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1.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(10): 997-1000, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31630499

RESUMO

Indocyanine green (ICG) fluorescence imaging has been widely used in surgery. In colorectal surgery specifically, more and more studies have shown that intraoperative fluorescence imaging is a safe and feasible method to assess anastomotic perfusion, and its use may decrease the incidence of anastomotic leakage. Meanwhile, indocyanine green can also be used to mark the location of lesion, identify sentinel lymph nodes, protect the ureter, and so on. It can also provide detection and guidance in the operation of peritoneal metastasis and liver metastasis of colorectal cancer. The application of indocyanine green fluorescence imaging can offer great value for surgery through improving the accuracy and outcomes of oncological resections. According to existing studies, we are still at an early application stage of indocyanine green fluorescence imaging technology in colorectal surgery. Lacking prospective randomized controlled studies, neither standards nor guidelines for injection dosage, site and observation period are satisfactory. Therefore, deep researches and establishment of standardized operational procedure are required to enhance the safety and accuracy of tumor resection and improve outcomes.


Assuntos
Colo/cirurgia , Neoplasias Colorretais/diagnóstico , Corantes Fluorescentes/administração & dosagem , Verde de Indocianina/administração & dosagem , Reto/cirurgia , Anastomose Cirúrgica/efeitos adversos , Fístula Anastomótica/etiologia , Fístula Anastomótica/prevenção & controle , Colo/irrigação sanguínea , Colo/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Humanos , Reto/irrigação sanguínea , Reto/patologia
2.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(8): 755-761, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31422614

RESUMO

Objective: To evaluate the risk factors of coloanal anastomotic stricture after laparoscopic intersphincteric resection (Lap-ISR) for patients with low rectal cancer. Methods: A retrospective case-control study was performed to collect clinicopathological data from a prospective database (registration number: ChiCTR-ONC-15007506) at the Department of Colorectal Surgery, the Characteristic Medical center of PLA Rocket Force. From June 2011 to August 2018, a total of 144 consecutive patients with low rectal cancer who underwent Lap-ISR were enrolled in the study. Inclusion criteria: (1) reconstruction of digestive tract by end-to-end hand-made coloanal anastomosis (HCAA); (2) distance from lower tumor margin to anorected sphincter ring < 1 cm and distance from lower tumor margin to intersphincteric groove ≥ 1 cm; (3) T1-3 stage tumor with expected negative circumferential resection margin evaluated by preoperative MRI or 3D endoanal ultrasound; (4) rectal cancer confirmed as well- or moderately-differentiated adenocarcinoma; (5) preoperative Wexner incontinence score >10 points. Exclusion criteria: (1) follow-up period less than 3 months; (2) multiple primary cancers; (3) undergoing colonic J-pouch, coloplasty or reconstruction of end-to-side coloanal anastomosis; (4) death within perioperative period (within 3 months after surgery). Coloanal anastomotic stricture was diagnosed if the index finger or 12 mm electronic colonoscope had obvious resistance through the anastomosis or new rectum, or could not pass, accompanied by clinical symptoms such as difficult defecation and anal incontinence. Degree of anastomotic stricture was divided into 3 grades: grade A required anal enlargement, laxative or enema to assist defecation without active surgical treatment; grade B required surgery or endoscopic intervention; grade C required definitive ostomy, including unreducible preventive ileostomy or permanent colostomy. Univariate and multivariate analysis were used to evaluate the effects of 28 variables, including baseline data (age, gender, body mass index, neoadjuvant therapy, etc.), tumor-related factors (distance between tumor low margin and anal edge, maximum diameter of tumor, TNM staging, etc.), surgery-related factors (operation time, intraoperative blood loss, ISR procedure, anastomotic height, etc.) and anastomotic leakage, on the postoperative coloanal anastomotic stricture. Univariate analysis used χ(2) test or Fisher's exact test, then factors with P<0.05 were further included in multivariate analysis using logistic regression. Results: A total of 144 patients were enrolled in the study, including 90 males and 54 females with a median age of 59 years and median BMI of 24.88 kg/m(2). R0 resection rate was 96.5% (139/144). Median tumor distal resection margin was 1.5 (0.5 to 3.0) cm. Median follow-up was 31.5 (4 to 86) months. Coloanal anastomotic stricture was observed in 19 patients (13.2%), including 3 cases (2.1%) of grade A, 9 cases (6.2%) of grade B, and 7 cases (4.9%) of grade C. The median interval from the initial surgery to diagnosis of anastomotic stricture was 7 (1 to 31) months. Univariate analysis showed that male (χ(2)=6.795, P=0.009), radiotherapy (χ(2)=13.330, P=0.001), operation type of ISR (χ(2)=7.996, P=0.013), and anastomotic leakage (χ(2)=10.198, P=0.004) were associated with the postoperative coloanal anastomotic stricture. Multivariate analysis further indicated that male (OR=5.975, 95% CI: 1.209-29.534, P=0.028), postoperative radiotherapy (OR=8.748, 95% CI: 2.397-31.929, P=0.001), and anastomotic leakage (OR=6.313, 95% CI: 1.834-21.734, P=0.003) were independent risk factor of postoperative coloanal anastomotic stricture. Conclusion: For male patients, or patients with postoperative radiotherapy or anastomotic leakage, close follow-up should be carried out to prevent postoperative coloanal anastomotic stricture following Lap-ISR.


Assuntos
Adenocarcinoma/cirurgia , Canal Anal/patologia , Anastomose Cirúrgica/efeitos adversos , Colo/patologia , Constrição Patológica/patologia , Neoplasias Retais/cirurgia , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Canal Anal/cirurgia , Colo/cirurgia , Constrição Patológica/etiologia , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Retais/complicações , Neoplasias Retais/patologia , Estudos Retrospectivos , Fatores de Risco
3.
J Med Life ; 12(2): 133-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406514

RESUMO

Colon cancer is the most commonly diagnosed gastrointestinal cancers in developed countries with varied incidence and the onset age of disease worldwide. Overall, 161 participants who were under patronage of a local relief foundation and referred to the endoscopy ward of Razi Hospital affiliated to the Guilan University of Medical Sciences. These patients have been aged more than 50 or more than 40 years with history of colorectal cancer in their first-degree family were enrolled from March 2016-March 2017. Demographic information were collected. Colonoscopy was performed and histopathological evaluation of observed lesions and polyps was done. Most of participants were female (113 individuals, 70.2%) and aged 50-60 years (83 individuals, 51.6%). Seventy-four (46%) had certain lesions. Most of colonoscopy findings were observed in the ascending colon in which depressed polyps and diverticulum were most frequent. However, rectum showed the most histological findings. All polyps of descending and ascending colons were neoplastic, while most of rectal polyps were non-neoplastic. Male patients, who were aged more than 60 years and smokers had significant higher percentage of both lesions and polyps in their colon (p<0.05). Moreover, significant positive association was detected between exposure to harmful industries and having polyps (p=0.01). We found male gender, higher age, smoking, and exposure to harmful industries as important risk factors for having colorectal lesions, which must be confirmed in further studies.


Assuntos
Neoplasias do Colo/epidemiologia , Lesões Pré-Cancerosas/epidemiologia , Colo/patologia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Pólipos do Colo/patologia , Colonoscopia , Feminino , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Humanos , Incidência , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico por imagem , Prevalência , Análise de Regressão , Fatores de Risco
4.
J Med Life ; 12(2): 156-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406517

RESUMO

Analyzing colon biopsies is becoming time consuming and a financial burden as colonoscopy is now the main screening and diagnostic procedure of the main gastrointestinal diseases. Colon sampling can provide important information when used accordingly; otherwise it may only load the medical system unnecessarily. Our aim was to retrospectively analyze criteria for colon biopsies and correlate the diagnostic value of randomly sampling colon, especially in patients with diarrhea. This was a retrospective study on 2109 colonoscopies done over one year. Data was collected from the ENDORAD system and included variables such as: age, gender, quality of preparation, procedure, symptoms, biopsies (type, location), and endoscopy and histology findings. Data was analyzed in a descriptive manner. Out of 496 random biopsies, only 7.4% had positive histology findings. The main symptom was diarrhea and 186 cases of patients complaining of diarrhea with normal colonoscopy had random colon sampling. In 5.3% of these cases histology assessment showed changes of microscopic colitis. Fisher's test was significant when correlating the odds of having random biopsies in patients with and without diarrhea and patients younger and older than 60. Random sampling of colon during colonoscopies should be done only in selected patients otherwise it has a low diagnostic value.


Assuntos
Colo/patologia , Biópsia , Colonoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Probabilidade , Estudos Retrospectivos
5.
Cancer Sci ; 110(9): 2834-2845, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278880

RESUMO

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor ß receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metformina/farmacologia , Fenformin/farmacologia , Neoplasias Retais/terapia , Transdução de Sinais/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia/métodos , Colo/patologia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Metformina/uso terapêutico , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Fenformin/uso terapêutico , Neoplasias Retais/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos da radiação , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Parasit Vectors ; 12(1): 349, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300009

RESUMO

BACKGROUND: Four species of Strongyloides, Strongyloides felis, Strongyloides planiceps, Strongyloides stercoralis and Strongyloides tumefaciens, have been identified in cats based on morphology and location in the host with limited data on the prevalence and disease potential of these different species. Strongyloides tumefaciens adults are located in colonic nodules while the other three species are in the small intestine. The literature on Strongyloides in cats is scattered and has never been compiled. The aim of this article is to provide a short review of the existing literature on Strongyloides spp. in cats, to describe the pathology of colonic nodules containing Strongyloides sp. seen at necropsies of cats in St. Kitts, West Indies, and to provide the first unequivocal report of zoonotic S. stercoralis in cats based on sequencing analysis of a portion of the cytochrome c oxidase subunit 1 (cox1) gene, and supported by phylogenetic analysis. RESULTS: Colonic nodules containing sections of nematodes, histologically compatible with Strongyloides sp. were seen during necropsy in six cats in St. Kitts, West Indies. Sequencing of the cox1 gene of the mitochondrial DNA extracted from colonic nodules from two of these cats matched sequences of the zoonotic strain of S. stercoralis. CONCLUSIONS: The morphological similarities between S. stercoralis-associated colonic nodules and previous reports of S. tumefaciens, together with the insufficient defining criteria for S. tumefaciens raises questions about the validity of the species. Further sampling and genetic characterization of isolates is needed to understand the species in cats and their zoonotic potential.


Assuntos
Gatos/parasitologia , Colo/patologia , Hiperplasia/parasitologia , Estrongiloidíase/veterinária , Zoonoses/parasitologia , Animais , Colo/citologia , Colo/parasitologia , DNA Mitocondrial/genética , DNA Ribossômico/genética , Fezes/parasitologia , Helmintos/genética , Filogenia , RNA Ribossômico 18S/genética , Strongyloides stercoralis/patogenicidade , Estrongiloidíase/epidemiologia , Índias Ocidentais , Zoonoses/patologia
7.
Gastroenterology ; 157(3): 744-759.e4, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31154022

RESUMO

BACKGROUND & AIMS: Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis. METHODS: Colon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS: Levels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS: Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.


Assuntos
Adenocarcinoma/prevenção & controle , Colo/enzimologia , Neoplasias do Colo/prevenção & controle , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Proteínas Nucleares/metabolismo , PPAR alfa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Anticarcinógenos/farmacologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Colo/patologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/efeitos dos fármacos , Bases de Dados Genéticas , Modelos Animais de Doenças , Fenofibrato/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , PPAR alfa/agonistas , PPAR alfa/deficiência , PPAR alfa/genética , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais
8.
Food Chem Toxicol ; 131: 110596, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226429

RESUMO

This study investigated the effects of chlorpyrifos (CPF) on immune-cell populations and intestinal inflammation using a mouse model of inflammatory bowel disease induced by dextran sulfate sodium (DSS). C57BL/6 mice were randomly assigned to five groups with one normal control (NC) and four DSS-treated groups. Mice in the NC group were given distilled water, whereas the DSS-treated groups received distilled water containing 3% DSS for 6 days to induce colitis. The NC and disease control (DC) groups were fed a control semipurified diet, while the remaining groups were exposed to CPF in the AIN-93 diet at doses of 1, 2.5, or 5 mg/kg/day throughout the study. Results showed that dietary exposure to CPF in colitic mice significantly increased circulating classical monocytes and upregulated gene expressions of chemokines in the colon compared to the NC group. Meanwhile, CPF exposure groups had lower plasma cholinesterase activities and higher percentages of circulating neutrophils than those of the DC group. A shorten length, tissue edema, and lipid peroxidation of the colon were also observed in all CPF-exposed mice. These findings suggest that dietary exposure to CPF affected immune-cell populations and inflammatory responses, which led to more severe tissue injury in mice with DSS-induced colitis.


Assuntos
Clorpirifos/toxicidade , Colite/imunologia , Leucócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana , Exposição Dietética , Leucócitos/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
11.
Nat Commun ; 10(1): 2712, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221971

RESUMO

Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. While it is clear that C. difficile toxins cause damaging colonic inflammation, the immune mechanisms protecting from tissue damage require further investigation. Through a transcriptome analysis, we identify IL-33 as an immune target upregulated in response to hypervirulent C. difficile. We demonstrate that IL-33 prevents C. difficile-associated mortality and epithelial disruption independently of bacterial burden or toxin expression. IL-33 drives colonic group 2 innate lymphoid cell (ILC2) activation during infection and IL-33 activated ILC2s are sufficient to prevent disease. Furthermore, intestinal IL-33 expression is regulated by the microbiota as fecal microbiota transplantation (FMT) rescues antibiotic-associated depletion of IL-33. Lastly, dysregulated IL-33 signaling via the decoy receptor, sST2, predicts C. difficile-associated mortality in human patients. Thus, IL-33 signaling to ILC2s is an important mechanism of defense from C. difficile colitis.


Assuntos
Clostridium difficile/imunologia , Enterocolite Pseudomembranosa/imunologia , Imunidade Inata , Interleucina-33/metabolismo , Linfócitos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/efeitos adversos , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Clostridium difficile/patogenicidade , Colo/citologia , Colo/imunologia , Colo/microbiologia , Colo/patologia , Modelos Animais de Doenças , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Enterocolite Pseudomembranosa/terapia , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Perfilação da Expressão Gênica , Humanos , Interleucina-33/imunologia , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia , Virulência/imunologia , Adulto Jovem
12.
J Exp Clin Cancer Res ; 38(1): 190, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072360

RESUMO

BACKGROUND: One of the most potent costimulatory molecules involved in the recognition and killing of tumor cells is CD80. However, its role and the molecular mechanisms regulating its expression in sporadic colorectal carcinogenesis remain elusive. Here, we provide evidence for CD80 overexpression in human colon epithelial cells derived from preneoplastic mucosa. METHODS: Expression of CD80 on colonic epithelial cells isolated from normal human colonic mucosa, preneoplastic and neoplastic specimens was assessed by flow cytometry. WT and CD80KO mice received azoxymethane to induce colon preneoplastic lesions and sacrificed to perform histology, flow cytometry analysis and immunohistochemistry of colonic mucosa. Some WT mice were treated with a monoclonal anti-CD80 antibody following AOM administration. Primary colon epithelial cells and CT26 cell line were used to quantify the expression of CD80 in response to pro-oxidant stimuli. Specific pharmacological inhibitors and siRNA silencing were used to inhibit MAPK pathways and STAT3. RESULTS: CD80 expression was significantly increased in colon epithelial cells of human preneoplastic lesions. In the AOM model, CD80 impairment by administration of neutralizing antibodies or use of CD80 knockout mice enhanced dysplasia development. In vitro, CD80 upregulation was induced by oxidative stress in colon cancer cells and primary colon epithelial cells. In addition, reactive oxygen species could induce CD80 expression via the JNK and p38 MAPK pathways, that activated STAT3 transcription factor in colon cancer epithelial cells. CONCLUSION: This study provide evidence for a major role of CD80 in orchestrating immune surveillance of colon preneoplastic lesions and might help to develop novel approaches that exploit anti-tumor immunity to prevent and control colon cancer.


Assuntos
Antígeno B7-1/genética , Neoplasias do Colo/genética , Lesões Pré-Cancerosas/genética , Fator de Transcrição STAT3/genética , Animais , Antígeno B7-1/imunologia , Carcinogênese/genética , Carcinogênese/imunologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem/métodos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/patologia , Cultura Primária de Células , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
13.
World J Gastroenterol ; 25(15): 1865-1878, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057300

RESUMO

BACKGROUND: Unconjugated bilirubin (UCB) is generally considered toxic but has gained recent prominence for its anti-inflammatory properties. However, the effects of it on the interaction between intestinal flora and organisms and how it influences immune responses remain unresolved. AIM: To investigate the role of UCB in intestinal barrier function and immune inflammation in mice with dextran-sulfate-sodium-induced colitis. METHODS: Acute colitis was induced by 3% (w/v) dextran sulfate sodium salt in drinking water for 6 d followed by untreated water for 2 d. Concurrently, mice with colitis were administered 0.2 mL UCB (400 µmol/L) by intra-gastric gavage for 7 d. Disease activity index (DAI) was monitored daily. Mice were sacrificed at the end of the experiment. The length of the colon and weight of the spleen were recorded. Serum level of D-lactate, intestinal digestive proteases activity, and changes to the gut flora were analyzed. In addition, colonic specimens were analyzed by histology and for expression of inflammatory markers and proteins. RESULTS: Mice treated with UCB had significantly relieved severity of colitis, including lower DAI, longer colon length, and lower spleen weight (colon length: 4.92 ± 0.09 cm vs 3.9 ± 0.15 cm; spleen weight: 0.33 ± 0.04 vs 0.74 ± 0.04, P < 0.001). UCB administration inactivated digestive proteases (chymotrypsin: 18.70 ± 0.69 U/g vs 44.81 ± 8.60 U/g; trypsin: 1.52 ± 0.23 U/g vs 9.05 ± 1.77 U/g, P < 0.01), increased expression of tight junction (0.99 ± 0.05 vs 0.57 ± 0.03, P < 0.001), decreased serum level of D-lactate (31.76 ± 3.37 µmol/L vs 54.25 ± 1.45 µmol/L, P < 0.001), and lowered histopathological score (4 ± 0.57 vs 7 ± 0.57, P < 0.001) and activity of myeloperoxidase (46.79 ± 2.57 U/g vs 110.32 ± 19.19 U/g, P < 0.001). UCB also regulated the intestinal microbiota, inhibited expression of tumor necrosis factor (TNF) α and interleukin 1ß (TNF-α: 52.61 ± 7.81 pg/mg vs 105.04 ± 11.92 pg/mg, interleukin 1ß: 13.43 ± 1.68 vs 32.41 ± 4.62 pg/mg, P < 0.001), decreased expression of Toll-like receptor 4 (0.61 ± 0.09 vs 1.07 ± 0.03, P < 0.001) and myeloid differentiation primary response gene 88 (0.73 ± 0.08 vs 1.01 ± 0.07, P < 0.05), and increased expression of TNF-receptor-associated factor 6 (0.79 ± 0.02 vs 0.43 ± 0.09 P < 0.05) and inhibitor of kappa B α (0.93 ± 0.07 vs 0.72 ± 0.07, P < 0.05) in the colon. CONCLUSION: UCB can protect intestinal barrier function, regulate normal intestinal homeostasis, and suppress inflammation via the Toll-like receptor 4/ nuclear factor-κB signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Bilirrubina/farmacologia , Colite Ulcerativa/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Bilirrubina/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Colo/imunologia , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , NF-kappa B/metabolismo , Permeabilidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento
14.
BMC Cancer ; 19(1): 421, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060539

RESUMO

BACKGROUND: Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR. METHODS: Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-ß, and PI3K). RESULTS: Mutation of genes within the WNT, P53, RTK-RAS, TGF-ß, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-ß pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-ß pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p <  0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-ß pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-ß pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation. CONCLUSIONS: Mutation in genes within TGF-ß pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.


Assuntos
Adenocarcinoma Mucinoso/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Recidiva Local de Neoplasia/genética , Transdução de Sinais/genética , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante/métodos , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Leucovorina/uso terapêutico , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Compostos Organoplatínicos/uso terapêutico , Cuidados Paliativos/métodos , Prognóstico , Reto/patologia , Reto/cirurgia , Análise de Sobrevida , Fator de Crescimento Transformador beta/metabolismo
15.
BMC Cancer ; 19(1): 429, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072339

RESUMO

BACKGROUND: Despite rising incidence rates of colorectal malignancies, only a few prognostic tools have been implemented in proven clinical routine. Cell division and proliferation play a significant role in malignancies. In terms of colorectal cancer, the impact of proliferation associated proteins is controversially debated. The aim of our study was to examine the expression of topoisomerase II α and minichromosome maintenance protein 6 and to correlate these findings with the clinical data. METHODS: Tissue samples of 619 patients in total were stained using the antibodies Ki-S4 and Ki-MCM6 targeting topoisomerase II α as well as minichromosome maintenance protein 6. The median rate of proliferation was correlated with clinical and follow up data. RESULTS: The expression rate of minichromosome maintenance protein 6 is significantly higher than the proportion of topoisomerase II α in tumour cells (p < 0.001). A high expression of both proteins coincides with a beneficial outcome for the patient, indicating a favourable prognostic marker (p < 0.001 and p = 0.008). CONCLUSIONS: We have demonstrated that high expression rates of proliferative markers is linked to a beneficial patient outcome. According to the general opinion, a high expression rate correlates with a poor patient outcome. In this study, we were able to refute this assertion.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , DNA Topoisomerases Tipo II/metabolismo , Componente 6 do Complexo de Manutenção de Minicromossomo/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Idoso , Proliferação de Células , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reto/patologia , Reto/cirurgia , Estudos Retrospectivos , Análise de Sobrevida
16.
BMC Cancer ; 19(1): 428, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072353

RESUMO

BACKGROUND: Colorectal cancer remains the second leading cause of cancer death in the United States, and increased risk in patients with ulcerative colitis (a subset of inflammatory bowel disease) has motivated studies into early markers of dysplasia. The development of clinically translatable multiphoton imaging systems has allowed for the potential of in vivo label-free imaging of epithelial crypt structures via autofluorescence and/or second harmonic generation (SHG). SHG has been used to investigate collagen structures in various types of cancer, though the changes that colorectal epithelial collagen structures undergo during tumor development, specifically colitis-associated tumors, have not been fully investigated. METHODS: This study used two murine models, using A/J mice, one for spontaneous carcinoma and one for colitis-associated carcinoma, to investigate and quantify SHG image features that could potentially inform future study designs of endoscopic multiphoton imaging systems. The spontaneous tumor model comprised a series of six weekly injections of azoxymethane (AOM model). The colitis-associated tumor model comprised a single injection of AOM, followed by cycles of drinking water with dissolved dextran sodium sulfate salt (AOM-DSS model). SHG images of freshly resected murine colon were acquired with a multiphoton imaging system, and image features, such as crypt size, shape and distribution, were quantified using an automated algorithm. RESULTS: The comparison of quantified features of crypt morphology demonstrated the ability of our quantitative image feature algorithms to detect differences between spontaneous (AOM model) and colitis-associated (AOM-DSS model) murine colorectal tissue specimens. There were statistically significant differences in the mean and standard deviation of nearest neighbor (distance between crypts) and circularity between the Control cohort, AOM and AOM-DSS cohorts. We also saw significance between AOM and AOM-DSS cohorts when calculating nearest neighbor in images acquired at fixed depths. CONCLUSION: The results provide insight into the ability of SHG imaging to yield relevant data about the crypt microstructure in colorectal epithelium, specifically the potential to distinguish between spontaneous and colitis-associated murine models using quantification of crypt shape and distribution, informing future design of translational multiphoton imaging systems and protocols.


Assuntos
Colite/patologia , Colo/patologia , Neoplasias do Colo/diagnóstico por imagem , Mucosa Intestinal/patologia , Microscopia de Geração do Segundo Harmônico , Animais , Colite/induzido quimicamente , Colite/diagnóstico por imagem , Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Humanos , Mucosa Intestinal/diagnóstico por imagem , Camundongos
17.
BMC Cancer ; 19(1): 431, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072372

RESUMO

BACKGROUND: Colorectal cancer (CRC) is globally one of the most common cancers. Although studies have found a significant prognostic impact of cancer location for right-sided colon cancers compared with those of the left-side, evidence is lacking in a Japanese population. Therefore, we investigated 5-year net survival in colon cancer by tumor site in a Japanese population. METHODS: Diagnoses obtained between 2006 and 2008 in 21 population-based cancer registries from the Monitoring of Cancer Incidence in Japan (MCIJ) project were used. Colon cancer patients were categorized as having right-sided (C18.0-18.4) or left-sided colon cancer (C18.5-C18.7). We calculated the 5-year net survival for subjects diagnosed from 2006 until 2008 by anatomical subsite according to sex, age groups, tumor stage at diagnosis. We applied the excess mortality model to calculate excess hazard ratios (EHRs) and 95% confidential intervals (CIs) with and without adjustment for age, sex and cancer stages to evaluate the effect of location of colon cancer. RESULTS: This study analyzed a total of 62,350 colon cancer subjects. Five-year net survivals for subjects with left- and right-sided colon cancer were 74.0% (95% CI, 73.4-74.7%) and 70.4% (95% CI, 69.7-71.0%), respectively. Compared with left-sided colon cancers, the EHR for right-sided colon cancers was 1.20 (95% CI, 1.16-1.25) after adjustment for age, sex and stage. CONCLUSION: Our study found that the net survival for right-sided colon cancer was significantly lower than that for left-sided colon cancer. The anatomical site of cancer in the colon might be an important stratification factor in future studies of colon cancer.


Assuntos
Colo/patologia , Neoplasias do Colo/mortalidade , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Taxa de Sobrevida
18.
Acta Cir Bras ; 34(4): e201900406, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31038584

RESUMO

PURPOSE: To evaluate the inflammatory reaction and measure the content of mucins, in the colonic mucosa without fecal stream submit to intervention with mesalazine. METHODS: Twenty-four rats were submitted to a left colostomy and a distal mucous fistula and divided into two groups according to euthanasia to be performed two or four weeks. Each group was divided into two subgroups according daily application of enemas containing saline or mesalazine at 1.0 g/kg/day. Colitis was diagnosed by histological analysis and the inflammatory reaction by validated score. Acidic mucins and neutral mucins were determined with the alcian-blue and periodic acid of Schiff techniques, respectively. Sulfomucin and sialomucin were identified by high iron diamine-alcian blue technique. The tissue contents of mucins were quantified by computer-assisted image analysis. Mann-Whitney test was used to analyze the results establishing the level of significance of 5%. RESULTS: Enemas with mesalazine in colonic segments without fecal stream decreased the inflammation score and increased the tissue content of all subtypes of mucins. The increase of tissue content of neutral, acid and sulfomucin was related to the time of intervention. CONCLUSION: Mesalazine enemas reduce the inflammatory process and preserve the content of mucins in colonic mucosa devoid of fecal stream.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colo/efeitos dos fármacos , Enema/métodos , Mucosa Intestinal/efeitos dos fármacos , Mesalamina/farmacologia , Mucinas/análise , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Colite/patologia , Colite/prevenção & controle , Colo/metabolismo , Colo/patologia , Colostomia , Fezes , Trânsito Gastrointestinal , Histocitoquímica , Processamento de Imagem Assistida por Computador , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Mesalamina/uso terapêutico , Mucinas/efeitos dos fármacos , Estresse Oxidativo , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
19.
J Comput Assist Tomogr ; 43(3): 475-484, 2019 May/Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31082955

RESUMO

Three-dimensional (3D) visualizations of computed tomography (CT) data have found use in the display of complex anatomy and pathology. A new method of 3D CT image creation known as cinematic rendering (CR) makes use of a global lighting model to produce photorealistic images. Cinematic rendering images contain high levels of detail with shadowing and depth that are not available from traditional 3D CT techniques. As yet, the role of CR in evaluating colonic pathology has not been investigated. However, given the breadth of pathologic processes that affect the colon, including inflammatory bowel disease, diverticulitis, neoplastic conditions, herniation, and gastrointestinal bleeding, we undertook a survey of recent cases at our institution to demonstrate colon pathology as visualized with CR. The following review discusses the role of 3D CT visualizations for colonic pathology with an emphasis on CR example images.


Assuntos
Colo/patologia , Tomografia Computadorizada por Raios X/métodos , Colo/diagnóstico por imagem , Feminino , Humanos , Imagem Tridimensional , Masculino , Interpretação de Imagem Radiográfica Assistida por Computador/métodos
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