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Growing evidences illustrated that long non-coding RNAs (lncRNAs) exhibited widespread effects on the progression of human cancers via various mechanisms. Long intergenic non-protein-coding RNA 01446 (LINC01446), a 3484-bp ncRNA, is known to locate at chromosome 7p12.1. However, its biological functions and specific action mechanism in gastric cancer (GC) are still unclear. In our study, LINC01446 was proved to be markedly upregulated in GC tissues relative to the normal tissues, and positively correlated with the poor survival of GC patients. The multivariate Cox regression model showed that LINC01446 functioned as an independent prognostic factor for the survival of GC patients. Functionally, LINC01446 facilitated the proliferation and metastasis of GC cells. Moreover, RNA-seq analysis demonstrated that LINC01446 knockdown primarily regulated the genes relating to the growth and migration of GC. Mechanistically, LINC01446 could widely interact with histone lysine-specific demethylase LSD1 and recruit LSD1 to the Ras-related dexamethasone-induced 1 (RASD1) promoter, thereby suppressing RASD1 transcription. Overall, these findings suggest that LINC01446/LSD1/RASD1 regulatory axis may provide bona fide targets for anti-GC therapies.

Background Photoacoustic imaging (PA) with high spatial resolution has great potential as desired monitoring means in the high intensity focused ultrasound (HIFU) surgery of tumor. However, its penetration depth in the tissue does not meet the clinical needs. Nanomedicine provides a new opportunity for PA imaging to guide HIFU surgery. Our studies found that hypoxic heterogeneity of tumor was effectively reversed by HIFU. Methods Herein, specific metal-organic framework nanosystem, constructed by coordination of banoxantrone (AQ4N) and Mn2+, is designed based on HIFU to reverse hypoxic heterogeneity of tumor. Results It could provide exogenous light-absorbing substances, thus improves the penetrability of PA imaging signal through the deep tissue and achieves clearer PA imaging for guiding HIFU surgery. In turn, AQ4N, in the hypoxic homogenous environment of tumor provided by HIFU, is activated sequentially to specifically treat the residual hypoxic tumor cells. Conclusions This strategy addresses the dissatisfaction of PA imaging-guided HIFU therapy and is promising for translation into a clinical combination regimen.

Photoacoustic (PA) imaging with high spatial resolution has great potential as desired monitoring means in the high-intensity focused ultrasound (HIFU) surgery of tumor. However, its penetration depth in the tissue is insufficient for achieving accurate intraoperative navigation, leading to residual tumor tissue. Nanomedicine provides a new opportunity for PA imaging to guide HIFU surgery. Studies have found that the hypoxic heterogeneity of tumor is effectively reversed by HIFU. Herein, a specific metal-organic framework nanosystem, constructed by coordination of banoxantrone (AQ4N) and Mn

Objectives:To preliminarily explore the germline BRCA1/2 gene mutation status of patients with epithelial ovarian cancer (EOC), analyze the relationship with clinicopathological characteristics and the impact on survival and prognosis. Then examine the BRCA1/2 gene sequence mutation rate and the QOL of ovarian cancer patients with oral Olaparib in a single-center of China.Methods:A retrospective analysis of the survival and prognostic factors of 82 ovarian cancer patients who had undergone genetic testing in the Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University from 2015 to 2018. These patients also underwent germline BRCA1/2 genetic testing. Then, we use the Quality of Life Questionnaire (QLQ-C30) and the Quality of Life Ovarian Cancer 28 Questionnaire (QLQ-OV28) to determine the relationship between quality of life (QOL) in each category, and key demographic and clinical factors.Results: The total mutation rate of BRCA1/2 was 30.48%, among which the pathogenic mutation rate of BRCA1 was 20.73%, and the pathogenic mutation rate of BRCA2 was 9.75% in our single-center. A total of 18 pathogenic mutation sites and 2 mutation sites of unknown significance were found. Olaparib as maintenance therapy was significantly associated with better QOL on all functioning domains and several symptom domains. The patients without Olaparib maintenance therapy may experience deteriorating QOL in several domains. Conclusions: Patients with EOC have a higher frequency of BRCA1/2 gene mutation rate, which is related to the malignant biological behavior of the tumor. Patients with BRCA1/2 gene mutation may have a better prognosis. Olaparib maintenance therapy is associated with better QOL and higher QOL in several domains in single center of Chinese.

With the acceleration of human economic activities and dramatic changes in climate, the validity of the stationarity assumption of flood time series frequency analysis has been questioned. In this study, a framework for flood frequency analysis is developed on the basis of a tool, namely, the Generalized Additive Models for Location, Scale, and Shape (GAMLSS). We introduced this model to construct a non-stationary model with time and climate factor as covariates for the 50-year snowmelt flood time series in the Kenswat Reservoir control basin of the Manas River. The study shows that there are clear non-stationarities in the flood regime, and the characteristic series of snowmelt flood shows an increasing trend with the passing of time. The parameters of the flood distributions are modelled as functions of climate indices (temperature and rainfall). The physical mechanism was incorporated into the study, and the simulation results are similar to the actual flood conditions, which can better describe the dynamic process of snowmelt flood characteristic series. Compared with the design flood results of Kenswat Reservoir approved by the China Renewable Energy Engineering Institute in December 2008, the design value of the GAMLSS non-stationary model considers that the impact of climate factors create a design risk in dry years by underestimating the risk.

Background Long noncoding RNAs (lncRNAs) have been identified to participate in tumorigenesis. However, the underlying mechanisms of differentially expressed lncRNAs engaged in diseases remain indistinct and need further exploration. Methods Raw data files downloaded from TCGA and GEO dataset were used to analyze the differentially expressed lncRNAs and LINC00565 was picked out as the potential oncogene. qRT-PCR was used to analyze the LINC00565 level in ovarian tissues and cell lines. Subsequently, the selected ovarian tumor cells were then transfected with LINC00565 siRNA by Lipofectamine 2000 and the cell cycle was detected by flow cytometry. Effect of LINC00565 on tumor growth and cell cycle was verified by tumor formation assay in nude mice. The mechanism of LINC00565 involving in cell cycle regulation was further explored by Western blot. Results In this research, we discovered that LINC00565, a novel lncRNA, was highly expressed in ovarian cancer (OC). LINC00565 expression level was negatively associated with outcomes of OC patients. Further analysis showed that LINC00565 expression was closely correlated to tumor size, FIGO stage, but not related to other clinical features. In vitro experiments indicated that knockdown of LINC00565 significantly inhibited proliferative, invasive and migratory abilities of ovarian cancer cells. Besides, knockdown of LINC00565 can induce cell cycle arrest in G0/G1 phase. In addition, in vivo assay showed that low expression of LINC00565 inhibited the growth of OC. Further study found that LINC00565 knockdown markedly downregulated the protein expressions of CyclinD1, CyclinE1 and CDK4, but upregulated the expression of P16 and P21. Subsequently, we confirmed that LINC00565 promoted the progression of OC via upregulating GAS6, which has been confirmed to promote tumor progression. Conclusion In summary, our study firstly reported that the LINC00565 functioned as an oncogene to promote the progression of OC by interacting with GAS6.

Ovarian cancer (OC) is a highly prevalent gynecologic malignancy and its mortality is extremely high. Therefore, the development of novel therapeutic approaches for OC is of great significance. In this study, LINC01342 was upregulated in OC tissue in the GSE38666 microarray and in tumor tissue samples collected in our center. The silencing of LINC01342 suppressed the proliferative and metastatic capacities of A2780 and HO8910 cells. Subcellular distribution assays showed that LINC01342 was mainly enriched in the cytoplasm. Subsequently, the downregulation of microRNA-30c-2-3p was proven to be the target of LINC01342. The silencing of microRNA-30c-2-3p enhanced the clonality and migratory capacity of OC cells. Moreover, the silencing of microRNA-30c-2-3p could reverse the inhibited migration and clonality in OC cells caused by LINC01342 knockdown. In addition, hypoxia-inducible factor 3 subunit α (HIF3A) was proven to be the target gene of microRNA-30c-2-3p, which was upregulated. HIF3A was negatively regulated by microRNA-30c-2-3p but positively regulated by LINC01342 in OC cells. An RNA binding protein immunoprecipitation assay showed that microRNA-30c-2-3p, LINC01342, and HIF3A could bind to argonaute RISC catalytic component 2. The overexpression of HIF3A reversed the inhibited migration and clonality in OC cells with LINC01342 knockdown. By analyzing the follow-up data from the enrolled OC patients, the LINC01342 and HIF3A levels were negatively correlated with prognosis, while the microRNA-30c-2-3p level was positively correlated with the same. In short, the upregulated LINC01342 in OC absorbs microRNA-30c-2-3p to release HIF3A. Thus, upregulated HIF3A expression accelerates the progression of OC.

BACKGROUND: The treatment strategies and prognostic factors for uterine cervical adenocarcinoma (UAC) primarily refer to that for squamous cell carcinoma (SCC). However, the biological behavior, treatment outcomes of UAC differ from that of SCC. This study aimed to develop and validate a prognostic nomogram for predicting the probability of 3- and 5-year cancer-specific survival (CSS) in patients with UAC. METHODS: A total of 8,991 UAC patients from the Surveillance, Epidemiology, and End Results (SEER) database were included in this study. Patients diagnosed between 1988 and 2010 (n=5,655) were enrolled for model development and internal validation, and those diagnosed between 2011 and 2016 (n=3,336) were used for temporal validation. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to select predictors of CSS. Cox hazard regression analysis was used to construct the model, which was presented as a static nomogram and web-based dynamic nomogram. The nomogram was internally validated using the bootstrap resampling method and underwent temporal validation. RESULTS: Tumor grade, stage T, stage N, stage M, tumor size, and surgery of the primary site were identified as independent prognostic factors for CSS and subsequently incorporated into construction of the nomogram. The nomogram could accurately predict 3- and 5-year CSS with an optimism adjusted c-statistic of 0.90 [95% confidence intervals (CI): 0.89–0.91] and 0.89 (95% CI: 0.88–0.91) after internal validation, respectively; while, after temporal validation, the statistics were 0.89 (95% CI: 0.87–0.91) and 0.88 (95% CI: 0.83–0.94), respectively. The internal and temporal calibration plots demonstrated good consistency between the predicted and observed values of CSS. Based on the model, the cases were stratified into high- and low-risk groups. The Kaplan-Meier plot showed that high-risk patients exhibited significantly poorer survival than those at low risk (P

Objective To retrospectively evaluate the oncologic and obstetric outcomes of fertility-sparing surgery (FSS) for borderline ovarian tumors(BOT). Methods 132 patients with borderline ovarian tumors were divided into the incompletely staging surgery (ISS) group and the completely staging surgery (CSS) group. The overall survival and disease-free survival curves were determined using the Kaplan–Meier method. The Cox proportional hazards method was used to assess the association between the variables and live birth and multivariate analysis to identify the independent associations. Results Chi-square and Kaplan-Meier analyses showed no significant differences in overall survival between the two groups (p = 1.000 and p = 0.716, respectively). The CSS group had fewer relapses and longer disease-free survival than ISS (p = 0.003). There was no statistical difference in live birth rate between two groups (crude odds ratio = 0.885, 95%CI 0.411–1.903, p = 0.755; adjusted odds ratio = 0.848, 95%CI 0.366–1.963, p = 0.700). Age was the only independent risk factor for live birth (adjusted odds ratio = 0.902, 95%CI 0.823–0.988, p = 0.027). Mean live birth intervals after FSS was 31.86 ± 19.325 months. Conclusions CSS significantly increased the disease-free survival time of BOT and reduced the relapse risk. However, CSS had a slightly negative and statistically insignificant association with live birth.

BACKGROUND GRP78, the 78-kDa glucose-regulated protein, occupies a significant position in endoplasmic reticulum stress. Emerging evidences have shown that GRP78 induces chemoresistance in several tumors; however, the role of GRP78 in cervical cancer (CVC) still needs to be elucidated clearly. MATERIAL AND METHODS In the present study, we determined the expression levels of GRP78 in CVC tissues collected from patients through immuocytochemistry, western blot and real-time PCR. To evaluate the exact role of GRP78 in CVC cells in the presence of cisplatin, we generated GRP78 knock-down cervical cancer cells through small interfering RNA. After successful transfection, the apoptosis rate was assessed with flow cytometry. The expression levels of caspase-3, CHOP and Bcl-2 in GRP78 knock-down cells were determined by western blot. RESULTS The GRP78 levels in CVC tissues were increased significantly. Three types of CVC cells HeLa, SiHa, and C33A were treated with different concentrations of cisplatin and cultured for 12 hours, 24 hours, and 48 hours respectively. And SiHa cells exhibited the highest resistance to cisplatin at all time. Specifically, after 25 μM cisplatin treatment, more than 80% of C33A cells underwent apoptosis, whereas the apoptotic rate of SiHa cells was only 30-40%. Data suggested that GRP78 silencing increased chemo-sensitivity and improved the effects of cisplatin-induced apoptosis in SiHa cells. Moreover, inhibition of GRP78 could upregulate caspase-3 and CHOP expression and downregulate Bcl-2 expression. CONCLUSIONS GRP78 may represent a key bio-marker of CVC and silencing GRP78 may strengthen the resistance against cisplatin. GRP78 may be a potential molecular target for CVC therapies in future.

Cervical cancer is among the most common cancers inflicting women worldwide. Understanding the pathological mechanisms of cervical cancer development is critical for identifying novel targets for cervical cancer treatment. MicroRNAs (miRs) have various roles in regulating cancer development. In this study, we investigated the potential role of miR-181a and its target in regulating cervical cancer development and chemotherapy resistance. The expression of miR-181a was evaluated and modulated in several human cervical cancer cell lines. The role of miR-181a in regulating cervical cancer growth and chemotherapy sensitivity was investigated in cell culture models and mouse tumor xenograft models. The target of miR-181a and its function were identified in cervical cancer models. We found a distinct expression profile for miR-181a in cervical cancer cell lines. Low expression of miR-181a was closely related to cervical cancer growth and oxaliplatin resistance. HSPA5/GRP78 was identified as a target of miR-181a in cervical cancer cells. Upregulation of GRP78 led to a high cell proliferation rate and oxaliplatin resistance in cervical cancer models. In a retrospective cervical cancer cohort, high GRP78 expression was correlated with poor survival. miR-181a suppressed cervical cancer development via downregulating GRP78. High expression of GRP78 is a tumor-promoting factor in cervical cancer and is thus a potential target for novel treatment.

Background In recent years, a large number of studies have shown that differentially expressed lncRNAs in tumors are capable of inducing tumorigenesis and promoting tumor development. However, the role of LINC01210 in OC still remains unclear. Methods Relative levels of LINC01210 and KLF4 in OC tissues containing in the GSE40595 dataset and those collected in our hospital were determined. Prognostic potential of LINC01210 in OC was evaluated by Kaplan-Meier method. Correlation between expression levels of LINC01210 and KLF4 was assessed by Spearman correlation test. After silence of LINC01210 in A2780 and HO8910 cells, changes in proliferative, migratory and invasive abilities were examined. Moreover, the interaction between LINC01210 and KLF4 was explored by RIP and ChIP. Rescue experiments were conducted to uncover the involvement of KLF4 in LINC01210-regulated OC progression. Results LINC01210 was upregulated in OC tissues and KLF4 was downregulated. LINC01210 level was higher in OC patients with metastases or advanced stage. Besides, its level was negatively correlated to DFS (disease-free survival) and OS (overall survival) of OC patients. Silence of LINC01210 attenuated proliferative, migratory and invasive abilities in A2780 and HO8910 cells. Through analyzing the GSE40595 dataset, LINC01210 was found to be negatively linked to KLF4. RIP assay further verified the interaction between LINC01210 and KLF4. Knockdown of LINC01210 markedly decreased the recruitment ability of EZH2 to KLF4. Importantly, silence of KLF4 could reverse regulatory effects of LINC01210 on cellular behaviors of OC. Conclusions LINC01210 is upregulated in OC and predicts a poor prognosis. It accelerates proliferation, invasion and migration in OC cells through epigenetically downregulating KLF4.

The aim of the present study was to evaluate the residual lesions after conization and the clinical outcome of patients with multifocal micro-invasive squamous cell cervical carcinomas (MMSCCs) treated with different surgical strategies. A retrospective study was carried out in 98 patients with MMSCCs diagnosed by conization and treated between January 2010 and December 2016 in 2 institutions. The patients underwent further different surgeries as therapeutic conization, extrafascial hysterectomy (ES), modified radical hysterectomy (MRH), radical hysterectomy (RH) with or without pelvic lymph node dissection (PLND) and regular follow-up. The clinicopathological characteristics of all of the patients were recorded. The risk factors of residual lesions and that of the recurrence were also analyzed in the present study. The logistic regression analysis revealed that cone margins (P=0.001) were correlated with residual disease after conization whereas parameters including age, gravidity, parity, menopause, stage, LVSI and the number of lesions were not predictors of residual lesions. The cone margin status also indicated the incidence of residual disease as follows: The risk of residual disease was lower with a negative margin when compared with the margin with micro-invasive carcinoma [MIC; odds ratio (OR)=0.064, P=0.012] and was lower in margin with a high-grade intraepithelial lesion than the margin with MIC (OR=0.297, P=0.287). The Cox regression analysis revealed that there were no significant correlations between the following surgery scales and postoperative recurrences, nor were any significant correlations found between the recurrences and the gravidity and parity, postmenopausal state, stage, residual disease after conization, margin status, LVSI and number of lesions (P>0.05). Positive cone margin was the only predictive factor for residual disease in patients with MMSCCs. There were no significant correlations between the surgical scales and postoperative recurrences. This result may be due to the excellent prognosis of MICs despite multiple lesions, regardless the treatment.

Numerous studies have suggested that urothelial cancer-associated 1 (UCA1) acts as a suppressor gene affecting cell proliferation and migration. However, the biological role and the potential mechanism of UCA1 in the progression of pre-eclampsia (PE) remains unclear. The UCA1 level was markedly upregulated in PE pregnancies relative to non-PE ones in GSE75010 and tissues. A higher body mass index (BMI), maximum systolic blood pressure (BP), and maximum diastolic BP were observed in PE pregnancies, whereas the newborn weight z-score was lower compared with those of non-PE pregnancies. Knockdown of UCA1 accelerated the proliferative migratory abilities and cell cycle progression, but inhibited apoptosis of HTR-8/SVneo and JAR cells. Then, we found that Janus kinases 2 (JAK2) was negatively correlated with UCA1. In addition, JAK2 was downregulated in the placenta of PE pregnancies and was negatively regulated by UCA1. UCA1 was mainly enriched in the nucleus. Knockdown of UCA1 reduced the occupancies of the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and H3K27me3 on the Janus kinase 2 (JAK2) promoter regions. Finally, rescue experiments found that transfection of short-hairpin JAK2 attenuated proliferative and migratory abilities of trophoblasts, which were partially reversed after UCA1 knockdown. In short, UCA1 is upregulated in the trophocytes of PE pregnancies and accelerates trophoblast cell invasion and proliferation by downregulating JAK2.

Cervical cancer is one of the most common gynecological malignancies, and it has become a crucial public health problem. In the present study, the expression profiles of cervical cancer and normal cervical tissues were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. Subsequently, the dysregulated long non-coding RNAs (lncRNAs) in cervical cancer were identified using R software Differentially expressed lncRNAs in cervical cancer that were associated with glucose-regulated protein 78 (GRP78) were screened out and the results demonstrated that eight lncRNAs were strongly positively correlated with GRP78. In order to confirm the relationship between GRP78 and candidate lncRNAs, GRP78 small interfering RNA (siRNA) was transfected into HeLa cells. The target lncRNAs that were regulated by GRP78 were then identified by reverse transcription-quantitative PCR and it was revealed that LINC00294 was significantly downregulated following GRP78-knockdown. Subsequently, Gene Set Enrichment Analysis demonstrated that LINC00294 was mainly enriched in regulating the cell cycle and the Hedgehog pathway. Following transfection of HeLa and SiHa cells with LINC00294 siRNA, the cell cycle was arrested at the G0/G1 phase. Western blotting suggested that LINC00294-knockdown downregulated the expression of cell cycle-associated factors (cyclin D, cyclin E and cyclin Dependent kinase 4) and upregulated cell cycle inhibitory factors (p16 and p21). The Hedgehog pathway was inhibited following knockdown of LINC00294 in HeLa and SiHa cells. In summary, LINC00294 induced by GRP78 promoted the progression of cervical cancer by regulating the cell cycle via Hedgehog pathway.