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BACKGROUND: Postoperative urinary retention (POUR), a common condition after prolapse surgery with potential serious sequelae if left untreated, lacks a clearly established optimal timing for catheter removal. This study aimed to develop and validate a predictive model for postoperative urinary retention lasting > 2 and > 4 days after prolapse surgery. METHODS: We conducted a retrospective review of 1,122 patients undergoing prolapse surgery. The dataset was divided into training and testing cohorts. POUR was defined as the need for continuous intermittent catheterization resulting from a failed spontaneous voiding trial, with passing defined as two consecutive voids ≥ 150 mL and a postvoid residual urine volume ≤ 150 mL. We performed logistic regression and the predicted model was validated using both training and testing cohorts. RESULTS: Among patients, 31% and 12% experienced POUR lasting > 2 and > 4 days, respectively. Multivariable logistic model identified 6 predictors. For predicting POUR, internal validation using cross-validation approach showed good performance, with accuracy lasting > 2 (area under the curve [AUC] 0.73) and > 4 days (AUC 0.75). Split validation using pre-separated dataset also showed good performance, with accuracy lasting > 2 (AUC 0.73) and > 4 days (AUC 0.74). Calibration curves demonstrated that the model accurately predicted POUR lasting > 2 and > 4 days (from 0 to 80%). CONCLUSIONS: The proposed prediction model can assist clinicians in personalizing postoperative bladder care for patients undergoing prolapse surgery by providing accurate individual risk estimates.
Subject(s)
Postoperative Complications , Urinary Retention , Humans , Urinary Retention/etiology , Urinary Retention/epidemiology , Female , Retrospective Studies , Aged , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Middle Aged , Logistic Models , Pelvic Organ Prolapse/surgery , Cohort Studies , Urinary Catheterization/adverse effects , Urinary Catheterization/statistics & numerical data , Risk FactorsABSTRACT
INTRODUCTION AND HYPOTHESIS: The objective was to assess intraoperative and postoperative complication rates, along with perioperative and surgical outcomes, following single-port robotics-assisted sacrocolpopexy. METHODS: This retrospective case series included 200 patients who underwent single-port robotics-assisted sacrocolpopexy to treat Pelvic Organ Prolapse Quantification (POPQ) stage 2-4 symptomatic prolapse between April 2020 and August 2023 by a single surgeon. Intraoperative and postoperative complications and perioperative outcomes were evaluated for all the patients, whereas surgical outcomes for 74 patients were assessed at 1-year follow-up. Surgical failure was defined as the presence of any of the following: the presence of vaginal bulging symptoms, any prolapse beyond the hymen, or retreatment for prolapse. RESULTS: During the study period, 200 single-port robotics-assisted sacrocolpopexies were performed. The median age and body mass index were 65.0 years and 24.6 kg/m2 respectively. Most patients had POPQ stage 3 or 4 prolapse and underwent concomitant total hysterectomy. The median total operation time was 212.0 min, and none of the patients required conversion to laparoscopy or laparotomy. The intraoperative cystotomy rate was 2.5%, and one patient had a blood transfusion owing to presacral vessel injury. Postoperative complications of mesh exposure and wound hernia were 0.5% and 2.0% respectively. At 1 year postoperatively, the rate of composite surgical failure was 9.5%, with a 5.4% anatomical recurrence rate. None of the patients experienced apical prolapse recurrence, and one received anterior colporrhaphy for anterior compartment prolapse recurrence. CONCLUSIONS: Single-port robotics-assisted sacrocolpopexy is safe and effective, with low complication rates and favorable perioperative and surgical outcomes.
Subject(s)
Gynecologic Surgical Procedures , Intraoperative Complications , Pelvic Organ Prolapse , Postoperative Complications , Robotic Surgical Procedures , Humans , Female , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/methods , Retrospective Studies , Pelvic Organ Prolapse/surgery , Aged , Middle Aged , Intraoperative Complications/etiology , Intraoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Treatment Outcome , Gynecologic Surgical Procedures/methods , Gynecologic Surgical Procedures/adverse effects , Operative Time , Vagina/surgeryABSTRACT
Dysregulated DNA methylation in cancer is critical in the transcription machinery associated with cancer progression. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, but no treatment targeting TNBC biomarkers has yet been developed. To identify specific DNA methylation patterns in TNBC, methyl-binding domain protein 2 (MBD) sequencing data were compared in TNBC and the three other major breast cancer subtypes. Integrated analysis of DNA methylation and gene expression identified a gene set showing a correlation between DNA methylation and gene expression. ATPase Na+/K+-transporting subunit alpha 1 (ATP1A1) was found to be specifically hypomethylated in the coding sequence (CDS) region and to show increased expression in TNBC. The Cancer Genome Atlas (TCGA) database also showed that hypomethylation and high expression of ATP1A1 were strongly associated with poor survival in patients with TNBC. Furthermore, ATP1A1 knockdown significantly reduced the viability and tumor-sphere formation of TNBC cells. These results suggest that the hypomethylation and overexpression of ATP1A1 could be a prognostic marker in TNBC and that the manipulation of ATP1A1 expression could be a therapeutic target in this disease.
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To investigate the impact on the ovarian reserve after minimally invasive ovarian cystectomy using two platforms, the Da Vinci robotic system (Xi and SP) and the laparoscopic system. Patients underwent laparoscopic or Da Vinci robotic (Xi or SP) ovarian cystectomy for benign ovarian cysts between January 1, 2018, and December 31, 2022 at Guro Hospital, Korea University Medical center. We measured the change of AMH values (%) = [(postAMH - preAMH)] × 100/preAMH. No significant differences in preoperative age, cyst size, estimated blood loss during surgery, hemoglobin drop, length of hospital stay, adhesion detachment rate and cyst rupture rate were observed. However, the operative time was significantly shorter in the laparoscopic group than that in the robotic group (67.78 ± 30.58 min vs. 105.17 ± 38.87 min, p < 0.001) The mean preAMH and postAMH were significantly higher with the Da Vinci robotic group than with the laparoscopic group (preAMH: 5.89 ± 4.81 ng/mL vs. 4.01 ± 3.59 ng/mL, p = 0.02, postAMH: 4.36 ± 3.31 ng/mL vs. 3.08 ± 2.60 ng/mL, p = 0.02). However, the mean ΔAMH was not significantly different between two groups. ΔAMH also did not demonstrate significant differences among the three groups; laparoscopic, Xi and SP robotic. Even in the patient groups with preAMH < 2 and diagnosed with endometriosis, the ΔAMH did not show significant differences between the laparoscopic and robotic groups. The Da Vinci robotic system is no inferior to conventional laparoscopic systems in preserving ovarian function.
Subject(s)
Cysts , Laparoscopy , Ovarian Reserve , Robotic Surgical Procedures , Female , Humans , Anti-Mullerian Hormone , Cystectomy , Treatment OutcomeABSTRACT
BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat accumulation in the liver. MASLD encompasses both steatosis and MASH. Since MASH can lead to cirrhosis and liver cancer, steatosis and MASH must be distinguished during patient treatment. Here, we investigate the genomes, epigenomes, and transcriptomes of MASLD patients to identify signature gene set for more accurate tracking of MASLD progression. METHODS: Biopsy-tissue and blood samples from patients with 134 MASLD, comprising 60 steatosis and 74 MASH patients were performed omics analysis. SVM learning algorithm were used to calculate most predictive features. Linear regression was applied to find signature gene set that distinguish the stage of MASLD and to validate their application into independent cohort of MASLD. RESULTS: After performing WGS, WES, WGBS, and total RNA-seq on 134 biopsy samples from confirmed MASLD patients, we provided 1,955 MASLD-associated features, out of 3,176 somatic variant callings, 58 DMRs, and 1,393 DEGs that track MASLD progression. Then, we used a SVM learning algorithm to analyze the data and select the most predictive features. Using linear regression, we identified a signature gene set capable of differentiating the various stages of MASLD and verified it in different independent cohorts of MASLD and a liver cancer cohort. CONCLUSION: We identified a signature gene set (i.e., CAPG, HYAL3, WIPI1, TREM2, SPP1, and RNASE6) with strong potential as a panel of diagnostic genes of MASLD-associated disease.
Subject(s)
Fatty Liver , Liver Neoplasms , Humans , Algorithms , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Disease ProgressionABSTRACT
STUDY OBJECTIVE: To assess the diagnostic accuracy of a retrograde voiding trial for the restoration of spontaneous voiding function after prolapse and urinary incontinence surgery and thereby determine whether the retrograde method can be a reliable alternative to the spontaneous voiding trial. DESIGN: A retrospective cohort study. SETTING: A single tertiary hospital in South Korea. PATIENTS: Women who underwent operations for prolapse, urinary incontinence, or both. INTERVENTION: Sequential voiding trials on postoperative day 1 or 2-retrograde voiding trial followed by spontaneous voiding trial. MEASUREMENTS AND MAIN RESULTS: Of the 408 women analyzed, 278 (68.1%) passed the spontaneous voiding trial on the first day of assessment and none experienced urinary retention after a successful voiding trial. Receiver operating characteristic analyses of retrograde voiding trials evaluating voided volume (VV), postvoid residual (PVR), and voiding efficiency (VE) all demonstrated high diagnostic accuracy for restoration of spontaneous voiding function, whereas measuring PVR and VE had better discriminative ability than VV (area under the curve [95% confidence interval] = 0.93 [0.90-0.95] for PVR, 0.94 [0.91-0.96] for VE, and 0.88 [0.85-0.91] for VV; DeLong's test between PVR/VE and VV p < .01). The optimal cutoffs determined by the Youden index were 200 mL for VV (sensitivity 85.0%, specificity 78.0%), 100 mL for PVR (sensitivity 84.0%, specificity 87.0%), and 66.7% for VE (sensitivity 86.0%, specificity 88.0%). CONCLUSIONS: The retrograde voiding trial is an accurate predictor for restoration of spontaneous voiding function after prolapse and incontinence surgery and can be a useful alternative to the spontaneous voiding trial.
Subject(s)
Pelvic Organ Prolapse , Urinary Incontinence , Urinary Retention , Female , Humans , Retrospective Studies , Urinary Incontinence/diagnosis , Urinary Incontinence/surgery , Urinary Retention/diagnosis , Urinary Retention/etiology , Urinary Retention/surgery , Urination , Pelvic Organ Prolapse/surgeryABSTRACT
This review aimed to summarize the complications and surgical outcomes of robot-assisted sacrocolpopexy. Nineteen original articles on 1,440 robotic sacrocolpopexies were reviewed, and three systematic reviews and meta-analyses were summarized in terms of intraoperative, perioperative, postoperative, and/or surgical outcomes. Robotic sacrocolpopexy has demonstrated low overall complication rates and favorable surgical outcomes. Nevertheless, long-term follow-up outcomes regarding objective and/or subjective prolapse recurrence, reoperation rates, and mesh-related complications remain unclear. Further research is required to demonstrate whether the robotic approach for sacrocolpopexy is feasible or can become the modality of choice in the future when performing sacrocolpopexy.
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IMPORTANCE: Despite recognition of the critical role of the apex in vaginal support, there is no consensus on the anatomic criteria for clinically relevant apical prolapse. OBJECTIVE: The aim of this study was to define an optimal anatomic criterion for clinically relevant apical prolapse. STUDY DESIGN: This retrospective cohort study included 3,690 patients who had visited a tertiary hospital for ambulatory urogynecologic care. Vaginal bulge symptom was defined as a response of "somewhat," "moderately," or "quite a bit" to Question 3 on the Pelvic Floor Distress Inventory-20. Receiver operating characteristic curves were generated for a vaginal bulge symptom and apical support (Pelvic Organ Prolapse Quantification point C and C/total vaginal length [TVL]). RESULTS: Both point C and the C-to-TVL ratio (C/TVL) had excellent performance for predicting vaginal bulge symptoms (area under the curve, 0.917 and 0.927, respectively). The optimal cutoffs were -3.0 for C and -0.50 for C/TVL. When we analyzed the data set according to the TVL, there was a significant difference in the cutoffs for C, whereas those for C/TVL had little difference. There was no difference in the cutoffs of C and C/TVL according to hysterectomy status. CONCLUSIONS: The C/TVL is more appropriate than point C as a measure to define an anatomic criterion for clinically relevant apical prolapse. Descent of the vaginal apex beyond the halfway point of the vagina could be considered as an anatomic threshold for clinically relevant apical prolapse. This finding needs to be validated in nonurogynecology populations.
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Dendritic cells are antigen-presenting cells orchestrating innate and adaptive immunity. The crucial role of transcription factors and histone modifications in the transcriptional regulation of dendritic cells has been extensively studied. However, it is not been well understood whether and how three-dimensional chromatin folding controls gene expression in dendritic cells. Here we demonstrate that activation of bone marrow-derived dendritic cells induces extensive reprogramming of chromatin looping as well as enhancer activity, both of which are implicated in the dynamic changes in gene expression. Interestingly, depletion of CTCF attenuates GM-CSF-mediated JAK2/STAT5 signaling, resulting in defective NF-κB activation. Moreover, CTCF is necessary for establishing NF-κB-dependent chromatin interactions and maximal expression of pro-inflammatory cytokines, which prime Th1 and Th17 cell differentiation. Collectively, our study provides mechanistic insights into how three-dimensional enhancer networks control gene expression during bone marrow-derived dendritic cells activation, and offers an integrative view of the complex activities of CTCF in the inflammatory response of bone marrow-derived dendritic cells.
Subject(s)
Bone Marrow , CCCTC-Binding Factor , Dendritic Cells , NF-kappa B , Chromatin , Regulatory Sequences, Nucleic AcidABSTRACT
This study aimed to report a single surgeon's early experience and learning curves of single-incision robotic sacrocolpopexy on two different robotic surgical platforms, namely, the single-site approach on da Vinci Xi® and single-port approach on da Vinci SP® surgical systems. This retrospective study included 123 consecutive cases of robotic sacrocolpopexy performed between June 2017 and June 2021 for the patients with Pelvic Organ Prolapse Quantification stage 2-4 symptomatic prolapse. First consecutive 57 cases were performed under the da Vinci Xi® system applying the single-site manner, whereas the following 66 cases were done under the da Vinci SP® system. The primary outcome was intraoperative and perioperative complication rates, and the secondary outcome was learning curve of single-incision robotic sacrocolpopexy under the two different robotic surgical platforms. Learning curves based on the operation time were obtained through cumulative sum analysis. The mean age of each group was 65.6 ± 8.7 years for single-site robotic sacrocolpopexy and 63.7 ± 7.6 years for the single-port one (p = 0.202). More than 80% of patients for each group had advanced prolapse stages and underwent concomitant total hysterectomy. The overall baseline characteristics did not differ significantly between groups. The median operation time for each group were 201.0 and 201.5 min, respectively. Both groups showed comparable perioperative outcomes in terms of operation time, intraoperative blood loss, and length of hospital stay. Intraoperative cystostomy rates were 1.8% and 3.0%, respectively, and revealed no statistical difference (p = 0.736). The learning curves were comparable, and the surgeon required less than 15 cases for both single-site and single-port robotic sacrocolpopexies to stabilize operation time. Comparable learning curves and favorable intraoperative and perioperative outcomes of single-incision robotic sacrocolpopexy using two different robotic surgical systems show that both are feasible options for robotic sacrocolpopexy.
Subject(s)
Pelvic Organ Prolapse , Robotic Surgical Procedures , Robotics , Female , Humans , Middle Aged , Aged , Robotic Surgical Procedures/methods , Learning Curve , Retrospective Studies , Pelvic Organ Prolapse/surgery , Treatment OutcomeABSTRACT
Cancer stem-like cells (CSCs) have been suggested to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE1 plays a key role in regulating CSC properties and tumor resistance to carboplatin via a microRNA-dependent mechanism. We found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but this effect was reversed on the restoration of WEE1 expression. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503-mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer. We identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.
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The demand for uterine preservation in pelvic reconstructive surgery for uterovaginal prolapse is steadily increasing, and several procedures have been introduced, such as sacrospinous hysteropexy, uterosacral hysteropexy, sacrohysteropexy, and hysteropectopexy. However, the benefits and risks of uterine-preserving surgeries are not well understood. This review discusses the current evidence surrounding uterine-preserving surgery for uterovaginal prolapse repair. This may help surgeons and patients have a balanced discussion on how and on whom to perform uterine-preserving surgery.
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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer; however, specific prognostic biomarkers have not yet been developed. In this study, we identified dysregulated microRNAs (miRNAs) in TNBC by profiling miRNA and mRNA expression. In patients with TNBC, miR-371b-5p expression was reduced, and miR-371b-5p overexpression significantly mitigated TNBC cell growth, migration, and invasion. In addition, we found that expression of cold shock domain-containing protein E1 (CSDE1), a direct target gene of miR-371b-5p, was upregulated in TNBC cells, and inhibition of CSDE1 expression alleviated TNBC cell growth by regulating RAC1 transcription. Mechanistically, CSDE1, phosphorylated C-terminal domain (p-CTD) of RNA polymerase II (RNAPII), and CDK7 form a complex, and downregulation of CSDE1 leads to weak interaction between RNAPII p-CTD and CDK7, resulting in a decrease in RNAPII p-CTD expression to reduce RAC1 transcript levels in CSDE1-deficient TNBC cells. Our data demonstrate that miR-371b-5p is a tumor-suppressive miRNA that regulates the CSDE1/Rac1 axis and could be a potential prognostic biomarker for TNBC.
Subject(s)
DNA-Binding Proteins , MicroRNAs , RNA-Binding Proteins , Triple Negative Breast Neoplasms , Cell Line, Tumor , Cell Movement , Cell Proliferation , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , Neoplasm Invasiveness/genetics , RNA-Binding Proteins/genetics , Triple Negative Breast Neoplasms/pathology , rac1 GTP-Binding Protein/geneticsABSTRACT
OBJECTIVE: To identify the factors associated with unsuccessful pessary fitting and reasons for pessary discontinuation in Korean women with pelvic organ prolapse (POP). METHODS: The medical records of 234 patients who underwent pessary fitting for the management of symptomatic POP were retrospectively reviewed. A ring pessary with or without support was used. Successful pessary fitting was defined as the ability to wear a pessary for 2 weeks without any discomfort. Factors associated with unsuccessful pessary fitting were determined using a multivariable logistic regression analysis. A Kaplan-Meier survival curve was obtained to examine the probability of continuing pessary use over the follow-up period. The reasons for the discontinuation of pessary were identified. RESULTS: Two-hundred-and-twenty-five women were included in the analysis. The rate of unsuccessful pessary fitting was 40%. Prior hysterectomy (odds ratio [OR], 4.13; 95% confidence interval [CI], 1.81-9.42) and POP quantification stage III-IV (OR, 2.49; 95% CI, 1.28-4.85) were independent risk factors for unsuccessful pessary fitting. Among the patients with successful pessary fitting, the median time to discontinuation of pessary use was 4 years. The most common causes of discontinued use were vaginal erosion (45.3%) and urinary incontinence (26.5%). CONCLUSION: Patients with a history of hysterectomy and advanced-stage POP are at risk for an unsuccessful fitting of the ring pessary. Vaginal erosion is the main reason for discontinued use among patients with successful pessary fitting.
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OBJECTIVE: To develop and validate a prediction model for bothersome stress urinary incontinence after prolapse surgery and to compare it with an existing clinical prediction model (CUPIDO model). DESIGN: Retrospective cohort study. SETTING: Two tertiary hospitals in South Korea. POPULATION: A total of 1142 patients who underwent prolapse surgery with or without a concomitant midurethral sling. METHODS: To construct a prediction model, we performed logistic regression using both exhaustive and stepwise variable selection, validating the model both internally and externally. MAIN OUTCOME MEASURES: Bothersome stress urinary incontinence defined as the presence of bothersome symptoms of stress urinary incontinence and/or subsequent continence procedure one year after surgery. RESULTS: Postoperative bothersome stress urinary incontinence occurred in 10% of patients. A model containing six predictors (age, diabetes mellitus, subjective urinary incontinence, prolapse reduction stress test result, type of prolapse surgery, and a concomitant midurethral sling) showed excellent performance for predicting bothersome stress urinary incontinence (area under the curve 0.74, 95% confidence interval 0.62-0.86) and outperformed the CUPIDO model (area under the curve 0.63, 95% confidence interval 0.49-0.76; DeLong's test P = 0.014). CONCLUSIONS: This prediction model might be a useful tool to guide patient decision making regarding a concomitant continence procedure at the time of prolapse surgery. The predictive value of this model needs to be validated further in cohorts with different characteristics. TWEETABLE ABSTRACT: The proposed prediction model for bothersome stress urinary incontinence after prolapse surgery outperforms an existing model.
Subject(s)
Pelvic Organ Prolapse , Suburethral Slings , Urinary Incontinence, Stress , Humans , Models, Statistical , Pelvic Organ Prolapse/complications , Pelvic Organ Prolapse/surgery , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Prognosis , Retrospective Studies , Suburethral Slings/adverse effects , Urinary Incontinence, Stress/etiology , Urinary Incontinence, Stress/surgeryABSTRACT
One new species of the genus Alnetoidia Dlabola, A. (Alnetoidia) flava sp. nov. and a newly recorded species, A. (Alnetoidia) satsumana (Matsumura, 1932) are reported from the Korean Peninsula, and a key to the Korean species is provided.
Subject(s)
Hemiptera , Animals , Republic of KoreaABSTRACT
BACKGROUND: Potassium usnate (KU), a water-soluble form of usnic acid, shows anticancer activity. However, the underlying mechanisms have not been fully elucidated. PURPOSE: We aimed to identify the pathways involved in anticancer effects of KU in human gastric cancer (GC) and colorectal cancer (CRC) cells using RNA-sequencing (RNA-seq) based transcriptome analysis. STUDY DESIGN: We analyzed the cytotoxic effects of KU to identify the common molecular events in GC and CRC cells upon KU exposure using unbiased approaches. METHODS: Cell viability assays and western blot experiments were used to examine apoptotic changes, cell cycle arrest, and endoplasmic reticulum (ER) stress-induced cellular responses in KU-treated cells. Total RNA from KU-treated human GC and CRC cells was prepared for RNA-seq analysis. Gene ontology term and gene set enrichment analyses were used to identify the key mediators of the cytotoxic effects of KU. The expression of ER stress-induced apoptotic markers was evaluated using quantitative reverse-transcription PCR and western blot analysis. Chromatin immunoprecipitation assays for ATF3 and H3K27ac, and ATF3 knockdown were employed to verify the underlying molecular mechanisms. The inhibitory effect of KU on tumor growth in vivo was validated with metastatic tumor nodule formations in a mouse liver model. RESULTS: KU exerted cytotoxicity in human GC and CRC cells through the activation of the ER stress-induced apoptotic pathway. KU stimulated ATF3 expression, an important mediator of molecular events of apoptosis. ATF3 binds to the promoter region of ATF3, CHOP, GADD34, GADD45A, DR5, and PUMA genes and subsequently promoted apoptotic events. Knockdown of ATF3 significantly reduced the expression of ATF3 target genes and the cytotoxic effects of KU. The intraperitoneal injection of KU induced ATF3 and the apoptosis of implanted colon cancer cells, resulting in reduced metastatic tumor growth in the mouse livers. CONCLUSION: KU exerts cytotoxic effects in human GC and CRC cells by triggering ER stress-induced apoptosis via an ATF3 dependent pathway.
Subject(s)
Activating Transcription Factor 3/metabolism , Benzofurans/pharmacology , Colonic Neoplasms , Endoplasmic Reticulum Stress , Stomach Neoplasms , Activating Transcription Factor 3/genetics , Animals , Apoptosis , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Gene Expression Profiling , Humans , Mice , Potassium , Stomach Neoplasms/drug therapyABSTRACT
After decades-long efforts to diagnose and treat breast cancer, the management strategy that has proved most successful to date is molecular-subtype-specific inhibition of the hormone receptors and HER2 that are expressed by individual cancers. Melanoma-associated antigen (MAGE) proteins comprise >40 highly conserved members that contain the MAGE homology domain. They are often overexpressed in multiple cancers and contribute to cancer progression and metastasis. However, it remains unclear whether the biological activity arising from MAGE gene expression is associated with breast cancer subtypes. In this study, we analyzed the RNA-sequencing (RNA-seq) data of 70 breast cancer cell lines and found that MAGEA12 and MAGEA3 were highly expressed in a subset of these lines. Significantly, MAGEA12 and MAGEA3 expression levels were independent of hormone receptor expression levels but were closely associated with markers of active histone modifications. This indicates that overexpression of these genes is attributable to epigenetic deregulation. RNA-seq of MAGEA12-depleted cells was then used to identify 382 candidate targets of MAGEA12 that were downregulated by MAGEA12 depletion. Furthermore, our gain-of-function experiments showed that MAGEA12 overexpression promoted aggressive behaviors of malignant breast cancer cells, including enhancing their cell migration and invasion. These changes were associated with increased epigenetic deregulation of the MAGEA12 signature genes. Thus, MAGEA12 may play an important role in breast cancer malignancy. Taken together, our findings suggest that MAGEA12 could be a promising therapeutic target in breast cancer, and its overexpression and epigenetic changes could serve as subtype classification biomarkers.
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Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells utilize super-enhancers (SEs) to activate the transcription factor EVI1 (ecotropic viral integration site 1) gene, resulting in activation of an EVI1-dependent transcription program conferring PDA tumorigenesis. Our data indicate that SE is the vital cis-acting element to maintain aberrant EVI1 transcription in PDA cells. Consistent with disease progression and inferior survival outcomes of PDA patients, we further show that EVI1 upregulation is a major cause of aggressive tumor phenotypes. Specifically, EVI1 promotes anchorage-independent growth and motility in vitro and enhances tumor propagation in vivo. Mechanistically, EVI1-dependent activation of tumor-promoting gene expression programs through the stepwise configuration of the active enhancer chromatin attributes to these phenotypes. In sum, our findings support the premise that EVI1 is a crucial driver of oncogenic transcription programs in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
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Concomitant apical suspension should be performed at the time of hysterectomy for uterine prolapse to reduce the risk of recurrent prolapse. Native tissue repair (NTR) and sacrocolpopexy (SCP) are commonly used apical suspension procedures; however, it remains unclear which one is preferred. This study aimed to compare the treatment outcomes of NTR and SCP in terms of surgical failure, complication and reoperation rates. Surgical failure was defined as the presence of vaginal bulge symptoms, any prolapse beyond the hymen, or retreatment for prolapse. This retrospective cohort study included 523 patients who had undergone NTR (n = 272) or SCP (n = 251) along with hysterectomy for uterine prolapse and who had at least 4-month follow-up visits. During the median 3-year follow-up period, the surgical failure rate was higher in the NTR group (21.3% vs 6.4%, P < 0.01), with a low rate of retreatment in both groups. Overall complication rates were similar, but complications requiring surgical correction under anesthesia were more common in the SCP group (7.2% vs 0.4%, P < 0.01). As a result, the total reoperation rate was significantly higher in the SCP group (8.0% vs 2.6%, P = 0.02). Taken together, NTR may be a preferred option for apical suspension when hysterectomy is performed for uterine prolapse.