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1.
Histopathology ; 75(6): 876-881, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31356680

RESUMO

AIMS: Segmental atrophy (SA) of the liver is a recently described pseudotumour that can show a broad spectrum of histological changes. The previously described histological differential diagnosis of SA has included cystic disease of the liver, amyloid, cancer-associated elastosis, and epithelioid haemangioendothelioma. We have observed that sclerosing cavernous haemangiomas (SCHs) can mimic the nodular elastosis stage of SA; the aim of this study was to explore this differential diagnosis. METHODS AND RESULTS: We identified 20 SCHs and 12 SAs, excluding haemangiomas with treatment effect. Several clinical and morphologic characteristics were examined, and elastin and CD34 staining was performed on cases with available tissue. SA was always asymptomatic, whereas SCH caused symptoms in 56% of patients (P = 0.026); SCH also tended to be larger (mean size: SCH, 47 mm; SA, 16 mm; P = 0.027). Thick-walled blood vessels were more common in SA than in SCH (92% versus 45%, P = 0.011), as was ductular reaction (50% versus 5%, P = 0.0057). The two lesions had similar rates of border irregularity, residual entrapped hepatocytes, matrix oedema, and at least mild elastic fibrosis as seen on special staining, although staining was typically dense and diffuse in SA. CD34 immunostaining demonstrated at least scattered vessels in all cases of SA and SCH. CONCLUSIONS: SCH can mimic SA, although it is generally larger and more often symptomatic. Elastin staining provides a useful adjunct to standard haematoxylin and eosin histological examination in resolving this differential diagnosis.

2.
Clin Exp Gastroenterol ; 12: 219-229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190949

RESUMO

Purpose: The incidence of esophageal adenocarcinoma (EAC) has increased by 700% in Western countries over the last 30 years. Although clinical guidelines call for endoscopic surveillance for EAC among high-risk populations, fewer than 5% of new EAC patients are under surveillance at the time of diagnosis. We studied the accuracy of combined cytopathology and MUC2 immunohistochemistry (IHC) for screening of Intestinal Metaplasia (IM), dysplasia and EAC, using specimens collected from the EsophaCap swallowable encapsulated cytology sponge from Canada and United States. Patients and methods: By comparing the EsophaCap cytological diagnosis with concurrent endoscopic biopsies performed on the same patients in 28 cases, we first built up the cytology diagnostic categories and criteria. Based on these criteria, 136 cases were evaluated by both cytology and MUC2 IHC with blinded to patient biopsy diagnosis. Results: We first set up categories and criteria for cytological diagnosis of EscophaCap samples. Based on these, we divided our evaluated cytological samples into two groups: non-IM group and IM or dysplasia or adenocarcinoma group. Using the biopsy as our gold standard to screen IM, dysplasia and EAC by combined cytology and MUC2 IHC, the sensitivity and specificity were 68% and 91%, respectively, which is in the range of clinically useful cytological screening tests such as the cervical Pap smear. Conclusions: Combined EsophaCap cytology and MUC2 IHC could be a good screening test for IM and Beyond.

3.
Diagn Pathol ; 14(1): 61, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31221180

RESUMO

BACKGROUND: Intestinal metaplasia (IM) of the gastric mucosa is classified as complete (Type I) and incomplete IM (Type II and III) subtypes, which showed significantly different risk for developing to gastric adenocarcinoma (GAC). GCRG213, a variant of L1-endonuclease (L1-EN), first identified in our lab, was upregulated in GAC tissue. However, the relationship between GCRG213 and IM subtypes is not clear. Our study explored the association of GCRG213 protein (GCRG213p) with IM subtypes. METHODS: Gastric cancer and/or para-tumor tissue samples were collected from 123 patients who underwent gastrectomy for intestinal type gastric adenocarcinoma. The subtypes of IM were characterized with Alcian blue-periodic acid-Schiff and High Iron Diamine-Alcian blue staining methods. Immunohistochemistry of GCRG213p was performed, and its expression in gastric adenocarcinoma and para-tumor tissue including dysplasia, IM, and normal mucosa were analyzed. RESULTS: GCRG213p was expressed in 48.94% IM, 57.14% dysplasia and 55.32% GAC, respectively. GCRG213p expression was higher in well and moderately differentiated adenocarcinoma (P = 0.037). In IM glands, GCRG213p expressed mainly in the cytoplasm of absorptive enterocytes with defined brush borders, but not in goblet cells. The expression of GCRG213p in type I IM (90.00%) was significantly higher than that in type II (36.36%) and type III (25.00%) (P < 0.001). In normal gastric mucosa, GCRG213p was exclusively positive in the cytoplasm of gastric chief cells. CONCLUSIONS: The expression of GCRG213p in complete IM was significantly higher than in incomplete IM, which implies that GCRG213p may play a role on the developing of IM to adenocarcinoma. GCRG213p was exclusively expressed in chief cells, suggesting that it might be involved in cell differentiation from the chief cells to IM.


Assuntos
Desoxirribonuclease I/metabolismo , Laminas/metabolismo , Metaplasia/patologia , Neoplasias Gástricas/patologia , Estômago/patologia , Mucosa Gástrica/patologia , Humanos , Imuno-Histoquímica/métodos , Mucosa Intestinal/patologia , Metaplasia/metabolismo , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/metabolismo
4.
Ann Thorac Surg ; 108(2): 343-349, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31059681

RESUMO

BACKGROUND: Recent literature has demonstrated the potential of "liquid biopsy" and detection of circulating tumor (ct)DNA as a cancer biomarker. However, to date there is a lack of data specific to esophageal adenocarcinoma (EAC). This study was conducted to determine how detection and quantification of ctDNA changes with disease burden in patients with EAC and evaluate its potential as a biomarker in this population. METHODS: Blood samples were obtained from patients with stage I to IV EAC. Longitudinal blood samples were collected from a subset of patients. Imaging studies and pathology reports were reviewed to determine disease course. Tumor samples were sequenced to identify mutations. Mutations in plasma DNA were detected using custom, barcoded, patient-specific sequencing libraries. Mutations in plasma were quantified, and associations with disease stage and response to therapy were explored. RESULTS: Plasma samples from a final cohort of 38 patients were evaluated. Baseline plasma samples were ctDNA positive for 18 patients (47%) overall, with tumor allele frequencies ranging from 0.05% to 5.30%. Detection frequency of ctDNA and quantity of ctDNA increased with stage. Data from longitudinal samples indicate that ctDNA levels correlate with and precede evidence of response to therapy or recurrence. CONCLUSIONS: ctDNA can be detected in plasma of EAC patients and correlates with disease burden. Detection of ctDNA in early-stage EAC is challenging and may limit diagnostic applications. However, our data demonstrate the potential of ctDNA as a dynamic biomarker to monitor treatment response and disease recurrence in patients with EAC.


Assuntos
Adenocarcinoma/diagnóstico , DNA Tumoral Circulante/genética , DNA de Neoplasias/genética , Neoplasias Esofágicas/diagnóstico , Mutação , Estadiamento de Neoplasias/métodos , Adenocarcinoma/sangue , Adenocarcinoma/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , Progressão da Doença , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/genética , Feminino , Humanos , Biópsia Líquida , Masculino
5.
Artigo em Inglês | MEDLINE | ID: mdl-31033498

RESUMO

GATA3 is a transcription factor involved in the development and differentiation of lymphocytes, breast, and hair follicles. The protein is a useful immunohistochemical (IHC) marker for supporting diagnoses of breast or urothelial carcinoma. This can be especially helpful in metastatic neoplasms to help delineate site of origin. GATA3 is also reportedly positive in a percentage of pancreatic ductal adenocarcinomas (PDACs) and cholangiocarcinomas (CCs), but no study has closely evaluated this relationship with respect to clininopathologic features or patient outcome. Using tissue microarrays, we analyzed 240 PDACs and 60 CCs with GATA3 IHC and compared expression to various clinical and pathologic parameters. Overall, GATA3 positivity was seen in 16% of PDACs and 5% of CCs. GATA3 positivity in PDAC cases was more common in male patients (P=0.013). GATA3-positive PDACs trended toward worse survival on multivariate analysis (P=0.074). The only 3 GATA3-positive CCs were poorly differentiated (P=0.069); low case number precluded multivariate survival analysis for CCs. GATA3 positivity can occur in carcinomas of the pancreatobiliary system, which should be considered during IHC workup of neoplasms of unclear origin. This positivity seems to have minimal relevance to patient outcome.

6.
Diagn Pathol ; 14(1): 6, 2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30684971

RESUMO

BACKGROUND: Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC. METHODS: Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed. RESULTS: PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P < 0.05). Patients with PD-L1 expression in tumor cells had poor disease-free survival (Hazard ratio [HR] = 1.436, P = 0.009). There was a positive association between tumor cells and tumor-infiltrating immune cells for PD-L1 expression (r = 0.16, P = 0.002). However, PD-L1 expression in tumor-infiltrating immune cells was not significantly correlated with disease-free survival and overall survival. CONCLUSIONS: PD-L1 expression in tumor cells and tumor infiltrating immune cells is not only an indicator for immunotherapy, but also significantly related with age, differentiation, stage, metastasis and disease free survival.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Receptor de Morte Celular Programada 1/metabolismo , Quimiorradioterapia , Estudos de Coortes , Intervalo Livre de Doença , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/terapia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Análise Serial de Tecidos
7.
Am J Clin Pathol ; 151(1): 100-107, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30285068

RESUMO

Objectives: Indications for cholecystectomy have changed dramatically over the past three decades. Cystoisospora belli has been reported in cholecystectomy specimens of immunocompetent patients. The present study was designed to determine the prevalence and clinical association of C belli in the gallbladder. Methods: The study included retrospective review of cholecystectomy specimens (n = 401) removed for various indications, and a prospective cohort of cholecystectomy specimens (n = 22) entirely submitted for histologic evaluation. Correlations of presence of C belli with age, sex, clinical indication, and abnormalities of preoperative laboratory values were assessed by Fisher exact test. Results: C belli was identified in 39/401 (9.7%) of the retrospective cohort, and 6/22 (27.3%) of the entirely submitted specimens. The presence of C belli showed no correlation with age, sex, clinical indication, or laboratory abnormalities. Conclusions: C belli resides in a latent state in the gallbladder and may be best considered a commensal organism.


Assuntos
Coccídios/isolamento & purificação , Coccidiose/parasitologia , Doenças da Vesícula Biliar/parasitologia , Adolescente , Adulto , Colecistectomia , Coccidiose/epidemiologia , Coccidiose/patologia , Coccidiose/cirurgia , Estudos de Coortes , Feminino , Vesícula Biliar/parasitologia , Vesícula Biliar/patologia , Doenças da Vesícula Biliar/epidemiologia , Doenças da Vesícula Biliar/patologia , Doenças da Vesícula Biliar/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
8.
Cell Signal ; 51: 222-232, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30102978

RESUMO

Drug repurposing with a better understanding of the underlying mechanism has provided new avenues to find treatment for malignancies. Esophageal adenocarcinoma (EAC) is a rapidly increasing cancer with a dismal 5-year survival rate of <15%. Lack of efficient treatment options contributes to the high mortality rate of EAC. To find new therapy against EAC we performed unbiased drug screening of an FDA-approved drug library and identified that the cardiac glycosides including Ouabain, Digoxin and Digitoxin efficiently inhibit the proliferation of EAC cell lines (OE33 and OE19) both in vitro and in vivo. RNA-Sequencing analysis combined with RNAi screening revealed that Ouabain suppresses the proliferation of EAC cells through downregulation of p38 MAP-Kinase 6 (MAP2K6, also known as MKK6). Consistently, shRNA-mediated knockdown of MKK6 reduced the proliferation of EAC cells and tumor growth. Further analysis demonstrated that MKK6 inhibition leads to the reduced levels of the transcription factor SOX9. In line with this finding, deletion of SOX9 with CRISPR/Cas9 resulted in decreased proliferation of EACs in 3D organoid culture and reduced tumor growth. Together these findings establish a druggable axis that can be harnessed for therapeutic gain against EAC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , MAP Quinase Quinase 6/antagonistas & inibidores , MAP Quinase Quinase 6/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição SOX9/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Digitoxina/farmacologia , Digitoxina/uso terapêutico , Digoxina/farmacologia , Digoxina/uso terapêutico , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , MAP Quinase Quinase 6/genética , Camundongos Endogâmicos NOD , Ouabaína/farmacologia , Ouabaína/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Transcrição SOX9/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cytojournal ; 15: 29, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30662515

RESUMO

Background: programmed death-ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-L1), which are targeted by several anti-PD-1 and PD-L1 drugs for lung cancer treatment. In clinical practice, many lung cancer cases only have cytology samples available to test PD-L1. Our current study compared the PD-L1 immunohistochemistry (IHC) between paired cytological and surgical samples. Materials and Methods: Formalin-fixed lung cancer tissue microarray and paired cell blocks and surgical specimens from the same patients with a confirmed diagnosis of lung squamous cell carcinoma (SCC, n = 29) and adenocarcinoma (AC, n = 23) were sectioned for PD-L1 IHC. Results: PD-L1 was expressed on tumor cells in 16 of 29 (55%) SCC surgical specimens and 18 of 29 (62%) paired cytologic specimens with 83% matched immunostains. PD-L1 was expressed on tumor cells in 13 of 23 (57%) AC surgical specimens and in 17 of 23 (74%) paired cytologic specimens with 79% matched immunostains. The PD-L1 was expressed on inflammatory cells in 20 of 23 (87%) AC surgical specimens and in 15 of 23 (65%) paired cytologic specimens with 70% matched immunostains. The PD-L1 was expressed on inflammatory cells in 18 of 29 (62%) SCC surgical specimens and in 12 of 29 (41%) paired cytologic specimens with 79% matched immunostains. Conclusions: PD-L1 immunostain in cytology samples matched very well with paired surgical samples in both SCC and AC cases. The cytologic samples present slightly higher sensitivity for PD-L1 immunostain on tumor cells as compared to surgical biopsies.

10.
Nature ; 550(7677): 529-533, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29019984

RESUMO

In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.


Assuntos
Esôfago de Barrett/patologia , Linhagem da Célula , Células Epiteliais/patologia , Epitélio/patologia , Junção Esofagogástrica/patologia , Células-Tronco/patologia , Animais , Esôfago de Barrett/genética , Esôfago de Barrett/metabolismo , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Rastreamento de Células , Esofagite/metabolismo , Esofagite/patologia , Junção Esofagogástrica/metabolismo , Refluxo Gastroesofágico , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Humanos , Queratina-5/metabolismo , Queratina-7/metabolismo , Metaplasia/metabolismo , Metaplasia/patologia , Camundongos , Fosfoproteínas/metabolismo , Células-Tronco/metabolismo , Transativadores/metabolismo
11.
Clin Exp Gastroenterol ; 10: 29-37, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28223834

RESUMO

Bile acid reflux in the esophagus plays an important role in the carcinogenesis of esophageal adenocarcinoma (EAC). The G-protein coupled bile acid receptor (TGR5) has been associated with the development of gastrointestinal cancer. However, little is known regarding the role of TGR5 in esophageal carcinoma and precancerous lesions. We analyzed genomic DNA from 116 EACs for copy number aberrations via Affymetrix SNP6.0 microarrays. The TGR5 gene locus was amplified in 12.7% (14/116) of the EACs. The TGR5 protein expression was also assessed using immunohistochemistry from tissue microarrays, including Barrett's esophagus (BE), low-(LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CM), squamous epithelium (SE), EAC and squamous cell carcinoma. The TGR5 protein was highly expressed in 71% of EAC (75/106), 100% of HGD (11/11), 72% of LGD (13/18), 66% of BE (23/35), 84% of CM (52/62), and 36% of SE (30/83). The patients with high expression of TGR5 exhibited significantly worse overall survival compared to the patients with nonhigh expression. TGR5 high expression was significantly increased in the males compared to the females in all cases with an odds ratio of 1.9 times. The vitamin D receptor (VDR) was significantly correlated with TGR5 expression. Our findings indicated that TGR5 may play an important role in the development and prognosis of EAC through a bile acid ligand. Gender differences in TGR5 and VDR expression may explain why males have a higher incidence of EAC compared to females.

12.
BMC Gastroenterol ; 17(1): 33, 2017 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-28212604

RESUMO

BACKGROUND: Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression. METHODS: Claudin-2 expression was examined by immunohistochemistry on tissue microarrays, containing EAC, high grade dysplasia (HGD), low grade dysplasia (LGD), Barrett's esophagus (BE), columnar cell metaplasia (CM), squamous cell carcinoma (SCC), and squamous epithelium (SE) cases. Intensity (0 to 3) and percentage were scored for each case. High expression was defined as 2-3 intensity in ≥ 10% of cells. RESULTS: Claudin-2 was highly expressed in 77% EAC (86/111), 38% HGD (5/13), 61% LGD (17/28), 46% BE (18/39), 45% CM (29/65), 88% SCC (23/26), and 14% SE (11/76). It was significantly more highly-expressed in EAC, SCC and glandular lesions than in SE and more in EAC than in BE and CM. A significant association was found between Claudin-2 expression and VDR and TGR5 expression. No significant association was found between expression of Claudin-2 and age, gender, grade, stage, or patients' survival time in EAC and SCC. CONCLUSIONS: We conclude that Claudin-2 expression is significantly associated with bile acid receptors VDR and TGR5 expression. Our studies identify a novel role of a tight junction protein in the development and progression of esophageal mucosal metaplasia, dysplasia and carcinoma.


Assuntos
Carcinoma/metabolismo , Claudina-2/metabolismo , Neoplasias Esofágicas/metabolismo , Lesões Pré-Cancerosas/metabolismo , Receptores de Calcitriol/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Carcinoma/patologia , Neoplasias Esofágicas/patologia , Esôfago/metabolismo , Esôfago/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia
13.
Hum Pathol ; 57: 126-135, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27476776

RESUMO

Minichromosomal maintenance (MCM) proteins are participants of DNA replication and may represent more accurate markers in determining the proliferative fraction within a tumor than proliferative marker Ki-67. Our study investigated the correlation between MCM4 and MCM7 expression and Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma, and precancerous lesions. MCM4 and MCM7 expression had similar distribution as Ki-67 and Bmi1 expression in esophageal carcinoma and precancerous lesions. The mean percentage of MCM4, MCM7, and Ki-67 expression increased from squamous epithelium (5.5%, 7.3%, and 5.9%, respectively), to columnar cell metaplasia (11.2, 13.5%, and 3.4%), Barrett's esophagus (27.7%, 35.3%, and 8.3%), low-grade dysplasia (42.6%, 52.2%, and 12.9%), high-grade dysplasia (63.2%, 77.7%, and 29.6%), adenocarcinoma (61.3%, 75.5%, and 24.5%), and squamous cell carcinoma (74.1, 85.4%, and 36.3%). The percentages of MCM4 and MCM7 expression were significantly higher than Ki-67 expression. Using univariate analysis we found a high percentage of MCM4 expression (>70%) to be significantly associated with lymph node metastasis and shorter survival in the adenocarcinoma group. We also demonstrated the percentage of MCM4 and MCM7 expression to be significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal carcinoma and precancerous lesions. MCM4 and MCM7 may serve as more sensitive proliferative markers for the evaluation of esophageal lesions.


Assuntos
Adenocarcinoma/química , Esôfago de Barrett/metabolismo , Carcinoma de Células Escamosas/química , Proliferação de Células , Ciclina E/análise , Neoplasias Esofágicas/química , Antígeno Ki-67/análise , Componente 4 do Complexo de Manutenção de Minicromossomo/análise , Componente 7 do Complexo de Manutenção de Minicromossomo/análise , Complexo Repressor Polycomb 1/análise , Lesões Pré-Cancerosas/química , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Esôfago de Barrett/mortalidade , Esôfago de Barrett/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Distribuição de Qui-Quadrado , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Análise Multivariada , Gradação de Tumores , Lesões Pré-Cancerosas/mortalidade , Lesões Pré-Cancerosas/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Risco , Análise Serial de Tecidos
14.
Neoplasia ; 18(5): 307-316, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27237322

RESUMO

Salmonella infection in humans can become chronic, which leads to low-grade persistent inflammation. These chronic infections increase the risk of several gastrointestinal diseases, including cancer. Salmonella AvrA is a multifunctional protein that influences eukaryotic cell pathways by regulating ubiquitination and acetylation. In an animal model, we have demonstrated that infection with AvrA-expressing Salmonella induces beta-catenin signals and enhances colonic tumorigenesis. Beta-catenin signaling is a key player in intestinal proliferation and tumorigenesis. The relative contributions of AvrA-induced proliferation and inflammation on tumorigenesis, however, are unknown. STAT3 is activated in chronically inflamed intestines in human inflammatory bowel diseases and in colitis-associated colon cancer. In the current study, mice were colonized with Salmonella AvrA-sufficient or AvrA-deficient bacterial strains. Then, inflammation-associated colon cancer was induced through the use of azoxymethane/dextran sulfate sodium. We determined that AvrA-expressing bacteria activated the STAT3 pathway, which is predicted to enhance proliferation and promote tumorigenesis. Transcriptional activity of STAT3 and its target genes were upregulated by Salmonella expressing AvrA, thus promoting proliferation and intestinal tumorigenesis. Our findings provide new insights regarding a STAT3-dependent mechanism by which the specific bacterial product AvrA enhances the development of infection-associated colon cancer. These insights might suggest future biomarkers to risk assessment and early detection of infection-related cancer.


Assuntos
Proteínas de Bactérias/metabolismo , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Fator de Transcrição STAT3/metabolismo , Infecções por Salmonella/complicações , Salmonella/fisiologia , Transdução de Sinais , Animais , Proteínas de Bactérias/genética , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Modelos Biológicos , Infecções por Salmonella/microbiologia
15.
J Gastrointest Surg ; 20(3): 500-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26715559

RESUMO

BACKGROUND: The presence of dilated intercellular spaces in the stratified squamous lining of the esophagus is the pathognomonic feature of reflux esophagitis secondary to gastroesophageal reflux disease (GERD). In addition to stomach acid, bile salts are major constituents of gastroesophageal refluxate. The aim of our study was to determine the effect of bile salts cocktail at different pHs on epithelial junctions in an in vitro transwell model of stratified esophageal squamous epithelium. DISCUSSION: Human telomerase reverse transcriptase (hTERT) immortalized primary esophageal EPC1 cells were grown on polyester transwell surfaces in calcium-enriched media. The cells exhibited gradual stratification into an 11-layered squamous epithelium over 7 days, together with epithelial barrier function as indicated by increased transepithelial electrical resistance (TEER). This stratified epithelium demonstrated well-formed tight junctions, adherens junctions, and desmosomes as visualized by immunofluorescence and electron microscopy. When exposed to short pulses of bile salts at pH 5, but not either condition alone, there was loss of stratification and decrease in TEER, concomitant with disruption of adherens junctions, tight junctions, and desmosomes, leading to the appearance of dilated intercellular spaces. At the cellular level, bile salts at pH 5 activated the Wnt pathway (indicated by increased ß-catenin Ser552 phosphorylation). CONCLUSION: In conclusion, in our in vitro transwell model bile salts at pH 5, but not bile salts or media at pH 5 alone, modulate Wnt signaling, disrupt different junctional complexes, and cause increased permeability of stratified squamous esophageal epithelium. These changes approximate the appearance of dilated intercellular space similar to that found in GERD patients.


Assuntos
Ácidos e Sais Biliares/farmacologia , Células Epiteliais/efeitos dos fármacos , Esôfago/efeitos dos fármacos , Esôfago/patologia , Espaço Extracelular/efeitos dos fármacos , Técnicas de Cultura de Células , Impedância Elétrica , Epitélio/efeitos dos fármacos , Epitélio/patologia , Humanos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/patologia , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo
16.
World J Gastrointest Endosc ; 7(15): 1157-69, 2015 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-26504505

RESUMO

Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neoplastic cysts. Because some pancreatic cysts have more of a malignant potential than others, it is absolutely essential that an accurate diagnosis is rendered so that effective care can be given to each patient. In many centers, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has emerged as the modality of choice that enables one to distinguish between mucinous and non-mucinous lesion, diagnose malignancy and collect cyst fluid for further diagnostic studies, such as pancreatic enzyme levels, molecular analysis and other tumor biomarkers. The current review will focus on EUS-guided FNA and the cytological diagnosis for pancreatic cysts.

17.
BMC Gastroenterol ; 15: 80, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26156831

RESUMO

BACKGROUND: Carbonic anhydrase IX (CA9) is a transmembrane glycoprotein related to hypoxia. Increased CA9 expression has been associated with decreased survival and cancer progression and has been targeted as a potential therapy for several cancers, including esophageal cancer. The reported percentages of expression of CA9 in esophageal adenocarcinoma vary, and CA9 expression in precancerous esophageal lesions has not been well studied. METHODS: In this study, we investigated CA9 expression in esophageal cancers and in precancerous lesions and explored the association of CA9 expression with prognostic factors and with stem cell and tumorigenesis-related markers including BMI1, cyclin E, ki67, MCM4 and MCM7 expression. Previously constructed tissue microarrays consisting of samples of 7 tissue types (columnar cell metaplasia, Barrett esophagus, low- and high-grade dysplasia, esophageal adenocarcinoma, squamous epithelium, and squamous cell carcinoma) were used for the immunostaining of CA9, BMI1, cyclin E, Ki67, MCM4 and MCM7. RESULTS AND DISCUSSION: CA9 high expression occurred more frequently in glandular mucosa with or without dysplasia than in squamous epithelium or squamous cell carcinoma. Survival duration of esophageal adenocarcinoma did not significantly differ between patients with high CA9 expression and those with low expression. High CA9 expression is significantly associated with BMI1, cyclin E, Ki67, MCM4 and MCM7 expression. CONCLUSIONS: High CA9 expression may be related to the acidic environment caused by gastroesophageal reflux disease in the gastroesophageal junction and associated with tumorigenesis through BMI1, MCM4 and MCM7.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Anidrases Carbônicas/metabolismo , Junção Esofagogástrica/patologia , Refluxo Gastroesofágico/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anidrase Carbônica IX , Carcinogênese , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclina E/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Refluxo Gastroesofágico/patologia , Humanos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Componente 4 do Complexo de Manutenção de Minicromossomo/metabolismo , Componente 7 do Complexo de Manutenção de Minicromossomo/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Prognóstico
18.
Hepatology ; 62(2): 466-80, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25820676

RESUMO

UNLABELLED: Vascular invasion provides a direct route for tumor metastasis. The degree to which microRNA (miRNA) expression plays a role in tumor vascular invasion is unclear. Here, we report that miR-494 is up-regulated in human hepatocellular carcinoma (HCC) tumors with vascular invasion and can promote HCC cell invasiveness by gene inactivation of multiple invasion-suppressor miRNAs. Our results show that ten eleven translocation (TET) methylcytosine dioxygenase, predominantly TET1 in HCC cells, is a direct target of miR-494. The reduced 5'-hydroxymethylcytosine levels observed in the proximal cytosine-phosphate-guanine (CpG) regions of multiple invasion-suppressor miRNA genes are strongly associated with their transcriptional repression upon miR-494 overexpression, whereas enforced DNA demethylation can abolish the repression. Furthermore, TET1 knockdown shows a similar effect as miR-494 overexpression. Conversely, miR-494 inhibition or enforced TET1 expression is able to restore invasion-suppressor miRNAs and inhibit miR-494-mediated HCC cell invasion. CONCLUSIONS: miR-494 can trigger gene silencing of multiple invasion-suppressor miRNAs by inhibiting genomic DNA demethylation by direct targeting of TET1, thereby leading to tumor vascular invasion.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Ligação a DNA/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas/genética , Translocação Genética/genética , Animais , Biópsia por Agulha , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Metilação de DNA , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células Hep G2/patologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oxigenases de Função Mista , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Amostragem , Regulação para Cima
19.
J Clin Invest ; 125(4): 1557-68, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25774506

RESUMO

Tissue homeostasis requires balanced self-renewal and differentiation of stem/progenitor cells, especially in tissues that are constantly replenished like the esophagus. Disruption of this balance is associated with pathological conditions, including eosinophilic esophagitis (EoE), in which basal progenitor cells become hyperplastic upon proinflammatory stimulation. However, how basal cells respond to the inflammatory environment at the molecular level remains undetermined. We previously reported that the bone morphogenetic protein (BMP) signaling pathway is critical for epithelial morphogenesis in the embryonic esophagus. Here, we address how this pathway regulates tissue homeostasis and EoE development in the adult esophagus. BMP signaling was specifically activated in differentiated squamous epithelium, but not in basal progenitor cells, which express the BMP antagonist follistatin. Previous reports indicate that increased BMP activity promotes Barrett's intestinal differentiation; however, in mice, basal progenitor cell-specific expression of constitutively active BMP promoted squamous differentiation. Moreover, BMP activation increased intracellular ROS levels, initiating an NRF2-mediated oxidative response during basal progenitor cell differentiation. In both a mouse EoE model and human biopsies, reduced squamous differentiation was associated with high levels of follistatin and disrupted BMP/NRF2 pathways. We therefore propose a model in which normal squamous differentiation of basal progenitor cells is mediated by BMP-driven NRF2 activation and basal cell hyperplasia is promoted by disruption of BMP signaling in EoE.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Esofagite Eosinofílica/patologia , Esôfago/citologia , Fator 2 Relacionado a NF-E2/fisiologia , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/biossíntese , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Proteínas Morfogenéticas Ósseas/biossíntese , Proteínas Morfogenéticas Ósseas/genética , Diferenciação Celular , Células Cultivadas , Esofagite Eosinofílica/metabolismo , Células Epiteliais/metabolismo , Esôfago/crescimento & desenvolvimento , Folistatina/fisiologia , Genes Reporter , Humanos , Hiperplasia , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese , Estresse Oxidativo , Precursores de Proteínas/biossíntese , Precursores de Proteínas/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
20.
Arch Pathol Lab Med ; 139(2): 184-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24694342

RESUMO

CONTEXT: Persistent high-risk human papillomavirus (hrHPV) infection is essential for the development of cervical cancer and its precursor lesions. High-risk HPV testing has a higher sensitivity than cytology does for detecting cervical epithelial lesions. However, a large study from a single institution showed 31% of patients with invasive cervical cancer had negative baseline hrHPV testing within 5 years preceding the diagnosis. OBJECTIVE: To investigate the limitation of hrHPV testing in detecting invasive cervical cancer. DESIGN: Cases from 2012 with a histologic diagnosis of invasive cervical carcinoma were retrieved from multiple institutions. From those records, prior hrHPV testing and Papanicolaou test results in the 5 years before the cancer diagnosis were recorded. RESULTS: Seventy patients with cervical carcinoma were included in the study. Negative HPV test result rates were 9% (5 of 53), 23% (6 of 26), and 25% (2 of 8) during the periods of less than 1 year, 1 to 3 years, and 3 to 5 years before the histologic diagnoses, respectively. Negative Papanicolaou testing results in the same time intervals were 3.4% (2 of 59), 33% (10 of 30), and 40% (6 of 15). Although the HPV(-) rate seemed to be different among different HPV test methods, no statistical significance was detected because of small sample size. Negative hrHPV rates in patients with adenocarcinoma were similar to those in patients with squamous cell carcinoma. CONCLUSIONS: These data expose limitations for the potential use of primary HPV testing. In addition, current screening guidelines recommending cotesting at 5-year intervals should be evaluated further with additional historic data collection because there are women with negative results for both Papanicolaou tests and hrHPV testing within the period of 3 to 5 years before an invasive carcinoma diagnosis.


Assuntos
Alphapapillomavirus/isolamento & purificação , Carcinoma/diagnóstico , Infecções por Papillomavirus/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Teste de Papanicolaou , Infecções por Papillomavirus/patologia , Estudos Retrospectivos , Risco , Estados Unidos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Esfregaço Vaginal
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