Integrative analyses of N6-methyladenosine-associated single-nucleotide polymorphisms (m6A-SNPs) identify tumor suppressor gene AK9 in lung cancer.

N6 -methyladenosine (m6 A) modification has been identified as one of the most important epigenetic regulation mechanisms in the development of human cancers. However, the association between m6 A-associated single-nucleotide polymorphisms (m6 A-SNPs) and lung cancer risk remains largely unknown. Here, we identified m6 A-SNPs and examined the association of these m6 A-SNPs with lung cancer risk in 13,793 lung cancer cases and 14,027 controls. In silico functional annotation was used to identify causal m6 A-SNPs and target genes. Furthermore, methylated RNA immunoprecipitation and quantitative real-time polymerase chain reaction (MeRIP-qPCR) assay was performed to assess the m6 A modification level of different genotypes of the causal SNP. In vitro assays were performed to validate the potential role of the target gene in lung cancer. A total of 8794 m6 A-SNPs were detected, among which 397 SNPs in nine susceptibility loci were associated with lung cancer risk, including six novel loci. Bioinformatics analyses indicated that rs1321328 in 6q21 was located around the m6 A modification site of AK9 and significantly reduced AK9 expression (ß = -0.15, p = 2.78 × 10-8 ). Moreover, AK9 was significantly downregulated in lung cancer tissues than that in adjacent normal tissues of samples from the Cancer Genome Atlas and Nanjing Lung Cancer Cohort. MeRIP-qPCR assay suggested that C allele of rs1321328 could significantly decrease the m6 A modification level of AK9 compared with G allele. In vitro assays verified the tumor-suppressing role of AK9 in lung cancer. These findings shed light on the pathogenic mechanism of lung cancer susceptibility loci linked with m6 A modification.

Functional characterization and clinical significance of super-enhancers in lung adenocarcinoma.

Super-enhancers (SEs) are important transcriptional regulators in tumorigenesis; however, the functional characterization and clinical significance of SEs in lung adenocarcinoma (LUAD) remain unclear. By using H3K27ac ChIP-seq data of two LUAD cell lines and eight lung tissues, we detected 1045 cancer-specific and 5032 normal-specific SEs. Compared to normal-specific SEs, cancer-specific SEs have different regulatory mechanisms where associated target genes were enriched in critical tumor-related pathways and tended to be regulated by transcription factors of Fos Proto-Oncogene, AP-1 Transcription Factor Subunit and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit families. By using expression data of 513 LUAD and 57 adjacent samples from The Cancer Genome Atlas and 80 tumor-normal paired LUAD samples from the Nanjing Lung Cancer Cohort study, we performed differential expression analysis of target genes for SEs and defined 243 crucial SEs. Unsupervised clustering of crucial SEs revealed two subtypes with different levels of genomic aberrations (i.e., mutation and copy number alteration) and clinical outcomes (progression-free interval: p = 0.030; disease-free interval: p = 0.047). In addition, patients with adverse clinical outcomes were more sensitive to three small molecule inhibitors (bortezomib, doxorubicin, and etoposide), and their targets (PSMB5 and TOP2A) also have elevated expression levels among these patients. Taken together, our findings provided a comprehensive characterization of SEs in LUAD and emphasized their clinical significance in LUAD therapy.

Tumor-associated macrophage-derived CCL5 promotes chemotherapy resistance and metastasis in prostatic cancer.

The crosstalk between tumor microenvironment and cancer cells is emerging as a critical determinant in tumor progression. However, the underlying mechanism of tumor microenvironment-induced cancer development remains controversial. Here, our study provides evidence to suggest that tumor-associated macrophage (TAM) enrichment is found in chemoresistant prostatic tumor tissues. Those TAMs are demonstrated to promote chemoresistance and distant metastasis in prostatic cancer through secretion of CCL5. Mechanistically, TAM coculture or additional CCL5 can mediate the STAT3-dependent epithelial-mesenchymal transition process, resulting in distant metastasis in prostatic cancer. Meanwhile, activation of STAT3 induced by CCL5 can mediate upregulation of the transcription factor Nanog, leading to drug resistance. In vivo study further demonstrated that blockade of STAT3 signals significantly reverses chemoresistance and suppresses lung metastasis in colorectal tumor-bearing mice, suggesting a novel strategy for clinical prostatic cancer treatment.

Research progress and perspectives of noncoding RNAs in adrenocortical carcinoma: A review.

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy. Although surgery can cure localized disease, but the majority of patients experience recurrence of ACC. The 5-year survival rate of patients with metastatic ACC is <15%, and the prognosis is poor. Therefore, it is urgent to explore the potential diagnostic markers and therapeutic targets for ACC. Recently, it has been proved that non-coding RNA (ncRNAs) is widely involved in pathological and physiological processes, including tumorigenesis and development. Aberrantly expressed ncRNAs have been found to be involved in the pathogenesis of ACC. Here, we summarized the expression patterns and the molecular mechanism of the involvement of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in ACC development. To explore the clinical value of ncRNAs as noninvasive biomarkers of ACC, we also displayed the relationship between the expression level of ncRNAs and the diagnosis and prognosis of patients with ACC.

Exosomal noncoding RNAs in gynecological cancers: implications for therapy resistance and biomarkers.

Gynecologic cancers, including ovarian cancer (OC), cervical cancer (CC), and endometrial cancer (EC), pose a serious threat to women's health and quality of life due to their high incidence and lethality. Therapeutic resistance in tumors refers to reduced sensitivity of tumor cells to therapeutic drugs or radiation, which compromises the efficacy of treatment or renders it ineffective. Therapeutic resistance significantly contributes to treatment failure in gynecologic tumors, although the specific molecular mechanisms remain unclear. Exosomes are nanoscale vesicles released and received by distinct kinds of cells. Exosomes contain proteins, lipids, and RNAs closely linked to their origins and functions. Recent studies have demonstrated that exosomal ncRNAs may be involved in intercellular communication and can modulate the progression of tumorigenesis, aggravation and metastasis, tumor microenvironment (TME), and drug resistance. Besides, exosomal ncRNAs also have the potential to become significant diagnostic and prognostic biomarkers in various of diseases. In this paper, we reviewed the biological roles and mechanisms of exosomal ncRNAs in the drug resistance of gynecologic tumors, as well as explored the potential of exosomal ncRNAs acting as the liquid biopsy molecular markers in gynecologic cancers.

Association of psychological distress, smoking and genetic risk with the incidence of lung cancer: a large prospective population-based cohort study.

Background: Emerging evidence suggests a potential link between psychological distress (anxiety and depression) and lung cancer risk, however, it is unclear whether other factors such as tobacco smoking and genetic susceptibility modify the association. Methods: We included 405,892 UK Biobank participants free of cancer at baseline. Psychological distress was measured using the Patient Health Questionnaire-4 (PHQ-4). A polygenic risk score (PRS) was calculated using 18 lung cancer-associated genetic loci. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 7.13 years, 1754 lung cancer cases were documented. The higher score of psychological distress was associated with an increased risk of lung cancer (HRper 1-SD= 1.07, 95% CI: 1.02-1.11) after adjustment for smoking and other confounders. Mediation analysis revealed that 16.8% (95% CI: 13.0%-20.6%) of the distress-lung cancer association was mediated by smoking. Compared with never smokers with no distress, participants with heavy smoking and high distress had the highest risk of lung cancer (HR=18.57, 95% CI: 14.51-23.76). Both multiplicative and additive interactions were observed between smoking and psychological distress in lung cancer. Furthermore, the greatest relative increase in risk was observed among those with high genetic risk and high distress (HR=1.87, 95%CI: 1.50-2.33), and there was a significant additive interaction between the PRS and psychological distress. Conclusion: Our results indicate that psychological distress was associated with an elevated risk of incident lung cancer, and such relation was modified by tobacco smoking and genetic susceptibility.

Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in Chinese.

We present the largest whole-genome sequencing (WGS) study of non-small cell lung cancer (NSCLC) to date among 6,004 individuals of Chinese ancestry, coupled with 23,049 individuals genotyped by SNP array. We construct a high-quality haplotype reference panel for imputation and identify 20 common and low-frequency loci (minor allele frequency [MAF] ≥ 0.5%), including five loci that have never been reported before. For rare loss-of-function (LoF) variants (MAF < 0.5%), we identify BRCA2 and 18 other cancer predisposition genes that affect 5.29% of individuals with NSCLC, and 98.91% (181 of 183) of LoF variants have not been linked previously to NSCLC risk. Promoter variants of BRCA2 also have a substantial effect on NSCLC risk, and their prevalence is comparable with BRCA2 LoF variants. The associations are validated in an independent case-control study including 4,410 individuals and a prospective cohort study including 23,826 individuals. Our findings not only provide a high-quality reference panel for future array-based association studies but depict the whole picture of rare pathogenic variants for NSCLC.

Influence of social isolation caused by coronavirus disease 2019 (COVID-19) on the psychological characteristics of hospitalized schizophrenia patients: a case-control study.

Coronavirus disease 2019 (COVID-19) has been classified as a pandemic, and mental hospitals located in epidemic centers have been affected. Social isolation is an important and irreplaceable measure to control the spread of the epidemic. In this study, schizophrenic patients who were subjected to social isolation after close contact with COVID-19 patients were used as participants to explore the impact of social isolation on common inflammatory indicators and psychological characteristics. A total of 30 patients with schizophrenia were recruited from Wuhan Mental Health Center. In addition, 30 ordinary schizophrenic patients were matched with the isolation group and were recruited from another branch of Wuhan Mental Health Center as controls. We compared the differences in common inflammatory indicators and psychological characteristics between the isolated group and the control group, and longitudinal comparison of the differences in the above indicators before and after isolation among the isolation group. The Chinese Perceived Stress Scale (CPSS) score, Hamilton Depression Scale (HAMD) score and Hamilton Anxiety Scale (HAMA) score of the isolation group were significantly higher than those of the control group (p = 0.00, 0.00, 0.00, respectively). The C-reactive protein (CRP) level, CPSS score, HAMA score and Pittsburgh sleep quality index (PSQI) score of the isolation group were significantly higher after isolation (p = 0.01, 0.00, 0.00, 0.00, 0.00, respectively). Inpatients of schizophrenia suffered from social isolation due to COVID-19 have a severe psychological burden. Social isolation caused patients to develop a weak inflammatory state and led to worse anxiety and sleep quality.

Comparative pharmacokinetics of triterpenic acids in normal and immunosuppressed rats after oral administration of Jujubae Fructus extract by UPLC-MS/MS.

The fruit of Ziziphus jujuba (Jujubae Fructus) has been used as food and crude drug for thousands of years. Although several chemical and biological studies have revealed triterpenic acid as the main bioactive constituent of Jujubae Fructus responsible for immune-regulatory activity, only few pharmacokinetic studies have been conducted. To comprehend the kinetics of triterpenic acids and promote their curative application, a sensitive and efficient ultra-performance liquid chromatography coupled with mass spectrometry method (UPLC-MS/MS) was established. UPLC-MS/MS was applied for the simultaneous determination of ceanothic acid, epiceanothic acid, pomonic acid, alphitolic acid, maslinic acid, betulinic acid, and betulonic acid in normal and immunosuppressed rat plasma samples. After sample preparation, chromatographic separation was performed on an Acquity UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm) with acetonitrile: methanol (1:1, v/v) and 0.5% ammonium acetate in water as mobile phase. The established method was validated and found to be specific, accurate, and precise for the seven triterpenic acids, and was successfully applied for the pharmacokinetic study of rat plasma samples. The results showed that the pharmacokinetic parameters (Cmax, Tmax, AUC0-t, AUC0-∞, and CLz/F) in the plasma samples of immunosuppressed rats were significantly different from those in normal rats, and might provide an insight for the clinical usage of triterpenic acids from Jujubae Fructus.

Preparation and characterization of poly (itaconic acid)-grafted crosslinked chitosan nanoadsorbent for high uptake of Hg2+ and Pb2.

A novel nanoadsorbent (PIACS) with average size of 52.6nm was prepared by controlling grafted polymerization of itaconic acid on chitosan to emulsion stage and then crosslinking with glutaraldehyde. The preparation conditions were optimized and PIACS was characterized by FT-IR, XRD, SEM, TEM and TGA. The adsorption of PIACS for some metal ions was studied. The adsorption results showed that PIACS for adsorption of Hg2+ and Pb2+ had higher uptakes than some reported adsorbents. Various variables for adsorption of Hg2+ and Pb2+ were systematically researched. The adsorption followed the pseudo-second-order kinetics and Langmuir isotherm models. The maximum uptakes of Hg2+ and Pb2+ from Langmuir model were 870.1mgg-1 and 1320mgg-1, respectively. Especially, the uptake of this nanoadsorbent for Pb2+ was 4 times of that of the macro-scale adsorbent with the similar structure reported. As temperature rising, uptake of Pb2+ decreased while uptake of Hg2+ almost had no change. In addition, the adsorbent could be regenerated with EDTA. Hence, this prepared method of nanomaterial might extend to the similar grafted polymerizing and crosslinking systems of polymers and PIACS would be a promising adsorbent in the removal of Hg2+ and Pb2+ from wastewaters.

Synthesis and characterization of poly(maleic acid)-grafted crosslinked chitosan nanomaterial with high uptake and selectivity for Hg(II) sorption.

Chitosan-poly(maleic acid) nanomaterial (PMACS) with the size of 400-900nm was synthesized by grafting poly(maleic acid) onto chitosan and then crosslinking with glutaraldehyde. The synthesis conditions were optimized. The structure and morphology of PMACS were characterized by FT-IR, XRD, SEM and TGA. PMACS was used to adsorb some heavy metal ions such as Hg(II), Pb(II), Cu(II), Cd(II), Co(II), and Zn(II). The results indicated that PMACS had selectivity for Hg(II) sorption. The effects of various variables for sorption of Hg(II) were further explored. The maximum capacity for Hg(II) sorption was found to be 1044mgg(-1) at pH 6.0, which could compare with the maximal value of the recently reported other sorbents. The sorption followed the pseudo-second-order kinetics and Langmuir isotherm models. The rising of temperature benefited the uptake and the sorption was a spontaneous chemical process. The sorbent could be reused with EDTA. Hence, the nanomaterial would be used as a selective and high uptake sorbent in the removal of Hg(II) from effluents.

Selective adsorption of lead on grafted and crosslinked chitosan nanoparticles prepared by using Pb(2+) as template.

Poly(acrylic acid) grafted and glutaraldehyde-crosslinked chitosan nano adsorbent (PAACS) was synthesized by using Pb(2+) as a template ion. The structure and morphology of PAACS were characterized by FT-IR, XRD, SEM and elemental analyses. The adsorption of PAACS for different heavy metal ions was compared and the effects of various variables for adsorption of Pb(2+) were systematically studied. The results indicated that the PAACS was the aggregates of nanoparticles with the diameter of about 50-200 nm and had selectivity for Pb(2+) adsorption. The adsorption for Pb(2+) showed a maximum adsorption capacity of 734.3 mg g(-1) at pH 5.0 and 303 K, which was higher than in a study previously reported on ion-imprinted adsorbents. The adsorption followed the pseudo-second-order kinetics and Langmuir isotherm models. The adsorption was spontaneous and changed from chemical process into physical process when the temperature exceeded 303 K. The adsorbent could be recycled with EDTA. Therefore, PAACS would be useful as a selective and high uptake nano adsorbent in the removal of Pb(2+) from effluents.

Dynamical analysis of periodic bursting in piece-wise linear planar neuron model.

A piece-wise linear planar neuron model, namely, two-dimensional McKean model with periodic drive is investigated in this paper. Periodical bursting phenomenon can be observed in the numerical simulations. By assuming the formal solutions associated with different intervals of this non-autonomous system and introducing the generalized Jacobian matrix at the non-smooth boundaries, the bifurcation mechanism for the bursting solution induced by the slowly varying periodic drive is presented. It is shown that, the discontinuous Hopf bifurcation occurring at the non-smooth boundaries, i.e., the bifurcation taking place at the thresholds of the stimulation, leads the alternation between the rest state and spiking state. That is, different oscillation modes of this non-autonomous system convert periodically due to the non-smoothness of the vector field and the slow variation of the periodic drive as well.

Characterization Method for 3D Substructure of Nuclear Cell Based on Orthogonal Phase Images.

A set of optical models associated with blood cells are introduced in this paper. All of these models are made up of different parts possessing symmetries. The wrapped phase images as well as the unwrapped ones from two orthogonal directions related to some of these models are obtained by simulation technique. Because the phase mutation occurs on the boundary between nucleus and cytoplasm as well as on the boundary between cytoplasm and environment medium, the equation of inflexion curve is introduced to describe the size, morphology, and substructure of the nuclear cell based on the analysis of the phase features of the model. Furthermore, a mononuclear cell model is discussed as an example to verify this method. The simulation result shows that characterization with inflexion curve based on orthogonal phase images could describe the substructure of the cells availably, which may provide a new way to identify the typical biological cells quickly without scanning.