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Find video protocols related to scientific articles indexed in Pubmed.
Survival Among Patients With Pancreatic Cancer and Long-Standing or Recent-Onset Diabetes Mellitus.
J. Clin. Oncol.
PUBLISHED: 11-19-2014
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Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown.
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Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis.
J. Natl. Cancer Inst.
PUBLISHED: 09-04-2014
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Hypomethylation in long interspersed nucleotide element-1 (LINE-1) and high-degree microsatellite instability (MSI-high) in colorectal cancer (CRC) have been associated with inferior and superior survival, respectively; however, it remains uncertain whether the prognostic association of LINE-1 hypomethylation differs by MSI status. We hypothesized that the adverse prognostic association of LINE-1 hypomethylation might be stronger in MSI-high CRCs than in microsatellite stable (MSS) CRCs.
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SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features.
Ann. Surg. Oncol.
PUBLISHED: 07-15-2014
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Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.
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Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.
Nat. Med.
PUBLISHED: 06-26-2014
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Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.
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Predicted 25(OH)D score and colorectal cancer risk according to vitamin D receptor expression.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 06-11-2014
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Despite accumulating evidence for the preventive effect of vitamin D on colorectal carcinogenesis, its precise mechanisms remain unclear. We hypothesized that vitamin D was associated with a lower risk of colorectal cancer with high-level vitamin D receptor (VDR) expression, but not with risk of tumor with low-level VDR expression.
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RNF43 is frequently mutated in colorectal and endometrial cancers.
Nat. Genet.
PUBLISHED: 04-03-2014
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We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers.
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Prognostic Significance and Molecular Features of Signet-Ring Cell and Mucinous Components in Colorectal Carcinoma.
Ann. Surg. Oncol.
PUBLISHED: 03-20-2014
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Colorectal carcinoma (CRC) represents a group of histopathologically and molecularly heterogeneous diseases, which may contain signet-ring cell component and/or mucinous component to a varying extent under pathology assessment. However, little is known about the prognostic significance of those components, independent of various tumor molecular features.
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Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.
Mol. Cancer
PUBLISHED: 02-16-2014
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KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.
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Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit.
Cancer Discov
PUBLISHED: 01-20-2014
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Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the I?B kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKK? promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKK? inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKK? promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKK?, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.
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Classification, clinicopathologic features and treatment of gastric neuroendocrine tumors.
World J. Gastroenterol.
PUBLISHED: 01-14-2014
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Gastric neuroendocrine tumors (GNETs) are rare lesions characterized by hypergastrinemia that arise from enterochromaffin-like cells of the stomach. GNETs consist of a heterogeneous group of neoplasms comprising tumor types of varying pathogenesis, histomorphologic characteristics, and biological behavior. A classification system has been proposed that distinguishes four types of GNETs; the clinicopathological features of the tumor, its prognosis, and the patient's survival strictly depend on this classification. Thus, correct management of patients with GNETs can only be proposed when the tumor has been classified by an accurate pathological and clinical evaluation of the patient. Recently developed cancer therapies such as inhibition of angiogenesis or molecular targeting of growth factor receptors have been used to treat GNETs, but the only definitive therapy is the complete resection of the tumor. Here we review the literature on GNETs, and summarize the classification, clinicopathological features (especially prognosis), clinical presentations and current practice of management of GNETs. We also present the latest findings on new gene markers for GNETs, and discuss the effective drugs developed for the diagnosis, prognosis and treatment of GNETs.
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Prediagnostic body mass index and pancreatic cancer survival.
J. Clin. Oncol.
PUBLISHED: 10-21-2013
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Although obesity is associated with increased incidence of pancreatic cancer, studies have not prospectively evaluated prediagnostic body mass index (BMI) and survival.
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Long-term colorectal-cancer incidence and mortality after lower endoscopy.
N. Engl. J. Med.
PUBLISHED: 09-20-2013
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Colonoscopy and sigmoidoscopy provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against cancer of the proximal colon, remain uncertain.
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Prognostic significance of MTOR pathway component expression in neuroendocrine tumors.
J. Clin. Oncol.
PUBLISHED: 08-26-2013
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Clinical studies have implicated the mechanistic target of rapamycin (serine/threonine kinase; MTOR) pathway in the regulation of neuroendocrine tumor (NET) growth. We explored whether expression of MTOR pathway components has prognostic significance in NET patients.
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Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication.
J. Natl. Cancer Inst.
PUBLISHED: 07-22-2013
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BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAF-wild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAF-wild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval [CI] =1.12 to 2.28; P = .009), 0.48 (95% CI = 0.27 to 0.87; P = .02), and 0.25 (95% CI = 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P(interaction) > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.
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Hyperglycemia, insulin resistance, impaired pancreatic ?-cell function, and risk of pancreatic cancer.
J. Natl. Cancer Inst.
PUBLISHED: 07-11-2013
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Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic ?-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic ?-cell dysfunction.
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Aspirin use and risk of colorectal cancer according to BRAF mutation status.
JAMA
PUBLISHED: 06-27-2013
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Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells.
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A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification.
Am. J. Epidemiol.
PUBLISHED: 06-20-2013
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The effect of duration of cigarette smoking cessation on colorectal cancer risk by molecular subtypes remains unclear. Using duplication-method Cox proportional-hazards regression analyses, we examined associations between duration of smoking cessation and colorectal cancer risk according to status of CpG island methylator phenotype (CIMP), microsatellite instability, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, or DNA methyltransferase-3B (DNMT3B) expression. Follow-up of 134,204 individuals in 2 US nationwide prospective cohorts (Nurses Health Study (1980-2008) and Health Professionals Follow-up Study (1986-2008)) resulted in 1,260 incident rectal and colon cancers with available molecular data. Compared with current smoking, 10-19, 20-39, and ?40 years of smoking cessation were associated with a lower risk of CIMP-high colorectal cancer, with multivariate hazard ratios (95% confidence intervals) of 0.53 (0.29, 0.95), 0.52 (0.32, 0.85), and 0.50 (0.27, 0.94), respectively (Ptrend = 0.001), but not with the risk of CIMP-low/CIMP-negative cancer (Ptrend = 0.25) (Pheterogeneity = 0.02, between CIMP-high and CIMP-low/CIMP-negative cancer risks). Differential associations between smoking cessation and cancer risks by microsatellite instability (Pheterogeneity = 0.02), DNMT3B expression (Pheterogeneity = 0.03), and BRAF (Pheterogeneity = 0.10) status appeared to be driven by the associations of CIMP-high cancer with microsatellite instability-high, DNMT3B-positive, and BRAF-mutated cancers. These molecular pathological epidemiology data suggest a protective effect of smoking cessation on a DNA methylation-related carcinogenesis pathway leading to CIMP-high colorectal cancer.
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Physical activity, tumor PTGS2 expression, and survival in patients with colorectal cancer.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 04-29-2013
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Higher levels of physical activity are associated with lower colorectal carcinoma incidence and mortality, perhaps through influencing energy balance, cellular prosta7 systemic inflammation. Although evidence suggests interactive effects of energetics, sedentary lifestyle, and tumor CTNNB1 (?-catenin) or CDKN1B (p27) status on colon cancer prognosis, interactive effects of physical activity and tumor PTGS2 (the official symbol for COX-2) status on clinical outcome remain unknown.
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Thrombospondin-1 is highly expressed in desmoplastic components of invasive ductal carcinoma of the breast and associated with lymph node metastasis.
J. Med. Invest.
PUBLISHED: 04-26-2013
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Desmoplastic (scirrhous) invasion and lymph node metastasis are critical for the treatment and prognosis of invasive ductal carcinoma of the breast. Despite being an anti-angiogenic therapeutic candidate, Thrombospondin-1 (TSP-1) promotes invasion and metastasis of some carcinomas. To clarify the effect of TSP-1 on invasion and metastasis, we obtained 101 invasive ductal carcinomas of the breast with axillary lymph node resection. All tumors were histologically divided into two categories, carcinomas with, and those with non- /minimal desmoplastic component. Immunohistochemistry for TSP-1 was performed on all primary tumors and axillary lymph nodes with tumor metastasis. Fifty-four (53.5%) of 101 tumors were recognized as positive for TSP-1 in the cytoplasm of tumor cells. Histological study showed that significantly more cancers with desmoplastic components (46/69, 66.7%) manifested TSP-1 expression than did cancers with no- or minimal (less than 20%) desmoplasia (8/32, 25.0%; p<0.001). Axillary lymph node metastasis was significantly higher in TSP-1-positive- (28/54, 51.9%) than TSP-1-negative cancers (11/47, 23.4%; p<0.005). The present study indicates that tumor cells in the desmoplastic component strongly expressed TSP-1 in invasive ductal carcinoma of the breast and TSP-1 participates in invasion of these tumors. Our findings also suggest that TSP-1 promotes lymph node metastasis and TSP-1 potentially could be a predictive marker for metastasis.
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Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.
Nat. Genet.
PUBLISHED: 03-22-2013
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The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome- and genome-sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs.
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Inflammatory plasma markers and pancreatic cancer risk: a prospective study of five U.S. cohorts.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 03-05-2013
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Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-? receptor II (TNF-?R2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1,094 controls from Health Professionals Follow-up Study, Nurses Health Study, Physicians Health Study, Womens Health Initiative, and Womens Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL-6, and TNF-?R2 and the risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 [95% confidence interval (CI), 0.74-1.63; Ptrend = 0.81] for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL-6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-?R2. In conclusion, prediagnostic levels of circulating CRP, IL-6, and TNF-?R2 were not associated with the risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.
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Prospective analysis of body mass index, physical activity, and colorectal cancer risk associated with ?-catenin (CTNNB1) status.
Cancer Res.
PUBLISHED: 02-26-2013
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Dysregulation of the WNT/?-catenin (CTNNB1) signaling pathway is implicated in colorectal carcinoma and metabolic diseases. Considering these roles and cancer prevention, we hypothesized that tumor CTNNB1 status might influence cellular sensitivity to obesity and physical activity. In clinical follow-up of 109,046 women in the Nurses Health Study and 47,684 men in the Health Professionals Follow-up Study, there were 861 incident rectal and colon cancers with tissue immunohistochemistry data on nuclear CTNNB1 expression. Using this molecular pathological epidemiology database, we conducted Cox proportional hazards regression analysis using data duplication method to assess differential associations of body mass index (BMI) or exercise activity with colorectal cancer risk according to tumor CTNNB1 status. Greater BMI was associated with a significantly higher risk of CTNNB1-negative cancer [multivariate HR = 1.34; 95% confidence interval (CI), 1.18-1.53 for 5.0 kg/m(2) increment; Ptrend = 0.0001] but not with CTNNB1-positive cancer risk (multivariate HR = 1.07; 95% CI, 0.92-1.25 for 5.0 kg/m(2) increment; Ptrend = 0.36; Pheterogeneity = 0.027, between CTNNB1-negative and CTNNB1-positive cancer risks). Physical activity level was associated with a lower risk of CTNNB1-negative cancer (multivariate HR = 0.93; 95% CI, 0.87-1.00 for 10 MET-h/wk increment; Ptrend = 0.044) but not with CTNNB1-positive cancer risk (multivariate HR = 0.98; 95% CI, 0.91-1.05 for 10 MET-h/wk increment; Ptrend = 0.60). Our findings argue that obesity and physical inactivity are associated with a higher risk of CTNNB1-negative colorectal cancer but not with CTNNB1-positive cancer risk. Furthermore, they suggest that energy balance and metabolism status exerts its effect in a specific carcinogenesis pathway that is less likely dependent on WNT/CTNNB1 activation. Cancer Res; 73(5); 1600-10. ©2012 AACR.
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Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database.
Endocr. Relat. Cancer
PUBLISHED: 01-01-2013
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The rarity of neuroendocrine tumors (NET) has contributed to a paucity of large epidemiologic studies of patients with this condition. We characterized presenting symptoms and clinical outcomes in a prospective database of over 900 patients with NET. We used data from patient questionnaires and the medical record to characterize presenting symptoms, disease-free survival (DFS), and overall survival (OS). The majority of patients in this database had gastroenteropancreatic NET. The median duration of patient-reported symptoms before diagnosis was 3.4 months; 19.5% reported durations from 1 to 5 years, 2.5% from 5 to 10 years, and 2% >10 years. The median DFS among patients with resected small bowel NET or pancreatic NET (panNET) was 5.8 and 4.1 years respectively. After correcting for left truncation bias, the median OS was 7.9 years for advanced small bowel NET and 3.9 years for advanced panNET. Chromogranin A (CGA) above twice the upper limit of normal was associated with shorter survival times (hazard ratios 2.8 (1.9, 4.0) P<0.001) in patients with metastatic disease, regardless of tumor subtype. Our data suggest that while most NET patients are diagnosed soon after symptom onset, prolonged symptom duration before diagnosis is a prominent feature of this disease. Though limited to observations from a large referral center, our observations confirm the prognostic value of CGA and suggest that median survival durations may be shorter than that reported in other institutional databases.
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Prognostic significance and molecular associations of tumor growth pattern in colorectal cancer.
Ann. Surg. Oncol.
PUBLISHED: 08-16-2011
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Infiltrative growth pattern at the tumor margin has been associated with shorter patient survival. However, little is known about the prognostic significance of tumor growth pattern, independent of tumoral molecular alterations and other histologic features.
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Tumor TP53 expression status, body mass index and prognosis in colorectal cancer.
Int. J. Cancer
PUBLISHED: 08-05-2011
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Inactivation of the TP53 (p53) pathway by TP53 mutations is one of key steps in colorectal carcinogenesis. TP53 also plays an important role in cellular energy metabolism. We hypothesized that TP53-altered tumor cells might behave aggressively independent of energy balance, while progression of TP53-intact cells might depend on excess energy balance. Utilizing a database of 1,060 colon and rectal cancer patients in two prospective cohort studies, we evaluated TP53 expression by immunohistochemistry. Among 1,060 colorectal cancers, 457 (43%) tumors were positive for TP53. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical and tumoral features, including microsatellite instability, the CpG island methylator phenotype, LINE-1 methylation, KRAS, BRAF and PIK3CA. TP53 positivity was not significantly associated with cancer-specific survival in univariate analysis with HR of 1.16 [95% confidence interval (CI)=0.92-1.45], which became significant after stage adjustment (multivariate HR=1.30; 95% CI=1.02-1.65). Notably, we found a possible modifying effect of patients body mass index (BMI) on tumor TP53. In non-obese patients (BMI<30 kg/m2), TP53 positivity was associated with shorter cancer-specific survival (multivariate HR=1.53; 95% CI=1.17-2.00), while TP53 positivity was not significantly associated with survival among obese patients (BMI?30 kg/m2). Effect of TP53 positivity on cancer-specific survival significantly differed by BMI (pinteraction=0.0051). The adverse effect of obesity on patient mortality was limited to TP53-negative patients. These molecular pathological epidemiology data may support a dual role of TP53 alterations in cell-cycle deregulation and cell autonomy with respect to energy balance status.
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Analysis of expression and structure of the rat GH-secretagogue/ghrelin receptor (Ghsr) gene: roles of epigenetic modifications in transcriptional regulation.
Mol. Cell. Endocrinol.
PUBLISHED: 04-13-2011
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In the current study, to elucidate the molecular basis of cell type-specific expression of the GH-secretagogue/ghrelin receptor type 1A (GHSR1A), we characterized the structure and putative promoter region of the rat Ghsr gene. We identified an alternative 5-untranslated first exon that contains multiple transcription start sites, and confirmed a 200-bp sequence proximal to this exon to be sufficient for basal promoter activity. A promoter-associated CpG island conserved across different species was found to be hypomethylated in Ghsr1a-expressing cell lines, while being heavily methylated in non-expressing cells. In cells with low or absent Ghsr1a expression, treatment with demethylating agents activated Ghsr1a transcription. Chromatin immunoprecipitation assays demonstrated Ghsr1a-expressing cells to display active histone modifications, whereas repressive modifications were present exclusively in other cell types. These results suggest epigenetic modifications at GHSR to play important roles in determining GHSR1A expression and abundance, and therefore the consequent sensitivity of cells to ghrelin.
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Increased expression of HMGA1 correlates with tumour invasiveness and proliferation in human pituitary adenomas.
Histopathology
PUBLISHED: 05-13-2010
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High-mobility group A1 (HMGA1) is highly expressed in various benign and malignant tumours. The development of pituitary adenoma in Hmga1 transgenic mice has been reported. However, no studies have investigated HMGA1 expression and its clinical significance in human pituitary adenomas.
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Pituitary adenomas that show a faint GH-immunoreactivity but lack fibrous body: Pit-1 adenoma with endocrinologically low activity.
Endocr. Pathol.
PUBLISHED: 01-30-2010
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Growth hormone (GH)-producing pituitary adenomas have been classified into densely and sparsely granulated adenomas. The latter are chromophobic with weak GH-positivity and characteristically possess fibrous body (FB), aggregation of cytokeratin filaments. We report eight cases of unusual chromophobic adenomas. GH-immunoreactivity was detected in most adenoma cells in five cases and scattered in three cases. However, it appeared much weaker than that seen in ordinary GH-producing adenomas because of spotty immunoreactivity. Although intracytoplasmic organelles were well-developed, secretory granules were small and sparse. FB was not identified in any cases. Thyroid-stimulating hormone was positive in four cases. Pit-1 protein was positive in all eight cases. A weak labeling with GH probe was detected in two of two cases examined by in situ hybridization. Acromegalic features were evident in four cases, while mild or absent in four cases. GH levels were below 5 microg/l in four cases and 5-10 microg/l in the remaining cases. Macroadenomas and invasive adenomas were seen in seven and six cases, respectively.Pituitary adenomas that show a faint GH-immunoreactivity but lack FB do not fit the established classification. These adenomas may be a distinct pituitary adenoma type of Pit-1 lineage with endocrinologically low activity.
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DNA methyltransferases 1, 3a, and 3b overexpression and clinical significance in gastroenteropancreatic neuroendocrine tumors.
Hum. Pathol.
PUBLISHED: 01-05-2010
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The alteration of DNA methylation is one of the most common epigenetic changes in human cancers. Three genes, namely, DNA methyltransferase 1, 3a, and 3b, which code for DNA methyltransferases that affect promoter methylation status, are thought to play an important role in the development of cancers and may be good anticancer therapy targets. The methylation of tumor suppressor genes has been reported in gastroenteropancreatic neuroendocrine tumors; however, there have been no studies about DNA methyltransferase protein expression and its clinical significance in gastroenteropancreatic neuroendocrine tumors. In this study, the expression of DNA methyltransferase 1, 3a, and 3b was studied in 63 gastroenteropancreatic neuroendocrine tumors by immunohistochemistry. The expression of DNA methyltransferase 1, 3a, and 3b was frequently detected in gastroenteropancreatic neuroendocrine tumors (87%, 81%, and 75%, respectively). The DNA methyltransferase 3a expression level was significantly higher in poorly differentiated neuroendocrine carcinomas than in well-differentiated neuroendocrine tumors or well-differentiated neuroendocrine carcinomas (P < .01 and P < .05, respectively). The expression of DNA methyltransferase 1, 3a, and 3b showed significantly higher levels in stage IV tumors than in stage I or II tumors. In addition, the expression levels of DNA methyltransferase 1, 3a, and 3b were positively correlated with the MIB-1 labeling index in gastroenteropancreatic neuroendocrine tumors (R = 0.293, P = .019; R = 0.457, P = .001; and R = 0.249, P = .049; respectively). In addition, the expression levels and positive immunostaining frequencies of DNA methyltransferase 3a and 3b were significantly lower in midgut neuroendocrine tumors than in foregut or hindgut neuroendocrine tumors. Our findings suggest that the overexpression of DNA methyltransferase 1, 3a, and 3b is related to tumorigenesis and the progression of gastroenteropancreatic neuroendocrine tumors.
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Clinicopathological characterization of TSH-producing adenomas: special reference to TSH-immunoreactive but clinically non-functioning adenomas.
Endocr. Pathol.
PUBLISHED: 09-24-2009
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Thyrotropin (thyroid-stimulating hormone (TSH))-producing pituitary adenomas have been known to be quite variable in clinical features covering from typical functioning TSH-producing adenomas (FTSHomas) associated with hyperthyroidism to clinically silent TSH cell adenomas (STAs) that are apparently unassociated with hyperthyroidism. It is important to distinguish STAs from other types of clinically non-functioning adenomas for adequate postoperative managements. However, because of rareness of TSH-producing adenomas, their histopathological features linking to the clinical manifestations have not been well characterized. Herein, we investigated clinical and histopathological findings to characterize 29 TSH-producing adenomas including 20 FTSHomas and nine STAs. Clinical symptoms of the patients with STAs included headache, visual defect, vertigo, and nausea. All STAs and 19 FTSHomas were macroadenoma. The average tumor size of STAs was significantly larger than that of FTSHomas (P < 0.05). The invasiveness was detected in 33% STAs and in 20% FTSHomas. Both STAs and FTSHomas showed a variety of morphological features and immunohistochemical profiles. Chromophobic polygonal or short-spindled tumor cells usually proliferated in a diffuse pattern, while they exhibited globoid or whorl-like appearance with intertwined cytoplasmic processes in both subgroups. Stromal fibrosis and calcification were often noted. Their nuclei were somehow pleomorphic. Ultrastructural features of all four STAs examined were similar to those of normal thyrotrophs. Thus, STAs and FTSHomas were indistinguishable by histology alone. Immunohistochemically, the number of TSH-positive cells in individual FTSHomas was highly various. Six tumors showed only a few TSH-positive cells (1-5%), and three were negative for TSH by conventional method without antigen retrieval. After proteinase K treatment, these tumors turned out TSH positive. As defined, STAs were TSH positive in more than 20% of tumor cells and three of them in more than 50%. Growth hormone- and/or prolactin-positive cells were detected in 55% STAs and 63% FTSHomas. Both pituitary-specific transcription factor 1 and GATA-binding protein 2 were expressed in all STAs and 20 FTSHomas. Membranous somatostatin receptor (SSTR)-2A immunoreactivity was found in 89% STAs and 94% FTSHomas, whereas SSTR5 was positive in 78% of both STAs and FTSHomas. MIB-1 labeling index was related to tumor invasiveness and tumor size (P < 0.05, P = 0.09, respectively). Thus, although both STAs and FTSHomas showed unique histopathological features distinct from other type adenomas, these two subgroups were indistinguishable by histopathology. Immunohistochemistry for TSH by use of antigen retrieval, transcription factors, and SSTRs may be useful to confirm STAs and to determine the postoperative therapy among various kinds of clinically non-functioning adenomas.
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Expression of p18(INK4C) is down-regulated in human pituitary adenomas.
Endocr. Pathol.
PUBLISHED: 04-30-2009
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Cyclin-dependent kinase inhibitors represented by the INK4 family comprising p16(INK4A), p15(INK4B), p18(INK4C), and p19(INK4D) are regulators of the cell cycle shown to be aberrant in many types of cancer. Mice lacking p18(Ink4c) exhibit a series of phenotypes including the development of widespread organomegaly and pituitary adenomas. The objective of our study is to examine the role of p18(INK4C) in the pathogenesis of human pituitary tumors. The protein and mRNA levels of p18(INK4C) were examined by immunohistochemistry and real-time reverse transcription-polymerase chain reaction, respectively. The methylation status of the p18(INK4C) gene promoter and somatic mutations of the p18(INK4C) gene were also investigated. p18(INK4C) protein expression was lost or significantly reduced in 64% of pituitary adenomas compared with levels in normal pituitary glands. p18(INK4C) mRNA levels were low in all ACTH adenomas and non-functioning (NF)-FSH and in 42%, 70% and 66% of GH, PRL, and subtype 3 adenomas, respectively. p18(INK4C) mRNA levels were significantly associated with p18(INK4C) protein levels. Neither methylated promoters in pituitary adenomas, except in one NF-FSH adenoma, nor somatic mutations of the p18(INK4C) gene in any pituitary adenomas were detected. The down-regulation of p18(INK4C) expression may contribute to the tumorigenesis of pituitary adenomas.
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Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas.
Mod. Pathol.
PUBLISHED: 01-09-2009
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High-mobility group A2 is highly expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that high-mobility group A2 is negatively regulated by the let-7 microRNAs (miRNAs) family in vitro. The development of pituitary adenomas in high-mobility group A2 transgenic mice showed that high-mobility group A2 may be involved in pituitary tumorigenesis. However, no studies have investigated the clinical significance of high-mobility group A2 and its relationship to the let-7 miRNA family in human pituitary adenomas. Using immunohistochemistry, we analyzed high-mobility group A2 expression with respect to various clinicopathologic factors in 98 pituitary adenomas. Overexpression of high-mobility group A2 was observed in 39% (38/98) of pituitary adenomas compared with normal adenohypophysial tissue and was frequently found in adenomas including prolactin (PRL), adrenocorticotrophic hormone, or follicle-stimulating hormone/luteinizing hormone and in null cell adenomas, but relatively rare in growth hormone (GH) and mixed GH/PRL adenomas. High-mobility group A2 expression was significantly associated with tumor invasion (P<0.05) and was significantly higher in grade IV than in grades I, II, and III adenomas (P<0.05). High levels of high-mobility group A2 expression were more frequently observed in macroadenomas than in microadenomas (P<0.05). High levels of high-mobility group A2 expression also significantly correlated with the proliferation marker Ki-67 (P<0.0001). Real-time quantitative RT-PCR analysis was carried out to evaluate the expression of let-7 in 55 pituitary adenomas. Subsequently, decreased expression of let-7 was confirmed in 23 of 55 (42%) adenomas and was correlated with high-grade tumors (P<0.05). An inverse correlation between let-7 and high-mobility group A2 expression was evident (R=-0.33, P<0.05). These findings support a causal link between let-7 and high-mobility group A2 whereby loss of let-7 expression induces high-mobility group A2 upregulation that represents an important mechanism in pituitary tumorigenesis and progression.
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Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level.
J. Natl. Cancer Inst.
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Beyond known familial colorectal cancer (CRC) syndromes, the mechanisms underlying the elevated CRC risk associated with CRC family history remain largely unknown. A recent retrospective study suggests familial clustering of CRC with hypomethylation in long interspersed nucleotide element 1 (LINE-1). We tested the hypothesis that CRC family history might confer a higher risk of LINE-1 methylation-low CRC.
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Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival.
N. Engl. J. Med.
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Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers.
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Insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3) is a marker of unfavourable prognosis in colorectal cancer.
Eur. J. Cancer
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Evidence suggests that insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3, also known as IMP3) represents a promising cancer biomarker. However, the clinical, pathological, molecular and prognostic features of IGF2BP3-positive colorectal cancers remain uncertain.
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Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.
Nature
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Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.
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Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers.
Clin. Cancer Res.
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To assess prognostic roles of various KRAS oncogene mutations in colorectal cancer, BRAF mutation status must be controlled for because BRAF mutation is associated with poor prognosis, and almost all BRAF mutants are present among KRAS wild-type tumors. Taking into account experimental data supporting a greater oncogenic effect of codon 12 mutations compared with codon 13 mutations, we hypothesized that KRAS codon 12-mutated colorectal cancers might behave more aggressively than KRAS wild-type tumors and codon 13 mutants. Experimental design: Using molecular pathological epidemiology database of 1,261 rectal and colon cancers, we examined clinical outcome and tumor biomarkers of KRAS codon 12 and 13 mutations in 1,075 BRAF wild-type cancers (i.e., controlling for BRAF status). Cox proportional hazards model was used to compute mortality HR, adjusting for potential confounders, including stage, PIK3CA mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation.
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No evidence for interference of h&e staining in DNA testing: usefulness of DNA extraction from H&E-stained archival tissue sections.
Am. J. Clin. Pathol.
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Although histochemical staining has been believed to inhibit the DNA amplification reaction, no previous study has systematically evaluated the influence of histochemical staining on downstream molecular assays. To evaluate an influence of H&E staining on DNA testing, we isolated DNA from 10 unstained, 10 hematoxylin-stained, 10 eosin-stained, and 10 H&E-stained tissue sections (ie, 4 groups), from each of 5 colon cancers. Among the 4 groups, we did not observe any significant or appreciable difference in DNA fragmentation by agarose gel electrophoresis, in DNA amplification by real-time polymerase chain reaction (PCR), in microsatellite PCR fragment analyses, or in a PCR-pyrosequencing assay. As a proof-of-principle study, we successfully performed microsatellite instability analysis and sequencing of KRAS and BRAF on more than 1,300 colorectal cancers using DNA extracted from H&E-stained tissue sections. Our data provide no evidence for an interfering effect of H&E staining on DNA testing, suggesting that DNA from H&E-stained sections can be effectively used for routine DNA testing.
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Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum.
Gut
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Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.
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Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.
Clin. Cancer Res.
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Mutations in PIK3CA [the gene encoding the p110? catalytic subunit of phosphatidylinositide-3-kinase (PI3K)] play an important role in colorectal carcinogenesis. Experimental evidence suggests that PIK3CA exon 9 and exon 20 mutations trigger different biologic effects, and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects. Thus, we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer, and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.