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BACKGROUND: FAS can serve as both an oncogene and a suppresser in different malignancies, and the prognostic value of FAS remains controversial. METHODS: The Oncomine database, KM-Plotter and bc-GenExMiner platform were adopted to analyze the prognostic value of FAS in breast cancer. Breast cancer tissue microarrays were further used to verify these data. The Cell Miner Tool was used to predict the value of FAS mRNA expression in predicting the efficacies of clinical drugs. RESULTS: We found that both FAS mRNA and protein expression level significantly reduced in breast carcinoma. In addition, high FAS expression indicates a better metastatic relapse-free survival. Interestingly, FAS was associated with a better prognosis in different subtypes of breast cancer patients, namely, only in grade II and III, lymph nodal positive or p53 wild-type patients. The data from the Cell Miner Tool revealed that FAS mRNA expression was correlated with the efficacy of the first-line chemotherapeutic taxane agents and target drugs including olaparib and everolimus. CONCLUSIONS: FAS expression correlates with a better prognosis in breast cancer and may provide an effective clinical strategy to predict the sensitivity of taxanes and targeted drugs.

Objective To verify the effect of Pilates training combined with biofeedback training, Kegel training combined with biofeedback training, and Kegel training alone on post-prostatectomy incontinence in male patients. Material and methods Forty-two patients were randomly divided into 3 groups. The changes occurring to the 3 groups before and after treatment and the differences between the 3 groups were assessed using a 1-hour pad test, number of incontinent episodes, the ICIQ questionnaire, and the Oxford Grading Scale. The 3 groups were required to undergo daily training for an 8-week period. Results At 8 weeks, groups A, B and C experienced a 34.3%, 61.9%, and 67% improvement in the 1-hour pad test, respectively, and 32.1%, 52.9%, and 58.8% reduction in the number of urinary incontinence episodes, respectively, and a 29.4%, 50%, and 64.7% reduction in the ICIQ Scale, respectively, and a 33.3%, 50%, and 50% in Oxford Grading Scale improvement, respectively. The graph results showed that the effect was noted after 3 weeks of treatment and a significant effect occurred by the eighth week of treatment. Conclusion Three methods were shown to optimize urinary continence and pelvic floor muscle strength of patients with post-prostatectomy incontinence. The treatment effect of group C was better than group B, but there was no statistically significant difference in the 1-hour pad tests. It is particularly important to understand the time sensitivity for patient training.

Abnormal neural activities can be revealed by resting-state functional magnetic resonance imaging using analyses of regional activity and functional connectivity of brain networks. This study was designed to demonstrate functional network alterations in patients with detrusor overactivity. In this study, we recruited 36 patients with tethered cord syndrome who had detrusor overactivity and 34 normal controls. We used regional homogeneity and seed-based functional connectivity computational methods to reveal resting-state brain activity features associated with patients. Compared with normal controls, patients with tethered cord syndrome showed regional abnormalities, mainly in the bilateral frontal cortex, anterior and midcingulate cortex, and temporal lobes. When these regions were defined as seeds, we demonstrated widespread modification in brain networks. The brain–bladder network was not positively connected with the cognitive control network. Both altered regional activity and changed functional connectivity were found in the brain–bladder network. Patients with NDO, activated areas in the frontal lobe and anterior cingulate gyrus decreased significantly and have fewer brain activation areas in the caudate nucleus and hypothalamus (limbic system). In functional connectivity work, we found a small positive correlation in different regions of frontal lobe. This study helped us better to understand the characteristics of neural network modifications in patients with tethered cord syndrome.

Homeobox D3 (HOXD3), a member of the homeobox family, was described to regulate tumorigenesis, invasion, metastasis, and angiogenesis in various tumor types. However, the molecular mechanisms regulating HOXD3 during hepatocellular carcinoma (HCC) migration, invasion, and angiogenesis remain elusive. In this study, we demonstrated that HOXD3 expression is enhanced by the binding of methyl‐CpG‐binding protein 2 (MeCP2), a methyl‐CpG binding protein, together with CREB1to the hypermethylated promoter of HOXD3. Inhibition of HOXD3 eliminated the tumorigenic effects of MeCP2 on HCC cells. Furthermore, HOXD3 directly targeted the promoter region of heparin‐binding epidermal growth factor (HB‐EGF) via the EGFR‐ERK1/2 cell signaling pathway and promoted invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. Additionally, elevated expression of MeCP2, CREB1, and HB‐EGF in HCC correlated with a poor survival rate. Our findings reveal the function of the MeCP2/HOXD3/HB‐EGF regulatory axis in HCC, rendering it an attractive candidate for the development of targeted therapeutics and as a potential biomarker in patients with HCC., Hepatocellular carcinoma (HCC) is considered the fifth most common cancer and a frequent cause of cancer‐related death. In our study, we observed that methyl‐CpG‐binding protein 2 (MeCP2) drives HCC progression by recruiting CREB1 and enforcing HOXD3 expression. Hypermethylation of the homeobox D3 (HOXD3) promoter via the heparin‐binding epidermal growth factor (HB‐EGF) signaling pathway induced invasion, migration, and angiogenesis of HCC. Our findings reveal the function of the MeCP2/HOXD3/HB‐EGF regulatory axis in HCC, rendering it an attractive candidate for the development of targeted therapeutics and as a potential biomarker in patients with HCC.

Gender may be related with the outcome of patients with acute traumatic brain injury. We explored the effect of gender on the outcome of 7145 patients with acute traumatic brain injury. There was no statistical difference between male and female in the causes of trauma, age, GCS score, CT findings, and surgical management. The mortality of patients with 7145 acute head trauma in male and female was 7.48% and 7.22% respectively with the corresponding unfavorable outcomes of 16.05% and 17.23% respectively (P>0.05 in both cases). The mortality of 1626 patients with severe traumatic brain injury in male and female was 19.68% and 20.72% respectively with the corresponding unfavorable outcomes of 46.96% and 48.85% respectively (P>0.05 in both cases). Our data suggest that gender does not play a role in the outcome of patients with acute traumatic brain injury.

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10 000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).

Long noncoding RNA (lncRNA) Cancer Susceptibility 2 (CASC2) has been proved to contribute to the development of cancers. However, the mechanism behind the action of CASC2 in thyroid cancer is not quite clear. We demonstrated that CASC2 was downregulated in thyroid cancer. We noted that CASC2 overexpression restrained the growth, migration, and invasion of thyroid cancer cells, whereas CASC2 depletion caused opposite trends. Bioinformatics analysis predicted that hypoxia inducible factor 1 subunit alpha inhibitor (FIH‐1) was potentially targeted by miR‐18a‐5p, which was confirmed by luciferase reporter assay. Upregulation of FIH‐1 abrogated the promotive effect of miR‐18a‐5p on the growth and invasion of thyroid cancer cells. In addition, CASC2 serves as a competing endogenous RNA (ceRNA) and a ''sponge'' for miR‐18a‐5p, thereby regulating the expression of FIH‐1. These data elucidated the CASC2/miR‐18a‐5p ceRNA network in thyroid cancer pathogenesis.

A functional magnetic resonance imaging (fMRI) study was performed during urodynamic examination in healthy adults to determine the responses of functional brain networks to bladder control during urine storage. The brain imaging was performed in empty and full bladder states during urodynamic examination. First, we used independent component analysis (ICA) to obtain several resting state network masks, then the brain regions with significantly different regional homogeneity (ReHo) values between the two states were determined using a paired t test (p

Background: Mechanism of castration-resistant prostate cancer (CRPC) is still unclear. Our objective is to investigate the association between genes expression and CRPC through the genome-wide approach and functional researches. Methods: Differentially expressed genes (DEGs) between PCa and CRPC tissues were identified using expression profile obtained from Gene Expression Omnibus database (GEO). Survival analysis was performed using online database Gene Expression Profiling Interactive Analysis (GEPIA). Oncomine database was further used to explore the relationship between DEGs expression levels with clinical parameters. After in silico study, SEC14L2-knockdown CRPC cells and normal prostatic epithelial cells were used for in vitro study to verify its biological functions. Results: A total of 3 consistently changed DEGs (SEC14L2, DMD, SEL1L) were identified correlating with CRPC after cross validation in three independent datasets. Low expression of SEC14L2 was associated with poorer disease-free survival and higher Gleason score than normal/high expression of SEC14L2. SEC14L2 knockdown promoted cell proliferation, migration, invasion as well as cell cycle progression in CRPC cells (all P

During a 2018 antimicrobial resistance surveillance of Escherichia coli isolates from diarrheal calves in Xinjiang Province, China, an unexpectedly high prevalence (48.5%) of fosfomycin resistance was observed. This study aimed to reveal the determinants of fosfomycin resistance and the underlying transmission mechanism. Polymerase chain reaction (PCR) screening showed that all fosfomycin-resistant E. coli carried the fosA3 gene. Pulsed-field gel electrophoresis (PFGE) and southern blot hybridization revealed that the 16 fosA3-positive isolates belonged to four different PFGE patterns (i.e., A, B, C, D). The fosA3 genes of 11 clonally related strains (pattern D) were located on the chromosome, while others were carried by plasmids. Whole-genome and long-read sequencing indicated that the pattern D strains were E. coli O101:H9-ST10, and the pattern C, B, and A strains were O101:H9-ST167, O8:H30-ST1431, and O101:H9 with unknown ST, respectively. Among the pattern C strains, the blaCTX-M-14 gene was co-localized with the fosA3 gene on the F18:A-:B1 plasmids. Interestingly, phylogenetic analysis based on core genome single nucleotide polymorphisms (cgSNPs) showed that the O101:H9-ST10 strains were closely related to a Australian-isolated Chroicocephalus-origin E. coli O101:H9-ST10 strain producing CTX-M-14 and FosA3, with a difference of only 11 SNPs. These results indicate possible international dissemination of the high-risk E. coli clone O101:H9-ST10 by migratory birds.

Computational histopathology is a fast emerging field which converts the traditional glass slide based department to a new examination platform. Such a paradigm shift also brings the in silico computation to the field. Much research have been presented in the past decades on the algorithm development for pathology image analysis. On the other hand, a comprehensive software platform with advanced visualization and computation capability, large developer community, flexible plugin mechanism, and friendly transnational license, would be extremely beneficial for the entire community. In this work, we present SlicerScope: an open platform for whole slide histopathology image computing based on the highly successful 3D Slicer. We present rationale on the choice of such an architecture, introducing new modules/tools for giga-pixel whole slide image viewing, and four specific analytical modules for qualitative presentation, nucleus level analysis, tissue scale computation, and 3D pathology. The entire software is publicly available at https://slicerscope.github.io/, facilitating the algorithmic, clinical, and transnational researches.

The hypoxic microenvironment was recognized as a major driving force of the malignant phenotype in hepatocellular carcinoma (HCC), which contributes to tumour immune microenvironment (TIM) remodeling and tumor progression. Dysregulated hypoxia-related genes (HRGs) result in treatment resistance and poor prognosis by reshaping tumor cellular activities and metabolism. Approaches to identify the relationship between hypoxia and tumor progression provided new sight for improving tumor treatment and prognosis. But, few practical tools, forecasting relationship between hypoxia, TIM, treatment sensitivity and prognosis in HCC were reported. Here, we pooled mRNA transcriptome and clinical pathology data from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), and later developed a hypoxia risk model including four HRGs (DCN, DDIT4, PRKCA and NDRG1). The high-risk group displayed poor clinical characteristics, a malignant phenotype with carcinogenesis/proliferation pathways activation (MTORC1 and E2F) and immunosuppressive TIM (decreased immune cell infiltrations and upregulated immunosuppressive cytokines). Meanwhile, activated B cells, effector memory CD8 T cells and EZH2 deregulation were associated with patient’s survival, which might be the core changes of HCC hypoxia. Finally, we validated the ability of the hypoxia risk model to predict treatment sensitivity and found high hypoxia risk patients had poor responses to HCC treatment, including surgical resection, Sorafenib, Transarterial Chemoembolization (TACE) and immunotherapy. In conclusion, based on 4 HRGs, we developed and validated a hypoxia risk model to reflect pathological features, evaluate TIM landscape, predict treatment sensitivity and compounds specific to hypoxia signatures in HCC patients.

Multi-organ segmentation from whole-body computed tomography (CT) scans has gained increasing research interest over recent years. While the learning-based segmentation algorithm has lately achieved tremendous success, the need for detailed annotation of multiple organs further increases the manual burden. With a limited number of annotated volumetric datasets, it would be beneficial to apply the trained model from such a set to CT images acquired from other sites with different scanners. Nevertheless, the discrepancy among training and testing images significantly deteriorates segmentation performance. While there are many domain adaptation efforts, in this work we proposed a filtered back-projection based algorithm for performing domain adaptation for CT imagery. An optimal CT reconstruction kernel was obtained by minimizing the disparity between two images. Furthermore, since the Gaussian kernel is an eigen-function of the Fourier transformation, the adaptation computation was proven to be simple linear filtering. The proposed method was tested and compared with multiple methods to demonstrate improvement by employing such a model/theory-based adaptation approach. The proposed method, used in conjunction with a common convolutional neural network, such as the U-Net or V-Net, with or without the domain adaptation, achieves high accuracy in a multiple-organ segmentation task. Approximately 30% of data was used for training, 70% was used for testing, and an average dice of 0.88 was achieved in 8 organs.

Several lines of evidence have demonstrated that programmed cell death 1 (PD-1) inhibitors as monotherapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer have little clinical activity. The underlying mechanisms remain not understood. In this study, using immunohistochemistry and in situ RT-PCR assays, we examined the expression of programmed cell death ligand 1 (PD-L1), PD-1, CD8, and interferon gamma (IFN-γ) in tumors. Both epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-positive tumors were associated with low or absent membrane PD-L1 expression. Interestingly, unlike EGFR-mutant tumors with few tumor-infiltrating CD8+ T cells, a significant number of PD-1-positive CD8+ T cells infiltrated the ALK-positive tumor bed; however, these cells did not express IFNG mRNA. These results demonstrate that the ALK-positive tumor microenvironment suppresses the immune function of tumor-infiltrating CD8+ T cells through a PD-1/PD-L1-independent mechanism, which might lead to the inability of ALK-positive tumors to respond to PD-1/PD-L1-based immunotherapy.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe disease characterized by immune hyperactivation and cytokine storm. Given the high mortality rate of HLH, there is a need for more effective diagnostic tools and treatments. The present study developed a dendrimer‑based protein biochip for rapid, sensitive and simultaneous detection of serum interferon (IFN)‑γ and endogenous anti‑IFN‑γ antibody (Ab) in patients with HLH. A gold biochip was modified with 1, 4‑phenylene diisothiocyanate (PDITC), polyamidoamine (PAMAM) or PDITC‑activated PAMAM. The optimal immobilization concentration for Ab capture and the reaction concentration for detecting Ab on the PDITC‑activated PAMAM‑modified biochip were 6.25 and 3.12 µg/ml, respectively; the limit of detection of IFN‑γ protein was 50 pg/ml. The efficiency of the protein‑probed biochip in detecting IFN‑γ and anti‑IFN‑γ Ab in serum samples from 77 patients with HLH was evaluated; the positive rates for IFN‑γ and anti‑IFN‑γ IgG Ab were 63.6% (49/77) and 61.0% (47/77), respectively. The present results demonstrated that the PDITC‑activated PAMAM‑modified biochip might be a sensitive tool for the specific detection of IFN‑γ and anti‑IFN‑γ Ab in serum, and might have clinical applicability for the diagnosis of HLH.

The compound eye in crustaceans is a main eye type in the animal kingdom, knowledge about the mechanism to determine the development of compound eye is very limited. Paired box protein 6 (Pax6) is generally regarded as a master regulator for eye development. In the present study, a genome-based analysis of the Pax6 gene in the ridge tail white prawn Exopalaemon carinicauda was performed and two members of Pax6 homologs, named Ec-Eyeless (EcEy) and Ec-Twin of eyeless (EcToy) were identified. To understand the function of these two homologs of Pax6 gene in the prawn, the CRISPR/Cas9 genome editing technique was applied to generate EcEy and EcToy knock-out (KO) prawns and their phenotypes were analyzed. The surviving EcEy-KO embryos and larvae exhibited severe abnormal eye morphology, suggesting that EcEy is necessary for the compound eye development in prawn, while no mutant phenotype was found in EcToy-KO individuals. These findings highlighted the conservative role of Pax6 gene in the compound eye formation, and the functional differentiation between EcEy and EcToy gene may reveal a novel regulating mechanism of Pax6 on the compound eye development in the decapods. These data will provide important information for understanding the regulation mechanism for crustacean compound eye development.

OBJECTIVEThe authors conducted a study to noninvasively and nonradioactively reveal moyamoya disease (MMD) intracerebral perfusion and perfusion territory supplied by the unilateral internal carotid artery (ICA) and external carotid artery (ECA) and bilateral vertebral arteries (VAs) before surgery and to further identify risk factors for preoperative hemorrhage in adult MMD.METHODSForty-three consecutive adult patients with bilateral MMD underwent unenhanced T1-weighted MRI, territorial arterial spin labeling (t-ASL), and unenhanced 3D time-of-flight MRA (3D-TOF-MRA). Clinical factors, including age, sex, hypertension, diabetes mellitus, hyperlipidemia, current smoking status, and history of taking aspirin, were gathered and stratified. Univariate logistic regression analyses were used to examine the relationship between various risk factors and the occurrence of preoperative hemorrhage. Stepwise multivariate logistic regression analyses were used to determine independent risk factors of preoperative hemorrhage in MMD.RESULTSAmong the 86 MMD hemispheres, t-ASL revealed 137 perfusion territory shifts in 79 hemispheres. Five distinct categories of perfusion territory shifts were observed on t-ASL maps. The subtypes of perfusion territory shift on t-ASL maps were further subdivided into 2 different categories, group A and group B, in combination with findings on 3D-TOF-MRA. A perfusion territory shift attributable solely to the secondary collaterals was a potential independent risk factor for preoperative hemorrhage (p = 0.026; 95% CI 1.201–18.615; OR 4.729). After eliminating the influence of the secondary collaterals, the primary collaterals had no significant effect on the risk of preoperative hemorrhage (p = 0.182).CONCLUSIONSt-ASL could reveal comprehensive MMD cerebral blood perfusion and the vivid perfusion territory shifts fed by the unilateral ICA and ECA and bilateral VAs in a noninvasive, straightforward, nonradioactive, and nonenhanced manner. 3D-TOF-MRA could subdivide t-ASL perfusion territory shifts according to their shunt arteries. A perfusion territory shift attributable to the secondary collaterals is a potential independent risk factor for preoperative hemorrhage in MMD patients. A perfusion territory shift fed by the primary collaterals may not have a strong effect on preoperative hemorrhage in MMD patients. These findings make the combined modalities of t-ASL and 3D-TOF-MRA a feasible tool for MMD disease assessment, management, and surgical strategy planning.

Purpose Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE2) possess tumor-promoting activity, and COX-2 is considered as a candidate for targeted cancer therapy. However, several randomized clinical trials using COX-2 inhibitors to treat advanced lung cancer have failed to improve survival indices. To employ a more effective therapeutic strategy to inhibit the COX-2-PGE2 axis in tumors, it is necessary to revisit the mechanism underlying the protumor effect of COX-2-PGE2. Patients and methods Immunohistochemistry was used to predict the expression and prognostic value of COX-2 in lung adenocarcinoma samples. The mRNAs or proteins expression of COX-2, pAKT1/2/3, pErk1/2 and pCREB were detected after different treatments by qPCR or Western blot. The impacts of PGE2 and some inhibitors on cell proliferation and migration ability were verified by CCK-8 and transwell assays, respectively. Results In this study, we first confirmed that COX-2 expression in tumor specimens is associated with the pathological stage of the disease. Next, using lung adenocarcinoma cell lines, we found that exogenous PGE2 induces the expression of COX-2 at the mRNA and protein levels. Moreover, downregulation of COX-2 expression restrained PGE2-induced cancer cell proliferation and migration. Mechanistic analysis revealed that PGE2 stimulation activates the PKA-CREB and PI3K-AKT pathways. Downregulation of CREB expression abrogated PGE2-induced COX-2 expression. Moreover, inhibition of PI3K-AKT signaling suppressed the activation of CREB and PGE2-induced COX-2 expression. Specific inhibitors for PI3K and AKT suppressed COX-2 mRNA expression in ex vivo cultures of tumor specimens with PGE2. Conclusion Simultaneous targeting of COX-2 and PI3K-AKT effectively suppressed PGE2-induced cell proliferation and migration and both acted in a synergistic manner. Targeting the COX-2-PGE2 positive feedback loop may be therapeutically beneficial to lung adenocarcinoma.

Purpose: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. Experimental Design: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine–recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort (n = 160). The four-CpG classifier was validated in the internal testing cohort (n = 68) and independent validation cohort (n = 321). Results: The four-CpG–based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk (P < 0.001). This classifier also showed good predictive value in the internal testing cohort (P < 0.001) and the independent validation cohort (P < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and NOTCH1/FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation. Conclusions: Our four-CpG–based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision.

Purpose To develop a radiogenomics classifier to assess anaplastic lymphoma kinase (ALK) gene rearrangement status in pretreated solid lung adenocarcinoma noninvasively. Materials and methods This study consisted of 140 consecutive pretreated solid lung adenocarcinoma patients with complete enhanced CT scans who were tested for both EGFR mutations and ALK status. Pre-contrast CT and standard post-contrast CT radiogenomics machine learning classifiers were designed as two separate classifiers. In each classifier, dataset was randomly split into training and independent testing group on a 7:3 ratio, accordingly subjected to a 5-fold cross-validation. After normalization, best feature subsets were selected by Pearson correlation coefficient (PCC) and analysis of variance (ANOVA) or recursive feature elimination (RFE), whereupon a radiomics classifier was built with support vector machine (SVM). The discriminating performance was assessed with the area under receiver-operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results In classifier one, 98 cases were selected as training data set, 42 cases as independent testing data set. In classifier two, 87 cases were selected as training data set, 37 cases as independent testing data set. Both classifiers extracted 851 radiomics features. The top 25 pre-contrast features and top 19 post-contrast features were selected to build optimal ALK+ radiogenomics classifiers accordingly. The accuracies, AUCs, sensitivity, specificity, PPV, and NPV of pre-contrast CT classifier were 78.57%, 80.10% (CI: 0.6538-0.9222), 71.43%, 82.14%, 66.67%, and 85.19%, respectively. Those results of standard post-contrast CT classifier were 81.08%, 82.85% (CI: 0.6630-0.9567), 76.92%, 83.33%, 71.43%, and 86.96%. Conclusion Solid lung adenocarcinoma ALK+ radiogenomics classifier of standard post-contrast CT radiomics biomarkers produced superior performance compared with that of pre-contrast one, suggesting that post-contrast CT radiomics should be recommended in the context of solid lung adenocarcinoma radiogenomics AI. Standard post-contrast CT machine learning radiogenomics classifier could help precisely identify solid adenocarcinoma ALK rearrangement status, which may act as a pragmatic and cost-efficient substitute for traditional invasive ALK status test.

Fluoride exposure may cause changes in blood pressure, but this conclusion is controversial. Therefore, this meta-analysis aims to investigate the potential relationship between fluoride exposure and blood pressure or hypertension. PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), WANFANG MED ONLINE, and Chinese Scientific Journals Full-Text Databases (VIP) were searched; in addition, two related studies were added manually. In total, 7 observational studies were identified, the pooled odds ratios (ORs) for hypertension between high and reference fluoride exposure groups were calculated, and the pooled standardized weighted mean difference (SMD) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using an inverse-variance weighted random-effects model; next, sensitivity analysis and subgroup analysis were used to assess potential sources of heterogeneity; furthermore, publication bias was assessed using the Begg and Egger test. In brief, there were no statistical differences between exposure groups and control groups in terms of blood pressure or hypertension when all included studies considered. However, subgroup analysis indicated that blood pressure will rise with the increase of fluoride exposure concentrations in endemic fluorosis areas. The corresponding pooled SMD estimates were 0.31 (95% CI 0.11, 0.51) and 0.27 (95% CI 0.11, 0.43) for SBP and DBP. Funnel plots suggested no asymmetry. Our findings support the possibility of a positive correlation between fluoride exposure and blood pressure in endemic fluorosis areas. Additional evidence is needed to assess the dose-response relationship between fluoride exposure and blood pressure.

Background. In the unplanned reoperation of colorectal cancer patients, computed tomography (CT) is increasingly utilized to locate postoperative complications and previously unlocalized lesions. The purpose of this study is to explore the application of CT in the mortality and complications of the reoperation of colorectal cancer. Patients and Methods. We performed a retrospective review of collected data from the colorectal surgeries of 90 identified colorectal cancer patients who received an unplanned reoperation from 2010 to 2018. Patients were stratified according to those with preoperative CT imaging (CT group, n=36) and those without preoperative CT imaging (NCT group, n=54). Twenty-four statistical indicators of each patient were studied, including their preoperative risk, surgical characteristics, and postoperative outcomes, and satisfaction was evaluated. All data were statistically analysed for predicting postoperative complications by univariate and multivariate logistic regression analyses. Results. Ninety patients received an unplanned reoperation in the study, and 40% (36/90) of these patients underwent preoperative CT examination. Patients’ risk factors were similar between CT and NCT groups. Preoperative imaging was more commonly performed for reoperative new anastomosis + ileostomy but less common for reoperative Dixon’s procedure. The operative duration of the NCT group was longer (139 vs. 104 min, respectively, P=0.01). Preoperative NCT examination (OR 1.24; 95% CI=1.09‐1.42; P=0.01) was an independent predictor of postoperative complications. Importantly, three patients died after an unplanned reoperation for colorectal cancer, which occurred only in the NCT group (5.6% vs. 0.0%, P=0.01). Conclusion. The use of conventional preoperative CT optimizes the choice of the surgical site and the strategy of laparotomy, so as to reduce the length of operation. Preoperative imaging evaluation should be performed for patients undergoing repeat abdominal surgery.

Background and purpose Increasing evidence has indicated that the high risk of cardiovascular disease in chronic kidney disease (CKD) patients cannot be sufficiently explained by classic risk factors. Experimental approach Based on the least absolute shrinkage and selection operator method, we identified significantly altered renal tissue metabolites during progressive CKD in a 5/6 nephrectomized rat model and in CKD patients. Key results Six aryl-containing metabolites (ACMs) were significantly increased from Week 1 to Week 20. They were associated with the activation of aryl hydrocarbon receptor (AhR) and its target genes including CYP1A1, CYP1A2 and CYP1B1, which were further validated by molecular docking. Our study further demonstrated that AhR signalling could be activated by ACM in patients with idiopathic membranous nephropathy, diabetic nephropathy and IgA nephropathy. Most importantly, 1-aminopyrene (AP) showed strong positive and negative correlation with serum creatinine and creatinine clearance, respectively. AP significantly up-regulated the mRNA expressions of AhR and its three target genes in both mice and NRK-52E cells, while this effect was partially weakened in AhR small hairpin RNA-treated mice and NRK-52E cells. Furthermore, dietary flavonoid supplementation ameliorated CKD and renal fibrosis through partially inhibiting the AhR activity via lowering the ACM levels. The antagonistic effect of flavonoids on AhR was deeply influenced by the number and location of hydroxyl and glycosyl groups. Conclusion and implications We uncovered that endogenous AP is a novel mediator of CKD progression via AhR activation; thus, AhR might serve as a promising target for CKD treatment.

Angiogenesis has an essential role in tumor growth and metastasis, and blocking this pathway has been a successfully utilized strategy in the clinical treatment of cancer. Anlotinib (AL3818) is a novel oral receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 and 3, fibroblast growth factor 1-4, platelet-derived growth factor receptor α and β, c-Kit and Ret. Anlotinib exerts inhibitory effects on tumor growth and angiogenesis and received its first approval as a third-line treatment for refractory advanced non-small-cell lung cancer in May 2018 and its second approval as a second-line treatment for advanced soft-tissue sarcoma in June 2019 in the People's Republic of China. Anlotinib has encouraging efficacy and a manageable and tolerable safety profile in a broad range of malignancies, including medullary thyroid cancer, renal cell cancer, gastric cancer and esophageal squamous cell carcinoma. In the present review, the preclinical and clinical trials of anlotinib were summarized with a focus on safety evaluation and adverse event management.

Purpose. To evaluate visual acuity (VA) and refractive status in patients with cataract and irregular astigmatism with a regular central component after phacoemulsification with implantation of a toric intraocular lens (IOL). Methods. Patients with cataract associated with irregular astigmatism with a regular central component were enrolled. All patients underwent phacoemulsification and toric IOL implantation. Postoperative visual acuity, residual astigmatism, toric IOL rotation, higher-order aberration, and objective and subjective visual quality were measured 3 months after surgery. Results. Twenty-three eyes were included in the study. The logMAR corrected and uncorrected distance visual acuity values were decreased at 3 months postoperatively (p < 0.005). The preoperative average corneal astigmatism and postoperative residual astigmatism were 1.15–6.97 D (1.99 ± 1.26 D) and 0–2.75 D (0.65 ± 0.57 D), respectively. The average IOL rotation was 3.17 ± 2.01°. Some objective indicators of visual quality, including the modulation transfer function (p < 0.05), Strehl ratio (p < 0.005), 100% VA (p < 0.005), 20% VA (p < 0.005), and 9% VA (p < 0.005), were significantly higher than the corresponding preoperative values. The objective scatter index (p < 0.005) was significantly lower than that before surgery. The postoperative VF-14 scale score was 83.99 ± 14.58. Conclusion. Toric IOL implantation has a good corrective effect on certain specific types of corneal irregular astigmatism with cataract. This effect can be attributed to its ability to correct the regular component of irregular astigmatism. The indications for toric IOL implantation could be expanded to some extent, thereby bringing benefit to more patients.

Although percutaneous coronary intervention (PCI) had become widely employed therapeutic procedure for coronary artery disease, stent restenosis limited the benefits of this revascularization and the question how to prevent such events remained unresolved. While numerous empirical observations suggested Tongguan Capsules (通冠胶囊), a patented Chinese Medicine, could decrease frequency and duration of angina pectoris attacks, evidence supporting its efficacy on restenosis remained inadequate. This trial was designed to determine whether Tongguan Capsules would reduce restenosis rate in patients after successful stent implantation. Approximately 400 patients undergoing percutaneous coronary stent deployment were enrolled and randomized to control group or Tongguan Capsules (4.5 g/d) for 3 months. All patients received standard anti-platelet, anti-coagulation and lipid-decreasing treatments, concurrently. The primary clinical endpoint was the 12-month incidence of the major adverse cardiovascular events (defined as cardiac death, myocardial infarction, and recurrence of symptoms requiring additional revascularization). The angiographic end point was restenosis rate at 6 months. This study would provide important evidence for the use of Tongguan Capsules in patients after stent implantation in combination with routine therapies, which may significantly reduce incidence of the restenosis so as to potentially improve the clinical outcomes. (registration number: ChiCTR-TRC- ChiCTR-IIR-17011407)

Interleukin-10 (IL-10) is a pleiotropic cytokine produced by a wide variety of cells. It has been implicated in cancer progression, and at times, it has seemingly contradictory effects. The impact of IL-10 on immune components in the context of cancer has been intensively investigated, but its effect on cancer cells remains poorly understood. In this study, we examined the expression of IL-10 and IL-10 receptor 1 (IL-10R1) in resected locally advanced lung adenocarcinoma by immunohistochemistry. IL-10 immunoreactivity was stronger in intraepithelial regions than in stroma. The amount of IL-10 found either in intraepithelial or in stromal regions had no prognostic value, but the relative distribution of IL-10 in these two locations was related to cancer-immune phenotypes. High expression of IL-10R1 by tumor cells was significantly correlated with poor prognosis, suggesting that IL-10-mediated signaling may induce cancer cell intrinsic effects that promote cancer progression. Functional analysis using human lung adenocarcinoma cell lines revealed that IL-10 did not directly affect cell proliferation and migration. Incubation of cancer cells with IL-10 suppressed interferon-γ (IFN-γ)-induced STAT1 phosphorylation and inhibited the transcription of IFN-γ-targeted genes, such as CXCL9, CXCL10, and PD-L1. IL-10 enhanced IFN-γ-induced SOCS1 and SOCS3 expression, an effect that might be responsible for the downregulation of STAT1 activity in cancer cells. Our findings provide a rationale for targeting IL-10 on cancer cells as a potential strategy for treating cancer.

INTRODUCTION In colorectal cancer screening, implementing risk-adapted screening might be more effective than traditional screening strategies. We aimed to compare the effectiveness of a risk-adapted screening strategy with colonoscopy and fecal immunochemical test (FIT) in colorectal cancer screening. METHODS A randomized controlled trial was conducted in 6 centers in China since May 2018. Nineteen thousand five hundred forty-six eligible participants aged 50-74 years were recruited and randomly allocated into 1 of the 3 screening groups in a 1:2:2 ratio: (i) one-time colonoscopy (n = 3,916), (ii) annual FIT (n = 7,854), and (iii) annual risk-adapted screening (n = 7,776). Based on the risk-stratification score, high-risk subjects were referred for colonoscopy and low-risk ones were referred for FIT. All subjects with positive FIT were referred for diagnostic colonoscopy. The detection rate of advanced neoplasm was the primary outcome. The study is registered with the China Clinical Trial Registry (www.chictr.org.cn Identifier: ChiCTR1800015506). RESULTS For baseline screening, the participation rates of the colonoscopy, FIT, and risk-adapted screening groups were 42.5% (1,665/3,916), 94.0% (7,386/7,854), and 85.2% (6,628/7,776), respectively. For the intention-to-screen analysis, the detection rates of advanced neoplasm were 2.40% (94/3,916), 1.13% (89/7,854), and 1.66% (129/7,776), with odds ratios (95% confidence intervals) of 2.16 (1.61-2.90; P < 0.001) for colonoscopy vs FIT, 1.45 (1.10-1.90; P < 0.001) for colonoscopy vs risk-adapted screening, and 1.49 (1.13-1.97; P < 0.001) for risk-adapted screening vs FIT, respectively. The numbers of subjects who required a colonoscopic examination to detect 1 advanced neoplasm were 18 in the colonoscopy group, 10 in the FIT group, and 11 in the risk-adapted screening group. DISCUSSION For baseline screening, the risk-adapted screening approach showed a high participation rate, and its diagnostic yield was superior to that of FIT at a similarly low load of colonoscopy.

MiR-20a has been reported as a key regulator to pro-inflammatory factor release in fibroblast-like synoviocytes (FLS), which caused rheumatoid arthritis (RA). However, the molecular mechanism of miR-20a in RA remains to be further elucidated. This study aimed to investigate the roles of miR-20a in RA pathology. RA (n = 24) and osteoarthritis (OA, n = 20) and normal healthy tissues (n = 16) were collected from operation. TargetScan and dual-luciferase reporter were performed to predict and confirm the potential binding sites of miR-20a on ADAM metallopeptidase domain 10 (ADAM10). Pearson's analysis was adopted to evaluate the correlation between miR-20a and ADAM10 expression. It was found that MiR-20a was downregulated in RA tissues, and overexpressed miR-20a inhibited cell viability, migration and invasion, and the expression of inflammatory factors in RA-FLS MH7A cells. ADAM10 was identified as the target gene of miR-20a, and upregulation of ADAM10 reversed the inhibitory effects of miR-20a. In conclusion, miR-20a inhibits the progression of RA-FLS as well as the inflammatory factor expression by targeting ADAM10.

BACKGROUND/AIMS: Autophagy plays a positive role in the prevention of liver damage after hepatic ischemia-reperfusion injury (HIRI); however, the molecular mechanism is still a mystery. Understanding the molecular events behind this injury may have important implications for devising proper strategies for managing liver injury. This study investigated the effects of Frizzled-2 expression on autophagy as well as Ca(2+) concentration and apoptosis in BRL-3A cells. MATERIALS AND METHODS: BRL-3A cells exposed to the hypoxia/reoxygenation (H/R) condition were used as an in vitro HIRI hepatic cell model. The transfection of Frizzled-2 small interfering RNA (siRNA) or expression vector was performed to silence or overexpress Frizzled-2 in BRL-3A cells. The intracellular Ca(2+) concentration was monitored by the fluorescence of Ca(+). Western blot was used to detect autophagy-related proteins and apoptotic marker Caspase-3. The cellular autophagosome was observed by a transmission electron microscope. RESULTS: Beclin-1 and Atg7 expressions were considerably induced by H/R treatment, and this induction was attenuated by Frizzled-2 siRNA in BRL-3A cells. The LC3B-II/I ratio was inhibited by H/R treatment, although it was considerably induced by Frizzled-2 siRNA. The overexpression of Frizzled-2 induced intracellular Ca(2+) concentration and expressed autophagy-related proteins and Caspase-3 except for the suppression of LC3B-II/I ratio in BRL-3A cells in the normoxia condition. CONCLUSION: The overexpression of Frizzled-2 mimicked H/R treatment and suppressed autophagy activity, whereas Frizzled-2 siRNA induced cellular autophagy and attenuated the H/R-induced hepatic injury in BRL-3A cells. These developments suggest that Frizzled-2 siRNA protects hepatic BRL-3A cells from the injury of H/R via autophagy modulation.

Frizzled-2 plays an important role in maintaining normal hepatic cell functionality. This study aimed to investigate the role of inhibition of Frizzled-2 in protecting rat liver BRL-3A cells from Hypoxia/Reoxygenation (H/R). In vitro H/R hepatic cell model was established by culturing BRL-3A cells under H/R condition. Frizzled-2 siRNA was transfected into BRL-3A cells to inhibit Frizzled-2 signaling. Wnt5a and Frizzled-2 were significantly increased in BRL-3A cells upon H/R treatment. H/R treatment induced cell cytotoxicity, the early apoptosis rate and the intracellular Ca2+ level in BRL-3A cells while silencing frizzled-2 gene decreased the H/R induced cell cytotoxicity, apoptosis and intracellular Ca2+ level. In vivo mice study further showed the up-regulation of Frizzled-2/Wnt 5 pathway and cleaved Caspase-3 expression in liver tissues under ischemia and reperfusion injury (IRI). In summary, inhibition of Frizzled-2 by its siRNA may protects BRL-3A cells by attenuating the H/R induced cell cytotoxicity and apoptosis.

Medicago Sativa L., a nutrient-rich plant used as feed for cattle and sheep, is widely planted globally. This study investigated the structural characteristics and activities of three kinds of novel polysaccharides (APS1, APS2 and APS3) isolated from the stems of M. sativa as well as its two selenium modified products (Se-APS2 and Se-APS3). APS1 (Mw = 13.4 KDa) and APS2 (Mw = 11.2 KDa) were composed of rhamnose, arabinose, mannose and galactose with different molar ratio, APS3 (Mw = 18.6 KDa) was composed of rhamnose, arabinose, fructose, mannose and galactose. All APS1-3 contained 1 → 3 : 1 → 6 : 1 → 4 : 1 → 2 glycosidic bonds in a ratio of 0.74:0.09:0.05:0.12, 0.34:0.20:0.36:0.10 and 0.63:0.17:0.06:0.14, respectively. The selenium content of Se-APS2 (Mw = 9.0 KDa) and Se-APS3 (Mw = 10.2 KDa) were 1.05 and 2.57 µg/mg, respectively. Their surface morphology and thermal stability were determined by scanning electron microscope (SEM) and thermal analysis (TGA), respectively. Further, the antioxidant and neuroprotective activities of the three natural polysaccharides and two Se-polysaccharides were studied. Interestingly, Se-polysaccharides not only exhibited higher antioxidant activity, but also higher neuroprotective activity compared to natural polysaccharides.

Study Objective To investigate the relationship between previous ipsilateral salpingectomy and interstitial pregnancy, and report on our experience of laparoscopic cornuostomy for interstitial pregnancy. Design A single-center, retrospective review. Setting A university-based hospital. Patients Patients who had a previous ipsilateral salpingectomy diagnosed with interstitial pregnancy and treated from July 2010 to September 2018. Interventions Laparoscopy or laparotomy as treatment for interstitial pregnancy following ipsilateral salpingectomy. Measurement and Main Results 414 cases of interstitial pregnancy were identified of which 46 (11.1%) were following ipsilateral salpingectomy; 20 of the 46 patients (43.5%) were pregnant by in vitro fertilization and embryo transfer. Ipsilateral salpingectomy was the result of ectopic pregnancy in 40 patients, hydrosalpinx in 5 patients, and torsion of ovarian tumor in 1 patient. The laparoscopic approach was used to treat 78.3% of patients with history of previous salpingectomy. Patients who underwent previous ipsilateral salpingectomy by laparoscopy had a shorter interval from salpingectomy to interstitial pregnancy (24 months vs. 60 months, p=.038) compared with patients who had ipsilateral salpingectomy managed by laparotomy. Laparoscopic cornuostomy was carried out in 38 cases (82.6%); 12 had fetal cardiac activity, 15 had ruptured, and 16 used prophylactic methotrexate (MTX) intraoperatively. Median size of the ectopic mass was 2.5 cm (1.0–5.0 cm). At the time of laparoscopic cornuostomy, more cases of interstitial pregnancies with intact ectopic mass cases were administered prophylactic MTX (81.3% vs. 45.5%, p =.043). Only 1 patient with a ruptured ectopic mass, high preoperative human chorionic gonadotropin levels, and not administered prophylactic MTX experienced persistent ectopic pregnancy (PEP) . Conclusions Patients with history of ipsilateral salpingectomy should be cautioned regarding the possibility of interstitial pregnancy. Laparoscopic cornuostomy appears to be an appropriate treatment for interstitial pregnancy in patients wishing to preserve fertility, and the use of concomitant prophylactic MTX may reduce the risk of PEP, especially in patients with ruptured masses and high human gonadotropin levels.

Precisely identifying and killing tumor cells are diligent pursuits in oncotherapy. Synthesized gene circuits have emerged as an intelligent weapon to solve these problems. Gene circuits based on post-transcriptional regulation enable a faster response than systems based on transcriptional regulation, which requires transcription and translation, showing superior safety. In this study, synthetic-promoter-free gene circuits possessing two control layers were constructed to improve the specific recognition of tumor cells. Using split-TEV, we designed and verified the basic control layer of protein-protein interaction (PPI) sensing. Another orthogonal control layer was built to sense specific proteins. Two layers were integrated to generate gene circuits sensing both PPI and specific proteins, forming 10 logic gates. To demonstrate the utility of this system, the circuit was engineered to sense alpha-fetoprotein (AFP) expression and the PPI between YAP and 14-3-3σ, the matching profile of hepatocellular carcinoma (HCC). Gene-circuit-loaded cells distinguished HCC from other cells and released therapeutic antibodies, exhibiting in vitro and in vivo therapeutic effects., Graphical Abstract, This research used split TEV to design synthetic-promoter-free gene circuits for PPI sensing and specific protein sensing. Ten logic gates were formed to integrate the two sensing units. The circuit was utilized to distinguish HCC and release therapeutic antibodies in vitro and in vivo through sensing AFP expression and YAP/14-3-3σ interaction.

We aimed to establish a discriminative gene-expression-based classifier to predict survival outcomes of T-cell lymphoblastic lymphoma (T-LBL) patients. After exploring global gene-expression profiles of progressive (n = 22) vs. progression-free (n = 28) T-LBL patients, 43 differentially expressed mRNAs were identified. Then an eleven-gene-based classifier was established using LASSO Cox regression based on NanoString quantification. In the training cohort (n = 169), high-risk patients stratified using the classifier had significantly lower progression-free survival (PFS: hazards ratio 4.123, 95% CI 2.565–6.628; p

Owing to superior safety, the RNA-only delivery synthetic circuit is more suitable for cell-based medicine. Modules which possess matching inputs and outputs could be strung by daisy-chaining to compose RNA-only delivery synthetic gene circuits. In this study, we engineered well-characterized biological parts to construct composable modules, each of which could receive signals from the upstream module and transmit the processed signal to the next module using standard interfaces. Capsid-cNOT7, through which logic gates could be changed by merely changing the type of it, was used as the core element for logical process. Daisy chain topology was used to build RNA-only delivery mammalian synthetic circuits which possess validated functions such as fan out, protein sensing, drug sensing, light sensing, 2-input logic gate, 3-input logic gate, and volatile memory, providing a new method to simplify the design of RNA-only delivery synthetic circuits.

Myogenic differentiation 1 (MyoD1) is a transcription factor that promotes expression of muscle-specific genes. MyoD1 is expressed at significantly lower levels in gastric cancer (GC) tissues and cells, and it induces apoptosis in GC cells. However, functions for MyoD1 in GC cell migration and gene expression have not been documented. We show that knockdown of MyoD1 promoted migration and invasion of GC cells, whereas MyoD1 overexpression suppressed migration and invasion. We performed chromatin immunoprecipitation (ChIP)-sequencing to identify MyoD1 target genes in MKN-45 cells. The 2-kb upstream regions (Up2k) of the transcription start sites of 57 genes were probably bound by MyoD1. Six of these genes function in signaling pathways such as synthesis of glycosphingolipid biosynthesis—lacto and neolacto series. MyoD1 inhibited transcription of fucosyltransferase IV (FUT4) by binding directly to the FUT4 F3; this finding was validated by ChIP-quantitative PCR and a luciferase reporter assay. Ulex europaeus agglutinin I, which binds Fucα1-2Galβ1-4GlcNAc, and Lewis antigens showed decreased binding to the plasma membrane of cells that overexpressed MyoD1. Knockdown of FUT4 mimicked MyoD1 overexpression by suppressing GC cell migration and invasion; this result implied that MyoD1 suppressed cell migration and invasion via inhibiting the FUT4/matrix metallopeptidase signaling pathway. In summary, this study demonstrated that MyoD1 suppresses migration and invasion of GC cells by directly binding to the F3 region in the FUT4 Up2k and inhibiting FUT4/type II Lewis antigen expression.

Objective Aim of the study was to evaluate the clinical efficacy and safety of major uterine wall resection and reconstruction of the uterus (MURU) combined with a levonorgestrel-releasing intrauterine system (LNG-IUS) for the treatment of adenomyosis. Methods Ninety patients diagnosed with adenomyosis were enrolled in this study. All participants were examined by transvaginal ultrasound (TVU) or magnetic resonance imaging (MRI). Serum levels of cancer antigen 125 (CA 125) were quantitatively measured. All patients underwent MURU in combination with LNG-IUS. The therapeutic safety of MURU was assessed during surgery and the patientsʼ stay in hospital. The clinical efficacy was evaluated by comparatively analyzing changes in dysmenorrhea, volume of menstrual blood, uterine volume and serum levels of CA 125 before, and at 3, 6 and 12 months following MURU. Results All 90 patients enrolled in the study were successfully treated with MURU combined with LNG-IUS. No significant complications were observed during surgery and hospital stay. The mean operation time, intraoperative blood loss and length of hospital stay were 82.4 ± 13.8 min, 53.3 ± 20.3 ml, and 4.3 ± 0.8 days, respectively. Dysmenorrhea completely disappeared in all patients. Uterine volume and serum levels of CA 125 were restored to normal ranges. No recurrence of adenomyosis was observed during postoperative follow-up. Conclusion MURU combined with LNG-IUS is an efficacious and safe treatment for severe adenomyosis. This combined technique is not only effective to manage severe adenomyosis but also preserves as much of the uterus as possible.

Purpose miR-497-5p can inhibit cervical cancer cell proliferation. However, the underlying mechanism remains to be elucidated. Methods Bioinformatics was used to analyze the target genes of miR-497-5p. qRT-PCR and Western blot were used to analyze mRNA and protein expression, respectively. Dual-luciferase reporter assay was used to analyze the direct binding between miR-497-5p and 3'-untranslated region of CBX4. Cell viability was measured with MTT assay. Flow cytometry was performed to detect cell cycle distribution. Results Here, using bioinformatics methods we firstly found that miR-497-5p regulated cervical carcinoma proliferation by targeting polycomb chromobox4 (CBX4). Expression of miR-497-5p in cervical carcinoma tissues was negatively correlated with CBX4. A binding region of miR-497-5p in 3'-untranslated region of CBX4 was predicted. Further experiments confirmed that miR-497-5p directly targeted CBX4. Besides, RNA interference of CBX4 inhibited cervical cancer cell proliferation, arrested cells at S phase and reduced the expression of CDK2 and Cyclin A2 proteins. The use of miR-497-5p inhibitor compromised CBX4 interference RNAs induced cycle arrest of cervical cancer cells. Cells co-transfected with miR-497-5p inhibitors and CBX4 interference RNAs had a higher proliferation rate than CBX4 inference RNA-transfected cells. Conclusion All together, the present study demonstrates that miR-497-5p inhibits cervical cancer cells proliferation by directly targeting CBX4.

Purpose This study was done to investigate the inhibition effects of miR-30a-3p on mitotic arrest deficient 2 like 1 (MAD2L1) expression and the proliferation of gastric cancer cells. Patients and methods Cluster analysis and the TCGA database were used to screen the key genes highly expressed in gastric cancer. Based on the LinkedOmics website, the correlation between the miR-30a-3p and the cell cycle-related target gene MAD2L1 in gastric cancer was analyzed. The mRNA and protein expression levels were detected with the quantitative real-time PCR and Western blot analysis. The cell proliferation and cell cycle were also detected and analyzed. Results Bioinformatics analysis showed that MAD2L1 was highly expressed in tumor tissues compared with normal tissues. Compared with normal tissues, the miR-30a-3p was significantly decreased in the gastric cancer tissues. Moreover, MAD2L1 was significantly negatively correlated with the miR-30a-3p expression. Furthermore, over-expression of miR-30a-3p decreased the expression of MAD2L1 at the protein level, which inhibited the proliferation of AGS and BGC-823 gastric cancer cells. In addition, the cell cycles of AGS and BGC-823 cells were arrested at the G0/G1 phase. Conclusion MAD2L1 is a pro-oncogene which is up-regulated in gastric cancer. The miR-30a-3p can down-regulate the MAD2L1 expression, inhibiting the proliferation of gastric cancer cells and affect the cell cycle.

The generation of a colloidal drug-rich phase by dissolving an amorphous solid dispersion (ASD) is thought to have a positive impact on oral absorption and bioavailability. Thus, understanding which formulations generate these species is important. In this study, ledipasvir-copovidone ASDs, with and without surfactants, were prepared, and their release performance was examined at different drug loadings. An intrinsic dissolution rate assembly was used to limit potential surface area variations among formulations, and the release of both polymer and drug was monitored as a function of time. Drug-rich colloids only formed when the drug loading (DL) was at or below 5%; at a DL of 7.5% or above, drug release became negligible. The drug and polymer released congruently at and below 5% DL and incongruently at higher DLs. Thus, the limit of congruency (LoC) is between 5 and 7.5% DL. X-ray photoelectron spectroscopy (XPS) of partially dissolved tablet surfaces revealed that a drug-rich layer formed on the surface of the tablet. This was most evident for the higher DL ASDs and led to amorphous drug-controlled dissolution. Consequently, the surface drug-enriched layer physically hindered the polymer from further release. Evidence is provided that the extent of drug-polymer interactions as a function of DL plays a central role in dictating the observed release behavior. Some surfactants were found to promote the formation of drug-rich colloids at considerably higher DLs, providing a formulation strategy to increase the LoC.

Background: Sunitinib is one of the multi-targeted tyrosine kinase inhibitors for the treatment of renal cell carcinoma (RCC) at present. However, its clinical efficacy is limited by chemoresistance of RCC. Our previous study found that eukaryotic translation initiation factor 3 subunit D (EIF3D) was an oncogene in the development and progression of RCC but little is known about whether EIF3D participated in sunitinib resistance of RCC. Methods: The expression of EIF3D in the tumor tissue specimen was detected by immunohistochemistry. The effect of EIF3D on sunitinib-resistance of RCC cells was evaluated by colony formation, IC50 proliferation and in vivo tumor growth assays. The interaction between EIF3D and glucose regulated protein 78 (GRP78) was assessed by Co-IP and Western blot assays. Finding: EIF3D expression was found higher in 786-OR and ACHN-R cells with acquired sunitinib resistance than that in 786-O and ACHN cells sunitinib to sensitive. The EIF3D level was also up-regulated in sunitinib-chemoresistant tumor tissues compared with chemosensitive tumor tissues. Functional study showed that EIF3D knockdown decreased cell viability with sunitinib treatment. Mechanistical study demonstrated that EIF3D interacted with GRP78 and enhanced protein stability through blocking the ubiquitin-mediated-proteasome degradation of GRP78. GRP78 overexpression induced sunitinib resistance of RCC cells by triggering the unfolded protein response, whereas GRP78 silencing inhibited cell viability. Forced expression of GRP78 eliminated the inhibitory effect of EIF3D silencing on cell growth in vitro and in vivo. Interpretation: our results indicate that EIF3D played an important role in sunitinib resistance of RCC cells, suggesting that it may prove to be a potential therapeutic target for RCC. Keywords: Renal cell carcinoma, EIF3D, GRP78, Sunitinib, Chemoresistance

PurposeThe current study was to investigate whether myopia affected peripheral motion detection and whether the potential effect interacted with spatial frequency, motion speed, or eccentricity.MethodsSeventeen young adults aged 22–26 years participated in the study. They were six low to medium myopes [spherical equivalent refractions −1.0 to −5.0 D (diopter)], five high myopes (ResultsMixed-model analysis of variances showed no significant difference in the thresholds of peripheral motion detection between three refractive groups at either 20° (F[2,14] = 0.145, p = 0.866) or 27° (F[2,14] = 0.475, p = 0.632). At 20°, lower motion detection thresholds were associated with higher myopia (p < 0.05) mostly for low spatial frequency and high-speed targets in the nasal and superior quadrants, and for high spatial frequency and high-speed targets in the temporal quadrant in myopic viewers. Whereas at 27°, no significant correlation was found between the spherical equivalent and the peripheral motion detection threshold under all conditions (all p > 0.1). Spatial frequency, speed, and quadrant of the visual field all showed significant effect on the peripheral motion detection threshold.ConclusionThere was no significant difference between the three refractive groups in peripheral motion detection. However, lower motion detection thresholds were associated with higher myopia, mostly for low spatial frequency targets, at 20° in myopic viewers.

Suspension is an important risk control measure during clinical trials. We investigated the use of this in China and identified common reasons for suspension by analyzing trends, hold issues, outcomes, background and design characteristics of suspended clinical drug trials from January 1, 2013 to December 1, 2019. A total of 298 clinical trials during the study timeframe were registered, accounting for 3.1% of all clinical drug trials. Numbers and proportion of clinical trials suspended based on benefit/risk factors have been increasing without holds on registrations by Center for Drug Evaluation. Reasons for suspension vary among trial phases, benefit and risk factors, protocol issues etc. 67% of trials that have been on hold for >1 year were still on hold at the time of this analysis. Children and the elderly were enrolled in 4.1% and 41% of the suspended trials, respectively. Strengthening regulation of pre-market pharmacovigilance through optimizing reporting and monitoring of safety information during clinical trial is thus needed. Establishing a closed-loop treatment mechanism for trial suspension is also important. Examination of potential risks, such as the quality of protocols, the ability of the institution to support the trial, and the adequacy of supplies of the investigational product is needed before beginning clinical trials. More careful evaluation at the drug registration phase will reduce the frequency of suspension and protect subjects after suspension occurs.

Purpose: This study aimed to evaluate short-term visual performance and optical quality of three different lenslet configurations on myopia control spectacle lenses.Materials and Methods: This study utilized a cross-over design. Distance visual acuity (VA) was measured in 50 myopic children; contrast sensitivity (CS) was measured in 36 myopic children. For each test, four spectacle lenses were evaluated in a random order: single-vision lens (SVL), lens with concentric rings of highly aspherical lenslets (HAL), lens with concentric rings of slightly aspherical lenslets (SAL), and lens with honeycomb configuration of spherical lenslets (HC). The modulation transfer function (MTF) and MTF area (MTFa) were used to determine optical quality. All tests were performed monocularly on the right eye with full correction.Results: HAL and SAL had larger MTFa than HC. VA in lenses with lenslets was significantly reduced compared to SVL (all p < 0.01). The reduction in VA was worse with HC than with SAL (p = 0.02) and HAL (p = 0.03); no effect of lenslet asphericity was found (p > 0.05). VA changes induced by lenslets showed no correlation with spherical equivalent refraction (all p > 0.05) and were weakly positively associated with age for SAL (r = 0.36, p = 0.01) and HC (r = 0.31, p = 0.03), but not for HAL (p = 0.30). The area under the log contrast sensitivity function (AULCSF) decreased with HAL and HC (all p < 0.001) in all illumination levels, and AULCSF with HAL was higher than that with HC in a photopic condition (1.17 ± 0.10 vs. 1.10 ± 0.13, p = 0.0004). The presence of lenslets did not affect CS at 3 cycles per degree (cpd) (p = 0.80). At 6 to 18 cpd, CS was significantly reduced by HAL and HC (all p < 0.05), but not SAL (p > 0.05) compared to SVL. At high spatial frequencies (>12 cpd) both SAL and HAL reduced CS significantly less than HC (all p < 0.01).Conclusion: Short-term visual performance was minimally impaired by looking through the lenslet structure of myopia control spectacle lenses. Concentric rings with aspherical lenslets had a significantly lower impact on both VA and CS than honeycomb configuration with spherical lenslets.

PurposeOur primary aim was to present a combined technique to protect the anatomic integrity of distal urethral sphincter complex (DUSC) during minimally invasive radical prostatectomy (RP) and discuss its impact on urinary continence (UC) recovery. The second aim was to define the learning curve of the combined technique.MethodsWe conducted a non-randomized retrospective study. There were 314 consecutive patients who received RP by the same urologist surgeon with more than 2,000 prior cases in Shanghai Ruijin Hospital between March 2017 and April 2020. Included in this study were 263 patients with clinical T1–T2 stage. We modified a combined RP (Comb-RP) technique including endopelvic fascia no-incising technique, dorsal venous complex (DVC) no-ligation technique, intrafascial dissection technique, and anterior reconstruction technique so as to preserve the anatomic integrity of DUSC. The patients were assigned to two groups: a Comb-RP group and a conventional RP (Conv-RP) group. Continence rates were assessed every 3 months after removal of the catheter. UC was defined as 0 pad per day. Peri-operative variables of the patient including operation time, estimated blood lost (EBL), positive surgical margin (PSM), and postoperative complications were also collected. Scatter-graphs of learning curves were drawn using locally weighted scatterplot smoothing (LOWESS).ResultsRP was accomplished smoothly in all 263 cases. The pad-free UC rates in Conv-RP group and Comb-RP group were 17.3 vs. 27.8% (P = 0.048) at the removal of the catheter, 35.8 vs. 50.0% (P = 0.027) at 1 month, 60.5 vs. 76.1% (P = 0.012) at 3 months, 87.7 vs. 96.5% (P = 0.022) at 6 months, and 94.7 vs. 97.7% (P = 0.343) at 12 months. Kaplan–Meier analysis showed significantly higher and faster continence recovery in the Comb-RP group (mean 4.9 vs. 2.6 months, Log Rank P = 0.001). There was no significant difference in PSM rate between the Comb-RP and Conv-RP group (31.1 vs. 31.2%, P =0.986). The learning curves of peri-operative variables, oncological and functional outcomes achieved the lowest point or plateau at the 20th–60th cases.ConclusionsThe anatomic integrity and intact pelvic floor interplay of DUSC is important for its function. Our combined technique was a safe and feasible technique for improving early UC in RP with no significantly increased PSM rate and no significant difference in long-term UC.

A glycoside hydrolase family 57 protein, designated APU_Aquae, from hyperthermophilic bacterium Aquifex aeolicus was expressed in Escherichia coli. APU_Aquae was biochemically defined as a novel bifunctional amylopullulanase, which exhibited efficient activity towards rice starches. It is extremely thermostable with half-life of 7 h at 100 °C. Therefore, APU_Aquae was used to simplify the process of enzymatic debranching treatment in resistant starch type III (RS3) preparation from rice starches. Starch pregelatinization and enzymatic hydrolysis were combined into one step. It took only 7 h, which was much shorter than that of other enzymatic treatments. RS3 content of treated rice starches was 40.5 ± 0.7%. APU_Aquae treatment resulted in more medium branch chains B1 with degree of polymerization (DP) values 13–24, which might be one main reason to promote the RS3 formation. This study provides the new design for the industrial RS3 production.

BACKGROUND: Intracerebral hemorrhage (ICH) is a cerebrovascular disease with extremely high disability and mortality rates. Glycans play critical roles in biological processes. However, whether glycans can serve as potential biomarkers for determining clinical diagnosis and prognosis in ICH remains determined. METHODS: In this study, we established a lectin-biochip to measure serum glycans levels in ICH patients (n=48) and healthy controls (n=16). An enzyme-linked immunosorbent assay (ELISA) was carried out to determine serum levels of IL-10 and TNF-α in the patients. Correlation analyses of the serum glycan and cytokine levels and the clinicopathological parameters of patients were performed. RESULTS: The biochip-based data revealed that the serum levels of α-Man/α-Glc (ConA), Galβ3GalNAc (PNA), GalNAc (VVA), Fucα6GlcNAc (AAL), α-Fuc (LTL), and Galβ3GalNAc-Ser/Thr (AIL) significantly increased in the super-acute phase of ICH in comparison with healthy controls. Clinicopathological analysis indicated the serum levels of ConA, VVA, and LTL had significant associations with the National Institute of Health Stroke Scale (NIHSS), and serum VVA levels had a significant association with the Mini-Mental State Examination (MMSE) at day 90 after ICH. Correlation coefficient analysis revealed significant correlations between TNF-α and ConA (P

Bariatric surgery including duodenal-jejunal bypass surgery (DJB) improves insulin sensitivity and reduces obesity-associated inflammation. However, the underlying mechanism for such an improvement is still incompletely understood. Our objective was to investigate the role of the gut microbiota in DJB-associated improvement of hepatic steatosis in high fat diet (HFD)-fed rats. To study this, hepatic steatosis was induced in male adult Sprague-Dawley rats by feeding them with a 60% HFD. At 8 weeks after HFD feeding, the rats were subjected to either DJB or sham operation. HFD was resumed 1 week after the surgery for 3 more weeks. In additional groups of animals, feces were collected from HFD-DJB rats at 2 weeks after DJB. These feces were then transplanted to HFD-fed rats without DJB at 8 weeks after HFD feeding. Hepatic steatosis and fecal microbiota were analyzed at 4 weeks after surgery or fecal transplantation. Our results showed that DJB alleviated hepatic steatosis in HFD-fed rats. Fecal microbiota analysis showed that HFD-fed and standard diet-fed rats clustered differently. DJB induced substantial compositional changes in the gut microbiota. The fecal microbiota of HFD-fed rats received fecal transplant from DJB rats overlapped with that of HFD-DJB rats. Treatment of rats with HFD-induced liver lesions by fecal transplant from DJB-operated HFD-fed rats also attenuated hepatic steatosis. Thus, alterations in the gut microbiota after DJB surgery are sufficient to attenuate hepatic steatosis in HFD-fed rats. Targeting the gut microbiota could be a promising approach for preventing or treating human NAFLD.

The current understanding and effective treatment of liver disease is far from satisfactory. Liver organoids and liver buds (LBs) transforming cell culture from two dimensions(2D) to three dimensions(3D) has provided infinite possibilities for stem cells to use in clinic. Recent technological advances in the 3D culture have shown the potentiality of liver organoids and LBs as the promising tool to model in vitro liver diseases. The induced LBs and liver organoids provide a platform for cell-based therapy, liver disease models, liver organogenesis and drugs screening. And its genetic heterogeneity supplies a way for the realization of precision medicine.