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The aim of the present study was to estimate the post-recurrence survival (PRS) of patients with relapsed uterine cervical cancer (RUCC). In addition, clinicopathological indicators that influenced PRS were investigated. Between 1998 and 2014, of 740 patients with cervical cancer, 165 patients experienced recurrence (recurrence rate, 22.3%), and 83 patients succumbed to the disease within a median follow-up of 34.3 months. A total of 151 stage Ib-IV patients who experienced recurrence after initial treatment for cervical cancer at our institute were analyzed. Uni- and multivariate analyses were performed using the Kaplan Meier method, and Cox regression model. The median age was 55 years (range, 20-88 years). In all, 80 patients succumbed to the disease. The median PRS time of all the patients was 28.4 months. The 1-, 3-, and 5-year PRS rates of patients were 75.1, 41.9, and 32.1%, respectively. In addition, the median survival period in patients who had received surgery as an initial treatment was significantly longer compared with that in patients who had not previously undergone surgery (36.7 vs. 23.3 months, respectively; P=0.0338). Following the univariate analysis, the median PRS in patients with in- and out-field recurrence was 12.6, and 45.9 months, respectively (P<0.0001). Furthermore, in the multivariable analysis, the recurrence site was a signifi- cant prognostic indicator of PRS [(In-field vs. Out-field); hazard ratio, 2.848; 95% confidence interval, 1.707-4.738; P<0.0001]. The long-term clinical outcome of patients with RUCC was poor. In particular, the in-field recurrence was identified to be associated with poor post-recurrence oncological outcome in patients with RUCC. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is used for pretreatment staging in cervical cancer. In the present study, we used pretreatment images to categorize operative cases into two groups and evaluated their prognosis. A total of 53 cervical cancer patients with squamous cell carcinoma who underwent radical hysterectomy were included in this study. Based on MRI, the patients were classified into two groups, namely clear and unclear tumor border. For each patient, the following characteristics were evaluated: overall survival; recurrence-free survival; lymph node metastasis; lymphovascular space invasion; and pathological findings, including immunohistochemical analysis of vimentin. The clear and unclear tumor border groups included 40 and 13 patients, respectively. Compared with the clear tumor border group, the unclear tumor border group was associated with higher incidence rates of recurrence (3/40 vs. 3/13, respectively), lymphovascular space invasion (24/40 vs. 13/13, respectively), lymph node metastasis (6/40 vs. 10/13, respectively), and positivity for vimentin (18/40 vs. 10/13, respectively). Despite the absence of significant difference in recurrence-free survival (p = 0.0847), the unclear tumor border group had a significantly poorer overall survival versus the clear tumor border group (p = 0.0062). According to MRI findings, an unclear tumor border in patients with squamous cell cervical cancer is linked to poorer prognosis, lymph node metastasis, and distant recurrence of metastasis. [ABSTRACT FROM AUTHOR]

CD4+Foxp3+ regulatory T cells (Tregs) are essential for homeostasis in the colon, but the mechanism by which local environmental cues determine the localization of colonic Tregs is unclear. Here, we administer indigo naturalis (IN), a nontoxic phytochemical aryl hydrocarbon receptor (AhR) agonist used for treating patients with ulcerative colitis (UC) in Asia, and we show that IN increases Helios+ Tregs and MHC class II+ epithelial cells (ECs) in the colon. Interactions between Tregs and MHC class II+ ECs occur mainly near the crypt bottom in the steady state, whereas Tregs dramatically increase and shift toward the crypt top following IN treatment. Moreover, the number of CD25+ T cells is increased near the surface of ECs in IN-treated UC patients compared with that in patients treated with other therapies. We also highlight additional AhR-signaling mechanisms in intestinal ECs that determine the accumulation and localization of Helios+ Tregs in the colon. [Display omitted] • Indigo naturalis (IN) increases Helios+ Tregs in the colon • IN-induced Tregs are localized near the crypt top in the colon • AhR signaling in colonic epithelial cells is indispensable for Treg accumulation • IN treatment induces colonic Tregs and suppresses experimental colitis Yoshimatsu et al. show that aryl hydrocarbon receptor (AhR) signaling in ECs governs the induction and localization of indigo naturalis (IN)-induced Helios+ Tregs in the colon both in the murine model and in ulcerative colitis patients. [ABSTRACT FROM AUTHOR]

Ovarian cancer constitutes one of the most common causes of cancer-related deaths, and preventing chemotherapy resistance and recurrence in patients with ovarian cancer remains a challenge. Herein, we aimed to identify the effect of luteolin, a novel therapeutic agent targeting vaccinia-related kinase 1 (VRK1), on high-grade serous ovarian cancer (HGSOC). Phosphokinase array, RNA sequencing, and cell cycle and apoptosis assays were conducted to determine the underlying mechanism of the effect of luteolin on HGSOC cells. The anticancer effects of oral and intraperitoneal luteolin administration were assessed in patient-derived xenograft models via several methods, including the assessment of tumor size and immunohistochemistry of phospho-p53, phosphor-HistoneH3 and cleaved caspase 3. Luteolin reduced HGSOC cell proliferation and increased apoptosis and cell cycle arrest at G2/M. Compared with controls, several genes were dysregulated in luteolin-treated cells, and luteolin activated the p53 signaling pathway. The human phosphokinase array revealed distinct p53 upregulation in luteolin-treated cells, as confirmed by p53 phosphorylation at ser15 and ser46 using western blot analysis. In patient-derived xenograft models, oral or intraperitoneal luteolin administration substantially suppressed tumor growth. Moreover, combination treatment involving luteolin and cisplatin inhibited tumor cell proliferation, especially in cisplatin-resistant HGSOC cell lines. Luteolin demonstrated considerable anticancer effect on HGSOC cells, reduced VRK1 expression, and activated the p53 signaling pathway, thereby inducing apoptosis and cell cycle arrest in G2/M and inhibiting cell proliferation. Furthermore, luteolin exhibited a synergistic effect with cisplatin both in vivo and in vitro. Thus, luteolin can be considered a promising cotreatment option for HGSOC. • Blocking the VRK1 pathway via siVRK1 decreasedecreases the proliferation of HGSOC cells. • Using luteolin alone and in combination with cisplatin inhibits tumor growth in vitro. • The IP of luteolin plus cisplatin shows an additive effect on ovarian cancer inhibition. • Oral administration of luteolin can decrease the proliferation of ovarian cancer. [ABSTRACT FROM AUTHOR]

Advanced ovarian cancer often presents with multiple lesions exhibiting varying responses to chemotherapy, highlighting the critical influence of the tumor microenvironment (TME). This study investigates the phenomenon of chemotherapeutic hormesis, wherein low doses of chemotherapeutic agents, such as cisplatin (CDDP) and paclitaxel (PTX), paradoxically stimulate rather than inhibit cancer cell proliferation. Our findings indicate that NOS3 ovarian cancer cells, particularly drug-resistant variants, exhibit enhanced proliferation when exposed to low concentrations of these drugs. This effect is further amplified under hypoxic conditions, suggesting that the TME plays a pivotal role in modulating chemotherapeutic outcomes. Mechanistically, low-dose CDDP upregulates pathways involved in cell cycle progression, specifically the G2/M checkpoint and mitotic spindle formation, accelerating rather than arresting the cell cycle. Furthermore, the activation of the reactive oxygen species (ROS) pathway and increased glutathione levels indicate increased cellular response to oxidative stress, further contributing to cell survival and proliferation. These findings challenge traditional treatment strategies that prioritize the maximization of drug dosage, suggesting that a more nuanced approach considering the influence of the TME and the potential for hormesis could improve therapeutic outcomes. Understanding the mechanisms driving chemotherapeutic hormesis is essential for developing more effective treatments for refractory ovarian cancer. Future research should focus on mitigating the impact of hormesis to enhance the efficacy of chemotherapy in resistant cancer types. [ABSTRACT FROM AUTHOR]

Background: Platinum chemotherapy is the cornerstone of treatment for high‐grade serous ovarian cancer (HGSOC); however, validated biomarkers that can accurately predict platinum response are lacking. Based on their roles in the underlying pathophysiology, circulating microRNAs are potential, noninvasive biomarkers in cancer. In the present study, we aimed to evaluate the circulating miRNA profiles of patients with HGSOC and to assess their potential utility as biomarkers to predict platinum response. Methods: Pretreatment serum samples collected from patients who received platinum chemotherapy for Stage III–IV HGSOC between 2008 and 2016 were analyzed using miRNA microarray. LASSO logistic regression analysis was used to construct predictive models for treatment‐free interval of platinum (TFIp). Results: The median follow‐up was 54.6 (range, 3.5–144.1) months. The comprehensive analysis of 2588 miRNAs was performed in serum samples of 153 eligible patients, and predictive models were constructed using a combination of circulating miRNAs with an area under the receiver operating characteristic curve of 0.944 for TFIp >1 month, 0.637 for TFIp ≥6 months, 0.705 for TFIp ≥12 months, and 0.938 for TFIp ≥36 months. Each predictive model provided a significant TFIp classification (p = 0.001 in TFIp >1 month, p = 0.013 in TFIp ≥6 months, p < 0.001 in TFIp ≥12 months, and p < 0.001 in TFIp ≥36 months). Conclusion: Circulating miRNA profiles has potential utility in predicting platinum response in patients with HGSOC and can aid clinicians in choosing appropriate treatment strategies. [ABSTRACT FROM AUTHOR]

Aim: Prenatal maternal depression is known to affect the neurodevelopment of offspring. This study aimed to investigate the profile of umbilical cord serum in mothers with major depressive disorder (MDD). Methods: Liquid chromatography–tandem mass spectrometry (LC–MS) was conducted using umbilical cord serum from mothers with MDD (n = 5) and controls (control, n = 5). The levels of several differentially expressed proteins in umbilical cord serum were compared between the MDD (n = 10) and control groups (n = 10) by enzyme‐linked immunosorbent assay. Results: The proteomic profiles in the umbilical cord serum were different between the MDD and control groups, including the pathways of regulation of plasma lipoprotein particle levels, and synapse organization. Only apolipoprotein A4 (APOA4) was significantly higher in the cord blood of MDD group. APOA4 levels in maternal serum were also significantly higher in the MDD group than those in the control group. The APOA4 levels in the umbilical cord serum were higher than that in the maternal serum. Conclusions: The levels of APOA4, a biomarker of depression, in the umbilical cord serum at birth were elevated in the neonates of MDD mothers. It is, therefore, likely that fetuses of MDD mothers were exposed to higher APOA4 levels in utero and this could have developmental and mental health implications for the offspring. [ABSTRACT FROM AUTHOR]

Repeat-associated non-AUG translation (RAN translation) is observed in transcripts that are causative for polyglutamine (polyQ) diseases and generates proteins with mono amino acid tracts such as polyalanine (polyA), polyleucine (polyL) and polyserine (polyS) in neurons, astrocytes and microglia. We have previously shown that microglia with aggregated polyQ led to defective differentiation and degeneration of neuron-like cells. However, it has not been determined whether only microglia containing a specific RAN product, but not other RAN products, is harmful in vitro and in vivo. Here we show that polyL-incorporating microglia specifically led to altered startle response in mice. Aggregated polyA, polyS and polyL induced aberrant differentiation of microglia-like BV2 cells. Differentiated PC12 cells treated with conditioned medium (CM) of polyS- and polyL- but not polyA-incorporating microglia-like BV2 cells showed retraction of neurites and loss of branch of neurites. Injection of the polyL-CM, but not polyA-CM and polyS-CM, into the lateral ventricle lowered startle response in mice. Consistently, polyL induced the highest expression of CD68 in BV2 cells. The lowered startle response was replicated in mice given the polyL-CM in the caudal pontine reticular nucleus (PnC), the key region of startle response. Thus, endogenous RAN proteins having polyL derived from polyQ diseases-causative genes in microglia might specifically impair startle response. [ABSTRACT FROM AUTHOR]

Objectives: We focused on how the immunophenotypes based on the distribution of CD8-positive tumor-infiltrating lymphocytes (TILs) relate to the endometrial cancer (EC) molecular subtypes and patients' prognosis. Patients and methods: Two cohorts of EC patients (total n = 145) were analyzed and categorized using the Molecular Risk Classifier for Endometrial cancer (ProMisE): POLEmut (POLE mutation), MMRd (mismatch repair deficiency), NSMP (no specific molecular profile), and p53abn (p53 abnormality). CD8-positive TILs, within the central tumor and the invasive margin, were examined by using immunohistochemical staining and advanced image-analysis software. It was investigated whether these immunophenotypes correlate with the molecular subtypes and patients' survival. RNA-sequencing (RNA-seq) was used to explore tumor-derived factors influencing these immunophenotypes. Results: Three distinct immunophenotypes (inflamed, excluded, and desert) based on the CD8-positive TIL patterns were identified in EC patients. Notably, the inflamed phenotype was most frequently observed in the POLEmut and MMRd subtypes, while the desert phenotype was predominant in the NSMP subtype; however, other immunophenotypes were also observed. All p53abn subtype showed the non-inflamed (excluded or desert) phenotype. The prognosis was markedly poorer in the patients with the non-inflamed phenotype than in those with the inflamed phenotype. The RNA-seq analysis showed that the expression of MYC target genes and type-1 interferon response genes was enriched in the non-inflamed phenotype in MMRd and NSMP subtypes, respectively. Conclusion: Evaluating not only the molecular classification but also the immunophenotype may lead to more personalized immunotherapy in EC and elucidating the mechanisms that underlie the formation of the three immunophenotypes could lead to the discovery of new immunotherapy targets. [ABSTRACT FROM AUTHOR]

Objectives: We characterized blood glucose fluctuations in patients with myotonic dystrophy type 1 (DM1). After confirming the incretin secretion capacity of patients with DM1, we intended to clarify whether dipeptidyl peptidase 4 (DPP-4) inhibitor administration was appropriate in cases of DM1 with diabetes mellitus. Methods: A 48 h continuous glucose monitoring (CGM) was performed in 29 Japanese patients with DM1. An oral glucose tolerance test (OGTT) was performed in patients with DM1 and five disease controls, and levels of blood glucose, insulin, and incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) were measured. DPP-4 inhibitors were administered to patients with diabetes mellitus complicated by DM1, and the CGM results were compared. Results: The CGM showed distinct patterns of blood glucose variability among patients classified by an OGTT pattern with significant differences in glucose parameters such as time above 140 mg/dL and mean amplitude of glycemic excursions between the groups. High sensor glucose values were observed in a certain number of patients who were classified as having normal or impaired glucose tolerance by the OGTT. The CGM confirmed the presence of low glucose levels in several patients. Incretin secretion, the target of DPP-4 inhibitors, was preserved in patients with DM1. DPP-4 inhibitor treatment resulted in lower glucose levels and improved insulin secretion in some patients. Conclusions: This is the first CGM study for DM1 patients. The CGM identified potential early abnormalities in glucose metabolism in DM1. In the future, it will be crucial to explore effective methods for harnessing CGM and assessing it quantitatively in DM1. [ABSTRACT FROM AUTHOR]

Radical surgery after cervical conization is a common approach for the treatment of cervical cancer. In some cases, disease progression is observed after positive margins at conization, but the effect of conization on disease progression remains unclear. Thus, the aim of this study was to investigate the clinical outcomes of positive margins at conization in cervical cancer. A total of 101 patients who underwent cervical conization before radical hysterectomy and pelvic lymph node dissection were considered eligible by reviewing medical records. The association between the positive margins and patient outcomes, including subsequent lymph node metastasis, was evaluated. The rate of lymphovascular space invasion (LVSI) positivity at radical surgery was significantly higher in patients with positive margins (p = 0.017) than in those with negative margins, although there was no significant difference in the rate of pelvic lymph node metastasis (p = 0.155). Moreover, there was no significant difference in the overall survival or progression-free survival between the two groups (p = 0.332 and 0.200, respectively). A positive margin at conization presented no significant prognostic disadvantage; thus, diagnostic conization is one of the most suitable treatment options for early-stage cervical cancer that is difficult to accurately assess. [ABSTRACT FROM AUTHOR]

Background: To investigate the role of CD47 expression and its relationship with tumor‐resident macrophages, specifically at the tumor margin, in patients with type II endometrial cancer. This study aims to elucidate whether CD47 could serve as a prognostic marker and to understand the dynamics between CD47 and macrophages, which could inform new therapeutic strategies. Methods: A retrospective cohort study was conducted involving 75 patients of type II endometrial. Immunohistochemical analysis was performed to assess CD47 expression and macrophage markers (CD68 and CD163). Results: The study found no direct correlation between CD47 expression levels and overall survival (p = 0.32), challenging its role as an independent prognostic marker in type II endometrial cancer. The higher expression of CD47 had significantly less incidence of endometrioid carcinoma G3 (p = 0.047). The negative correlation between CD47 H‐score and the density of CD68‐positive macrophages at tumor margin was statistically significant (p = 0.049). A high density of CD68‐positive macrophages at the tumor margin but a low density of CD163‐positive macrophages at the tumor margin were associated with poorer prognosis (p = 0.036). Conclusions: The complex interaction between CD47 and macrophages, particularly at the tumor margin, suggests new avenues for targeted therapy in type II endometrial cancer. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects. [ABSTRACT FROM AUTHOR]

Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs (miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function. Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients. miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2. miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts. • Small RNA sequencing revealed uterine leiomyosarcoma-specific miRNA profiles. • Uterine leiomyosarcoma cells secrete extracellular vesicles with specific miRNAs. • The extracellular vesicles induce the features of cancer-associated fibroblasts. [ABSTRACT FROM AUTHOR]

Background: Poly (ADP‐ribose) polymerase (PARP) inhibitors have been increasingly used in the treatment of ovarian cancer, with BRCA positivity and homologous recombination deficiency (HRD) being common biomarkers used for predicting their efficacy. However, given the limitations of these biomarkers, new ones need to be explored. Methods: This retrospective study included 181 ovarian cancer patients who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and predictability of treatment duration based on blood data before treatment initiation were examined. Results: High‐grade serous carcinoma, BRCA positivity, HRD, and maintenance therapy after recurrence treatment were observed more frequently in the olaparib group than in the niraparib group. The most common reasons for treatment interruption were anemia, fatigue, and nausea in the olaparib group and thrombocytopenia in the niraparib group. Regarding response to olaparib treatment, complete response to the most recent treatment, maintenance therapy after the first chemotherapy, high‐grade serous carcinoma, and germline BRCA positivity were observed significantly more frequently among responders than among non‐responders. Furthermore, neutrophil counts were significantly higher among responders than among non‐responders. Conclusions: Inflammation‐related blood data, such as neutrophil count, obtained at the initial pre‐treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer. [ABSTRACT FROM AUTHOR]

Aims: To investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early‐stage cervical cancer and to evaluate the potential role of fertility‐preserving treatments in improving pregnancy outcomes while oncologic status is stable. Methods: In this single‐institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early‐stage cervical cancer who underwent RT at Nagoya University Hospital. Results: The cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies. Conclusions: RT is a viable treatment option for selected patients with early‐stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable. [ABSTRACT FROM AUTHOR]

Background: Little is known about the effect of age on the prognosis of epithelial ovarian neoplasms. In the reproductive age, fertility-sparing surgery had been widely implemented. This study aimed to elucidate impact of age on the clinicopathologic characteristics and survival of epithelial ovarian neoplasms in the reproductive age. Methods: The clinical records of patients diagnosed as epithelial ovarian cancer or epithelial borderline ovarian tumor at the age of 40 years or younger at multiple institutions in the Tokai Ovarian Tumor Study Group were reviewed retrospectively. All patients were stratified into two age groups: group A (≤ 30 years) and group B (31–40 years). Univariate and multivariate analyses were performed to evaluate overall survival and disease-free survival. Results: A total of 583 patients (325 patients: cancer, 258 patients: borderline) were included. The median follow-up time was 62.0 months (range 1–270 months). Compared with group B, group A had a significantly higher rate of borderline tumor (66.7% vs. 32.7%, p < 0.001); stage I disease (85.9% vs. 70.4%, p < 0.001); mucinous type (69.2% vs. 35.6%, p < 0.001); conservative surgery (83.8% vs. 41.6%, p < 0.001); no adjuvant chemotherapy (67.2% vs. 44.7%, p < 0.001); and CA125 ≤ 35 U/mL (39.4% vs. 28.8%, p < 0.05). There was a significant difference in the overall survival (p = 0.0051) and the disease-free survival (p = 0.0039) between the two groups. Multivariate analysis revealed that the independent prognostic factors for the overall survival were age, stage, histology, and ascitic fluid cytology. Conclusion: In epithelial ovarian neoplasms, younger patients had a survival advantage over older patients. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the prognostic value of mean platelet volume (MPV) in patients with ovarian clear cell carcinoma (OCCC) and evaluate the predictive performance of a random forest model incorporating MPV and other key clinicopathological factors. Methods: A total of 204 patients with OCCC treated between January 2004 and December 2019 were retrospectively analyzed. Clinicopathological characteristics and preoperative laboratory data were collected, and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional hazards models. An optimal MPV cutoff was determined by receiver operating characteristic (ROC) curve analysis. A random forest model was then constructed using the identified independent prognostic factors, and its predictive performance was evaluated. Results: The ROC analysis identified 9.3 fL as the MPV cutoff value for predicting 2-year survival. The MPV-low group had lower 5-year overall survival and progression-free survival rates than the MPV-high group (p = 0.003 and p = 0.034, respectively). High MPV emerged as an independent prognostic factor (p = 0.006). The random forest model, incorporating the FIGO stage, residual tumors, peritoneal cytology, and MPV, demonstrated robust predictive performance (area under the curve: 0.905). Conclusion: MPV is a promising prognostic indicator in OCCC. Lower MPV correlated with worse survival rates, advocating its potential utility in refining patient management strategies. The commendable predictive performance of the random forest model, integrating MPV and other significant prognostic factors, suggests a pathway toward enhanced survival prediction, thereby warranting further research. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p , which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs. • ADSC-sEVs showed stronger antitumor effects on ovarian cancer cell lines compared to ADSC-m/lEVs. • Transcriptome analysis indicated the involvement of let-7 family in the antitumor effect. • BACH1 , COIL , MAP4K3 , and PAPPA were identified as target genes of hsa-let-7b-5p and hsa-let-7e-5p. [ABSTRACT FROM AUTHOR]

Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS. [Display omitted] • Drug screening identified effective drugs for uterine leiomyosarcoma (ULMS). • Proscillaridin A and lanatoside C showed antitumor effects in vivo. • RNA sequencing revealed the downregulation of UCP2 in the sirtuin signaling pathway. • UCP2 silencing inhibited ULMS cell growth and increased ROS production. • UCP2 was overexpressed in human ULMS tissues than in myoma tissues. [ABSTRACT FROM AUTHOR]

The number of patients with non-alcoholic steatohepatitis (NASH) is increasing globally. Recently, specific chemokine receptors have garnered interest as therapeutic targets in NASH. This is the first report to examine the role of the C-C chemokine receptor 9 (CCR9)/C-C chemokine receptor ligand 25 (CCL25) axis, and to reveal its therapeutic potential in NASH. Patients with biopsy-proven non-alcoholic liver disease (NAFLD) were recruited and their serum and hepatic chemokine expression was examined. Furthermore, wild-type (WT) and Ccr9 −/− mice were fed a high-fat high-cholesterol (HFHC) diet for 24 weeks to establish NASH. Serum CCL25, and hepatic CCR9 and CCL25 expression levels were increased in patients with NASH compared to healthy volunteers. Furthermore, Ccr9 −/− mice were protected from HFHC diet-induced NASH progression both serologically and histologically. Flow cytometry and immunohistochemistry analysis showed that CCR9+CD11b+ inflammatory macrophages accumulated in the inflamed livers of HFHC diet-fed mice, while the number was reduced in Ccr9 −/− mice. Consistent with human NASH livers, CCR9 was also expressed on hepatic stellate cells (HSCs) in mice with NASH, while CCR9-deficient HSCs showed less fibrogenic potential in vitro. Administration of a CCR9 antagonist hampered further fibrosis progression in mice with NASH, supporting its potential clinical application. Finally, we showed that CCR9 blockade attenuated the development of NAFLD-related hepatocellular carcinoma in HF diet-fed mice injected with diethylnitrosamine. These results highlight the role of the CCR9/CCL25 axis on macrophage recruitment and fibrosis formation in a murine NASH model, providing new insights into therapeutic strategies for NASH. Herein, we show that a specific chemokine axis involving a receptor (CCR9) and its ligand (CCL25) contributes to the progression of non-alcoholic steatohepatitis and carcinogenesis in humans and mice. Furthermore, treatment with a CCR9 antagonist ameliorates the development of steatohepatitis and holds promise for the treatment of patients with non-alcoholic steatohepatitis. • Serum CCL25 and hepatic CCR9 and CCL25 levels are increased in patients with NASH. • High-fat high-cholesterol diet induces CCR9-expressing macrophages and hepatic stellate cells in the liver. • CCR9 deficiency attenuates NASH development and associated hepatocellular carcinoma. • The CCR9/CCL25 axis regulates NASH development, and may serve as a therapeutic target in NASH. [ABSTRACT FROM AUTHOR]

The biological function of non-thermal atmospheric pressure plasma has been widely accepted in several types of cancer. We previously developed plasma-activated medium (PAM) for clinical use, and demonstrated that PAM exhibits a metastasis-inhibitory effect on ovarian cancer through reduced MMP-9 secretion. However, the anti-tumor effects of PAM on endometrial cancer remain unknown. In this study, we investigated the inhibitory effect of PAM on endometrial cancer cell viability in vitro. Our results demonstrated that AMEC and HEC50 cell viabilities were reduced by PAM at a certain PAM ratio, and PAM treatment effectively increased autophagic cell death in a concentration dependent manner. In addition, we evaluated the molecular mechanism of PAM activity and found that the mTOR pathway was inactivated by PAM. Moreover, our results demonstrated that the autophagy inhibitor MHY1485 partially inhibited the autophagic cell death induced by PAM treatment. These findings indicate that PAM decreases the viability of endometrial cancer cells along with alteration of the mTOR pathway, which is critical for cancer cell viability. Collectively, our data suggest that PAM inhibits cell viability while inducing autophagic cell death in endometrial cancer cells, representing a potential novel treatment for endometrial cancer. [ABSTRACT FROM AUTHOR]

Aim: While manual vacuum aspiration (MVA) is commonly employed for early first-trimester abortions, its effectiveness in treating hydatidiform mole is still unclear. This study sought to evaluate the efficacy and safety of MVA in comparison to dilation and curettage (D&C) for managing hydatidiform mole., Methods: We conducted a retrospective review of medical records for 198 patients with hydatidiform mole treated at Nagoya University Hospital between 2004 and 2023. After excluding cases with incomplete data, we compared 106 patients who underwent D&C with 60 patients treated with MVA followed by curettage. We evaluated the surgical duration, intraoperative blood loss, and the occurrence of post-molar gestational trophoblastic neoplasia (GTN) in both groups., Results: The surgical duration and blood loss were similar between the MVA and D&C groups. The average surgical time was 13.2 min for D&C and 11.8 min for MVA (p = 0.145). Most cases in both groups experienced blood loss of less than 10 mL, with no significant difference (p = 0.066). Over a median follow-up period of 33.4 months, 25 cases developed post-molar GTN. All GTN cases originated from complete hydatidiform mole (25 of 132 cases, 18.9%), and none were from partial hydatidiform mole. Kaplan-Meier analysis, focusing only on patients with complete hydatidiform mole, indicated no significant difference in the time to onset of GTN between the D&C and MVA groups (p = 0.632)., Conclusions: MVA followed by curettage is a viable approach for treating molar pregnancy., (© 2025 Japan Society of Obstetrics and Gynecology.)

The patient was a 69-year-old right-handed woman. She had sensory aphasia, and the brain MRI revealed a subacute phase hemorrhage in the left subcortical temporal lobe. We speculated that the patient had post-ictal aphasia due to symptomatic epileptic seizures associated with cerebral hemorrhage. Seven months later, she was readmitted to the hospital with sensory aphasia; however, this time, the brain MRI FLAIR demonstrated high signal in the left medial temporal lobe and thalamic pillow. Furthermore, the electroencephalogram showed periodic discharges focused on the left temporal region. 123 I-IMP SPECT of cerebral blood flow indicated a cluster within the medial left temporal lobe. Aphasia associated with nonconvulsive seizures was considered. Sudden onset sensory aphasia should be differentiated from ictal and post-ictal aphasias.

Objective: A complete hydatidiform mole (CHM) is a common disease and is known to develop post-molar gestational trophoblast neoplasia (GTN). However, the molecular mechanisms underlying the progression of CHM to post-molar GTN remain largely unknown. In this study, we investigated the molecular factors associated with the progression using RNA-seq., Methods: We included 13 patients with CHM and performed RNA-seq using freshly frozen samples. We identified differentially expressed genes between patients who developed GTN (GTN group) and those who achieved spontaneous remission after uterine evacuation (SR group), and performed pathway analysis. Then, functional analyses were performed on choriocarcinoma (JAR and JEG-3) and CHM (Hmol1-3B and Hmol1-2C) cells. Moreover, we evaluated the in vivo tumorigenicity of XBP1-overexpressed Hmol1-3B cells., Results: The gene expression profiles were separated into two groups, and an upstream regulator analysis was performed using 281 differentially expressed genes. We focused on transcription factors and identified that 33 transcription factors were activated in the GTN group. Then, excluding those with low expression levels in clinical samples and cell lines, XBP1 was selected for further analysis. Additionally, XBP1 downregulation significantly decreased the migration and invasive abilities of choriocarcinoma cells, whereas XBP1 overexpression significantly increased the migration and invasive abilities of CHM cells. Furthermore, animal experiments showed that tumor weight and blood human chorionic gonadotropin (hCG) levels were significantly higher in the XBP1-overexpressing Hmol1-3B-bearing mice than those in the control mice., Conclusion: RNA-seq identified XBP1 as a key factor in post-molar GTN, suggesting it contributes to the development of post-molar GTN., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate the safety and effectiveness of high-dose oral medroxyprogesterone acetate (MPA) therapy as a fertility-sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence., Methods: We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post-MPA therapy pregnancies were examined., Results: MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post-CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved., Conclusions: High-dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment., (© 2024 Japan Society of Obstetrics and Gynecology.)

Congenital diaphragmatic hernia (CDH) is a life-threatening condition with high morbidity and mortality rates. The survival rate of neonates with severe CDH is reportedly only 10%-15%. However, prenatal prediction of severe cases is difficult, and the discovery of new predictive markers is an urgent issue. In this study, we focused on microRNAs (miRNAs) in amniotic fluid-derived small EVs (AF-sEVs). We identified four miRNAs (hsa-miR-127-3p, hsa-miR-363-3p, hsa-miR-493-5p, and hsa-miR-615-3p) with AUC > 0.8 to classify good prognosis group and poor prognosis group in human study. The AUC for hsa-miR-127-3p and hsa-miR-615-3p, for predicting the poor prognosis, were 0.93 and 0.91, respectively. In addition, in the in vivo study, the miRNA profiles of the lung tissues of CDH rats were different from those of control rats. Additionally, two elevated miRNAs (rno-miR-215-5p and rno-miR-148a-3p) in the lung tissues of CDH rats were increased in the AF-sEVs of CDH rats. Our results suggest that severe CDH neonates can be predicted prenatally with high accuracy using miRNAs contained in AF-sEVs. Furthermore, miRNA profile changes in AF-sEVs reflected the lung status in CDH. Our findings may contribute to the development of advanced perinatal care for patients with CDH., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)