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Protein tyrosine phosphatase non-receptor type 18 (PTPN18) is often highly expressed in colorectal cancer (CRC), but its role in this disease remains unclear. We demonstrated that PTPN18 overexpression promotes growth and tumorigenesis in CRC cells and that PTPN18 deficiency yields the opposite results in vitro. Moreover, a xenograft assay showed that PTPN18 deficiency significantly inhibited tumorigenesis in vivo. PTPN18 activated the MYC signaling pathway and enhanced CDK4 expression, which is tightly associated with the cell cycle and proliferation in cancer cells. Finally, we found that MYC interacted with PTPN18 and increased the protein level of MYC. In conclusion, our results suggest that PTPN18 promotes CRC development by stabilizing the MYC protein level, which in turn activates the MYC-CDK4 axis. Thus, PTPN18 could be a novel therapeutic target in the future.

Background The promotion of early diagnosis is undoubtedly effective in reducing the burden of disease. Contrast-enhanced ultrasound (CEUS) is a diagnostic technology for liver cancer, but its implementation faces some challenges. Understanding the influencing factors of CEUS utilization is crucial for its successful implementation. However, such research is rare. The aims of this study were to investigate the status of CEUS utilization and its predictors in China. Methods Through multistage random sampling, a cross-sectional study design was conducted among physicians in charge of direct use of CEUS working at liver disease-related departments of sampled health institutions. To access the potential influencing factors of physicians' CEUS utilization, a structured questionnaire was developed based on the theoretical model, which was developed by integration of the Theory of Planned Behavior (TPB) and Technology Acceptance Model (TAM). Structural equation modeling was used to verify the proposed hypotheses, and analyze the relationship and mechanism between the factors. Results A total of 309 physicians were enrolled. The mean score of utilization behavior was 2.04 (SD = 1.07), and 37.22% above the mean. The favorable fitting results demonstrated that the integration of TAM and TPB was an acceptable model. SEM results also identified physicians’ intentions to use CEUS was directly associated with utilization behavior (β = 0.287, P β = 0.272, P β = 0.172, P = 0.013), perceived behavioral control (β = 0.491, P β = 0.108, P = 0.027) significantly influenced physicians’ intentions. Besides, subjective norm (β = 0.065, P = 0.021), perceived behavioral control (β = 0.141, P = 0.003), and perceived ease of use (β = 0.022, P = 0.033) indirectly affected physicians’ CEUS utilization. Conclusions The findings provide a reference for understanding the factors associated with physicians' utilization of CEUS. Additionally, the proposed measures such as building innovative and incentive environment, providing high quality and adequate training, etc., will help promote the utilization of CEUS, thereby increasing the detection rate of liver cancer, and improving the survival rate and the quality of life for liver cancer patients.

To explore the relationship between Mycoplasma hyorhinis infection and tyrosine kinase inhibitor (TKI) resistance in lung adenocarcinoma patients. Mycoplasma hyorhinis infection can be verified with the monoclonal antibody PD4, which specifically recognizes a distinct protein of M. hyorhinis. Immunohistochemistry (IHC), using PD4 to detect M. hyorhinis, was performed on paraffin-embedded lung adenocarcinoma tissues of patients who had epidermal growth factor (EGFR) mutations and had received oral TKI. The number of patients enrolled in our study was 101. Assessments following TKI treatment were performed until objective disease progression or stable disease at the cutoff date was reached. In all of the patients, the primary endpoint was investigator-assessed progression-free survival (PFS). Immunohistochemistry revealed that 61 of 101 cases (60.4%) of lung adenocarcinoma were positive for M. hyorhinis, which comprised of 31 low-positive cases and 30 high-positive cases; the remaining 40 cases (39.6%) were negative. The median PFS was significantly longer in the negative group [18 months (95% CI 14.15–21.85)] than in the low-positive group [10 months (95% CI 7.70–12.30); hazard ratio (HR) 4.095, 95% CI 2.254–7.438; p

Qingwen Deng, Junhong Lu, Zhichao Zeng, Yuhang Zheng, Wenbin Liu Department of Health Management, School of Public Health, Fujian Medical University, Fuzhou 350122, People’s Republic of ChinaCorrespondence: Wenbin LiuDepartment of Health Management, School of Public Health, Fujian Medical University, Room 108 in the Building for School of Public Health, No. 1 Xuefubei Road, Minhou District, Fuzhou 350122, People’s Republic of ChinaTel + 86 13799983766Email wenbinliu126@126.comBackground: Limited diffusion of health technology has greatly halted the improvement of resource integration and healthcare outcomes. The importance of understanding the dynamics of health technology diffusion is increasingly highlighted. However, the dynamic mechanism of health technology diffusion in the context of the integrated care system (ICS) remained largely unknown.Purpose: To develop and validate the scale on Dynamics of Health Technology Diffusion in Integrated Care System (DHTDICS) for providing an instrument to investigate the health technology diffusion in the ICS in China, by taking the Des-gamma-Carboxy Prothrombin (DCP) test as an example.Methods: Based on previous classical theories such as the theory of planned behavior (TPB), technology acceptance model (TAM), and technology-organization-environment framework (TOE), the scale with 34 items was initially developed. It was tested in a cross-sectional questionnaire survey including 246 participants from February to August 2019 in China. Cronbach’s alpha, corrected item-total correlation, and factor loadings were used to assess reliability. Exploratory factor analysis and confirmatory factor analysis were applied to evaluate the validity by assessing factor structures and correlations.Results: Reliability analysis revealed excellent internal consistency. Acceptable validity was confirmed through tests of convergent validity and discriminant validity. Regarding the domains that DHTDICS contributes, the results highlighted 4 domains: personal beliefs (including dimensions of attitudes, subjective norms and perceived behavioral control), technical drivers (including dimensions of ease of use and price rationality), organizational readiness (including dimensions of organizational culture, technology absorptive willingness and technology sharing willingness), and external environment (dimension of industry competition pressure).Conclusion: The findings confirmed the reliability and validity of the scale on DHTDICS. The scale will be not only a scientific tool in determining the dynamics of health technology diffusion in the ICS, but also a helpful reference for developing future interventions to promote health technology diffusion.Keywords: health technology diffusion, dynamics, scale development, integrated care system, validity, reliability, China

Dysfunction of epidermal growth factor receptor (EGFR) signalling plays a critical role in the oncogenesis of non–small‐cell lung cancer (NSCLC). Here, we reported the natural product, licochalcone A, exhibited a profound anti‐tumour efficacy through directly targeting EGFR signalling. Licochalcone A inhibited in vitro cell growth, colony formation and in vivo tumour growth of either wild‐type (WT) or activating mutation EGFR‐expressed NSCLC cells. Licochalcone A bound with L858R single‐site mutation, exon 19 deletion, L858R/T790M mutation and WT EGFR ex vivo, and impaired EGFR kinase activity both in vitro and in NSCLC cells. The in silico docking study further indicated that licochalcone A interacted with both WT and mutant EGFRs. Moreover, licochalcone A induced apoptosis and decreased survivin protein robustly in NSCLC cells. Mechanistically, we found that treatment with licochalcone A translationally suppressed survivin through inhibiting EGFR downstream kinases ERK1/2 and Akt. Depletion of the translation initiation complex by eIF4E knockdown effectively inhibited survivin expression. In contrast, knockdown of 4E‐BP1 showed the opposite effect and dramatically enhanced survivin protein level. Overall, our data indicate that targeting survivin might be an alternative strategy to sensitize EGFR‐targeted therapy.

Deoxynivalenol (DON) is a widely distributed mycotoxin that frequently occurs in various foodstuffs, and poses a health risk to human and animals. Biodegradation of DON to less- or non-toxic substances using naturally existing microorganisms is considered the best approach for DON detoxification. Although various microorganisms capable of detoxifying DON have been reported; however, such studies on probiotic strains are scarce. In this study, a bacterial strain (ASAG 216) showed to possess the capability of detoxifying 100 μg/mL DON by 81.1% within 8 h was isolated from the intestine of a donkey. After morphological observation and 16S rDNA sequence analysis, the strain was identified as Bacillus subtilis. The DON-degradation potential of B. subtilis ASAG 216 was predominantly attributed to the culture supernatant, which turned to be sensitive to heat, sodium dodecyl sulfate, and proteinase K treatment, indicating the possible presence of extracellular proteins or enzymes in the supernatant which were responsible for DON degradation. Moreover, B. subtilis ASAG 216 has a broad temperature (35–50 °C) and pH (6.5–9.0) tolerance on DON degradation, apart from its ability to withstand conditions which generally prevail during the intestinal transit. In addition, the tested strain showed antimicrobial activity against Escherichia coli, Staphylococcus aureus and Salmonella typhimurium. These results provide satisfactory grounds for the potential use of B. subtilis ASAG 216 as a new feed additive to address DON contamination.

Feng Gao,1,2,* Li Zhou,3,* Ming Li,1,4,5,* Wenbin Liu,6 Shuting Yang,2 Wei Li1,7 1Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Department of Pathology, Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 4Changsha Stomatological Hospital, Changsha, Hunan 410004, People’s Republic of China; 5School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, People’s Republic of China; 6Department of Pathology, Hunan Cancer Hospital, Changsha, Hunan 410013, People’s Republic of China; 7Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Li Email weililx@csu.edu.cnBackground: Deregulation of Cyclin D1 and cell cycle progression plays a critical role in tumorigenesis. The natural compound piperlongumine (PL) exhibits potential anticancer effects in various cancer models, but the underlying mechanism needs further elucidation.Methods: The inhibitory effect of PL on colorectal cancer (CRC) cells was determined by anchorage-dependent and -independent assays. The protein level of Cyclin D1 was examined by immunoblot (IB) and immunohistochemical staining (IHC). The mRNA level was determined by qRT-PCR. Phosphorylation of histone H3 was analyzed by immunofluorescence (IF). The cell cycle was examined by flow cytometry. The in vivo antitumor effect was validated by the xenograft mouse model.Results: Cyclin D1 was overexpressed in CRC tissues and cells, and was required for maintaining cell growth, colony formation, and in vivo tumorigenesis. PL decreased the protein level of c-Fos, which eventually reduced the transcriptional activity of AP-1 and the mRNA level of Cyclin D1. Mechanism study showed that PL impaired EGF-induced activation of ERK1/2 and Akt signalings, which resulted in a reduction of c-Fos transcription. Furthermore, PL reduced the half-life of c-Fos and caused the ubiquitination-dependent degradation of c-Fos. Finally, the in vivo antitumor effect of PL on CRC cells was examined using a xenograft mouse model.Conclusion: Our data indicate that PL is a promising antitumor agent that deserves further study for CRC treatment.Keywords: colorectal cancer, piperlongumine, c-Fos, Cyclin D1

Background: Overexpression of survivin plays a crucial role in the maintaining unlimited cell growth, apoptosis suppression, and correlates with poor prognosis in human malignancies. Methods: A natural product library was used for natural compound screening through MTS assay. The expression of survivin in oral squamous cell carcinoma (OSCC) and the inhibitory effect of xanthohumol (XN) on OSCC were examined through methods of anchorage-dependent and -independent growth assays, immunoblot, immunofluorescence, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment. Results: Survivin is highly expressed in OSCC cells and patient-derived tissues, and required for OSCC cell growth in vitro and in vivo . With a natural compound screening, we identified that xanthohumol exhibited a significant anti-tumor effect against OSCC cells through inhibiting survivin protein. Xanthohumol suppressed anchorage-dependent and independent cell growth and delayed in vivo tumor development of OSCC cells. Xanthohumol inhibited the Akt-Wee1-CDK1 signaling, which in turn decreased survivin phosphorylation on Thr34, and facilitated E3 ligase Fbxl7-mediated survivin ubiquitination. Xanthohumol alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Conclusion: Our findings indicate that targeting survivin for degradation might a promising strategy for OSCC treatment. Keywords: Oral squamous cell carcinoma; Xanthohumol; Ubiquitination; Fbxl7

Feng Gao,1,2,* Ming Li,1,3,4,* Wenbin Liu,5 Wei Li2,6 1Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 3School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, People’s Republic of China; 4Changsha Stomatological Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410004, People’s Republic of China; 5Department of Pathology, The Affiliated Hunan Cancer Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 6Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Li Tel +86 731-88618643Email weililx@csu.edu.cnBackground: Deregulation of epidermal growth factor receptor (EGFR) signaling plays a critical role in non-small cell lung cancer (NSCLC) tumorigenesis. The natural product Tanshinone IIA (Tan IIA) exhibits significant anti-tumor effect in various human cancers, however, the mechanism remains elusive.Methods: The inhibitory effect of Tan IIA NSCLC cells was determined by MTS and soft agar assays. The activation of EGFR signaling and the protein level of myeloid cell leukemia 1 (Mcl-1) were examined by immunoblot (IB), immunohistochemical staining (IHC), and ubiquitination analysis. The in vivo anti-tumor effect was validated by the xenograft mouse model.Results: Tan IIA inhibits NSCLC cells through suppression of EGFR signaling. Tan IIA decreases cell viability and colony formation in EGFR wild type and activating mutant cell lines. The IB data further confirmed that Tan IIA suppresses EGFR phosphorylation time- and dose-dependently. Tan IIA destabilizes Mcl-1 and shortens the half-life. Ubiquitination analysis showed that treatment with Tan IIA promotes Mcl-1 ubiquitination and degradation. Further study showed that the downregulation of EGFR-Akt signaling is required for Tan IIA-induced Mcl-1 reduction. Ectopic overexpression of constitutively activated Akt1 compromised these antitumor efficacies in Tan IIA-treated NSCLC cells. Finally, Tan IIA inhibited the in vivo tumor growth.Conclusion: Our data indicate that Tan IIA acts as an EGFR signaling inhibitor, and targeting EGFR-Akt-Mcl1 axis could provide a new option for NSCLC treatment.Keywords: non-small cell lung cancer, Tanshinone IIA, epidermal growth factor receptor, Mcl-1, ubiquitination

Background Addiction to aerobic glycolysis is a common metabolic phenotype in human non-small cell lung cancer (NSCLC). The natural product Sinomenine (Sin) exhibits significant anti-tumor effects in various human cancers. However, the underlying mechanism remains elusive. Methods The inhibitory effect of Sin on NSCLC cells was determined by MTS and soft agar assays. The glycolysis efficacy of NSCLC cells was examined by glucose uptake and lactate production. The activation of Akt signaling and the protein level of hexokinases II (HK2) were examined by immunoblot (IB), qRT-PCR, and immunohistochemical staining (IHC). The in vivo anti-tumor effect of Sin was validated by the xenograft mouse model. Results We showed that HK2 is highly expressed in NSCLC tissues and cell lines. Depletion of HK2 suppressed cell viability, anchorage-independent colony formation, and xenograft tumor growth. Sinomenine exhibited a profound inhibitory effect on NSCLC cells by reducing HK2-mediated glycolysis both in vitro and in vivo. Ectopic overexpression of HK2 compromised these anti-tumor efficacies in sinomenine-treated NSCLC cells. Moreover, we revealed that sinomenine decreased Akt activity, which caused the down-regulation of HK2-mediated glycolysis. Knockdown of Akt reduced HK2 protein level and impaired glycolysis. In contrast, overexpression of constitutively activated Akt1 reversed this phenotype. Conclusion This study suggests that targeting HK2-mediated aerobic glycolysis is required for sinomenine-mediated anti-tumor activity.

Bacillus thuringiensis(Bt) is a well-known entomopathogen. In this study, we cloned thevip3Aa1gene fromBtstrain GIM1.147 and investigated the insecticidal activity ofBtVip3Aa1 protein produced byEscherichia coliagainstPeriplaneta americanaandBlattella germanica. The results showed that purified Vip3Aa1 exhibited an LC50at 24 h againstP. americanaandB. germanicaof 0.182 mg·ml-1and 0.276 mg·ml-1, respectively. Investigations of its mode of action showed that Vip3Aa1 could be proteolyzed into a 62-kDa toxic protein byP. americanagut-soluble proteases. In addition, Vip3Aa1 caused severe damage to the columnar colon and the midgut, as observed through hematoxylin-eosin staining and scanning electron microscopy. The 62-kDa activated Vip3Aa1 protein could form ion channels in the colon and the midgut in vitro. Based on protease activity analysis, Vip3Aa1 at concentrations of 0.125 mg·ml-1and 0.031 mg·ml-1could downregulate the activities of glutathione S-transferase, α-NA esterase, trypsin, and chymotrypsin. This report provides the first description of the activity of Vip3Aa1 toxins towardP. americanaandB. germanicaand demonstrates that the mechanism through which Vip3Aa1 killsP. americanaandB. germanicadiffers from that involved in the killing of lepidopteran insects.

In clinical medicine, the contrast-enhanced ultrasound (CEUS) has been a commonly used imaging modality for diagnosis of breast tumor. However, most researchers in computer vision field only focus on B-mode ultrasound image which does not get good results. To improve the accuracy of classification, first, we propose a novel method, i.e., a Temporal Sequence Dual-Branch Network (TSDBN) which, for the first time, can use B-mode ultrasound data and CEUS data simultaneously. Second, we designed a new Gram matrix to model the temporal sequence, and then proposed a Temporal Sequence Regression Mechanism (TSRM), which is a novel method to extract the enhancement features from CEUS video based on the matrix. For B-mode ultrasound branch, we use the traditional ResNeXt network for feature extraction. While CEUS branch uses ResNeXt + R(2 + 1) D network as the backbone network. We propose a TSRM to learning temporal sequence relationship among frames, and design a Shuffle Temporal Sequence Mechanism (STSM) to shuffle temporal sequences, the purpose of which is to further enhance temporal information among frames. Experimental results show that the proposed TSRM could use temporal information effectively and the accuracy of TSDBN is higher than that of state-of-art approaches in breast cancer classification by nearly 4%.

Ischemic stroke subtyping was not only highly valuable for effective intervention and treatment, but also important to the prognosis of ischemic stroke. The manual adjudication of disease classification was time-consuming, error-prone, and limits scaling to large datasets. In this study, an integrated machine learning approach was used to classify the subtype of ischemic stroke on The International Stroke Trial (IST) dataset. We considered the common problems of feature selection and prediction in medical datasets. Firstly, the importances of features were ranked by the Shapiro-Wilk algorithm and Pearson correlations between features were analyzed. Then, we used Recursive Feature Elimination with Cross-Validation (RFECV), which incorporated linear SVC, Random-Forest-Classifier, Extra-Trees-Classifier, AdaBoost-Classifier, and Multinomial-Naïve-Bayes-Classifier as estimator respectively, to select robust features important to ischemic stroke subtyping. Furthermore, the importances of selected features were determined by Extra-Trees-Classifier. Finally, the selected features were used by Extra-Trees-Classifier and a simple deep learning model to classify the ischemic stroke subtype on IST dataset. It was suggested that the described method could classify ischemic stroke subtype accurately. And the result showed that the machine learning approaches outperformed human professionals.

Cancers, a group of multifactorial complex diseases, are generally caused by mutation of multiple genes or dysregulation of gene interactions. Applying machine learning methods to microarray gene expression profiles for disease classification is a popular method to predict disease state or outcome. Traditional computational methods that detect genes differentially expressed between cancer and normal samples are ineffective in independent cohorts of patients. However, current methods consider pathways as simple gene sets and include pathway topological information but ignore significant individual genes and interactions between genes, which are essential to infer a more robust pathway activity. In this study, we proposed a novel approach to describe the activity of a pathway that incorporates both the differential expression degree of genes between the case and control and the interaction strength between genes. We applied the method to the classifications of seven cancers. Within-dataset experiments and cross-dataset experiments demonstrated that our novel method achieved robust and superior performance when compared to the five existing methods.

Tremor, which is one of the most common movement disorders, is a repetitive movement that is caused by periodic muscle contraction and relaxation. To suppress tremors of upper-limb tremor patients, such as essential tremor (ET) patients, many kinds of devices have been developed. On the other hand, when mechanical vibration stimulation is applied to a human muscle, sustained muscle contraction, which is referred to as the tonic vibration reflex (TVR), is induced in the stimulated muscle. In this study, a novel tremor suppression method that utilizes the periodic TVR to induce muscle contraction/relaxation to generate the counterphase motion of the ET is proposed and applied to the forearm pronation-supination ET. In the proposed method, periodic vibration stimulation is applied to generate the periodic TVR in the pronator teres muscle and/or supinator muscle. First, the results confirmed that the TVR can be induced by applying mechanical vibration stimulation to the pronator teres muscle and supinator muscle since the forearm pronation-supination tremor is one of the key features of the ET. Furthermore, the findings also confirmed that the TVR intensity that is induced in these muscles can be adjusted by changing the vibration stimulation frequency. Second, the results show that the counterphase motion of the ET (i.e., periodic pronation-supination motion) can be generated by applying the proposed method. The effectiveness of the proposed method for tremor suppression is evaluated by comparing the generated motion with the ET motion.

Acquired uniparental disomy (aUPD) leads to homozygosity facilitating identification of monoallelically expressed genes. We analyzed single-nucleotide polymorphism array-based genotyping data of 448 head and neck squamous cell carcinoma (HNSCC) samples from The Cancer Genome Atlas to determine the frequency and distribution of aUPD regions and their association with survival, as well as to gain a better understanding of their influence on the tumor genome. We used expression data from the same dataset to identify differentially expressed genes between groups with and without aUPD. Univariate and multivariable Cox proportional hazards models were performed for survival analysis. We found that 82.14% of HNSCC samples carried aUPD; the most common regions were in chromosome 17p (31.25%), 9p (30.13%), and 9q (27.46%). In univariate analysis, five independent aUPD regions at chromosome 9p, two regions at chromosome 9q, and the CDKN2A region were associated with poor overall survival in all groups, including training and test sets and human papillomavirus (HPV)-negative samples. Forty-three genes in areas of aUPD including PD-L1 and CDKN2A were differentially expressed in samples with aUPD compared to samples without aUPD. In multivariable analysis, aUPD at the CDKN2A region was a significant predictor of overall survival in the whole cohort and in patients with HPV-negative HNSCC. aUPD at specific regions in the genome influences clinical outcomes of HNSCC and may be beneficial for selection of personalized therapy to prolong survival in patients with this disease.

Purpose: APOBEC3-UNG imbalance contributes to hepatitis B virus (HBV) inhibition and somatic mutations. We aimed to explore the associations between hepatocellular carcinoma (HCC) risk and genetic polymorphisms predisposing the imbalance. Experimental Design: Genetic polymorphisms at APOBEC3 promoter and UNG enhancer regions were genotyped in 5,621 participants using quantitative PCR. HBV mutations (nt.1600–nt.1945, nt.2848–nt.155) were determined by Sanger sequencing. Dual-luciferase reporter assay was applied to detect the transcriptional activity. Effects of APOBEC3B/UNG SNPs and expression levels on HCC prognosis were evaluated with a cohort of 400 patients with HCC and public databases, respectively. Results: APOBEC3B rs2267401-G allele and UNG rs3890995-C allele significantly increased HCC risk. rs2267401-G allele was significantly associated with the generation of APOBEC-signature HBV mutation whose frequency consecutively increased from asymptomatic HBV carriers to patients with HCC. Multiplicative interaction of rs2267401-G allele with rs3890995-C allele increased HCC risk, with an adjusted OR (95% confidence interval) of 1.90 (1.34–2.81). rs2267401 T-to-G and rs3890995 T-to-C conferred increased activities of APOBEC3B promoter and UNG enhancer, respectively. IL6 significantly increased APOBEC3B promoter activity and inhibited UNG enhancer activity, and these effects were more evident in those carrying rs2267401-G and rs3890995-C, respectively. APOBEC3B rs2267401-GG genotype, higher APOBEC3B expression, and higher APOBEC3B/UNG expression ratio in HCCs indicated poor prognosis. APOBEC-signature somatic mutation predicts poor prognosis in HBV-free HCCs rather than in HBV-positive ones. Conclusions: Polymorphic genotypes predisposing the APOBEC3B-UNG imbalance in IL6-presenting microenvironment promote HCC development, possibly via promoting the generation of high-risk HBV mutations. This can be transformed into specific prophylaxis of HBV-caused HCC.

Adsorbents from sustainable precursors are highly desirable for practical applications. In this study, carboxymethyl cellulose (CMC) and humic acid (HA) were adopted to fabricate a composite immobilized on precipitates of calcium hydroxide (PCH) and ferric hydroxide (PFH). The as-obtained adsorbent, denoted as HA-CMC/PMH (PCH and PFH were referred to as PMH), was analyzed by infrared spectroscopy, scanning electron microscopy, X-ray photoelectron spectroscopy and thermo gravimetric analysis. When applying for a typical organic pollutant of methylene blue (MB) removal from aqueous solution, a high adsorption capacity of 666.67 mg/g was achieved over HA-CMC/PMH. The adsorption mechanisms of MB involved ion exchanging and π–π interactions, this adsorption process mainly occurred on both anionic and aromatic groups. Adsorption behavior analysis indicated that Langmuir isotherm model and pseudo-second order kinetic model fitted experimental data well, suggesting a mono-layer adsorption of MB onto the adsorbent. Further thermodynamic analysis proved that the adsorption of MB onto HA-CMC/PMH was an exothermal spontaneous process. The developed adsorbent is also reusable with 79.93% of adsorption capacity remaining in the fifth recycle runs. Therefore, the adsorbent of HA-CMC/PMH is suggested to be a promising candidate for adsorption applications.

Background Prevention of epithelial-mesenchymal transition (EMT) provides a novel treatment strategy for tumor metastasis. Our previous studies have shown that diallyl disulfide (DADS) inhibits Ras related C3 botulinum toxin substrate1 (Rac1) expression, being a potential agent that suppresses migration and invasion of colon cancer cells. The study provides information on the underlying mechanisms. Methods The expression of Rac1 and EMT markers (vimentin, N-cadherin and E-cadherin) in colon cancer samples was detected. Colon cancer cell lines treated with or without DADS were used to examine EMT markers, Rac1 and its related molecules. Various cell functions related to metastasis were performed in vitro, and further confirmed in vivo. Results Rac1 was highly expressed in colon cancer, and associated with aberrant expression of EMT markers and poor prognosis. Rac1 overexpression induced cell migration and invasion in vitro and metastasis in vivo with down-regulation of E-cadherin and up-regulation of N-cadherin, vimentin, and snail1, whereas inhibition of Rac1 impaired the oncogenic function. DADS suppressed Rac1 expression and activity via inhibition of PI3K/Akt pathway, thus suppressing EMT and invasion and migration of colon cancer cells. The tumor inhibition of DADS was enhanced by knockdown of Rac1, but antagonized by overexpression of Rac1. We further found that DADS blocked EMT via targeting the Rac1-mediated PAK1-LIMK1-Cofilins signaling. Conclusion Rac1 is a potential target molecule for the inhibitory effect of DADS on EMT and invasion and metastasis of colon cancer cells.

As an important aspect of epigenetics, DNA methylation has been proven to be suitable for forensic DNA analysis. By detecting changes in DNA methylation, it is desirable to construct a model of age patterns associated with it to infer the age of the individual. The hTERT gene methylation is closely related to tumors, but there are few reports on the relationship between hTERT gene promoter methylation and age. In this study, we utilized the methylation-specific polymerase chain reaction and real-time PCR (relative quantification and absolute quantification) approach to explore the connection between hTERT DNA methylation and age prediction. We fit three models for age prediction based on methylation assay for 90 blood samples from donors aged 1–79 years old. Among them, the model of absolute quantification of real-time enabled the age prediction with R2 = 0.9634. We verified the linear regression model with a validation set of 30 blood samples where prediction average error was 4.29 years. Generally, this reliable method improves the DNA methylation analysis of forensic samples.

Background Both depression itself and antidepressant medication have been reported to be significantly related to the risk of type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a treatment target for T2DM, has a neuroprotective effect. As an enhancer and sensitiser of GLP-1, metformin has been reported to be safe for the neurodevelopment. The present study aimed to determine whether and how GLP-1 mediates antidepressant effects of metformin and exercise in mice. Methods Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 8 weeks. From the 4th week, CUMS mice were subjected to oral metformin treatment and/or treadmill running. A videocomputerized tracking system was used to record behaviors of mice for a 5-min session. ELISA, western blotting and immunohistochemistry were used to examine serum protein concentrations, protein levels in whole hippocampus, protein distribution and expression in dorsal and ventral hippocampus, respectively. Results Our results supported the validity of metformin as a useful antidepressant; moreover, treadmill running favored metformin effects on exploratory behaviors and serum corticosterone levels. CUMS reduced GLP-1 protein levels and phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), but increased protein levels of B-cell lymphoma 2-associated X-protein (BAX) in mice hippocampus. All these changes were restored by both single and combined treatment with metformin and exercise. Limitations We did not establish a causal relationship between GLP-1 expression and related signaling, using GLP-1 agonist and antagonist or knockout techniques. Conclusions Our findings have demonstrated that protein levels of pERK and BAX may be relevant to the role of GLP-1 in antidepressant effects of metformin and exercise, which may provide a novel topic for future clinical research.

Aberrant sterol lipid metabolism is associated with physiological dysfunctions in the aging brain and aging-dependent disorders such as neurodegenerative diseases. There is an unmet demand to comprehensively profile sterol lipids spatially and temporally in different brain regions during aging. Here, we develop an ion mobility-mass spectrometry based four-dimensional sterolomics technology leveraged by a machine learning-empowered high-coverage library (>2000 sterol lipids) for accurate identification. We apply this four-dimensional technology to profile the spatially resolved landscapes of sterol lipids in ten functional regions of the mouse brain, and quantitatively uncover ~200 sterol lipids uniquely distributed in specific regions with concentrations spanning up to 8 orders of magnitude. Further spatial analysis pinpoints age-associated differences in region-specific sterol lipid metabolism, revealing changes in the numbers of altered sterol lipids, concentration variations, and age-dependent coregulation networks. These findings will contribute to our understanding of abnormal sterol lipid metabolism and its role in brain diseases., Sterol lipids are crucial for maintaining proper brain function. Here, the authors combine ion mobility-mass spectrometry and machine learning to assemble a sterol lipid library and characterize differences in sterol lipids across ten brain regions and two age groups in mice.

Microbial secondary metabolites are one of the main sources of bioactive natural products. It is estimated that around 75% of all antibiotics are derived from secondary metabolites produced by filamentous actinomycete. Gordonia sp. are members of the actinomycete family, their contribution to the environment improvement and environmental protection by their biological degradation ability, but there are few studies on the antimicrobial activity of their secondary metabolites. Our team isolated a Gordonia strain WA 4–31 with anti-Candida albicans activity from the intestinal tract of Periplaneta americana in the early stage. In this study, we firstly identified the strain WA 4–31 by the morphological characteristics and the phylogenetic analyses, and found that it homologous to a strain of Gordonia from the Indian desert by 100%. Then four compounds, Actinomycin D (1), Actinomycin X2 (2), Mojavensin A (3) and cyclic (leucine-leucne) dipeptide (4) were purified from the ethyl acetate extract of the fermented broth of the strain. The compounds 1–4 had activities against Candida albicans, Aspergillus niger, Aspergillus fumigatus and Trichophyton rubrum. They also had activities against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli.coli in different degree. Interestingly, we found that when Mojavensin A was mixed with compound 4 ratio of 1:1, the activity of the mixture on anti-Candida albicans was better than the single. Besides, compounds 1–3 had varying degrees of antiproliferative activity on CNE-2 cells and HepG-2 cells. These indicated that Gordonia rare actinomycete from the intestinal tract of Periplaneta americana possessed a potential as a source of active secondary metabolites.

Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the immune system produces an antibody response to its own antigens due to impaired immune tolerance. Although antibodies are derived from plasma cells differentiated by B cells, the T-B cells also contribute a lot to the immune system. In particular, the subsets of helper T (Th) cells, including the dominant subsets such as Th2, Th17, and follicular helper T (Tfh) cells and the inferior subsets such as regulatory T (Treg) cells, shape the immune imbalance of IMN and promote the incidence and development of autoimmune responses. After reviewing the physiological knowledge of various subpopulations of Th cells and combining the existing studies on Th cells in IMN, the role model of Th cells in IMN was explained in this review. Finally, the existing clinical treatment regimens for IMN were reviewed, and the importance of the therapy for Th cells was highlighted.

BackgroundDespite there is growing evidence focusing on health inequalities in China, socioeconomic inequalities in cognitive impairment among older adults have received little attention. This study aims to measure socioeconomic inequalities in cognitive impairment among Chinese older adults, and determine the contributing social factors to the inequalities.MethodsA cross-sectional analysis was performed using data from the 2018 Chinese Longitudinal Healthy Longevity Survey (CLHLS). A total of 10,556 older adults aged 65 and over were included in the study. The prevalence of cognitive impairment was measured by using the Chinese version of the Mini-Mental State Examination. The socioeconomic inequalities in cognitive impairment were illustrated and quantified by the concentration curve and normalized concentration index. Multivariate logistic regression was conducted to identify the associated factors of cognitive impairment. And decomposition analysis was further applied to decompose the contribution of each determinant to the observed inequalities in cognitive impairment.ResultsThe study indicated that the prevalence of cognitive impairment among Chinese older adults was 18.95%. The overall concentration index for cognitive impairment was − 0.046, which suggested a higher concentration of cognitive impairment among socioeconomically disadvantaged older adults. The results showed the prevalence of cognitive impairment was associated with sex, age, marital status, education level, occupation, economic status, emotional support, financial support, living arrangement, and participation in informal activities. Decomposition results further revealed the contributions of the determinants to the inequalities in cognitive impairment. Specifically, age (131.61%), marital status (85.68%), emotional support (84.85%), education level (39.73%), occupation (21.24%), sex (17.25%), financial support (− 4.19%), economic status (1.02%), living arrangement (0.88%), and informal activities (0.30%) have varying degrees of contributions to the inequality in cognitive impairment.ConclusionThis study sheds light on the pro-rich inequality in cognitive impairment among older adults in China. It suggests that policymakers should pay more attention to older adults who are female, old-old, widowed, illiterate, economically disadvantaged, with no social support, and less socially involved. Also, more targeted interventions should be undertaken to improve the socioeconomic conditions of these vulnerable individuals and strengthen their ability to cope with the risk of cognitive impairment.

Adoptive transfer of γδ T cells is an attractive approach for cell-based immunotherapy in treatment of renal cell carcinoma (RCC). Interleukin-15 (IL-15) is the key physiological cytokine that regulates γδ T cell differentiation, proliferation and survival. In this work, we determined that IL-15 have the capacity to enhance the anti-tumoral functions of γδ T cells. IL-15 can induce the upregulation of cytotoxicity-associated molecules on the γδ T cell surface, incite γδ T cell proliferation and decrease apoptosis. Moreover, the enhanced cytotoxicity of IL-15-induced γδ T cell was dependent on the interaction of NKG2D and MICA. Most importantly, we found that IL-15-induced γδ T cells effectively suppressed the tumor growth in vivo and prolonged the survival time of RCC-bearing patient‑derived xenograft (PDX) mice. These results are important for the prospective use of γδ T cells in clinical practice when designing novel cell-based immunotherapies against RCC.

Background The repair of critical-sized bone defects is always a challenging problem. Electromagnetic fields (EMFs), used as a physiotherapy for bone defects, have been suspected to cause potential hazards to human health due to the long-term exposure. To optimize the application of EMF while avoiding its adverse effects, a combination of EMF and tissue engineering techniques is critical. Furthermore, a deeper understanding of the mechanism of action of EMF will lead to better applications in the future. Methods In this research, bone marrow mesenchymal stem cells (BMSCs) seeded on 3D-printed scaffolds were treated with sinusoidal EMFs in vitro. Then, 5.5 mm critical-sized calvarial defects were created in rats, and the cell scaffolds were implanted into the defects. In addition, the molecular and cellular mechanisms by which EMFs regulate BMSCs were explored with various approaches to gain deeper insight into the effects of EMFs. Results The cell scaffolds treated with EMF successfully accelerated the repair of critical-sized calvarial defects. Further studies revealed that EMF could not directly induce the differentiation of BMSCs but improved the sensitivity of BMSCs to BMP signals by upregulating the quantity of specific BMP (bone morphogenetic protein) receptors. Once these receptors receive BMP signals from the surrounding milieu, a cascade of reactions is initiated to promote osteogenic differentiation via the BMP/Smad signalling pathway. Moreover, the cytokines secreted by BMSCs treated with EMF can better facilitate angiogenesis and osteoimmunomodulation which play fundamental roles in bone regeneration. Conclusion In summary, EMF can promote the osteogenic potential of BMSCs and enhance the paracrine function of BMSCs to facilitate bone regeneration. These findings highlight the profound impact of EMF on tissue engineering and provide a new strategy for the clinical treatment of bone defects.

Hypertensive nephropathy is the most common complication of hypertension, and is one of the main causes of end-stage renal disease (ESRD) in numerous countries. The basic pathological feature of hypertensive nephropathy is arteriolosclerosis followed by renal parenchymal damage. The etiology of this disease is complex, and its pathogenesis is mainly associated with renal hemodynamic changes and vascular remodeling. Despite the increased knowledge on the pathogenesis of hypertensive nephropathy, the current clinical treatment methods are still not effective in preventing the development of the disease to ESRD. Herbal medicine, which is used to relieve symptoms, can improve hypertensive nephropathy through multiple targets. Since there are few clinical studies on the treatment of hypertensive nephropathy with herbal medicine, this article aims to review the progress on the basic research on the treatment of hypertensive nephropathy with herbal medicine, including regulation of the renin angiotensin system, inhibition of sympathetic excitation, antioxidant stress and anti-inflammatory protection of endothelial cells, and improvement of obesity-associated factors. Herbal medicine with different components plays a synergistic and multi-target role in the treatment of hypertensive nephropathy. The description of the mechanism of herbal medicine in the treatment of hypertensive nephropathy will contribute towards the progress of modern medicine.

Purpose The association between body mass index (BMI) and health-related quality of life (HRQOL) has not been verified neither in China nor in any other Asian country. This study aimed to examine the association between BMI and HRQOL in the Chinese older adults population. Methods A total of 5018 older adults from the China’s Health-Related Quality of Life Survey for Older Adults 2018 was included in this study. The HRQOL was measured by the Chinese version of the World Health Organization Quality of Life Instrument-Older Adults Module (WHOQOL-OLD). Multiple linear regression analysis was used to explore the associations between BMI and HRQOL among the older adults in rural, urban, and total samples. Results After adjusting all the confounders, compared with normal weight group, underweight was negatively correlated with the total scores of HRQOL among the older adults in rural (B= −2.310, p < 0.01), urban (B= −1.019, p < 0.001), and total samples (B= −2.351, p < 0.001), whereas overweight was positively associated with the total scores of HRQOL among the older adults in rural samples (B= 0.888, p < 0.05). The results showed that obesity was not associated with the total scores of HRQOL among the older adults in rural (B= −1.214, p > 0.05), urban (B= −0.074, p > 0.05), and total samples (B= −1.461, p > 0.05). Conclusion This study suggests that obese Chinese older adults did not show a better quality of life than those of normal weight. But this result does not deny the “jolly fat” hypothesis entirely, as the overweight older adults from rural areas showed better HRQOL. Moreover, underweight older people show a poorer HRQOL. The relationship between BMI and HRQOL in the older adults needs to be differentiated according to different characteristics of the population.

Previous studies have suggested that 1,9-Pyrazoloanthrone, known as SP600125, can induce cell polyploidization. However, what is the phase of cell cycle arrest caused by SP600125 and the underlying regulation is still an interesting issue to be further addressed. Research in this article shows that SP600125 can block cell cycle progression at the prometaphase of mitosis and cause endomitosis. It is suggested that enhancement of the p53 signaling pathway and weakening of the spindle assembly checkpoint are associated with the SP600125-induced cell cycle arrest. Using preliminary SP600125 treatment, the samples of the cultured fish cells and the fish tissues display a great number of chromosome splitting phases. Summarily, SP600125 can provide a new protocol of chromosomes preparation for karyotype analysis owing to its interference with prometaphase of mitosis.

In order to solve the opioid crisis which broke out in the United States, the diffusion model suitable for the problem is established, inspired by the error inverse propagation model. By observing the diffusion characteristics of opioids between the five states and their counties, the locations where each state began to use specific opioids are identified and the diffusion characteristics of the corresponding programmes are summarized. Ultimately, the opportunity for the government to focus on such cases and the threshold of the corresponding drug is found, and the location and time of the case are predicted.

Deoxynivalenol (DON) poses a serious health threat to animals and humans consuming DON-contaminated food and feed. Biological means of detoxification of DON are considered as one of the effective strategies. The aim of the work was to study ameliorative effects of Bacillus subtilis ASAG 216 on DON-induced toxicosis in piglets. A decrease in average daily gain and average daily feed intake was observed in piglets fed DON-contaminated feed. In addition, DON exposure increased the serum concentrations of aspartate aminotransferase, immunoglobulin A, diamine oxidase, endotoxin, and peptide YY. Moreover, DON exposure caused oxidative stress in the serum, liver and jejunum, induced intestinal inflammation, impaired the intestinal barrier, and disturbed the gut microbiota homeostasis. Supplementation of B. subtilis ASAG 216 effectively attenuated the aforementioned effects of DON on piglets. Moreover, DON and de-epoxy-DON (DOM-1) in the serum, liver and kidney were significantly decreased when B. subtilis ASAG 216 was added to DON-contaminated diet. Our results imply that B. subtilis ASAG 216 can protect against DON-induced toxicosis in piglets, and thus this strain has a potential to be used as an animal feed ingredient to counteract harmful effects of DON in animals.

The differences in socioeconomic status (SES) will cause a disparity in the health of the elderly. Taking diabetes as an example, previous studies have focused on risk factors of diabetes, while the relationship and mechanism between SES, multi-faceted factors, and the health of older patients with diabetes are not well-understood. This study aims to investigate the association between SES and health in older patients with diabetes and the interrelated mediators between them. Based on the data of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2018, structural equation modeling (SEM) was used to test whether physical exercise, social interaction, access to care, and community service mediated the effect of SES on the health in older patients with diabetes. We found support for the model in which SES predicted the health in older patients with diabetes (comparative fit index = 0.910, incremental fit index = 0.911, goodness-of-fit index = 0.982, adjusted goodness-of-fit index = 0.959, standardized root mean square residual = 0.037, and root mean square error of approximation = 0.061). The total indirect effect of SES on the health accounted for 55.52% of the total effect. Results indicated that physical exercise (β = 0.108, p < 0.01), social interaction (β = 0.253, p < 0.001), and community service (β = 0.111, p < 0.001) had significant positive effects on the health of older patients with diabetes. SES was positively associated with physical exercise (β = 0.417, p < 0.001) and community service (β = 0.126, p < 0.01). Although no direct effect of SES on the health was found, SES mediated the positive effect in their relationship by physical exercise (indirect effect = 0.045, p < 0.01), and community service (indirect effect = 0.014, p < 0.05). This study showed the health disparities of older patients with diabetes were influenced by individual-level (physical exercise, social interaction) and environmental-level (community service). It suggests that a lack of physical exercise and health-related community service may impair the health of older patients with diabetes with low SES, which recommends individuals' positive actions and environmental supports for promoting health of regarding population.

Idiopathic membranous nephropathy (IMN) is a pathological pattern of glomerular damage caused by an autoimmune response. Immune complex deposition, thickness of glomerular basement membrane, and changes in the podocyte morphology are responsible for the development of proteinuria, which is caused by the targeted binding of auto-antibodies to podocytes. Several auto-antigens have recently been identified in IMN, including M-type receptor for secretory phospholipase A2 (PLA2R1), thrombospondin type-1 domain-containing 7A (THSD7A), and neural epidermal growth factor-like 1 protein (NELL-1). The measurement of peripheral circulating antibodies has become an important clinical reference index. However, some clinical features of IMN remain elusive and need to be further investigated, such as the autoimmunity initiation, IgG4 predominance, spontaneous remission, and the unique glomerular lesion. As these unresolved issues are closely related to clinical practice, we have proposed a hypothetical pathogenesis model of IMN. Induced by environmental stimuli or other causes, the PLA2R1 antigen and/or THSD7A antigen exposed to extrarenal tissues, such as lungs, then produce the auto-antibodies that target and cause damage to the podocytes in circulation. In this review, we highlighted the potential association between environmental stimuli, immune activity, and glomerular lesions, the underlying basis for spontaneous immune and proteinuria remission.

BackgroundCardiovascular disease (CVD) is the leading cause of mortality worldwide. The effect of socioeconomic factors on cause-specific mortality and burden of CVD is rarely evaluated in low- and middle-income countries, especially in a rapidly changing society.MethodsOriginal data were derived from the vital registration system in Yangpu, a representative, population-stable district of urban Shanghai, China, during 1974–2015. Temporal trends for the mortality rates and burden of CVD during 1974–2015 were evaluated using Joinpoint Regression Software. The burden was evaluated using age-standardized person years of life loss per 100,000 persons (SPYLLs). Age-sex-specific CVD mortality rates were predicted by using age-period-cohort Poisson regression model.ResultsA total of 101,822 CVD death occurred during 1974–2015, accounting for 36.95% of total death. Hemorrhagic stroke, ischemic heart disease, and ischemic stroke were the 3 leading causes of CVD death. The age-standardized CVD mortality decreased from 144.5/100,000 to 100.7/100,000 in the residents (average annual percentage change [AAPC] -1.0, 95% confidence interval [CI] -1.7 to − 0.2), which was mainly contributed by women (AAPC -1.3, 95% CI − 2.0 to − 0.7), not by men. Hemorrhagic stroke, the major CVD death in the mid-aged population, decreased dramatically after 1991. The crude mortality of ischemic heart disease kept increasing but its age-adjusted mortality decreased continually after 1997. SPYLLs of CVD death increased from 1974 to 1986 (AAPC 2.1, 95% CI 0.4 to 3.8) and decreased after 1986 (AAPC 1.8, 95% CI − 2.3 to − 1.3). These changes were in concert with the implementation of policies including extended medical insurance coverage, pollution control, active prophylaxis of CVD including lifestyle promotion, and national health programs. The mortality of CVD increased in those born during 1937–1945, a period of the Japanese military occupation, and during 1958–1965, a period including the Chinese Famine. Sequelae of CVD and ischemic heart disease are predicted to be the leading causes of CVD death in 2029.ConclusionsExposure to serious malnutrition in early life might increase CVD mortality in later life. Improvements in medical services, pollution control, and lifestyle could decrease CVD death. New strategy is needed to prevent the aging-related CVD death and burden in the future.

High expression of cyclin D1 has a crucial role in the maintenance of unlimited cell growth in human cancer cells. The present study indicated that cyclin D1 was overexpressed in human non‑small cell lung cancer (NSCLC) tumor tissues and cell lines. Knockout of cyclin D1 suppressed NSCLC cell growth, colony formation and in vivo tumor growth. Of note, the natural product xanthohumol (Xanth) inhibited NSCLC cells via the downregulation of cyclin D1. A further mechanistic study revealed that Xanth suppressed ERK1/2 signaling and reduced the protein levels of FOS‑related antigen 1 (Fra1), which eventually inhibited the transcriptional activity of activator protein‑1 and decreased the mRNA level of cyclin D1. Furthermore, suppression of ERK1/2 impaired Fra1 phosphorylation and enhanced Xanth‑induced Fra1 ubiquitination and degradation. In addition, the S265D mutation compromised Xanth‑induced Fra1 degradation. Finally, the in vivo anti‑tumor effect of Xanth was validated in a xenograft mouse model. In summary, the present results indicated that targeting ERK1/2‑Fra1‑cyclin D1 signaling is a promising anti‑tumor strategy for NSCLC treatment.

Idiopathic membranous nephropathy (IMN) has made increasing progress in mechanism and treatment research. Herbal medicine is gradually being accepted as an alternative therapy in treating IMN. However, the intervention mechanism of herbal medicine in the treatment of membranous nephropathy is still unclear. In this review, we summarize some achievements of herb medicine in treating IMN and discuss the research direction of herb in IMN. Finally, we propose the dilemma about the study on the treatment of IMN with herb medicine. We hope that this article can bring some thoughts for clinical and scientific researchers on the treatment of IMN with herb medicine.

Chironomidae is the most ecologically diverse insects in aquatic and semi-aquatic habitats. Propsilocerus akamusi (Tokunaga) is a dominant and ubiquitous chironomid species in Eastern Asia and its morphologically unique larvae are also considered as indicator organisms to detect water contamination, potential toxicity and waterborne pathogens. Since few studies to date have focused on the olfactory system of P. akamusi, our study aims to elucidate the potential functions of chemosensory genes in P. akamusi. In our study, we found that although signals released from male groups might attract female swarmers, it was a completely male-dominated mating process. Sequencing the transcriptome of P. akamusi on an Illumina HiSeq platform generated 4.42, 4.46 and 4.53 Gb of clean reads for heads, legs, and antennae, respectively. 27,609 unigenes, 20,379 coding sequences (CDSs), and 8,073 simple sequence repeats were finally obtained. The gene-level differential expression analysis demonstrated variants among three different tissues, including 2,019 genes specifically expressed in heads, 1,540 genes in legs, and 2,071 genes in antennae. Additionally, we identified an assortment of putative olfactory genes consisting of 34 odorant binding proteins, 17 odorant receptors, 32 gustatory receptors, 22 ionotropic receptors, six chemosensory proteins as well as 3 sensory neuron membrane proteins; their relative abundances in the above three tissues were also determined by RT-qPCR. Our finding could allow a more plausible understanding of certain olfaction-mediated behaviors in groups of this macroinvertebrate.

In idiopathic membranous nephropathy, the complement membrane attack complex, more commonly referred to as complement 5b-9 (C5b-9), induces glomerular epithelial cell injury and proteinuria. C5b-9 can also activate numerous mechanisms that restrict or facilitate injury. Recent studies suggest that autophagy and the canonical Wnt signaling pathway serve an important role in repairing podocyte injury. However, the effect of C5b-9 on these pathways and the relationship between them remains unclear. The aim of the present study was to show the effect of C5b-9 on the Wnt/β-catenin signaling pathway and autophagy in podocytes in vitro. Levels of relevant indicators were detected by immunofluorescence staining and capillary western immunoassay. C5b-9 serum significantly activated the Wnt/β-catenin signaling pathway and promoted autophagy. Treatment with Dickkopf-related protein 1 (DKK1), a Wnt/β-catenin pathway blocker, protected podocytes from injury and significantly inhibited autophagy. The results indicated that inhibition of the Wnt/β-catenin pathway physiologically activated autophagy. The results indicated that C5b-9 resulted in a decrease in Akt in podocytes. However, the podocytes preincubated with DKK1 and then attacked by C5b-9 showed an increase in Akt levels. This may explain the observation that blocking the Wnt/β-catenin signaling pathway attenuated C5b-9 podocyte damage, while inhibiting autophagy. The results of the present study also suggest that regulation of these two pathways may serve as a novel method for the treatment of idiopathic membranous nephropathy.

Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China, during 2011–15 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with three public data sets containing 127 samples. HBV QC was positively correlated to APOBEC3s’ expression level (r = 0.28, P < 0.001), higher in the adjacent tissues than in the tumors (P = 6.50e-3), and higher in early tumors than in advanced tumors (P = 0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (P < 0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (P = 0.002) and recurrence-free survival (RFS; P = 0.004) in HCC, whereas, in the tumors, it predicted a favorable RFS (P < 0.001). APOBECs-related HBV mutations, including G1764A, were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (P < 0.001), whereas, in the tumors, it predicted a favorable RFS (P = 0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC.

Background Evidence-based decision on drug list or formulary has been applied worldwide. Although the importance of scientific evidence was emphasized, the decision-making procedures for including medicines into the national reimbursement drug list were often challenged by their process opacity and relying on subjective expert opinion. This study aimed to explore and assess the evidence for the effectiveness of anti-hypertensive medicines included on the Chinese National Reimbursement Drug List (NRDL), and to provide recommendations for further improvement. Methods Three international evidence-based guidelines were selected to serve as reference criteria. The antihypertensive medicines included in NRDL of Urban Employee Basic Medical Insurance (UEBMI) were compared with recommended drugs in three international guidelines. Medicines recommended by at least two guidelines were considered to have sound evidence support for the effectiveness. Otherwise, published literature with high evidence grade, namely systematic review, meta-analysis and randomized controlled trial (RCT), were searched for further assessment. Medicines reported as fairly good effectiveness by literature with high evidence grade can be also considered having sound evidence for the effectiveness. Methodological quality of systematic review or meta-analysis was evaluated by AMSTAR scale and PRISMA statement. Literature quality of RCTs was assessed by Jadad scale. Results For the 97 antihypertensive medicines in NRDL, there were sound evidence supports for the effectiveness of 56 kinds of medicines. Specifically, twenty-six of them were supported by international evidence-based guidelines, twenty were supported by systematic review or meta-analysis and the other ten by RCT. However, for the rest 41 medicines, there is insufficient evidence for their effectiveness. Conclusions Some antihypertensive medicines in NRDL did not have sufficient evidence for their effectiveness. Further evaluation and revision were required. It is also recommended to standardize decision-making procedures for inclusion of medicines, set up high quality evidence database to timely provide sound evidence, and so on. Electronic supplementary material The online version of this article (10.1186/s12913-019-3937-0) contains supplementary material, which is available to authorized users.

There is compelling evidence that oncogenic MET and PIK3CA signaling pathways contribute to breast cancer. However, the activity of pharmacologic targeting of either pathway is modest. Mechanisms of resistance to these monotherapies have not been clarified. Currently, commonly used mouse models are inadequate for studying the HGF–MET axis because mouse HGF does not bind human MET. We established human HGF–MET paired mouse models. In this study, we evaluated the cooperative effects of MET and PIK3CA in an environment with involvement of human HGF in vivo. Oncogenic MET/PIK3CA synergistically induced aggressive behavior and resistance to each targeted therapy in an HGF-paracrine environment. Combined targeting of MET and PI3K abrogates resistance. Associated cell signaling changes were explored by functional proteomics. Consistently, combined targeting of MET and PI3K inhibited activation of associated oncogenic pathways. We also evaluated the response of tumor cells to HGF stimulation using breast cancer patient-derived xenografts (PDX). HGF stimulation induced significant phosphorylation of MET for all PDX lines detected to varying degrees. However, the levels of phosphorylated MET are not correlated with its expression, suggesting that MET expression level cannot be used as a sole criterion to recruit patients to clinical trials for MET-targeted therapy. Altogether, our data suggest that combined targeting of MET and PI3K could be a potential clinical strategy for breast cancer patients, where phosphorylated MET and PIK3CA mutation status would be biomarkers for selecting patients who are most likely to derive benefit from these cotargeted therapy.

Background Accumulation of LDL cholesterol (LDL-c) within artery walls is strongly associated with the initiation and progression of atherosclerosis development. This complex trait is affected by multifactor involving polygenes, environments, and their interactions. Uncovering genetic architecture of LDL may help to increase the understanding of the genetic mechanism of cardiovascular diseases. Methods We used a genetic model to analyze genetic effects including additive, dominance, epistasis, and ethnic interactions for data from the Multi-Ethnic Study of Atherosclerosis (MESA). Three lifestyle behaviors (reading, intentional exercising, smoking) were used as cofactor in conditional models. Results We identified 156 genetic effects of 10 quantitative trait SNPs (QTSs) in base model and three conditional models. The total estimated heritability of these genetic effects was approximately 72.88% in the base model. Five genes (CELSR2, MARK2, ADAMTS12, PFDN4, and MAGI2) have biological functions related to LDL. Conclusions Compared with the based model LDL, the results in three conditional models revealed that intentional exercising and smoking could have impacts for causing and suppressing some of genetic effects and influence the levels of LDL. Furthermore, these two lifestyles could have different genetic effects for each ethnic group on a specific QTS. As most of the heritability in based model LDL and conditional model LDL|Smk was contributed from epistasis effects, our result indicated that epistasis effects played important roles in determining LDL levels. Our study provided useful insight into the biological mechanisms underlying regulation of LDL and might help in the discovery of novel therapeutic targets for cardiovascular disease.

The intestinal epithelium is the first barrier against food contaminants and is highly sensitive to Fusarium toxins, especially deoxynivalenol (DON) and zearalenone (ZEA). Here, we explored the effects of low doses of DON and/or ZEA in naturally moldy diets on intestinal functions in piglets, including inflammatory responses, epithelial barrier, and microbial composition. Piglets were treated with a control diet (CON), DON diet (1000.6 μg/kg), ZEA diet (269.1 μg/kg), and DON + ZEA diet (1007.5 + 265.4 μg/kg), respectively, for 3 weeks and then switched to the same CON diet for another 2 weeks. In the first period, even the selected low doses of DON or ZEA in the diet resulted in intestinal inflammation, diminish protein expression (claudin-4) and altered gut microbiota populations. Whereas upon switching to the CON diet for another 2 weeks, the deleterious effect of ZEA and DON on IL-1β and Bifidobacterium population could not be recovered. Additionally, combined DON and ZEA negatively affected body weight gain and feed consumption of piglets, as well as shown synergistic effects on evoking pro-inflammatory cytokines contents (TNF-α, IL-1β, and IL-6) and perturbing the cecum microbiota profile (E. coli, Lactobacillus, and Bifidobacterium). Collectively, chronic consumption of DON and ZEA contaminated feed or food, even at low doses, can induce intestinal damage and may have consequences for animal and human health.

Summary: Enhanced recovery after surgery (ERAS) is a series of perioperative optimized treatment measures based on evidence-based medicine which can control perioperative pathological and physiological responses, reduce surgical trauma and postoperative stress, and then achieve rapid recovery. This is a new concept in the 21st century, which is a revolution to the medical treatment and rehabilitation mode. Based on the clinical application study and expert experience in present ERAS in hepatectomy field at home and abroad, Chinese Expert Consensus on Enhanced Recovery After Hepatectomy (Version 2017) is established. The Chinese Expert consensus is the first guideline in the area of ERAS in hepatic surgery in China, which is drafted by the committee organized by Chinese Medical Association and China International Exchange and Promotive Association for Medical and Health Care. Keywords: Hepatectomy, Enhanced recovery after surgery, Consensus

Deregulation of glycolysis is a common phenomenon in human colorectal cancer (CRC). In the present study, we reported that Hexokinase 2 (HK2) is overexpressed in human CRC tissues and cell lines, knockout of HK2 inhibited cell proliferation, colony formation, and xenograft tumor growth. We demonstrated that the natural compound, xanthohumol, has a profound anti-tumor effect on CRC via down-regulation of HK2 and glycolysis. Xanthohumol suppressed CRC cell growth both in vitro and in vivo. Treatment with xanthohumol promoted the release of cytochrome C and activated the intrinsic apoptosis pathway. Moreover, our results revealed that xanthohumol down-regulated the EGFR-Akt signaling, exogenous overexpression of constitutively activated Akt1 significantly impaired xanthohumol-induced glycolysis suppression and apoptosis induction. Our results suggest that targeting HK2 appears to be a new approach for clinical CRC prevention or treatment.

It is well known that the Gobi Desert is the dominant source area of the Badain Jaran Desert (BJD) and the Chinese Loess Plateau (CLP). However, due to the absence of quantitative analyses, there are nearly no exact assessments of its actual contribution. Combinations of field investigations, wind tunnel experiments, and wind field analyses revealed that the potential erosion depth on modern Gobi Desert varied between 0.41 and 0.89 mm a−1. Results indicated it would take an average theoretical time of 80.8 ka and 4,475.9 ka to form the current dimensions of the BJD and CLP, respectively, which means the Gobi Desert may provide substantial sand sources to the modern BJD, while its contribution to the loess of modern CLP might be overestimated despite it was the key sources of the CLP in Quaternary.

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3–5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response.

Background Epidermal growth factor receptor (EGFR) activating mutations play crucial roles in the tumorigenesis of human non-small cell lung cancer (NSCLC). The mechanism regarding how EGFR signaling regulates myeloid cell leukemia sequence 1 (Mcl-1) protein stability and ubiquitination remains undefined. Methods MTS assay was used for natural product library screening. The effect of formononetin (Formo) on NSCLC cells was determined by MTS assay and soft agar assay. Molecular modeling was performed to analyze the potential different binding modes between Formo and EGFR WT or mutants. Mcl-1 protein level and the inhibitory effect of Formo on EGFR signaling were examined by immunoblot, in vitro kinase assay, in vitro pulldown and ATP competition assays, co-immunoprecipitation assay, ubiquitination analysis, in vivo xenograft model, and immunohistochemical staining. Results Formo was identified as an EGFR inhibitor by a 98 commercially available natural product screening. Formo suppresses WT and mutant EGFR kinases activity in vitro, ex vivo, and in vivo. Molecular modeling indicates that Formo docks into the ATP-binding pocket of both WT and mutant EGFR. Formo inhibits EGFR-Akt signaling, which in turn activates GSK3β and promotes Mcl-1 phosphorylation in NSCLC cells. Treatment with Formo enhances the interaction between Mcl-1 and SCFFbw7, which eventually promotes Mcl-1 ubiquitination and degradation. Depletion of either GSK3β or SCFFbw7 compromised Formo-induced Mcl-1 downregulation. Finally, Formo inhibits the in vivo tumor growth in a xenograft mouse model. Conclusion This study highlights the importance of promoting ubiquitination-dependent Mcl-1 turnover might be an alternative strategy to enhance the anti-tumor efficacy of EGFR-TKI.

BackgroundNowadays, irrational use of antimicrobials has threatened public health. It’s necessary to expand the use of clinical practice guideline (CPG) on antimicrobial for facilitating the proper use of antimicrobial. However, the utilization status of CPG on antimicrobial and the influencing factors, especially the ones at the organizational level, remain largely unknown.MethodsA cross-sectional questionnaire survey was conducted on a sample among physicians from 16 public hospitals in the eastern, central and western parts of China. A multilevel regression model was employed to examine factors associated with physicians’ utilization of CPG on antimicrobial.ResultsA total of 815 physicians were included in this study. About 80% of the surveyed physicians reported their adherence to the CPG on antimicrobial. Dimensions of “subjective norm”, “perceived risk” and “behavioral intention” from the domain of physician belief, a dimension of “ease of use” from the domain of CPG traits, and dimensions of “top management support” and “organization & implementation” from the domain of hospital practice were significantly associated with physicians’ utilization of CPG on antimicrobial. And except for working department, most demographics characteristics of the physician were not found to be significantly related to the CPG use. In addition, it also showed that region is a significant factor affecting physicians’ CPG use.ConclusionsThis study depicted the current status of CPG on antimicrobial and comprehensively identified its potential determinants not only from the three domains at the individual level, such as physician belief, but also from the location region at the organizational level. The results will provide a direct reference for the implementation of CPG on antimicrobial.