RESUMO
BACKGROUND: Although live-attenuated vaccines are contraindicated under immunosuppression, the immune status of patients with inflammatory bowel disease (IBD) has not been fully assessed prior to immunosuppressive therapy. AIMS: To investigate antiviral serostatus against viruses requiring live vaccines for prevention in IBD patients undergoing immunosuppressive therapy. METHODS: This multicenter study included IBD patients who were aged <40 years and were treated with thiopurine monotherapy, molecular-targeted monotherapy, or combination therapy. Gender- and age-matched healthy subjects (HS) living in the same areas were included as control group. Antibody titers against measles, rubella, mumps, and varicella were measured by enzyme-linked immunosorbent assays. RESULTS: A total of 437 IBD patients (163 ulcerative colitis [UC] and 274 Crohn's disease [CD]) and 225 HS were included in the final analysis. Compared with HS, IBD patients had lower seropositivity rates for measles (IBD vs. HS = 83.91% vs. 85.33%), rubella (77.55% vs. 84.89%), mumps (37.50% vs. 37.78%), and varicella (91.26% vs. 96.44%). Gender- and age-adjusted seropositivity rates were lower in UC patients than in both CD patients and HS for measles (UC, CD, and HS = 81.60%, 85.29%, and 85.33%), rubella (76.40%, 78.23%, and 84.89%), mumps (27.16%, 43.70%, and 37.78%), and varicella (90.80%, 91.54%, and 96.44%); the difference was significant for all viruses except measles. Divided by the degree of immunosuppression, there were no significant differences in seropositivity rates among IBD patients. CONCLUSIONS: IBD patients, especially those with UC, exhibit reduced seropositivity rates and may benefit from screening prior to the initiation of immunosuppressive therapy.
Assuntos
Varicela , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Sarampo , Caxumba , Rubéola (Sarampo Alemão) , Humanos , Antivirais/uso terapêutico , Varicela/prevenção & controle , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Sarampo/prevenção & controle , Vacina contra Sarampo-Caxumba-Rubéola/administração & dosagem , Caxumba/prevenção & controle , Rubéola (Sarampo Alemão)/prevenção & controleRESUMO
A 73-year-old man was presented with epigastric pain and indicated high CA19-9 levels, and computed tomography detected a tumor in the uncinate process of the pancreas infiltrated duodenum and superior mesenteric artery. The patient was diagnosed with borderline resectable pancreatic carcinoma and received neoadjuvant chemotherapy with gemcitabine and S-1. During neoadjuvant chemotherapy, the patient also received radiotherapy to control duodenal bleeding. After neoadjuvant chemotherapy, stable disease(SD)was proven on the Response Evaluation Criteria in Solid Tumors(RECIST), and subtotal stomach-preserving pancreaticoduodenectomy was performed. The pathological findings showed pancreatic adenosquamous carcinoma. After 7 days postoperatively, hepatic metastasis was detected, and after 78 days postoperatively, the patient died.
Assuntos
Carcinoma Adenoescamoso , Neoplasias Pancreáticas , Masculino , Humanos , Idoso , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/cirurgia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Gencitabina , Pâncreas/patologia , Pancreaticoduodenectomia , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias PancreáticasRESUMO
Common bile duct (CBD) stone is a relatively common but potentially life-threatening disease. Endoscopic sphincterotomy (EST) has been performed as standard therapy for CBD stones, but the rate of recurrence of CBD stones is high. Risk factors have been poorly defined, and no effective means for the prevention of the recurrence of CBD stones have been established so far. We aimed to identify significant risk factors for the recurrence of bile duct stones. This study included 477 patients (231 women; mean age, 80.5 years) who underwent EST and cleared CBD stones on cholangiography. A retrospective analysis was performed for the consecutively collected data. During the follow-up period of 6-75 months, the recurrence of CBD stones was observed in 99 patients (20.8%). The median time to the recurrence was 19.0 months (range 4-72 months). Multivariate analysis identified the need for mechanical lithotripsy, which was used for stone fragmentation, as a risk factor. Mechanical lithotripsy caused cholangiography-negative small residua. Notably, saline solution irrigation of the bile duct reduced the recurrence of CBD stones. These results demonstrate that subsequent biliary irrigation after stone removal may prevent the recurrence of CBD stones by clearing small residual fragments.
Assuntos
Ducto Colédoco/patologia , Cálculos Biliares/prevenção & controle , Cálculos Biliares/cirurgia , Solução Salina/uso terapêutico , Irrigação Terapêutica , Idoso de 80 Anos ou mais , Ducto Colédoco/diagnóstico por imagem , Feminino , Cálculos Biliares/diagnóstico por imagem , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Recidiva , Esfinterotomia Endoscópica , UltrassonografiaRESUMO
An 88-year-old woman was referred to our hospital for autoimmune hepatitis in 2016. She was treated with prednisolone. In 2018, she was rehospitalized owing to hepatitis relapse. Steroid pulse therapy was performed. She exhibited good recovery of hepatitis, but was transferred to a convalescent ward in a general hospital because of decreased activity of daily life. After a month later, she had high fever and cough. She was diagnosed as having tuberculosis because of positive Mycobacterium tuberculosis polymerase chain reaction. At our first medical examination in 2016, we performed enzyme-linked immunospot and the result was undeterminable. There is an increase in the opportunities to use immunosuppressant and biologic agents for elderly patients. Our case report should contribute to future medical care for elderly patients who are at risk of latent tuberculosis infection.
Assuntos
Hepatite Autoimune , Mycobacterium tuberculosis , Tuberculose , Idoso , Idoso de 80 Anos ou mais , ELISPOT , Feminino , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Humanos , PrednisolonaRESUMO
BACKGROUND AND AIM: Tacrolimus is now considered to be one of the main therapeutic options for refractory ulcerative colitis. Both cytochrome P-450 3A5 (CYP3A5) and ATP-binding cassette subfamily B member 1 (ABCB1) associated with tacrolimus metabolism are known to have several genetic polymorphisms. However, it remains controversial whether these polymorphisms affect the therapeutic efficacy for ulcerative colitis. We aimed to investigate the influence of both CYP3A5 and ABCB1 polymorphisms on the efficacy of tacrolimus in ulcerative colitis treatment under the tight dose-adjusting strategy. METHODS: Sixty-one Japanese patients with ulcerative colitis treated with tacrolimus were enrolled retrospectively. Tacrolimus treatment was performed using the tight dose-adjusting strategy. Genotyping for CYP3A5*3, ABCB1 1236C>T, 2677G>A,T, and 3435C>T were performed, and the clinical outcomes at 12 weeks after the initiation of tacrolimus were compared among the genotypes. RESULTS: There was no association between the CYP3A5 genotypes and therapeutic efficacy. In contrast, a significant association was observed with the ABCB1 1236C > T polymorphism and therapeutic efficacy. The ABCB1 1236CC+CT groups (n = 41) had a significantly higher response rate (73% vs 35%; P = 0.004) and remission rate (61% vs 20%; P = 0.002) than the TT group (n = 20). The multivariate logistic regression analysis also revealed that ABCB1 1236C>T was identified as an independent factor associated with remission. CONCLUSIONS: ABCB1 1236C>T polymorphism significantly affects the therapeutic efficacy of tarcolimus at 12 weeks under the tight dose-adjusting treatment for ulcerative colitis.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Estudos de Associação Genética , Polimorfismo Genético , Tacrolimo/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
A 74-year-old man underwent regular follow-up observations after being diagnosed with gallbladder adenomyomatosis based on findings, such as the thickening of the wall of the gallbladder fundus and the presence of intramural cysts. Over the course of 3 years, a papillary tumor located on the thickened wall of the gallbladder had increased in size and extended into the lumen. Consequently, the patient was diagnosed with gallbladder cancer and underwent extended cholecystectomy. The histological diagnosis was intracystic papillary neoplasm (ICPN) of the gallbladder. Although several Rokitansky-Aschoff sinuses that had increased in size because of tumor progression were observed, no adenomyomatosis of the gallbladder was detected. ICPN, a recently identified disease, is not widely known to present with imaging findings similar to adenomyomatosis. The primary treatment of ICPN is radical resection, whereas adenomyomatosis is generally conservatively managed with regular follow-up observations. As the treatment strategies for these two diseases greatly differ, differential diagnosis must be carefully performed.
Assuntos
Adenomioma/diagnóstico por imagem , Diagnóstico Diferencial , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Idoso , Vesícula Biliar/anormalidades , Vesícula Biliar/diagnóstico por imagem , Doenças da Vesícula Biliar , Neoplasias da Vesícula Biliar/complicações , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Imagem Multimodal , Tomografia Computadorizada por Raios XRESUMO
BACKGROUNDS AND AIMS: Peripherally inserted central catheters (PICC) have been widely used as a blood access route for total parenteral nutrition (TPN) in recent years. However, there have been few reports that evaluated the usefulness of PICC for patients with inflammatory bowel disease (IBD). In this study, we compared the clinical courses in patients with IBD who received TPN during their hospitalization by conventional central venous catheters (CVC) and PICC. PATIENTS AND METHODS: A total of 137 IBD patients were enrolled. The CVC group and the PICC group included 56 and 81 patients, respectively. The clinical courses in both groups were compared retrospectively. RESULTS: As a complication of the puncture, pneumothorax occurred in two patients (3.6%) in the CVC group, but in none (0%) in the PICC group. The PICC group had significantly higher rates of achieving the scheduled TPN without removing the catheter, lower rates of catheter-related blood stream infection (CRBSI) and longer periods without CRBSI than the CVC group. CONCLUSION: PICC might be more useful than CVC in terms of safety and the ability to deliver scheduled TPN for IBD patients.
Assuntos
Doenças Inflamatórias Intestinais/terapia , Nutrição Parenteral Total , Adulto , Cateterismo Periférico , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
We report here two cases of advanced colorectal cancer which received chemotherapy, in which partial splenic embolization (PSE) had been effective for controlling splenomegaly and thrombocytopenia. Case 1: A 50-year-old man presented with bloody urine and bloody stool. Computed tomography (CT) showed rectosigmoid cancer with urinary bladder invasion. He underwent colostomy and received chemotherapy. After 3 courses of FOLFOX and 6 courses of bevacizumab/FOLFOX, he suffered from thrombocytopenia with splenomegaly, which led to discontinuation of the therapy. PSE improved thrombocyte counts and enabled him to resume therapy. Case 2: A 72-year-old man presented with bloody stool. Endoscopy and CT showed an advanced rectosigmoid cancer with multiple liver metastases. He underwent low anterior resection and received chemotherapy with FOLFOX and FOLFIRI, together with bevacizumab. After 13 courses of chemotherapy, he also suffered from splenomegaly and thrombocytopenia. PSE produced an increase in thrombocyte count and allowed for a restart of chemotherapy. Oxaliplatin-based chemotherapy may possibly produce hepatic sinusoidal dilation and induce splenomegaly owing to portal hypertension. PSE seemed to be useful for treating thrombocytopenia with splenomagaly, and allowed continuation of the chemotherapy.
Assuntos
Antineoplásicos/efeitos adversos , Compostos Organoplatínicos/efeitos adversos , Neoplasias Retais/tratamento farmacológico , Neoplasias do Colo Sigmoide/tratamento farmacológico , Esplenomegalia/terapia , Trombocitopenia/terapia , Antineoplásicos/uso terapêutico , Embolização Terapêutica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Neoplasias Retais/patologia , Neoplasias do Colo Sigmoide/patologia , Esplenomegalia/induzido quimicamente , Trombocitopenia/induzido quimicamente , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/secundárioRESUMO
We report a duodenal gastrinoma in a 50-year-old man who was admitted to our hospital with tarry stools. Esophagogastroduodenoscopy revealed multiple ulcers in the duodenal bulb and a submucosal tumor in the descending duodenum. His serum gastrin level was 1400pg/ml. We suspected Zollinger-Ellison syndrome and performed selective arterial calcium injection to locate the gastrinoma. Increase in the hepatic venous gastrin level was seen only in the gastroduodenal artery area. We diagnosed a gastrinoma located in the pancreaticoduodenal area. Genetic examination showed a single-base deletion in the MEN-1 gene. At operation, the tumor was found in the submucosal layer of the descending duodenum and was extirpated. He is alive without recurrence 3 years after surgery.
Assuntos
Gluconato de Cálcio , Neoplasias Duodenais/cirurgia , Gastrinoma/cirurgia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Gluconato de Cálcio/administração & dosagem , Neoplasias Duodenais/complicações , Neoplasias Duodenais/diagnóstico por imagem , Gastrinoma/complicações , Gastrinoma/diagnóstico por imagem , Humanos , Injeções Intra-Arteriais , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
A 79-year-old man was admitted on the suspicion of acute pancreatitis. Computed tomography showed acute fluid collection but not typical acute pancreatitis; it formed pseudocysts gradually around the pancreas. Endoscopic retrograde pancreatography (ERP) revealed pancreatic disruption and leakage. Endoscopic nasopancreatic drainage (ENPD) and endoscopic pancreatic stenting (EPS) resulted in collapse of pseudocysts, improvement of symptoms and laboratory data, and a mass in the pancreatic body became distinct. The specimens obtained with endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) showed pancreatic cancer. In conclusion, ENPD and EPS are effective for pancreatic leakage with disruption of the pancreatic duct, and we should take into consideration the possibility of pancreatic cancer when we see patients with pancreatic disruption.
Assuntos
Drenagem/métodos , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/patologia , Stents , Idoso , Biópsia por Agulha Fina , Endoscopia , Humanos , MasculinoRESUMO
A 40's woman was seen at the emergency room because of severe back pain and vomiting. Abdominal CT scan revealed a tumor about 7cm in diameter located on the retroperitoneum. For 6 hours after admission, her body temperature was 39°C and respiratory failure occurred. After 30 hours, the patient died because of a complication in circulatory failure. From the abnormally high level of catecholamines in the blood and autopsy results, we determined that pheochromocytoma multisystem crisis had been caused by the retroperitoneal paraganglioma.
Assuntos
Catecolaminas/metabolismo , Paraganglioma/fisiopatologia , Neoplasias Retroperitoneais/fisiopatologia , Autopsia , Feminino , Humanos , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologiaRESUMO
We report a rare case of metastatic colorectal cancer who suffered from hyperammonemic encephalopathy induced by 5- FU and was continuously treated with FOLFOX therapy. A 50-year-old man with ileus was diagnosed with ascending colon cancer Stage IV, and a right hemicolectomy was performed. Postoperative chemotherapy with modified FOLFOX6 was performed. Complications of nausea and vomiting were seen on day 2 , with confusion and cognitive disturbances on day 3 . None of the other radiographic examinations provided an explanation for his symptoms. Laboratory examination revealed hyperammonemia, so branched-chain amino acid solutions and high-volume drip infusion were started for its treatment. His symptoms entirely disappeared on day 4. We changed to chemotherapy for FOLFOX4 using branched-chain amino acid solutions and drip infusion. The tumor marker level normalized following two courses, and CT following ten courses showed that the size of the lung metastasis and abdominal lymph node had reduced significantly. The patient is currently receiving FOLFOX4.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/efeitos adversos , Hiperamonemia/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Aminoácidos de Cadeia Ramificada/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Terapia Combinada , Fluoruracila/uso terapêutico , Humanos , Hiperamonemia/prevenção & controle , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Metástase Linfática/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
A 65-year-old man was admitted to our hospital because of obstructive jaundice caused by a mass extending in the porta hepatis, neck of gall bladder and extrahepatic bile duct. The specimens obtained with ultrasound-guided needle biopsy showed malignant lymphoma (diffuse large B-cell lymphoma: DLBCL). CHOP with Rituximab therapy (R-CHOP therapy) was performed. The treatment resulted in remarkable reduction of the tumor size and improvement of the biliary stenosis. We should take into consideration malignant lymphoma when we see a patient with a tumor of the hepato-biliary system.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Biópsia por Agulha , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Imageamento por Ressonância Magnética , Masculino , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Rituximab , Tomografia Computadorizada por Raios X , Vincristina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
A 76-year-old woman with serous cystic tumor (SCT) was admitted to our hospital with abdominal pain and was given a diagnosis of severe acute pancreatitis. Infusion of intravenous protein inhibitor and continuous hemodiafiltration (CHDF) were started and she was placed on a respirator, but she died on the 6th day after diagnosis. On autopsy, each SCT cyst showed evidence of hemorrhage. We supposed that the growth of the SCT after hemorrhage compressed the main pancreatic duct and caused severe acute pancreatitis. SCT is benign, and there are no standard treatments. During follow-up of patients with SCT, we should consider the risk of severe acute pancreatitis.
Assuntos
Cistadenoma Seroso/complicações , Neoplasias Pancreáticas/complicações , Pancreatite/etiologia , Doença Aguda , Idoso , Feminino , Humanos , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array. METHODS: We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction. RESULTS: In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02). CONCLUSIONS: IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course.
Assuntos
Povo Asiático/genética , Colite Ulcerativa/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Colite Ulcerativa/etnologia , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA/genética , Humanos , Japão , Estimativa de Kaplan-Meier , MicroRNAs/sangue , Análise de Componente Principal , Receptores de Interleucina/genéticaRESUMO
NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2.
Assuntos
Diabetes Insípido Nefrogênico/patologia , Hidronefrose/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/metabolismo , Poliúria/patologia , Animais , Aquaporina 2/metabolismo , Diferenciação Celular/genética , Diabetes Insípido Nefrogênico/genética , Modelos Animais de Doenças , Feminino , Humanos , Hidronefrose/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/genética , Poliúria/genética , Reabsorção Renal/genéticaRESUMO
Background/Aims. Antitumor necrosis factor antibodies and calcineurin inhibitors have shown good therapeutic efficacy for steroid-refractory ulcerative colitis (UC). Although some studies have compared the efficacy of infliximab (IFX) and cyclosporin A, there are no published studies comparing IFX and tacrolimus (Tac). This study aimed to compare therapeutic efficacies between IFX- and Tac-based strategies for steroid-refractory UC. Methods. Between July 2009 and August 2013, 95 patients with steroid-refractory UC received either IFX (n = 48) or Tac (n = 47) in our hospital. In the IFX group, the patients continued to receive maintenance treatment with IFX. In the Tac group, patients discontinued Tac treatment up to 3 months and subsequently received thiopurine. We retrospectively compared the therapeutic outcomes between the groups. Results. There was no significant difference in the colectomy-free rate, clinical remission rate, and clinical response rate at 2 months between the groups. However, relapse-free survival was significantly higher in the IFX group than in the Tac group (p < 0.001; log-rank test). The proportions of serious adverse events did not differ between the groups. Conclusion. The findings of our study showed that IFX and Tac have similar short-term therapeutic efficacy for steroid-refractory UC. Maintenance treatment with IFX, however, yields better long-term outcomes than Tac-thiopurine bridging treatment.
RESUMO
The Keap1-Nrf2 system plays a central role in cytoprotection against electrophilic/oxidative stresses. Although Cys151, Cys273, and Cys288 of Keap1 are major sensor cysteine residues for detecting these stresses, it has not been technically feasible to evaluate the functionality of Cys273 or Cys288, since Keap1 mutants that harbor substitutions in these residues and maintain the ability to repress Nrf2 accumulation do not exist. To overcome this problem, we systematically introduced amino acid substitutions into Cys273/Cys288 and finally identified Cys273Trp and Cys288Glu mutations that do not affect Keap1's ability to repress Nrf2 accumulation. Utilizing these Keap1 mutants, we generated stable murine embryonic fibroblast (MEF) cell lines and knock-in mouse lines. Our analyses with the MEFs and peritoneal macrophages from the knock-in mice revealed that three major cysteine residues, Cys151, Cys273, and Cys288, individually and/or redundantly act as sensors. Based on the functional necessity of these three cysteine residues, we categorized chemical inducers of Nrf2 into four classes. Class I and II utilizes Cys151 and Cys288, respectively, while class III requires all three residues (Cys151/Cys273/Cys288), while class IV inducers function independently of all three of these cysteine residues. This study thus demonstrates that Keap1 utilizes multiple cysteine residues specifically and/or collaboratively as sensors for the detection of a wide range of environmental stresses.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cisteína/metabolismo , Proteínas do Citoesqueleto/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Linhagem Celular , Cisteína/química , Cisteína/genética , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação , Alinhamento de Sequência , TransfecçãoRESUMO
Oxidative stress accelerates the pathogenesis of a number of chronic diseases including cancer growth and its metastasis. Transcription factor NF-E2-related factor-2 (Nrf2), which regulates the cellular defense system against oxidative stress, elicits essential protection against chemical-induced carcinogenic insults. We recently demonstrate that the systemic deletion of Nrf2 leads to an increased susceptibility to cancer metastasis, which is associated with aberrant reactive oxygen species (ROS) accumulation in myeloid-derived suppressor cells (MDSC). However, it remains elusive whether cellular antioxidant defense system in the myeloid lineage cells plays indispensable roles for metastatic cancer progression. We herein found that myeloid lineage-specific Nrf2-deficient mice exhibited an increased susceptibility to pulmonary metastasis of the mouse Lewis lung carcinoma cells, and ROS level was more highly elevated in MDSCs of cancer-bearing Nrf2-deficient mice. Similarly, myeloid lineage-specific deletion of selenocysteine-tRNA gene (Trsp), which is essential for synthesis of antioxidant selenoenzymes, resulted in increased number of metastatic nodules along with ROS accumulation in MDSCs of cancer-bearing mice. These results thus indicate that the antioxidant systems directed by Nrf2 and selenoenzymes contribute to the clearance of ROS in MDSCs, efficiently preventing cancer cell metastasis. Consistent with this notion, a synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im), a potent Nrf2 inducer, attenuated the ROS production in MDSCs, and thereafter reduced metastatic nodules. Taken together, this study provides compelling lines of evidence that Nrf2 inducer retains therapeutic efficacy against cancer cell metastasis.