Search

The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity, as it contains a classic RING finger domain. However, its biological role and the underlying mechanism in cancer remain largely elusive. Here, we identified DTX3 as a novel mutant p53-interacting protein in ovarian carcinoma. Mechanistically, DTX3 mediated mutant p53 ubiquitination and stabilization by perturbing the MDM2-mutant p53 interaction, consequently leading to activation of diverse mutant p53 target genes. Importantly, a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian carcinomas. Ectopic DTX3 promoted, while depletion of DTX3 suppressed, ovarian cancer cell proliferation and invasion. Remarkably, the pro-tumorigenic effect of DTX3 is dependent on mutant p53, because ablation of mutant p53 significantly impaired DTX3-induced gene expression and ovarian cancer cell growth and propagation. Furthermore, DTX3 elevated the expression of mutant p53 target genes and boosted ovarian tumor growth in vivo. Finally, DTX3 was amplified and overexpressed in ovarian carcinomas, which is significantly associated with unfavorable prognosis. Altogether, our findings unveil the oncogenic role of DTX3 in ovarian cancer development by bolstering mutant p53 activity.

Considered as an autoimmune disease, rheumatoid arthritis (RA) is an chronic inflammatory disorder that causes inflammation of the joints. This study is performed with the aim to clarify the expression of phospholipase D1 (PLD1) in RA and its specific regulation role of RA as well as the underlying mechanisms. In this study, synovial tissue samples were collected from RA patients, and RA-fibroblast-like synoviocytes (FLSs) were subsequently isolated. The expression levels of PLD1 and pathway-related proteins were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting or immunohistochemistry (IHC). Upon shPLD1 treatment, cell viability, proliferation, migration, invasion, and the level of inflammation-related factors were measured by Cell Counting Kit-8 (CCK-8), Edu, wound healing, Transwell and enzyme-linked immunosorbent assay (ELISA). Furthermore, C-reactive protein (CRP), rheumatoid factor (RF), arthritis score and synovial tissue lesions were assessed by collecting the blood or tissues from collagen induced arthritis (CIA) model rats. Our results showed that PLD1 level was increased in RA synovial tissues. Cell viability, proliferation, migration, invasion, and the level of inflammatory factors were reduced upon PLD1 knockdown in RA-FLSs. Moreover, p-IκBα/IκBα, β-catenin, p-IKKβ/IKKβ and TCF-4 were inhibited under PLD1 knockdown treatment. PLD1 knockdown alleviated the collagen-induced addition of arthritis score, CRP and RF, as well as the filling of inflammatory cells and proliferation of synovium in CIA model rat. To sum up, knockdown of PLD1 could reduce RA-FLSs metastasis as well as inflammatory response by modulating the activity of NF-κB and Wnt/β-catenin pathways.

Background: Peripheral blood CD4+ T cell counts are a clinical marker for assessing disease progression in HIV-infected patients as well as in SIV-/SHIV–infected macaques. However, it is clinically debatable about whether this marker is a sole indicator for assessing HIV disease progression and need for ART in HIV-infected individuals. Studies with SIV-or SHIV-infected Indian rhesus macaques and sooty mangabeys have generated the conflicting data regarding the association of CD4+ T cell depletion with viral loads and disease progression. Results: In the present study, we used cynomolgus monkeys, a suitable non-human primate model for chronic HIV infection studies, to determine the effects of the antibody-mediated acute CD4+ cell depletion on viral load as well as on the immunological factors associated with disease progression. We found that as compared with the control animals, CD4+ T cell-depleted animals with chronic SHIV infection showed (i) little alteration in plasma viral load over the period of 22 weeks after the depletion; (ii) increased CD4+ T cell proliferation and turnover of macrophages at the early phase of the depletion, but subsequent decline to the basal levels; and (iii) little impact on the expression of the inflammatory cytokines and CC chemokines associated with disease progression. Conclusions: These findings indicate that the antibody-mediated acute CD4+ T cell depletion had minimal impact on plasma viral load and disease progression in chronically SHIVSF162P3N-infected cynomolgus monkeys. Future investigations are necessary to identify novel and more reliable clinical markers correlated with viremia and disease progression in HIV-infected individuals.

Approximately 80% of human pancreatic ductal adenocarcinomas (PDAC) harbor TP53 mutations, among which, R273H is the most frequent. Although p53-R273H is known to possess gain-of-function properties, how it is regulated in PDAC has not been extensively explored. Here we identify valosin-containing protein (VCP) as a regulator of p53-R273H by conducting immunoprecipitation-tandem mass spectrometry analysis. VCP bound p53-R273H at its DNA binding domain. Ectopic or endogenous VCP stabilized p53-R273H by binding to MDM2 and disrupting its association with mutant p53. Inhibition of VCP either by genetic depletion or the pharmacologic inhibitor CB-5083 increased ubiquitination and degradation of p53-R273H, leading to cell death. Consistently, ablation of VCP markedly retarded growth of cultured PDAC cells and xenograft PDAC tumors. Together, these results unveil VCP as a novel partner of p53-R273H in promoting PDAC growth and as a potential target for developing anti-PDAC therapy. Significance: These findings identify valosin-containing protein (VCP) as a novel regulator of p53-R273H stability and suggest VCP as a potential target for development of pancreatic cancer therapy.

Purpose To compare the changes in subfoveal choroidal thickness (SFChT) in myopic children treated with 0.01% atropine, orthokeratology (OK), or their combination in myopic children, and to study the connection between increase in SFChT and axial length (AL) elongation. Methods This is a prospective, randomized, controlled study. A total of 67 children were included; 22 patients were randomly assigned to the SA group (patients with spectacles and 0.01% atropine), 24 patients were randomly assigned to the OK group (OK), and 21 patients were randomly assigned to the OKA group (OK and 0.01% atropine). Comprehensive ophthalmologic examinations were performed at baseline, 1 month, 6 months, and 12 months. Results After 1 month, SFChT increased by 5.41 ± 1.65 μm in the SA group, 17.46 ± 2.79 μm in the OK group, and 20.19 ± 2.18 μm in the OKA group (P = 0.00), whereas AL was not significantly increased. After 12 months, the changes of SFChT were not increased significantly compared with that at 1 month; AL increased by 0.20 ± 0.03 mm in the SA group, 0.28 ± 0.03 mm in the OK group, and 0.14 ± 0.03 mm in the OKA group (P = 0.00). The change in SFChT at 12 month was negatively correlated with the change in AL at 12 months. Conclusion The control of AL elongation was better in SA group than OK group. The increase in SFChT was best in OKA group, followed by OK group, and the changes were significant after only 1 month. In addition, the increase in SFChT may influence AL elongation and myopia progression.

Colorectal cancer (CRC) is the third most common malignant tumor. DNA damage played a crucial role on tumorigenesis, and abnormal DNA repair pathways affected the occurrence and progress of CRC. In current study, we aimed to construct a DNA repair-related genes (DRG) signature to predict the overall survival (OS) of CRC patients. Differentially expressed DRGs (DE-DRGs) were analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The prognostic gene signature was identified by univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression analysis. The predictive ability of the model was evaluated by utilizing Kaplan-Meier curves and Time-dependent receiver operating characteristic (ROC) curves. Gene set enrichment analysis (GSEA) was performed to explore the underlying biological processes and signaling pathways. Single sample gene set enrichment analysis (ssGSEA) was implemented to estimate the immune status between the different risk group. A total of 118 DE-DRGs were identified between 42 normal samples and 488 CRC samples in TCGA cohort, and 36 DE-DRGs were associated with OS in the univariate Cox regression. A 9 DE-DRGs (ESCO2, AXIN2, PLK1, CDC25C, IGF1, TREX2, ALKBH2, ESR1 and MC1R) signature was constructed to classify patients into high-risk and low-risk group. The risk score was an independent prognostic indicator for OS (HR>1, P

Purpose: To compare the clinical efficacies of 0.01% atropine and orthokeratology (OK) in slowing the development of myopia, and to evaluate their effects on basal tear secretion and tear film stab...

The lipid metabolism disorder is the key role of Nonalcoholic fatty liver disease (NAFLD). Selenoprotein P plays an important role in the pathological process of lipid accumulation. Coix lacryma-jboi seed oil (CLSO) is an active component extracted from Coix lacryma-jobi seed (CLS) which has been found to be effective of reducing blood fat and antioxidative. But the effect and mechanism of CLSO on NAFLD are not clear. The aim of this study was to explore the therapeutic effect and mechanism of CLSO in the treatment of NAFLD. Our result showed that CLSO decreased the liver/body weight ratio, lowered the total cholesterol (TC) and triacylglycerol (TG), and elevated the high density lipoprotein (HDL) in serum. CLSO reduced the lipid deposition in the liver of NAFLD rats. In addition, CLSO could bring down the abnormal expression of superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, CLSO significantly declined the liver apolipoprotein E (apoE), apolipoprotein E receptor (apoER) and selenoprotein P 1 (SePP1) expression. In vivo, CLSO decreased the lipid droplets and TG level, reduced the protein expression of SePP1, apoER, phosphor-adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK) in the cytoplasm of HepG2 cells induced by oleic acid and palmitic acid (OP). At the same time, lipid accumulation was observed in the Sepp1 high expression cells induced by endoplasmic reticulum (ER) activator tunicamycin (Tm). CLSO could identically reduce the protein expression of SePP1, apoER, p-AMPK in the cytoplasm of HepG2 cells induced by Tm. This result not only proved the CLSO had therapeutic effect on NAFLD, but also confirmed its mechanism associated with degrading the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) which led to the decrease of the expression SePP1/apoER2 in order to reduce lipid accumulation. The study suggests CLSO has great medicinal value in treating NAFLD besides its edibility.

B-cell CLL/lymphoma 7 protein family member C (BCL7C) located at chromosome 16p11.2 shares partial sequence homology with the other two family members, BCL7A and BCL7B. Its role in cancer remains completely unknown. Here, we report our finding of its tumor-suppressive role in ovarian cancer. Supporting this is that BCL7C is downregulated in human ovarian carcinomas, and its underexpression is associated with unfavorable prognosis of ovarian cancer as well as some other types of human cancers. Also, ectopic BCL7C restrains cell proliferation and invasion of ovarian cancer cells. Consistently, depletion of BCL7C reduces apoptosis and promotes cell proliferation and invasion of these cancer cells. Mechanistically, BCL7C suppresses mutant p53-mediated gene transcription by binding to mutant p53, while knockdown of BCL7C enhances the expression of mutant p53 target genes in ovarian cancer cells. Primary ovarian carcinomas that sustain low levels of BCL7C often show the elevated expression of mutant p53 target genes. In line with these results, BCL7C abrogates mutant p53-induced cell proliferation and invasion, but had no impact on proliferation and invasion of cancer cells with depleted p53 or harboring wild-type p53. Altogether, our results demonstrate that BCL7C can act as a tumor suppressor to prevent ovarian tumorigenesis and progression by counteracting mutant p53 activity.

Background Family with sequence similarity 234 member B (FAM234B), a protein-coding gene, is mainly expressed in brain tissues. Its clinical significance and biological function in tumors, especially in breast cancer (BC), have not been elucidated. Methods We firstly investigated the expression pattern of FAM234B at the mRNA and protein levels using Oncomine, TCGA portal, GEPIA, TIMER, HPA, and UALCAN databases, then applied bc-GenExMiner to assess the associations between expression level of FAM234B and clinicopathological features of BC. Besides, we also verified the expression of FAM234B expression in clinical BC samples using qRT-PCR. Subsequently, GEPIA, bc-GenExMiner, and TIMER databases were used to analyze the prognostic significance of FAM234B in all BC and different molecular subtypes. Finally, we conducted co-expression analysis and gene set enrichment analysis (GSEA). Additionally, we explored the regulatory mechanism of FAM234B in BC. Results Both bioinformatics analysis and experimental verification confirmed that the FAM234B expression was significantly higher at the mRNA and protein levels in luminal BC tissues than in adjacent normal tissues. High FAM234B expression was significantly correlated with older age, estrogen receptor-positive, progesterone receptor-positive, human epidermal growth factor receptor 2-negative, wild-type p53, low Nottingham prognostic index, low Scarff-Bloom-Richardson grade, lymph node metastasis positivity, and high tumor stage. Moreover, survival analysis indicated that high FAM234B expression was significantly related to a worse prognosis in patients with luminal BC. GSEA indicated that FAM234B was positively related to membrane transport process and negatively associated with immune response function. Besides, mechanism exploration indicated that pseudogene HTR7P1 might act as endogenous RNA to compete with has-miR-1271-5p or has-miR-381-3p for binding to FAM234B, thereby upregulating the expression of FAM234B in luminal BC. Conclusion Our results suggest that FAM234B may be a candidate therapeutic target or prognostic marker for luminal breast cancer.

Purpose To investigate the clinical efficacy of 0.01% atropine in slowing the progression of myopia in children and to evaluate the influence of 0.01% atropine on secretion of basal tear and stability of tear film. Methods Eighty children aged 5–14 years with myopia, 40 were randomly divided into two groups consisting of those who received spectacles in addition to 0.01% atropine (SA group) and those who received only spectacles (S group). The remaining 40 children who were wearing orthokeratology (OK) lenses for 3 months were randomly divided into two groups comprising those who received OK lenses in addition to 0.01% atropine (OKA group) and those who received only OK lenses (OK group). Comprehensive ophthalmologic examinations, including slit-lamp examination, visual acuity testing, autorefraction, intraocular pressure, axial length (AL), corneal topography, Schirmer’s test, and tear film break-up time (TBuT), were performed before treatment and after every 3 months treatment. Results During the follow-up visits, evidently better spherical equivalent (SE) control over 3, 6 and 12 months was observed in the SA and OKA groups compared with the S and OK groups. The AL over 3, 6, and 12 months was evidently inhibited in the SA and OKA groups compared with the S and OK groups. No statistically significant differences in Schirmer’s test and TBuT results were observed between the S and SA groups and between the OK and OKA groups. However, statistically significant differences were found in TBuT results between before treatment and after 3 months treatment in the OK group (P t test) and the OKA group (P t test). Conclusions 0.01% atropine can effectively control myopia progression and axial elongation regardless of combined treatment with spectacles or OK lenses. And 0.01% atropine has no evident effect on Schirmer’s test and TBuT results; however, researchers also found that Schirmer’s test and TBuT results showed a tendency to reduce after treatment with 0.01% atropine.

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP), in which exon open reading frame 15 (ORF15) of RPGR has been implicated to play a substantial role. We identified a novel hemizygous missense mutation E585K of RPGR from whole-exome sequencing of RP. RNA-Seq analysis and functional study were conducted to investigate the underlying pathogenic mechanism of the mutation. Our results showed that the mutation actually affected RPGR ORF15 splicing. RNA-Seq analysis of the human retina followed by validation in cells revealed a complex splicing pattern near the 3′ boundary of RPGR exon 14 in the ORF15 region, resulting from a variety of alternative splicing events (ASEs). The wildtype RPGR mini-gene expressed in human 293T cells confirmed these ASEs in vitro. In contrast, without new RNA species detected, the mutant mini-gene disrupted the splicing pattern of the ORF15 region, and caused loss of RPGR transcript heterogeneity. The RNA species derived from the mutant mini-gene were predominated by a minor out-of-frame transcript that was also observed in wildtype RPGR, resulting from an upstream alternative 5′ splice site in exon 14. Our findings therefore provide insights into the influence of RPGR exonic mutations on alternative splicing of the ORF15 region, and the underlying molecular mechanism of RP.

The mutational spectrum and prognostic factors of NRAS-mutated (NRASmut) acute myeloid leukemia (AML) are largely unknown. We performed next-generation sequencing (NGS) in 1,149 cases of de novo AML and discovered 152 NRASmut AML (13%). Of the 152 NRASmut AML, 89% had at least one companion mutated gene. DNA methylation-related genes confer up to 62% incidence. TET2 had the highest mutation frequency (51%), followed by ASXL1 (17%), NPM1 (14%), CEBPA (13%), DNMT3A (13%), FLT3-ITD (11%), KIT (11%), IDH2 (9%), RUNX1 (8%), U2AF1 (7%) and SF3B1(5%). Multivariate analysis suggested that age ≥ 60 years and mutations in U2AF1 were independent factors related to failure to achieve complete remission after induction therapy. Age ≥ 60 years, non-M3 types and U2AF1 mutations were independent prognostic factors for poor overall survival. Age ≥ 60 years, non-M3 types and higher risk group were independent prognostic factors for poor event-free survival (EFS) while allogenic hematopoietic stem cell transplantation was an independent prognostic factor for good EFS. Our study provided new insights into the mutational spectrum and prognostic factors of NRASmut AML.

Larynx cancer is one of the most common cancers in head and neck. This study aimed to investigate the health burden of larynx cancer at global, regional, and national levels. We collected data of larynx cancer between 1990 and 2017 from the Global Burden of Disease study, including incidence, mortality, and disability adjusted life-years (DALYs). Estimated annual percentage changes (EAPCs) were calculated to assess the changes in age-standardized rate (ASR) of larynx cancer. From 1990 to 2017, LC incident cases increased by 58.67%; however, age-standardized incidence rate (ASIR) decreased, with an EAPC of -0.99. Additionally, the incident cases and ASIR of LC were 6-fold higher for male than those for female in 2017. Over the past 28 years, deaths and DALYs of larynx cancer increased by 33.84% and 25%. Contrarily, age-standardized death and DALY rate showed a downward trend. Incidence, death, and DALYs of larynx cancer were always the highest in people aged 50-69 years. Overall, all the ASRs showed downward trends globally. The majority of larynx cancer burden was observed in men, especially among male aged 50-69 years. South and East Asia carried the heaviest burden of larynx cancer worldwide.

Currently, the number of negative lymph nodes (NLNs) has been paid increasing attention and is considered a prognostic indicator in diverse cancers. Therefore, it is necessary to explore the association between number of NLNs and prognosis in esophageal cancer (EC) patients. Our data were obtained from the Surveillance, Epidemiology, and End Results 18 database. The X-tile plot was used to determine the optimal cut-off value of the number of NLNs, and propensity score matching (PSM) was performed according to the results of the X-tile plot. A total of 4777 patients were eligible, and 882 pairs of patients were included after PSM. The result of the X-tile plot revealed an optimal cut-off value of three NLNs. Multivariate Cox regression analysis revealed better EC-specific survival (ECSS) in patients with more than three NLNs (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.59–0.77; p

Objectives: The prognostic role of WT1 in acute lymphoblastic leukemia (ALL) is still controversial. No study has focused on the prognostic role of WT1 expression in adult B-ALL patients receiving ...

Epidemiological studies have indicated that blood vitamin D levels are linked to cancer. Here we conducted a dose-response meta-analysis based on published observational studies to evaluate the association of vitamin D intake and blood vitamin D levels with breast cancer susceptibility. PubMed, EMBASE, and Web of Science databases were searched up to January 2019. The pooled odds ratio (OR) and 95% confidence intervals (CIs) were extracted to estimate the risk. We identified 70 relevant studies on blood vitamin D levels (50 studies) and vitamin D intake (20 studies), respectively. Linear and nonlinear trend analyses were performed and showed that an increase in blood vitamin D levels by 5 nmol/l was associated with a 6% decrease in breast cancer risk (OR = 0.94, 95% CI = 0.93-0.96). Similar results were obtained for premenopausal (OR = 0.96, 95% CI = 0.93-0.99) and postmenopausal women (OR = 0.96, 95% CI = 0.94-0.98). The pooled OR of breast cancer risk for a 400IU/day increase in vitamin D intake was 0.97 (95% CI = 0.92-1.02). In conclusion, we found that breast cancer risk was inversely related to blood vitamin D levels; however, no significant association was observed in vitamin D intake.

BackgroundStatistical data on the incidence, mortality, and burden of breast cancer and the relevant risk factors are valuable for policy-making. We aimed to estimate breast cancer incidence, deaths, and disability-adjusted life years (DALYs) by country, gender, age group, and social-demographic status between 1990 and 2017.MethodsWe extracted breast cancer data from the 2017 Global Burden of Disease (GBD) study from 1990 through 2017 in 195 countries and territories. Data about the number of breast cancer incident cases, deaths, DALYs, and the age-standardized rates were collected. We also estimated the risk factors attributable to breast cancer deaths and DALYs using the comparative risk assessment framework of the GBD study.ResultsIn 2017, the global incidence of breast cancer increased to 1,960,681 cases. The high social-development index (SDI) quintile included the highest number of breast cancer death cases. Between 2007 and 2017, the ASDR of breast cancer declined globally, especially in high SDI and high middle SDI countries. The related DALYs were 17,708,600 in 2017 with high middle SDI quintile as the highest contributor. Of the deaths and DALYs, alcohol use was the greatest contributor in most GBD regions and other contributors included high body mass index (BMI) and high fasting plasma glucose.ConclusionThe increasing global breast cancer burden is mainly observed in lower SDI countries; in higher SDI countries, the breast cancer burden tends to be relieving. Therefore, steps against attributable risk factors should be taken to reduce breast cancer burden in lower SDI countries.

Background: As an important downstream factor in the Hippo pathway, yes-associated protein 1(YAP1) has been detected to be elevated in various cancers and demonstrated to play a role in tumor development. Therefore, we evaluated by a meta-analysis the prognostic value of YAP1 in cancer patients. Results: Sixty-eight studies with 8631 patients were identified. The results indicated that YAP1 overexpression predicted unfavorable patient prognosis in studies with overall survival (OS) (HR=1.76, 95%CI: 1.50-2.06, p

Background Thymidylate synthase (TYMS) polymorphisms are reported to be related to susceptibility to some cancers. However, no study exists on TYMS polymorphisms and glioma risk. This study aimed to evaluate the relationship between two common TYMS gene variants (rs1059394 C>T, rs2847153 G>A) and glioma susceptibility. Methods This case-control study included 605 patients and 1300 cancer-free individuals. Genotyping was performed using Sequenom Mass-ARRAY. We determined odds ratios (ORs) and their 95% confidence intervals (CIs) to estimate the correlations. Results The analysis revealed that rs1059394 TT and CT+TT genotype had significantly low glioma risk (TT to CC: OR = 0.71, 95% CI = 0.52-0.97, P = 0.03; CT+TT to CC: OR = 0.74, 95% CI = 0.55-0.99, P = 0.04). However, no significant difference was found between rs2847153 and glioma risk in any genetic model (P﹥0.05). In high-grade gliomas, the GA and GA+AA genotypes of rs2847153 made the majority of genotypes, compared with GG genotype (GA to GG: OR = 2.01, 95% CI = 1.39-2.91, P < 0.001; GA+AA to GG: OR = 1.78, 95% CI =1.25-2.54, P < 0.001). Moreover, online expression quantitative trait locus (eQTL) analysis indicated that these two polymorphisms may alter TYMS gene expression in transformed fibroblast cells. Conclusion Our study provides evidence of the effect of TYMS rs1059394 on the susceptibility of glioma. In high-grade gliomas, compared with GG genotype, the GA and GA+AA genotypes of rs2847153 comprise a larger proportion.

Long noncoding RNA (lncRNA) polymorphisms are reportedly in connection with tumor susceptibility and prognosis. Glioma is one of the most aggressive and common cancers of the central nervous system. This study aimed to investigate the relationship between four lncRNA variants and glioma susceptibility and prognosis in a Chinese Han population. Sequenom Mass-ARRAY was used to genotype 605 patients with glioma and 1300 cancer-free individuals. Odds ratios or hazard ratios and related 95% confidence intervals were calculated to estimate the correlations. Logistic and Cox regression models, log-rank tests, and Kaplan-Meier curves were used for the statistical analysis. Six inheritance models showed that ANRIL rs2151280 variant genotype (A>G) was related to the susceptibility of glioma, while the other three lncRNAs showed no association. Patients treated with temozolomide or nimustine had better progression-free survival (PFS) and overall survival (OS) than those treated with platinum. Besides, patients aged older than 40 years showed a poorer OS. The Cox multivariate analysis revealed that the rs1136410 GG genotype (A>G) was beneficial for OS and PFS. The Kaplan-Meier analyses indicated that rs1136410 A>G and the rs7763881 A>C were associated with longer OS. ANRIL rs2151280 variant genotype might increase susceptibility of glioma. In addition, PARP1 rs1136410 variant genotype could be beneficial for the overall survival of patients with glioma. More research data are needed to further validate our results.

Hotspot p53 mutants augment cancer cell proliferation, metastasis and metabolism through their gain-of-function (GOF). Ovarian cancer sustains the highest frequency of TP53 mutations, but the mechanisms underlying regulation of mutant p53s’ GOF in this type of cancer remain incompletely understood. Herein, we identified the E3-ubiquitin ligase TRIM71 as a novel mutant p53-binding protein. Ectopic TRIM71-induced ubiquitination and proteasomal degradation of mutant p53 by binding to its transactivation (TA) domain, and inhibited the expression of a broad spectrum of mutant p53 target genes. Ectopic TRIM71 also restrained, whereas ablation of TRIM71 endorsed, ovarian carcinoma cell growth in vitro and in vivo. Significantly, TRIM71 overexpression is highly associated with favorable prognosis, particularly, in TP53-mutated ovarian carcinomas. Altogether, our findings unveil the anti-tumor function of TRIM71 in ovarian cancer development and prognosis by downregulating mutant p53s.

Single-cell RNA (scRNA) profiling or scRNA-sequencing (scRNA-seq) makes it possible to parallelly investigate diverse molecular features of multiple types of cells in a given plant tissue and discover cell developmental processes. In this study, we evaluated the effects of sample size (i.e., cell number) on the outcome of single-cell transcriptome analysis by sampling different numbers of cells from a pool of ~57,000 Arabidopsis thaliana root cells integrated from five published studies. Our results indicated that the most significant principal components could be achieved when 20,000–30,000 cells were sampled, a relatively high reliability of cell clustering could be achieved by using ~20,000 cells with little further improvement by using more cells, 96% of the differentially expressed genes could be successfully identified with no more than 20,000 cells, and a relatively stable pseudotime could be estimated in the subsample with 5000 cells. Finally, our results provide a general guide for optimizing sample size to be used in plant scRNA-seq studies.

The RNA component of mitochondrial RNA-processing endoribonuclease (RMRP) was recently shown to play a role in cancer development. However, the function and mechanism of RMRP during cancer progression remain incompletely understood. Here, we report that RMRP is amplified and highly expressed in various malignant cancers, and the high level of RMRP is significantly associated with their poor prognosis, including breast cancer. Consistent with this, ectopic RMRP promotes proliferation and migration ofTP53-mutated breast cancer cells, whereas depletion of RMRP leads to inhibition of their proliferation and migration. RNA-seq analysis reveals AKT as a downstream target of RMRP. Interestingly, RMRP indirectly elevates AKT expression by preventing AKT mRNA from miR-206-mediated targeting via a competitive sequestering mechanism. Remarkably, RMRP endorses breast cancer progression in an AKT-dependent fashion, as knockdown of AKT completely abolishes RMRP-induced cancer cell growth and migration. Altogether, our results unveil a novel role of the RMRP-miR-206-AKT axis in breast cancer development, providing a potential new target for developing an anti-breast cancer therapy.

The serotonin receptor 5-HT1B is widely expressed in the central nervous system and has been considered a drug target in a variety of cognitive and psychiatric disorders. The anti-inflammatory effects of 5-HT1B agonists may present a promising approach for Alzheimer’s disease (AD) treatment. Herbal antidepressants used in the treatment of AD have shown functional overlap between the active compounds and 5-HT1B receptor stimulation. Therefore, compounds in these medicinal plants that target and stimulate 5-HT1B deserve careful study. Molecular docking, drug affinity responsive target stability, cellular thermal shift assay, fluorescence resonance energy transfer (FRET), and extracellular regulated protein kinases (ERK) 1/2 phosphorylation tests were used to identify emodin-8-O-β-d-glucopyranoside (EG), a compound from Chinese medicinal plants with cognitive deficit attenuating and antidepressant effects, as an agonist of 5-HT1B. EG selectively targeted 5-HT1B and activated the 5-HT1B-induced signaling pathway. The activated 5-HT1B pathway suppressed tumor necrosis factor (TNF)-α levels, thereby protecting neural cells against beta-amyloid (Aβ)-induced death. Moreover, the agonist activity of EG towards 5-HT1B receptor, in FRET and ERK1/2 phosphorylation, was antagonized by SB 224289, a 5-HT1B antagonist. In addition, EG relieved AD symptoms in transgenic worm models. These results suggested that 5-HT1B receptor activation by EG positively affected Aβ-related inflammatory process regulation and neural death resistance, which were reversed by antagonist SB 224289. The active compounds such as EG might act as potential therapeutic agents through targeting and stimulating 5-HT1B receptor for AD and other serotonin-related disorders. This study describes methods for identification of 5-HT1B agonists from herbal compounds and for evaluating agonists with biological functions, providing preliminary information on medicinal herbal pharmacology.

Background High‐grade serous ovarian carcinoma (HGSOC) is the most common and aggressive histotype of epithelial ovarian cancer. The heterogeneity and molecular basis of this disease remain incompletely understood. Methods To address this question, we have performed a single‐cell transcriptomics analysis of matched primary and metastatic HGSOC samples. Results A total of 13 571 cells are categorized into six distinct cell types, including epithelial cells, fibroblast cells, T cells, B cells, macrophages, and endothelial cells. A subset of aggressive epithelial cells with hyperproliferative and drug‐resistant potentials is identified. Several new markers that are highly expressed in epithelial cells are characterized, and their roles in ovarian cancer cell growth and migration are further confirmed. Dysregulation of multiple signaling pathways, including the translational machinery, is associated with ovarian cancer metastasis through the trajectory analysis. Moreover, single‐cell regulatory network inference and clustering (SCENIC) analysis reveals the gene regulatory networks and suggests the JUN signaling pathway as a potential therapeutic target for treatment of ovarian cancer, which is validated using the JUN/AP‐1 inhibitor T‐5224. Finally, our study depicts the epithelial‐fibroblast cell communication atlas and identifies several important receptor‐ligand complexes in ovarian cancer development. Conclusions This study uncovers new molecular features and the potential therapeutic target of HGSOC, which would advance the understanding and treatment of the disease., (1) Single‐cell transcriptomics analysis of HGSOC samples reveals six distinct cell types. (2) Characterization of epithelial cell subclusters identifies novel markers for HGSOC. (3) Subclustering fibroblast cells suggests their functional heterogeneity. (4) Our study also uncovers the JUN pathway and several ligand‐receptor signals as potential drivers for HGSOC.

p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPβ, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.

The polymorphism of multicomponent crystals has not been studied as widely as that of single-component crystals. In this work, two polymorphic forms of a pharmaceutical salt of phenazopyridine with...

Introduction: Asia-Pacific Colorectal Screening (APCS) score has been implemented for colorectal cancer screening in asymptomatic cohort in many regions. However, no study has validated its efficiency in Asian outpatients with mild-self-limited gastrointestinal symptoms yet. The purpose of this study was to validate its efficiency in asymptomatic subjects and outpatients in Ningxia. Methods: The records of 329 asymptomatic participants and 300 outpatients were collected and analyzed from database in the General Hospital of Ningxia Medical University from September 2017 to April 2018. These 2 main groups were divided into 3 tiers based on the scores calculated by the category of APCS score. The detection rates of advanced colorectal neoplasia (ACRN) were further compared according to histopathological classifications of tissues acquired during colonoscopy. Results: Among the 329 participants screened in the asymptomatic cohort, 78 subjects (23.7%) were in the low-risk (LR) tier, 187 subjects (56.8%) in the moderate-risk (MR) tier, and 64 subjects (19.5%) in the high-risk (HR) tier. The percentage of ACRN in the LR, MR, and HR groups was 1.3, 8.6, and 20.3%, respectively. In the 300 outpatient cohorts, 78 patients (26%) were in the LR tier, 140 patients (46.7%) in the MR tier, and 82 patients (27.3%) in the HR tier. The detection rates of ACRN in the LR, MR, and HR groups were 0, 10, and 39%, respectively. Conclusion: APCS score is an effective method for ACRN screening in asymptomatic and also the outpatient subjects. Individuals with HR scores should be given priority for colonoscopy.

M1 muscarinic receptors have long been identified as a potential therapeutic target for the treatment of cognitive impairment in Alzheimer's disease (AD). Our previous study has shown that M1 receptors promote membrane insertion and synaptic delivery of AMPA receptor GluA1 subunit. In this study, we sought to determine whether activation of M1 receptor would rescue the cognitive impairment in AD model mice through modulation of GluA1 subunit. For the mice injected with aggregated β-amyloid (Aβ) fragments to impair learning and memory, activation of M1 receptors could rescue it by reducing the latency to find the platform and spending more time in the target quadrant in the probe test in the Morris water maze. However, such an effect was ablated in mice with Ser845 residue of GluA1 mutated to alanine. Furthermore, the activation of M1 receptors enhanced the expression of GluA1 and its phosphorylation at Ser845 and drove GluA1 to incorporate with PSD95, a postsynaptic marker, in the hippocampi from Aβ-injected wild type mice but not from the mutant mice. Moreover, for 9-month-old APP/PS1 transgenic AD model mice, which may resemble the late AD, M1 receptor activation could not improve the cognitive impairment significantly. In addition, the enhancement of GluA1 expression and its phosphorylation at Ser845 were not observed in their hippocampi. Taken together, the study indicated that M1 receptor activation rescued the cognitive deficit through modulating the trafficking of GluA1-containing AMPA receptors and the therapeutics targeting M1 receptors should aim at mild AD or even pre-AD.

B-cell acute lymphoblastic leukemia (B-ALL) in adults remains a highly challenging disease. Identifying new prognostic biomarkers is necessary to help select the best therapeutic schedules and to improve prognosis. We performed bioinformatics analyses of transcriptomic data to identify aberrantly-expressed mRNA transcripts in B-ALL and focused on RASD1 (Ras-related dexamethasone-induced 1). To date, no information is available on the prognostic value of RASD1 in B-ALL. Fifty-three consecutive adults with de novo B-ALL were enrolled in this study. Our data suggested that RASD1 was abnormally overexpressed in B-ALL. High RASD1 transcript levels at diagnosis were associated with lower survival probabilities (44% [20%–61%] vs. 79% [60%–97%]; P = 0.037) and were also an independent prognostic factor in adult B-ALL (HR = 4.9 [1.5–15.9]; P = 0.008). Functional in vitro analyses and bioinformatic analyses indicated that RASD1 promoted cell proliferation, cell cycle progression and chemotherapy resistance and inhibited cell apoptosis. These data demonstrated that RASD1 might serve as a novel prognostic biomarker for adult B-ALL and as a potential therapeutic target in adult B-ALL patients.

The association between hyperuricemia or gout and cancer risk has been investigated in various published studies, but their results are conflicting. We conducted a meta-analysis to investigate whether hyperuricemia or gout was associated with the cancer incidence and mortality. Linear and nonlinear trend analyses were conducted to explore the dose-response association between them. The pooled relative risk (RR) and 95% confidence interval (CI) were used to evaluate cancer risk. A total of 24 articles (33 independent studies) were eligible for inclusion. When compared participants with the highest SUA (hyperuricemia) levels and those with the lowest SUA levels, the pooled RR was 1.08 (95% CI, 1.04-1.12), it was significantly associated among males but not among females (males, RR = 1.07; 95% CI, 1.03-1.11; females, RR = 1.06; 95% CI, 0.96-1.17). Hyperuricemia increased total cancer mortality (RR = 1.15; 95% CI, 1.05-1.26), but a significant association was observed in females rather than in males (females: RR = 1.26; 95% CI, 1.09-1.45; males, RR = 1.02; 95% CI, 0.80-1.30). Linear relationships of SUA levels with overall cancer incidence (p for nonlinearity = 0.238) and overall cancer mortality (p for nonlinearity = 0.263) were identified. However, 1 mg/dL increment in SUA levels was weakly significant in overall cancer incidence (RR = 1.01; 95% CI, 1.01-1.01) but not associated with overall cancer mortality (RR = 1.01; 95% CI, 0.99-1.03). Gout was significantly associated with increased cancer incidence (RR = 1.19; 95% CI, 1.12-1.25). In conclusion, Hyperuricemia or gout was associated with higher cancer incidence and mortality. Though a potential linear relationship between them was found, we'd better treat this result with caution.

Background: Currently, there is still some controversy regarding whether early breast cancer patients with a tumor size of ≤5 cm and 1-3 positive lymph nodes should undergo postoperative radiotherapy (PRT). Materials and Methods: We obtained data from the Surveillance, Epidemiology, and End Results (SEER) 18 database. Then, we conducted propensity score matching (PSM), according to the radiotherapy record. The Kaplan-Meier and Cox regression analysis were conducted to explore prognostic factors in breast cancer. Results: A total of 6,777 patients aged 75+ years old were eligible and 2,361 patients were included after PSM. We found PRT could improve patient overall survival (OS) (P = 0.01, hazard ratio [HR] = 0.88, 95% confidence interval [CI], 0.80-0.97). Subgroup analysis revealed PRT could improve OS in patients with hormone receptor positive (HR+) (P = 0.001, HR = 0.84, 95% CI, 0.76 - 0.94) or white patients (P =0.004, HR = 0.86, 95% CI, 0.77 - 0.95). Conclusions: PRT may benefit for elderly women with early breast cancer, especially in HR+ patients or white patients. These findings may inform future optimized options whether elderly female patients with early breast cancer should undergo postoperative radiotherapy.

Background Estrogen exposure is a widely known risk factor for BC. And the interaction of estrogen with estrogen receptor (ER) plays an important role in breast cancer development. This case–control study aims to assess the association of genetic polymorphisms in the estrogen receptor genes with breast cancer (BC) susceptibility in Chinese Han women. Methods Four polymorphisms (rs2881766, rs9383951, rs9340799 in ESR1 and rs3020449 in ESR2) were genotyped in 459 patients and 549 healthy controls using the Sequenom MassARRAY method. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the associations. False-positive report probability (FPRP) was utilized to examine the noteworthiness of significant findings. Results We observed that rs2881766 was associated with a decreased BC risk (GG vs. TT: OR = 0.63, 95% CI = 0.44–0.91; GG vs. TT/GT: OR = 0.68, 95% CI = 0.49–0.95), while rs3020449 was associated with an increased risk of BC (CT vs. TT: OR = 1.58, 95% CI = 1.21–2.06; CT/CC vs. TT: OR = 1.54, 95% CI = 1.20–1.98; TT/CC vs. CT: OR = 1.48, 95% CI = 1.15–1.90). The other two polymorphisms have no relation with BC susceptibility. In addition, rs2881766 was correlated with lymph node metastasis and ER expression, and rs3020449 was related to tumor size, histological grade and ER expression. The values of false-positive report probability indicated that the significant associations of BC risk with both rs2881766 and rs3020449 were noteworthy. Conclusions Our study suggests that polymorphisms rs2881766 and rs3020449 in estrogen receptor genes were associated with BC susceptibility as well as clinical features in Chinese women. These findings need further validation in a large population. Electronic supplementary material The online version of this article (10.1186/s12935-019-0727-z) contains supplementary material, which is available to authorized users.

Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called ‘gain-of-functions’ (GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.

Background: Lysosome-associated protein transmembrane-4β-35(LAPTM4B-35) has been observed overexpressed in multiple malignant tumors. However, the prognostic value of LAPTM4B-35 remains controversial. Therefore, we conducted a meta-analysis to evaluate the prognostic value of LAPTM4B-35 in human cancers. Methods: The relevant publications were obtained by systematically searching the PubMed, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the prognosis value of LAPTM4B-35 for cancer patient. Results: Our result suggest that LAPTM4B-35 overexpression is significantly associated with poor overall survival (OS) (HR = 2.49, 95% CI = 1.87-3.32, p < 0.001), disease-free survival (DFS) (HR = 2.43, 95% CI = 1.35-4.35, p = 0.003), and progression-free survival (PFS) (HR = 4.12, 95% CI = 2.30-7.37, p < 0.001). Moreover, subgroup analysis revealed significant association with poor OS in lung (HR = 2.05, 95% CI = 1.37-3.06, p < 0.001), gastric carcinoma (HR = 1.88, 95% CI = 1.01-3.50, p < 0.047) and ovarian cancer (HR = 4.94, 95% CI = 1.44-16.94, p = 0.011). Conclusion: LAPTM4B-35 may be a novel predictive biomarker and a potential target for treatment.

OBJECTIVE The objective of this study was to measure the anatomical distance from the cervicovaginal junction to the uterovesical peritoneal reflection (CJ-PR). METHODS A total of 120 hysterectomy patients were selected as study subjects. The uterus was removed, and the CJ-PR distance was immediately measured. For total vaginal hysterectomy, measurement was performed intraoperatively. The cervical length was also measured postoperatively. RESULTS The median (interquartile) CJ-PR distance for all subjects was 3.3 (2.9-3.7) cm. Comparison of premenopausal and postmenopausal women without prolapse revealed median CJ-PR distances of 3.3 (3.0-3.6) cm and 3.0 (2.6-3.4) cm, respectively. The CJ-PR distance was longer in women with prolapse (4.6 [3.7-5.6] cm) than in those without prolapse (3.2 [2.8-3.6] cm). The median cervical lengths were 3.1 (2.7-3.6) cm for postmenopausal patients without prolapse and 4.4 (3.6-5.8) cm for postmenopausal patients with prolapse. CONCLUSIONS Knowledge of the CJ-PR distance may help gynecologists predict how far the uterovesical PR is from the anterior vaginal incision.

COVID-19 has widely spread across the world, and much research is being conducted on the causative virus SARS-CoV-2. To help control the infection, we developed the Coronavirus GenBrowser (CGB) to monitor the pandemic. With CGB, 178,765 high quality SARS-CoV-2 genomic sequences were analyzed, and 121,522 mutations were identified. In total, 1,041 mutation cold spots were found, suggesting that these spots are key functional elements of SARS-CoV-2 and can be used for detection and vaccine development. CGB revealed 203 accelerated evolutions of SARS-CoV-2, but variants with accelerated evolution were not found to be highly contagious, suggesting that most of these evolutions are neutral. The B.1.1.7 (CGB75056.84017) lineage previously identified in the UK was not found to be significantly accelerated although its adaptive evolution was detected. Moreover, 2,297 strains with a significantly reduced evolutionary rate were identified, including three closely related variants widely spreading in Europe with no mutations in three months. By lineage tracing, a strain dated early March 2020 was determined to be the most recent common ancestor of nine strains collected from six different regions in three continents. This strain was also found to cause the outbreak in Xinfadi, Beijing, China in June 2020. CGB allows visualization and analysis of hundreds of thousands of SARS-CoV-2 genomic sequences. Distributed genome alignments and its effective analysis pipeline ensure timely update of the latest genomic data of SARS-CoV-2. CGB is an efficient platform for the general public to monitor the transmission and evolution of SARS-CoV-2.

Fear memory is a pivotal biological function by which organisms can predict possible danger to avoid or reduce harm. However, dysregulation of fear memory processing may lead to pathological fear or anxiety and produce serious clinical symptoms, such as post-traumatic stress disorder (PTSD). Iron deficiency (ID) is reported to inhibit the initiation of fear memory. In our study, we found that ferroportin1 (FPN1), the only known cellular iron export protein in mammals, and ablation in neurons and astrocytes caused iron deficiency in the cortex and hippocampus. However, little is known about its role in the development of fear memory. Moreover, direct evidence of the role of FPN1, or the related molecular mechanisms of such a role, in balancing brain iron homeostasis, especially in neuronal cells, is lacking. Herein, we deleted Fpn1 in mouse neurons, using Nestin-cre transgenic mice, and explored the impact on neuronal iron recycling and brain iron homeostasis in the cortex and hippocampus. We investigated the response of the mice to contextual fear and found that formation of fear memory was impeded after neuronal FPN1 depletion. We also found that FPN1 ablation in neurons and astrocytes caused an atypical expression of iron metabolism-related proteins in these two regions: decreased expression of DMT1, Ft-H, and Ft-L, and increased TfR1 expression. In addition, the decreased FPN1 in brain microvascular endothelial cells (BMVECs) also shed light on the cause of the decreased iron delivery to the brain through the blood-brain barrier (BBB). Our research highlights the major role played by FPN1 in brain iron homeostasis and identifies a potential target for the treatment of PTSD.

Background : Male sterility is an efficient trait for hybrid seed production and germplasm innovation. Until now, most studies on male sterility were on cytoplasmic and recessive genic sterility, with few on dominant genic male sterility, especially in cotton, due to lack of such mutant.Results : We discovered a natural male sterile (MS) Sea Island cotton ( G. barbadense ) mutant, Genetic analysis showed the mutation was caused by a dominant mutation in a single nuclear gene. Comparative cytological observation of anther sections from MS and WT uncovered cellular differences in anther at and after the tetrad stage of pollen mother cells (PMC). In the MS anthers, the outer wall of pollen grains was free of spinules, the tapetum was vacuolated and showed delayed degradation, consequently, no functional pollen grains. Comparison of transcriptomes from meiosis, tetrad, mononuclear and binuclear pollen, and pollen maturation stages identified 13,783 non-redundant differentially expressed genes (DEGs) between MS and WT. Based on the number of DEGs, analyses of enriched GO terms and KEGG pathways, it was evident that significant transcriptomic changes occurred at and after the tetrad stage, consistent with cytological observation, and that the major differences were on metabolism of starch, sucrose, ascorbate, aldarate, alanine, aspartate and glutamate, and biosynthesis of cutin, suberine and wax. WGCNA analysis identified five modules containing 920 genes highly related to anther development, especially the greenyellow module with 54 genes that was highly associated with PMC meiosis and tetrad formation. A NAC transcription factor ( Gh_D11G2469 ) was identified as a hub gene for this module, which warrants further functional characterization.Conclusions : We demonstrated that the MS trait was controlled by a single dominant nuclear gene and caused by delayed tapetum degradation at the tetrad stage. Comparative transcriptome analysis and gene network construction identified DEGs, enriched GO terms and metabolic pathways, and hub genes potentially associated with anther development and the MS trait, which will contribute to important ideas and basis of the experimental data related to the molecular mechanism of DGMS and the innovation of cotton germplasm resources.