Reproducibility and location-stability of radiomic features derived from cone-beam computed tomography: a phantom study.

OBJECTIVES: This study aims to determine the reproducibility and location-stability of cone-beam computed tomography (CBCT) radiomic features. METHODS: Centrifugal tubes with six concentrations of K2HPO4 solutions (50, 100, 200, 400, 600, and 800 mg ml-1) were imaged within a customized phantom. For each concentration, images were captured twice as test and retest sets. Totally, 69 radiomic features were extracted by LIFEx. The reproducibility was assessed between the test and retest sets. We used the concordance correlation coefficient (CCC) to screen qualified features and then compared the differences in the numbers of them under 24 series (four locations groups * six concentrations). The location-stability was assessed using the Kruskal-Wallis test under different concentration sets; likewise, the numbers of qualified features under six test sets were analyzed. RESULTS: There were 20 and 23 qualified features in the reproducibility and location-stability experiments, respectively. In the reproducibility experiment, the performance of the peripheral groups and high-concentration sets was significantly better than the center groups and low-concentration sets. The effect of concentration on the location-stability of features was not monotonic, and the number of qualified features in the low-concentration sets was greater than that in the high-concentration sets. No features were qualified in both experiments. CONCLUSIONS: The density and location of the target object can affect the number of reproducible radiomic features, and its density can also affect the number of location-stable radiomic features. The problem of feature reliability should be treated cautiously in radiomic research on CBCT.

Functioning gonadotroph adenoma with hyperestrogenemia and ovarian hyperstimulation in a reproductive-aged woman: A case report and review of literature.

BACKGROUND: Functioning gonadotroph adenomas are extremely rare pituitary tumors that secrete gonadotropins and exhibit distinct clinical manifestations. Here, we report a case of functioning gonadotroph adenoma in a reproductive-aged woman and discuss its diagnosis and management. CASE SUMMARY: A 21-year-old female patient with abdominal pain, irregular menstruation, hyperestrogenemia, and an ovarian mass was included. Brain magnetic resonance imaging (MRI) revealed a pituitary macroadenoma, and transsphenoidal surgery relieved her clinical symptoms. Before transsphenoidal surgery, plasma CA125, estradiol levels were elevated, while prolactin, luteinizing hormone, follicle-stimulating hormone, PROG, cortisol, FT4, thyroid-stimulating hormone, parathyroid hormone, and GH levels were maintained at normal levels. After transsphenoidal surgery, the patient was diagnosed with a functioning gonadotroph adenoma. During follow-up, pelvic ultrasound confirmed normal-sized ovaries in the patient, the menstrual cycle returned to regular, and her hormones were maintained within a normal range. There was no evidence of tumor recurrence after two years of follow-up. CONCLUSION: Early diagnosis of functioning gonadotroph adenomas should be considered in patients with hyperestrogenism, irregular menstruation, large or recurrent ovarian cysts, and visual field defects. Pituitary MRI should be performed, and transsphenoidal surgery is recommended for the management of this disease.

Time Intervals between Double Primary Breast and Ovarian Cancers and Survival Outcomes of Patients with Both Cancers: A SEER Database Analysis.

Background: The time interval rules and survival outcomes of individuals with synchronous and metachronous breast cancer (BC) and ovarian cancer (OC) were examined in this retrospective population-based investigation. Methods: The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to create a cohort of people diagnosed with BC and OC between 1973 and 2015. Patients were separated into three groups: those with main BC followed by primary OC (group 1), those with synchronous primary breast and ovarian cancer (group 2), and those with OC prior to BC (group 3). The Kaplan-Meier technique was used to assess overall survival (OS) and cancer-specific survival (CSS). Results: A total of 4,975 patients were identified: 2,929 patients in group 1, 680 patients in group 2, and 1,366 patients in group 3. The average duration between these tumors was 60 months (range 0-499). Approximately 50% of second primary cancer cases occurred during the first 60 months of the first primary cancer diagnosis, and more than 70% occurred within the first 120 months. The median survival time for 4,975 individuals was 140 months. Group 2 had the smallest median OS (35 months), whereas group 3 had the longest (45 months) (239 months). Conclusions: The majority of second primary cancer cases occurred during the first 120 months following the diagnosis of the first original malignancy. Individuals who had primary OC prior to BC had better prognoses, whereas patients who had synchronous BC and OC had worse prognoses.

Clinicopathological characteristics and treatment of patients with high-grade endometrial stromal sarcoma: A retrospective study of 40 cases.

ABSTRACT: To investigate the clinicopathological characteristics of patients with high-grade endometrial stromal sarcoma (HG-ESS).The clinicopathological characteristics, treatments, and prognostic information of consecutive HG-ESS patients were collected from medical records and then evaluated.A total of 40 women were included in the analysis. The immunohistochemical profiles indicated that HG-ESS tumors tend to be locally or weakly positive for vimentin (100%) and CD10 (72.0%) but mostly negative for desmin (7.7%) and AE1/AE3 (9.1%). The progression-free survival intervals and the clinical benefit rates of patients receiving radiotherapy and/or chemotherapy were slightly longer and higher than those receiving simple observation (progression-free survival: 6 and 5 months vs 2 months; clinical benefit rate: 83.3% and 75.0% vs 28.6%). The 1-year disease-specific survival (DSS) rate was 62.7%. Tumor size, myometrial invasion, lymphovascular space invasion, cervical involvement, Federation International of Gynecology and Obstetrics (FIGO) stage, and residual disease all significantly affected the DSS rate (P < .001, =.002, <.001, =.004, <.001, and <.001, respectively). For patients with stage I disease, the 1-year DSS rate was as high as 91.7%, in contrast to 66.7%, 26.7%, and 0% for those with stage II, III, and IV disease, respectively.HG-ESS is associated with an adverse prognosis. FIGO stage could effectively predict the prognosis of patients with this lethal disease. Immunohistochemical markers, vimentin+/CD10+ (local or very weak), in combination with desmin-/AE1/AE3-, may be helpful for improving the diagnostic accuracy of this lethal condition. The therapeutic roles of adjuvant chemotherapy and radiotherapy warrant further investigation.

Survival outcomes and prognostic factors of papillary serous adenocarcinoma and papillary squamous cell carcinoma of the uterine cervix.

The aim of this retrospective population-based study was to investigate the survival outcomes and prognostic factors of patients with the two cervical carcinomas. A cohort of patients diagnosed with papillary serous adenocarcinoma of the uterine cervix (PSAC) and papillary squamous cell carcinoma (PSCC) between 1973 and 2015 were drawn from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method, and prognostic factors were assessed using Cox proportional hazards survival regression analysis. The 5-year and 10-year OS rates were 38.4 and 33.1% for PSAC and 64.6 and 50.8% for PSCC, respectively. The 2-year and 5-year CSS rates were 60.6 and 45.9% for PSAC and 79.6 and 69.0% for PSCC, respectively. Patients with PSCC survive longer than PSAC patients and have other well-described prognostic factors for improved survival rates, including an early cancer stage, a younger patient age and standardised surgery.Impact statementWhat is already known on this subject? Papillary serous adenocarcinoma of the uterine cervix (PSAC) and papillary squamous cell carcinoma (PSCC)are both very rare subtypes of cervical carcinomas.What do the results of this study add? This retrospective population-based analysis has evaluated the survival outcomes and prognostic indicators of patients with PSAC and PSCC.What the implications are of these findings for clinical practice and/or further research? Knowing the survival outcomes and prognostic indicators of PSAC and PSCC patients, we can better follow up patients.

Reproductive outcomes of cesarean scar pregnancies pretreated with methotrexate and uterine artery embolization prior to curettage.

OBJECTIVE: To evaluate the reproductive outcomes of cesarean scar pregnancy (CSP) pretreated with methotrexate (MTX) and uterine artery embolization (UAE) prior to curettage. MATERIALS AND METHODS: The medical records of patients with CSP who were pretreated with MTX and UAE prior to curettage in our institute from January 2013 to December 2015 were collected and retrospectively reviewed. RESULTS: A total of 53 patients were eligible for further analysis. Consecutive systemic MTX or a single dose of MTX was administered in 31 or 15 patients, respectively. The UAE procedure was uneventful, and no side effects occurred. The duration of the curettage operation was 21.4 ± 10.4 min, and the volume of blood loss was 23.5 ± 61.6 ml. The serum ß-HCG level returned to normal 36.1 ± 10.1 days after the date of initial MTX administration. Eight of 10 patients with a desire to have children became pregnant naturally. Two (25%) patients developed recurrent CSP during the first trimester. One patient underwent emergency cesarean delivery and hysterectomy due to placental implantation and sudden massive hemorrhage during delivery. A total of 6 live newborns were delivered. CONCLUSION: Pretreatment with MTX and UAE prior to curettage is safe and effective for the management of CSP. The reproductive outcomes are encouraging.

Survival Outcomes of Patients with Primary Breast Cancer Following Primary Ovarian Cancer.

BACKGROUND Patients with primary breast cancer following primary ovarian cancer do not comprise a large clinical entity, and reports of the survival outcomes of this cohort are rare. The purpose of this retrospective population-based research was to investigate the survival outcomes of patients with primary breast cancer after primary ovarian cancer. MATERIAL AND METHODS A cohort of patients diagnosed with primary breast cancer following primary ovarian cancer between 1973 and 2014 was drawn from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database. Cox proportional hazards survival regression analysis and Kaplan-Meier were applied to calculate overall survival (OS), cancer-specific survival (CSS), and independent predictors of CSS. RESULTS A total of 1455 patients with primary breast cancer following primary ovarian cancer were identified. The 5-year and 10-year OS rates for the entire cohort were 81.7% and 67.4%, respectively. The 5-year and 10-year CSS rates were 84.2% and 74.3% for ovarian cancer, and 76.0% and 67.8% for breast cancer, respectively. Multivariate analysis revealed that independent predictors of ovarian cancer CSS include age, cancer stage, diagnosis time, and histological subtype. CONCLUSIONS Patients diagnosed with breast cancer following ovarian cancer have better survival rates. Patients age, ovarian cancer stage, ovarian cancer histological type, and time of diagnose affect the survival rate.

LncRNA CCAT1 negatively regulates miR-181a-5p to promote endometrial carcinoma cell proliferation and migration.

Long non-coding RNAs (lncRNAs) are identified as vital modulators in a number of biological processes, including tumorigenesis. However, the role of lncRNAs in endometrial carcinoma (EC) remains unknown. In the current study, the expression patterns, biological roles and functional mechanism of the lncRNA colon cancer associated transcript 1 (CCAT1) was examined in EC. The expression level of CCAT1 was significantly upregulated in EC tissue samples compared with matched adjacent healthy tissue samples from patients with endometrial cancer. Similarly, CCAT1 was significantly upregulated in several EC cell lines (KLE, Ishiwaka and HEC-1-A), compared with the normal human endometrial stromal cell line T-HESC. Cell counting kit-8 and Transwell migration assays demonstrated that CCAT1 knockdown significantly decreased EC cell proliferation and migration. In addition, CCAT1 was confirmed as a target gene of miR-181a-5p in EC. Overexpression of miR-181a-5p significantly decreased CCAT1 expression in EC cells, whilst knockdown of CCAT1 significantly increased miR-181a-5p expression in EC cells. Furthermore, miR-181a-5p expression was significantly downregulated in EC tissue samples compared with matched adjacent healthy tissue samples from patients with endometrial cancer. Similarly, miR-181a-5p expression was significantly downregulated in several EC cell lines (KLE, Ishiwaka and HEC-1-A), compared with normal human endometrial stromal cell line T-HESC. In addition, rescue experiments demonstrated that inhibition of miR-181a-5p significantly reversed the effect of CCAT1 knockdown on EC cell proliferation and migration. The results suggest that CCAT1 promotes EC progression by acting as a molecular sponge of miR-181a-5p.

Prognostic significance of lymph node metastasis and lymphadenectomy in early-stage ovarian carcinosarcoma.

BACKGROUND: The role that lymph node dissection (LND) plays in the management of ovarian carcinosarcoma (OCS) is unclear due to its rarity. This study investigated lymph node metastasis (LNM) prevalence in women with early OCS and effects of LND and LNM on survival. METHODS: Data of women diagnosed with OCS, whose primary tumor was confined to ovaries (American Joint Committee on Cancer [AJCC] T1) or pelvic cavity (AJCC T2), between 1988 and 2010 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified into lymphadenectomy (LND [+]) and no lymphadenectomy (LND [-]) groups. RESULTS: A total of 363 women were included. The prevalence of LNM was 9.6% in AJCC T1 and 16.3% in AJCC T2. Multivariate analysis showed that LND and AJCC T categories were independent prognostic variables, irrespective of cancer-specific survival (CSS) or overall survival (OS). Subgroup analysis by AJCC T categories revealed that LND (+) group in AJCC T2 had a better survival outcome compared to LND (-) group (CSS, HR [95% CI] = 0.61 [0.43-0.87]; OS, HR [95% CI] = 0.59 [0.42-0.83]). There was no survival difference between groups in AJCC T1 (CSS, HR [95% CI] = 0.96 [0.56-1.65]; OS, HR [95% CI] = 0.88 [0.56-1.38]). Multivariate analysis was further carried out in LND (+) group and demonstrated that LNM and AJCC T2 had poor CSS and OS. Subgroup analysis by AJCC T categories showed that worse survival was observed in LNM (+) group compared to LNM (-) group in AJCC T2 (CSS, HR [95% CI] = 3.62 [1.50-8.73]; OS, HR [95% CI] = 3.71 [1.59-8.68]) but not in AJCC T1 (CSS, HR [95% CI] = 1.78 [0.50-6.37]; OS, HR [95% CI] = 1.97 [0.61-6.39]). CONCLUSION: Regional lymphadenectomy should be performed in patients with AJCC T2 OCS. LND and LNM were not significantly associated with prognosis in AJCC T1 while LNM had a trend toward worse survival.

Interaction between BMSCs and EPCs promotes IUA angiogenesis via modulating PI3K/Akt/Cox2 axis.

Intrauterine adhesion (IUA) is a common disease among women after uterus operation. BMSCs are commonly used as a therapeutic agent for IUA treatment, but the underlying mechanism is not fully delineated. Here we showed that BMSCs co-cultured with EPCs promotes proliferative ability and decreases apoptosis ratio of BMSCs and EPCs. In addition, BMSCs promote the differentiation of EPCs into vascular endothelial cells, and BMSCs derived epithelial cells are also induced by EPCs. We also found that the levels of Collagen Type I, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony stimulating factor (GM-CSF) and bone morphogenetic protein (BMP-2) are significantly increased in the co-culturing system comparing to those of the BMSCs or EPCs alone group. Of note, PI3K/Akt/Cox2 axis is activated in the co-culturing system and LY294002 abrogates the co-culturing system's effects on cell proliferation, apoptosis and cytokines secretion, which are reversed by synergistically overexpressing Cox2. In conclusion, our in vitro experiments proved that the interaction of BMSCs and EPCs might promote angiogenesis and alleviate IUA pathogenesis by regulating PI3K/Akt/Cox2 axis mediated modulation of cell apoptosis, proliferation, differentiation and angiogenesis-associated cytokines secretion.

Cross-validation of genes potentially associated with overall survival and drug resistance in ovarian cancer.

Ovarian cancer is the leading cause of death among malignancies of the female reproductive system. The 5-year survival rates of ovarian cancer (OC) patients are very poor as a result of recurrent disease and emergence of drug resistance; thus, studies to find predictive markers and factors for drug resistance are ongoing. In the present study, based on the microarrays from The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) profiles covering 1648 OC patients, 11 out of 136 genes that were found to be significantly dysregulated in OC were associated with overall survival (OS) in 489 OC patients of the TCGA cohort. Of these genes, CRISP3, LYVE1, OVGP1 and BCHE were identified as independent prognostic factors, with decreased expression of the first three genes predicting shorter OS, and decreased BCHE predicting longer OS. OVGP1, BCHE and further two genes, CKAP2 and CLDN10, were consistently and remarkably associated with OS when the number of patients increased from 489 to 1583, with increased CKAP2 and decreased CLDN10 predicted shorter OS; combining the four genes provided better predictions. Associations among the four genes with OS in subgroups of OC were further verified. Downregulation of OVGP1 was significantly associated with shorter OS in all subgroups of OC patients, including subgroups of 752 patients treated with chemotherapy regimens containing taxol, 763 with both platin and taxol, 1364 with platin, 371 patients with grade 1-2 disease, 968 with grade 3 disease, 1148 with stage III-IV disease, and 439 with TP53 mutations. In addition, CKAP2 expression was significantly associated with shorter OS in 515 OC patients who had low CA125 levels. Furthermore, comprehensive analyses that including RT-qPCR, bioinformatics analysis and clinical data revealed an association of CKAP2, BCHE, CLDN10 and OVGP1 with drug resistance in OC. The genes identified in the present study might be prognostic factors as well as potential therapeutic targets in the treatment of OC.

Elevated levels of Hs-CRP and IL-6 after delivery are associated with depression during the 6 months post partum.

The objective of this study is to determine whether inflammatory markers (high-sensitivity C-reactive protein (Hs-CRP) and interleukin (IL)-6) early in the postpartum period contribute to the development of postpartum depression (PPD). From 4 May 2014 to 30 June 2014, all eligible women not on medication for depression giving birth at the Beijing Chao-Yang hospital were consecutively recruited and followed up for 6 months. Depression symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS), and inflammatory biomarkers (Hs-CRP and IL-6) were tested. During the study period, 296 women were enrolled and completed follow-up. In these women, 45 (15.2%) were considered as meeting the criteria for PPD. Serum levels of Hs-CRP and IL-6 in women with PPD were significantly higher than those without PPD (all P<0.0001). Receiver operating characteristics to predict PPD demonstrated areas under the curve of IL-6 of 0.861 (95% confidence interval (CI), 0.801-0.922), which was superior to Hs-CRP (0.837 (95% CI, 0.781-0.894), P<0.01). In multivariate logistic regression analysis, IL-6 and Hs-CRP were independent predictors of PPD. The present study demonstrates a strong relationship between elevated serum Hs-CRP and IL-6 levels at admission and the development of PPD within 6 months.

Bat Severe Acute Respiratory Syndrome-Like Coronavirus WIV1 Encodes an Extra Accessory Protein, ORFX, Involved in Modulation of the Host Immune Response.

UNLABELLED: Bats harbor severe acute respiratory syndrome (SARS)-like coronaviruses (SL-CoVs) from which the causative agent of the 2002-2003 SARS pandemic is thought to have originated. However, despite the fact that a large number of genetically diverse SL-CoV sequences have been detected in bats, only two strains (named WIV1 and WIV16) have been successfully cultured in vitro These two strains differ from SARS-CoV only in containing an extra open reading frame (ORF) (named ORFX), between ORF6 and ORF7, which has no homology to any known protein sequences. In this study, we constructed a full-length cDNA clone of SL-CoV WIV1 (rWIV1), an ORFX deletion mutant (rWIV1-ΔX), and a green fluorescent protein (GFP)-expressing mutant (rWIV1-GFP-ΔX). Northern blotting and fluorescence microscopy indicate that ORFX was expressed during WIV1 infection. A virus infection assay showed that rWIV1-ΔX replicated as efficiently as rWIV1 in Vero E6, Calu-3, and HeLa-hACE2 cells. Further study showed that ORFX could inhibit interferon production and activate NF-κB. Our results demonstrate for the first time that the unique ORFX in the WIV1 strain is a functional gene involving modulation of the host immune response but is not essential for in vitro viral replication. IMPORTANCE: Bats harbor genetically diverse SARS-like coronaviruses (SL-CoVs), and some of them have the potential for interspecies transmission. A unique open reading frame (ORFX) was identified in the genomes of two recently isolated bat SL-CoV strains (WIV1 and -16). It will therefore be critical to clarify whether and how this protein contributes to virulence during viral infection. Here we revealed that the unique ORFX is a functional gene that is involved in the modulation of the host immune response but is not essential for in vitro viral replication. Our results provide important information for further exploration of the ORFX function in the future. Moreover, the reverse genetics system we constructed will be helpful for study of the pathogenesis of this group of viruses and to develop therapeutics for future control of emerging SARS-like infections.

[Studies of Dynamic Adsorption Behavior of VOCs on Biochar Modified by Ultraviolet Irradiation].

Coconut shell based biochar was modified by ultraviolet irradiation with UV light at a wavelength of 365 nm in order to enhance the adsorption capacity for volatile organic compounds (VOCs). The breakthrough curves of biochars for adsorbing two typical VOCs (benzene and toluene) were examined. The results showed that the adsorption capacity of modified biochar was greatly increased. The saturation adsorption capacity of modified biochar for benzene and toluene was increased to 122.80 mg·g-1 and 236.36 mg·g-1, comparing to that of the pristine biochar (7.27 mg·g-1 and 7.98 mg·g-1, respectively). The breakthrough time of modified biochar for benzene and toluene (390 min and 620 min) was also drastically prolonged as compared to the raw biochar (1 min and 2 min). The characterization analysis of biochars suggested that the carboxylic groups and external surface area were largely enriched, which might be the main factor responsible for the enhanced adsorption of the two VOCs on the modified biochar. The processes of adsorbing benzene and toluene at different concentrations on modified biochar were fitted by Yoon-Nelson, Thomas and BDST models. The result demonstrated that these three models could provide good fitting and the correlation coefficients were all above 0.992. The TG-DTG result proved that ultraviolet irradiation had little effect on the thermal stability of biochar. The modified biochar after adsorption saturation could be reused after thermal regeneration and the regenerated char also had high adsorption capacity after five times of repeated utilization.

Discovery of microarray-identified genes associated with ovarian cancer progression.

Ovarian cancer is the most lethal cancer of female reproductive system. There is a consistent and urgent need to better understand its mechanism. In this study, we retrieved 186 genes that were dysregulated by at least 4-fold in 594 ovarian serous cystadenocarcinomas in comparison with eight normal ovaries, according to The Cancer Genome Atlas Ovarian Statistics data deposited in Oncomine database. DAVID analysis of these genes enriched two biological processes indicating that the cell cycle and microtubules might play critical roles in ovarian cancer progression. Among these 186 genes, 46 were dysregulated by at least 10-fold and their expression was further confirmed by the Bonome Ovarian Statistics data deposited in Oncomine, which covered 185 cases of ovarian carcinomas and 10 cases of normal ovarian surface epithelium. Six genes, including aldehyde dehydrogenase 1 family, member A2 (ALDH1A2), alcohol dehydrogenase 1B (class I), ß polypeptide (ADH1B), NEL-like 2 (chicken) (NELL2), hemoglobin, ß (HBB), ATP-binding cassette, sub-family A (ABC1), member 8 (ABCA8) and hemoglobin, α1 (HBA1) were identified to be downregulated by at least 10-fold in 779 ovarian cancers compared with 18 normal controls. Using mRNA expression profiles retrieved from microarrays deposited in the Gene Expression Omnibus Profiles database, RT-qPCR measurement and bioinformatics analysis, we further indicated that high expression of HBB might predict a poorer 5-year survival, high expression of ALDH1A2 and ABCA8 might predict a poor outcome; while ALDH1A2, ADH1B, HBB and ABCA8, in particular the former two genes, might be associated with drug resistance, and ALDH1A2 and NELL2 might contribute to invasiveness and metastasis in ovarian cancer. This study thus contributes to our understanding of the mechanism of ovarian cancer progression and development, and the six identified genes may be potential therapeutic targets and biomarkers for diagnosis and prognosis.

Oncogenes associated with drug resistance in ovarian cancer.

PURPOSE: Oncogenes play pivotal roles in the development of cancer, and disturbances in their expression have been implicated in drug resistance. However, an overview of the contribution of oncogenes to drug resistance in ovarian cancer has not previously been reported. This study aimed to review the drug resistance-related oncogenes in ovarian cancer and precisely determine their relationships. METHODS: The oncogenes associated with drug resistance in ovarian cancer from available papers were summarized, and a comprehensive bioinformatics analysis including pathway enrichment, biological processes annotation, protein/gene interaction and microRNA-mRNA interaction was performed. RESULTS: Total of 25 oncogenes contributing to drug resistance in ovarian cancer was integrated and further analyzed. An oncogene-mediated drug resistance pathway that explains the associations of 21 of these oncogenes in drug resistance was drafted on the basis of previously published papers. The downstream location of v-akt murine thymoma viral oncogene (AKT) and B-cell CLL/lymphoma 2-associated X protein (BAX) with respect to many other oncogenes was determined, indicating that the two genes may play a central role, and the AKT- and BAX-mediated signaling are the main pathways accounting for the involvement of oncogenes in drug resistance in ovarian cancer. Besides, the annotation of biological process indicated that the apoptosis (cell death) and phosphorylation (phosphate metabolic process) might be the two major biological routes through which oncogenes contribute to drug resistance in ovarian cancer. In addition, on the basis of the comprehensive analysis of microRNA-mRNA interactions, 11 microRNAs were identified to be targeted at least 7 of the 25 oncogenes, indicating that those microRNAs could be an important regulator of the 25 oncogenes. Collectively, by integrating and further analyzing the available data on these oncogenes, this study contributes to improving our understanding of the mechanisms by which their expression leads to drug resistance in this ovarian cancer.

Downregulation of NEK11 is associated with drug resistance in ovarian cancer.

NEKs [NIMA (never in mitosis gene A)-related expressed kinase] are involved in ovarian cancer development and progression, while their association with drug resistance is limited, especially NEK11, and its relationship with drug resistance has never been reported. In this study, on the basis of comprehensive bioinformatic analyses, including mRNA expression according to microarray data, protein/gene interaction, protein-small molecule interaction, annotation of biological process and microRNA-mRNA interaction analysis, we revealed that the NEK11 mRNA was significantly downregulated in 586 cases of ovarian serous cystadenocarcinomas and cisplatin-resistant A2780 ovarian cancer cells, and interacted with 22 proteins and 4 small molecules which all were contributed to drug resistance in ovarian cancer. Furthermore, seven cell cycle-related biological processes were annotated with NEK11, drug resistance and ovarian cancer, suggesting that NEK11 potentially was involved in the drug resistance in ovarian cancer via its regulatory roles in the cell cycle. In addition, among the eight microRNAs predicted to be most strongly targeting NEK11, the majority were involved in drug resistance in ovarian and other cancers. All those results provide a very strong possibility that the notable downregulation of NEK11 in cisplatin-resistant ovarian cancer cells was involved in drug resistance, via its interactions with drug resistance-related genes, proteins, small molecules, microRNAs and biological processes, particularly the cell cycle-related processes. To our knowledge, this is the first report of the association of NEK11 with drug resistance in cancer, and it would pave the way for further investigation of the drug resistance-related functions of this gene.

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer.

The expression of HNF1 homeobox B (HNF1B) is associated with cancer risk in several tumors, including ovarian cancer, and its decreased expression play roles in cancer development. However, the study of HNF1B and cancer is limited, and its association with drug resistance in cancer has never been reported. On the basis of array data retrieved from Oncomine and Gene Expression Omnibus (GEO) online database, we found that the mRNA expression of HNF1B in 586 ovarian serous cystadenocarcinomas and in platinum-resistant A2780 epithelial ovarian cancer cells was significantly decreased, indicating a potential role of HNF1B in drug resistance in ovarian cancer. Based on this finding, comprehensive bioinformatics analyses, including protein/gene interaction, protein-small molecule/chemical interaction, biological process annotation, gene co-occurrence and pathway enrichment analysis and microRNA-mRNA interaction, were performed to illustrate the association of HNF1B with drug resistance in ovarian cancer. We found that among the proteins/genes, small molecules/chemicals and microRNAs which directly interacted with HNF1B, the majority was associated with drug resistance in cancer, particularly in ovarian cancer. Biological process annotation revealed that HNF1B closely related to 24 biological processes which were all notably associated with ovarian cancer and drug resistance. These results indicated that the downregulation of HNF1B may contribute to drug resistance in ovarian cancer, via its direct interactions with these drug resistance-related proteins/genes, small molecules/chemicals and microRNAs, and via its regulations on the drug resistance-related biological processes. Pathway enrichment analysis of 36 genes which co-occurred with HNF1B, ovarian cancer and drug resistance indicated that the HNF1B may perform its drug resistance-related functions through 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling. Collectively, in this study, we illustrated for the first time that HNF1B may contribute to drug resistance in ovarian cancer, potentially through the 4 pathways. The present study may pave the way for further investigation of the drug resistance-related functions of HNF1B in ovarian cancer.

Upregulation of NEK2 is associated with drug resistance in ovarian cancer.

NEK2 [NIMA (never in mitosis gene A)-related expressed kinase 2] is associated with various biological behaviors in the development of cancer, while research concerning its association with drug resistance is limited. The association of NEK2 with drug resistance in ovarian cancer has not yet been reported. In the present study, on the basis of microarray results from Oncomine and the GEO Profiles online database, we revealed that NEK2 mRNA expression in ovarian cancer tissues is upregulated. In addition, its expression in drug-resistant ovarian cancer cells was upregulated when compared with expression with their sensitive or parental counterparts. Finally, we performed a comprehensive bioinformatic analysis consisting of protein/gene-protein/gene interaction network, annotation of biological processes and microRNA-mRNA interaction analysis. We observed that NEK2 directly or indirectly interacts with a number of genes, proteins, microRNAs and biological processes associated with drug resistance in ovarian and other types of cancer. These results indicate that NEK2 contributes to drug resistance in ovarian cancer and it may be an important therapeutic target.