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1.
BMC Cancer ; 20(1): 400, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32384877

RESUMO

BACKGROUND: Mucinous adenocarcinoma (MAC) is a distinct type of colorectal cancer (CRC) associated with poor response to treatment and poorer prognosis. MAC is diagnosed by WHO definition when the extracellular mucin is more than 50% of the lesion. We aimed at assessing the gene expression profiles of the CRCs with any mucinous features (> 5%) in a retrospective study. METHODS: The data of a 50-gene next generation sequencing (NGS) panel of 166 CRCs was analyzed and the gene mutational profile with morphologic features was correlated. RESULTS: We identified the different genetic mutation profiles between CRCs with and without mucinous component, but noticed a similar genetic profile between MACs and CRCs with mucinous component, irrespective of the percentage (if mucinous component more than 5%). The different genetic mutation profile related to MSI status was also identified between two groups of tumors. The most frequent mutations in CRCs with mucinous component are KRAS (28/49, 57.1%) and BRAF (19/49, 38.7%), PIK3CA (16/49, 32.6%), followed by APC (12/49, 24.5%) and TP53 (11/49, 22.5%). The combined mutation frequency of the two key factors in the EGFR signaling pathway, KRAS and BRAF, in the CRCs with and without mucinous component is 95.9 and 52.1%, respectively. CONCLUSIONS: The dysregulation of EGFR pathway plays a critical role in the development of CRCs with mucinous component, irrespective of the percentage. The result suggested that the current cut off of 50% mucin component to define mucinous adenocarcinoma might be challengeable.


Assuntos
Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/genética , Neoplasias Colorretais/patologia , Taxa de Mutação , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma Mucinoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
2.
Histopathology ; 76(3): 461-469, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31491041

RESUMO

AIMS: High-grade appendiceal mucinous neoplasm (HAMN) was recently proposed as a disease entity histologically analogous to low-grade appendiceal mucinous neoplasm (LAMN), but characterised by high-grade cytological atypia. The pathogenesis and clinical features of HAMN have not been fully elucidated. METHODS AND RESULTS: Nine cases of HAMN, eight LAMN, 10 appendiceal mucinous adenocarcinomas (MACA) and five appendiceal serrated polyps resected between 2008 and 2017 contributed by three medical centres underwent targeted next-generation sequencing of 50 cancer-related genes. The patients in each category had similar profiles with respect to gender, age, tumour stage and follow-up intervals. Both LAMN and HAMN harboured mutations of KRAS [nine of nine and eight of eight (100%), respectively] and GNAS [five of eight (63%) and five of nine (56%), respectively] in significantly higher proportions than MACA [KRAS, seven of 10 (70%, P = 0.04); GNAS: one of 10 (10%, P = 0.02)] and serrated polyps [KRAS, one of five (20%, P = 0.0007); GNAS: none of five (0%, P = 0.04)]. Four cases of HAMN, but none of LAMN, harboured mutations of TP53 [four of nine (44%)] and/or ATM [two of nine (22%)]. Three cases of HAMN (33%) showed extra-appendiceal spread with retention of the same mutational profiles in the intra- and extra-appendiceal components. The 10 cases of MACA harboured a similar prevalence of TP53 mutations (n = 5, 50%) as HAMN but, unlike LAMN and HAMN, some harboured mutations in PIK3CA, APC, FBXW7, PTEN and SMAD4. CONCLUSIONS: HAMN and LAMN share high rates of KRAS and GNAS co-mutations supporting a common histogenesis and distinguishing them from MACA. Acquisition of TP53 or ATM mutations by HAMN may drive its progression to a more advanced phenotype.


Assuntos
Adenocarcinoma Mucinoso/genética , Neoplasias do Apêndice/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Apêndice/patologia , Apêndice/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Estudos Retrospectivos , Análise de Sequência de DNA
3.
Nat Microbiol ; 3(10): 1131-1141, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30202015

RESUMO

As a conserved pathway that lies at the intersection between host defence and cellular homeostasis, autophagy serves as a rheostat for immune reactions. In particular, autophagy suppresses excess type I interferon (IFN-I) production in response to viral nucleic acids. It is unknown how this function of autophagy relates to the intestinal barrier where host-microbe interactions are pervasive and perpetual. Here, we demonstrate that mice deficient in autophagy proteins are protected from the intestinal bacterial pathogen Citrobacter rodentium in a manner dependent on IFN-I signalling and nucleic acid sensing pathways. Enhanced IFN-stimulated gene expression in intestinal tissue of autophagy-deficient mice in the absence of infection was mediated by the gut microbiota. Additionally, monocytes infiltrating into the autophagy-deficient intestinal microenvironment displayed an enhanced inflammatory profile and were necessary for protection against C. rodentium. Finally, we demonstrate that the microbiota-dependent IFN-I production that occurs in the autophagy-deficient host also protects against chemical injury of the intestine. Thus, autophagy proteins prevent a spontaneous IFN-I response to microbiota that is beneficial in the presence of infectious and non-infectious intestinal hazards. These results identify a role for autophagy proteins in controlling the magnitude of IFN-I signalling at the intestinal barrier.


Assuntos
Autofagia/fisiologia , Microbioma Gastrointestinal/imunologia , Interferon Tipo I/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Citrobacter rodentium/crescimento & desenvolvimento , Infecções por Enterobacteriaceae/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/lesões , Mucosa Intestinal/microbiologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Monócitos/imunologia , Mutação , Receptores CCR2/deficiência , Receptores CCR2/genética , Receptores CCR2/metabolismo
4.
ACG Case Rep J ; 4: e120, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29201931

RESUMO

Drug-induced injury (DILI) is a frequent cause of abnormal liver tests and a leading cause of liver failure in the United States. Colchicine has long been used as a systemic anti-inflammatory agent for treatment of gout by inhibiting mitotic activity and neutrophil function. We present the first case of colchicine-induced hepatoxicity, supported by histopathologic findings characteristic of colchicine-induced injury and resolution of liver enzyme abnormalities after its discontinuation. Colchicine-associated DILI has implications for the evaluation of patients with abnormal liver tests and gout, especially for patients with alcoholism and non-alcoholic fatty liver disease, in whom there is an increased incidence of gout.

5.
Hum Pathol ; 68: 92-98, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28873351

RESUMO

Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI. Electronic medical records were reviewed for patient medication list, history of herbal medicine or supplement use, and pre-biopsy liver function test (LFT) results. Clinical and pathologic correlation was used to determine the causative or related agents for DILI. We then assessed histopathologic features of liver injury and categorized biopsy findings as primarily bile duct injury, lobular/portal hepatitis, or mixed changes. Six hundred four total liver biopsies for hepatitis or liver injury were identified, of which 70 cases (11.6%) carried the diagnosis of DILI confirmed by clinical correlation. The most common etiologies associated with DILI were supplements and herbal products (31.4%), antimicrobials (14.3%), chemotherapeutics (11.4%), antilipidemics (7.1%) and immunomodulatory agents (7.1%). LFT results positively correlated with histological findings. Nutritional/herbal supplements have emerged as one of the major hepatotoxicity agents. DILI can manifest as predominantly hepatitis, bile duct injury or combination. Histological pattern recognition in the liver biopsy may help identify specific hepatotoxic agents causing DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Centros de Atenção Terciária , Adulto , Idoso , Anti-Infecciosos/efeitos adversos , Antineoplásicos/efeitos adversos , Biópsia , Doença Hepática Crônica Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Suplementos Nutricionais/efeitos adversos , Registros Eletrônicos de Saúde , Feminino , Humanos , Hipolipemiantes/efeitos adversos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Preparações de Plantas/efeitos adversos , Valor Preditivo dos Testes , Fatores de Risco
6.
World J Hepatol ; 9(6): 300-309, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28293379

RESUMO

Combined hepatocellular-cholangiocarcinoma (CHC) is a rare tumor with poor prognosis, with incidence ranging from 1.0%-4.7% of all primary hepatic tumors. This entity will be soon renamed as hepato-cholangiocarcinoma. The known risk factors for hepatocellular carcinoma (HCC) have been implicated for CHC including viral hepatitis and cirrhosis. It is difficult to diagnose this tumor pre-operatively. The predominant histologic component within the tumor largely determines the predominant radiographic features making it a difficult distinction. Heterogeneous and overlapping imaging features of HCC and cholangiocarcinoma should raise the suspicion for CHC and multiple core biopsies (from different areas of tumor) are recommended before administering treatment. Serum tumor markers CA19-9 and alpha-fetoprotein can aid in the diagnosis, but it remains a challenging diagnosis prior to resection. There is sufficient data to support bipotent hepatic progenitor cells as the cell of origin for CHC. The current World Health Organization classification categorizes two main types of CHC based on histo-morphological features: Classical type and CHC with stem cell features. Liver transplant is one of the available treatment modalities with other management options including transarterial chemoembolization, radiofrequency ablation, and percutaneous ethanol injection. We present a review paper on CHC highlighting the risk factors, origin, histological classification and therapeutic modalities.

7.
J Clin Med ; 6(1)2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28067794

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-ß) signaling pathways. The TGF-ß signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-ß/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target.

8.
World J Hepatol ; 7(25): 2563-70, 2015 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-26557948

RESUMO

Cholangiocarcinoma (CC) is primarily a malignant tumor of older adults most prevalent in Southeast Asia, where liver fluke infestation is high. However the etiology in western countries is unknown. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, incidence of intrahepatic CC (ICC) which differs in morphology, pathogenesis, risk factors, treatment and prognosis is increasing. While this increase is associated with hepatitis C virus infection, chronic nonalcoholic liver disease, obesity, and smoking, the pathogenesis of ICC and molecular alterations underlying the carcinogenesis are not completely elucidated. Benign biliary lesions such as biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, von Meyenburg complex or bile duct hamartoma, and bile duct adenoma have been associated with ICC. For each of these entities, evidence suggests or supports a role as premalignant lesions. This article summarized the important biological significance of the precursor lesions of ICC and the molecular mechanisms that may be involved in intrahepatic cholangiocarcinogenesis.

9.
Am J Cancer Res ; 4(4): 337-52, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25057437

RESUMO

BACKGROUND: Racial disparities among breast cancer (BCa) patients are known but not well studied in early-onset BCa. We analyzed molecular subtypes in early-onset BCa across five major races. METHODS: A total of 2120 cases were included from non-Hispanic White (NHW), African American (AA) and Hispanic, Chinese and Indian. Based on ER, PR and HER-2 status, BCa was classified into 4 intrinsic subtypes as Luminal A, Luminal B, HER2/neu overexpression and Triple negative BCa (TNBC) subtypes. Data was stratified according to race and age as younger/early-onset group (40-years and younger) and older group (50-years and older). RESULTS: In early-onset BCa, incidence of TNBC was significantly higher (p = 0.0369) in Indian women followed by AA, Hispanic, NHW and Chinese women. Incidence of Her2 over-expression subtype also was highest in Indian women, followed by Hispanic, Chinese, AA and NHW women. In contrast, Luminal B subtype was most significantly higher in AA women (p = 0.0000) followed by NHW (p = 0.0002), Chinese (p = 0.0003), Hispanic (0.0128) and Indian (p = 0.0468) women. Luminal A subtype was most significantly reduced in Indian women (p = 0.0113) followed by Hispanic, AA, NHW and Chinese women. These results were based on statistical analysis with the mean of older group populations. CONCLUSIONS: These results show significant disparities in receptor subtypes across races. This study will contribute in developing optimal clinical trial protocols and personalized management strategies for early-onset BCa patients.

10.
Am J Cancer Res ; 4(3): 196-210, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24959375

RESUMO

Transcriptional intermediary factor 1 gamma (Tif1γ) (Ectodermin/PTC7/RFG7/TRIM33) is a transcriptional cofactor with an important role in the regulation of the TGFß pathway. It has been suggested that it competes with Smad2/Smad3 for binding to Smad4, or alternatively that it may target Smad4 for degradation, although its role in carcinogenesis is unclear. In this study, we showed that Tif1γ interacts with Smad1/Smad4 complex in vivo, using both yeast two-hybrid and coimmunoprecipitation assays. We demonstrated that Tif1γ inhibits transcriptional activity of the Smad1/Smad4 complex through its PHD domain or bromo-domainin pancreatic cells by luciferase assay. Additionally, there is a dynamic inverse relationship between the levels of Tif1γ and Smad4 in benign and malignant pancreatic cell lines. Overexpression of Tif1γ resulted in decreased level of Smad4. Both overexpression and knockdown of Tif1γ resulted in growth inhibition in both benign and cancerous pancreatic cell lines, attributable to a G2-phase cell cycle arrest, but only knockdown of Tif1γ reduces tumor cell invasiveness in vitro. Our study demonstrated that imbalanced expression of Tif1γ results in inhibition of pancreatic ductal epithelial cell growth. In addition, knockdown of Tif1γ may inhibit tumor invasion. These data suggest that Tif1γ might serve as a potential therapeutic target for pancreatic cancer.

11.
J Clin Invest ; 123(11): 4681-94, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24216479

RESUMO

RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates RAS and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed a Pdx1-Cre;LSL-KrasG12D mouse, which is a model of pancreatic ductal adenocarcinoma (PDA), with a mouse harboring a floxed allele of Icmt. Surprisingly, we found that ICMT deficiency dramatically accelerated the development and progression of neoplasia. ICMT-deficient pancreatic ductal epithelial cells had a slight growth advantage and were resistant to premature senescence by a mechanism that involved suppression of cyclin-dependent kinase inhibitor 2A (p16INK4A) expression. ICMT deficiency precisely phenocopied Notch1 deficiency in the Pdx1-Cre;LSL-KrasG12D model by exacerbating pancreatic intraepithelial neoplasias, promoting facial papillomas, and derepressing Wnt signaling. Silencing ICMT in human osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands. Additionally, targeted silencing of Ste14, the Drosophila homolog of Icmt, resulted in defects in wing development, consistent with Notch loss of function. Our data suggest that ICMT behaves like a tumor suppressor in PDA because it is required for Notch1 signaling.


Assuntos
Genes ras , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Metiltransferases/deficiência , Receptor Notch1/metabolismo , Animais , Animais Geneticamente Modificados , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Feminino , Humanos , Masculino , Metaplasia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Mutação , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Proteínas Metiltransferases/genética , Transdução de Sinais
12.
Int J Clin Exp Pathol ; 6(8): 1665-70, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23923086

RESUMO

The presence of glandular epithelium in urinary tract biopsies poses a diagnostic challenge. Intestinal metaplasia of the urethra may be seen in many congenital, iatrogenic, and reactive conditions, as well as in association with malignant conditions such as urethral adenocarcinoma. We present a case of a 61 year-old woman presenting with microscopic hematuria. Successive biopsies showed glandular epithelium with focal atypia in close association with inflammation, but no overt malignancy. Only on surgical resection was the associated high grade adenocarcinoma revealed. When intestinal-type mucosa is present within a urinary tract biopsy, associated malignancy may be present only focally. Thorough sampling and consideration of the differential diagnosis is imperative.


Assuntos
Adenocarcinoma/patologia , Mucosa Intestinal/patologia , Neoplasias Uretrais/patologia , Feminino , Humanos , Metaplasia , Pessoa de Meia-Idade
13.
Med Sci Monit Basic Res ; 19: 228-36, 2013 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-23982457

RESUMO

BACKGROUND: Plumbagin, a quinonoid constituent isolated from the root of Plumbago zeylanica L., has been proven to possess anti-tumor activity both in vitro and in vivo. However, its anti-tumor properties for human tongue carcinoma have not been reported. This study aimed to investigate the inhibitory effect and the underlying mechanism of plumbagin on the growth of human tongue carcinoma cells. MATERIAL AND METHODS: Cell proliferation ability was detected by EdU incorporation assay and colony formation assay. Cell-cycle distribution was determined by flow cytometric analysis using propidium iodide (PI) staining. Cellular apoptosis was then evaluated by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Western blotting was applied to assay the expression of Bax and Bcl-2. RESULTS: Plumbagin inhibited the growth and proliferation of Tca8113 cells in vitro in a concentration- and time-dependent manner. The cell cycles of plumbagin-treated Tca8113 cells were arrested at the G2/M phase. Cells treated with plumbagin presented the characteristic morphological changes of apoptosis. The ratio of Bax/Bcl-2 was raised by plumbagin in a concentration-dependent manner. CONCLUSIONS: These results indicate that plumbagin induces the apoptosis of Tca8113 cells through mitochondria-mediated pathway.


Assuntos
Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Língua/metabolismo , Neoplasias da Língua/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxiuridina/análogos & derivados , Desoxiuridina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitose/efeitos dos fármacos , Fatores de Tempo , Ensaio Tumoral de Célula-Tronco , Proteína X Associada a bcl-2/metabolismo
14.
PLoS One ; 8(5): e64663, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23734213

RESUMO

p44/MEP50/WDR77 has been identified as a coactivator of androgen receptor (AR), with distinct growth suppression and promotion function in gender specific endocrine organs and their malignancies. We dissected the functional domains of p44 for protein interaction with transcription factors, transcriptional activation, as well as the functional domains in p44 related to its growth inhibition in prostate cancer. Using a yeast two-hybrid screen, we identified a novel transcription complex AR-p44-Smad1, confirmed for physical interaction by co-immunoprecipitaion and functional interaction with luciferase assays in human prostate cancer cells. Yeast two-hybrid assay revealed that the N-terminal region of p44, instead of the traditional WD40 domain at the C-terminus, mediates the interaction among p44, N-terminus of AR and full length Smad1. Although both N and C terminal domains of p44 are necessary for maximum AR transcriptional activation, the N terminal fragment of p44 alone maintains the basic effect on AR transcriptional activation. Cell proliferation assays with N- and C- terminal deletion mutations indicated that the central portion of p44 is required for nuclear p44 mediated prostate cancer growth inhibition.


Assuntos
Complexos Multiproteicos/metabolismo , Receptores Androgênicos/metabolismo , Proteína Smad1/metabolismo , Fatores de Transcrição/metabolismo , Androgênios/farmacologia , Sítios de Ligação/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Imunoprecipitação da Cromatina , Humanos , Masculino , Complexos Multiproteicos/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica/efeitos dos fármacos , Receptores Androgênicos/genética , Proteína Smad1/genética , Fatores de Transcrição/genética , Técnicas do Sistema de Duplo-Híbrido
15.
Science ; 340(6139): 1456-9, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-23661644

RESUMO

Lymphocyte homing, which contributes to inflammation, has been studied extensively in the small intestine, but there is little known about homing to the large intestine, the site most commonly affected in inflammatory bowel disease. GPR15, an orphan heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, controlled the specific homing of T cells, particularly FOXP3(+) regulatory T cells (Tregs), to the large intestine lamina propria (LILP). GPR15 expression was modulated by gut microbiota and transforming growth factor-ß1, but not by retinoic acid. GPR15-deficient mice were prone to develop more severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient Tregs. Our findings thus describe a T cell-homing receptor for LILP and indicate that GPR15 plays a role in mucosal immune tolerance largely by regulating the influx of Tregs.


Assuntos
Mucosa Intestinal/imunologia , Intestino Grosso/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Retorno de Linfócitos/metabolismo , Receptores de Peptídeos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Citrobacter rodentium , Colite/imunologia , Colo/imunologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Helicobacter/imunologia , Homeostase , Humanos , Tolerância Imunológica , Intestino Grosso/microbiologia , Intestino Delgado/imunologia , Metagenoma/fisiologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética
16.
J Clin Gastroenterol ; 47(6): 509-14, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23090042

RESUMO

BACKGROUND: Mutations in the KRAS gene occur at an early stage in the development of colorectal carcinoma. Importantly, KRAS mutation predicts resistance to anti-epidermal growth factor receptor therapy in stage IV disease. GOALS: The aim of the current study is to correlate histologic features of colon cancer with the presence of KRAS mutations. STUDY: Tumor tissue from 145 colon cancer resections was tested for KRAS mutations. KRAS mutation status was correlated with demographic and histologic characteristics. Statistical analysis was performed using the Pearson χ2 test and multivariate analysis. RESULTS: KRAS mutations were present in 55/145 cases (37.9%), consistent with reported rates. KRAS mutations were significantly associated with usual adenocarcinoma morphology (multivariate P=0.014), peritumoral lymphocytic response (χ2, P=0.028; multivariate P=0.017), T3-T4 status (χ2, P=0.012; multivariate P=0.015), right-sided location (multivariate P=0.027), absence of lymphovascular invasion (multivariate P=0.008), and metastases at the time of resection (multivariate P=0.034). No association was found between KRAS mutation status and other factors. CONCLUSIONS: Specific morphologic features in colon cancer suggest a higher likelihood of the presence of KRAS mutations. These morphologic features overlap partially with those associated with DNA mismatch repair gene mutations. If confirmed, these results may suggest a paradigm for directed KRAS testing.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos
17.
HPB (Oxford) ; 14(11): 741-5, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23043662

RESUMO

BACKGROUND: A subset of patients with hepatocellular carcinoma (HCC) present with massive tumours. It is unknown why certain patients develop these massive tumours, and whether this presentation is specific to the underlying viral aetiology or patient demographics such as gender, race and age. METHODS: All patients with HCC at Bellevue Hospital Center, New York from 1998 to 2012 were identified and relevant demographic and clinical information was collected. Computed tomography/magnetic resonance imaging (CT/MRI) images were reviewed and the maximal tumour diameter on axial sections was recorded. Cirrhosis was defined histologically or by radiographical criteria. The two cohorts of massive and non-massive HCC were compared. RESULTS: A total of 361 patients with HCC were identified, of which 58 were categorized as having a massive HCC using a 13 cm size cut-off. Univariate and multivariate analysis demonstrated a significant association of massive HCC with age <40 years; hepatitis B or Asian ethnicity; and a lack of cirrhosis or platelet count >100. DISCUSSION: Massive HCC represents a tumour subtype that is associated with young, chronic hepatitis B carriers with non-cirrhotic livers. The clinical implications of this finding are that patients with massive HCC are typically excellent resection candidates barring the presence of gross vascular invasion or distant metastases.


Assuntos
Carcinoma Hepatocelular/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Carga Tumoral , Adulto , Fatores Etários , Povo Asiático , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Distribuição de Qui-Quadrado , Feminino , Hepatite B Crônica/etnologia , Hepatite B Crônica/mortalidade , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etnologia , Cirrose Hepática/mortalidade , Cirrose Hepática/terapia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/etnologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Cidade de Nova Iorque/epidemiologia , Contagem de Plaquetas , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Tomografia Computadorizada por Raios X
18.
Ann Surg Oncol ; 19(13): 4085-93, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22732838

RESUMO

Although there is considerable controversy regarding the role of race in the etiology of human disease, evidence suggests that breast cancers are racially distinct diseases. Clinical features and genetic alterations are different in Chinese women with breast cancer compared with white women. These differences are significant and may influence clinical care. In this review, we summarize the literature addressing genetic heterogeneity in Chinese women with breast cancer. Data support important variations in genes involved in tumorigenic pathways of DNA repair, steroid synthesis and receptor expression, apoptosis, immunity, inflammation, cell cycle control, cancer growth and metastasis, and growth receptor signaling. These genetic differences contribute to our understanding of the molecular origins of breast cancer and may accelerate the development of personalized disease prevention strategies.


Assuntos
Povo Asiático/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Grupos Raciais/genética , Feminino , Humanos
19.
Am J Pathol ; 180(5): 1798-807, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22429965

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Despite improved diagnosis and treatment, the prognosis for HCC patients remains poor. The goal of this study was to identify key regulatory proteins and signaling pathways important for cell apoptosis and proliferation as biomarkers for prognostication and targeted therapy. Protein Pathway Array was applied to screen 38 signaling proteins and phosphoproteins in 12 paired HCC tumors and surrounding benign tissues and found that 20 of them, including XIAP, CDK4, CDK6, and Cyclin D1, were overexpressed in HCC tissues. Immunostaining results of XIAP, CDK4, and Cyclin D1 in an additional 59 HCC tissues showed that the expression of XIAP correlated with the expression of CDK4/Cyclin D1, and that the increased expression of these proteins correlated with poor overall survival in these patients. Further studies using the HCC Huh7 cell line transfected with XIAP siRNA or expression vector demonstrated that XIAP regulated the expression of CDK4, CDK6, and Cyclin D1 via NF-êB and PTEN pathways. Finally, inhibition of XIAP using embelin, a XIAP-specific small molecule, leads to an increased apoptosis and decreased cell proliferation via arrest at G1 phase. Taken together, XIAP is a central modulator regulating cell apoptosis and cell cycle progression. Therefore, XIAP together with cell cycle regulatory proteins can be used as prognostic markers and therapeutic targets.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Ciclina D1/metabolismo , Neoplasias Hepáticas/diagnóstico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Idoso , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Benzoquinonas/farmacologia , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células , Ciclina D1/genética , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Fosforilação , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Análise de Sobrevida , Células Tumorais Cultivadas
20.
World J Gastroenterol ; 17(35): 3994-4000, 2011 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22046087

RESUMO

AIM: To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1γ), Smad4 and transforming growth factor-beta (TGFßR) across a spectrum representing colorectal cancer (CRC) development. METHODS: Tissue microarrays were prepared from archival paraffin embedded tissue, including 51 colorectal carcinomas, 25 tubular adenomas (TA) and 26 HPs, each with matched normal colonic epithelium. Immunohistochemistry was performed using antibodies against TIF1γ, Smad4 and TGFßRII. The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4). RESULTS: Overexpression of TIF1γ was detected in 5/26 (19%) HP; however, it was seen in a significantly higher proportion of neoplasms, 15/25 (60%) TAs and 24/51 (47%) CRCs (P < 0.05). Normal colonic mucosa, HP, and TAs showed strong Smad4 expression, while its expression was absent in 22/51 (43%) CRCs. Overexpression of TGFßRII was more commonly seen in neoplasms, 13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P < 0.05). Furthermore, there was a correlation between TIF1γ overexpression and Smad4 loss in CRC (Kendall tau rank correlation value = 0.35, P < 0.05). The levels of TIF1γ overexpression were significantly higher in stage III than in stage I and II CRC (P < 0.05). CONCLUSION: The findings suggest that over-expression of TIF1γ occurs in early stages of colorectal carcinogenesis, is inversely related with Smad4 loss, and may be a prognostic indicator for poor outcome.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Humanos , Análise em Microsséries , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteína Smad4/metabolismo
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