Four centrosome-related genes to predict the prognosis and drug sensitivity of patients with colon cancer.

BACKGROUND: As the primary microtubule organizing center in animal cells, centrosome abnormalities are involved in human colon cancer. AIM: To explore the role of centrosome-related genes (CRGs) in colon cancer. METHODS: CRGs were collected from public databases. Consensus clustering analysis was performed to separate the Cancer Genome Atlas cohort. Univariate Cox and least absolute shrinkage selection operator regression analyses were performed to identify candidate prognostic CRGs and construct a centrosome-related signature (CRS) to score colon cancer patients. A nomogram was developed to evaluate the CRS risk in colon cancer patients. An integrated bioinformatics analysis was conducted to explore the correlation between the CRS and tumor immune microenvironment and response to immunotherapy, chemotherapy, and targeted therapy. Single-cell transcriptome analysis was conducted to examine the immune cell landscape of core prognostic genes. RESULTS: A total of 726 CRGs were collected from public databases. A CRS was constructed, which consisted of the following four genes: TSC1, AXIN2, COPS7A, and MTUS1. Colon cancer patients with a high-risk signature had poor survival. Patients with a high-risk signature exhibited decreased levels of plasma cells and activated memory CD4+ T cells. Regarding treatment response, patients with a high-risk signature were resistant to immunotherapy, chemotherapy, and targeted therapy. COPS7A expression was relatively high in endothelial cells and fibroblasts. MTUS1 expression was high in endothelial cells, fibroblasts, and malignant cells. CONCLUSION: We constructed a centrosome-related prognostic signature that can accurately predict the prognosis of colon cancer patients, contributing to the development of individualized treatment for colon cancer.

Experimental and numerical investigations on stress concentration factors of concrete filled steel tube X-joints.

An SHS-CFSHS X-joint is fabricated by welding two square hollow section (SHS) braces to a concrete-filled square hollow section (CFSHS) chord. In this paper, the stress concentration factors (SCFs) of SHS-CFSHS X-joints are investigated through experimental tests and finite element analysis (FEA), with the hot spot stress method serving as the analytical approach. Eight specimens are designed and manufactured, with FE models built in software ANSYS. These FE models are validated against the test results. The specimens are tested under brace axial tension to determine the SCFs of the X-joints. It shows that the concrete filled in the chord effectively reduces the SCFs of the X-joints. To further explore various load conditions and the influence of the parameters, FEA is carried out and a total of 64 FE models are built. Based on the FEA results, multiple regression analysis is used to obtain the SCF formulae of SHS-CFSHS X-joints under axial tension load and in-plane bending load in the brace, respectively. Comparison and analysis of the SCF results obtained from experimental tests, the proposed formulae, and FE simulations reveal that the formulae presented in this study are both conservative and suitable for predicting SCFs.

The Efficiency and Toxicity Of Anlotinib in Combination With Docetaxel Followed by Epirubicin and Cyclophosphamide Regimen as Neoadjuvant Treatment in IIB to IIIA Triple Negative Breast Cancer: A Single-Arm, Multicenter, Open-Label, Phase II Study.

BACKGROUND: The combination of neoadjuvant chemotherapy and anti-angiogenesis therapy for patients with triple-negative breast cancer (TNBC) remains inadequately supported by evidence. We conducted a single-arm, open-label, multicenter, phase II trial to evaluate the efficacy and toxicity of anlotinib plus epirubicin and cyclophosphamide followed by paclitaxel in patients with IIB to IIIA stage TNBC. METHODS: Newly diagnosed patients received epirubicin at 90 mg/m2 and cyclophosphamide at 600 mg/m2 followed by docetaxel at 100 mg/m2 (21 days per cycle; total of 4 cycles), along with oral anlotinib (12 mg qd, d1-14; 21 days per cycle; total of 4 cycles). Subsequently, patients underwent surgery. The primary endpoint of this study was pathologic complete response (pCR). RESULTS: Among the 34 included patients, the median age was 46.5 years (range: 27-72); all were female. Pathological assessment revealed that 17 patients achieved RCB 0 response, which is currently defined as pathologic complete response; 3 patients achieved RCB 1; 12 patients achieved RCB 2; and 1 patient achieved RCB 3. The probability of a grade 3 adverse reaction was 17.6%, and no grade 4 adverse reactions occurred. The most common hematological adverse reaction was leukopenia (13/34, 38.2%), of which 5.9% (2/34) were grade 3. The most common non-hematological adverse reactions were oral mucositis (16/34, 58.8%), fatigue (50.0%), hand-foot syndrome (50.0%), hypertension (44.1%), bleeding (44.1%), and alopecia (32.4%). CONCLUSION: The combination of anlotinib and EC-T chemotherapy demonstrated tolerable side effects in the neoadjuvant treatment of early TNBC. pCR was higher than what has been reported in previous clinical studies of chemotherapy alone. This study provides additional rationale for using anlotinib plus docetaxel-epirubicin-based chemotherapy regimen in patients with early-stage TNBCs.

Auricularia auricula Anionic Polysaccharide Nanoparticles for Gastrointestinal Delivery of Pinus koraiensis Polyphenol Used in Bone Protection under Weightlessness.

Auricularia auricula polysaccharides used in Pinus koraiensis polyphenol encapsulation and delivery under weightlessness are rarely reported. In this study, an anionic polysaccharide fragment named AAP Iα with a molecular weight of 133.304 kDa was isolated and purified to construct a polyphenol encapsulation system. Nanoparticles named NPs-PP loaded with a rough surface for Pinus koraiensis polyphenol (PP) delivery were fabricated by AAP Iα and ε-poly-L-lysine (ε-PL). SEM and the DLS tracking method were used to observe continuous changes in AAP Iα, ε-PL and PP on the nanoparticles' rough surface assembly, as well as the dispersion and stability. Hydrophilic, monodisperse and highly negative charged nanoparticles can be formed at AAP Iα 0.8 mg/mL, ε-PL 20 µg/mL and PP 80 µg/mL. FT-IR was used to determine their electrostatic interactions. Release kinetic studies showed that nanoparticles had an ideal gastrointestinal delivery effect. NPs-PP loaded were assembled through electrostatic interactions between polyelectrolytes after hydrogen bonding formation in PP-AAP Iα and PP-ε-PL, respectively. Colon adhesion properties and PP delivery in vivo of nanoparticles showed that NPs-PP loaded had high adhesion efficiency to the colonic mucosa under simulated microgravity and could enhance PP bioavailability. These results suggest that AAP Iα can be used in PP encapsulation and delivery under microgravity in astronaut food additives.

Identification of biomarkers associated with immune-propionate metabolism in nonalcoholic fatty liver disease.

The mechanisms of the effect of propionate metabolism and immunity on nonalcoholic fatty liver disease (NAFLD) have not been adequately studied. Firstly, differentially expressed-propionate metabolism-related genes (DE-PMRGs) were selected by overlapping PMRGs and differentially expressed genes (DEGs) between the simple steatosis (SS) and health control (HC) groups. Then, common genes were selected by overlapping DE-PMRGs and key module genes obtained from weighted gene co-expression network analysis (WGCNA). Subsequently, the biomarkers were screened out by machine learning algorithms. The expression of the biomarkers was validated by quantitative Real-time PCR. In total, 5 biomarkers (JUN, LDLR, CXCR4, NNMT, and ANXA1) were acquired. The nomogram constructed based on 5 biomarkers had good predictive power for the risk of SS. Next, 5 biomarkers, 11 miRNAs, and 149 lncRNAs were encompassed in the ceRNA regulatory network. The expression of biomarkers was significantly higher in the HC group than in the SS group, which was consistent with the results in the GSE89632 and GSE126848 datasets. In this study, 5 immune and propionate metabolism-related biomarkers (JUN, LDLR, CXCR4, NNMT, and ANXA1) were screened out to provide a basis for exploring the prediction of diagnosis of NAFLD.

PreS1- targeting chimeric antigen receptor T cells diminish HBV infection in liver humanized FRG mice.

Current therapies control but rarely achieve a cure for hepatitis B virus (HBV) infection. Restoration of the HBV-specific immunity by cell-based therapy represents a potential approach for a cure. In this study, we generated HBV specific CAR T cells based on an antibody 2H5-A14 targeting a preS1 region of the HBV large envelope protein. We show that the A14 CAR T cell is capable of killing hepatocytes infected by HBV with high specificity; adoptive transfer of A14 CAR T cells to HBV infected humanized FRG mice resulted in reductions of all serum and intrahepatic virological markers to levels below the detection limit. A14 CAR T cells treatment increased the levels of human IFN-γ, GM-CSF, and IL-8/CXCL-8 in the mice. These results show that A14 CAR T cells may be further developed for curative therapy against HBV infection by eliminating HBV-infected hepatocytes and inducing production of pro-inflammatory and antiviral cytokines.

High Level of GMFG Correlated to Poor Clinical Outcome and Promoted Cell Migration and Invasion through EMT Pathway in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has a very poor prognosis due to the disease's lack of established targeted treatment options. Glia maturation factor γ (GMFG), a novel ADF/cofilin superfamily protein, has been reported to be differentially expressed in tumors, but its expression level in TNBC remains unknown. The question of whether GMFG correlates with the TNBC prognosis is also unclear. In this study, data from the Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Human Protein Atlas (HPA), and Genotype-Tissue Expression (GTEx) databases were used to analyze the expression of GMFG in pan-cancer and the correlation between clinical factors. Gene Set Cancer Analysis (GSCA) and Gene Set Enrichment Analysis (GSEA) were also used to analyze the functional differences between the different expression levels and predict the downstream pathways. GMFG expression in breast cancer tissues, and its related biological functions, were further analyzed by immunohistochemistry (IHC), immunoblotting, RNAi, and function assay; we found that TNBC has a high expression of GMFG, and this higher expression was correlated with a poorer prognosis in TCGA and collected specimens of the TNBC. GMFG was also related to TNBC patients' clinicopathological data, especially those with histological grade and axillary lymph node metastasis. In vitro, GMFG siRNA inhibited cell migration and invasion through the EMT pathway. The above data indicate that high expression of GMFG in TNBC is related to malignancy and that GMFG could be a biomarker for the detection of TNBC metastasis.

Nonproductive Hepatitis B Virus Covalently Closed Circular DNA Generates HBx-Related Transcripts from the HBx/Enhancer I Region and Acquires Reactivation by Superinfection in Single Cells.

Hepatitis B virus (HBV) infection remains a public health problem worldwide. Persistent HBV infection relies on active transcription of the covalently closed circular DNA (cccDNA) in hepatocytes, which is less understood at the single-cell level. In this study, we isolated primary human hepatocytes from liver-humanized FRG mice infected with HBV and examined cccDNA transcripts in single cells based on 5' end sequencing. Our 5' transcriptome sequencing (RNA-seq) analysis unambiguously assigns different viral transcripts with overlapping 3' sequences and quantitatively measures viral transcripts for structural genes (3.5 kb, 2.4 kb, and 2.1 kb) and the nonstructural X gene (0.7 kb and related) in single cells. We found that an infected cell either can generate all viral transcripts, signifying active transcription, or presents only transcripts from the X gene and its associated enhancer I domain and no structural gene transcripts. Results from cell infection assays with recombinant HBV show that nonproductive transcription of cccDNA can be activated by incoming virus through superinfection. Moreover, upon HBV infection, cccDNA apparently can be transcribed in the absence of HBx and produces HBx, needed for productive transcription of other viral genes. These results shed new light on cccDNA transcription at the single-cell level and provide insights useful for improving the treatment strategy against chronic HBV infection. IMPORTANCE Hepatitis B virus (HBV) infection can be effectively suppressed but rarely cured by available drugs. Chronic HBV infection is based on persistence of covalently closed circular DNA (cccDNA) and continuous infection and reinfection with HBV in the liver. Understanding transcriptional regulation of cccDNA will help to achieve permanent transcriptional silencing, i.e., functional cure of HBV. In our study, we found that an infected cell either can generate all viral transcripts, signifying active transcription, or presents only transcripts from the X gene and its associated enhancer I domain and no structural gene transcripts. The nonproductive transcription of cccDNA can be activated by incoming virus through superinfection. Upon an infection, cccDNA apparently can be transcribed in the absence of HBx to produce HBx, necessary for subsequent transcription of other HBV genes. Our studies shed new light on the mechanism of HBV infection and may have implications for a functional cure regimen for HBV.

Digitized Construction of Iontronic Pressure Sensor with Self-Defined Configuration and Widely Regulated Performance.

Flexible pressure sensors are essential components for wearable smart devices and intelligent systems. Significant progress has been made in this area, reporting on excellent sensor performance and fascinating sensor functionalities. Nevertheless, geometrical and morphological engineering of pressure sensors is usually neglected, which, however, is significant for practical application. Here, we present a digitized manufacturing methodology to construct a new class of iontronic pressure sensors with optionally defined configurations and widely modulated performance. These pressure sensors are composed of self-defined electrode patterns prepared by a screen printing method and highly tunable pressure-sensitive microstructures fabricated using 3D printed templates. Importantly, the iontronic pressure sensors employ an iontronic capacitive sensing mechanism based on mechanically regulating the electrical double layer at the electrolyte/electrode interfaces. The resultant pressure sensors exhibit high sensitivity (58 kPa-1), fast response/recovery time (45 ms/75 ms), low detectability (6.64 Pa), and good repeatability (2000 cycles). Moreover, our pressure sensors show remarkable tunability and adaptability in device configuration and performance, which is challenging to achieve via conventional manufacturing processes. The promising applications of these iontronic pressure sensors in monitoring various human physiological activities, fabricating flexible electronic skin, and resolving the force variation during manipulation of an object with a robotic hand are successfully demonstrated.

An inulin-type fructan (AMP1-1) from Atractylodes macrocephala with anti-weightlessness bone loss activity.

Atractylodes macrocephalon polysaccharides of alleviating weightlessness-induced bone loss (WIBL) are rarely reported. In this study, a neutral polysaccharide fragment named AMP1-1 was isolated and purified. Monosaccharide composition and gel permeation chromatography analysis indicated that AMP1-1 was composed of glucose and fructose with molecular weight of 1.433 kDa. Based on data of gas chromatography-mass spectrometer (GCMS), a linear backbone consisted of α-d-Glcp-(1→ and →1)-ß-d-Fruf-2→ was discovered. Combining results from nuclear magnetic resonance (NMR), the inulin-type fructan AMP1-1 was identified as α-d-Glcp-1→(2-ß-d-Fruf-1)7. Anti-WIBL activity of AMP1-1 was evaluated though analyzation of mechanical properties, BALP and TRAP 5b activities on femur. In vitro mRNA expression indicated that anti-WIBL activity of AMP1-1 was achieved by promote bone formation and inhibit bone resorption in primary osteoblasts and RAW264.7 cell lines under simulated weightlessness. In conclusion, the inulin-type fructan AMP1-1 with α-d-Glcp-1→(2-ß-d-Fruf-1)7 had anti-WIBL activity via remodeling bone homeostasis.

Synthetic MRI with quantitative mappings for identifying receptor status, proliferation rate, and molecular subtypes of breast cancer.

OBJECTIVE: To investigate whether quantitative parameters of synthetic magnetic resonance imaging (MRI) can be used to differentiate among receptor status, proliferation rate, and molecular subtypes in patients with breast cancer. MATERIALS AND METHODS: This retrospective study included patients with suspicious breast lesions who underwent breast MR examinations (including synthetic MRI) from May 2019 to Oct 2020. Quantitative parameters of synthetic MRI, including T1, T2, and proton density (PD) in the breast lesions before and after (T1-Gd, T2-Gd, and PD-Gd) contrast agent injection were obtained. The Wilcoxon rank sum was utilized to analyze the differences between the parameters and receptor status, proliferation rate, Luminal A/B, TN, and HER2-enriched. The Spearman's rank correlation test was used to analyze association between parameters among five molecular subtypes. RESULTS: 115 patients who met the inclusion criteria were included. Quantitative T1, T2, PD, and T2-Gd can be used as imaging biomarkers for the different receptor status and proliferation rate of breast cancer. Among them, T2 and T2-Gd were significantly different in the molecular subtypes (P = 0.000 and P = 0.006, respectively) and can further differentiate luminal A/B breast cancers from non-luminal subtypes (P = 0.005 and P = 0.015, respectively). T1 and T2 were significantly different between triple negative (TN) and non-TN breast cancers (P = 0.004 and P = 0.024, respectively). T2 and T2-Gd values were lower for luminal A/B tumors (79.5 ms and 68.00 ms, respectively) and higher for non-luminal tumors (84.00 ms and 75.00 ms, respectively). T1 and T2 values were higher for TN tumors (1.54 × 103ms and 84.00 ms, respectively) and lower for non-TN tumors (1.39 × 103 ms and 80.00 ms, respectively). CONCLUSION: Quantitative parameters derived from synthetic MRI mappings may provide a non-invasive biomarker for discriminating receptor status, proliferation rate, and molecular subtypes in patients with breast cancer.

Synthesis of POMOFs with 8-fold helix and its composite with carboxyl functionalized SWCNTs for the voltammetric determination of dopamine.

Although many satisfactory studies have been developed for biomolecule detection, the complexity of biofluids still poses a major challenge to improve the performance of nanomaterials as electrochemical sensors. Herein, unprecedented polyoxometalate-based metal-organic frameworks (POMOFs) with 8-fold meso-helical feature, [Ag5(trz)4]2[PMo12O40] (PAZ), were synthesized and explored as electrochemical sensors to detect dopamine (DA). To improve the conductivity of PAZ and the binding ability with single-walled carbon nanotubes (SWCNTs), the nanocomposite of carboxyl functionalized SWCNTs (SWCNTs-COOH) with nano-PAZ (NPAZ), NPAZ@SWCNTs-COOH, was fabricated, and transmission electron microscopy (TEM) shows that NPAZ can interact stably and uniformly with SWCNTs-COOH, owing to more defect sites on the surface of SWCNTs-COOH. The electrochemical result of NPAZ@SWCNTs-COOH/GCE towards detecting DA shows that the linear range was from 0.05 to 100 µM with a detection limit (LOD) of 8.6 nM (S/N = 3). A new electrochemical biosensing platform by combining 8-fold helical POMOFs with SWCNTs-COOH was developed for enhancing detection of dopamine for the first time, exhibiting the lowest detection limit to date.

[Investigation and analysis of children's choice of environment in oral clinics].

OBJECTIVES: To investigate and analyze children,s choice of environment in oral clinics so as to provide evidence for improving the oral clinic environment. METHODS: A total of 110 children in the Pediatric Dentistry of Qingdao Stomatological Hospital Affiliated to Qingdao University were selected as the research subjects from September to December 2019 to conduct a questionnaire survey, and the results were statistically analyzed by using a Chi-square test. RESULTS: A total of 107 effective questionnaires were collected. The children surveyed liked the room with pink and blue walls (61.68%), cartoon murals (57.94%), and arranged toys (61.68%). Most of them did not dislike the special smell in the room (62.62%) and liked the smell of orange essential oil (52.34%). During treatment, the children liked watching cartoons the best (61.68%), expected doctors to be dressed in white (51.40%), and expected doctors to be treated by female doctors (68.22%). Most children wanted to be accompanied by family members during treatment (62.62%). The Chi-square test showed statistically significant differences in seven questions between preschool and school-age children: the environment of the clinic room, the color of the walls, the clinic decoration, the entertainment during treatment, color of the doctors' dress and gender, and company of the family members during treatment (P<0.05). The difference of children's choice of color of the wall and clinic decoration during the first and subsequent visit was statistically significant (P<0.05). However, no significant difference was observed in the choice of clinic environment between different genders (P>0.05). CONCLUSIONS: Children have their own preferences for the environment in the oral clinic. For preschool children, we need to create a soothing and warm atmosphere with warm colors liked by children. For school-age children, a calm and relaxed clinic atmosphere with cold colors should be created.

Identification of Urinary Exosomal miRNAs for the Non-Invasive Diagnosis of Prostate Cancer.

BACKGROUND: Novel and non-invasive biomarkers with higher sensitivity and specificity for the diagnosis of prostate cancer (PCa) is urgently needed. In this study, we used next-generation sequencing (NGS) to characterize the genome-wide exosomal miRNA expression profiling in urine specimens and explored the diagnostic potential of urinary exosomal miRNAs for PCa. METHODS: Urinary exosomal microRNA expression profiling was performed by next-generation sequencing (NGS) and then validated by quantitative real-time PCR. RESULTS: Significant downregulation of urinary exosomal miR-375 was observed in PCa patients compared with healthy controls, while the expression levels of urinary exosomal miR-451a, miR-486-3p and miR-486-5p were found to be significantly up-regulated in the PCa patients. Furthermore, the expression level of urinary exosomal miR-375 showed a significant correlation with the clinical T-stage and bone metastasis of patients with PCa (P<0.05). Receiver operator characteristic curve demonstrated that the urinary exosomal miR-375, miR-451a, miR-486-3p and miR-486-5p levels can be used to differentiate PCa patients from healthy controls, with area under the curves (AUCs) of 0.788, 0.757, 0.704 and 0.796, respectively. The urinary exosomal miR-375 was found to be superior in discriminating between localized and metastatic PCa with an AUC of 0.806. Moreover, PCa patients can be distinguished from patients with benign prostatic hyperplasia by using a panel combining urinary exosomal miR-375 and miR-451a with an AUC of 0.726. CONCLUSION: These findings demonstrate that the urinary exosomal miRNAs can serve as novel and non-invasive biomarkers for diagnosing and predicting the progression of PCa.

Dynamic monitoring of serum specific tumor markers predicts the response to PD-1 blockade and prognosis of patients with malignant tumors.

BACKGROUND: Programmed cell death protein 1 (PD-1) blockade is a major advance in the treatment of malignancies, but there remain many problems in efficacy evaluation. The aim of this study was to determine whether dynamic monitoring of serum specific tumor markers (SSTMs) could predict the response to PD-1 blockade and prognosis in patients with malignancies. METHODS: The dynamic changes in SSTMs in 27 patients between January 1, 2018 and July 31, 2019 were analyzed retrospectively. The association between the SSTM response and the radiological response was evaluated using the χ2 test and Spearman's correlation analysis. Kaplan-Meier estimates and the log rank test were used to explore the correlation of SSTM dynamics with progression-free survival (PFS) and overall survival (OS). RESULTS: In this study, 85.3% of patients with malignant tumors had detectable SSTM. According to the changes of SSTM within the first 12 weeks of treatment, the patients were divided into a tumor marker increased group and a tumor marker decreased group. The change in SSTM was strongly associated with the change in target lesions (χ2=15.326, P≤0.001), and there was a positive correlation between them (Pearson Correlation r=0.727, P<0.0001). Patients with SSTM reduction had a significantly longer median OS (417 days) when compared with patients with SSTM elevation (median OS, 235 days; log rank χ2=6.323, P=0.012). The PFS in the SSTM reduction group (median PFS, not reached) was significantly longer than that in the elevation group (127 days; log rank χ2=8.843, P=0.003). In the study, one patient showed pseudoprogression and one showed a delayed response in the initial stage of PD-1 blockade. The diameter of the target lesions increased according to the Reaction Evaluation Criteria in Solid Tumor criteria, but the symptoms of discomfort were relieved significantly, and the SSTMs continued to decline dramatically. CONCLUSIONS: Dynamic monitoring of SSTMs can be used as a necessary supplement to imaging examination to evaluate the response to PD-1 blockade and predict the prognosis of patients with malignancies; it may also be helpful for clinical judgment of pseudoprogression and delayed response.

Investigation of Synthetic Relaxometry and Diffusion Measures in the Differentiation of Benign and Malignant Breast Lesions as Compared to BI-RADS.

BACKGROUND: Breast cancer is the most common malignant tumor in women and a quantitative contrast-free method is highly desirable for its diagnosis. PURPOSE: To investigate the performance of quantitative MRI in differentiating malignant from benign breast lesions and to compare with the Breast Imaging Reporting and Data System (BI-RADS). STUDY TYPE: Retrospective. SUBJECTS: Eighty patients (56 with malignant lesions and 24 with benign lesions). FIELD STRENGTH/SEQUENCE: Diffusion-weighted imaging (DWI) with a single-shot echo planar sequence and synthetic MRI with magnetic resonance image compilation (MAGiC) were performed at 3T. ASSESSMENT: T1 relaxation time (T1 ), T2 relaxation time (T2 ), and proton density (PD) from synthetic MRI and apparent diffusion coefficient (ADC) from DWI were analyzed by two radiologists (Reader A, Reader B). Univariable and multivariable models were developed to optimize differentiation between malignant and benign lesions and their performances compared to BI-RADS. STATISTICAL TESTS: The diagnostic performance was evaluated using multivariate logistic regression analysis and area under the receiver operating characteristic (ROC) curves (AUC). RESULTS: T2 , PD, and ADC values for malignant lesions were significantly lower than those in benign breast lesions for both radiologists (all P < 0.05). The combined T2 , PD, and ADC model had the best performance for differentiating malignant and benign lesions with AUC, sensitivity, specificity, positive predictive value, and negative predictive values of 0.904, 94.6%, 87.5%, 94.6%, and 87.5%, respectively. The corresponding results for BI-RADS were no AUC, 94.6%, 75.0%, 89.8%, and 85.7%, respectively. DATA CONCLUSION: The approach that combined synthetic MRI and DWI outperformed BI-RADS in the differential diagnosis of malignant and benign breast lesions and was achieved without contrast agents. This approach may serve as an alternative and effective strategy for the improvement of breast lesion differentiation. LEVEL OF EVIDENCE: 3. TECHNICAL EFFICACY STAGE: 3.

Long-term low-dose ethanol intake improves healthspan and resists high-fat diet-induced obesity in mice.

Numerous epidemiological studies have reported that moderate alcohol drinking has beneficial effects. However, few studies have focused on the beneficial effects of ethanol, the common component in alcoholic beverages. Here we fed the C57BL/6 mice with 3.5% v/v ethanol as drinking water substitute to investigate the effects of long-term low-dose ethanol intake in vivo. We evaluated the metabolic rate and mitochondrial function of the long-term low-dose ethanol-intake (LLE) mice, assessed the exercise ability of LLE mice, and fed the LLE mice with a high-fat diet to investigate the potential impact of ethanol on it. The LLE mice showed improved thermogenic activity, physical performance, and mitochondrial function, as well as resistance against the high-fat diet-induced obesity with elevated insulin sensitivity and subdued inflammation. Our results suggest that long-term low-dose ethanol intake can improve healthspan and resist high-fat diet-induced obesity in mice. It may provide new insight into understanding the protective effects of moderate alcohol drinking.

EMT Transcription Factors Are Involved in the Altered Cell Adhesion under Simulated Microgravity Effect or Overloading by Regulation of E-cadherin.

In order to study the effect of stress changes on cell adhesion, HUVEC, and MCF-7 cells were treated with simulated microgravity effect (SMG) and overloading (OL). METHODS: Rotating Wall Vessel (2D-RWVS) bioreactor was used to create different culture conditions. In addition, the alteration of cell adhesion states, adhesion proteins, and relating factors of adhesion molecules under these two conditions were detected using cell adhesion assay, immunofluorescence, western blot, and qRT-PCR technology. RESULTS: The results showed that the adhesion of cells decreased under SMG, while increased under OL. The expressions of integrin ß1, paxillin, and E-cadherin under SMG condition were down-regulated as compared to that of the control group showing a time-dependent pattern of the decreasing. However, under OL condition, the expressions of adhesion proteins were up-regulated as compared to that of the control group, with a time-dependent pattern of increasing. EMT transcription factors Snail, twist, and ZEB1 were up-regulated under SMG while down-regulated under OL. CONCLUSION: Collectively our results indicated that cells could respond to stress changes to regulate the expressions of adhesion proteins and adapt their adhesion state to the altered mechanical environment. The altered cell adhesion in response to the mechanical stress may involve the changed expression of EMT-inducing factors, Snail, Twist, and ZEB1under the SMG/OL conditions.

MicroRNA-140 inhibit prostate cancer cell invasion and migration by targeting YES proto-oncogene 1.

Prostate cancer (PCa), which is an aggressive malignancy of the male genitourinary system. In the present study, the effects of microRNA-140 (miR-140) on PCa were determined. We transfected miR-140 mimics or negative control into PCa cells, and we used MTT, wound healing, and Transwell assays for determining the capacities of miR-140 in cell proliferation, migration, and invasion, respectively. We also confirmed the relationship between miR-140 and YES proto-oncogene 1 (YES1) using Luciferase reporter assay. The results showed that miR-140 was downregulated in PCa cells and tissues, and overexpression of miR-140 could significantly suppress their capacities of proliferation, migration, and invasion. Moreover, YES1 was shown to be a direct target of miR-140. Moreover, miR-140 expression is negatively correlated with YES1 levels. miR-140 exhibits significant tumor-suppressive effects in PCa by inhibiting YES1. The study indicated that miR-140 and YES1 could be the potential targets for PCa therapy.

Discovery and biological evaluation of N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)phenyl)acrylamide as potent Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) is a key component of the B cell receptor (BCR) signaling pathway and plays a crucial role in B cell malignancies and autoimmune disorders; thus, it is an attractive target for the treatment of B cell related diseases. Here, we evaluated the BTK inhibitory activity of a series of pyrimido[4,5-d][1,3]oxazin-2-one derivatives. Combining this evaluation with structure-activity relationship (SAR) analysis, we found that compound 2 exhibited potent BTK kinase inhibitory activity, with an IC50 of 7 nM. This derivative markedly inhibited BTK activation in TMD8 B cell lymphoma cells and thus inhibited the in vitro growth of the cells. Further studies revealed that compound 2 dose dependently arrested TMD8 cells at G1 phase, accompanied by decreased levels of Rb, phosphorylated Rb, and cyclin D1. Moreover, following treatment with compound 2, TMD8 cells underwent apoptosis associated with PARP and caspase 3 cleavage. Interestingly, the results of the kinase activity assay on a small panel of 35 kinases showed that the kinase selectivity of compound 2 was superior to that of the first-generation inhibitor ibrutinib, suggesting that compound 2 could be a second-generation inhibitor of BTK. In conclusion, we identified a potent and highly selective BTK inhibitor worthy of further development.