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BACKGROUND: Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers. METHODS: We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort. RESULTS: The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%). CONCLUSIONS: We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer.
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Biomarcadores de Tumor , Detección Precoz del Cáncer , Aprendizaje Automático , MicroARNs , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Detección Precoz del Cáncer/métodos , Femenino , Masculino , Persona de Mediana Edad , MicroARNs/sangre , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Anciano , Antígeno CA-19-9/sangre , Estudios de Casos y Controles , AdultoRESUMEN
BACKGROUND: The incidence of pancreatic cancer is on the rise, and its prognosis remains poor. Recent reports have established a link between the gut and oral microbiome and pancreatic cancer. However, the intricacies of this association within the Japanese population remain unclear. In this study, we investigated the gut and oral microbiomes of Japanese patients with pancreatic cancer, comparing them with those of healthy individuals. METHODS: We recruited 30 patients with untreated pancreatic cancer and 18 healthy controls at Kyoto University Hospital (2018-2022). We performed a comprehensive 16S rRNA gene sequencing to analyze their gut and oral microbiomes. RESULTS: Analysis revealed that the diversity of the gut and oral microbiomes of patients with pancreatic cancer was reduced compared to that of the healthy controls. Specifically, we observed an increase in the genus Streptococcus in both the gut and oral microbiomes and a significant decrease in several butyrate-producing bacteria in fecal samples. Moreover, bacteria such as Streptococcus mitis and Holdemanella biformis were present in pancreatic cancer tissues, suggesting that they might influence the carcinogenesis and progression of pancreatic cancer. CONCLUSIONS: The gut and oral microbiome differed between patients with pancreatic cancer and healthy controls, with a notable decrease in butyrate-producing bacteria in the gut microbiome of the patients. This suggests that there may be a distinct microbial signature associated with pancreatic cancer in the Japanese population. Further studies are required to elucidate the microbiome's causal role in this cancer and help develop prognostic markers or targeted therapies.
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Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. Therefore, we investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct (EHBD) and GB. Activation of Notch signaling and oncogenic Kras resulted in the development of biliary intraepithelial neoplasia (BilINs) in the EHBD and GB, which were premalignant lesions that progressed to adenocarcinoma in mice. The expression of genes involved in the mTORC1 pathway was increased in biliary spheroids from Hnf1b-CreERT2; KrasLSL-G12D ; Rosa26LSL-NotchIC mice and inhibition of the mTORC1 pathway suppressed spheroid growth. Additionally, simultaneous activation of the PI3K-AKT and Notch pathways in EHBD and GB induced biliary cancer development in mice. Consistent with this, we observed a significant correlation between activated NOTCH1 and phosphorylated Ribosomal Protein S6 (p-S6) expression in human eCCA. Furthermore, inhibition of the mTORC1 pathway suppressed the growth of Notch-activated human biliary cancer cells in vitro and in vivo. Mechanistically, the Kras/Notch-Myc axis activated mTORC1 through TSC2 phosphorylation in mutant biliary spheroids. These data indicate that inhibition of the mTORC1 pathway could be an effective treatment strategy for Notch-activated human eCCA. © 2023 The Pathological Society of Great Britain and Ireland.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Carcinoma in Situ , Colangiocarcinoma , Humanos , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt , Diana Mecanicista del Complejo 1 de la Rapamicina , Fosfatidilinositol 3-Quinasas , Colangiocarcinoma/patología , Carcinoma in Situ/patología , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patologíaRESUMEN
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) arises from several types of premalignant lesions, including intraductal tubulopapillary neoplasm (ITPN); however, the molecular pathogenesis of ITPN remains unknown. METHODS: We performed studies with Hnf1b-CreERT2; Ptenf/f; Arid1af/f mice to investigate the consequence of genetic deletion of Arid1a in adult pancreatic ductal cells in the context of oncogenic PI3K/Akt pathway activation. RESULTS: Simultaneous deletion of Arid1a and Pten in pancreatic ductal cells resulted in the development of ITPN, which progressed to PDAC, in mice. Simultaneous loss of Arid1a and Pten induced dedifferentiation of pancreatic ductal cells and Yes-associated protein 1/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway activation. Consistent with the mouse data, TAZ expression was found elevated in human ITPNs and ITPN-derived PDACs but not in human intraductal papillary mucinous neoplasms, indicating that activation of the TAZ pathway is a distinctive feature of ITPN. Furthermore, pharmacological inhibition of the YAP/TAZ pathway suppressed the dedifferentiation of pancreatic ductal cells and development of ITPN in Arid1a and Pten double-knockout mice. CONCLUSION: Concurrent loss of Arid1a and Pten in adult pancreatic ductal cells induced ITPN and ITPN-derived PDAC in mice through aberrant activation of the YAP/TAZ pathway, and inhibition of the YAP/TAZ pathway prevented the development of ITPN. These findings provide novel insights into the pathogenesis of ITPN-derived PDAC and highlight the YAP/TAZ pathway as a potential therapeutic target.
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Carcinoma Ductal Pancreático , Proteínas de Unión al ADN , Fosfohidrolasa PTEN , Neoplasias Pancreáticas , Factores de Transcripción , Animales , Carcinoma Ductal Pancreático/patología , Proteínas de Unión al ADN/genética , Humanos , Ratones , Fosfohidrolasa PTEN/genética , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Fosfatidilinositol 3-Quinasas , Factores de Transcripción/genética , Neoplasias PancreáticasRESUMEN
Tumor stem cells (TSCs), capable of self-renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c-JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c-JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC.
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Neoplasias Colorrectales , Sistema de Señalización de MAP Quinasas , Animales , Apoptosis , Línea Celular Tumoral , Cromatina , Neoplasias Colorrectales/patología , ADN Helicasas , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos , Ratones , Células Madre Neoplásicas/metabolismo , Proteínas Nucleares , Factores de TranscripciónRESUMEN
Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1+ intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1+ intestinal tumor cells reduced intestinal tumors in ApcMin mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1+ intestinal tumor cells revealed that Brg1-null Dclk1+ intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1+ intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1+ tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Neoplasias Colorrectales/patología , ADN Helicasas/metabolismo , Células Madre Neoplásicas/patología , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , RatonesRESUMEN
BACKGROUND & AIMS: SETDB1, a histone methyltransferase that trimethylates histone H3 on lysine 9, promotes development of several tumor types. We investigated whether SETDB1 contributes to development of pancreatic ductal adenocarcinoma (PDAC). METHODS: We performed studies with Ptf1aCre; KrasG12D; Setdb1f/f, Ptf1aCre; KrasG12D; Trp53f/+; Setdb1f/f, and Ptf1aCre; KrasG12D; Trp53f/f; Setdb1f/f mice to investigate the effects of disruption of Setdb1 in mice with activated KRAS-induced pancreatic tumorigenesis, with heterozygous or homozygous disruption of Trp53. We performed microarray analyses of whole-pancreas tissues from Ptf1aCre; KrasG12D; Setdb1f/f, and Ptf1aCre; KrasG12D mice and compared their gene expression patterns. Chromatin immunoprecipitation assays were performed using acinar cells isolated from pancreata with and without disruption of Setdb1. We used human PDAC cells for SETDB1 knockdown and inhibitor experiments. RESULTS: Loss of SETDB1 from pancreas accelerated formation of premalignant lesions in mice with pancreata that express activated KRAS. Microarray analysis revealed up-regulated expression of genes in the apoptotic pathway and genes regulated by p53 in SETDB1-deficient pancreata. Deletion of Setdb1 from pancreas prevented formation of PDACs, concomitant with increased apoptosis and up-regulated expression of Trp53 in mice heterozygous for disruption of Trp53. In contrast, pancreata of mice with homozygous disruption of Trp53 had no increased apoptosis, and PDACs developed. Chromatin immunoprecipitation revealed that SETDB1 bound to the Trp53 promoter to regulate its expression. Expression of an inactivated form of SETDB1 in human PDAC cells with wild-type TP53 resulted in TP53-induced apoptosis. CONCLUSIONS: We found that the histone methyltransferase SETDB1 is required for development of PDACs, induced by activated KRAS, in mice. SETDB1 inhibits apoptosis by regulating expression of p53. SETDB1 might be a therapeutic target for PDACs that retain p53 function.
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Apoptosis , Carcinoma Ductal Pancreático/enzimología , Transformación Celular Neoplásica/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Neoplasias Pancreáticas/enzimología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Sitios de Unión , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Ratones Noqueados , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Selective biliary cannulation (SBC) is the first challenge of endoscopic retrograde cholangiopancreatography (ERCP), especially for trainees, and a rotatable sphincterotome may be useful to guide the directional axis of the scope and SBC. METHODS: We performed a prospective randomized single-center trial, enrolling 200 patients with a native papilla who required therapeutic biliary ERCP. Patients were randomly assigned to the rotatable sphincterotome group (nâ=â100) or the conventional sphincterotome group (nâ=â100). The primary endpoint was successful SBC by the trainees within 10 minutes. RESULTS: The early and late cannulation success rates did not differ significantly between the groups (Pâ=â0.46 and Pâ>â0.99, respectively). For the patients in whom trainees failed to achieve SBC, the rotatable sphincterotome was used as a rescue cannulation technique in four patients from the conventional group; in no patients in the rotatable group was the conventional sphincterotome used for SBC. Post-ERCP pancreatitis (PEP) occurred in 11 patients (5.5â%; 6 mild, 5 moderate); the incidence did not differ significantly between the two groups (rotatable group 3â%, conventional group 8â%; Pâ=â0.21). The two groups were thus combined for evaluation of the factors relating to cannulation difficulty for trainees, which revealed that orientation of the papilla was a significant factor (Pâ<â0.001). CONCLUSIONS: The type of sphincterotome used did not affect the success of SBC by trainees. However, orientation of the papilla was revealed to be a significant factor relating to cannulation difficulty for trainees overall.
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Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Esfinterotomía Endoscópica/instrumentación , Adulto , Anciano , Anciano de 80 o más Años , Conductos Biliares , Cateterismo , Competencia Clínica , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Estudios Prospectivos , Adulto JovenRESUMEN
RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Cadherinas/genética , Carcinoma Ductal Pancreático/genética , Transición Epitelial-Mesenquimal/genética , Proteínas Ligadas a GPI/genética , Neoplasias Hepáticas/genética , Páncreas , Neoplasias Pancreáticas/genética , Neoplasias PancreáticasRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Hipoxia , Neoplasias Pancreáticas/patología , Animales , Ratones , Neoplasias PancreáticasRESUMEN
Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.
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Neoplasias Colorrectales , Monocitos , Humanos , Masculino , Animales , Ratones , Terapia de Inmunosupresión , Agresión , Inhibidores de Puntos de Control Inmunológico , Microambiente TumoralRESUMEN
Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFß pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFß signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFß pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer. SIGNIFICANCE: This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Carcinoma in Situ , Lesiones Precancerosas , Animales , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Pigmentos Biliares/metabolismo , Neoplasias del Sistema Biliar/genética , Carcinoma in Situ/patología , Humanos , Ratones , Lesiones Precancerosas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Vía de Señalización Wnt/genéticaRESUMEN
Paraplegia can be an initial manifestation of pancreatic cancer, although extremely rare.
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Colonic epithelial cells comprise the mucosal barrier, and their dysfunction promotes microbial invasion from the gut lumen and induces the development of intestinal inflammation. The EP4 receptor is known to mediate the protective effect of prostaglandin (PG) E2 in the gastrointestinal tract; however, the exact role of epithelial EP4 in intestinal pathophysiology remains unknown. In the present study, we aimed to investigate the role of epithelial EP4 in maintaining colonic homeostasis by characterizing the intestinal epithelial cell-specific EP4 knockout (EP4 cKO) mice. Mice harboring the epithelial EP4 deletion showed significantly lower colonic crypt depth and lower numbers of secretory cell lineages, as well as impaired epithelial cells in the colon. Interestingly, EP4-deficient colon epithelia showed a higher number of apoptotic cells. Consistent with the defect in mucosal barrier function of colonic epithelia and secretory cell lineages, EP4 cKO colon stroma showed enhanced immune cell infiltration, which was accompanied by increased production of inflammatory cytokines. Furthermore, EP4-deficient colons were susceptible to dextran sulfate sodium (DSS)-induced colitis. Our study is the first to demonstrate that epithelial EP4 loss resulted in potential "inflammatory" status under physiological conditions. These findings provided insights into the crucial role of epithelial PGE2/EP4 axis in maintaining intestinal homeostasis.
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Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Colon/patología , Mucosa Intestinal/patología , Subtipo EP4 de Receptores de Prostaglandina E/genética , Animales , Apoptosis , Colitis Ulcerosa/inducido químicamente , Colon/ultraestructura , Sulfato de Dextran , Eliminación de Gen , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: Patients with refractory-ulcerative colitis (UC) require therapy escalation. Sulfasalazine (SASP) could deliver a high concentration of 5-aminosalicylic acid to the colon. The usefulness of SASP for refractory-UC patients, however, is unclear. AIM: The aim was to evaluate the usefulness of SASP for refractory-UC patients. METHOD: We retrospectively analysed 36 (11.4%) of 316 patients with refractory-UC who had been treated with SASP. Clinical and endoscopic activities were evaluated with Lichtiger index and Mayo score, respectively. We analysed the induction-remission rate, predictive factors for the efficacy of SASP, and adverse events. RESULTS: Of 36 refractory-UC patients, 14 (38.9%) were treated with concomitant mesalazine enemas, 10 (27.8%) with azathiopurine, 4 (11.1%) with tacrolimus and 6 (16.7%) with an antitumour necrosis factor-α agent. After initiating SASP treatment, 25 patients (69.4%) achieved clinical remission. In 9 (64.3%) of 14 patients with UC treated with mesalazine enemas, mesalazine enemas could be discontinued with SASP. In all patients treated with tacrolimus, tacrolimus could be discontinued with SASP. Clinical activity score upon the initiation of SASP was significantly lower (p=0.024) and the number of patients treated with thiopurine was significantly higher (p=0.016) in the clinical remission group than in the non-clinical remission group. These factors might be predictive for the efficacy of SASP, although multivariate analysis demonstrated no statistically significant effect. Adverse events occurred in 7 patients (19.4%), and reduction or discontinuation of SASP led to improvement. CONCLUSIONS: SASP appears to be more effective for refractory-UC patients with low clinical-activity and/or thiopurine-use. TRIAL REGISTRATION NUMBER: UMIN000021615; Results.