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Abstract Background Given increases in China’s aging population, the growing demand for public health services and the shortage of human resources among nurses have become more prominent. Under such a background, “Internet + Nursing Services” have received more attention. Thus, exploring the barriers to and facilitators of nurses’ willingness to participate in “Internet + Nursing Services” and utilizing internet technology to increase the supply of nursing services has become a key issue. Objective This study aimed to develop a scale for assessing the barriers to and facilitators of nurses’ willingness to participate in “Internet + Nursing Services” and to test the validity and reliability of the scale. Methods A preliminary scale was developed based on a literature review, theoretical research, semistructured qualitative interviews, and two rounds of Delphi expert inquiry. A convenient sampling method was used for the questionnaire survey. A 5-point Likert scale was used to evaluate the importance of the items. The survey data of 659 clinical nurses obtained from February to March 2023 were used for item analysis, exploratory factor analysis (EFA), and reliability and validity tests of the scale. The survey data of 538 clinical nurses obtained in April 2023 were used for confirmatory factor analysis (CFA) of the final scale. Results The final scale consists of 25 items and 4 dimensions (performance expectations, perceived risk, need for professional knowledge training, and nonprofessional knowledge training). The scale showed good structural validity and content validity: the Cronbach’s α coefficient of the scale was 0.955, the split-half reliability was 0.778, the test-retest reliability was 0.944, the kaiser-meyer-olkin(KMO) value was 0.960, and the cumulative variance contribution rate of the 4 common factors was 83.147%. The scale content validity index(S-CVI) was 0.914. The confirmatory factor analysis model had favorable fit indices: χ2/df = 4.234, RMSEA = 0.078, NFI = 0.940, IFI = 0.953, TLI = 0.947, and CFI = 0.953. Conclusion The scale for assessing the barriers to and facilitators of nurses’ willingness to participate in “Internet + Nursing Services” has good reliability and validity, and provides a reference for evaluating nurses’ willingness to participate in “Internet + Nursing Services”.

Abstract Matrix metalloproteinases (MMPs) had a variety of subtypes, which may be related to tumor invasion and angiogenesis, and the polymorphisms from MMPs have been also associated with the susceptibility to a variety of tumors, including prostate cancer (PCa). However, previous studies have not systematically analyzed the association between MMP and prostate cancer, so we conducted systematic data collection and analyzed to evaluate the relationship among polymorphisms in MMPs and PCa susceptibility. We searched PubMed, Web of Science, Embase and Google Scholar for all papers published up to Apr 3rd, 2023, and systematically analyzed the relationship among MMP1-1607 2G/1G, MMP2-1306 T/C, MMP2-735 T/C, MMP7-181 G/A, MMP9-1562 T/C and PCa susceptibility using multiple comparative models and subgroup analyses. We found that MMP2-1306 T/C polymorphism showed associations with PCa susceptibility, with the Ethnicity subgroup (Asian) being more pronounced. Similarly, MMP9-1562 T/C has also had associations with PCa susceptibility. Our current study found that the polymorphisms of, MMP2-1306 T/C, and MMP9-1562 T/C had strong associations with PCa risk.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is associated with a high prevalence of cancer-related deaths. The survival rates of patients are significantly lower in late-stage ccRCC than in early-stage ccRCC, due to the spread and metastasis of late-stage ccRCC, surgery has not reached the goal of radical cure, and the effect of traditional radiotherapy and chemotherapy is poor. Thus, it is crucial to accurately assess the prognosis and provide personalized treatment at an early stage in ccRCC. This study aims to develop an efficient nomogram model for stratifying and predicting the survival of ccRCC patients based on tumor stage. Methods We first analyzed the microarray expression data of ccRCC patients from the Gene Expression Omnibus (GEO) database and categorized them into two groups based on the disease stage (early and late stage). Subsequently, the GEO2R tool was applied to screen out the genes that were highly expressed in all GEO datasets. Finally, the clinicopathological data of the two patient groups were obtained from The Cancer Genome Atlas (TCGA) database, and the differences were compared between groups. Survival analysis was performed to evaluate the prognostic value of candidate genes (PSAT1, PRAME, and KDELR3) in ccRCC patients. Based on the screened gene PSAT1 and clinical parameters that were significantly associated with patient prognosis, we established a new nomogram model, which was further optimized to a single clinical variable-based model. The expression level of PSAT1 in ccRCC tissues was further verified by qRT-PCR, Western blotting, and immunohistochemical analysis. Results The datasets GSE73731, GSE89563, and GSE150404 identified a total of 22, 89, and 120 over-expressed differentially expressed genes (DEGs), respectively. Among these profiles, there were three genes that appeared in all three datasets based on different stage groups. The overall survival (OS) of late-stage patients was significantly shorter than that of early-stage patients. Among the three candidate genes (PSAT1, PRAME, and KDELR3), PSAT1 was shown to be associated with the OS of patients with late-stage ccRCC. Multivariate Cox regression analysis showed that age, tumor grade, neoadjuvant therapy, and PSAT1 level were significantly associated with patient prognosis. The concordance indices were 0.758 and 0.725 for the 3-year and 5-year OS, respectively. The new model demonstrated superior discrimination and calibration compared with the single clinical variable model. The enhancer PSAT1 used in the new model was shown to be significantly overexpressed in tissues from patients with late-stage ccRCC, as demonstrated by the mRNA level, protein level, and pathological evaluation. Conclusion The new prognostic prediction nomogram model of PSAT1 and clinicopathological variables combined was thus established, which may provide a new direction for individualized treatment for different-stage ccRCC patients.

Background: Nuclear cap-binding protein 2 (NCBP2), as the component of the cap-binding complex, participates in a number of biological processes, including pre-mRNA splicing, transcript export, translation regulation and other gene expression steps. However, the role of NCBP2 on the tumor cells and immune microenvironment remains unclear. To systematically analyze and validate functions of NCBP2, we performed a pan-cancer analysis using multiple approaches. Methods: The data in this study were derived from sequencing, mutation, and methylation data in the TCGA cohort, normal sample sequencing data in the GTEx project, and cell line expression profile data in the CCLE database. Results: Survival analyses including the Cox proportional-hazards model and log-rank test revealed the poor prognostic role of NCBP2 in multiple tumors. We further validated the oncogenic ability of NCBP2 in prostate cancer cell lines, organoids and tumor-bearing mice. A negative correlation was observed between NCBP2 expression and immune score by the ESTIMATE algorithm. Simultaneously, the NCBP2-induced immunosuppressive microenvironment might be related to the decline in CD8+ T cells and the increase in regulatory T cells and neutrophils, examined by flow cytometry experiments for NCBP2 overexpressed tumor-bearing mice. Conclusion: This research offered strong proof supporting NCBP2 as the prognostic marker and the therapeutic target in the future.

Tropomyosin (TPM) is an important regulatory protein that binds to actin in fine myofilaments, playing a crucial role in the regulation of muscle contraction. TPM3, as one of four tropomyosin genes, is notably prevalent in eukaryotic cells. Traditionally, abnormal gene expression of TPM3 has been exclusively associated with myopathy. However, recent years have witnessed a surge in studies highlighting the close correlation between abnormal expression of TPM3 and the onset, progression, metastasis, and prognosis of various malignant tumors. In light of this, investigating the mechanisms underlying the pathogenetic role of TPM3 holds significant promise for early diagnosis and more effective treatment strategies. This article aims to provide an insightful review of the structural characteristics of TPM3 and its intricate role in the occurrence and development of malignant tumors.

Abstract Aim To retrieve, analyse and summarize the relevant evidence on the prevention and management of bladder dysfunction in patients with cervical ancer after radical hysterectomy. Design Overview of systematic reviews. Methods 11 databases were searched for relevant studies from top to bottom according to the ‘6S’ model of evidence‐based resources. Two independent reviewers selected the articles, extracted the data and appraised the quality of the included reviews based on different types of evaluation tools. Results A total of 13 studies were identified, including four clinical consultants, four guidelines, four systematic reviews and one randomized controlled trial. 29 best evidence were summarized from five aspects, including definition, risk factors, assessment, prevention and management.

Hippocampal place cells in freely moving rodents display both theta phase precession and procession, which is thought to play important roles in cognition, but the neural mechanism for producing theta phase shift remains largely unknown. Here, we show that firing rate adaptation within a continuous attractor neural network causes the neural activity bump to oscillate around the external input, resembling theta sweeps of decoded position during locomotion. These forward and backward sweeps naturally account for theta phase precession and procession of individual neurons, respectively. By tuning the adaptation strength, our model explains the difference between ‘bimodal cells’ showing interleaved phase precession and procession, and ‘unimodal cells’ in which phase precession predominates. Our model also explains the constant cycling of theta sweeps along different arms in a T-maze environment, the speed modulation of place cells’ firing frequency, and the continued phase shift after transient silencing of the hippocampus. We hope that this study will aid an understanding of the neural mechanism supporting theta phase coding in the brain.

Sequential working memory (SWM), referring to the temporary storage and manipulation of information in order, plays a fundamental role in brain cognitive functions. The serial position effect refers to the phenomena that recall accuracy of an item is associated to the order of the item being presented. The neural mechanism underpinning the serial position effect remains unclear. The synaptic mechanism of working memory proposes that information is stored as hidden states in the form of facilitated neuronal synapse connections. Here, we build a continuous attractor neural network with synaptic short-term plasticity (STP) to explore the neural mechanism of the serial position effect. Using a delay recall task, our model reproduces the the experimental finding that as the maintenance period extends, the serial position effect transitions from the primacy to the recency effect. Using both numerical simulation and theoretical analysis, we show that the transition moment is determined by the parameters of STP and the interval between presented stimulus items. Our results highlight the pivotal role of STP in processing the order information in SWM.

Abstract Mitochondria play a multifaceted role in supporting bladder cancer progression. Translocase of inner mitochondrial membrane 44 (TIMM44) is essential for maintaining function and integrity of mitochondria. We here tested the potential effect of MB-10 (MitoBloCK-10), a first-in-class TIMM44 blocker, against bladder cancer cells. TIMM44 mRNA and protein expression is significantly elevated in both human bladder cancer tissues and cells. In both patient-derived primary bladder cancer cells and immortalized (T24) cell line, MB-10 exerted potent anti-cancer activity and inhibited cell viability, proliferation and motility. The TIMM44 blocker induced apoptosis and cell cycle arrest in bladder cancer cells, but failed to provoke cytotoxicity in primary bladder epithelial cells. MB-10 disrupted mitochondrial functions in bladder cancer cells, causing mitochondrial depolarization, oxidative stress and ATP reduction. Whereas exogenously-added ATP and the antioxidant N-Acetyl Cysteine mitigated MB-10-induced cytotoxicity of bladder cancer cells. Genetic depletion of TIMM44 through CRISPR-Cas9 method also induced robust anti-bladder cancer cell activity and MB-10 had no effect in TIMM44-depleted cancer cells. Contrarily, ectopic overexpression of TIMM44 using a lentiviral construct augmented proliferation and motility of primary bladder cancer cells. TIMM44 is important for Akt-mammalian target of rapamycin (mTOR) activation. In primary bladder cancer cells, Akt-S6K1 phosphorylation was decreased by MB-10 treatment or TIMM44 depletion, but enhanced after ectopic TIMM44 overexpression. In vivo, intraperitoneal injection of MB-10 impeded bladder cancer xenograft growth in nude mice. Oxidative stress, ATP reduction, Akt-S6K1 inhibition and apoptosis were detected in MB-10-treated xenograft tissues. Moreover, genetic depletion of TIMM44 also arrested bladder cancer xenograft growth in nude mice, leading to oxidative stress, ATP reduction and Akt-S6K1 inhibition in xenograft tissues. Together, targeting overexpressed TIMM44 by MB-10 significantly inhibits bladder cancer cell growth in vitro and in vivo.

Abstract Treatment of castration‐resistant prostate cancer (CRPC) is a long‐standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone biosynthesis or blocking androgen receptor (AR) signaling. Here it is demonstrated that AR inhibitor treatment gives rise to a drug‐tolerant persister (DTP) state. The thioredoxin/peroxiredoxin pathway is up‐regulated in DTP cells. Peroxiredoxin 5 (PRDX5) promotes AR inhibitor resistance and CRPC development. Inhibition of PRDX5 suppresses DTP cell proliferation in culture, dampens CRPC development in animal models, and stabilizes PSA progression and metastatic lesions in patients. Therefore, the study provides a novel mechanism and potential target for the management of castration‐resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is a fatal disease that evolves from prostate cancer due to drug resistance after long-term androgen deprivation therapy. In this study, we aimed to find novel molecular targets for treating CRPC. Through peptidome, we screened out polypeptides dysregulated in the serum of CRPC patients. According to RT-qPCR analysis and cell viability detection, we chose PDZ and LIM Domain 7 (PDLIM7) as the research object. As demonstrated by loss-of-function assays, silencing of PDLIM7 could suppress CRPC cell proliferation, migration, and angiogenesis. Moreover, PDLIM7 knockdown enhanced the sensitivity of CRPC cells to docetaxel treatment. Subsequently, we found that CBP/p300 increases the H3K27ac level in the PDLIM7 promoter to activate PDLIM7. Mechanism experiments such as IP and western blot revealed that PDLIM7 interacted with YAP1 to induce O-Glycosylation of YAP1 and thus stabilize YAP1 protein. Rescue assays demonstrated that PDLIM7 promoted the malignant processes of CRPC cells through YAP1. Finally, an animal study validated that PDLIM7 aggravated tumor growth. In conclusion, our findings highlighted the oncogenic role of PDLIM7 upregulated by CBP/p300-induced H3K27ac enhancement in CRPC by stabilizing YAP1.

Abstract Background Non‐small cell lung cancer (NSCLC) is one of the most prevalent and severe malignant tumors in the world and its molecular mechanism is still unclear. In recent years, increasing evidence indicates the significant roles of circRNAs in NSCLC. It has been determined that 2‐methoxyestradiol (2‐MeOE2) exerts antitumor roles in many cancers. However, the molecular mechanism of 2‐MeOE2 in regulating the development of lung cancer needs further elucidation. Methods The expression levels of circ_0010235, microRNA‐34a‐5p (miR‐34a‐5p), and nuclear factor of activated T cells 5 (NFAT5) were detected by quantitative real‐time polymerase chain reaction (qRT‐PCR). Cell proliferation, apoptosis and invasion were detected by cell counting kit‐8 (CCK‐8), 5‐ethynyl‐2′‐deoxyuridine (EdU) assay, flow cytometry and transwell assays, respectively. The interaction between miR‐34a‐5p and circ_0010235 or NFAT5 was predicted by bioinformatic software and confirmed by dual‐luciferase reporter assay. Results Our data showed 2‐MeOE2 hindered cell proliferation, invasion and induced apoptosis in NSCLC, which could be reversed by upregulation of circ_0010235 and NFAT5 or miR‐34a‐5p knockdown. Circ_0010235 and NFAT5 expression levels were increased, and miR‐34a‐5p expression level was decreased in NSCLC tissues and cells. In addition, 2‐MeOE2 treatment suppressed the expression of circ_0010235 and NFAT5 while promoted the expression of miR‐34a‐5p. Furthermore, circ_0010235 functioned as a molecular sponge of miR‐34a‐5p to regulate NFAT5 expression. Knockdown of circ_0010235 or 2‐MeOE2 treatment constrained tumor growth in vivo, and circ_0010235 depletion enhanced the inhibitory effect of 2‐MeOE2 on tumor growth in vivo. Conclusion These findings demonstrated that 2‐MeOE2 retarded NSCLC progression by modulating the circ_0010235/miR‐34a‐5p/NFAT5 axis, thus providing a new perspective for 2‐MeOE2 treatment in NSCLC.

Abstract Background NUPR1, or p8, is a small chromatin protein that plays a central role in the resistance to treatment and progression of cancer. Nevertheless, the molecular mechanism of NUPR1 in bladder cancer (BLCA) remains unclear. Methods We used online databases and immunohistochemistry (IHC) to explore the expression of NUPR1 in BLCA tissues and controls. Lentivirus‐mediated small interfering ribonucleic acid (siRNA) was used to knockdown the expression of NUPR1 in two human BLCA cell lines. We used an in vivo experiment to investigate the effect of NUPR1 knockdown on the growth of BLCA. Moreover, an in silico analysis was conducted to assess the differential expression profile after NUPR1 interference. The CIBERSORT algorithm was utilized to evaluate the effects of tumor‐infiltrating immune cells among BLCA patients. Results The expression of NUPR1 in BLCA tissues was significantly higher than in the control. NUPR1 expression was also positively correlated with the stage of BLCA. After lentivirus‐mediated interference, the expression of NUPR1 was significantly down‐regulated in BLCA cell lines. The cell cycle was blocked in G1 phase and the cell proportion of S phase was decreased in both two cell lines. Moreover, in vivo experiment revealed that the tumor growth of BLCA can be delayed by inhibiting the expression of NUPR1. Both in silico analysis and functional experiments revealed that NUPR1 was correlated with epithelial–mesenchymal transition (EMT). We also revealed that macrophages were the most related immune cells associated with the expression of NUPR1 in BLCA. Conclusions This study suggests that NUPR1 plays a carcinogenic role in BLCA. NUPR1 lentivirus‐mediated interference could interfere with cycle progression of the BLCA cell, resulting in cell cycle arrest in the G1‐phase. The carcinogenic effect of NUPR1 in BLCA is likely achieved through EMT. NUPR1 is correlated with the M0‐type macrophage markers CD68 and CD11b‐integrin.

Abstract Castration-resistance of prostate cancer is one of the most challenging clinical problems. In the present study, we have performed proteomics and glycomics using LNCaP model. Growth differentiation factor-15 (GDF15) level is increased in androgen receptor (AR) inhibitor-resistant cells and the inhibitory effect of GDF15 on epithelial growth factor receptor (EGFR) pathway is relieved by GDF15 N70 glycosylation. Interference of GDF15 (siRNA or N70Q dominant negative) or EGFR pathway (inhibitor or siRNA for EGFR, SRC or ERK) decreases the resistant-cell survival in culture and tumor growth in mice. Our study reveals a novel regulatory mechanism of prostate cancer AR inhibitor resistance, raises the possibility of AR/SRC dual-targeting of castration-resistance of prostate cancer, and lays foundation for the future development of selective inhibitors of GDF15 glycosylation.

Abstract Background Over the past two decades, several studies have focused on the association between a common polymorphism (rs1800795) from interleukin-6 (IL-6) gene and Diabetes Mellitus (DM) risk. However, the results remain ambiguous and indefinite. Methods A comprehensive analysis was performed to explore this relationship. A search was conducted in the PubMed, Embase, Chinese (CNKI and Wanfang), and GWAS Catalog databases, covering all publications until February 10, 2022. Odds ratios (OR) with 95% confidence intervals (CI) were used to evaluate the strength of the association. Publication bias was assessed using both Begg and Egger tests. Results Overall, 34 case–control studies with 7257 T2DM patients and 15,598 controls, and 12 case–control studies (10,264 T1DM patients and 9031 health controls) were included in the analysis. A significantly lower association was observed between the rs1800795 polymorphism and T2DM risk in Asians, mixed population, and hospital-based (HB) subgroups (C-allele vs. G-allele: OR = 0.76, 95% CI 0.58–0.99, P = 0.039 for Asians; CG vs. GG: OR = 0.74, 95% CI 0.58–0.94, P = 0.014 for mixed population; CC vs. GG: OR = 0.61, 95% CI 0.41–0.90, P = 0.014 for HB). However, increased associations were found from total, mixed population, and HB subgroups between rs1800795 polymorphism and T1DM susceptibility (CG vs. GG: OR = 1.32, 95% CI 1.01–1.74, P = 0.043 for total population, CC vs. GG: OR = 2.45, 95% CI 1.18–5.07, P = 0.016 for mixed individuals; C-allele vs. G-allele: OR = 1.29, 95% CI 1.07–1.56, P = 0.0009 for HB subgroup). Conclusions In summary, there is definite evidence to confirm that IL-6 rs1800795 polymorphism is associated with susceptibility to decreased T2DM and increased T1DM.

ObjectiveA two-electron reductase known as NQO1 [NAD(P)H quinone oxidoreductase 1] is regarded as an excellent anticancer target. Studies have found that rs1800566 polymorphism of NQO1 is linked to different cancers, but their associations remain controversial.MethodsIn the present work, we selected to do a comprehensive meta-analysis to analyze their correlation. We performed searches on PubMed, Embase, Google Scholar, Chinese database, and Web of Science. The results we obtained covered all publications before April 3, 2022.ResultsThere were 176 case-control studies among them, with 56,173 corresponding controls and 43,736 cancer cases. We determined that the NQO1 rs1800566 polymorphism was not related to the cancer risk by calculating 95% confidence intervals and odds ratios. However, stratified genotyping showed that this polymorphism was protective against hepatocellular carcinoma, renal cell carcinoma, and gastric cancer. In addition, on dividing cancer into six systems, the association with gastrointestinal cancer decreased. In the race-based subgroup, a decreasing trend was observed in Asians, while an increasing trend was found among Caucasians, Africans, and mixed populations. The decreased correlation in the hospital-based subgroup was also detected.ConclusionCurrent study shows that rs1800566 polymorphism of NQO1 was linked to cancer susceptibility and maybe as a tumor marker in their development.

Kidney renal clear cell carcinoma (KIRC) is a subtype of renal cell carcinoma that threatens human health. The mechanism by which the trophinin-associated protein (TROAP)–an important oncogenic factor–functions in KIRC has not been studied. This study investigated the specific mechanism by which TROAP functions in KIRC. TROAP expression in KIRC was analyzed using the RNAseq dataset from the Cancer Genome Atlas (TCGA) online database. The Mann–Whitney U test was used to analyze the expression of this gene from clinical data. The Kaplan–Meier method was used for the survival analysis of KIRC. The expression level of TROAP mRNA in the cells was detected using qRT-PCR. The proliferation, migration, apoptosis, and cell cycle of KIRC were detected using Celigo, MTT, wound healing, cell invasion assay, and flow cytometry. A mouse subcutaneous xenograft experiment was designed to demonstrate the effect of TROAP expression on KIRC growth in vivo. To further investigate the regulatory mechanism of TROAP, we performed co-immunoprecipitation (CO-IP) and shotgun liquid chromatography–tandem mass spectrometry (LC-MS). TCGA-related bioinformatics analysis showed that TROAP was significantly overexpressed in KIRC tissues and was related to higher T and pathological stages, and a poor prognosis. The inhibition of TROAP expression significantly reduced the proliferation of KIRC, affected the cell cycle, promoted cell apoptosis, and reduced cell migration and invasion. The subcutaneous xenograft experiments showed that the size and weight of the tumors in mice were significantly reduced after TROAP-knockdown. CO-IP and post-mass spectrometry bioinformatics analyses revealed that TROAP may combine with signal transducer and activator of transcription 3 (STAT3) to achieve tumor progression in KIRC; this was verified by functional recovery experiments. TROAP may regulate KIRC proliferation, migration, and metastasis by binding to STAT3.

In our previous studies, we found that the rs231775 polymorphism of cytotoxic T-lymphocyte antigen 4 (CTLA-4) is associated with risks of different cancer types; however, the association remains controversial and ambiguous, so we conducted an in-depth meta-analysis to verify the association. A complete search of the PubMed, Google Scholar, Embase, Chinese databases, and Web of Science was conducted without regard to language limitations, covering all publications since November 20, 2021. The search criteria for cancer susceptibility associated with the polymorphism in the CTLA-4 gene rs231775 resulted in 87 case-control studies with 29,464 cases and 35,858 controls. The association strength was analyzed using odds ratios and 95% confidence intervals. Overall, we found that the CTLA-4 rs231775 polymorphism may reduce cancer risk. A stratified cancer type analysis showed that CTLA-4 rs231775 polymorphism was a risk factor for colorectal cancer and thyroid cancer; on the other hand, it was a protective factor for breast cancer, liver cancer, cervical cancer, bone cancer, head and neck, and pancreatic cancer. We also classified cancer into five systems and observed an increased association with digestive tract cancer, decreased associations with orthopedic tumors, tumors of the urinary system, and gynecological tumors. In the subgroup based on race, decreased relationships were observed in both Asians and Caucasians. The same decreased association was also shown in the analysis of the source of control analysis. Our present study indicates that the CTLA-4 rs231775 polymorphism contributes to cancer development and aggression.

There is increasing evidence that coatomer protein complex subunit beta 2 (COPB2) plays an important role in various cancer types. This study explored the role and the downstream mediators of COPB2 in prostate cancer (PCa). The expression of COPB2 was determined by the Cancer Genome Atlas database and enzyme-linked immunosorbent assay. COPB2 expression was upregulated in PCa tissues and correlated with Gleason score, biochemical recurrence, and poor prognosis. The functional roles of COPB2 in PCa were verified through a series of experiments. Knocking down COPB2 expression inhibited the growth and clonogenesis of PCa cells, promoted cell apoptosis, and inhibited the ability of scratch repair, invasion of PCa cells, and tumor growth in Nude mice. To analyze downstream signaling pathways, ingenuity pathway analysis, GSEA, and whole-genome expression spectrum GeneChip analysis were used. Western blot revealed that COPB2 expression promoted the proliferation and invasion of PCa cells by regulating the MAPK/TGF-β signaling pathway. The interacting protein (nuclear protein 1, NUPR1) was identified via Co-IP, real-time PCR, Western blot, and TCGA database in sampled tissues. The expressions of the interaction proteins NUPR1 and COPB2 were negatively regulated by each other. COPB2 could be a new biomarker for PCa diagnosis and monitoring and to provide a theoretical basis for identifying effective drug intervention targets through in-depth mechanistic studies.

Abstract The correlation between G388R or V10I polymorphisms of fibroblast growth factor receptor (FGFR) 4 gene and the risk of carcinoma has been investigated previously, but the results are contradictory. Odds ratios (ORs) with 95% confidence intervals (95%CIs), in silico tools, and immunohistochemical staining (IHS) were adopted to assess the association. In total, 13,793 cancer patients and 16,179 controls were evaluated in our pooled analysis. Summarization of all the studies showed that G388R polymorphism is associated with elevated susceptibility to cancer under homozygous comparison (OR = 1.21, 95%CI = 1.03–1.43, P = 0.020) and a recessive genetic model (OR = 1.21, 95%CI = 1.04–1.41, P = 0.012). In the stratification analysis by cancer type and ethnicity, similar findings were indicated for prostate cancer, breast cancer, and individuals of Asian descendant. Polyphen2 bioinformatics analysis showed that the G388R mutation is predicted to damage the protein function of FGFR4. IHS analysis indicated that FGFR4 expression is increased in advanced prostate cancer. These findings may guide personalized treatment of certain types of cancers. Up-regulation of FGFR4 may be related to a poor prognosis in prostate cancer.

Abstract Background With the rapid development of medical treatment, many patients not only consider the survival time, but also care about the quality of life. Changes in physical, psychological and social functions after and during treatment have caused a lot of troubles to patients and their families. Based on the bio-psycho-social medical model theory, mental health plays an important role in treatment. Therefore, it is necessary for medical staff to know the diseases which have high potential to cause psychological trauma and social avoidance (PTSA). Results Firstly, we obtained diseases which can cause PTSA from literatures. Then, we calculated the similarities of related-diseases to build a disease network. The similarities between diseases were based on their known related genes. Then, we obtained these diseases-related proteins from UniProt. These proteins were extracted as the features of diseases. Therefore, in the disease network, each node denotes a disease and contains the information of its related proteins, and the edges of the network are the similarities of diseases. Then, graph convolutional network (GCN) was used to encode the disease network. In this way, each disease’s own feature and its relationship with other diseases were extracted. Finally, Xgboost was used to identify PTSA diseases. Conclusion We developed a novel method ‘GCN-Xgboost’ and compared it with some traditional methods. Using leave-one-out cross-validation, the AUC and AUPR were higher than some existing methods. In addition, case studies have been done to verify our results. We also discussed the trajectory of social avoidance and distress during acute survival of breast cancer patients.

Abstract Background Long noncoding RNAs (lncRNAs) have been proved to be an important regulator in gene expression. In almost all kinds of cancers, lncRNAs participated in the process of pathogenesis, invasion, and metastasis. Meanwhile, compared with the large amounts of patients, there is rare knowledge about the role of lncRNAs in prostate cancer (PCa). Material/Method In this study, lncRNA expression profiles of prostate cancer were detected by Agilent microarray chip, 5 pairs of case and control specimens were involved in. Differentially expressed lncRNAs were screened out by volcano plot for constructing lncRNA-miRNA-mRNA central network. Then, the top ten up-regulated and down-regulated lncRNAs were validated by qRT-PCR in another 5 tumor specimens and 7 para-cancerous/benign contrasts. Furthermore, we searched for the survival curve of the top 10 upregulated and downregulated lncRNAs. Results A total of 817 differentially expressed lncRNAs were filtered out by the criteria of fold change (FC) and t-test p

Using a combination of two-photon imaging and single-cell electrophysiology, the authors discover that associative learning induces the emergence of a unique subset of neurons in the auditory cortex, exhibiting high-rate bursting responses to the learned complex sounds but not to any of the constituents.

Introduction: Increasing study have found that stem cell transplantation have a therapeutical effect to diabetes mellitus (DM)-induced erectile dysfunction (ED). So, the aim of this study was to evaluate the beneficial effect of corin from adipose-derived stem cells (ADSCs) on DM-induced ED. Methods: Exosomes were isolated from ADSCs (ADSC-EXOs) or from ADSCs in which corin gene expression was silenced by siRNA (siCorin). For in vivo studies, rats with streptozotocin-induced DM were intravenously injected with ADSC-EXOs or siCorin-ADSC-EXOs. Two weeks later, intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured to assess erectile function, and penile tissues were harvested for further evaluation of levels of inflammatory factors and expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and neuronal nitric oxide synthase (nNOS). We also evaluated the recovery of neurovascular function in penile tissues by immunofluorescence analysis. Results: The results showed that ADSC-EXOs restored erectile function in diabetic rats, as determined by the ICP/MAP ratio. Exosomes from ADSCs also promoted neurovascular function and suppressed expression of inflammatory factors. In contrast, the decreased content of corin in exosomes after silencing corin in ADSCs reduced the therapeutic effect of exosomes on ED. Conclusion: These findings demonstrated the therapeutic mechanism underlying the use of ADSC-EXOs for treating ED and the beneficial effect of corin.

Recently, biomimetic nanoparticles for tumor−targeted therapy have attracted intensifying interest. Although exosomes are an excellent biomimetic material, numerous challenges are still hindering its clinical applications, such as low yield, insufficient targeting efficiency, and high cost. In this work, urinary exosomes (UEs) with high expression of CD9 and CD47 were extracted from breast cancer patients by a non−invasive method. Here, a nanotechnology approach is reported for tumor homologous targeting via CD9 and phagocytosis escape via CD47 through UE−coated poly (2−ethyl−2−oxazoline)−poly (D, L−lactide) (PEOz−PLA) nanoparticles (UEPP NPs). The cytotoxic agent doxorubicin (DOX)−loaded UEPP (UEPP−D) NPs with an initial particle size of 61.5 nm showed a burst release under acidic condition mimicking the tumor microenvironment. In vitro experiments revealed that UEPP−D NPs exhibited significantly improved cellular uptake, cytotoxicity, and apoptosis in MCF−7 cell lines as compared to DOX−loaded PEOz−PLA nanoparticles (PP−D NPs) and free DOX. More importantly, anti−phagocytosis and pharmacokinetic studies confirmed that UEPP−D NPs had superior immune escape ability and significantly prolonged the drug’s bloodstream circulation in vivo. Finally, UEPP−D NPs showed a markedly higher antitumor efficacy and lower side−toxicity in MCF−7 tumor bearing nude mice model. Thus, this versatile nano−system with immune escape, homologous targeting, and rapid response release characteristics could be a promising tool for breast cancer treatment.

Visual information processing in the brain goes from global to local. A large volume of experimental studies has suggested that among global features, the brain perceives the topological information of an image first. Here, we propose a neural network model to elucidate the underlying computational mechanism. The model consists of two parts. The first part is a neural network in which neurons are coupled through gap junctions, mimicking the neural circuit formed by alpha ganglion cells in the retina. Gap junction plays a key role in the model, which, on one hand, facilitates the synchronized firing of a neuron group covering a connected region of an image, and on the other hand, staggers the firing moments of different neuron groups covering disconnected regions of the image. These two properties endow the network with the capacity of detecting the connectivity and closure of images. The second part of the model is a read-out neuron, which reads out the topological information that has been converted into the number of synchronized firings in the retina network. Our model provides a simple yet effective mechanism for the neural system to detect the topological information of images in ultra-speed.

Artificial intelligence based on artificial neural networks, which are originally inspired by the biological architectures of the human brain, has mostly been realized using software but executed on conventional von Neumann computers, where the so-called von Neumann bottleneck essentially limits the executive efficiency due to the separate computing and storage units. Therefore, a suitable hardware platform that can exploit all the advantages of brain-inspired computing is highly desirable. Based upon micromagnetic simulation of the magnetization dynamics, we demonstrate theoretically and numerically that recurrent neural networks consisting of as few as 40 magnetic tunnel junctions can generate and recognize periodic time series after they are trained with an efficient algorithm.

Prostate cancer (PCa) is one of the most common malignancies in male. We aim to establish a novel gene signature for immune infiltration and outcome (biochemical recurrence (BCR) and overall survival (OS)) of patients with prostate cancer (PCa) to augment Gleason patterns for evaluating prognosis and managing patients undergoing radical prostatectomy (RP). Combined with our microarray data and the Cancer Genome Atlas Project (TCGA) database (discovery set), we identified a six-gene signature. The Gene Expression Omnibus (GEO) database served as the test set. The databases of Fudan University Shanghai Cancer Center (FUSCC) and Third Affiliated Hospital of Nantong University (TAHNU) served as an external validation set. Immunohistochemistry was used to investigate the relationship between risk groups and the immune infiltrate. We identified a six-gene signature to predict immune cell infiltration and outcome of PCa patients. The AUC values used to predict early BCR in the discovery, test, FUSCC, and TAHNU sets were 0.73, 0.76, 0.72, and 0.81, respectively. Low-risk score patients in each dataset experienced significantly longer OS (P = .01, 0.04, 0.02, respectively). The signature also predicted high regulatory T cells (Tregs) and M2-polarized macrophages infiltration in high-risk score patients with PCa. Additionally, high mutation load, related signal pathways, and sensitivity to anticancer drugs that correlated with high-risk score of cancer progression and death were also identified. The six-gene signature may improve prognostic information, serve as a prognostic tool to manage patients after RP, and advance basic studies of PCa.

Background/Aims: MicroRNAs (miRNAs) are a class of small non-coding RNA molecules which play a significant role in transcriptional and translational regulation. Published data on the association between the miRNA SNPs and prostate cancer (PCa) risk are somewhat inconclusive. Methods: We performed a meta-analysis of all available studies including 2,227 patients and 2,331 control subjects to evaluate the impact of three common genetic variants of microRNAs in prostate cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to investigate the strength of the association. Results: For miR-499 polymorphism, a significant association was observed between the rs3746444 A>G polymorphism and PCa risk in heterozygote comparison and dominant genetic model, in particular in Asian population subgroup. For miR-146a polymorphism, the rs2910164 CC genotype was associated with decreased PCa risk in Asian population in homozygote comparison. In addition, rs2910164 CC genotype had a weekly higher percentage value in subgroup of Gleason score < 7. Similar results were also indicated in localized prostate cancer in subgroup analysis by tumor stage. For miR-196a2 polymorphism, no association was observed between this variant and PCa risk in the overall group. However, in stratified analysis by ethnicity, we found that rs11614913 T allele was a risk factor for Asian PCa patients. Conclusions: Polymorphisms of miR-196a2 rs11614913, miR-146a rs2910164, and miR-499 rs3746444 may contribute to the risk for developing prostate cancer in Asian descendants. Moreover, miR-146a rs2910164 polymorphism was related to PCa prognosis.

Adaptation refers to the general phenomenon that the neural system dynamically adjusts its response property according to the statistics of external inputs. In response to an invariant stimulation, neuronal firing rates first increase dramatically and then decrease gradually to a low level close to the background activity. This prompts a question: during the adaptation, how does the neural system encode the repeated stimulation with attenuated firing rates? It has been suggested that the neural system may employ a dynamical encoding strategy during the adaptation, the information of stimulus is mainly encoded by the strong independent spiking of neurons at the early stage of the adaptation; while the weak but synchronized activity of neurons encodes the stimulus information at the later stage of the adaptation. The previous study demonstrated that short-term facilitation (STF) of electrical synapses, which increases the synchronization between neurons, can provide a mechanism to realize dynamical encoding. In the present study, we further explore whether short-term plasticity (STP) of chemical synapses, an interaction form more common than electrical synapse in the cortex, can support dynamical encoding. We build a large-size network with chemical synapses between neurons. Notably, facilitation of chemical synapses only enhances pair-wise correlations between neurons mildly, but its effect on increasing synchronization of the network can be significant, and hence it can serve as a mechanism to convey the stimulus information. To read-out the stimulus information, we consider that a downstream neuron receives balanced excitatory and inhibitory inputs from the network, so that the downstream neuron only responds to synchronized firings of the network. Therefore, the response of the downstream neuron indicates the presence of the repeated stimulation. Overall, our study demonstrates that STP of chemical synapse can serve as a mechanism to realize dynamical neural encoding. We believe that our study shed lights on the mechanism underlying the efficient neural information processing via adaptation.

Working memory and conscious perception are thought to share similar brain mechanisms, yet recent reports of non-conscious working memory challenge this view. Combining visual masking with magnetoencephalography, we investigate the reality of non-conscious working memory and dissect its neural mechanisms. In a spatial delayed-response task, participants reported the location of a subjectively unseen target above chance-level after several seconds. Conscious perception and conscious working memory were characterized by similar signatures: a sustained desynchronization in the alpha/beta band over frontal cortex, and a decodable representation of target location in posterior sensors. During non-conscious working memory, such activity vanished. Our findings contradict models that identify working memory with sustained neural firing, but are compatible with recent proposals of ‘activity-silent’ working memory. We present a theoretical framework and simulations showing how slowly decaying synaptic changes allow cell assemblies to go dormant during the delay, yet be retrieved above chance-level after several seconds.

Neural systems display rich short-term dynamics at various levels, e.g., spike-frequencyadaptation (SFA) at single neurons, and short-term facilitation (STF) and depression (STD)at neuronal synapses. These dynamical features typically covers a broad range of time scalesand exhibit large diversity in different brain regions. It remains unclear what the computationalbenefit for the brain to have such variability in short-term dynamics is. In this study, we proposethat the brain can exploit such dynamical features to implement multiple seemingly contradictorycomputations in a single neural circuit. To demonstrate this idea, we use continuous attractorneural network (CANN) as a working model and include STF, SFA and STD with increasing timeconstants in their dynamics. Three computational tasks are considered, which are persistent activity,adaptation, and anticipative tracking. These tasks require conflicting neural mechanisms, andhence cannot be implemented by a single dynamical feature or any combination with similar timeconstants. However, with properly coordinated STF, SFA and STD, we show that the network isable to implement the three computational tasks concurrently. We hope this study will shed lighton the understanding of how the brain orchestrates its rich dynamics at various levels to realizediverse cognitive functions.

Owing to its many computationally desirable properties, the model of continuous attractor neural networks (CANNs) has been successfully applied to describe the encoding of simple continuous features in neural systems, such as orientation, moving direction, head direction, and spatial location of objects. Recent experimental and computational studies revealed that complex features of external inputs may also be encoded by low-dimensional CANNs embedded in the high-dimensional space of neural population activity. The new experimental data also confirmed the existence of the M-shaped correlation between neuronal responses, which is a correlation structure associated with the unique dynamics of CANNs. This body of evidence, which is reviewed in this report, suggests that CANNs may serve as a canonical model for neural information representation.

OBJECTIVE: Premature ejaculation (PE) has been reported as the most common male sexual dysfunction with global prevalence rates estimated at approximately 30%. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine, 5-HT) system. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT), the major regulator of serotonic neurotransmission, have been linked with the pathogenesis and risk of PE. Apparently studies of this type of polymorphism in PE have show conflicting results. METHODS: A meta-analysis was performed that are available in relation with 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism and the risk of lifelong PE (LPE) in men to clarify this relationship. We searched Pubmed and Embase (last search updated on Aug 2012) using 'premature ejaculation', 'polymorphism or variant', 'genotype', 'ejaculatory function', and 'rapid ejaculation' as keywords and reference lists of studies corresponded to the inclusion criteria for meta-analysis. These studies involved the total number of 481 LPE men and 466 health control men subjects. Odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. RESULTS: In the overall analysis, significant associations between LPE risk and 5-HTTLPR polymorphism were found (L-allele vs. S-allele OR = 0.86, 95% CI = 0.79-0.95, P = 0.002; LL vs. SS: OR = 0.80, 95% CI = 0.68-0.95, P = 0.009; LS vs. SS: OR = 0.85, 95% CI = 0.76-0.97, P = 0.012 and LL+LS vs. SS: OR = 0.88, 95% CI = 0.81-0.95, P = 0.002). Moreover, in subgroup analysis based on ethnicity, similar significant associations were detected. The Egger's test did not reveal presence of a publication bias. CONCLUSIONS: Our investigations demonstrate that 5-HTTLPR (L>S) polymorphism might protect men against LPE risk. Further studies based on larger sample size and gene-environment interactions should be conducted the role of 5-HTTLPR polymorphism and LPE risk.

BACKGROUND: DNA repair genes (EG: xeroderma pigmentosum group D, XPD) may affect the capacity of encoded DNA repair enzymes to effectively remove DNA adducts or lesions, which may result in enhanced cancer risk. The association between XPD gene polymorphisms and the susceptibility of prostate cancer (PCa) was inconsistent in previous studies. METHODOLOGY/PRINCIPAL FINDINGS: A meta-analysis based on 9 independent case-control studies involving 3165 PCa patients and 3539 healthy controls for XPD Gln751Lys SNP (single nucleotide polymorphism) and 2555 cases and 3182 controls for Asn312Asp SNP was performed to address this association. Meanwhile, odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. Statistical analysis was performed with STATA10.0. No significant association was found between XPD Gln751Lys SNP and PCa risk. On the other hand, in subgroup analysis based on ethnicity, associations were observed in Asian (eg. Asn vs. Asp: OR = 1.34, 95%CI = 1.16-1.55; Asn/Asn+Asn/Asp vs. Asp/Asp: OR = 1.23, 95%CI = 1.07-1.42) and African (eg. Asn vs. Asp: OR = 1.31, 95%CI = 1.01-1.70; Asn/Asn vs. Asp/Asp: OR = 1.71, 95%CI = 1.03-7.10) populations for Asn312Asp SNP. Moreover, similar associations were detected in hospital-based controls studies; the frequency of Asn/Asn genotype in early stage of PCa men was poorly higher than those in advanced stage of PCa men (OR = 1.45, 95%CI = 1.00-2.11). CONCLUSION/SIGNIFICANCE: Our investigations demonstrate that XPD Asn312Asp SNP not the Gln751Lys SNP, might poorly increase PCa risk in Asians and Africans, moreover, this SNPs may associate with the tumor stage of PCa. Further studies based on larger sample size and gene-environment interactions should be conducted to determine the role of XPD gene polymorphisms in PCa risk.