Feasibility of Sentinel Lymph Node Mapping With Carbon Nanoparticles in Cervical Cancer: A Retrospective Study.

INTRODUCTION: This retrospective study aims to investigate the feasibility of using carbon nanoparticles to detect sentinel lymph nodes (SLNs) in cervical cancer. METHODS: This study involved 174 patients with cervical cancer. Cervix tissues adjacent to the cancer were injected with 1 mL of carbon nanoparticles (CNPs) at the 3 and 9 o'clock positions according to the instructions. The pelvic lymph nodes were then dissected, and the black-stained sentinel lymph nodes were sectioned for pathological examination. RESULTS: Of 174 cases, 88.5% of patients (154/174) had at least 1 sentinel lymph node, and 131 patients (75.29%) had bilateral pelvic sentinel lymph nodes. The left pelvic lymph node was the most common sentinel lymph node (34.16%). At least 1 sentinel lymph node was observed in 285 out of 348 hemipelvises, with a detection rate of a side-specific sentinel lymph node of 81.89%. In total, 47 hemipelvises had metastasis of the lymph node, and 33 involved the sentinel lymph node, with a sensitivity of 70.21% and a false-negative rate of 29.79%. There were 238 hemipelvises with no metastasis of the lymph node, as well as negative sentinel lymph nodes, with a specificity of 100% and a negative predictive value of 94.44%. The univariate analysis demonstrated that risk factors included tumor size (OR .598, 95% CI: .369-.970) and deep stromal invasion (OR .381, 95% CI: .187-.779). The deep stromal invasion was the only variable for the false-negative detection of a sentinel lymph node. CONCLUSION: Sentinel lymph node mapping with carbon nanoparticles might be applied to predict the metastasis of pelvic lymph nodes in cervical cancer. However, tumor size and deep stromal invasion might negative influence the detection rate of SLN.

A comprehensive prognostic and immune analysis of enhancer RNA identifies IGFBP7-AS1 as a novel prognostic biomarker in Uterine Corpus Endometrial Carcinoma.

BACKGROUND: Long non-coding RNAs (lncRNA) have been implicated in a hand of studies that supported an involvement and co-operation in Uterine Corpus Endometrial Carcinoma (UCEC). Enhancer RNAs (eRNA), a functional subtype of lncRNA, have a key role throughout the genome to guide protein production, thus potentially associated with diseases. METHODS: In this study, we mainly applied the Cancer Genome Atlas (TCGA) dataset to systematically discover crucial eRNAs involving UCEC. For the key eRNAs in UCEC, we employed RT-qPCR to compare eRNA expression levels in tumor tissues and paired normal adjacent tissues from UCEC patients for validation. Furthermore, the relationships between the key eRNAs and immune activities were measured from several aspects, including the analysis for tumor microenvironment, immune infiltration cells, immune check point genes, tumor mutation burden, and microsatellite instability, as well as m6A related genes. Finally, the key eRNAs were verified by a comprehensive pan-cancer analysis. RESULTS: IGFBP7 Antisense RNA 1 (IGFBP7-AS1) was identified as the key eRNA for its expression patterns of low levels in tumor tissues and favorable prognostic value in UCEC correlated with its target gene IGFBP7. In RT-qPCR analysis, IGFBP7-AS1 and IGFBP7 had down-regulated expression in tumor tissues, which was consistent with previous analysis. Moreover, IGFBP7-AS1 was found closely related with immune response in relevant immune analyses. Besides, IGFBP7-AS1 and its target gene IGFBP7 correlated with a multi-omics pan-cancer analysis. CONCLUSIONS: Finally, we suggested that IGFBP7-AS1 played a key role in impacting on clinical outcomes of UCEC patients for its possible influence on immune activity.

Upregulation of bromodomain PHD finger transcription factor in ovarian cancer and its critical role for cancer cell proliferation and survival.

Bromodomain PHD finger transcription factor (BPTF) is a core subunit of the nucleosome-remodeling factor (NURF) complex, which plays an important role in the development of several cancers. However, it is unknown whether BPTF regulates the progression of ovarian cancer (OC). To investigate this, we measured the relative expression levels of BPTF in OC cell lines and tissues using Western blot and immunohistochemistry, respectively, and the results were analyzed using the χ2 test. We also examined the effects from BPTF knockdown on the proliferation, migration, invasiveness, and apoptosis of OC cell lines. Mechanistic studies revealed that these effects were achieved through simultaneous modulation of multiple signaling pathways. We found that BPTF was highly expressed in OC cell lines and tissues compared with a normal human ovarian epithelial cell line and non-cancerous tissues (P < 0.05). These results are also supported by the public RNA-seq data. BPTF overexpression was correlated with a poor prognosis for OC patient survival (P < 0.05). In vitro experiments revealed that the downregulation of BPTF inhibited OC cell proliferation, colony formation, migration, and invasiveness, and induced apoptosis. BPTF knockdown also affected the epithelial-mesenchymal transition (EMT) signaling pathways and induced the cleavage of apoptosis-related proteins. Consequently, BPTF plays a critical role in OC cell survival, and functions as a potential therapeutic target for OC.

Identification of a metabolism-related gene expression prognostic model in endometrial carcinoma patients.

BACKGROUND: Metabolic abnormalities have recently been widely studied in various cancer types. This study aims to explore the expression profiles of metabolism-related genes (MRGs) in endometrial cancer (EC). METHODS: We analyzed the expression of MRGs using The Cancer Genome Atlas (TCGA) data to screen differentially expressed MRGs (DE-MRGs) significantly correlated with EC patient prognosis. Functional pathway enrichment analysis of the DE-MRGs was performed. LASSO and Cox regression analyses were performed to select MRGs closely related to EC patient outcomes. A prognostic signature was developed, and the efficacy was validated in part of and the entire TCGA EC cohort. Moreover, we developed a comprehensive nomogram including the risk model and clinical features to predict EC patients' survival probability. RESULTS: Forty-seven DE-MRGs were significantly correlated with EC patient prognosis. Functional enrichment analysis showed that these MRGs were highly enriched in amino acid, glycolysis, and glycerophospholipid metabolism. Nine MRGs were found to be closely related to EC patient outcomes: CYP4F3, CEL, GPAT3, LYPLA2, HNMT, PHGDH, CKM, UCK2 and ACACB. Based on these nine DE-MRGs, we developed a prognostic signature, and its efficacy in part of and the entire TCGA EC cohort was validated. The nine-MRG signature was independent of other clinical features, and could effectively distinguish high- and low-risk EC patients and predict patient OS. The nomogram showed excellent consistency between the predictions and actual survival observations. CONCLUSIONS: The MRG prognostic model and the comprehensive nomogram could guide precise outcome prediction and rational therapy selection in clinical practice.

MiR-4458 inhibits breast cancer cell growth, migration, and invasiveness by targeting CPSF4.

Numerous studies have reported that CPSF4 is over-expressed in a large percentage of human lung cancers, and CPSF4 has been identified as a potential oncogene of human lung tumor. Downregulation of CPSF4 inhibits the proliferation and promotes the apoptosis of lung adenocarcinoma cells. A previous study by our group also found overexpression of CPSF4 in breast cancer (BC), and was closely associated with a poor prognosis for the patient. This study investigates microRNAs (miRNAs) that target CPSF4 to modulate BC cell proliferation. We found that miR-4458 was noticeably reduced in BC tissues and cells. Using a miR-4458 mimic, we found that cell proliferation, migration, and invasiveness were suppressed by miR-4458 overexpression, and were enhanced by reducing the expression of miR-4458. Moreover, the results from bioinformatics analyses suggest a putative target site in the CPSF4 3'-UTR. Furthermore, using luciferase reporter assays and Western blotting, we verified that miR-4458 directly targets the 3'-UTR of CPSF4 and downregulates COX-2 and h-TERT, which are downstream target genes of CPSF4. Additionally, PI3K/AKT and ERK were shown to be inhibited by miR-4458 overexpression in BC cells. Moreover, miR-4458 suppresses BC cell growth in vivo. Consequently, these results suggest that the miR-4458-CPSF4-COX-2-hTERT axis might serve as a potential target for the treatment of BC patients.

Potential Significance of Peptidome in Human Ovarian Cancer for Patients With Ascites.

OBJECTIVE: Ovarian cancer (OC) is one of the lethal gynecological malignancies. Most women affected by OC with malignant ascites will relapse. Peptidomics, as an emerging branch of proteomics, is more applied in screening of disease biomarkers, diagnosis, treatment, and monitoring. However, there is still little in-depth analysis about peptidomics study in OC with malignant ascites. METHODS: A comparative peptidomic profiling of ascites fluid between 6 OC patients and 6 benign gynecological conditions using liquid chromatography-tandem mass spectrometry was analyzed. Afterward, the Ingenuity Pathway Analysis was performed to reveal the potential function of peptide-protein precursors. RESULTS: A total of 4388 nonredundant peptides were identified, 104 of which were significantly differentially expressed in the ascites fluid of OC and benign gynecological conditions (>2-fold changes and P < 0.05): 52 peptides were upregulated while 52 peptides were downregulated. These peptides were imported into the Ingenuity Pathway Analysis and identified putative roles in OC. CONCLUSIONS: We identified the peptidome patterns of patients with OC and benign gynecological conditions, and these differentially expressed that peptides might play an important role during occurrence and development of OC and will be in hope to explore bioactive peptides in the pathogenesis of OC.

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

miR­181b­5p inhibits trophoblast cell migration and invasion through targeting S1PR1 in multiple abnormal trophoblast invasion­related events.

Normal placentation and successful maintenance of pregnancy depend on the successful migration and invasion of trophoblasts into maternal tissues. Previous studies reported that microRNAs (miRs) are expressed in trophoblasts, and can regulate their migration and invasion. The present study aimed to investigate miR­181b­5p function in HTR­8/SVneo trophoblasts and explore its underlying mechanism in the pathogenesis of multiple abnormal trophoblast invasion­related events. Reverse­transcription quantitative PCR and western blotting were used to test the expression of miR­181b­5p and sphingosine­1­phosphate receptor 1 (S1PR1) in samples of multiple abnormal trophoblast invasion­related events. Transwell invasion and wound healing assays were performed to determine cell invasion and migration abilities. A luciferase reporter assay was conducted to identify the downstream target of miR­181b­5p. Overexpression of miR­181b­5p suppressed HTR­8/SVneo cell migration and invasion, whereas inhibition of miR­181b­5p induced an opposite effect. The S1PR1 gene was further identified as a novel direct target of miR­181b­5p. Specifically, miR­181b­5p bound directly to the 3'­untranslated region of S1PR1 and suppressed its expression. Moreover, overexpression of S1PR1 reversed the inhibitory effect of miR­181b­5p. Taken together, ectopic expression of miR­181b­5p impaired the migration and invasion of trophoblasts by directly targeting S1PR1, thereby providing new insights into the pathogenesis of multiple abnormal trophoblast invasion­related events.

Elevated MicroRNA-181a-5p Contributes to Trophoblast Dysfunction and Preeclampsia.

OBJECTIVE: It has been demonstrated that preeclampsia is associated with alterations in placental microRNA expression. Previous reports have shown that hsa-miR-181a-5p is overexpressed in human preeclamptic placenta compared with normotensive placenta. The purpose of this study was to explore whether upregulated hsa-miR-181a-5p expression is involved in the ontogenesis of preeclampsia. METHODS: Twenty preeclamptic placentas and 20 normotensive placentas were obtained from nulliparous women by cesarean section. Expression of hsa-miR-181a-5p in placenta tissues and human trophoblast cell lines was analyzed by reverse transcription polymerase chain reaction. The trophoblast cell lines (HTR-8/SVneo and JAR) were transfected with specific oligonucleotides to upregulate miR-181a-5p expression. The effect of miR-181a-5p expression on proliferation, cell cycle, apoptosis, and invasion in HTR-8/SVneo and JAR cells was then investigated. RESULT: It was demonstrated that hsa-miR-181a-5p expression was upregulated in preeclamptic placentas and that it may trigger antiproliferation and inhibition of cell cycle progression, induce apoptosis, and suppress invasion in HTR-8/SVneo and JAR cells. CONCLUSION: Anomalously upregulated hsa-miR-181a-5p expression could contribute to trophoblast dysfunction and may be a crucial factor in the pathogenesis of preeclampsia.