewness and the signal intensity of T1WI were independent factors, and incorporating both factors achieved good discrimination performance in two cohorts (primary cohort: AUC = 0.913, 95% CI 0.868–0.958; validation cohort: 0.902, 0.844–0.960). Conclusions Incorporating T2WI-skewness and the signal intensity of T1WI achieved good performance for differentiating anorectal malignant melanoma from low rectal cancer. The quantitative image analysis helps improve diagnostic accuracy.

Ecological processes (e.g., nutrient cycling) in riparian zones are often affected by land-use type and flooding. The extent to which land-use types and flooding conditions affect soil microorganisms and their ecological functions in riparian zones is not well known. By using high-throughput sequencing and quantitative PCR (q-PCR), we tested the effects of three land-use types (i.e., forest, wetland, and grassland) and two flooding conditions (i.e., landward locations and waterward locations within the land-use types) on soil microbial communities and microbial functional genes in the riparian zones of a reservoir. Land-use type but not flooding significantly affected soil microbial community composition at the phylum level, while both land-use type and flooding significantly affected the orders Nitrosotaleales and Nitrososphaerales. Alpha diversity was higher in the wetland and forest regardless of flooding conditions. Functional gene abundance differed among the three land-use types. Archaeal amoA (AOA) and nirS genes were more abundant in the wetland than in the grassland or forest. Bacterial amoA (AOB), nirK, nirS, and nosZ genes were more abundant in the waterward location than in the landward location but only in the wetland. Soil pH, moisture, and concentrations of soil organic matter and total soil nitrogen were significantly associated with the composition of archaeal and bacterial communities as well as with their gene abundance. This study revealed that soil microorganisms putatively involved in nitrogen cycling in riparian zones were more affected by land-use type than flooding.

Objective To determine the feasibility of endoscopic thyroidectomy with level Vb dissection using a chest-breast approach. Methods Lateral neck level Vb dissection by endoscopic surgery using a chest-breast approach was performed as an update to the previously reported endoscopic selective lateral neck dissection. The demographic data, surgical outcomes, and adverse events were analyzed. Results A total of 12 cases were performed successfully, and no patient was converted to the open procedure. The sex ratio was 16/2 (female/male). The average age and primary lesion diameter were 36.3±5.8 years old, and 1.97±0.58 cm, respectively. The average total and lateral lymph nodes dissection time of duration was 154.6±17.0 and 276.3±19.2 minutes, respectively. The lymph node ratio (mean number of metastasis/total number of dissected nodes) at levels II, III+IV, VI, and Vb were 1.6±1.4/6.8±2.0, 5.8±2.4/14.4±3.6, 3.2±1.1/6.5±1.9, and 0.8±0.9/5.8±1.6, respectively. One of 12 patients had lymphatic leakage and 2 of 12 patients had transient hypocalcemia. There was no incidence of uncontrolled bleeding, mental nerve injury, permanent hypoparathyroidism, permanent recurrent laryngeal nerve injury, skin bruise on neck, infection, asphyxia/dyspnea, large blood vessel injury or other complications like tracheal injury, esophageal injury, etc., nor was there any death or recurrence in either of the 2 groups during a short follow-up period. Conclusions It is feasible to perform endoscopic thyroidectomy with level Vb dissection using a chest-breast approach. Such strategy represents another option for selective papillary thyroid carcinoma patients with levels II, III, IV, and Vb lymph node metastasis.

Background The prevalence of preterm birth in Bangladesh is estimated to be 19.1%, the highest in the world. Although prenatal exposure to several metals has been linked with preterm birth, fewer prospective studies have investigated the socioeconomic factors that affect metal exposure, leading to preterm birth risk. Objective We aim to identify novel metal biomarkers and their critical exposure windows, as well as the upstream socioeconomic risk factors for preterm birth in rural Bangladeshi, to shed light for future interventional strategies. Methods This study included data from 780 mother–offspring pairs, who were recruited to participate in a prospective birth cohort in Bangladesh (2008–2011). Serum concentrations of 19 metals were measured in the first and second trimesters using inductively coupled plasma mass spectrometry. Mediation analysis was performed to explore the upstream socioeconomic factors that affect the risk of preterm birth mediated via metal exposure concentrations. Results Early pregnancy exposure to serum zinc, arsenic, and strontium and mid-pregnancy exposure to barium were significantly associated with risk of preterm birth. Furthermore, younger marriage age was associated with an exponential increase in the risk of preterm birth, and women who married after 18 years old had a considerably lower risk of preterm birth. Mediation analysis indicated that these four elements mediated 30.2% of the effect of marriage age on preterm birth. Conclusion This study indicated that maternal serum metal exposure mediates the impact of child marriage on the increased risk of preterm birth via metal exposures. The findings shed light on the mechanisms underlying such association and provide insights into future interventional strategies.

BACKGROUND Colorectal cancer (CRC) is common in elderly patients. Mismatch repair (MMR) protein deletion is one of the causes of CRC. The RAS (KRAS/NRAS), BRAF, and PIK3CA genes are important gene targets in CRC treatment and are closely related to the prognosis and survival of patients. However, little is known regarding the relationship between the expression of MMR, RAS, BRAF, PIK3CA and the clinicopathological features in CRC patients. AIM To analyze the relationship between the expression of MMR, RAS, BRAF, PIK3CA and the clinicopathological features in CRC. METHODS A total of 327 elderly patients with CRC were enrolled, and immuno-histochemistry was used to detect the MMR protein. Real-time quantitative polymerase chain reaction was used to detect the RAS (KRAS/NRAS), BRAF, and PIK3CA genes. The clinicopathological data of the patients were recorded and analyzed by SPSS 19.0 statistical software. RESULTS In 327 elderly patients with CRC, the rate of MMR protein loss was 9.79% (32/327), and the deletion rate of four MMR proteins (MSH2, MSH6, MLH1, PMS2) was 1.83% (6/327), 3.06% (10/327), 7.65% (25/327), and 7.65% (25/327), respectively. There were no significant differences between MMR protein deletion and sex, pathological type, tumor morphology, differentiation degree or lymph node metastasis (P > 0.05), but there was a significant difference between MMR protein deletion and tumor diameter and tumor location (P = 0.048/P = 0.000). The mutation rates of the KRAS, NRAS, BRAF and PIK3CA genes in elderly CRC patients were 44.95% (147/327), 2.45% (8/327), 3.36% (11/327) and 2.75% (9/327), respectively; the KRAS gene mutation was closely related to tumor morphology (P = 0.002) but not to other clinicopathological features (P > 0.05), and there were no significant differences between NRAS gene mutation and clinicopathological features (P > 0.05). The BRAF gene mutation showed a significant difference in pathological type, tumor location, differentiation degree and lymph node metastasis (P < 0.05), but was not correlated with sex, tumor size and tumor morphology (P > 0.05). The PIK3CA gene mutation showed no significant differences in the above clinicopathological characteristics (P > 0.05). Significant differences were observed between MMR protein deletion and KRAS, BRAF, and PIK3CA gene mutations in elderly CRC patients (P = 0.044, P = 0.000, P = 0.003, respectively), but there was no significant difference between MMR protein deletion and NRAS mutation (P > 0.05). CONCLUSION In elderly CRC patients, the tumor is mainly located in the right colon, and the deletion rate of MMR protein is higher when the tumor diameter is greater than or equal to 5 cm; the deletion rate of MLH1 and PMS2 is more common; the mutation rate of KRAS gene is higher than that of the NRAS, BRAF and PIK3CA genes, the BRAF gene mutation has different degrees of correlation with clinicopathological characteristics; when the MMR protein is deleted, the BRAF and PIK3CA gene mutations are often present, and the KRAS gene mutation rate is low.

Background Animal studies suggested that vitamin D might decrease insulin resistance. Estrogen increased insulin sensitivity and glucose tolerance in rodents. However, sex-specific association of vitamin D with insulin resistance in humans remains unclear. Objectives To investigate the sex-dependency of the association of insulin resistance and 25-hydroxyvitamin D [25(OH)D] in a large Caucasian population. Methods Cross-sectional study from out-patients’ blood samples with measurements of 25(OH)D and homeostatic model assessment of insulin resistance (HOMA-IR) drawn at exactly the same day (n = 1887). This cohort was divided into 3 groups: (1) group with vitamin D deficiency (n = 1190), (2) group with vitamin D sufficiency (n = 686), and (3) vitamin D excess groups (n = 11); the vitamin D excess group was excluded from further analysis due to the small size. Results Analysis of the entire study population showed that serum 25(OH)D was inversely associated with HOMA-IR [Spearman correlation coefficient (rs) = −0.19, P Conclusion Vitamin D was inversely and independently associated with insulin resistance only in women with vitamin D deficiency. Based on our data, we suggest that in particular vitamin D deficient women might benefit from vitamin D substitution by improving insulin resistance. This, however, needs to be proven in adequately designed double-blind placebo-controlled clinical studies.

Psoriasis is an autoimmune inflammatory disease, where dendritic cells (DCs) play an important role in its pathogenesis. In our previous work, we have demonstrated that topical delivery of curcumin-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) could treat Imiquimod (IMQ)-induced psoriasis-like mice. The objective of this study is to further elucidate biofate of PLGA NPs after intradermal delivery including DCs uptake, and their further trafficking in psoriasis-like mice model by using fluorescence probes. Two-sized DiO/DiI-loaded PLGA NPs of 50 ± 4.9 nm (S-NPs) and 226 ± 7.8 nm (L-NPs) were fabricated, respectively. In vitro cellular uptake results showed that NPs could be internalized into DCs with intact form, and DCs preferred to uptake larger NPs. Consistently, in vivo study showed that L-NPs were more captured by DCs and NPs were firstly transported to skin-draining lymph nodes (SDLN), then to spleens after 8 h injection, whereas more S-NPs were transported into SDLN and spleens. Moreover, FRET imaging showed more structurally intact L-NPs distributed in skins and lymph nodes. In conclusion, particle size can affect the uptake and trafficking of NPs by DCs in skin and lymphoid system, which needs to be considered in NPs tailing to treat inflammatory skin disease like psoriasis.

Cardiac conduction regulatory RNA (CCRR) is down‐regulated in the pathogenesis of heart failure (HF), which accordingly suppresses cardiac conduction while promoting arrhythmogenicity. Meanwhile, CX43 was reported to play a role in the pathogenesis of metastatic breast cancer and melanoma brain colonization. In this study, we studied the role of long non‐coding RNA CCRR and its interaction with CX43 in brain metastasis of breast cancer. Breast cancer patients were grouped according to the metastasis status. Real‐time PCR and IHC assay were used to measure the expression of lncRNA‐CCRR and CX43 in patients. Western blot was conducted to observe the effect of lncRNA‐CCRR on the expression of CX43 in MDA‐MB‐231BR and BT‐474BR cells. Compared with the non‐metastasis group, the mRNA expression of tissue lncRNA‐CCRR, cerebrospinal fluid (CSF) lncRNA‐CCRR, tissue CX43 and tissue protein expression of CX43 were both evidently up‐regulated in metastasis patients, especially in patients with brain metastasis. The expression of lncRNA‐CCRR was positively correlated with the up‐regulated expression of CX43. Moreover, CX43 expression was significantly lower in MDA‐MB‐231WT cells compared with that in MDA‐MB‐231BR cells. Also, the overexpression of lncRNA‐CCRR evidently increased dye transfer rate from astrocytes to MDA‐MB‐231BR/BT‐474BR cells but reduced lncRNA‐CCRR expression and suppressed the transmigration of MDA‐MB‐231BR/BT‐474BR cells in a blood‐brain barrier (BBB) model. In this study, we demonstrated that the presence of lncRNA‐CCRR could up‐regulate the expression of CX43, which promoted gap junction formation in brain metastasis of breast cancer. Accordingly, the communication between breast cancer cells and astrocytes was also promoted.

Background Nanoparticles can improve the bioavailability of bioactive compounds. Concomitant intake of food can affect pharmacokinetic profiles by altering dissolution, absorption, metabolism, and elimination behavior. Studies on the effects of food and its supplements on the bioavailability of bioactives in nanoformulations are few. In this study, the effects of typical food (milk, sugar, high-fat diet, and regular kibble) and a widely consumed probiotic (Bifidobacterium lactis Bb-12®, Bb-12) on the bioavailability of curcumin in four formulations [simply suspended curcumin (Cur-SS) and curcumin in nanoemulsions (Cur-NE), single-walled carbon nanotubes (Cur-SWNT), and nanostructured lipid carriers (Cur-NLC)] were investigated. Results Fasting treatment and sugar co-ingestion can significantly enhance the bioavailability of curcumin in Cur-NE and Cur-SWNT, respectively. Compared with the fasting treatment, co-ingestion with regular kibble reduced the absorption of curcumin in Cur-NE and Cur-SWNT. Ingesting milk along with Cur-NE is also not recommended. The mechanisms behind these phenomena were briefly discussed. This study revealed for the first time that the intestinal colonization of Bb-12 reduces the bioavailability of curcumin and this reduction can be attenuated by nanoformulations SWNT and NLC, but not NE. The reason for this difference was the protective effects of the former two nanoformulations against curcumin degradation by Bb-12 according to in vitro experiments. Conclusion Dietary status (including supplementary probiotics) can dramatically influence the bioavailability of curcumin in nanoformulations. This article is protected by copyright. All rights reserved.