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Since the "seed and soil" hypothesis was proposed, the biological functions of the tumor microenvironment (TME), especially its stromal components, have received increasing attention. Cancer-associated fibroblasts (CAFs) are the major components of the stromal region, providing material support for tumor cell proliferation, migration, and invasion. Furthermore, CAFs are important mediators of suppressing immune responses by attracting the accumulation of immunosuppressive cells through cytokine/chemokine secretion. In this review, we summarized the major cytokines, chemokines and metabolites, including transforming growth factor-β (TGF-β), interleukin-6 (IL-6), C-X-C chemokine ligand (CXCL)12, C-C chemokine ligand (CCL) 2, prostaglandin E2 (PGE2), and other factors, by which CAFs suppress the immune systems in a variety of cancers. More importantly, we highlight potential therapeutic strategies to alleviate the immunosuppression produced by CAFs, thereby inhibiting tumor progression.

Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the most active agents in HCC. WW domain-containing protein 2 (WWP2) is highly expressed in HCC tissues and activates protein kinase B (AKT) signaling pathway to enhance tumor metastasis. However, the role of WWP2 in the glycolysis and antitumor effects of doxorubicin and the epigenetic alterations of WWP2 in HCC remain to be elucidated. The levels of WWP2 and N6-methyladenosine methyltransferase-like 3 (METTL3) in clinical samples and cells were investigated. WWP2 were silenced or overexpressed to study the role of WWP2 in regulating cell proliferation, colony formation, and glycolysis. RNA immunoprecipitation was performed to test m

The toxicity evaluation system of environmental pollutants has undergone numerous changes due to the application of new technologies. Single-cell toxicogenomics is rapidly changing our view on environmental toxicology by increasing the resolution of our analysis to the level of a single cell. Applications of this technology in environmental toxicology have begun to emerge and are rapidly expanding the portfolio of existing technologies and applications. Here, we first summarized different methods involved in single-cell isolation and amplification in single-cell sequencing process, compared the advantages and disadvantages of different methods, and analyzed their development trends. Then, we reviewed the main advances of single-cell toxicogenomics in environmental toxicology, emphatically analyzed the application prospects of this technology in identifying the target cells of pollutants in early embryos, clarifying the heterogeneous response of cell subtypes to pollutants, and finding pathogenic bacteria in unknown microbes, and highlighted the unique characteristics of this approach with high resolution, high throughput, and high specificity by examples. We also offered a prediction of the further application of this technology and the revolution it brings in environmental toxicology. Overall, these advances will provide practical solutions for controlling or mitigating exogenous toxicological effects that threaten human and ecosystem health, contribute to improving our understanding of the physiological processes affected by pollutants, and lead to the emergence of new methods of pollution control.

Recent studies have shown that NXPH family member 4 (NXPH4) plays an important role in the progression of cancer. However, the potential role of NXPH4 in bladder cancer (BCa) remains to be explored. The purpose of the present study was to identify whether NXPH4 could be used as a biomarker to predict the prognosis of BCa. We first examined the expression of NXPH4 in pan-cancer, and then focused on BCa. Univariate and multivariate Cox regression analysis were used to investigate whether NXPH4 could be used as an independent prognostic indicator. Gene set enrichment analysis (GSEA) was used for functional analysis of NXPH4-related genes. CIBERSORT algorithm was used to calculate immune cell infiltration levels with different NXPH4 expression. Finally, the expression of NXPH4 was validated in clinical tissue specimens and bladder cancer cell lines by immunohistochemistry and qRT-PCR. The tumor-promoting effects of NXPH4 were further investigated using counting kit-8 (CCK-8), colony formation, EdU assays, and tumor xenograft model. Our results showed that NXPH4 was highly expressed in BCa tissues. Patients in the high NXPH4 expression group had shorter overall survival (OS) and progression-free survival (PFS). We found that immune-related pathways were enriched in NXPH4-related genes. Immune cell infiltrations in BCa were also associated with different NXPH4 expression. NXPH4 was further found to be highly expressed in our validation specimens. The proliferative effect of NXPH4 was confirmed in BCa

Macroautophagy/autophagy is a conserved cellular process associated with tumorigenesis and aggressiveness, while mechanisms regulating expression of autophagic machinery genes in cancers still remain elusive. Herein, we identified E2F4 (E2F transcription factor 4) as a novel transcriptional activator of cytoprotective autophagy crucial for zinc homeostasis in cancer cells. Gain- and loss-of-function studies showed that E2F4 promoted autophagy in a cell cycle-dependent manner, resulting in facilitated degradation of MT (metallothionein) proteins, elevated distribution of Zn2+ within autophagosomes, decreased labile intracellular zinc ions, and increased growth, invasion, and metastasis of gastric cancer cells. Mechanistically, E2F4 directly regulated the transcription of ATG2A (autophagy related 2A) and ULK2 (unc-51 like autophagy activating kinase 2), leading to autophagic degradation of MT1E, MT1M, and MT1X, while USP2 (ubiquitin specific peptidase 2) stabilized E2F4 protein to induce its transactivation via physical interaction and deubiquitination in cancer cells. Rescue experiments revealed that USP2 harbored oncogenic properties via E2F4-facilitated autophagy and zinc homeostasis. Emetine, a small chemical inhibitor of autophagy, was able to block interaction between UPS2 and E2F4, increase labile intracellular zinc ions, and suppress tumorigenesis and aggressiveness. In clinical gastric cancer specimens, both USP2 and E2F4 were upregulated and associated with poor outcome of patients. These findings indicate that therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression. Abbreviations: 3-MA: 3-methyladenine; ANOVA: analysis of variance; ATG2A: autophagy related 2A; ATG5: autophagy related 5; ATP: adenosine triphosphate; BECN1: beclin 1; BiFC: bimolecular fluorescence complementation; CCND1: cyclin D1; CDK: cyclin dependent kinase; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DAPI: 4’,6-diamidino-2-phenylindole; E2F4: E2F transcription factor 4; eATP: extracellular adenosine triphosphate; EBSS: Earle’s balanced salt solution; FP: first progression; FRET: fluorescence resonance energy transfer; FUCCI: fluorescent ubiquitination-based cell cycle indicator; GFP: green fluorescent protein; GST: glutathione S-transferase; HA: hemagglutinin; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MDM2: MDM2 proto-oncogene; MKI67/Ki-67: marker of proliferation Ki-67; MT: metallothionein; MT1E: metallothionein 1E; MT1M: metallothionein 1M; MT1X: metallothionein 1X; MTT: 3-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide; OS: overall survival; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; qPCR: quantitative PCR; RFP: red fluorescent protein; SQSTM1/p62: sequestosome 1; UBXN1: UBX domain protein 1; Ub: ubiquitin; ULK2: unc-51 like autophagy activating kinase 2; USP14: ubiquitin specific peptidase 14; USP2: ubiquitin specific peptidase 2; USP5: ubiquitin specific peptidase 5; USP7: ubiquitin specific peptidase 7; ZnCl2: zinc chloride.

Background: Colorectal cancer (CRC) is a malignancy with high mortality. TSPYL2 participates in tumor suppression but its role in CRC remains unknown. Methodology & results: TSPYL2 was downregulated and SIRT1 was upregulated in gefitinib drug-resistant (GEF-DR) tissues of patients with CRC. The GEF-resistant cells, HCT116 and HCT-15, were successfully established. The knockdown of TSPYL2 promoted resistance to GEF in CRC cells. Interestingly, immunofluorescence and western blot assays demonstrated that TSPYL2 inhibited DNA damage repair in HCT-15 and HCT116 GEF-resistant cells. Mechanically, TSPYL2 reduced the resistance to GEF and inhibited DNA damage repair via suppressing SIRT1-mediated FOXO3 deacetylation. TSPYL2 consistently inhibited tumor growth and decreased resistance to GEF in vivo. Conclusion: TSPYL2 reduced resistance to GEF and suppressed DNA damage through downregulating SIRT1-mediated FOXO3 deacetylation, indicating that TSPYL2 might be a novel therapeutic target in CRC.

The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3-5-cm HCC over time.From 2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008-2019 (n = 335 in each group) and 2014-2019 (n = 257 in each group) cohorts, respectively. For cohort 2008-2019, during a median follow-up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65-1.19, p = 0.420), and MWA was inferior to LLR regarding disease-free survival (DFS) (HR 1.36, 95% CI 1.05-1.75, p = 0.017). For cohort 2014-2019, there was comparable OS (HR 0.85, 95% CI 0.56-1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98-1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1-4.0-cm HCCs (HR 0.88, 95% CI 0.53-1.47, p = 0.630) and 4.1-5.0-cm HCCs (HR 0.77, 95% CI 0.37-1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p 0.05), shorter hospitalization, and lower cost to LLR (all p 0.001).MWA might be a first-line alternative to LLR for solitary 3-5-cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.

Summary: The prevalence of postoperative low anterior resection syndrome (LARS) in patients with colorectal cancer is high, which seriously affects the quality of life after operation. The purpose of this meta-analysis is to systematically evaluate the related factors of LARS in patients with colorectal cancer and provide reference for clinicians when making reasoned decisions. A systematic electronic search of PubMed, Embase, The Cochrane Library, WANFANG and CNKI was performed from 2012 to Dec 2020. We analyzed the risk factors of LARS by extracting baseline data and clinical results. The odds ratio (OR) was used to analyze binary variables. A total of 5102 patients were included in 21 literatures, of which the prevalence of LARS was 49.7% (2538/5102). Meta-analysis showed that there was no significant difference in the influence of age (P = 0.48) and sex (P = 0.68) on LARS, but low tumor height (P

Novel MnO2@NH2-MIL101(Fe)@Ce6-F127 nanoparticles (MNMCF NPs) were synthesized using a facile solvothermal strategy, and can be used as multifunctional nanoplatforms for high-efficiency chemo-photodynamic synergistic antitumor therapy.

Malignant pleural effusion (MPE) is a functional 'cold' tumor microenvironment in which the antitumor activity of CD8

HLA-C*08:99 differs by one non-synonymous nucleotide from C*08:01:01 in exon 5, codon 288 GTTATT.

Our study aimed to investigate the associations between DEHP exposure and serum thyroid hormone levels in 347 adolescents and young adults. We measured DEHP metabolites including mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-carboxymethyl)hexyl phthalate (MCMHP) in their urine. Total thyroxine (TT4), total triiodothyronine, free triiodothyronine, free thyroxine (FT4), thyroid-stimulating hormone and the mRNA levels of thyroid peroxidase (TPO), thyroglobulin (TG), sodium iodide symporter (NIS), thyroid transcription factor 1 (TTF-1), and paired box gene 8 (PAX-8) in serum were measured. The results of statistical analysis showed that urinary DEHP metabolites were generally negatively associated with TT4 levels in serum. In the males, the FT4 levels showed positive associations with urinary MEHP, MECPP, MCMHP, and ∑DEHP. The mRNA level of TG was significantly positively correlated with the levels of MECPP, MCMHP, and ∑DEHP, while the levels of TTF-1 and PAX-8 mRNA were significantly positively correlated with the levels of DEHP metabolites. Taken together, DEHP may affect the synthesis of TG by altering the normal transcription of TTF-1 and PAX-8, leading to decreased TT4 levels in Chinese adolescents.

Supplemental Digital Content is available in the text., Immunotherapy has revolutionized the treatment in metastatic melanoma, but alternative biomarkers that are economical, simple and reliable still need to be clarified. In this study, we aimed to comprehensively analyze the prognostic significance of baseline neutrophil-to-lymphocyte ratio (NLR) in melanoma patients with immunotherapy. We searched PubMed, Embase, and Cochrane Library until September 16, 2020. Hazard ratio (HR) and 95% confidence intervals (CIs) were pooled to investigate the association of baseline NLR with overall survival (OS) and progression-free survival (PFS). Sensitivity analysis, subgroup analyses, publication bias assessment, and the Duval and Tweedie trim-and-fill method were used to evaluate the stability of results. A total of 18 studies including 2054 patients were included in our analysis. Pooled data demonstrated that higher baseline NLR was associated with a poorer OS (HR=2.46, 95% CI=1.77, 3.43) and PFS (HR=2.38, 95% CI=1.95, 2.89) of melanoma patients receiving immunotherapy. Subgroup analysis according to immunotherapy type showed that the prognostic effects of baseline NLR existed in all the subtypes of immunotherapy, including anticytotoxic T lymphocyte-associated protein 4 therapy (OS HR=2.26, 95% CI=1.43, 3.59; PFS HR=2.68, 95% CI=1.79, 4.02), antiprogrammed cell death-1 therapy (OS HR=3.08, 95% CI=2.21, 4.27; PFS HR=2.01, 95% CI=1.64, 2.47), and combination therapy (OS HR=1.75, 95% CI=1.13, 2.72; PFS HR=3.13, 95% CI=1.63, 6.03). Conclusions were still consistent in subgroup analyses stratified by study year, region, study type, sample size, analysis of HR and cuttoff of baseline NLR. Altogether, baseline NLR is a promising prognostic biomarker for melanoma patients receiving immunotherapy.

Background Breast malignancy is the most frequently diagnosed malignancy in women worldwide, and the diagnosis relies on invasive examinations. However, most clinical breast changes in women are benign, and invasive diagnostic approaches cause unnecessary suffering for the patients. Thus, a novel noninvasive approach for discriminating malignant breast lesions from benign lesions is needed. Methods We performed cell-free DNA (cfDNA) sequencing on plasma samples from 173 malignant breast lesion patients, 158 benign breast lesion patients, and 102 healthy women. We then analyzed the cfDNA-based nucleosome profiles, which reflect the various tissues of origin and transcription factor activities. Moreover, by using machine learning classifiers along with the cfDNA sequencing data, we built classifiers for discriminating benign from malignant breast lesions. Receiver operating characteristic curve analyses were used to evaluate the performance of the classifiers. Results cfDNA-based nucleosome profiles reflected the various tissues of origin and transcription factor activities in benign and malignant breast lesions. The cfDNA-based transcription factor activities and breast malignancy-specific transcription factor-binding site accessibility profiles could accurately distinguish benign and malignant breast lesions, with area under the curve values of 0.777 and 0.824, respectively. Conclusions Our proof-of-principle study established a methodology for noninvasively discriminating benign from malignant breast lesions.

Background/Aim: Capillary morphogenesis gene 2 (CMG2) is involved in prostate and breast cancer progression. This study aimed to investigate sex hormone receptor-mediated regulation of CMG2 in breast and prostate cancer, and its implication in disease progression. Materials and Methods: Expression of CMG2, oestrogen receptor (ER) and androgen receptor (AR) was determined in breast and prostate cancer cell lines, respectively, using real-time quantitative PCR (QPCR) and western blot. Association between CMG2 and sex hormone receptors was analysed in a number of transcriptome datasets. Immunochemical staining was performed in tissue microarrays of breast cancer (BR1505D) and prostate cancer (PR8011A). CMG2 expression was determined in 17β-oestradiol treated breast cancer cells and AR over-expressing prostate cancer cells. Results: CMG2 was found to be inversely correlated with sex hormone receptors in breast and prostate cancer. Lower expression of CMG2 was associated with a poor prognosis in ER (+) breast cancer but not ER (–) tumours. Both ER (+) breast cancer cell lines and AR (+) prostate cancer cell lines presented lower expression of CMG2, which was increased following sex hormone deprivation. Exposure to 17-β-oestradiol and AR over-expression repressed CMG2 expression in breast cancer and prostate cancer cell lines, respectively. Conclusion: CMG2 is inversely correlated with ER and AR status in breast and prostate cancer, respectively. ER and AR mediate repression of CMG2 expression in corresponding cancerous cells.

Autophagy is a major contributor to anti-cancer therapy resistance. Many efforts have been made to understand and overcome autophagy-mediated therapy resistance, but these efforts have been unsuccessful in clinical applications. In this study, we establish an autophagy signature to estimate tumor autophagy status. We then classify approximately 10,000 tumor samples across 33 cancer types from The Cancer Genome Atlas into autophagy score-high and autophagy score-low groups. We characterize the associations between multi-dimensional molecular features and tumor autophagy, and further analyse the effects of autophagy status on drug response. In contrast to the conventional view that the induction of autophagy serves as a key resistance mechanism during cancer therapy, our analysis reveals that autophagy induction may also sensitize cancer cells to anti-cancer drugs. We further experimentally validate this phenomenon for several anti-cancer drugs in vitro and in vivo, and reveal that autophagy inducers potentially sensitizes tumor cells to etoposide through downregulating the expression level of DDIT4. Our study provides a comprehensive landscape of molecular alterations associated with tumor autophagy and highlights an opportunity to leverage multi-omics analysis to utilize multiple drug sensitivity induced by autophagy.

Cuproptosis, Copper Induced Cell Death, is a newly defined type of programmed cell death, involving in the regulation of tricarboxylic acid (TCA) cycle. Dysfunction of cuproptosis induces cytotoxicity and influences the proliferation of multiple tumors. However, the direct prognostic effect of cuproptosis related genes and corresponding regulating mechanisms amid prostate cancer remains unknown. A multi-omics analysis strategy was adopted to explore the role of ten cuproptosis related genes in The Cancer Genome Atlas- Prostate Adenocarcinoma (TCGA-PRAD). Firstly, mRNA expression, Copy Number Variance (CNV), mutation, DNA methylation and prognostic power of the ten genes were illustrated. Based on transcriptomic data, we developed a novel prognostic model named the Cuproptosis-related gene score (CRGScore), Their biological functions were then detected by enrichment analysis and unsupervised cluster analysis. Following that, their correlation with Tumor Immune Microenvironment (TIME), immunotherapy, Biochemical Recurrence (BCR) and chemotherapeutic resistance were elaborated by relevant bioinformatics algorithms. Ten cuproptosis related genes exhibited extensive alteration of CNV and DNA methylation and showed significant influence on the prognosis of prostate cancer patients. These genes mainly enriched in E2F and G2M targets and mitosis pathways, Samples with high CRGScore showed enhancement resulting in the increased infiltration of T cell, B cell, NK cells. They also demonstrated close correlations with the BCR status, expression of eight immune checkpoints and chemotherapeutic resistances in prostate cancer. Our comprehensive analysis of CRGScore revealed an extensive regulatory mechanism by which they affect the tumor-immune-stromal microenvironment, clinicopathological features, and prognosis. We also determined the therapeutic liability of CRGScore in targeted therapy and immunotherapy. These findings highlight the crucial clinical implications of CRGScore and provide new ideas for guiding personalized immunotherapy strategies for patients with Pca.

AimsCystatin C, an inhibitor of cysteine protease, has been used as a biomarker for estimating glomerular filtration rate. However, the causal relation between cystatin C and diabetic nephropathy remains uncertain.MethodsWe assessed the causal effect of cystatin C together with other five serum biomarkers including KIM-1, GDF-15, TBIL, uric acid, and Scr on diabetic nephropathy by Mendelian randomization (MR) analysis. 234 genetic variants were selected as instrumental variables to evaluate the causal effect of cystatin C (NGWAS=361194) on diabetic nephropathy (Ncase/Ncontrol up to 3283/210463). Multivariable MR (MVMR) was performed to assess the stability of cystatin C’s causal relationship. Two-step MR was used to assess the mediation effect of BMI and SBP.ResultsAmong the six serum biomarkers, only cystatin C causally associated with diabetic nephropathy (IVW OR: 1.36, 95%CI [1.15, 1.61]). After adjusting for the potential confounders BMI and SBP, cystatin C maintained its causal effect on the DN (OR: 1.17, 95%CI [1.02, 1.33]), which means that the risk of DN increased by 17% with an approximate 1 standard deviation (SD) increment of serum cystatin C level. Two-step MR results indicated that BMI might mediate the causal effect of cystatin C on diabetic nephropathy.InterpretationOur findings discovered that cystatin C was a risk factor for diabetic nephropathy independent of BMI and SBP in diabetes mellitus patients. Future research is required to illustrate the underlying mechanism and prove targeting circulating cystatin C could be a potential therapy method.

Long-term in vivo observation in large animal model is critical for evaluating the potential of small diameter tissue engineering vascular graft (SDTEVG) in clinical application, but is rarely reported. In this study, a SDTEVG is fabricated by the electrospinning of poly(ε-caprolactone) and subsequent heparin modification. SDTEVG is implanted into canine's abdominal aorta for 511 days in order to investigate its clinical feasibility. An active and robust remodeling process was characterized by a confluent endothelium, macrophage infiltrate, extracellular matrix deposition and remodeling on the explanted graft. The immunohistochemical and immunofluorescence analysis further exhibit the regeneration of endothelium and smooth muscle layer on tunica intima and tunica media, respectively. Thus, long-term follow-up reveals viable neovessel formation beyond graft degradation. Furthermore, the von Kossa staining exhibits no occurrence of calcification. However, although no TEVG failure or rupture happens during the follow-up, the aneurysm is found by both Doppler ultrasonic and gross observation. Consequently, as-prepared TEVG shows promising potential in vascular tissue engineering if it can be appropriately strengthened to prevent the occurrence of aneurysm.

Thyroid‐associated ophthalmopathy (TAO) is a serious, progressive, vision‐threatening and difficult‐to‐treat organ‐specific autoimmune disease. The course, therapeutic effects and prognosis of moderate to severe TAO vary greatly. High‐dose intravenous glucocorticoid (IVGC) therapy is considered a first‐line treatment for active moderate‐to‐severe TAO, but there is still insufficient evidence regarding the treatment duration. Long‐term IVGC therapy can influence the metabolism of glucose, lipids, and bone. This study was designed to compare changes in metabolic and immunological indexes as well as the magnetic resonance imaging apparent diffusion coefficient (ADC) of the extraocular muscles after 4 and 12 weeks of IVGC therapy. Forty‐eight patients with active moderate‐to‐severe TAO were included in this retrospective cohort study. Metabolism and immunological indexes were measured before and after therapy. The ADC and clinical activity score (CAS) were used to evaluate the efficacy of treatment in these patients. We found that the patients in the 12‐week group had increased fasting plasma glucose (p = 0.004), glycated hemoglobin (p = 0.028), total cholesterol (p

In this experiment, a new amphiphilic chitosan-poly(lactide) graft copolymer was synthesized and characterized by IR, 1H-NMR, XRD, TGA. The obtained chitosan-poly (lactide) graft copolymer was used as the matrix material to prepare nanodroplets (NDs) encapsulating with liquid PFP by double-emulsion and solvent evaporation method. The resulting NDs were characterized by photon correlation spectroscopy and transmission electron microscopy (TEM). The biocompatibility was explored by cytotoxicity assay, cell migration assay and blood biochemistry analysis. The experiments of ultrasonic imaging in vitro and in vivo were carried out with a B-mode clinical ultrasound imaging system. The results of FI-IR and 1H-NMR confirmed the successful grafting reaction of polylactic acid(PLLA) to chitosan with a graft rate of 365%. The average size of the NDs was 101.1 ± 2.7 nm, with the polydispersity index (PDI) of 0.127 ± 0.020, and the zeta potential was −31.8 ± 1.5 mV. From the TEM results, NDs were highly dispersed and had a spherical shape with a distinct capsule structure. The NDs exhibited good stability during storage at 4°C. The NDs solution with different concentrations did not affect cell growth and showed good biocompatibility in cytotoxicity, cell migration and blood biochemistry studies. Under the irradiation of ultrasonic waves, the NDs formed an ultrasonic high signal, which could significantly enhance the ultrasound imaging of tumor tissue in vivo. Taken together, the NDs hold great potential for ultrasound imaging as a nanosized contrast agent.

Death associated protein‑3 (DAP3) was identified as a responsive protein to interferon‑gamma‑induced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer‑1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in

Summary Coronavirus disease 2019 (COVID-19) occurs in the influenza season and has become a global pandemic. The present study aimed to examine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection with influenza A virus (IAV) in an attempt to provide clues for the antiviral interventions of co-infected patients. We described two patients who were co-infected with SARS-CoV-2 and IAV treated at Wuhan Union Hospital, China. In addition, we performed a review in PubMed, Web of Science and CNKI (from January 1 up to November 1, 2020) with combinations of the following key words: “COVID-19, SARS-COV-2, influenza A and co-infection”. A total of 28 co-infected patients were enrolled in the analysis. Of the 28 patients, the median age was 54.5 years (IQR, 34.25–67.5) and 14 cases (50.0%) were classified as severe types. The most common symptoms were fever (85.71%), cough (82.14%) and dyspnea (60.71%). Sixteen patients had lymphocytopenia on admission and 23 patients exhibited abnormal radiological changes. The median time from symptom onset to hospital admission was 4 days (IQR, 3–6), and the median time of hospital stay was 14 days (IQR, 8.5–16.75). In conclusion, patients with SARS-COV-2 and IAV co-infection were similar to those infected with SARS-COV-2 alone in symptoms and radiological images. SARS-COV-2 co-infection with IAV could lead to more severe clinical condition but did not experience longer hospital stay compared with patients infected with SARS-COV-2 alone.

Rationale: Breast cancer (BrCa) is the most common cancer worldwide, and the 5-year relative survival rate has declined in patients diagnosed at stage IV. Advanced BrCa is considered as incurable, which still lack effective treatment strategies. Identifying and characterizing new tumor suppression genes is important to establish effective prognostic biomarkers or therapeutic targets for late-stage BrCa. Methods: RNA-seq was applied in BrCa tissues and normal breast tissues. Through analyzing differentially expressed genes, DRD2 was selected for further analysis. And expression and promoter methylation status of DRD2 were also determined. DRD2 functions were analyzed by various cell biology assays in vitro. Subcutaneous tumor model was used to explore DRD2 effects in vivo. A co-cultivated system was constructed to investigate interactions of DRD2 and macrophages in vitro. WB, IHC, IF, TUNEL, qRT-PCR, Co-IP, Antibody Array, and Mass Spectrum analysis were further applied to determine the detailed mechanism. Results: In BrCa, DRD2 was found to be downregulated due to promoter methylation. Higher expression of DRD2 positively correlated with longer survival times especially in HER2-positive patients. DRD2 also promoted BrCa cells sensitivity to Paclitaxel. Ectopic expression of DRD2 significantly inhibited BrCa tumorigenesis. DRD2 also induced apoptosis as well as necroptosis in vitro and in vivo. DRD2 restricted NF-κB signaling pathway activation through interacting with β-arrestin2, DDX5 and eEF1A2. Interestingly, DRD2 also regulated microenvironment as it facilitated M1 polarization of macrophages, and triggered GSDME-executed pyroptosis. Conclusion: Collectively, this study novelly manifests the role of DRD2 in suppressing BrCa tumorigenesis, predicting prognosis and treatment response. And this study further reveals the critical role of DRD2 in educating M1 macrophages, restricting NF-κB signaling pathway and triggering different processes of programmed cell death in BrCa. Taking together, those findings represent a predictive and therapeutic target for BrCa.

Background To understand the prevalence of diabetic retinopathy (DR) in Shenzhen and to analyze the risk factors for the occurrence and development of DR. Based on the comprehensive information system for diabetes prevention and control in the communities of Shenzhen in 2019, six community health service centers in Shenzhen were used as research sites to carry out multicenter, cross-sectional screening studies. Methods Cluster random sampling was used to collect data from 904 patients with diabetes in Shenzhen. The occurrence of DR and vision-threatening diabetic retinopathy (VTDR) was analyzed, and multivariate logistic regression was performed to analyze the risk factors for DR and VTDR. EpiData version 3.1 (EpiData Association, Odense, Denmark) statistical software was used to build a database, and Statistical Package for the Social Sciences (SPSS) version 25.0 (IBM Corp., Armonk, N.Y., USA) was used to sort up and analyze the data. Results The prevalence of DR among diabetic patients in Shenzhen was 18.58% [95% confidence interval (CI): 16.13-21.3%], and the prevalence of VTDR was 2.43% (95% CI: 1.57-1.2%). The prevalence of DR and VTDR was higher in males than in females. Logistic regression analysis showed that age, disease duration, medication mode, and the occurrence of diabetic peripheral neuropathy (DPN) were associated with the incidence of DR in diabetic patients, and that disease duration, the occurrence of DPN, and diabetic nephropathy were associated with the occurrence of VTDR. Conclusions The prevalence of DR in the communities of Shenzhen is high. Age, disease duration, medications, and DPN are the major risk factors for the occurrence of DR.

BackgroundExtremity liposarcoma represents 25% of extremity soft tissue sarcoma and has a better prognosis than liposarcoma occurring in other anatomic sites. The purpose of this study was to develop two nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with extremity liposarcoma.MethodsA total of 2170 patients diagnosed with primary extremity liposarcoma between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to explore the independent prognostic factors and establish two nomograms. The area under the curve (AUC), C-index, calibration curve, decision curve analysis (DCA), Kaplan-Meier analysis, and subgroup analyses were used to evaluate the nomograms.ResultsSix variables were identified as independent prognostic factors for both OS and CSS. In the training cohort, the AUCs of the OS nomogram were 0.842, 0.841, and 0.823 for predicting 3-, 5-, and 8-year OS, respectively, while the AUCs of the CSS nomogram were 0.889, 0.884, and 0.859 for predicting 3-, 5-, and 8-year CSS, respectively. Calibration plots and DCA revealed that the nomogram had a satisfactory ability to predict OS and CSS. The above results were also observed in the validation cohort. In addition, the C-indices of both nomograms were significantly higher than those of all independent prognostic factors in both the training and validation cohorts. Stratification of the patients into high- and low-risk groups highlighted the differences in prognosis between the two groups in the training and validation cohorts.ConclusionAge, sex, tumor size, grade, M stage, and surgery status were confirmed as independent prognostic variables for both OS and CSS in extremity liposarcoma patients. Two nomograms based on the above variables were established to provide more accurate individual survival predictions for extremity liposarcoma patients and to help physicians make appropriate clinical decisions.

Noggin is an antagonist of bone morphogenetic proteins (BMP), being indispensable for certain developmental events. The present study aimed to examine the role of Noggin in the development and prognosis of gastric cancer (GC) and to elucidate the underlying mechanisms. The expression of Noggin in GC was evaluated by RT‑qPCR, immunohistochemistry and by the analyses of publicly available databases. The effects of Noggin on proliferation, cell cycle, adhesion, invasion, colony formation and tumour spheroid were examined following both the knockdown and overexpression of Noggin in GC cell lines. The involvement of epidermal growth factor receptor (EGFR) signalling was examined by western blot analysis and by using small molecule inhibitors. As a result, a higher expression of Noggin in GC was found to be associated with a poorer overall survival. Noggin overexpression promoted the proliferation and colony formation of GC cells by promoting cell cycle progression. The knockdown of Noggin in HGC27 cells exerted an opposite effect on proliferation, colony formation and cell cycle progression. Noggin expression positively correlated with EGFR expression in both GC cell line models and The Cancer Genome Atlas human GC cohort. Targeting EGFR and its downstream pathways diminished cell proliferation which was promoted by Noggin. Furthermore, Noggin overexpression resulted in an enhanced nuclear translocation of β‑catenin, leading to an upregulation of EGFR. Thus, the findings of the present study demonstrate that Noggin promotes the proliferation of GC cells by upregulating EGFR and enhancing a vicious circle formed by β‑catenin, EGFR, ERK and Akt.

Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)‐22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR‐22. Inhibition of miR‐22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR‐22 and E‐cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR‐22 and inhibiting E‐cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy., Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) cooperating with enhancer of zeste homolog 2, positively regulated Snail family transcriptional repressor 1 (SNAI1) by repressing microRNA (miR)‐22 and inhibiting E‐cadherin expression, playing a vital role in epithelial to mesenchymal transition. These findings indicated that MALAT1 promotes hepatocellular carcinoma (HCC) progression by modulating the miR‐22/SNAI1 axis and provides a potential target for HCC therapy.

Granular corneal dystrophy (GCD) is featured by corneal deposits of transforming growth factor beta-induced gene (TGFBI) mediated by the TGF-β (transforming growth factor-β)/Smad signaling. However, the roles of c-Jun amino-terminal kinase (JNK) pathway in GCD pathogenesis remains unexplored, which was investigated in this study. JNK signaling activation and inhibition in primary corneal fibroblasts were obtained by treatments with anisomycin and SP600125, respectively. Protein abundance and phosphorylation were detected by immunoblotting. Cell viability and apoptosis were analyzed by CCK-8 and flow cytometry respectively. TGFBI deposit and autophagy progression were assessed by immunofluorescence. The results found that JNK1 expression and phosphorylation were greatly increased in corneal tissues from GCD2 patients. JNK signaling activation impaired the viability and promoted apoptosis and autophagy processes in primary corneal fibroblasts, along with Smad2/3 phosphorylation, TGFBI accumulation and Bcl-2 suppression. Autophagy related proteins, such as ATG5 (autophagy related 5), ATG12 (autophagy related 12) and LC3B (microtubule-associated protein 1 light chain 3 beta), were also increased in anisomycin or TGF-β1 treated corneal fibroblasts. However, SP600125 effectively reversed the above effect induced by TGF-β1 treatment in corneal fibroblasts, including the TGF-β-induced autophagy progression. The results suggested that JNK signaling was activated in GCD2 corneal tissues, and it mediated the TGF-β-induced TGFBI protein accumulation and apoptosis of corneal fibroblasts during GCD2 pathogenesis.

Background Indoleamine 2,3‐dioxygenase 1 (IDO1) and tryptophan (Trp) catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penile squamous cell carcinoma (PSCC) and explored their clinical significance. Methods IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn) were examined in 114 PSCC patients by immunohistonchemistry and solid‐phase extraction‐liquid chromatography‐tandem mass spectrometry. The survival was analyzed using Kaplan‐Meier method and the log‐rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were defined by principal component analysis. The correlativity was assessed by Pearson's correlation analysis. Results The expression level of IDO1 in PSCC cells was positively correlated with serum Kyn concentration and Kyn/Trp radio (KTR; both P

Drug-induced liver injury (DILI) and cardiotoxicity (DICT) are major adverse effects triggered by many clinically important drugs. To provide an alternative to in vivo toxicity testing, the U.S. Tox21 consortium has screened a collection of ∼10K compounds, including drugs in clinical use, against70 cell-based assays in a quantitative high-throughput screening (qHTS) format. In this study, we compiled reference compound lists for DILI and DICT and compared the potential of Tox21 assay data with chemical structure information in building prediction models for human in vivo hepatotoxicity and cardiotoxicity. Models were built with four different machine learning algorithms (e.g., Random Forest, Naïve Bayes, eXtreme Gradient Boosting, and Support Vector Machine) and model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC-ROC). Chemical structure-based models showed reasonable predictive power for DILI (best AUC-ROC = 0.75 ± 0.03) and DICT (best AUC-ROC = 0.83 ± 0.03), while Tox21 assay data alone only showed better than random performance. DILI and DICT prediction models built using a combination of assay data and chemical structure information did not have a positive impact on model performance. The suboptimal predictive performance of the assay data is likely due to insufficient coverage of an adequately predictive number of toxicity mechanisms. The Tox21 consortium is currently expanding coverage of biological response space with additional assays that probe toxicologically important targets and under-represented pathways that may improve the prediction of in vivo toxicity such as DILI and DICT.

OBJECTIVE: To study the association between functional dyspepsia (FD) and serum levels of brain-gut peptides including calcitonin gene-related peptide (CGRP), nesfatin-1, and ghrelin in children. METHOD: A total of 38 children with FD who attended Shengjing Hospital of China Medical University from November 2019 to December 2020 were enrolled as the FD group. Thirty-four healthy children were enrolled as the control group. Serum samples were collected from all of the children. Enzyme-linked immunosorbent assay was used to measure serum levels of CGRP, ghrelin, and nesfatin-1 for comparison between the two groups. The scores of clinical symptoms were determined for the children with FD. Spearman rank correlation analysis was used to investigate the correlation of symptom scores with the serum levels of brain-gut peptides. RESULTS: The FD group had significantly higher serum levels of nesfatin-1 and CGRP than the control group (P0.05). The serum level of nesfatin-1 was positively correlated with the symptom score of early satiety (r(s) =0.553, P

Previous studies have mainly focused on the negative effects of teacher–student conflict; the positive effects of conflict have rarely been mentioned. This paper suggests that encouraging conflict could act as a teaching method to improve students’ innovative competence. This study has two objectives: (1) to examine how various types of teacher–student conflict affects students’ innovative competence and (2) to identify the mediating role of a psychological safety climate in the association between conflict and students’ innovative competence. To achieve the objectives, we used evidence from 1207 university students. Multivariable logistic regression analysis revealed that conflicts were associated with students’ innovative competence, and the mediation role of a psychological safety climate is significant. Specifically, the results revealed that Cognitive Conflict had significant positive effects on students’ innovative competence, whereas Affective Conflict had a significant negative effect on students’ innovative competence. In addition, we clarified a psychological safety climate as the boundary condition for the relationship between conflict and students’ innovative competence.

Prostate cancer (PCa) is one of the principal causes of cancer‑related death worldwide. The roles and mechanisms of long non‑coding RNA (lncRNA) involved in the development of PCa remain incompletely understood. The present study aimed to investigate the role and mechanism of lncRNA in PCa tumorigenesis. In the present study, lncRNA cancer susceptibility candidate 11 (CASC11) was revealed to be a crucial regulator of PCa progression. The expression profiles of CASC11 in PCa were identified through analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets, and validated in human PCa specimens and cell lines. Gain‑ and loss‑of‑function assays were utilized to explore the biological role of CASC11 in PCa initiation and progression. RNA‑sequencing, RNA pull‑down and RNA immunoprecipitation analyses were used to explore potential mechanisms with which CASC11 may be associated. Rescue experiments were further conducted to confirm this association. The present results revealed that CASC11 was dominantly distributed in the nuclei of PCa cells, and was highly expressed in PCa tissues and cells. Overexpression of CASC11 was markedly associated with increased tumor proliferation and migratory ability. Functionally, decreased proliferation and migration, as well as inhibited xenograft tumor growth, were observed in CASC11‑silenced PCa cells, whereas the opposite effects were detected in CASC11‑overexpressing cells. Mechanistically, CASC11 promoted progression of the cell cycle and competitively interacted with Y‑box binding protein 1 (YBX1) to block the p53 pathway. Given this, poly (β‑amino ester) (PBAE)/small interfering RNA‑CASC11 (si‑CASC11) nanoparticles were applied to inhibit CASC11 expression and enhance the antitumor effect

Kawasaki disease (KD) is an acute self-limiting vasculitis with coronary complications, usually occurring in children. The incidence of KD in children is increasing year by year, mainly in East Asian countries, but relatively stably in Europe and America. Although studies on KD have been reported, the pathogenesis of KD is unknown. With the development of high-throughput sequencing technology, growing number of regulatory noncoding RNAs (ncRNAs) including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) have been identified to involved in KD. However, the role of ncRNAs in KD has not been comprehensively elucidated. Therefore, it is significative to study the regulatory role of ncRNA in KD, which might help to uncover new and effective therapeutic strategies for KD. In this review, we summarize recent studies on ncRNA in KD from the perspectives of immune disorders, inflammatory disorders, and endothelial dysfunction, and highlight the potential of ncRNAs as therapeutic targets for KD.

We previously showed that the rupture of Bowman’s capsule (BC) promotes the progression of crescentic glomerulonephritis by enhancing the entry of CD8+T cells into the glomeruli. In the present study, we utilized digital spatial profiling to simultaneously profile the altered abundances of the messenger RNA (mRNA) transcripts and proteins in the glomerular and periglomerular areas of four biopsy samples of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis (ANCA-GN) and two biopsy specimens of minimal change disease (MCD) controls. The paraffin-embedded biopsy samples were stained with collagen IV, CD45, and SYTO 13 to distinguish the glomeruli with periglomerular infiltration but intact BC, with focal BC rupture, and with extensive rupture of BC and glomeruli without crescent formation and leukocytic infiltration in ANCA-GN. By assessing multiple discrete glomerular areas, we found that the transcript expression levels of the secreted phosphoprotein-1 and its receptor CD44 were upregulated significantly in the glomeruli with more severe ruptures of BC, and their expression levels correlated positively with the fibrotic markers. We also found that both alternative and classic complement pathways were activated in the glomeruli from patients with ANCA-GN. Furthermore, M1 macrophages were involved mostly in the early stage of BC rupture, while M2 macrophages were involved in the late stage and may contribute to the fibrosis process of the crescents. Finally, loss of glomerular cells in ANCA-GN was likely mediated by apoptosis. Our results show that digital spatial profiling allows the comparative analysis of the mRNA and protein profiles in individual glomeruli affected differently by the disease process and the identification of potential novel mechanisms in ANCA-GN.

Colorectal polyp has been considered as the precancerous lesion of colorectal cancer, to which serum lipid levels are closely related. At present, there is no consensus on the relationship between colorectal polyps and serum lipid levels. We performed a meta-analysis to explore the effects of lipid levels on colorectal polyps. Relevant articles published from 2000 to 2020 were searched in PubMed, Web of Science, EMBASE, and Cochrane Library databases. The mean value and SD of serum lipid indexes and body mass index in colorectal polyps groups and control groups were extracted from the included articles. Combined weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated to assess the effect size of serum lipid levels on colorectal polyps. The publication bias of the included studies were assessed based on the Egger test. Thirty-seven articles containing 19,464 cases and 63,979 controls were included. There were no significant publication bias. The levels of high-density lipoprotein cholesterol in the cases were lower than those in the controls (WMD: -2.589 mg/dL, 95% CI: -3.273, -1.906). While the levels of triglyceride (WMD: 16.933 mg/dL, 95% CI: 13.131, 20.736), total cholesterol (WMD: 5.561 mg/dL, 95% CI: 3.477, 7.645), low-density lipoprotein cholesterol (WMD: 3.109 mg/dL, 95% CI: 0.859, 5.359) and body mass index (WMD: 0.747 mg/dL, 95% CI: 0.588, 0.906) were higher in the cases. Colorectal polyps were associated with serum lipid levels and obesity. Hyperlipidemia and obesity may be the risk factors for colorectal polyps.

Since 2020, the receptor-binding domain (RBD) of the spike protein of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most of the notable missense mutations in the context of “variants of concern”, probably in response to the vaccine-driven alteration of immune profiles of the human population. The Delta variant, in particular, has become the most prevalent variant of the epidemic, and it is spreading in countries with the highest vaccination rates, causing the world to face the risk of a new wave of the contagion. Understanding the physical mechanism responsible for the mutation-induced changes in the RBD’s binding affinity, its transmissibility, and its capacity to escape vaccine-induced immunity is the “urgent challenge” in the development of preventive measures, vaccines, and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. In this study, entropy–enthalpy compensation and the Gibbs free energy change were used to analyze the impact of the RBD mutations on the binding affinity of SARS-CoV-2 variants with the receptor angiotensin converting enzyme 2 (ACE2) and existing antibodies. Through the analysis, we found that the existing mutations have already covered almost all possible detrimental mutations that could result in an increase of transmissibility, and that a possible mutation in amino-acid position 498 of the RBD can potentially enhance its binding affinity. A new calculation method for the binding energies of protein–protein complexes is proposed based on the entropy–enthalpy compensation rule. All known structures of RBD–antibody complexes and the RBD–ACE2 complex comply with the entropy–enthalpy compensation rule in providing the driving force behind the spontaneous protein–protein docking. The variant-induced risk of breakthrough infections in vaccinated people is attributed to the L452R mutation’s reduction of the binding affinity of many antibodies. Mutations reversing the hydrophobic or hydrophilic performance of residues in the spike RBD potentially cause breakthrough infections of coronaviruses due to the changes in geometric complementarity in the entropy–enthalpy compensations between antibodies and the virus at the binding sites.

Fatty acid amides (FAMs) are present in breast milk. Oleamide (ODA), a member of the FAM family, has been reported to affect learning and memory-related abilities in animal experiments.This study aimed to characterize the temporal changes of FAMs in human milk and sought to examine the effect of ODA supplementation during suckling on postweaning cognitive performance in mice.FAMs were measured in human milk (postpartum 1-24 wk) by ultra-performance liquid chromatography-triple quadruple mass spectrometry (UPLC-TQ-MS) analysis. We supplemented neonatal C57BL/6J mice of both sexes with vehicle (control), 5 mg/(kg · day) ODA (L-ODA), or 25 mg/(kg · day) ODA (H-ODA) throughout suckling by oral gavage. After weaning, the Morris water maze test and novel object recognition test were performed. Neurogenesis, spinal morphogenesis in the dentate gyrus (DG) region, and hippocampal expression of synaptic markers were analyzed. Data were analyzed by ANOVA and repeated-measures ANOVA.ODA (0.566-1.31 mg/L) was the most abundant FAM in breast milk, followed by palmitamide (0.135-0.269 mg/L) and linoleamide (0.046-0.242 mg/L). Compared with the control group, the H-ODA group demonstrated shorter escape latency, shorter travel distance, 113% more platform crossing, and 48% greater discrimination index in behavioral tests (P0.05). Additionally, the H-ODA group showed a higher density of 5-ethynyl-2'-deoxyuridine (EdU)+ and EdU+doublecortin (DCX)+ cells (62% and 53%, respectively), and 52% greater spine density in the DG region than the control group (P0.05). The synaptic markers, postsynaptic density protein 95 (PSD95) and synaptophysin (SYP), were upregulated in the H-ODA group compared with the control group (P0.05). The L-ODA group also showed shorter escape latency in behavioral tests and 27% greater spine density in the DG region than the control group (P0.05).ODA is the most common FAM in human milk. ODA supplementation during suckling promotes learning and memory-related abilities in adolescent mice by augmenting hippocampal neuronal proliferation and boosting synaptic plasticity.

Fine particulate matter (PM

Osteosarcoma (OS) is the most common malignant bone tumor and the long‑term survival rates remain unsatisfactory. Transforming growth factor‑β (TGF‑β) has been revealed to play a crucial role in OS progression, and RepSox is an effective TGF‑β inhibitor. In the present study, the effect of RepSox on the proliferation of the OS cell lines (HOS and 143B) was detected. The results revealed that RepSox effectively inhibited the proliferation of OS cells by inducing S‑phase arrest and apoptosis. Moreover, the inhibitory effect of RepSox on cell migration and invasion was confirmed by wound‑healing and Transwell assays. Furthermore, western blotting revealed that the protein levels of molecules associated with the epithelial‑mesenchymal transition (EMT) phenotype, including E‑cadherin, N‑cadherin, Vimentin, matrix metalloproteinase (MMP)‑2 and MMP‑9, were reduced by RepSox treatment. Concurrently, it was also revealed that the JNK and Smad3 signaling pathway was inhibited. Our in vivo findings using a xenograft model also revealed that RepSox markedly inhibited the growth of tumors. In general, our data demonstrated that RepSox suppressed OS proliferation, EMT and promoted apoptosis by inhibiting the JNK/Smad3 signaling pathway. Thus, RepSox may be a potential anti‑OS drug.

Zinc-finger proteins (ZFPs) are the largest transcription factor family in mammals, involved in the regulation of multiple physiologic processes including cell differentiation, proliferation, apoptosis and neoplastic transformation. Approximately one-third of ZFPs are Krüppel-associated box domain (KRAB)-ZFPs. Methods: ZNF471 expression and methylation were detected by reverse-transcription PCR and methylation-specific PCR. The impact and mechanism of ectopic ZNF471 expression in esophageal squamous cell carcinoma (ESCC) cells was evaluated in vitro and in vivo. Results: We identified a 19q13 KRAB-ZFP, ZNF471, as a methylated target in ESCC. We further found that ZNF471 is significantly downregulated in ESCC tissues compared with adjacent non-cancer tissues, due to its aberrant promoter CpG methylation, and further confirmed by methylation analysis and treatment with demethylation agent. Restoration of ZNF471 expression in silenced ESCC cells significantly altered cell morphology, induced apoptosis and G0/G1 arrest, and inhibited tumor cell colony formation, viability, migration and invasion. Importantly, ZNF471 was found to activate the expression of MAPK10/JNK3 and PCDH family genes, and further enhance MAPK10 signaling and downstream gene expression through binding to the MAPK10/JNK3 promoter. Conclusion: Our results demonstrate that ZNF471 is an important tumor suppressor and loss of ZNF471 functions hampers MAPK10/JNK3 signaling during esophageal carcinogenesis.

Objectives To assess the correlation between endorectal ultrasound (ERUS) and magnetic resonance imaging (MRI) in predicting the circumferential resection margin (CRM) status of patients with mid-low rectal cancer without preoperative chemoradiotherapy. Methods Twenty patients with rectal cancer who did not receive preoperative chemoradiotherapy and underwent ERUS and MRI examinations before total mesorectal excision from May 2018 to April 2019 were included in this study. The patient and tumor characteristics, lymph nodes, tumor stages, ERUS and MRI predictors of the CRM status, and postoperative pathologic results were recorded. The closest distance between the deepest portion of lesion invasion and the mesorectal fascia was independently measured on MRI and ERUS images by 2 observers. The observers were blinded to the pathologic results. Measurements from ERUS and MRI were compared. Results The mean distance between the distal edge of the lesion and the anal verge was 5.7 cm (range, 3.1-8.1 cm). The ERUS and pathologic evaluations of CRM involvement were consistent in 90% of the cases. The MRI and pathologic evaluations of CRM involvement were concordant in 95% of the cases. The Cohen κ coefficient of ERUS and MRI was 0.608 (P = .007). The correlation coefficient of ERUS and MRI for assessing the closest distance from the edge of cancer invasion to the mesorectal fascia was 0.99 (P = .0005). Conclusions Endorectal ultrasound and MRI assessments of the preoperative CRM status appear to be highly consistent. Endorectal ultrasound can be used as a complementary tool with MRI to predict the CRM status of patients with mid-low rectal cancer without preoperative chemoradiotherapy.

Laparoscopic hepatectomy (LH) is a newly developed technique associated with advantages as open surgery, but the study on outcome of liver function recovery was scarce. This preliminary report was aimed to comparatively assess the short-term outcomes between LH and open hepatectomy (OH) for primary hepatocellular carcinoma (PHC). This study retrospectively analyzed the demographic data and short-term outcomes of 81 patients who underwent LH or OH for the primary treatment of PHC between Oct. 2017 and May 2018 at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (China). A total of 81 PHC patients who received major liver resection were enrolled. There were 38 (47%) patients in the LH group and 43 (53%) patients in the OH group. The operative time was significantly longer (373.53±173.38 vs. 225.43±55.08, P

Herein biodegradable poly(e-caprolactone) was electrospun into tubular microfibrous scaffolds and modified by the surface heparinization and wrapping of Type I collagen suture for enhancing anticoa...

The use of intelligent judgment technology to assist in judgment is an inevitable trend in the development of judgment in contemporary social legal cases. Using big data and artificial intelligence technology to accurately determine multiple accusations involved in legal cases is an urgent problem to be solved in legal judgment. The key to solving these problems lies in two points, namely, (1) characterization of legal cases and (2) classification and prediction of legal case data. Traditional methods of entity characterization rely on feature extraction, which is often based on vocabulary and syntax information. Thus, traditional entity characterization often requires extensive energy and has poor generality, thus introducing a large amount of computation and limitation to subsequent classification algorithms. This study proposes an intelligent judgment approach called RnRTD, which is based on the relationship-driven recurrent neural network (rdRNN) and restricted tensor decomposition (RTD). We represent legal cases as tensors and propose an innovative RTD method. RTD has low dependence on vocabulary and syntax and extracts the feature structure that is most favorable for improving the accuracy of the subsequent classification algorithm. RTD maps the tensors, which represent legal cases, into a specific feature space and transforms the original tensor into a core tensor and its corresponding factor matrices. This study uses rdRNN to continuously update and optimize the constraints in RTD so that rdRNN can have the best legal case classification effect in the target feature space generated by RTD. Simultaneously, rdRNN sets up a new gate and a similar case list to represent the interaction between legal cases. In comparison with traditional feature extraction methods, our proposed RTD method is less expensive and more universal in the characterization of legal cases. Moreover, rdRNN with an RTD layer has a better effect than the recurrent neural network (RNN) only on the classification and prediction of multiple accusations in legal cases. Experiments show that compared with previous approaches, our method achieves higher accuracy in the classification and prediction of multiple accusations in legal cases, and our algorithm is more interpretable.

Background:. Visual-spatial neglect (VSN) is a neuropsychological syndrome, and right-hemisphere stroke is the most common cause. The pathogenetic mechanism of VSN remains unclear. This study aimed to investigate the behavioral and event-related potential (ERP) changes in patients with or without VSN after right-hemisphere stroke. Methods:. Eleven patients with VSN with right-hemisphere stroke (VSN group) and 11 patients with non-VSN with right-hemisphere stroke (non-VSN group) were recruited along with one control group of 11 age- and gender-matched healthy participants. The visual-spatial function was evaluated using behavioral tests, and ERP examinations were performed. Results:. The response times in the VSN and non-VSN groups were both prolonged compared with those of normal controls (P 0.05). Conclusions:. Visual-spatial attention function is impaired after right-hemisphere stroke, and clinicians should be aware of the subclinical VSN. Our findings provide neuroelectrophysiological evidence for the lateralization of VSN.

Chemoresistance is the primary obstacle in the treatment of locally advanced and metastatic nasopharyngeal carcinoma (NPC). Recent evidence suggests that the transcription factor forkhead box M1 (FoxM1) is involved in chemoresistance. Our group previously confirmed that FoxM1 is overexpressed in NPC. In this study, we investigated the role of FoxM1 in cisplatin resistance of the cell lines 5-8F and HONE-1 and explored its possible mechanism. Our results showed that FoxM1 and NBS1 were both overexpressed in NPC tissues based on data from the GSE cohort (GSE12452). Then, we measured FoxM1 levels in NPC cells and found FoxM1 was overexpressed in NPC cell lines and could be stimulated by cisplatin. MTT and clonogenic assays, flow cytometry, γH2AX immunofluorescence, qRT-PCR, and western blotting revealed that downregulation of FoxM1 sensitized NPC cells to cisplatin and reduced the repair of cisplatin-induced DNA double-strand breaks via inhibition of the MRN (MRE11-RAD50-NBS1)-ATM axis, which might be related to the ability of FoxM1 to regulate NBS1. Subsequently, we demonstrated that enhanced sensitivity of FoxM1 knockdown cells could be reduced by overexpression of NBS1. Taken together, our data demonstrate that downregulation of FoxM1 could improve the sensitivity of NPC cells to cisplatin through inhibition of MRN-ATM-mediated DNA repair, which could be related to FoxM1-dependent regulation of NBS1. [BMB Reports 2019; 52(3): 208-213].