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1.
Int J Cancer ; 146(11): 3160-3169, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31609478

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase;

Asunto(s)
Carcinoma Ductal Pancreático/patología , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Quinurenina/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/mortalidad , Movimiento Celular , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Invasividad Neoplásica/patología , Neoplasias Pancreáticas/mortalidad , Receptores de Hidrocarburo de Aril/genética , Transducción de Señal/fisiología , Esferoides Celulares , Triptófano/metabolismo , Células Tumorales Cultivadas
3.
Anaerobe ; 48: 249-256, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29031928

RESUMEN

Most pathogenic Clostridium difficile produce two major exotoxins TcdA and TcdB, in the absence of which the bacterium is non-pathogenic. While it is important to investigate the role of each toxin in the pathogenesis of C. difficile infection (CDI) using isogenic strains, it is impossible to precisely control the expression levels of individual toxins and exclude bacterial factors that may contribute to the toxins' effects during infection. In this study, we utilized an acute intestinal disease model by injecting purified toxins directly into mouse cecum after a midline laparotomy. We evaluated the physical condition of mice by clinical score and survival, and the intestinal tissue damage and inflammation by histology. Depending on the dose of the toxins, mice developed mild to severe colitis, experienced diarrhea or rapidly died. We found that both purified TcdA and TcdB were able to induce clinical disease, intestinal inflammation, and tissue damage that resembled CDI. TcdA was significantly faster in inducing intestinal inflammation and tissue damage, and was approximately five times more potent than TcdB in terms of inducing severe gut disease and death outcomes in mice. Moreover, we found that the two toxins had significant synergistic effects on disease induction. Comparison of the in vivo toxicity of TcdB from clinical strains revealed that TcdB from an epidemic RT 027 strain was more toxic than the others. Our study thus demonstrates that both TcdA and TcdB, independent of other factors from C. difficile bacterium, are able to cause disease that resembles CDI and highlights the importance of targeting both toxins for vaccines and therapeutics against the disease.


Asunto(s)
Ciego/microbiología , Ciego/patología , Clostridioides difficile/metabolismo , Enterocolitis Seudomembranosa/microbiología , Enterotoxinas/metabolismo , Animales , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/metabolismo , Biomarcadores , Modelos Animales de Enfermedad , Enterocolitis Seudomembranosa/mortalidad , Enterocolitis Seudomembranosa/patología , Enterotoxinas/administración & dosificación , Humanos , Ratones , Fosforilación
4.
Infect Immun ; 83(2): 822-31, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25486992

RESUMEN

Clostridium difficile infection (CDI) represents the most prevalent cause of antibiotic-associated gastrointestinal infections in health care facilities in the developed world. Disease symptoms are caused by the two homologous exotoxins, TcdA and TcdB. Standard therapy for CDI involves administration of antibiotics that are associated with a high rate of disease recurrence, highlighting the need for novel treatment paradigms that target the toxins rather than the organism itself. A combination of human monoclonal antibodies, actoxumab and bezlotoxumab, directed against TcdA and TcdB, respectively, has been shown to decrease the rate of recurrence in patients treated with standard-of-care antibiotics. However, the exact mechanism of antibody-mediated protection is poorly understood. In this study, we show that the antitoxin antibodies are protective in multiple murine models of CDI, including systemic and local (gut) toxin challenge models, as well as primary and recurrent models of infection in mice. Systemically administered actoxumab-bezlotoxumab prevents both the damage to the gut wall and the inflammatory response, which are associated with C. difficile in these models, including in mice challenged with a strain of the hypervirulent ribotype 027. Furthermore, mutant antibodies (N297Q) that do not bind to Fcγ receptors provide a level of protection similar to that of wild-type antibodies, demonstrating that the mechanism of protection is through direct neutralization of the toxins and does not involve host effector functions. These data provide a mechanistic basis for the prevention of recurrent disease observed in CDI patients in clinical trials.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Anticuerpos Monoclonales/inmunología , Antitoxinas/inmunología , Proteínas Bacterianas/inmunología , Toxinas Bacterianas/inmunología , Clostridioides difficile/inmunología , Enterocolitis Seudomembranosa/prevención & control , Enterotoxinas/inmunología , Animales , Anticuerpos Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Antitoxinas/uso terapéutico , Chlorocebus aethiops , Modelos Animales de Enfermedad , Enterocolitis Seudomembranosa/inmunología , Ratones , Ratones Endogámicos C57BL , Mutación , Receptores de IgG/inmunología , Recurrencia , Células Vero
5.
Nucleic Acids Res ; 40(8): 3689-703, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22210864

RESUMEN

We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent data set and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a candidate predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair and actin dynamics. This observation was further corroborated with protein expression analysis and 3'-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that the miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters the cellular organization of F-actin and inhibits tumor cell invasion and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.


Asunto(s)
Biomarcadores de Tumor/metabolismo , MicroARNs/metabolismo , Neoplasias de la Próstata/genética , Biomarcadores de Tumor/genética , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Reparación del ADN/genética , Epigénesis Genética , Genes Supresores de Tumor , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , MicroARNs/genética , Mitosis , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/diagnóstico , Pronóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Int J Cancer ; 132(4): 785-94, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-22821831

RESUMEN

MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer.


Asunto(s)
Carcinoma Ductal Pancreático/genética , Transición Epitelial-Mesenquimal/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Neoplasias Pancreáticas/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Masculino , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pronóstico , Interferencia de ARN , Trasplante Heterólogo , Gemcitabina
7.
Cancer Immunol Immunother ; 62(5): 829-37, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23344392

RESUMEN

INTRODUCTION: The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease-specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated. METHODS: Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests. RESULTS: IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors. CONCLUSIONS: IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design.


Asunto(s)
Neoplasias de la Mama/enzimología , Inmunohistoquímica/métodos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Modelos Estadísticos , Análisis Multivariante , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Análisis de Regresión , Factores de Tiempo , Resultado del Tratamiento
8.
JCI Insight ; 8(23)2023 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-37906280

RESUMEN

Diabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.


Asunto(s)
Neoplasias de la Mama , Diabetes Mellitus , Hiperglucemia , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Daño del ADN , Reparación del ADN
9.
Cancer Res Commun ; 3(11): 2244-2255, 2023 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-37902422

RESUMEN

Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer. SIGNIFICANCE: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients.


Asunto(s)
Negro o Afroamericano , Neoplasias de la Mama , Femenino , Humanos , Negro o Afroamericano/genética , Neoplasias de la Mama/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Kenia , Mutación , Estados Unidos , Blanco/genética , Población Negra/genética , Asiático/genética
10.
Oncogene ; 40(38): 5752-5763, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34341513

RESUMEN

Expression of ß-crystallin B2 (CRYßB2) is elevated in African American (AA) breast tumors. The underlying mechanisms of CRYßB2-induced malignancy and the association of CRYßB2 protein expression with survival have not yet been described. Here, we report that the expression of CRYßB2 in breast cancer cells increases stemness, growth, and metastasis. Transcriptomics data revealed that CRYßB2 upregulates genes that are functionally associated with unfolded protein response, oxidative phosphorylation, and DNA repair, while down-regulating genes related to apoptosis. CRYßB2 in tumors promotes de-differentiation, an increase in mesenchymal markers and cancer-associated fibroblasts, and enlargement of nucleoli. Proteome microarrays identified a direct interaction between CRYßB2 and the nucleolar protein, nucleolin. CRYßB2 induces nucleolin, leading to the activation of AKT and EGFR signaling. CRISPR studies revealed a dependency on nucleolin for the pro-tumorigenic effects of CRYßB2. Triple-negative breast cancer (TNBC) xenografts with upregulated CRYßB2 are distinctively sensitive to the nucleolin aptamer, AS-1411. Lastly, in AA patients, higher levels of nucleolar CRYßB2 in primary TNBC correlates with decreased survival. In summary, CRYßB2 is upregulated in breast tumors of AA patients and induces oncogenic alterations consistent with an aggressive cancer phenotype. CRYßB2 increases sensitivity to nucleolin inhibitors and may promote breast cancer disparity.


Asunto(s)
Fosfoproteínas/metabolismo , Proteínas de Unión al ARN/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Regulación hacia Arriba , Cadena B de beta-Cristalina/metabolismo , Animales , Aptámeros de Nucleótidos/administración & dosificación , Aptámeros de Nucleótidos/farmacología , Nucléolo Celular/efectos de los fármacos , Nucléolo Celular/metabolismo , Nucléolo Celular/patología , Proliferación Celular/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Invasividad Neoplásica , Trasplante de Neoplasias , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/farmacología , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Cadena B de beta-Cristalina/genética , Nucleolina
11.
BMC Cancer ; 10: 626, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21078168

RESUMEN

BACKGROUND: Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. METHODS: Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. RESULTS: COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. CONCLUSIONS: Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Ciclooxigenasa 2/biosíntesis , Receptor alfa de Estrógeno/biosíntesis , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/biosíntesis , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Caspasa 9/biosíntesis , Femenino , Genes p53 , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Fosforilación , Resultado del Tratamiento , Proteína Letal Asociada a bcl/biosíntesis
13.
Case Rep Dermatol Med ; 2019: 6268354, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31308981

RESUMEN

Basal cell carcinoma (BCC) is the most common cutaneous malignancy in the United States and is often nonaggressive. Its location in the perianal region is very rare and it is estimated that only 0.08% of all BCCs occur in this region. Herein, we present a case of perianal basal cell carcinoma, nodular type. The diagnosis was made using excisional biopsy of a skin lesion. Immunohistochemical staining confirmed the diagnosis: it showed diffuse and strong positivity for smooth muscle actin (SMA) and monoclonal antibody BER-Ep4 and was negative for carcinoembryonic antigen (CEA), pancytokeratin (AE1/AE3), and epithelial membrane antigen (EMA). The treatment of choice has traditionally been local excision to clear margins but the newest guidelines recommend Mohs Micrographic surgery (MMS) or standard 4mm surgical margins for this high-risk BCC. Our patient was successfully treated using excisional biopsy without recurrence. In select patients with lesions smaller than 1cm, excisional biopsy may be sufficient to treat the disease and may be better tolerated than MMS and wider surgical margins. Literature review suggests a predisposition for perianal BCC in individuals susceptible to cutaneous malignancies. Therefore, any history of cutaneous malignancy should further prompt clinicians to examine nonsun exposed areas on full body skin exams.

14.
Oncotarget ; 8(31): 50704-50714, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28881596

RESUMEN

Accurate classification of squamous cell carcinoma (SCC) from adenocarcinoma (AC) of non-small cell lung cancer (NSCLC) can lead to personalized treatments of lung cancer. We aimed to develop a miRNA-based prediction model for differentiating SCC from AC in surgical resected tissues and bronchoalveolar lavage (BAL) samples. Expression levels of seven histological subtype-associated miRNAs were determined in 128 snap-frozen surgical lung tumor specimens by using reverse transcription-polymerase chain reaction (RT-PCR) to develop an optimal panel of miRNAs for acutely distinguishing SCC from AC. The biomarkers were validated in an independent cohort of 112 FFPE lung tumor tissues, and a cohort of 127 BAL specimens by using droplet digital PCR for differentiating SCC from AC. A prediction model with two miRNAs (miRs-205-5p and 944) was developed that had 0.988 area under the curve (AUC) with 96.55% sensitivity and 96.43% specificity for differentiating SCC from AC in frozen tissues, and 0.997 AUC with 96.43% sensitivity and 96.43% specificity in FFPE specimens. The diagnostic performance of the prediction model was reproducibly validated in BAL specimens for distinguishing SCC from AC with a higher accuracy compared with cytology (95.69 vs. 68.10%; P < 0.05). The prediction model might have a clinical value for accurately discriminating SCC from AC in both surgical lung tumor tissues and liquid cytological specimens.

15.
Artículo en Inglés | MEDLINE | ID: mdl-27375958

RESUMEN

Clostridium difficile is the leading cause of nosocomial infections in the United States, adding billions of dollars per year to health care costs. A vaccine targeted against the bacterium would be extremely beneficial in decreasing the morbidity and mortality caused by C. difficile-associated disease; a vaccine directed against a colonization factor would hinder the spread of the bacterium as well as prevent disease. Type IV pili (T4Ps) are extracellular appendages composed of protein monomers called pilins. They are involved in adhesion and colonization in a wide variety of bacteria and archaea, and are putative colonization factors in C. difficile. We hypothesized that vaccinating mice with pilins would lead to generation of anti-pilin antibodies, and would protect against C. difficile challenge. We found that immunizing C57Bl/6 mice with various pilins, whether combined or as individual proteins, led to low anti-pilin antibody titers and no protection upon C. difficile challenge. Passive transfer of anti-pilin antibodies led to high serum anti-pilin IgG titers, but to undetectable fecal anti-pilin IgG titers and did not protect against challenge. The low antibody titers observed in these experiments may be due to the particular strain of mice used. Further experiments, possibly with a different animal model of C. difficile infection, are needed to determine if an anti-T4P vaccine would be protective against C. difficile infection.

16.
Clin Cancer Res ; 22(24): 5992-6001, 2016 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-27401251

RESUMEN

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (≤7 months) and those surviving 2 years or more following surgical resection. EXPERIMENTAL DESIGN: Gene expression profiling was performed in tumors in a test cohort of PDAC (N = 50), which included short (≤7 months, N = 11) and long surviving (≥2 years, N = 14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan-Meier, and pathway analyses with validations in independent cohorts for mechanistic and functional analyses. RESULTS: Gene expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking first. Lower expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3'UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC. CONCLUSIONS: Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. Clin Cancer Res; 22(24); 5992-6001. ©2016 AACR.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Anciano , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Estudios de Cohortes , Proteínas de Unión al ADN , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Óxido Nítrico/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Gemcitabina , Neoplasias Pancreáticas
17.
Cancer Res ; 76(5): 1055-1065, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26719530

RESUMEN

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers.


Asunto(s)
Inflamación/metabolismo , Neoplasias de la Próstata/inmunología , Fumar/efectos adversos , Transcriptoma , Animales , Línea Celular Tumoral , Núcleo Celular/metabolismo , Humanos , Inmunoglobulinas/genética , Interleucina-8/sangre , Masculino , Ratones , FN-kappa B/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Nicotina/farmacología , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo
18.
Clin Cancer Res ; 19(18): 4983-93, 2013 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-23918603

RESUMEN

PURPOSE: To identify metabolic pathways that are perturbed in pancreatic ductal adenocarcinoma (PDAC), we investigated gene-metabolite networks with integration of metabolomics and transcriptomics. EXPERIMENTAL DESIGN: We conducted global metabolite profiling analysis on two independent cohorts of resected PDAC cases to identify critical metabolites alteration that may contribute to the progression of pancreatic cancer. We then searched for gene surrogates that were significantly correlated with the key metabolites, by integrating metabolite and gene expression profiles. RESULTS: Fifty-five metabolites were consistently altered in tumors as compared with adjacent nontumor tissues in a test cohort (N = 33) and an independent validation cohort (N = 31). Weighted network analysis revealed a unique set of free fatty acids (FFA) that were highly coregulated and decreased in PDAC. Pathway analysis of 157 differentially expressed gene surrogates revealed a significantly altered lipid metabolism network, including key lipolytic enzymes PNLIP, CLPS, PNLIPRP1, and PNLIPRP2. Gene expressions of these lipases were significantly decreased in pancreatic tumors as compared with nontumor tissues, leading to reduced FFAs. More importantly, a lower gene expression of PNLIP in tumors was associated with poorer survival in two independent cohorts. We further showed that two saturated FFAs, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells. CONCLUSIONS: Our results suggest that impairment in a lipolytic pathway involving lipases, and a unique set of FFAs, may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Ácidos Grasos/metabolismo , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Metabolómica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Proliferación Celular , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Cromatografía de Gases y Espectrometría de Masas , Humanos , Metabolismo de los Lípidos , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Células Tumorales Cultivadas
19.
Cancer Res ; 73(17): 5416-25, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23801748

RESUMEN

The forkhead box L1 (FOXL1) transcription factor regulates epithelial proliferation and development of gastrointestinal tract and has been implicated in gastrointestinal tumorigenesis in mouse models. However, the role of FOXL1 in pancreatic cancer development and progression remains to be elucidated. Here, we report that higher expression of FOXL1 is significantly associated with better clinical outcome in human pancreatic ductal adenocarcinoma (PDAC). A lower FOXL1 expression is correlated with metastasis and advanced pathologic stage of pancreatic cancer. Mechanistic analyses showed that overexpression of FOXL1 induces apoptosis and inhibits proliferation and invasion in pancreatic cancer cells, whereas silencing of FOXL1 by siRNA inhibits apoptosis and enhances tumor cell growth and invasion. Furthermore, FOXL1 overexpression significantly suppressed the growth of tumor xenografts in nude mice. FOXL1 promoted apoptosis partly through the induction of TNF-related apoptosis-inducing ligand (TRAIL) in pancreatic cancer cells. In addition, FOXL1 suppressed the transcription of zinc finger E-box-binding homeobox 1 (ZEB1), an activator of epithelial-mesenchymal transition, and the negative regulation of ZEB1 contributed to the inhibitory effect of FOXL1 on tumor cell invasion. Taken together, our findings suggest that FOXL1 expression is a candidate predictor of clinical outcome in patients with resected PDAC and it plays an inhibitory role in pancreatic tumor progression.


Asunto(s)
Apoptosis , Carcinoma Ductal Pancreático/mortalidad , Movimiento Celular , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/mortalidad , Animales , Western Blotting , Carcinoma Ductal Pancreático/prevención & control , Carcinoma Ductal Pancreático/secundario , Proliferación Celular , Inmunoprecipitación de Cromatina , Transición Epitelial-Mesenquimal , Factores de Transcripción Forkhead/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Técnicas para Inmunoenzimas , Luciferasas/metabolismo , Masculino , Ratones , Ratones Desnudos , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/prevención & control , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Homeobox 1 de Unión a la E-Box con Dedos de Zinc
20.
Eur J Cancer ; 49(15): 3344-52, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23871153

RESUMEN

Tumour antigen targeted antibodies (mAbs) can induce natural killer (NK) cells to kill tumours through antibody dependent cellular cytotoxicity (ADCC) upon engagement of NK cell expressed FcγRIIIa. FcγRIIIa polymorphisms partially dictate the potency of the ADCC response. The high affinity FcγRIIIa-158-valine (V) polymorphism is associated with more potent ADCC response than the low affinity FcγRIIIa-158-phenylalanine (F) polymorphism. Because approximately 45% of patients are homozygous for the FcγRIIIa-158-F polymorphism (FF genotype), their ability to mount ADCC is impaired. We investigated whether a novel mAb capable of binding multiple antigen specific targets and engaging multiple low affinity FcγRIIIa receptors could further enhance ADCC against colon cancer in vitro. Specifically, we generated a novel anti-epidermal growth factor receptor (EGFR) antibody (termed a stradobody) consisting of an unmodified Fab sequence and two Immunoglobulin G, subclass 1 (IgG1) Fc domains separated by an isoleucine zipper domain and the 12 amino-acid IgG2 hinge. The stradobody framework induced multimerisation and was associated with increased binding to the EGFR and FcγRIIIa. From a functional perspective, when compared to an unmodified anti-EGFR mAb with a sequence identical to cetuximab (a commercially available anti-EGFR mAb), stradobodies significantly enhanced ADCC. These effects were observed using both KRAS wild type HT29 and KRAS mutant SW480 colon cancer cells as targets, and by NK cells obtained from healthy donors and a cohort of patients with colon cancer. These data suggest that high avidity cross-linking of multiple tumour surface antigens and multiple NK cell associated FcγRIIIa molecules can enhance ADCC and partially overcome impaired ADCC by FF genotype individuals in vitro.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Neoplasias del Colon/inmunología , Neoplasias del Colon/terapia , Receptores ErbB/inmunología , Células Asesinas Naturales/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Línea Celular Tumoral , Neoplasias del Colon/genética , Receptores ErbB/genética , Genotipo , Células HT29 , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Polimorfismo de Nucleótido Simple , Multimerización de Proteína , Estructura Terciaria de Proteína
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