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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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Inactivating mutations of Arid1a, a subunit of the Switch/sucrose nonfermentable chromatin remodeling complex, have been reported in multiple human cancers. Intestinal deletion of Arid1a has been reported to induce colorectal cancer in mice; however, its functional role in intestinal homeostasis remains unclear. We investigated the functional role of Arid1a in intestinal homeostasis in mice. We found that intestinal deletion of Arid1a results in loss of intestinal stem cells (ISCs), decreased Paneth and goblet cells, disorganized crypt-villous structures, and increased apoptosis in adult mice. Spheroids did not develop from intestinal epithelial cells deficient for Arid1a Lineage-tracing experiments revealed that Arid1a deletion in Lgr5+ ISCs leads to impaired self-renewal of Lgr5+ ISCs but does not perturb intestinal homeostasis. The Wnt signaling pathway, including Wnt agonists, receptors, and target genes, was strikingly down-regulated in Arid1a-deficient intestines. We found that Arid1a directly binds to the Sox9 promoter to support its expression. Remarkably, overexpression of Sox9 in intestinal epithelial cells abrogated the above phenotypes, although Sox9 overexpression in intestinal epithelial cells did not restore the expression levels of Wnt agonist and receptor genes. Furthermore, Sox9 overexpression permitted development of spheroids from Arid1a-deficient intestinal epithelial cells. In addition, deletion of Arid1a concomitant with Sox9 overexpression in Lgr5+ ISCs restores self-renewal in Arid1a-deleted Lgr5+ ISCs. These results indicate that Arid1a is indispensable for the maintenance of ISCs and intestinal homeostasis in mice. Mechanistically, this is mainly mediated by Sox9. Our data provide insights into the molecular mechanisms underlying maintenance of ISCs and intestinal homeostasis.
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Proteínas de Ligação a DNA/metabolismo , Mucosa Intestinal/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição SOX9/metabolismo , Células-Tronco/metabolismo , Animais , Células Epiteliais/metabolismo , Homeostase/fisiologia , Intestinos/fisiologia , Camundongos , Regiões Promotoras Genéticas/fisiologia , Fatores de Transcrição , Via de Sinalização Wnt/fisiologiaRESUMO
Cystoid macular edema (CME) is a rare adverse event induced by taxane-based chemotherapy. Here, we describe the case of a 71-year-old man who developed bilateral CME during treatment with nab-paclitaxel (nab-PTX) for unresectable pancreatic cancer. Two months after drug discontinuation, his vision improved, and there was significant reduction in the CME on optical coherence tomography. CME is an adverse event that can be treated with the early withdrawal of nab-PTX. Oncologists who use nab-PTX should be aware of this adverse event for timely patient referral to an ophthalmologist and appropriate treatment that would enable the preservation of the patient's visual acuity.
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Antineoplásicos Fitogênicos , Edema Macular , Neoplasias Pancreáticas , Idoso , Paclitaxel Ligado a Albumina/efeitos adversos , Albuminas , Antineoplásicos Fitogênicos/uso terapêutico , Humanos , Edema Macular/induzido quimicamente , Edema Macular/diagnóstico por imagem , Edema Macular/tratamento farmacológico , Masculino , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
BACKGROUND & AIMS: The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice. METHODS: We performed studies with Ptf1a-Cre;KrasG12D mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;KrasG12D;Arid1af/f mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a-Cre;KrasG12D; Brg1f/fmice). Pancreatic ductal cells (PDCs) were isolated from Arid1af/f mice and from Arid1af/f;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry. RESULTS: Ptf1a-Cre;KrasG12D mice developed PanINs, whereas Ptf1a-Cre;KrasG12D;Arid1af/f mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6. CONCLUSIONS: ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.
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Adenocarcinoma in Situ/genética , Carcinoma Ductal Pancreático/genética , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Ductos Pancreáticos/citologia , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição SOX9/genética , Adenocarcinoma in Situ/metabolismo , Animais , Carcinogênese/genética , Carcinoma Ductal Pancreático/metabolismo , Técnicas de Cultura de Células , Camundongos , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fatores de TranscriçãoRESUMO
Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1-deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1.
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DNA Helicases/metabolismo , Duodeno/metabolismo , Proteínas Nucleares/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , DNA Helicases/genética , Mucosa Intestinal/metabolismo , Camundongos , Proteínas Nucleares/genética , Receptor Notch1/metabolismo , Receptores Notch/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição/genéticaRESUMO
A healthy 49-year-old female developed intractable watery diarrhea after the Pfizer SARS-Cov2 mRNA vaccination. She was subsequently diagnosed with collagenous colitis (CC). She had no prior history of medication use, suggesting of vaccination being the trigger. CC or lymphocytic colitis should be considered as differential diagnoses for persistent watery diarrhea after SARS-Cov2 mRNA vaccination.
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BACKGROUND: Intraductal tubulopapillary neoplasm (ITPN) is a rare disease accounting for approximately 3% of all intraductal pancreatic tumors, with intraductal papillary mucinous neoplasm (IPMN) being one of the most common differential diagnoses. Both ITPN and IPMN display slow growth. A branched pancreatic duct type is commonly observed in IPMN, whereas ITPN derived from the branched pancreatic duct has been reported in a limited number of cases; hence, its pathogenesis remains unclear. CASE SUMMARY: Here, we present the case of a patient with ITPN localized in a branched pancreatic duct, with poorly controlled irritable bowel syndrome. A contrast-enhanced computed tomography scan of the abdomen incidentally revealed a 5-mm oligemic nodule-like change in the body of the pancreas. Endoscopic ultrasound (EUS) indicated a 10-mm hypoechoic mass without any cystic structures that had grown within 2 mo. EUS-guided fine needle aspiration was performed for definitive diagnosis, and the findings suggested ductal papillary carcinoma. Distal pancreatectomy was performed, and the tumor was pathologically diagnosed as ITPN with an invasive cancerous component, pT3N1aM0, pStage IIB (International Cancer Control, 8th edition). The patient underwent treatment with postoperative adjuvant chemotherapy (S-1 monotherapy); however, relapse was observed 1 year and 10 mo after surgical resection, and subsequent treatment involving a combination of chemotherapy and radiotherapy was administered. Maintenance therapy has since facilitated a stable disease state. CONCLUSION: Regardless of the microscopic size of the neoplasm, early diagnosis of ITPN with EUS-guided fine needle aspiration and surgical resection are crucial.
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BACKGROUND Anaplastic carcinoma of the pancreas (ACP) is a rare type of cancer with an extremely poor prognosis. Hereditary pancreatitis is a rare autosomal-dominant disease. It progresses to chronic pancreatitis at a young age, increasing the risk of pancreatic cancer. CASE REPORT A 39-year-old woman was diagnosed with chronic pancreatitis at the age of 18 years. The patient was referred to our hospital for epigastralgia and jaundice. We identified a tumor mass at the head of the pancreas using contrast computed tomography (CT) and endoscopic ultrasound (EUS) of the abdomen. Tissue biopsy revealed ACP of the spindle cell type. We started the patient on combination chemotherapy using gemcitabine and nanoparticle albumin-bound (nab) -paclitaxel, but she died 1 month after her first visit. An autopsy revealed a mixture of tubular adenocarcinoma and anaplastic carcinoma. We performed genetic analysis using DNA samples from the biopsy tissues but did not find mutations in the PRSS1 and SPINK1 genes associated with hereditary pancreatitis. CONCLUSIONS The risk of pancreatic cancer generally increases in patients with hereditary pancreatitis after 50 years of age. However, in this case, the development of pancreatic cancer occurred at a younger age, suggesting the importance of early detection in such cases. Furthermore, this case suggests that EUS is a useful method for monitoring patients with hereditary pancreatitis and the diagnosis of ACP.
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Carcinoma , Neoplasias Pancreáticas , Pancreatite Crônica , Adolescente , Adulto , Autopsia , Carcinoma/diagnóstico , Feminino , Humanos , Pâncreas , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Pancreatite Crônica/genética , Inibidor da Tripsina Pancreática de KazalRESUMO
BACKGROUND/PURPOSE: The purpose of the present study was to investigate the possibility of reducing clinical impacts of acute necrotic collection (ANC) on patients with acute pancreatitis (AP) using recombinant human soluble thrombomodulin (rTM). METHODS: In this retrospective multicenter study, 233 consecutive AP patients with ANC and acute peripancreatic fluid collection (APFC) from 2012 to 2016 were enrolled. To assess clinical impacts of ANC, severity on admission (JPN score, JPN CT grade, and Modified CT severity index), development of walled-off necrosis (WON), imaging costs for follow-up, and mortality were recorded. Finally, we investigated whether rTM could reduce the clinical impacts, adjusting the severity using propensity analysis with Inverse probability of treatment weighting. RESULTS: Patients with ANC developed WON with higher ratio than APFC (58/98 [59.2%] vs 20/135 [14.8%], OR = 8.3, P < .01]. Severity on admission and imaging costs for follow-up in ANC patients were significantly higher than those in APFC (P < .01). However, regarding mortality, there was no significant difference between patients with ANC and APFC (P = .41). Adjusting severity, it was revealed that rTM administration significantly reduced the risk of ANC developed WON (OR = 0.23, P = .01). CONCLUSIONS: While ANC had a higher clinical impact than that of APFC, we found that early administration of rTM may reduce the impact.
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Pancreatite , Trombomodulina , Doença Aguda , Humanos , Necrose , Estudos RetrospectivosRESUMO
Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
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Carcinoma Ductal Pancreático/metabolismo , Transformação Celular Neoplásica/metabolismo , DNA Helicases/biossíntese , Proteínas Nucleares/biossíntese , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Fatores de Transcrição/biossíntese , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , DNA Helicases/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Elementos de Resposta , Fatores de Transcrição SOX9/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias PancreáticasRESUMO
Nonalcoholic steatohepatitis (NASH) is an inflammatory form of nonalcoholic fatty liver disease that progresses to liver cirrhosis. It is still unknown how only limited patients with fatty liver develop NASH. Tumor necrosis factor (TNF)-α is one of the key molecules in initiating the vicious circle of inflammations. Nardilysin (N-arginine dibasic convertase; Nrd1), a zinc metalloendopeptidase of the M16 family, enhances ectodomain shedding of TNF-α, resulting in the activation of inflammatory responses. In this study, we aimed to examine the role of Nrd1 in the development of NASH. Nrd1+/+ and Nrd1-/- mice were fed a control choline-supplemented amino acid-defined (CSAA) diet or a choline-deficient amino acid-defined (CDAA) diet. Fatty deposits were accumulated in the livers of both Nrd1+/+ and Nrd1-/- mice by the administration of the CSAA or CDAA diets, although the amount of liver triglyceride in Nrd1-/- mice was lower than that in Nrd1+/+ mice. Serum alanine aminotransferase levels were increased in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. mRNA expression of inflammatory cytokines were decreased in Nrd1-/- mice than in Nrd1+/+ mice fed the CDAA diet. While TNF-α protein was detected in both Nrd1+/+ and Nrd1-/- mouse livers fed the CDAA diet, secretion of TNF-α in Nrd1-/- mice was significantly less than that in Nrd1+/+ mice, indicating the decreased TNF-α shedding in Nrd1-/- mouse liver. Notably, fibrotic changes of the liver, accompanied by the increase of fibrogenic markers, were observed in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. Similar to the CDAA diet, fibrotic changes were not observed in Nrd1-/- mice fed a high-fat diet. Thus, deletion of nardilysin prevents the development of diet-induced steatohepatitis and liver fibrogenesis. Nardilysin could be an attractive target for anti-inflammatory therapy against NASH.