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1.
Artigo em Inglês | MEDLINE | ID: mdl-38627199

RESUMO

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.

2.
Cancer Med ; 13(7): e7149, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572951

RESUMO

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.


Assuntos
Antineoplásicos , Carcinoma , Neoplasias Ovarianas , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Japão , Ribose/uso terapêutico , Estudos Retrospectivos , Mutação , Antineoplásicos/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Biomarcadores , Poli(ADP-Ribose) Polimerases , Carcinoma/tratamento farmacológico , Ftalazinas/efeitos adversos
3.
Biochim Biophys Acta Mol Basis Dis ; 1870(4): 167103, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38417460

RESUMO

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Assuntos
Fibroblastos Associados a Câncer , Vesículas Extracelulares , Leiomiossarcoma , MicroRNAs , Humanos , Fibroblastos Associados a Câncer/metabolismo , Leiomiossarcoma/genética , Leiomiossarcoma/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Linhagem Celular , Microambiente Tumoral/genética
4.
Reprod Biol ; 24(1): 100821, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37992589

RESUMO

Ovarian endometrioma (OE) is a common gynecological disease that is often treated with surgery and hormonal treatment. However, ovarian cystectomy can impair the ovarian reserve (OR). Previously, we showed that perioperative administration of dienogest (DNG) is an effective option for OR preservation. However, there were differences in the extent of OR preservation among patients following perioperative DNG treatment. In the current study, we performed a global examination of serum microRNAs (miRNAs) to identify accurate biomarkers that predict post-operative restoration of OR following perioperative DNG treatment. We also sought to identify specific miRNAs related to the anti-Müllerian hormone (AMH). miRNA sequencing was performed on serum samples obtained from twenty-seven patients who received perioperative DNG treatment. Candidate miRNAs were selected by comparing patients whose ORs were restored postoperatively (responder group, n = 7) with those whose ORs were not (non-responder group, n = 7). miR-370-3p and miR-1307-3p were significantly upregulated in the responder group, whereas miR-27b-3p was upregulated in the non-responder group. The pretreatment value of each miRNA could predict DNG responsiveness for OR following ovarian cystectomy (area under the curve [AUC] > 0.8). The quantitative polymerase chain reaction (qPCR) revealed only miR-1307-3p was found to be significantly upregulated in the responder group (P < 0.05). In addition, we identified miR-139-3p, miR-140-3p, and miR-629-5p as AMH-associated miRNAs. The transition of AMH showed a correlation with miR-139-3p (P < 0.05, r = -0.76). The miRNAs identified herein represent potential serum biomarkers of clinical value in predicting OR prior to DNG treatment.


Assuntos
Endometriose , MicroRNAs , Reserva Ovariana , Feminino , Humanos , MicroRNAs/genética , Endometriose/cirurgia , Cistectomia , Biomarcadores , Hormônio Antimülleriano
5.
J Obstet Gynaecol Res ; 50(2): 175-181, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37933428

RESUMO

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.


Assuntos
Preservação da Fertilidade , Traquelectomia , Neoplasias do Colo do Útero , Gravidez , Feminino , Humanos , Traquelectomia/efeitos adversos , Neoplasias do Colo do Útero/patologia , Preservação da Fertilidade/métodos , Estadiamento de Neoplasias , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia
6.
BMC Cancer ; 23(1): 1103, 2023 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-37957624

RESUMO

BACKGROUND: Non-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC. METHODS: Fresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdcscid1l2rgtm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate. RESULTS: The PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour. CONCLUSIONS: We successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.


Assuntos
Coriocarcinoma não Gestacional , Cisplatino , Feminino , Humanos , Camundongos , Animais , Ensaios Antitumorais Modelo de Xenoenxerto , Metotrexato , Xenoenxertos , Camundongos Nus , Camundongos Endogâmicos NOD , Modelos Animais de Doenças , Gonadotropina Coriônica , Camundongos SCID , Microambiente Tumoral
7.
Nat Commun ; 14(1): 6915, 2023 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-37938557

RESUMO

Extracellular vesicles (EVs), including exosomes, are recognized as promising functional targets involved in disease mechanisms. However, the intravital heterogeneity of EVs remains unclear, and the general limitation for analyzing EVs is the need for a certain volume of biofluids. Here, we present cellulose nanofiber (CNF) sheets to resolve these issues. We show that CNF sheets capture and preserve EVs from ~10 µL of biofluid and enable the analysis of bioactive molecules inside EVs. By attaching CNF sheets to moistened organs, we collect EVs in trace amounts of ascites, which is sufficient to perform small RNA sequence analyses. In an ovarian cancer mouse model, we demonstrate that CNF sheets enable the detection of cancer-associated miRNAs from the very early phase when mice did not have apparent ascites, and that EVs from different locations have unique miRNA profiles. By performing CNF sheet analyses in patients, we identify further location-based differences in EV miRNA profiles, with profiles reflecting disease conditions. We conduct spatial exosome analyses using CNF sheets to reveal that ascites EVs from cancer patients exhibit location-dependent heterogeneity. This technique could provide insights into EV biology and suggests a clinical strategy contributing to cancer diagnosis, staging evaluation, and therapy planning.


Assuntos
Exossomos , Vesículas Extracelulares , MicroRNAs , Nanofibras , Neoplasias Ovarianas , Humanos , Animais , Camundongos , Feminino , Exossomos/genética , Ascite , MicroRNAs/genética , Celulose , Neoplasias Ovarianas/genética
8.
Int J Clin Oncol ; 28(12): 1680-1689, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37804356

RESUMO

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.


Assuntos
Carcinoma , Volume Plaquetário Médio , Humanos , Estudos Retrospectivos , Prognóstico , Biomarcadores , Curva ROC
9.
Biochem Biophys Res Commun ; 680: 211-219, 2023 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-37782986

RESUMO

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Assuntos
Vesículas Extracelulares , MicroRNAs , Neoplasias Ovarianas , Humanos , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Proliferação de Células , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Células-Tronco/metabolismo
10.
Sci Rep ; 13(1): 15392, 2023 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-37717112

RESUMO

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.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico por imagem , Vimentina , Metástase Linfática , Prognóstico , Carcinoma de Células Escamosas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Células Epiteliais
11.
Sci Adv ; 9(27): eade6958, 2023 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-37418532

RESUMO

Cancer cell-derived extracellular vesicles (EVs) have unique protein profiles, making them promising targets as disease biomarkers. High-grade serous ovarian carcinoma (HGSOC) is the deadly subtype of epithelial ovarian cancer, and we aimed to identify HGSOC-specific membrane proteins. Small EVs (sEVs) and medium/large EVs (m/lEVs) from cell lines or patient serum and ascites were analyzed by LC-MS/MS, revealing that both EV subtypes had unique proteomic characteristics. Multivalidation steps identified FRα, Claudin-3, and TACSTD2 as HGSOC-specific sEV proteins, but m/lEV-associated candidates were not identified. In addition, for using a simple-to-use microfluidic device for EV isolation, polyketone-coated nanowires (pNWs) were developed, which efficiently purify sEVs from biofluids. Multiplexed array assays of sEVs isolated by pNW showed specific detectability in cancer patients and predicted clinical status. In summary, the HGSOC-specific marker detection by pNW are a promising platform as clinical biomarkers, and these insights provide detailed proteomic aspects of diverse EVs in HGSOC patients.


Assuntos
Vesículas Extracelulares , Nanofios , Neoplasias Ovarianas , Feminino , Humanos , Proteômica , Cromatografia Líquida , Espectrometria de Massas em Tandem , Vesículas Extracelulares/metabolismo , Biomarcadores , Proteínas , Neoplasias Ovarianas/metabolismo
12.
Cancer Biomark ; 37(4): 217-225, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37302026

RESUMO

BACKGROUND: Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE: This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS: Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. RESULTS: The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS: The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.


Assuntos
Neoplasias do Endométrio , Feminino , Humanos , Prognóstico , Neoplasias do Endométrio/metabolismo , Imuno-Histoquímica , Hipóxia , Microambiente Tumoral , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
J Obstet Gynaecol Res ; 49(10): 2549-2552, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37344106

RESUMO

Systemic sclerosis, an autoimmune disease characterized by fibrosis and vasculopathy of the skin and other multiple organs has been associated with an increased risk of malignancy. We present the case of a 74-year-old woman who had diffused cutaneous systemic sclerosis and uterine cervical cancer. The patient was initially diagnosed with stage IIB squamous cell carcinoma and concurrent chemoradiotherapy was planned. However, cisplatin could not be administered due to acute renal failure, so the patient was treated solely with radiotherapy. However, complications of systemic sclerosis progressed rapidly, and the patient died 63 days later from pulmonary edema. An autopsy later revealed that uterine cervix had primary signet ring cell carcinoma. We suspected that this patient had a combination of signet ring cell carcinoma and squamous cell carcinoma, with squamous cell carcinoma disappearing after radiotherapy. This case highlighted the importance of systemic management for cancers associated with systemic sclerosis.


Assuntos
Carcinoma de Células em Anel de Sinete , Carcinoma de Células Escamosas , Esclerodermia Difusa , Neoplasias do Colo do Útero , Feminino , Humanos , Idoso , Esclerodermia Difusa/complicações , Carcinoma de Células em Anel de Sinete/complicações , Carcinoma de Células em Anel de Sinete/diagnóstico , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias do Colo do Útero/patologia , Colo do Útero/patologia
14.
Gynecol Oncol ; 173: 31-40, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37075494

RESUMO

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Cisplatino , Neoplasias Ovarianas , Feminino , Humanos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Modelos Animais de Doenças , Luteolina/farmacologia , Luteolina/uso terapêutico , Neoplasias Ovarianas/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
15.
Oncol Rep ; 49(5)2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36929268

RESUMO

Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In addition, the molecular background of ULMS has not been fully elucidated due to its low incidence. Therefore, no effective treatment strategies have been established based on its molecular background. The present study aimed to investigate the roles of microRNAs (miRNAs/miRs) in the development of ULMS. Comprehensive miRNA sequencing was performed using six ULMS and three myoma samples, and revealed 53 and 11 significantly upregulated and downregulated miRNAs, respectively. One of the most abundant miRNAs in myoma samples was miR­10b­5p. The mean normalized read count of miR­10b­5p was 93,650 reads in myoma, but only 27,903 reads in ULMS. Subsequently, to investigate the roles of miR­10b­5p, gain­of­function analysis was performed using SK­UT­1 and SK­LMS­1 cell lines. The overexpression of miR­10b­5p suppressed cell proliferation and reduced the number of colonies. Moreover, miR­10b­5p increased the number of cells in the G1 phase. In conclusion, tumor­suppressive miR­10b­5p was significantly downregulated in ULMS compared with in myoma; thus, miR­10b­5p may serve a specific role in sarcoma progression.


Assuntos
Regulação para Baixo , Leiomiossarcoma , MicroRNAs , Neoplasias Uterinas , Feminino , Humanos , Linhagem Celular , Proliferação de Células/genética , Fase G1 , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Mioma/genética , Mioma/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Pessoa de Meia-Idade , Idoso , Genes Supressores de Tumor , Análise de Sequência de RNA
16.
Pharmacol Res ; 189: 106693, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36773710

RESUMO

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.


Assuntos
Leiomiossarcoma , Proscilaridina , Neoplasias Uterinas , Humanos , Feminino , Animais , Camundongos , Leiomiossarcoma/tratamento farmacológico , Proteína Desacopladora 2 , Proscilaridina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Uterinas/tratamento farmacológico
17.
J Gynecol Oncol ; 34(3): e34, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36603851

RESUMO

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian carcinoma with poor prognosis. However, no effective biomarkers have been established for predicting unfavorable events, including recurrence and poor prognoses. Serum microRNAs (miRNAs) have been increasingly reported to be useful in predicting a patient's condition and have been recognized as a potentially less-invasive source for liquid biopsy in cancer. Therefore, this study aimed to evaluate serum miRNA profiles from patients with OCCC and to establish biomarker for predicting the prognoses. METHODS: The GSE106817, which included preoperative serum miRNA profiles of patients with ovarian tumors, was used, and clinical information was investigated. In all, 66 patients with OCCC were included, excluding those with other histological subtypes or insufficient prognostic information. Moreover, miRNA profiles of OCCC tissues were also examined. RESULTS: The median follow-up period was 64.3 (8.0-153.3) months. Based on multivariable Cox regression analyses and the expression of miRNAs in OCCC tissues, miR-150-3p, miR-3195, and miR-7704 were selected as miRNA candidates associated with both progression-free survival (PFS) and overall survival (OS). Then, the prognostic index was calculated based on expression values of 3 serum miRNAs. Kaplan-Meier survival analysis indicated that the prognostic index was significantly predictive of PFS and OS (p=0.004 and p=0.012, respectively). CONCLUSION: Preoperative serum miRNA profiles of miR-150-3p, miR-3195, and miR-7704 can be used to potentially predict the prognosis of patients with OCCC.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Feminino , Humanos , MicroRNAs/genética , Prognóstico , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário , Estimativa de Kaplan-Meier , Biomarcadores Tumorais/genética
18.
Clin J Gastroenterol ; 16(2): 193-197, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36538257

RESUMO

Here, we report a case of primary angiosarcoma of the ascending colon diagnosed after the discovery of an oral tumor. An 86-year-old woman presented to our hospital with severe anemia. Although she did not report any oral symptoms, an intraoral mass 15 mm in size with ulceration was observed. Since colonic tumors and osteolytic tumors in the maxilla and sacra were also identified by fluorodeoxyglucose (FDG)-positron emission tomography (PET), colonoscopy was performed. A semi-peripheral tumor with ulceration from the cecum to the ascending colon was detected. Biopsies of the oral cavity and colon revealed a poorly differentiated tumor, and multiple additional immunohistochemical stains were performed to confirm the diagnosis of angiosarcoma. Angiosarcoma progresses rapidly and has a very poor prognosis. Hence, although it is rare, angiosarcoma should always be considered in the differential diagnoses of malignancy of the gastrointestinal tract.


Assuntos
Neoplasias do Colo , Hemangiossarcoma , Feminino , Humanos , Idoso de 80 Anos ou mais , Colo Ascendente/patologia , Hemangiossarcoma/diagnóstico por imagem , Hemangiossarcoma/patologia , Tomografia Computadorizada por Raios X , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia
19.
Gastrointest Endosc ; 97(4): 759-766.e1, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36460084

RESUMO

BACKGROUND AND AIMS: Endoscopic remission is known to be defined as a Mayo endoscopic subscore (MES) of ≤1 in patients with ulcerative colitis (UC). However, some individuals experience relapse even after showing endoscopic remission under white-light imaging (WLI), and no tool exists that can detect these individuals. The aim of this study was to clarify the usefulness of texture and color enhancement imaging (TXI) in the assessment of inflammation in patients with UC. METHODS: This was a prospective, single-arm, observational study conducted at a university hospital. From January 2021 to December 2021, 146 UC patients with endoscopic remission were enrolled. Images were evaluated by WLI, TXI, and pathologic evaluation, followed by prognostic studies. The primary endpoint of the study was the cumulative relapse of UC in each TXI score. The secondary endpoints were the association between TXI and pathologic scores, predictors of relapse, and interobserver agreement between the MES and TXI scores. RESULTS: Patients with TXI score 2 had significantly lower UC relapse-free rates than did those with TXI scores 0-1 (log-rank test, P < .01). When pathologic remission was defined as Matts grade ≤2, the rate of pathologic remission decreased significantly with higher TXI scores (P = .01). In multivariate analysis, TXI score 2 was the only risk factor for UC relapse (P < .01; hazard ratio, 4.16; 95% confidence interval, 1.72-10.04). Interobserver agreement on the TXI score was good (κ = 0.597-0.823). CONCLUSION: TXI can be used to identify populations with poor prognosis in MES 1, for whom treatment intensification has been controversial.


Assuntos
Colite Ulcerativa , Humanos , Colite Ulcerativa/patologia , Colonoscopia/métodos , Estudos Prospectivos , Mucosa Intestinal/patologia , Prognóstico , Índice de Gravidade de Doença
20.
DEN Open ; 3(1): e199, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36545292

RESUMO

Cold snare polypectomy (CSP), for the treatment of colorectal polyps, has become widespread due to its low incidence of adverse events compared to that of endoscopic procedures such as endoscopic mucosal resection. However, we experienced a case of large hematoma development shortly after CSP for a colorectal adenoma despite no bleeding during the procedure. The patient underwent CSP for a 7-mm type Isp lesion in the ascending colon. She returned the following day because of hematochezia. Computed tomography showed a 70-mm, high-intensity mass in the ascending colon, consistent with the large hematoma that was detected by colonoscopy. Although the patient initially had right-sided abdominal pain, it gradually improved with conservative treatment. The hematoma decreased in size, and she was discharged 20 days after emergency admission. Although CSP can be a favorable alternative to more invasive procedures and is expected to be performed more frequently, adverse events, such as that described in this case, should be anticipated.

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