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  1. Diet, lifestyle, and molecular alterations that drive colorectal carcinogenesis

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    Diergaarde, B.

    2004-01-01

    Environmental factors have been repeatedly implicated in the etiology of colorectal cancer, and much is known about the molecular events involved in colorectal carcinogenesis. The relationships between environmental risk factors and the molecular alterations that drive colorectal carcinogenesis are

  2. [Colorectal cancer (CCR): genetic and molecular alterations].

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    Juárez-Vázquez, Clara Ibet; Rosales-Reynoso, Mónica Alejandra

    2014-01-01

    The aim of this review is to present a genetic and molecular overview of colorectal carcinogenesis (sporadic and hereditary origin) as a multistage process, where there are a number of molecular mechanisms associated with the development of colorectal cancer and genomic instability that allows the accumulation of mutations in proto-oncogenes and tumor suppressor genes, chromosomal instability, and methylation and microsatellite instability, and the involvement of altered expression of microRNAs' prognosis factors.

  3. Molecular alterations and biomarkers in colorectal cancer

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    Grady, William M.; Pritchard, Colin C.

    2013-01-01

    The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer genetics is leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR). In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers). PMID:24178577

  4. Colorectal cancer cell lines made resistant to SN38-and Oxaliplatin: Roles of altered ion transporter function in resistance?

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    Sandra, Christensen; Jensen, Niels Frank; Stoeckel, Johanne Danmark

    2013-01-01

    , respectively. Studies are ongoing to assess glutamate uptake in parental and resistant CRC cells and the effect of inhibition/knockdown of SLC1A1 and -3 on SN38- and Oxp resistance. In conclusion, SN38-and Oxp-resistance in CRC cells is associated with SLC1A1 and -3 dysregulation. As these transporters have...

  5. Altered Polyamine Profiles in Colorectal Cancer.

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    Venäläinen, Markus K; Roine, Antti N; Häkkinen, Merja R; Vepsäläinen, Jouko J; Kumpulainen, Pekka S; Kiviniemi, Mikko S; Lehtimäki, Terho; Oksala, Niku K; Rantanen, Tuomo K

    2018-06-01

    The declining mortality rate of patients with colorectal cancer (CRC) can be explained, at least partially, with early diagnosis. Simple diagnostic methods are needed to achieve a maximal patient participation rate in screening. Liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS) was used to determine urinary polyamine (PA) profiles. In a prospective setting, 116 patients were included in the study: 57 with CRC, 13 with inflammatory bowel disease (IBD), 12 with adenoma, and 34 controls. N1,N12-diacetylspermine (DiAcSPM) level was significantly higher in patients with CRC than controls (sensitivity=78.0%, specificity=70.6%; p=0.00049). The level of diacetylated cadaverine (p=0.0068) was lower and that of diacetylated putrescine (p=0.0078) was higher in patients with CRC than in those with IBD. Cadaverine (p=0.00010) and spermine (p=0.042) levels were lower and that of DiAcSPM (p=0.018) higher in patients with CRC than in those with adenoma. The simultaneous determination of urinary PAs by means of LC-MS/MS can be used to discriminate CRC from controls and patients with benign colorectal diseases. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  6. Histochemical alterations in colorectal carcinoma and adenoma in Egyptian patients

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    Saber A Sakr

    2016-01-01

    Full Text Available Objective: To evaluate the histochemical alterations in DNA and total carbohydrates, in colorectal cancer cells. Methods: This study was carried out on 48 colorectal carcinoma and 10 adenoma specimens. Hematoxylin and Eosin staining was carried out for histopathological examination to confirm the diagnosis and to evaluate the histopathological characteristics of tumor. Histologic grade and pathologic stage was assessed according to TNM staging system. Staging was also assessed according to original Dukes’ staging system. DNA was demonstrated by Feulgen method and carbohydrates were demonstrated by periodic acid Schiff’s reaction. Results: Adenoma cases showed that the cells lining the glands of the polyp have more crowded, irregular and darker nuclei (hyperchromatic, anisonucleosis, abnormal mitotic figures with prominent nucleoli and variability in the size and shape of nuclei. Colorectal carcinoma cases showed a condensation and reduction in the size of a cell nucleus associated with hyperchromatosis, pyknotic nuclei, abnormal mitotic figures, anisonucleosis, irregular nuclear membrane and inequality in the size of the nuclei (Pleomorphosis. There was a statistical significant differences between adenoma and carcinoma regarding number of mitotic cells (P = 0.03 that was in favour of malignant group. Adenoma and colorectal carcinoma cases showed periodic acid Schiff’s reactivity with different degree. Conclusions: These histochemical alterations can be so characteristic of a given tumor type and stage that they are used in cancer diagnosis and might also be related to the altered functional properties of cancer cells.

  7. Distinct genetic alterations in colorectal cancer.

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    Hassan Ashktorab

    Full Text Available BACKGROUND: Colon cancer (CRC development often includes chromosomal instability (CIN leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities. METHODOLOGY/PRINCIPAL FINDINGS: We applied genome-wide array comparative genome hybridization (aCGH using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes. There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations. CONCLUSIONS/SIGNIFICANCE: Chromosome X amplification in male patients and chromosomes 4, 8 and 18 deletions were prominent aberrations in AAs. Some CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs.

  8. Altered JS-2 expression in colorectal cancers and its clinical pathological relevance.

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    Lam, Alfred King-Yin; Gopalan, Vinod; Nassiri, Mohammad Reza; Kasim, Kais; Dissanayake, Jayampathy; Tang, Johnny Chuek-On; Smith, Robert Anthony

    2011-10-01

    JS-2 is a novel gene located at 5p15.2 and originally detected in primary oesophageal cancer. There is no study on the role of JS-2 in colorectal cancer. The aim of this study is to determine the gene copy number and expression of JS-2 in a large cohort of patients with colorectal tumours and correlate these to the clinicopathological features of the cancer patients. We evaluated the DNA copy number and mRNA expression of JS-2 in 176 colorectal tissues (116 adenocarcinomas, 30 adenomas and 30 non-neoplastic tissues) using real-time polymerase chain reaction. JS-2 expression was also evaluated in two colorectal cancer cell lines and a benign colorectal cell line. JS-2 amplification was noted in 35% of the colorectal adenocarcinomas. Significant differences in relative expression levels for JS-2 mRNA between different colorectal tissues were noted (p = 0.05). Distal colorectal adenocarcinoma had significantly higher copy number than proximal adenocarcinoma (p = 0.005). The relative expression level of JS-2 was different between colonic and rectal adenocarcinoma (p = 0.007). Mucinous adenocarcinoma showed higher JS-2 expression than non-mucinous adenocarcinoma (p = 0.02). Early T-stage cancers appear to have higher JS-2 copy number and lower expression of JS-2 mRNA than later stage cancers (p = 0.001 and 0.03 respectively). Colorectal cancer cell lines showed lower expression of JS-2 than the benign colorectal cell line. JS-2 copy number change and expression were shown for the first time to be altered in the carcinogenesis of colorectal cancer. In addition, genetic alteration of JS-2 was found to be related to location, pathological subtypes and staging of colorectal cancer. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  9. Transporter function and cyclic AMP turnover in normal colonic mucosa from patients with and without colorectal neoplasia

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    Kleberg, Karen; Jensen, Gerda Majgaard; Christensen, Dan Ploug

    2012-01-01

    The pathogenesis of colorectal neoplasia is still unresolved but has been associated with alterations in epithelial clearance of xenobiotics and metabolic waste products. The aim of this study was to functionally characterize the transport of cyclic nucleotides in colonic biopsies from patients...

  10. Transporter function and cyclic AMP turnover in normal colonic mucosa from patients with and without colorectal neoplasia

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    Kleberg Karen

    2012-06-01

    Full Text Available Abstract Background The pathogenesis of colorectal neoplasia is still unresolved but has been associated with alterations in epithelial clearance of xenobiotics and metabolic waste products. The aim of this study was to functionally characterize the transport of cyclic nucleotides in colonic biopsies from patients with and without colorectal neoplasia. Methods Cyclic nucleotides were used as model substrates shared by some OATP- and ABC-transporters, which in part are responsible for clearance of metabolites and xenobiotics from the colonic epithelium. On colonic biopsies from patients with and without colorectal neoplasia, molecular transport was electrophysiologically registered in Ussing-chamber set-ups, mRNA level of selected transporters was quantified by rt-PCR, and subcellular location of transporters was determined by immunohistochemistry. Results Of four cyclic nucleotides, dibuturyl-cAMP induced the largest short circuit current in both patient groups. The induced short circuit current was significantly lower in neoplasia-patients (p = 0.024. The observed altered transport of dibuturyl-cAMP in neoplasia-patients could not be directly translated to an observed increased mRNA expression of OATP4A1 and OATP2B1 in neoplasia patients. All other examined transporters were expressed to similar extents in both patient groups. Conclusions OATP1C1, OATP4A1, OATP4C1 seem to be involved in the excretory system of human colon. ABCC4 is likely to be involved from an endoplasmic-Golgi complex and basolateral location in goblet cells. ABCC5 might be directly involved in the turnover of intracellular cAMP at the basolateral membrane of columnar epithelial cells, while OATP2B1 is indirectly related to the excretory system. Colorectal neoplasia is associated with lower transport or sensitivity to cyclic nucleotides and increased expression of OATP2B1 and OATP4A1 transporters, known to transport PGE2.

  11. Haemostatic alterations in colorectal cancer: perspectives for future treatment

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    Lykke, Jakob; Nielsen, Hans Jørgen

    2004-01-01

    The role of the haemostatic system in colorectal cancer (CRC) is reviewed. Correlations between the activation of the haemostatic system and overall survival have been suggested. Experimental studies indicate that the haemostatic system plays a key role in growth, invasion and dissemination of tu...

  12. Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization.

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    Mukhopadhya, Indrani; Murray, Graeme I; Berry, Susan; Thomson, John; Frank, Bruce; Gwozdz, Garry; Ekeruche-Makinde, Julia; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

    2016-02-01

    The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection. Drug transporter mRNA expression was quantified from colorectal biopsies and cell lines by quantitative real-time PCR. Relative mRNA expression was quantified in Caco-2 cells and colorectal explants after induction with ARVs. Data were analysed using Pearson's product moment correlation (r), hierarchical clustering and principal component analysis (PCA). Expression of 58 of the 84 transporters was documented in colorectal biopsies, with genes for CNT2, P-glycoprotein (P-gp) and MRP3 showing the highest expression. No difference was noted between individual subjects when analysed by age, gender or anatomical site (rectum or recto-sigmoid) (r = 0.95-0.99). High expression of P-gp and CNT2 proteins was confirmed by immunohistochemical staining. Similarity between colorectal tissue and cell-line drug transporter gene expression was variable (r = 0.64-0.84). PCA showed distinct clustering of human colorectal biopsy samples, with the Caco-2 cells defined as the best surrogate system. Induction of Caco-2 cell lines with ARV drugs suggests that darunavir-based microbicides incorporating tenofovir may result in drug-drug interactions likely to affect distribution of individual drugs to sub-epithelial target cells. These findings will help optimize complex formulations of rectal microbicides to realize their full potential as an effective approach for pre-exposure prophylaxis against HIV-1 infection. © The Author 2015. Published by Oxford University Press on behalf of the

  13. DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer.

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    Samuelsson, Johanna K; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

    2010-11-10

    Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in carcinogenesis. Epigenetic regulation mechanisms underlie the maintenance of cell identity crucial for development and differentiation. These epigenetic regulatory mechanisms have been found substantially altered during cancer development and progression. In this review, we discuss approaches designed to analyze genetic and epigenetic alterations in colorectal cancer, especially DNA fingerprinting approaches to detect changes in DNA copy number and methylation. DNA fingerprinting techniques, despite their modest throughput, played a pivotal role in significant discoveries in the molecular basis of colorectal cancer. The aim of this review is to revisit the fingerprinting technologies employed and the oncogenic processes that they unveiled. 2010 Elsevier B.V. All rights reserved.

  14. PIK3CA Mutation in Colorectal Cancer: Relationship with Genetic and Epigenetic Alterations

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    Katsuhiko Nosho

    2008-06-01

    Full Text Available Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN. Microsatellite instability (MSI and CpG island methylator phenotype (CIMP are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15% of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight. PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR = 2.44], KRAS mutation (P < .0001; OR = 2.68, CIMP-high (P = .03; OR = 2.08, phospho–ribosomal protein S6 expression (P = .002; OR = 2.19, and FASN expression (P = .02; OR = 1.85 and inversely with p53 expression (P = .01; OR = 0.54 and β-catenin (CTNNB1 alteration (P = .004; OR = 0.43. In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24 but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.

  15. Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing.

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    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Shokeen, Yogender; Minhas, Sachin; Aggarwal, Shyam

    2016-10-01

    Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients.

  16. Novel mouse model recapitulates genome and transcriptome alterations in human colorectal carcinomas.

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    McNeil, Nicole E; Padilla-Nash, Hesed M; Buishand, Floryne O; Hue, Yue; Ried, Thomas

    2017-03-01

    Human colorectal carcinomas are defined by a nonrandom distribution of genomic imbalances that are characteristic for this disease. Often, these imbalances affect entire chromosomes. Understanding the role of these aneuploidies for carcinogenesis is of utmost importance. Currently, established transgenic mice do not recapitulate the pathognonomic genome aberration profile of human colorectal carcinomas. We have developed a novel model based on the spontaneous transformation of murine colon epithelial cells. During this process, cells progress through stages of pre-immortalization, immortalization and, finally, transformation, and result in tumors when injected into immunocompromised mice. We analyzed our model for genome and transcriptome alterations using ArrayCGH, spectral karyotyping (SKY), and array based gene expression profiling. ArrayCGH revealed a recurrent pattern of genomic imbalances. These results were confirmed by SKY. Comparing these imbalances with orthologous maps of human chromosomes revealed a remarkable overlap. We observed focal deletions of the tumor suppressor genes Trp53 and Cdkn2a/p16. High-level focal genomic amplification included the locus harboring the oncogene Mdm2, which was confirmed by FISH in the form of double minute chromosomes. Array-based global gene expression revealed distinct differences between the sequential steps of spontaneous transformation. Gene expression changes showed significant similarities with human colorectal carcinomas. Pathways most prominently affected included genes involved in chromosomal instability and in epithelial to mesenchymal transition. Our novel mouse model therefore recapitulates the most prominent genome and transcriptome alterations in human colorectal cancer, and might serve as a valuable tool for understanding the dynamic process of tumorigenesis, and for preclinical drug testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Alteration of hypothalamus-pituitary-adrenal gland axis in colorectal cancer patients. Preliminary report.

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    Crippa, S; Mussi, C; Angelini, C; Caprotti, R; Bonardi, C; Muselli, P; Scotti, M; Piacentini, G; Uggeri, F

    2003-08-01

    In advanced cancer patients a cell-mediated immunological impairment, both at baseline and during postoperative period, is often found and is associated with poor prognosis. Cortisol is strictly involved in the response to major surgical stress, is an immunosuppressor and causes a redistribution of immunological population cells in different tissues. The aim of the study was to verify serum levels and circadian rhythm of cortisol in patients with colorectal cancer at baseline before surgery and in the postoperative period, and relate it to the immune status. In 21 patients with colorectal cancer undergoing surgery we evaluated the assessment of total lymphocytes, CD4+, cortisolemia, circadian rhythm of cortisol (11 p.m. and 8 a.m.) at baseline and in 3(rd) and 7(th) postoperative days. Increase of cortisolemia, as decrease of total and CD4+ lymphocytes in the postoperative period versus baseline was statistically significant. Patients with an altered circadian rhythm were 47% and 36% at 3rd and 7th postoperative days, respectively. At baseline 19% of patients had an altered cortisol circadian rhythm and it was more frequent in patients with nodal involvement (pcancer patients seems not to be associated with cortisol level and circadian rhythm alteration, either at baseline or after surgical stress. An impairment of circadian rhythm of cortisol was found at baseline in 19% of patients. It was significantly associated with the presence of metastatic disease.

  18. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility.

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    Joshua M Uronis

    2009-06-01

    Full Text Available It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD and ulcerative colitis (UC collectively referred to as inflammatory bowel disease (IBD. Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC. However, the impact of the microbiota on the development of colitis-associated cancer (CAC remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM-exposed, conventionalized-Il10(-/- mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62% of AOM-Il10(-/- mice developed colon tumors compared to only 3/15 (20% of AOM- wild-type (WT mice. Conventionalized AOM-Il10(-/- mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10(-/- mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10(-/- mice. Germ-free AOM-treated Il10(-/- mice showed normal colon histology and were devoid of tumors. Il10(-/-; Myd88(-/- mice treated with AOM displayed reduced expression of Il12p40 and Tnfalpha mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma.

  19. Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer.

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    Yoshiyuki Watanabe

    Full Text Available MLL3 is a histone 3-lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes potentially altered in neoplasia. Mutations in MLL3 were found in a whole genome analysis of colorectal cancer but have not been confirmed by a separate study.We analyzed mutations of coding region and promoter methylation in MLL3 using 126 cases of colorectal cancer. We found two isoforms of MLL3 and DNA sequencing revealed frameshift and other mutations affecting both isoforms of MLL3 in colorectal cancer cells and 19 of 134 (14% primary colorectal samples analyzed. Moreover, frameshift mutations were more common in cases with microsatellite instability (31% both in CRC cell lines and primary tumors. The largest isoform of MLL3 is transcribed from a CpG island-associated promoter that has highly homology with a pseudo-gene on chromosome 22 (psiTPTE22. Using an assay which measured both loci simultaneously we found prominent age related methylation in normal colon (from 21% in individuals less than 25 years old to 56% in individuals older than 70, R = 0.88, p<0.001 and frequent hypermethylation (83% in both CRC cell lines and primary tumors. We next studied the two loci separately and found that age and cancer related methylation was solely a property of the pseudogene CpG island and that the MLL3 loci was unmethylated.We found that frameshift mutations of MLL3 in both CRC cells and primary tumor that were more common in cases with microsatellite instability. Moreover, we have shown CpG island-associated promoter of MLL3 gene has no DNA methylation in CRC cells but also primary tumor and normal colon, and this region has a highly homologous of pseudo gene (psiTPTE22 that was age relate DNA methylation.

  20. Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing.

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    Xie, Tao; Cho, Yong Beom; Wang, Kai; Huang, Donghui; Hong, Hye Kyung; Choi, Yoon-La; Ko, Young Hyeh; Nam, Do-Hyun; Jin, Juyoun; Yang, Heekyoung; Fernandez, Julio; Deng, Shibing; Rejto, Paul A; Lee, Woo Yong; Mao, Mao

    2014-10-01

    Colorectal cancer (CRC) patients have poor prognosis after formation of distant metastasis. Understanding the molecular mechanisms by which genetic changes facilitate metastasis is critical for the development of targeted therapeutic strategies aimed at controlling disease progression while minimizing toxic side effects. A comprehensive portrait of somatic alterations in CRC and the changes between primary and metastatic tumors has yet to be developed. We performed whole genome sequencing of two primary CRC tumors and their matched liver metastases. By comparing to matched germline DNA, we catalogued somatic alterations at multiple scales, including single nucleotide variations, small insertions and deletions, copy number aberrations and structural variations in both the primary and matched metastasis. We found that the majority of these somatic alterations are present in both sites. Despite the overall similarity, several de novo alterations in the metastases were predicted to be deleterious, in genes including FBXW7, DCLK1 and FAT2, which might contribute to the initiation and progression of distant metastasis. Through careful examination of the mutation prevalence among tumor cells at each site, we also proposed distinct clonal evolution patterns between primary and metastatic tumors in the two cases. These results suggest that somatic alterations may play an important role in driving the development of colorectal cancer metastasis and present challenges and opportunities when considering the choice of treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers

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    Jorissen, Robert N; Lipton, Lara; Gibbs, Peter

    2008-01-01

    Purpose: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes...... and downstream effects of differential gene expression. Experimental Design: DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly divided into test and training sets. MSI-associated gene......-number data. Results: MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P

  2. NDRG2 gene copy number is not altered in colorectal carcinoma

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    Lorentzen, Anders Blomkild; Mitchelmore, Cathy

    2017-01-01

    AIM To investigate if the down-regulation of N-myc Downstream Regulated Gene 2 (NDRG2) expression in colorectal carcinoma (CRC) is due to loss of the NDRG2 allele(s). METHODS The following were investigated in the human colorectal cancer cell lines DLD-1, LoVo and SW-480: NDRG2 mRNA expression...... levels using quantitative reverse transcription-polymerase chain reaction (qRT-PCR); interaction of the MYC gene-regulatory protein with the NDRG2 promoter using chromatin immunoprecipitation; and NDRG2 promoter methylation using bisulfite sequencing. Furthermore, we performed qPCR to analyse the copy...... numbers of NDRG2 and MYC genes in the above three cell lines, 8 normal colorectal tissue samples and 40 CRC tissue samples. RESULTS As expected, NDRG2 mRNA levels were low in the three colorectal cancer cell lines, compared to normal colon. Endogenous MYC protein interacted with the NDRG2 core promoter...

  3. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

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    Ekstrand, Anna Isinger; Jönsson, Mats; Lindblom, Annika

    2010-01-01

    The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors. Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT...... and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59...... and 75% and were strongly associated (P = 0.005). Reduced/lost PTEN expression was found in 63% of the tumors. Though HNPCC-associated colorectal cancers show simple genetic profiles with few chromosomal alterations, we demonstrate frequent and repeated targeting of the PI3K/AKT/mTOR pathway, which...

  4. FX enzyme and GDP-L-Fuc transporter expression in colorectal cancer.

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    Villar-Portela, Susana; Muinelo-Romay, Laura; Cuevas, Elisa; Gil-Martín, Emilio; Fernández-Briera, Almudena

    2013-08-01

    Fucosylation is regulated by fucosyltransferases, the guanosine diphosphate-L-fucose (GDP-L-Fuc) synthetic pathway, and the GDP-L-fucose transporter (GDP-L-Fuc Tr). We have reported previously an increased level of α(1,6)fucosyltransferase activity and expression in colorectal cancer (CRC). The present study aimed to analyse the expression profiles of the FX enzyme and GDP-L-Fuc Tr in a cohort of operated CRC patients to elucidate their role in α(1,6)fucosylation in this neoplasm. We assessed the immunohistochemical expression of FX and GDP-L-Fuc Tr in a series of tumour samples and healthy tissues from CRC specimens. FX expression was observed in 58 of 91 (63.7%) tumours and 23 of 28 (82.1%) corresponding healthy samples. GDP-L-Fuc Tr expression was detected in 86 of 102 (84.3%) colorectal tumours, and 13 of 27 (48.1%) healthy tissue specimens. The expression of GDP-L-Fuc Tr was statistically higher in tumours than in healthy tissues (P GDP-L-Fuc Tr expression in tumour samples (P = 0.003). GDP-L-Fuc Tr overexpression in the tumour tissue of CRC patients suggests that GDP-L-Fuc transport to the Golgi apparatus may be an important factor associated with increased α(1,6)fucosylation in CRC. © 2013 John Wiley & Sons Ltd.

  5. ABC-Transporter Expression Does Not Correlate with Response to Irinotecan in Patients with Metastatic Colorectal Cancer

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    Trumpi, K.; Emmink, B. L.; Prins, A. M.; van Oijen, M. G. H.; van Diest, P. J.; Punt, C. J. A.; Koopman, M.; Kranenburg, O.; Borel Rinkes, I. H. M.

    2015-01-01

    Background: Active efflux of irinotecan by ATP-binding cassette (ABC)-transporters, in particular ABCB1 and ABCG2, is a well-established drug resistance mechanism in vitro and in pre-clinical mouse models, but its relevance in colorectal cancer (CRC) patients is unknown. Therefore, we assessed the

  6. A gene-wide investigation on polymorphisms in the ABCG2/BRCP transporter and susceptibility to colorectal cancer

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Pardini, Barbara; Naccarati, Alessio; Vodičková, Ludmila; Novotný, J.; Försti, A.; Hemminki, K.; Barale, R.; Vodička, Pavel; Canzian, F.

    2008-01-01

    Roč. 645, 1-2 (2008), s. 56-60 ISSN 0027-5107 R&D Projects: GA ČR GA310/07/1430 Institutional research plan: CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : ABCG2 * Transporter * Colorectal cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.198, year: 2008

  7. Alteration of the platelet serotonin transporter in romantic love.

    Science.gov (United States)

    Marazziti, D; Akiskal, H S; Rossi, A; Cassano, G B

    1999-05-01

    The evolutionary consequences of love are so important that there must be some long-established biological process regulating it. Recent findings suggest that the serotonin (5-HT) transporter might be linked to both neuroticism and sexual behaviour as well as to obsessive-compulsive disorder (OCD). The similarities between an overvalued idea, such as that typical of subjects in the early phase of a love relationship, and obsession, prompted us to explore the possibility that the two conditions might share alterations at the level of the 5-HT transporter. Twenty subjects who had recently (within the previous 6 months) fallen in love, 20 unmedicated OCD patients and 20 normal controls, were included in the study. The 5-HT transporter was evaluated with the specific binding of 3H-paroxetine (3H-Par) to platelet membranes. The results showed that the density of 3H-Par binding sites was significantly lower in subjects who had recently fallen in love and in OCD patients than in controls. The main finding of the present study is that subjects who were in the early romantic phase of a love relationship were not different from OCD patients in terms of the density of the platelet 5-HT transporter, which proved to be significantly lower than in the normal controls. This would suggest common neurochemical changes involving the 5-HT system, linked to psychological dimensions shared by the two conditions, perhaps at an ideational level.

  8. Osmotic stress alters chromatin condensation and nucleocytoplasmic transport

    Energy Technology Data Exchange (ETDEWEB)

    Finan, John D.; Leddy, Holly A. [Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC (United States); Department of Biomedical Engineering, Duke University, Durham, NC (United States); Guilak, Farshid, E-mail: guilak@duke.edu [Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC (United States); Department of Biomedical Engineering, Duke University, Durham, NC (United States)

    2011-05-06

    Highlights: {yields} The rate of nucleocytoplasmic transport increases under hyper-osmotic stress. {yields} The mechanism is a change in nuclear geometry, not a change in permeability of the nuclear envelope. {yields} Intracytoplasmic but not intranuclear diffusion is sensitive to osmotic stress. {yields} Pores in the chromatin of the nucleus enlarge under hyper-osmotic stress. -- Abstract: Osmotic stress is a potent regulator of biological function in many cell types, but its mechanism of action is only partially understood. In this study, we examined whether changes in extracellular osmolality can alter chromatin condensation and the rate of nucleocytoplasmic transport, as potential mechanisms by which osmotic stress can act. Transport of 10 kDa dextran was measured both within and between the nucleus and the cytoplasm using two different photobleaching methods. A mathematical model was developed to describe fluorescence recovery via nucleocytoplasmic transport. As osmolality increased, the diffusion coefficient of dextran decreased in the cytoplasm, but not the nucleus. Hyper-osmotic stress decreased nuclear size and increased nuclear lacunarity, indicating that while the nucleus was getting smaller, the pores and channels interdigitating the chromatin had expanded. The rate of nucleocytoplasmic transport was increased under hyper-osmotic stress but was insensitive to hypo-osmotic stress, consistent with the nonlinear osmotic properties of the nucleus. The mechanism of this osmotic sensitivity appears to be a change in the size and geometry of the nucleus, resulting in a shorter effective diffusion distance for the nucleus. These results may explain physical mechanisms by which osmotic stress can influence intracellular signaling pathways that rely on nucleocytoplasmic transport.

  9. Altered neurocircuitry in the dopamine transporter knockout mouse brain.

    Directory of Open Access Journals (Sweden)

    Xiaowei Zhang

    2010-07-01

    Full Text Available The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI. Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn(2+ into the prefrontal cortex indicated that DAT KO mice have a truncated Mn(2+ distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn(2+ transport into more posterior midbrain nuclei and contralateral

  10. 49 CFR 37.43 - Alteration of transportation facilities by public entities.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Alteration of transportation facilities by public... transportation facilities by public entities. (a)(1) When a public entity alters an existing facility or a part of an existing facility used in providing designated public transportation services in a way that...

  11. The mitochondrial DNA 4,977-bp deletion and its implication in copy number alteration in colorectal cancer

    Science.gov (United States)

    2011-01-01

    Background Qualitative and quantitative changes in human mitochondrial DNA (mtDNA) have been implicated in various cancer types. A 4,977 bp deletion in the major arch of the mitochondrial genome is one of the most common mutations associated with a variety of human diseases and aging. Methods We conducted a comprehensive study on clinical features and mtDNA of 104 colorectal cancer patients in the Wenzhou area of China. In particular, using a quantitative real time PCR method, we analyzed the 4,977 bp deletion and mtDNA content in tumor tissues and paired non-tumor areas from these patients. Results We found that the 4,977 bp deletion was more likely to be present in patients of younger age (≤65 years, p = 0.027). In patients with the 4,977 bp deletion, the deletion level decreased as the cancer stage advanced (p = 0.031). Moreover, mtDNA copy number in tumor tissues of patients with this deletion increased, both compared with that in adjacent non-tumor tissues and with in tumors of patients without the deletion. Such mtDNA content increase correlated with the levels of the 4,977 bp deletion and with cancer stage (p deletion may play a role in the early stage of colorectal cancer, and it is also implicated in alteration of mtDNA content in cancer cells. PMID:21232124

  12. Rare MDM4 gene amplification in colorectal cancer: The principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable.

    Science.gov (United States)

    Suda, Tetsuji; Yoshihara, Mitsuyo; Nakamura, Yoshiyasu; Sekiguchi, Hironobu; Godai, Ten-I; Sugano, Nobuhiro; Tsuchida, Kazuhito; Shiozawa, Manabu; Sakuma, Yuji; Tsuchiya, Eiju; Kameda, Yoichi; Akaike, Makoto; Matsukuma, Shoichi; Miyagi, Yohei

    2011-07-01

    MDM4, a homolog of MDM2, is considered a key negative regulator of p53. Gene amplification of MDM4 has been identified in a variety of tumors. MDM2 or MDM4 gene amplification is only associated with the wild-type TP53 gene in retinoblastomas, thus the amplification of the two genes is mutually exclusive. Previously, we demonstrated that MDM2 amplification and TP53 alteration were not mutually exclusive in colorectal cancer, and we identified a subset of colorectal cancer patients without alterations in either the TP53 or the MDM2 gene. In this study, we investigated the gene amplification status of MDM4 in the same set of colorectal cancer cases. Unexpectedly, MDM4 amplification was rare, detected in only 1.4% (3 out of 211) of colorectal cancer cases. All the three gene-amplified tumors also harbored TP53-inactivating mutations. This contradicts the simple mutually exclusive relationship observed in retinoblastomas. Surprisingly, two of the three MDM4-amplified tumors also demonstrated MDM2 amplification. Paradoxically, the MDM4 protein levels were decreased in the tumor tissue of the gene-amplified cases compared with levels in the matched normal mucosa. We speculate that MDM4 might play a role in colorectal carcinogenesis that is not limited to negative regulation of p53 in combination with MDM2. The functional significance of MDM4 is still unclear and further studies are needed.

  13. Commercial software upgrades may significantly alter Perfusion CT parameter values in colorectal cancer

    International Nuclear Information System (INIS)

    Goh, Vicky; Shastry, Manu; Endozo, Raymondo; Groves, Ashley M.; Engledow, Alec; Peck, Jacqui; Reston, Jonathan; Wellsted, David M.; Rodriguez-Justo, Manuel; Taylor, Stuart A.; Halligan, Steve

    2011-01-01

    To determine how commercial software platform upgrades impact on derived parameters for colorectal cancer. Following ethical approval, 30 patients with suspected colorectal cancer underwent Perfusion CT using integrated 64 detector PET/CT before surgery. Analysis was performed using software based on modified distributed parameter analysis (Perfusion software version 4; Perfusion 4.0), then repeated using the previous version (Perfusion software version 3; Perfusion 3.0). Tumour blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined for identical regions-of-interest. Slice-by-slice and 'whole tumour' variance was assessed by Bland-Altman analysis. Mean BF, BV and PS was 20.4%, 59.5%, and 106% higher, and MTT 14.3% shorter for Perfusion 4.0 than Perfusion 3.0. The mean difference (95% limits of agreement) were +13.5 (-44.9 to 72.0), +2.61 (-0.06 to 5.28), -1.23 (-6.83 to 4.36), and +14.2 (-4.43 to 32.8) for BF, BV, MTT and PS respectively. Within subject coefficient of variation was 36.6%, 38.0%, 27.4% and 60.6% for BF, BV, MTT and PS respectively indicating moderate to poor agreement. Software version upgrades of the same software platform may result in significantly different parameter values, requiring adjustments for cross-version comparison. (orig.)

  14. Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications

    Science.gov (United States)

    Ferro, Suellen; Azevedo-Silva, João; Casal, Margarida; Côrte-Real, Manuela; Baltazar, Fatima; Preto, Ana

    2016-01-01

    Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC. PMID:28874966

  15. DNA Fingerprinting Techniques for the Analysis of Genetic and Epigenetic Alterations in Colorectal Cancer

    OpenAIRE

    Samuelsson, Johanna K.; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

    2010-01-01

    Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in ca...

  16. Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma.

    Science.gov (United States)

    Chen, Hui-Min; Yu, Ya-Nan; Wang, Ji-Lin; Lin, Yan-Wei; Kong, Xuan; Yang, Chang-Qing; Yang, Li; Liu, Zhan-Ju; Yuan, Yao-Zong; Liu, Fei; Wu, Jian-Xin; Zhong, Liang; Fang, Dian-Chun; Zou, Weiping; Fang, Jing-Yuan

    2013-05-01

    Accumulating evidence indicates that diet is one of the most important environmental factors involved in the progression from advanced colorectal adenoma (A-CRA) to colorectal cancer. We evaluated the possible effects of dietary fiber on the fecal microbiota of patients with A-CRA. Patients with a diagnosis of A-CRA by pathological examination were enrolled in the A-CRA group. Patients with no obvious abnormalities or histopathological changes were enrolled in the healthy control (HC) group. Dietary fiber intake was assessed in all patients. Short-chain fatty acids (SCFAs) in feces were detected by gas chromatography. The fecal microbiota community was analyzed by 454 pyrosequencing based on 16S ribosomal RNA. Lower dietary fiber patterns and consistently lower SCFA production were observed in the A-CRA group (n = 344). Principal component analysis showed distinct differences in the fecal microbiota communities of the 2 groups. Clostridium, Roseburia, and Eubacterium spp. were significantly less prevalent in the A-CRA group (n = 47) than in the HC group (n = 47), whereas Enterococcus and Streptococcus spp. were more prevalent in the A-CRA group (n = 47) (all P < 0.05). Butyrate and butyrate-producing bacteria were more prevalent in a subgroup of HC subjects with a high fiber intake than in those in both the low-fiber HC subgroup and the high-fiber A-CRA subgroup (all P < 0.05). A high-fiber dietary pattern and subsequent consistent production of SCFAs and healthy gut microbiota are associated with a reduced risk of A-CRA. This trial was registered at www.chictr.org as ChiCTR-TRC-00000123.

  17. Genome-Wide Screening of Genes Showing Altered Expression in Liver Metastases of Human Colorectal Cancers by cDNA Microarray

    Directory of Open Access Journals (Sweden)

    Rempei Yanagawa

    2001-01-01

    Full Text Available In spite of intensive and increasingly successful attempts to determine the multiple steps involved in colorectal carcinogenesis, the mechanisms responsible for metastasis of colorectal tumors to the liver remain to be clarified. To identify genes that are candidates for involvement in the metastatic process, we analyzed genome-wide expression profiles of 10 primary colorectal cancers and their corresponding metastatic lesions by means of a cDNA microarray consisting of 9121 human genes. This analysis identified 40 genes whose expression was commonly upregulated in metastatic lesions, and 7 that were commonly downregulated. The upregulated genes encoded proteins involved in cell adhesion, or remodeling of the actin cytoskeleton. Investigation of the functions of more of the altered genes should improve our understanding of metastasis and may identify diagnostic markers and/or novel molecular targets for prevention or therapy of metastatic lesions.

  18. Inhibition of fried meat-induced colorectal DNA damage and altered systemic genotoxicity in humans by crucifera, chlorophyllin, and yogurt.

    Directory of Open Access Journals (Sweden)

    Daniel T Shaughnessy

    2011-04-01

    Full Text Available Dietary exposures implicated as reducing or causing risk for colorectal cancer may reduce or cause DNA damage in colon tissue; however, no one has assessed this hypothesis directly in humans. Thus, we enrolled 16 healthy volunteers in a 4-week controlled feeding study where 8 subjects were randomly assigned to dietary regimens containing meat cooked at either low (100°C or high temperature (250°C, each for 2 weeks in a crossover design. The other 8 subjects were randomly assigned to dietary regimens containing the high-temperature meat diet alone or in combination with 3 putative mutagen inhibitors: cruciferous vegetables, yogurt, and chlorophyllin tablets, also in a crossover design. Subjects were nonsmokers, at least 18 years old, and not currently taking prescription drugs or antibiotics. We used the Salmonella assay to analyze the meat, urine, and feces for mutagenicity, and the comet assay to analyze rectal biopsies and peripheral blood lymphocytes for DNA damage. Low-temperature meat had undetectable levels of heterocyclic amines (HCAs and was not mutagenic, whereas high-temperature meat had high HCA levels and was highly mutagenic. The high-temperature meat diet increased the mutagenicity of hydrolyzed urine and feces compared to the low-temperature meat diet. The mutagenicity of hydrolyzed urine was increased nearly twofold by the inhibitor diet, indicating that the inhibitors enhanced conjugation. Inhibitors decreased significantly the mutagenicity of un-hydrolyzed and hydrolyzed feces. The diets did not alter the levels of DNA damage in non-target white blood cells, but the inhibitor diet decreased nearly twofold the DNA damage in target colorectal cells. To our knowledge, this is the first demonstration that dietary factors can reduce DNA damage in the target tissue of fried-meat associated carcinogenesis.ClinicalTrials.gov NCT00340743.

  19. Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Palshof, Jesper Andreas; Hogdall, Estrid Vilma Solyom; Poulsen, Tim Svenstrup

    2017-01-01

    Background No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients...... were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses. Results In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5–9.5) and 2.......00 (range: 0.55–4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82–10.43) and 1.98 (range: 1.22–6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92–2.90) and 2.05 (range: 1.00–6.00), respectively. None...

  20. Integrative Genomics Reveals Mechanisms of Copy Number Alterations Responsible for Transcriptional Deregulation in Colorectal Cancer

    Science.gov (United States)

    Camps, Jordi; Nguyen, Quang Tri; Padilla-Nash, Hesed M.; Knutsen, Turid; McNeil, Nicole E.; Wangsa, Danny; Hummon, Amanda B.; Grade, Marian; Ried, Thomas; Difilippantonio, Michael J.

    2016-01-01

    To evaluate the mechanisms and consequences of chromosomal aberrations in colorectal cancer (CRC), we used a combination of spectral karyotyping, array comparative genomic hybridization (aCGH), and array-based global gene expression profiling on 31 primary carcinomas and 15 established cell lines. Importantly, aCGH showed that the genomic profiles of primary tumors are recapitulated in the cell lines. We revealed a preponderance of chromosome breakpoints at sites of copy number variants (CNVs) in the CRC cell lines, a novel mechanism of DNA breakage in cancer. The integration of gene expression and aCGH led to the identification of 157 genes localized within high-level copy number changes whose transcriptional deregulation was significantly affected across all of the samples, thereby suggesting that these genes play a functional role in CRC. Genomic amplification at 8q24 was the most recurrent event and led to the overexpression of MYC and FAM84B. Copy number dependent gene expression resulted in deregulation of known cancer genes such as APC, FGFR2, and ERBB2. The identification of only 36 genes whose localization near a breakpoint could account for their observed deregulated expression demonstrates that the major mechanism for transcriptional deregulation in CRC is genomic copy number changes resulting from chromosomal aberrations. PMID:19691111

  1. Heparan sulfate proteoglycans undergo differential expression alterations in right sided colorectal cancer, depending on their metastatic character

    International Nuclear Information System (INIS)

    Fernández-Vega, Iván; García-Suárez, Olivia; García, Beatriz; Crespo, Ainara; Astudillo, Aurora; Quirós, Luis M.

    2015-01-01

    Heparan sulfate proteoglycans (HSPGs) are complex molecules involved in the growth, invasion and metastatic properties of cancerous cells. This study analyses the alterations in the expression patterns of these molecules in right sided colorectal cancer (CRC), both metastatic and non-metastatic. Twenty right sided CRCs were studied. A transcriptomic approach was used, employing qPCR to analyze both the expression of the enzymes involved in heparan sulfate (HS) chains biosynthesis, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate (CS) chains, we include the study of the genes involved in the biosynthesis of these glycosaminoglycans. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences, of potential interest. Changes in proteoglycan core proteins differ depending on their location; those located intracellularly or in the extracellular matrix show very similar alteration patterns, while those located on the cell surface vary greatly depending on the nature of the tumor: glypicans 1, 3, 6 and betaglycan are affected in the non-metastatic tumors, whereas in the metastatic, only glypican-1 and syndecan-1 are modified, the latter showing opposing alterations in levels of RNA and of protein, suggesting post-transcriptional regulation in these tumors. Furthermore, in non-metastatic tumors, polymerization of glycosaminoglycan chains is modified, particularly affecting the synthesis of the tetrasaccharide linker and the initiation and elongation of CS chains, HS chains being less affected. Regarding the enzymes responsible for the modificaton of the HS chains, alterations were only found in non-metastatic tumors, affecting N-sulfation and the isoforms HS6ST1, HS3ST3B and HS3ST5. In contrast, synthesis of the CS chains suggests changes in epimerization and sulfation of the C4 and C2 in both types of tumor. Right sided CRCs show

  2. Measuring the combinatorial expression of solute transporters and metalloproteinases transcripts in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Cosgrove Leah

    2009-08-01

    Full Text Available Abstract Background It was hypothesised that colorectal cancer (CRC could be diagnosed in biopsies by measuring the combined expression of a small set of well known genes. Genes were chosen based on their role in either the breakdown of the extracellular matrix or with changes in cellular metabolism both of which are associated with CRC progression Findings Gene expression data derived from quantitative real-time PCR for the solute transporter carriers (SLCs and the invasion-mediating matrix metalloproteinases (MMPs were examined using a Linear Descriminant Analysis (LDA. The combination of MMP-7 and SLC5A8 was found to be the most predictive of CRC. Conclusion A combinatorial analysis technique is an effective method for both furthering our understanding on the molecular basis of some aspects of CRC, as well as for leveraging well defined cancer-related gene sets to identify cancer. In this instance, the combination of MMP-7 and SLC5A8 were optimal for identifying CRC.

  3. Comparative analysis of 14-3-3 isoform expression and epigenetic alterations in colorectal cancer

    International Nuclear Information System (INIS)

    Young, Gavin M.; Radhakrishnan, Vijayababu M.; Centuori, Sara M.; Gomes, Cecil J.; Martinez, Jesse D.

    2015-01-01

    The 14-3-3 family is a group of intracellular proteins found in all eukaryotic organisms. Humans have seven isoforms that serve as scaffolds to promote interactions of regulatory phospho-proteins involved in many vital cellular processes and previous studies have shown that disturbances in native 14-3-3 levels can contribute significantly to the development of various cancers. DNA and RNA was extracted from frozen tissue samples collected by the Human Cooperative Tissue Network. RNA samples were reverse transcribed and subjected to qRT-PCR analysis using fluorescently labelled probes. Genomic DNA was treated with bisulfite and cloned into bacterial vectors for subsequent high-resolution sequencing. Mammalian NIH3T3 cells were transformed with 14-3-3 eta and Ras expression vectors synthesized from cDNA. Colonies were counted and transforming capability assessed after 21 days of growth. Cell lysates were analyzed by western blot to verify protein expression. Here we examined normal and cancerous 14-3-3 expression levels of all seven isoforms in a cohort of sporadic colorectal adenocarcinomas and in a group of tumors and their matched normals using qRT-PCR analysis. We found a statistically significant decrease in the levels of 14-3-3 sigma, eta, and zeta observed among adenocarcinomas compared to normal tissue. A parallel analysis of microarray data from the TCGA dataset confirmed that expression of sigma and eta were down-regulated in colon tumors. To explore the mechanisms behind 14-3-3 expression changes, we examined the methylation status of the sigma, eta, and zeta gene promoters in selected samples. Our data identified novel CpG methylation sites in the eta promoter consistent with epigenetic silencing of both 14-3-3 sigma and eta isoforms during colon tumorigenesis. Because epigenetic silencing is the hallmark of a tumor suppressor we tested eta in focus formation assays and found that it is capable of suppressing ras-induced transformation of NIH3T3 cells. To

  4. Altered serotonin transporter availability in patients with multiple sclerosis

    International Nuclear Information System (INIS)

    Hesse, Swen; Sabri, Osama; Moeller, Franziska; Thomae, Eva; Then Bergh, Florian; Petroff, David; Lobsien, Donald; Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M.; Regenthal, Ralf

    2014-01-01

    Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [ 11 C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

  5. Altered serotonin transporter availability in patients with multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Hesse, Swen; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig (Germany); Moeller, Franziska; Thomae, Eva; Then Bergh, Florian [University of Leipzig, Department of Neurology, Leipzig (Germany); Petroff, David [University of Leipzig, Coordinating Centre for Clinical Studies, Leipzig (Germany); Lobsien, Donald [University of Leipzig, Department of Neuroradiology, Leipzig (Germany); Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M. [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Regenthal, Ralf [University of Leipzig, Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig (Germany)

    2014-05-15

    Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [{sup 11}C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

  6. Overexpression of arginine transporter CAT-1 is associated with accumulation of L-arginine and cell growth in human colorectal cancer tissue.

    Directory of Open Access Journals (Sweden)

    Ying Lu

    Full Text Available We previously showed that L-arginine (Arg accumulates in colorectal cancer tissues. The aim of this study was to investigate the mechanism by which Arg accumulates and determine its biological significance. The concentration of Arg and Citrulline (Cit in sera and tumor tissues from colorectal cancer (CRC patients was analyzed by high-performance liquid chromatography (HPLC. The expression of Arg transporters was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR and immunohistochemical analysis of tissue microarray. We also transfected the colon cancer cell line HCT-116 with siRNA specific for the Arg transporter CAT-1 and measured the induction of apoptosis by flow cytometry and cell proliferation by MTT assay. Consistent with our previous results, serum Arg and Cit concentrations in colorectal cancer patients were significantly lower than those in normal volunteers, while Arg and Cit concentrations in colorectal cancer tissues were significantly higher than in matched adjacent normal colon tissues. Quantitative RT-PCR showed that the CAT-1 gene was highly overexpressed in 70.5% of colorectal cancer tissue samples relative to adjacent normal colon tissues in all 122 patients with colorectal cancer. Immunohistochemical analysis of tissue microarray confirmed that the expression of CAT-1 was higher in all 25 colorectal cancer tissues tested. CAT-1 siRNA significantly induced apoptosis of HCT-116 cells and subsequently inhibited cell growth by 20-50%. Our findings indicate that accumulation of L-Arg and Cit and cell growth in colorectal cancer tissues is associated with over-expression of the Arg transporter gene CAT-1. Our results may be useful for the development of molecular diagnostic tools and targeted therapy for colorectal cancer.

  7. Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T Cells: Implications for HIV Microbicides.

    Science.gov (United States)

    Mukhopadhya, Indrani; Murray, Graeme I; Duncan, Linda; Yuecel, Raif; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

    2016-09-06

    CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for antiretroviral (ARV)-based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating α4β7+CD4+ T cells, which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing α4β7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, and BCRP and uptake transporter CNT2 were significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p = 0.01-0.03). Conversely, circulating α4β7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p = 0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral α4β7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between α4β7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs.

  8. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

    DEFF Research Database (Denmark)

    Ekstrand, Anna Isinger; Jönsson, Mats; Lindblom, Annika

    2010-01-01

    The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors. Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT......, and PTEN in colorectal cancers linked to hereditary nonpolyposis colorectal cancer (HNPCC). Sequencing was used to identify mutations in PIK3CA, a real-time PCR-based method to identify KRAS mutations, and immunohistochemical staining was used to evaluate the expression of PIK3CA, phosphorylated AKT...... and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59...

  9. Organophosphate-Related Alterations in Myelin and Axonal Transport in the Living Mammalian Brain

    Science.gov (United States)

    2014-10-01

    stress, impairments of mitochondrial function, neuroinflammation, altered neurotrophin responses, etc. (reviewed, Soltaninejad and Abdollahi, 2009...Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

  10. Altered inflammatory responsiveness in serotonin transporter mutant rats

    NARCIS (Netherlands)

    Macchi, F.; Homberg, J.R.; Calabrese, F.; Zecchillo, C.; Racagni, G.; Riva, M.A.; Molteni, R.

    2013-01-01

    BACKGROUND: Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of depression. Indeed, depressed patients exhibit increased levels of inflammatory markers in both the periphery and the brain, and high comorbidity exists between major depression

  11. Epigenetics and Colorectal Cancer

    Science.gov (United States)

    Lao, Victoria Valinluck; Grady, William M.

    2012-01-01

    Colorectal cancer is a leading cause of cancer deaths in the world. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells that transforms them into adenocarcinomas. There have been major advances in our understanding of cancer epigenetics over the last decade, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all colorectal cancers have aberrantly methylated genes and the average colorectal cancer methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to play a functional role in colorectal cancer. The assessment of methylated genes in colorectal cancers has also revealed a unique molecular subgroup of colorectal cancers called CpG Island Methylator Phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. The advances in our understanding of aberrant methylation in colorectal cancer has led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in the assessment of epigenetic alterations in colorectal cancer and their clinical applications has shown that these alterations will be commonly used in the near future as molecular markers to direct the prevention and treatment of colorectal cancer. PMID:22009203

  12. Altered carnitine transport in pressure-overload hypertrophied rat hearts

    International Nuclear Information System (INIS)

    O'Rourke, B.; Foster, K.; Reibel, D.K.

    1986-01-01

    The authors have previously observed reduced carnitine levels in hypertrophied hearts of rats subjected to aortic constriction. In an attempt to determine the mechanism for reduced myocardial carnitine content, carnitine transport was examined in isolated perfused hearts. Hearts were excised from sham-operated and aortic-constricted rats 3 weeks following surgery and perfused at 60 mm Hg aortic pressure with buffer containing various concentrations of L- 14 C-carnitine. Carnitine uptake by control and hypertrophied hearts was linear throughout 30 minutes of perfusion with 40 μM carnitine. Total carnitine uptake was significantly reduced by 25% in hypertrophied hearts at each time point examined. The reduction in uptake by hypertrophied hearts was also evident when hearts were perfused with 100 or 200 μM carnitine. When 0.05 mM mersalyl acid was included in the buffer to inhibit the carrier-mediated component of transport, no difference in carnitine uptake was observed indicating that the transport of carnitine by diffusion was unaltered in the hypertrophied myocardium. Carrier-mediated carnitine uptake (total uptake - uptake by diffusion) was significantly reduced by approximately 40% in hypertrophied hearts at all concentrations examined. Thus, the reduction in carnitine content in the pressure-overload hypertrophied rat heart appears to be due to a reduction in carrier-mediated carnitine uptake by the heart

  13. Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease.

    Science.gov (United States)

    Yaeger, Rona; Shah, Manish A; Miller, Vincent A; Kelsen, Judith R; Wang, Kai; Heins, Zachary J; Ross, Jeffrey S; He, Yuting; Sanford, Eric; Yantiss, Rhonda K; Balasubramanian, Sohail; Stephens, Philip J; Schultz, Nikolaus; Oren, Moshe; Tang, Laura; Kelsen, David

    2016-08-01

    Patients with inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are at increased risk for small bowel or colorectal cancers (colitis-associated cancers [CACs]). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC. We studied tumor tissues from patients with CACs treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture-based next-generation sequencing analysis of >300 cancer-related genes to comprehensively characterize genomic alterations. We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n = 2), right colon (n = 18), left colon (n = 6), and rectosigmoid or rectum (n = 21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17 of 47 (36%) CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC. In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared with sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

  14. Pyrethroid pesticide-induced alterations in dopamine transporter function

    International Nuclear Information System (INIS)

    Elwan, Mohamed A.; Richardson, Jason R.; Guillot, Thomas S.; Caudle, W. Michael; Miller, Gary W.

    2006-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 μM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 μM) or 24 h (1, 5, and 10 μM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD

  15. Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation.

    Science.gov (United States)

    Strempel, Sebastian; Schroeder, Christoph; Hemmersbach, Ruth; Boese, Andrea; Tank, Jens; Diedrich, André; Heer, Martina; Luft, Friedrich C; Jordan, Jens

    2008-03-01

    Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 +/- 1 yr, body mass index 24 +/- 1 kg/m2), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed.

  16. Colorectal transport during defecation in subjects with supraconal spinal cord injury

    DEFF Research Database (Denmark)

    Rasmussen, Mikkel Mylius; Krogh, Klaus; Clemmensen, Dorte

    2013-01-01

    Hospital, Denmark. Methods: Colorectal contents were marked by oral intake of 111In-coated resin pellets. Movement of stools at defecation was assessed by comparing scintigrams performed before and just after defecation. Results from 15 subjects with SCI (14 males, median age¼47 years (range: 22–74 years...... at defecation was associated with the St Mark’s fecal incontinence score (P¼0.02) but not with the Cleveland constipation score (P¼0.17), the neurogenic bowel dysfunction score (P¼0.12) or GITT (P¼0.99). Conclusion: Supraconal SCI results in significantly reduced emptying of stools at defecation...

  17. Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Svenningsen, Katrine; Almind Knudsen, Lina

    2015-01-01

    AIM: To evaluate ATP-binding cassette (ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer (CRC) development. METHODS: Literature search was conducted on PubMed using combinations of the following terms: ABC transporters, ATP binding cassette...... with glucocorticoids. The evidence for the involvement of ABCC2 and ABCG2 in colonic pathophysiology was weak. CONCLUSION: ABCB1, diet, and gut microbes mutually interact in colonic inflammation, a well-known risk factor for CRC. Further insight may be translated into preventive and treatment strategies....... transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1...

  18. Altered blood-brain barrier transport in neuro-inflammatory disorders.

    Science.gov (United States)

    Schenk, Geert J; de Vries, Helga E

    2016-06-01

    During neurodegenerative and neuroinflammatory disorders of the central nervous system (CNS), such as Alzheimer's disease (AD) and multiple sclerosis (MS), the protective function of the blood-brain barrier (BBB) may be severely impaired. The general neuro-inflammatory response, ranging from activation of glial cells to immune cell infiltration that is frequently associated with such brain diseases may underlie the loss of the integrity and function of the BBB. Consequentially, the delivery and disposition of drugs to the brain will be altered and may influence the treatment efficiency of such diseases. Altered BBB transport of drugs into the CNS during diseases may be the result of changes in both specific transport and non-specific transport pathways. Potential alterations in transport routes like adsorptive mediated endocytosis and receptor-mediated endocytosis may affect drug delivery to the brain. As such, drugs that normally are unable to traverse the BBB may reach their target in the diseased brain due to increased permeability. In contrast, the delivery of (targeted) drugs could be hampered during inflammatory conditions due to disturbed transport mechanisms. Therefore, the inventory of the neuro-inflammatory status of the neurovasculature (or recovery thereof) is of utmost importance in choosing and designing an adequate drug targeting strategy under disease conditions. Within this review we will briefly discuss how the function of the BBB can be affected during disease and how this may influence the delivery of drugs into the diseased CNS. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Colorectal polyps

    Science.gov (United States)

    Intestinal polyps; Polyps - colorectal; Adenomatous polyps; Hyperplastic polyps; Villous adenomas; Serrated polyp; Serrated adenoma; Precancerous polyps; Colon cancer - polyps; Bleeding - colorectal polyps

  20. [Obesity and colorectal cancer].

    Science.gov (United States)

    Na, Soo-Young; Myung, Seung-Jae

    2012-01-01

    Obesity worldwide is constantly increasing. Obesity acts as an independent significant risk factor for malignant tumors of various organs including colorectal cancer. Visceral adipose tissue is physiologically more important than subcutaneous adipose tissue. The relative risk of colorectal cancer of obese patients is about 1.5 times higher than the normal-weight individuals, and obesity is also associated with premalignant colorectal adenoma. The colorectal cancer incidence of obese patients has gender-specific and site-specific characteristics that it is higher in men than women and in the colon than rectum. Obesity acts as a risk factor of colorectal carcinogenesis by several mechanisms. Isulin, insulin-like growth factor, leptin, adiponectin, microbiome, and cytokines of chronic inflammation etc. have been understood as its potential mechanisms. In addition, obesity in patients with colorectal cancer negatively affects the disease progression and response of chemotherapy. Although the evidence is not clear yet, there are some reports that weight loss as well as life-modification such as dietary change and physical activity can reduce the risk of colorectal cancer. It is very important knowledge in the point that obesity is a potentially modifiable risk factor that can alter the incidence and outcome of the colorectal cancer.

  1. The dynamic DNA methylation landscape of the mutL homolog 1 shore is altered by MLH1-93G>A polymorphism in normal tissues and colorectal cancer.

    Science.gov (United States)

    Savio, Andrea J; Mrkonjic, Miralem; Lemire, Mathieu; Gallinger, Steven; Knight, Julia A; Bapat, Bharat

    2017-01-01

    Colorectal cancers (CRCs) undergo distinct genetic and epigenetic alterations. Expression of mutL homolog 1 ( MLH1 ), a mismatch repair gene that corrects DNA replication errors, is lost in up to 15% of sporadic tumours due to mutation or, more commonly, due to DNA methylation of its promoter CpG island. A single nucleotide polymorphism (SNP) in the CpG island of MLH1 ( MLH1 -93G>A or rs1800734) is associated with CpG island hypermethylation and decreased MLH1 expression in CRC tumours. Further, in peripheral blood mononuclear cell (PBMC) DNA of both CRC cases and non-cancer controls, the variant allele of rs1800734 is associated with hypomethylation at the MLH1 shore, a region upstream of its CpG island that is less dense in CpG sites . To determine whether this genotype-epigenotype association is present in other tissue types, including colorectal tumours, we assessed DNA methylation in matched normal colorectal tissue, tumour, and PBMC DNA from 349 population-based CRC cases recruited from the Ontario Familial Colorectal Cancer Registry. Using the semi-quantitative real-time PCR-based MethyLight assay, MLH1 shore methylation was significantly higher in tumour tissue than normal colon or PBMCs ( P  MLH1 was not associated with MSI status or promoter CpG island hypermethylation, regardless of genotype. To confirm these results, bisulfite sequencing was performed in matched tumour and normal colorectal specimens from six CRC cases, including two cases per genotype (wildtype, heterozygous, and homozygous variant). Bisulfite sequencing results corroborated the methylation patterns found by MethyLight, with significant hypomethylation in normal colorectal tissue of variant SNP allele carriers. These results indicate that the normal tissue types tested (colorectum and PBMC) experience dynamic genotype-associated epigenetic alterations at the MLH1 shore, whereas tumour DNA incurs aberrant hypermethylation compared to normal DNA.

  2. Mutations that alter the transport function of the LamB protein in Escherichia coli.

    OpenAIRE

    Wandersman, C; Schwartz, M

    1982-01-01

    Some Escherichia coli K-12 lamB mutants, those producing reduced amounts of LamB protein (one-tenth the wild type amount), grow normally on dextrins but transport maltose when present at a concentration of 1 microM at about one-tenth the normal rate. lamB Dex- mutants were found as derivatives of these strains. These Dex- mutants are considerably impaired in the transport of maltose at low concentrations (below 10 microM), and they have a structurally altered LamB protein which is impaired in...

  3. Altered regulation of renal sodium transporters in salt-sensitive hypertensive rats induced by uninephrectomy.

    Science.gov (United States)

    Jung, Ji Yong; Lee, Jay Wook; Kim, Sejoong; Jung, Eun Sook; Jang, Hye Ryoun; Han, Jin Suk; Joo, Kwon Wook

    2009-12-01

    Uninephrectomy (uNx) in young rats causes salt-sensitive hypertension (SSH). Alterations of sodium handling in residual nephrons may play a role in the pathogenesis. Therefore, we evaluated the adaptive alterations of renal sodium transporters according to salt intake in uNx-SSH rats. uNx or sham operations were performed in male Sprague-Dawley rats, and normal-salt diet was fed for 4 weeks. Four experimental groups were used: sham-operated rats raised on a high-salt diet for 2 weeks (CHH) or on a low-salt diet for 1 week after 1 week's high-salt diet (CHL) and uNx rats fed on the same diet (NHH, NHL) as the sham-operated rats were fed. Expression of major renal sodium transporters were determined by semiquantitative immunoblotting. Systolic blood pressure was increased in NHH and NHL groups, compared with CHH and CHL, respectively. Protein abundances of Na(+)/K(+)/2Cl(-) cotransporter (NKCC2) and Na(+)/Cl(-) cotransporter (NCC) in the CHH group were lower than the CHL group. Expression of epithelial sodium channel (ENaC)-γ increased in the CHH group. In contrast, expressions of NKCC2 and NCC in the NHH group didn't show any significant alterations, compared to the NHL group. Expressions of ENaC-α and ENaC-β in the NHH group were higher than the CHH group. Adaptive alterations of NKCC2 and NCC to changes of salt intake were different in the uNx group, and changes in ENaC-α and ENaC-β were also different. These altered regulations of sodium transporters may be involved in the pathogenesis of SSH in the uNx rat model.

  4. Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Svenningsen, Katrine; Knudsen, Lina Almind

    2015-01-01

    transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1....../Mdr1a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported that changes in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes...

  5. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier.

    Science.gov (United States)

    Osgood, Doreen; Miller, Miles C; Messier, Arthur A; Gonzalez, Liliana; Silverberg, Gerald D

    2017-09-01

    Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta (Aβ) peptides and other macromolecules in the brain of the elderly and in the patients with Alzheimer's disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier are significantly altered with age: the efflux transporters lipoprotein receptor-related protein 1 and P-glycoprotein are reduced, whereas the influx transporter receptor for advanced glycation end products is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene messenger RNA (mRNA) at 3, 6, 9, 12, 15, 20, 30, and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by quantitative polymerase chain reaction. Lipoprotein receptor-related protein 1 and P-glycoprotein mRNA were significantly reduced in aging, and receptor for advanced glycation end products was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in blood-brain barrier receptor expression and Aβ accumulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells

    International Nuclear Information System (INIS)

    Pedraz-Cuesta, Elena; Christensen, Sandra; Jensen, Anders A.; Jensen, Niels Frank; Bunch, Lennart; Romer, Maria Unni; Brünner, Nils; Stenvang, Jan; Pedersen, Stine Falsig

    2015-01-01

    Colorectal cancer (CRC) is a leading cause of cancer death globally and new biomarkers and treatments are severely needed. Here, we employed HCT116 and LoVo human CRC cells made resistant to either SN38 or oxaliplatin, to investigate whether altered expression of the high affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability and glutathione content. Results were evaluated using one- and two-way ANOVA and Students two-tailed t-test, as relevant. In SN38-resistant HCT116 and LoVo cells, SLC1A1 expression was down-regulated ~60 % and up-regulated ~4-fold, respectively, at both mRNA and protein level, whereas SLC1A3 protein was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-β-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [ 3 H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration-dependently augmented loss of cell viability induced by SN38, while strongly counteracting that induced by oxaliplatin, in both HCT116 and LoVo cells. This reflected neither altered expression of the oxaliplatin transporter Cu 2+ -transporter-1 (CTR1), nor changes in cellular reduced glutathione (GSH), although HCT116 cell resistance per se correlated with increased cellular GSH. DL-TBOA did not significantly alter cellular levels of p21, cleaved PARP-1, or phospho-Retinoblastoma protein, yet altered SLC1A1 subcellular localization, and reduced chemotherapy-induced p53 induction. SLC1A1 expression and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments

  7. Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study

    Directory of Open Access Journals (Sweden)

    Ulivi Paola

    2012-05-01

    Full Text Available Abstract Background KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC patients. As only 20% of KRAS wild type (WT patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR progression-free (PFS and overall survival (OS with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen. Methods 67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry. Results BRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively and OS (p = 0.008 and p = 0.029, respectively. No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations. Conclusions BRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.

  8. Gene expression profiling demonstrates WNT/β-catenin pathway genes alteration in Mexican patients with colorectal cancer and diabetes mellitus.

    Science.gov (United States)

    Ivonne Wence-Chavez, Laura; Palomares-Chacon, Ulises; Pablo Flores-Gutierrez, Juan; Felipe Jave-Suarez, Luis; Del Carmen Aguilar-Lemarroy, Adriana; Barros-Nunez, Patricio; Esperanza Flores-Martinez, Silvia; Sanchez-Corona, Jose; Alejandra Rosales-Reynoso, Monica

    2017-01-01

    Several studies have shown a strong association between diabetes mellitus (DM) and increased risk of colorectal cancer (CRC). The fundamental mechanisms that support this association are not entirely understood; however, it is believed that hyperinsulinemia and hyperglycemia may be involved. Some proposed mechanisms include upregulation of mitogenic signaling pathways like MAPK, PI3K, mTOR, and WNT, which are involved in cell proliferation, growth, and cancer cell survival. The purpose of this study was to evaluate the gene expression profile and identify differently expressed genes involved in mitogenic pathways in CRC patients with and without DM. In this study, microarray analysis of gene expression followed by quantitative PCR (qPCR) was performed in cancer tissue from CRC patients with and without DM to identify the gene expression profiles and validate the differently expressed genes. Among the study groups, some differently expressed genes were identified. However, when bioinformatics clustering tools were used, a significant modulation of genes involved in the WNT pathway was evident. Therefore, we focused on genes participating in this pathway, such as WNT3A, LRP6, TCF7L2, and FRA-1. Validation of the expression levels of those genes by qPCR showed that CRC patients without type 2 diabetes mellitus (T2DM) expressed significantly more WNT3Ay LRP6, but less TCF7L2 and FRA-1 compared to controls, while in CRC patients with DM the expression levels of WNT3A, LRP6, TCF7L2, and FRA-1 were significantly higher compared to controls. Our results suggest that WNT/β-catenin pathway is upregulated in patients with CRC and DM, demonstrating its importance and involvement in both pathologies.

  9. Streptozotocin alters glucose transport, connexin expression and endoplasmic reticulum functions in neurons and astrocytes.

    Science.gov (United States)

    Biswas, Joyshree; Gupta, Sonam; Verma, Dinesh Kumar; Singh, Sarika

    2017-07-25

    The study was undertaken to explore the cell-specific streptozotocin (STZ)-induced mechanistic alterations. STZ-induced rodent model is a well-established experimental model of Alzheimer's disease (AD) and in our previous studies we have established it as an in vitro screening model of AD by employing N2A neuronal cells. Therefore, STZ was selected in the present study to understand the STZ-induced cell-specific alterations by utilizing neuronal N2A and astrocytes C6 cells. Both neuronal and astrocyte cells were treated with STZ at 10, 50, 100 and 1000μM concentrations for 48h. STZ exposure caused significant decline in cellular viability and augmented cytotoxicity of cells involving astrocytes activation. STZ treatment also disrupted the energy metabolism by altered glucose uptake and its transport in both cells as reflected with decreased expression of glucose transporters (GLUT) 1/3. The consequent decrease in ATP level and decreased mitochondrial membrane potential was also observed in both the cells. STZ caused increased intracellular calcium which could cause the initiation of endoplasmic reticulum (ER) stress. Significant upregulation of ER stress-related markers were observed in both cells after STZ treatment. The cellular communication of astrocytes and neurons was altered as reflected by increased expression of connexin 43 along with DNA fragmentation. STZ-induced apoptotic death was evaluated by elevated expression of caspase-3 and PI/Hoechst staining of cells. In conclusion, study showed that STZ exert alike biochemical alterations, ER stress and cellular apoptosis in both neuronal and astrocyte cells. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study.

    Science.gov (United States)

    Wang, Yi-Jun; Zhang, Yun-Kai; Zhang, Guan-Nan; Al Rihani, Sweilem B; Wei, Meng-Ning; Gupta, Pranav; Zhang, Xiao-Yu; Shukla, Suneet; Ambudkar, Suresh V; Kaddoumi, Amal; Shi, Zhi; Chen, Zhe-Sheng

    2017-06-28

    Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [ 3 H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1. Regorafenib inhibited ATPase activity of ABCB1. In mice bearing resistant colorectal tumors, regorafenib raised the intratumoral concentration of paclitaxel and suppressed the growth of resistant colorectal tumors. But regorafenib did not induce cardiotoxicity/myelosuppression of paclitaxel in mice. Strategy to reposition one FDA-approved anticancer drug regorafenib to overcome the resistance of another FDA-approved, widely used chemotherapeutic paclitaxel, may be a promising direction for the field of adjuvant chemotherapy. This study provides clinical rationale for combination of conventional chemotherapy and targeted anticancer agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Altered effect of dopamine transporter 3'UTR VNTR genotype on prefrontal and striatal function in schizophrenia.

    Science.gov (United States)

    Prata, Diana P; Mechelli, Andrea; Picchioni, Marco M; Fu, Cynthia H Y; Toulopoulou, Timothea; Bramon, Elvira; Walshe, Muriel; Murray, Robin M; Collier, David A; McGuire, Philip

    2009-11-01

    The dopamine transporter plays a key role in the regulation of central dopaminergic transmission, which modulates cognitive processing. Disrupted dopamine function and impaired executive processing are robust features of schizophrenia. To examine the effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3' untranslated region) on brain function during executive processing in healthy volunteers and patients with schizophrenia. We hypothesized that this variation would have a different effect on prefrontal and striatal activation in schizophrenia, reflecting altered dopamine function. Case-control study. Psychiatric research center. Eighty-five subjects, comprising 44 healthy volunteers (18 who were 9-repeat carriers and 26 who were 10-repeat homozygotes) and 41 patients with DSM-IV schizophrenia (18 who were 9-repeat carriers and 23 who were 10-repeat homozygotes). Regional brain activation during word generation relative to repetition in an overt verbal fluency task measured by functional magnetic resonance imaging. Main effects of genotype and diagnosis on activation and their interaction were estimated with analysis of variance in SPM5. Irrespective of diagnosis, the 10-repeat allele was associated with greater activation than the 9-repeat allele in the left anterior insula and right caudate nucleus. Trends for the same effect in the right insula and for greater deactivation in the rostral anterior cingulate cortex were also detected. There were diagnosis x genotype interactions in the left middle frontal gyrus and left nucleus accumbens, where the 9-repeat allele was associated with greater activation than the 10-repeat allele in patients but not controls. Insular, cingulate, and striatal function during an executive task is normally modulated by variation in the dopamine transporter gene. Its effect on activation in the dorsolateral prefrontal cortex and ventral striatum is altered in patients with schizophrenia

  12. Altered expression of mitochondrial electron transport chain proteins and improved myocardial energetic state during late ischemic preconditioning

    NARCIS (Netherlands)

    J.A. Cabrera (Jesús); E.A. Ziemba (Elizabeth); L.H. Colbert (Lisa); L.B. Anderson (Lorraine); W.J. Sluiter (Wim); D.J.G.M. Duncker (Dirk); T.A. Butterick (Tammy); J. Sikora (Joseph); H.B. Ward (Herbert B.); R.F. Kelly (Rosemary); E.O. McFalls (Edward)

    2012-01-01

    textabstractAltered expression of mitochondrial electron transport proteins has been shown in early preconditioned myocardial tissue. We wished to determine whether these alterations persist in the Second Window of Protection (SWOP) and if so, whether a favorable energetic state is facilitated

  13. Chlorovirus-mediated membrane depolarization of Chlorella alters secondary active transport of solutes.

    Science.gov (United States)

    Agarkova, Irina; Dunigan, David; Gurnon, James; Greiner, Timo; Barres, Julia; Thiel, Gerhard; Van Etten, James L

    2008-12-01

    Paramecium bursaria chlorella virus 1 (PBCV-1) is the prototype of a family of large, double-stranded DNA, plaque-forming viruses that infect certain eukaryotic chlorella-like green algae from the genus Chlorovirus. PBCV-1 infection results in rapid host membrane depolarization and potassium ion release. One interesting feature of certain chloroviruses is that they code for functional potassium ion-selective channel proteins (Kcv) that are considered responsible for the host membrane depolarization and, as a consequence, the efflux of potassium ions. This report examines the relationship between cellular depolarization and solute uptake. Annotation of the virus host Chlorella strain NC64A genome revealed 482 putative transporter-encoding genes; 224 are secondary active transporters. Solute uptake experiments using seven radioactive compounds revealed that virus infection alters the transport of all the solutes. However, the degree of inhibition varied depending on the solute. Experiments with nystatin, a drug known to depolarize cell membranes, produced changes in solute uptake that are similar but not identical to those that occurred during virus infection. Therefore, these studies indicate that chlorovirus infection causes a rapid and sustained depolarization of the host plasma membrane and that this depolarization leads to the inhibition of secondary active transporters that changes solute uptake.

  14. Colorectal Cancer

    Science.gov (United States)

    ... rectum are part of the large intestine. Colorectal cancer occurs when tumors form in the lining of ... men and women. The risk of developing colorectal cancer rises after age 50. You're also more ...

  15. Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport.

    Directory of Open Access Journals (Sweden)

    Igor Arregi

    Full Text Available Nucleophosmin (NPM is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML, where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES. To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs, and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

  16. Up-regulated EMMPRIN/CD147 protein expression might play a role in colorectal carcinogenesis and its subsequent progression without an alteration of its glycosylation and mRNA level.

    Science.gov (United States)

    Zheng, Hua-chuan; Wang, Wei; Xu, Xiao-yan; Xia, Pu; Yu, Miao; Sugiyama, Toshiro; Takano, Yasuo

    2011-04-01

    Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of colorectal carcinomas (CRC). EMMPRIN expression was examined on tissue microarray containing colorectal carcinomas, adenoma and non-neoplastic mucosa (NNM) by immunohistochemistry and in situ hybridization (ISH). Colorectal carcinoma cell lines (DLD-1, HCT-15, SW480 and WiDr) and tissues were studied for EMMPRIN expression by Western blot or RT-PCR, followed by sequencing. All carcinoma cell lines showed EMMPRIN expression at both mRNA and protein levels. Two synonymous mutations were found in carcinoma cell lines at codon109 (GCT → GCC: Ala) or 179 (GAT → GAC: Asp). Frozen CRC tissues displayed higher EMMPRIN expression than paired NNM (P EMMPRIN expression was immunohistochemically stronger in colorectal high-grade adenoma, adenocarcinoma and metastatic carcinoma than non-neoplastic superficial epithelium and low-grade adenoma (P 0.05). Immunohistochemically, EMMPRIN expression was positively correlated with tumor size, depth of invasion, vascular or lymphatic invasion, grade of infiltration (INF), ki-67 and VEGF expression of CRCs (P EMMPRIN expression in CRCs (P EMMPRIN protein expression might contribute to colorectal carcinogenesis without the alteration of its glycosylation and mRNA level. Aberrant EMMPRIN protein expression might promote growth or invasion of CRCs possibly through increased ki-67 expression and inducible angiogenesis via up-regulating VEGF expression.

  17. Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair

    Science.gov (United States)

    Gelincik, Ozkan; Blecua, Pedro; Edelmann, Winfried; Kucherlapati, Raju; Zhou, Kathy; Jasin, Maria; Gümüş, Zeynep H.; Lipkin, Steven M.

    2017-01-01

    Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1, Pms2, and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters. Additionally, when DSBs are induced by gamma-radiation, Mlh1, Pms2 and Mlh3 mutant MEFs have higher DR copy number alterations (CNAs), including DR CNA hotspots previously identified in mouse MMR-deficient colorectal cancer (dMMR CRC). Analysis of The Cancer Genome Atlas CRC data revealed that dMMR CRCs have higher genome-wide DR HeR rates than MMR proficient CRCs, and that dMMR CRCs have deletion hotspots in tumor suppressors FHIT/WWOX at chromosomal fragile sites FRA3B and FRA16D (which have elevated DSB rates) flanked by paired homologous DRs and inverted repeats (IR). Overall, these data provide novel insights into the MMR-dependent HeR inhibition mechanism and its role in tumor suppression. PMID:29069730

  18. Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase

    Directory of Open Access Journals (Sweden)

    Kosuke Toda

    2016-11-01

    Full Text Available A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC can predict a lack of responses to anti-epidermal growth factor receptor–based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC. Using several human CRC cell lines and clinical specimens of primary CRC, we demonstrated that the expression of asparagine synthetase (ASNS, an enzyme that synthesizes asparagine from aspartate, was upregulated by mutated KRAS and that ASNS expression was induced by KRAS-activated signaling pathway, in particular PI3K-AKT-mTOR pathway. Importantly, we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro. Notably, a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo. Furthermore, combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo, whereas either L-asparaginase or rapamycin alone was not effective. These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS.

  19. Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats.

    Science.gov (United States)

    Potapenko, Evgeniy S; Biancardi, Vinicia C; Zhou, Yiqiang; Stern, Javier E

    2012-08-01

    Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

  20. Colorectal Cancer Screening

    Science.gov (United States)

    ... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Screening (PDQ®)–Patient Version What is screening? Go ... These are called diagnostic tests . General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

  1. Colorectal Cancer Prevention

    Science.gov (United States)

    ... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Prevention (PDQ®)–Patient Version What is prevention? Go ... to keep cancer from starting. General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

  2. The Drosophila Neurally Altered Carbohydrate Mutant Has a Defective Golgi GDP-fucose Transporter*

    Science.gov (United States)

    Geisler, Christoph; Kotu, Varshika; Sharrow, Mary; Rendić, Dubravko; Pöltl, Gerald; Tiemeyer, Michael; Wilson, Iain B. H.; Jarvis, Donald L.

    2012-01-01

    Studying genetic disorders in model organisms can provide insights into heritable human diseases. The Drosophila neurally altered carbohydrate (nac) mutant is deficient for neural expression of the HRP epitope, which consists of N-glycans with core α1,3-linked fucose residues. Here, we show that a conserved serine residue in the Golgi GDP-fucose transporter (GFR) is substituted by leucine in nac1 flies, which abolishes GDP-fucose transport in vivo and in vitro. This loss of function is due to a biochemical defect, not to destabilization or mistargeting of the mutant GFR protein. Mass spectrometry and HPLC analysis showed that nac1 mutants lack not only core α1,3-linked, but also core α1,6-linked fucose residues on their N-glycans. Thus, the nac1 Gfr mutation produces a previously unrecognized general defect in N-glycan core fucosylation. Transgenic expression of a wild-type Gfr gene restored the HRP epitope in neural tissues, directly demonstrating that the Gfr mutation is solely responsible for the neural HRP epitope deficiency in the nac1 mutant. These results validate the Drosophila nac1 mutant as a model for the human congenital disorder of glycosylation, CDG-IIc (also known as LAD-II), which is also the result of a GFR deficiency. PMID:22745127

  3. Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

    Science.gov (United States)

    Siciliano, Cody A.; Fordahl, Steve C.

    2016-01-01

    , the dopamine transporter (DAT). Preclinical literature has shown that reduced cocaine potency at the DAT increases cocaine taking, highlighting the key role of tolerance in addiction. Addiction is characterized by cycles of abstinence, often for many months, followed by relapse, making it important to determine possible interactions between abstinence and subsequent drug re-exposure. Using a rodent model of cocaine abuse, we found long-lasting, possibly permanent, cocaine-induced alterations to the DAT, whereby cocaine tolerance is reinstated by minimal drug exposure, even after recovery of DAT function over prolonged abstinence periods. PMID:27466327

  4. Cronobacter sakazakii infection alters serotonin transporter and improved fear memory retention in the rats

    Directory of Open Access Journals (Sweden)

    Bhagavathi Sundaram eSivamaruthi

    2015-09-01

    Full Text Available It is well established that Cronobacter sakazakii infection cause septicemia, necrotizingenterocolitis (NEC and meningitis. In the present study, we tested whether the C. sakazakii infection alter the learning and memory through serotonin transporter (SERT. To investigate the possible effect on SERT, on postnatal day (PND-15, wistar rat pups were administered with single dose of C. sakazakii culture (Infected group: IF; 107 CFU or 100μL of Luria-Bertani broth (LB; Medium Control: MC or without any treatment (Naïve control: NC. All the individuals were subjected to passive avoidance test on PND-30 to test their fear memory. We show that single dose of C. sakazakii infection improved fear memory retention. Subsequently, we show that C. sakazakii infection induced the activation of Toll-like receptor-3 (TLR-3 and heat-shock proteins-90 (Hsp-90. On the other hand, level of serotonin (5-HT and SERT protein was down-regulated. Furthermore, we show that C. sakazakii infection up-regulate microRNA (miR-16 expression. The observed results highlight that C. sakazakii infections was responsible for improved fear memory retention and may have reduced the level of SERT protein, which is possibly associated with the interaction of up-regulated Hsp-90 with SERT protein or miR-16 with SERT mRNA. Taken together, observed results suggest that C. sakazakkii infection alter the fear memory possibly through SERT. Hence, this model may be effective to test the C. sakazakii infection induced changes in synaptic plasticity through SERT and effect of other pharmacological agents against pathogen induced memory disorder.

  5. MCD diet-induced steatohepatitis is associated with alterations in asymmetric dimethylarginine (ADMA) and its transporters.

    Science.gov (United States)

    Di Pasqua, Laura G; Berardo, Clarissa; Rizzo, Vittoria; Richelmi, Plinio; Croce, Anna Cleta; Vairetti, Mariapia; Ferrigno, Andrea

    2016-08-01

    Using an experimental model of NASH induced by a methionine-choline-deficient (MCD) diet, we investigated whether changes occur in serum and tissue levels of asymmetric dimethylarginine (ADMA). Male Wistar rats underwent NASH induced by 8-week feeding with an MCD diet. Serum and hepatic biopsies at 2, 4 and 8 weeks were taken, and serum enzymes, ADMA and nitrate/nitrite (NOx), were evaluated. Hepatic biopsies were used for mRNA and protein expression analysis of dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and protein methyltransferases (PRMT-1), enzymes involved in ADMA metabolism and synthesis, respectively, and ADMA transporters (CAT-1, CAT-2A and CAT-2B). Lipid peroxides (TBARS), glutathione, ATP/ADP and DDAH activity were quantified. An increase in serum AST and ALT was detected in MCD animals. A time-dependent decrease in serum and tissue ADMA and increase in mRNA expression of DDAH-1 and PRMT-1 as well as higher rates of mRNA expression of CAT-1 and lower rates of CAT-2A and CAT-2B were found after 8-week MCD diet. An increase in serum NOx and no changes in protein expression in DDAH-1 and CAT-1 and higher content in CAT-2 and PRMT-1 were found at 8 weeks. Hepatic DDAH activity decreased with a concomitant increase in oxidative stress, as demonstrated by high TBARS levels and low glutathione content. In conclusion, a decrease in serum and tissue ADMA levels in the MCD rats was found associated with a reduction in DDAH activity due to the marked oxidative stress observed. Changes in ADMA levels and its transporters are innovative factors in the onset and progression of hepatic alterations correlated with MCD diet-induced NASH.

  6. The involvement of altered vesicle transport in redistribution of Ca2+, Mg2+-ATPase in cholestatic rat liver

    NARCIS (Netherlands)

    Song, J. Y.; van Noorden, C. J.; Frederiks, W. M.

    1998-01-01

    Vectorial sorting of plasma membrane protein-containing vesicles is essential for the establishment and maintenance of cell polarity. In the present study, the involvement of altered vesicle transport in the redistribution of membrane-bound Ca2+, Mg2+-ATPase resulting from cholestasis was

  7. Altered Colonic Environment, a Possible Predisposition to Colorectal Cancer and Colonic Inflammatory Bowel Disease: Rationale of Dietary Manipulation with Emphasis on Disaccharides

    OpenAIRE

    Szilagyi, A

    1998-01-01

    A recurrent theme in the schema of pathogenetic mechanisms attributed to colorectal cancer (CRC) and inflammatory bowel disease (IBD) is the interaction between genes and environment. Dietary and other environmental factors, and lower intestinal flora and their chemical interactions occur in the pathogenesis of both. Events at the mucosal surface may be influenced by factors in the luminal environment and by contributions of the host. In addition, both forms of IBD - Crohn's disease (CD) and ...

  8. Colorectal tuberculosis

    International Nuclear Information System (INIS)

    Nagi, B.; Kochhar, R.; Bhasin, D.K.; Singh, K.

    2003-01-01

    Our objective was to evaluate the incidence of colorectal tuberculosis in our series and to study its radiological spectrum. A total of 684 cases of proven gastrointestinal tuberculosis with positive barium contrast findings seen over a period of more than one decade were evaluated. The study did not include cases where colon was involved in direct contiguity with ileo-caecal tuberculosis. Seventy-four patients (10.8%) had colorectal tuberculosis. Commonest site involved was transverse colon, closely followed by rectum and ascending colon. Radiological findings observed were in the form of strictures (54%), colitis (39%) and polypoid lesions (7%). Complications noted were in the form of perforations and fistulae in 18.9% of cases. Colorectal tuberculosis is a very common site for gastrointestinal tuberculosis. Typical findings of colorectal tuberculosis are strictures, signs of colitis and polypoid lesions. Common complications are perforation and fistulae. (orig.)

  9. Colorectal Cancer

    Science.gov (United States)

    ... possible. Research will help us better understand whether chemotherapy can benefit elderly colorectal cancer patients. Such patients often do not receive chemotherapy due to concerns about side effects. We will ...

  10. Three dimensional model evaluation of physical alterations of the Caloosahatchee River and Estuary: Impact on salt transport

    Science.gov (United States)

    Sun, Detong; Wan, Yongshan; Qiu, Chelsea

    2016-05-01

    Numerical hydrodynamic modeling provides quantitative understanding of how physical alterations of an estuary may alter the waterbody hydrodynamics and the rate of mixing with the ocean. In this study, a three dimensional hydrodynamic model (CH3D) was used to compare simulated salinities between the existing condition and five historical cases representing varying physical alterations of the Caloosahatchee Estuary involving (1) removal of the headwater structure (S-79); (2) removal of the downstream causeway to Sanibel Island; (3) backfilling an oyster bar near the estuary month; (4) refilling the navigation channel; and (5) the pre-development bathymetric condition. The results suggested that some alterations including the Sanibel Causeway, backfilling the oyster bar and the S-79 structure may have some local effects but did not change estuarine salinity structure significantly. Refilling the navigation channel had a more profound effect, resulting in a dry season salinity reduction of about 5 when compared with the existing condition. The reduced salt transport was more pronounced with the pre-development bathymetry because the estuary as a whole was much shallower than today. The significant system-wide increase in salt transport caused by the historic dredging of the navigation channel in the Caloosahatchee Estuary has significant implications in the development of attainable environmental flow targets for protecting the estuarine ecosystem.

  11. Overexpression of Laccaria bicolor aquaporin JQ585595 alters root water transport properties in ectomycorrhizal white spruce (Picea glauca) seedlings.

    Science.gov (United States)

    Xu, Hao; Kemppainen, Minna; El Kayal, Walid; Lee, Seong Hee; Pardo, Alejandro G; Cooke, Janice E K; Zwiazek, Janusz J

    2015-01-01

    The contribution of hyphae to water transport in ectomycorrhizal (ECM) white spruce (Picea glauca) seedlings was examined by altering expression of a major water-transporting aquaporin in Laccaria bicolor. Picea glauca was inoculated with wild-type (WT), mock transgenic or L. bicolor aquaporin JQ585595-overexpressing (OE) strains and exposed to root temperatures ranging from 5 to 20°C to examine the root water transport properties, physiological responses and plasma membrane intrinsic protein (PIP) expression in colonized plants. Mycorrhization increased shoot water potential, transpiration, net photosynthetic rates, root hydraulic conductivity and root cortical cell hydraulic conductivity in seedlings. At 20°C, OE plants had higher root hydraulic conductivity compared with WT plants and the increases were accompanied by higher expression of P. glauca PIP GQ03401_M18.1 in roots. In contrast to WT L. bicolor, the effects of OE fungi on root and root cortical cell hydraulic conductivities were abolished at 10 and 5°C in the absence of major changes in the examined transcript levels of P. glauca root PIPs. The results provide evidence for the importance of fungal aquaporins in root water transport of mycorrhizal plants. They also demonstrate links between hyphal water transport, root aquaporin expression and root water transport in ECM plants. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  12. Inactivation of the Ecs ABC transporter of Staphylococcus aureus attenuates virulence by altering composition and function of bacterial wall.

    Directory of Open Access Journals (Sweden)

    Ing-Marie Jonsson

    2010-12-01

    Full Text Available Ecs is an ATP-binding cassette (ABC transporter present in aerobic and facultative anaerobic gram-positive Firmicutes. Inactivation of Bacillus subtilis Ecs causes pleiotropic changes in the bacterial phenotype including inhibition of intramembrane proteolysis. The molecule(s transported by Ecs is (are still unknown.In this study we mutated the ecsAB operon in two Staphylococcus aureus strains, Newman and LS-1. Phenotypic and functional characterization of these Ecs deficient mutants revealed a defect in growth, increased autolysis and lysostaphin sensitivity, altered composition of cell wall proteins including the precursor form of staphylokinase and an altered bacterial surface texture. DNA microarray analysis indicated that the Ecs deficiency changed expression of the virulence factor regulator protein Rot accompanied by differential expression of membrane transport proteins, particularly ABC transporters and phosphate-specific transport systems, protein A, adhesins and capsular polysaccharide biosynthesis proteins. Virulence of the ecs mutants was studied in a mouse model of hematogenous S. aureus infection. Mice inoculated with the ecs mutant strains developed markedly milder infections than those inoculated with the wild-type strains and had consequently lower mortality, less weight loss, milder arthritis and decreased persistence of staphylococci in the kidneys. The ecs mutants had higher susceptibility to ribosomal antibiotics and plant alkaloids chelerythrine and sanguinarine.Our results show that Ecs is essential for staphylococcal virulence and antimicrobial resistance probably since the transport function of Ecs is essential for the normal structure and function of the cell wall. Thus targeting Ecs may be a new approach in combating staphylococcal infection.

  13. Inactivation of the Ecs ABC transporter of Staphylococcus aureus attenuates virulence by altering composition and function of bacterial wall.

    Science.gov (United States)

    Jonsson, Ing-Marie; Juuti, Jarmo T; François, Patrice; AlMajidi, Rana; Pietiäinen, Milla; Girard, Myriam; Lindholm, Catharina; Saller, Manfred J; Driessen, Arnold J M; Kuusela, Pentti; Bokarewa, Maria; Schrenzel, Jacques; Kontinen, Vesa P

    2010-12-02

    Ecs is an ATP-binding cassette (ABC) transporter present in aerobic and facultative anaerobic gram-positive Firmicutes. Inactivation of Bacillus subtilis Ecs causes pleiotropic changes in the bacterial phenotype including inhibition of intramembrane proteolysis. The molecule(s) transported by Ecs is (are) still unknown. In this study we mutated the ecsAB operon in two Staphylococcus aureus strains, Newman and LS-1. Phenotypic and functional characterization of these Ecs deficient mutants revealed a defect in growth, increased autolysis and lysostaphin sensitivity, altered composition of cell wall proteins including the precursor form of staphylokinase and an altered bacterial surface texture. DNA microarray analysis indicated that the Ecs deficiency changed expression of the virulence factor regulator protein Rot accompanied by differential expression of membrane transport proteins, particularly ABC transporters and phosphate-specific transport systems, protein A, adhesins and capsular polysaccharide biosynthesis proteins. Virulence of the ecs mutants was studied in a mouse model of hematogenous S. aureus infection. Mice inoculated with the ecs mutant strains developed markedly milder infections than those inoculated with the wild-type strains and had consequently lower mortality, less weight loss, milder arthritis and decreased persistence of staphylococci in the kidneys. The ecs mutants had higher susceptibility to ribosomal antibiotics and plant alkaloids chelerythrine and sanguinarine. Our results show that Ecs is essential for staphylococcal virulence and antimicrobial resistance probably since the transport function of Ecs is essential for the normal structure and function of the cell wall. Thus targeting Ecs may be a new approach in combating staphylococcal infection.

  14. Alterations in rotation thromboelastometry (ROTEM®) parameters: point-of-care testing vs analysis after pneumatic tube system transport.

    Science.gov (United States)

    Martin, J; Schuster, T; Moessmer, G; Kochs, E F; Wagner, K J

    2012-10-01

    Thromboelastometry as point-of-care (POC) testing enables the analysis of the clotting process at the bedside, providing rapid results to guide haemostatic therapy. However, POC testing utilizes medical staff who are managing critically ill patients, as non-laboratory personnel may not be sufficiently trained to run the devices. To resolve these problems, thromboelastometry can be performed in the central laboratory and rapid transport of samples can be accomplished via a pneumatic tube system (PTS). This study compares thromboelastometry parameters of blood samples analysed immediately with those analysed after PTS transport. In patients with normal haemostasis, two arterial blood samples were collected from each patient (n=92) in citrated plastic tubes to investigate the assays INTEM (n=35), EXTEM (n=27), and FIBTEM (n=30). One blood sample was analysed immediately, the other sample after PTS transport. Thromboelastometry was performed using a single ROTEM(®) device. The mean clot firmness values were significantly lower for PTS samples in both the INTEM (-0.7 mm cf. -1.1 mm) and EXTEM (-1.4 cf. -1.7 mm) assays. INTEM coagulation time (CT) was significantly lower in PTS samples with a mean difference of -13 s. EXTEM CT was significantly higher in PTS samples with a mean difference of +3.9 s. Thromboelastometry parameters of blood samples analysed after PTS transport are significantly altered compared with those analysed immediately. However, in patients with normal haemostasis, the alterations were small and without clinical consequence, implying that analysis after PTS transport is an acceptable alternative to prompt analysis at the bedside. Further studies should focus on patients with impaired haemostasis.

  15. SNPs altering ammonium transport activity of human Rhesus factors characterized by a yeast-based functional assay.

    Directory of Open Access Journals (Sweden)

    Aude Deschuyteneer

    Full Text Available Proteins of the conserved Mep-Amt-Rh family, including mammalian Rhesus factors, mediate transmembrane ammonium transport. Ammonium is an important nitrogen source for the biosynthesis of amino acids but is also a metabolic waste product. Its disposal in urine plays a critical role in the regulation of the acid/base homeostasis, especially with an acid diet, a trait of Western countries. Ammonium accumulation above a certain concentration is however pathologic, the cytotoxicity causing fatal cerebral paralysis in acute cases. Alteration in ammonium transport via human Rh proteins could have clinical outcomes. We used a yeast-based expression assay to characterize human Rh variants resulting from non synonymous single nucleotide polymorphisms (nsSNPs with known or unknown clinical phenotypes and assessed their ammonium transport efficiency, protein level, localization and potential trans-dominant impact. The HsRhAG variants (I61R, F65S associated to overhydrated hereditary stomatocytosis (OHSt, a disease affecting erythrocytes, proved affected in intrinsic bidirectional ammonium transport. Moreover, this study reveals that the R202C variant of HsRhCG, the orthologue of mouse MmRhcg required for optimal urinary ammonium excretion and blood pH control, shows an impaired inherent ammonium transport activity. Urinary ammonium excretion was RHcg gene-dose dependent in mouse, highlighting MmRhcg as a limiting factor. HsRhCG(R202C may confer susceptibility to disorders leading to metabolic acidosis for instance. Finally, the analogous R211C mutation in the yeast ScMep2 homologue also impaired intrinsic activity consistent with a conserved functional role of the preserved arginine residue. The yeast expression assay used here constitutes an inexpensive, fast and easy tool to screen nsSNPs reported by high throughput sequencing or individual cases for functional alterations in Rh factors revealing potential causal variants.

  16. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors

    International Nuclear Information System (INIS)

    Naguib, Adam; Arends, Mark J; Cooke, James C; Happerfield, Lisa; Kerr, Lucy; Gay, Laura J; Luben, Robert N; Ball, Richard Y; Mitrou, Panagiota N; McTaggart, Alison

    2011-01-01

    The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage

  17. Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells

    DEFF Research Database (Denmark)

    Cheng, Chang; Edin, Nina F Jeppesen; Lauritzen, Knut H

    2012-01-01

    Tumour cells are characterized by aerobic glycolysis, which provides biomass for tumour proliferation and leads to extracellular acidification through efflux of lactate via monocarboxylate transporters (MCTs). Deficient and spasm-prone tumour vasculature causes variable hypoxia, which favours...

  18. Organophosphate Related Alterations in Myelin and Axonal Transport in the Living Mammalian Brain

    Science.gov (United States)

    2015-10-01

    function, neuroinflammation, al- tered neurotrophin responses, etc. (reviewed, Soltaninejad and Abdollahi, 2009; Banks and Lein, 2012; Terry, 2012). Conflict...JN, Middlemore ML, Williamson LN, et al. Chronic, intermittent exposure to chlorpyrifos in rats: protracted effects on axonal transport, neurotrophin

  19. Alterations in protein transport events in rat liver after estrogen treatment

    International Nuclear Information System (INIS)

    Goldsmith, M.A.; Jones, A.L.; Underdown, B.J.; Schiff, J.M.

    1987-01-01

    The effects of 17α-ethynylestradiol (EE) treatment on the hepatic processing of rat polymeric immunoglobulin A (IgA) and human asialoorosomucoid (ASOr) were studied. After 5 days of treatment with EE (5 mg/kg) or solvent alone, male rats were anesthetized and injected with tracer doses of the test proteins. Bile flow rates had been reduced by >60% in the EE-treated animals. A previously reported radiolabeling strategy was used to monitor both the transport of intact protein to bile and the degradation of protein in lysosomes. Transport of intact IgA to bile was reduced by 43%, with transport peaking 27 min later in EE-treated animals compared with controls. There was a corresponding impairment of uptake of labeled IgA from blood. EE induced no kinetic change in the uptake or processing of ASOr. However, there was an increase in the proportion of ASOr reaching bile intact from 3% to 15-23% of the injected dose. The data indicate that EE disables the transport pathway for IgA and causes a partial change in the routing of ASOr after endocytosis in favor of direct transport to the bile canaliculus. These findings may have implications for the importance of membrane composition in protein transport events

  20. Risks of Colorectal Cancer Screening

    Science.gov (United States)

    ... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Screening (PDQ®)–Patient Version What is screening? Go ... These are called diagnostic tests . General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

  1. Gene expression in colorectal cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtroder, Karin; Christensen, Lise Lotte; Olesen, Sanne Harder

    2002-01-01

    Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each...... pool) of total RNA from left-sided sporadic colorectal carcinomas. We compared normal tissue to carcinoma tissue from Dukes' stages A-D (noninvasive to distant metastasis) and identified 908 known genes and 4,155 ESTs that changed remarkably from normal to tumor tissue. Based on intensive filtering 226...

  2. Copper and ectopic expression of the Arabidopsis transport protein COPT1 alter iron homeostasis in rice (Oryza sativa L.).

    Science.gov (United States)

    Andrés-Bordería, Amparo; Andrés, Fernando; Garcia-Molina, Antoni; Perea-García, Ana; Domingo, Concha; Puig, Sergi; Peñarrubia, Lola

    2017-09-01

    Copper deficiency and excess differentially affect iron homeostasis in rice and overexpression of the Arabidopsis high-affinity copper transporter COPT1 slightly increases endogenous iron concentration in rice grains. Higher plants have developed sophisticated mechanisms to efficiently acquire and use micronutrients such as copper and iron. However, the molecular mechanisms underlying the interaction between both metals remain poorly understood. In the present work, we study the effects produced on iron homeostasis by a wide range of copper concentrations in the growth media and by altered copper transport in Oryza sativa plants. Gene expression profiles in rice seedlings grown under copper excess show an altered expression of genes involved in iron homeostasis compared to standard control conditions. Thus, ferritin OsFER2 and ferredoxin OsFd1 mRNAs are down-regulated whereas the transcriptional iron regulator OsIRO2 and the nicotianamine synthase OsNAS2 mRNAs rise under copper excess. As expected, the expression of OsCOPT1, which encodes a high-affinity copper transport protein, as well as other copper-deficiency markers are down-regulated by copper. Furthermore, we show that Arabidopsis COPT1 overexpression (C1 OE ) in rice causes root shortening in high copper conditions and under iron deficiency. C1 OE rice plants modify the expression of the putative iron-sensing factors OsHRZ1 and OsHRZ2 and enhance the expression of OsIRO2 under copper excess, which suggests a role of copper transport in iron signaling. Importantly, the C1 OE rice plants grown on soil contain higher endogenous iron concentration than wild-type plants in both brown and white grains. Collectively, these results highlight the effects of rice copper status on iron homeostasis, which should be considered to obtain crops with optimized nutrient concentrations in edible parts.

  3. Expression of a putative grapevine hexose transporter in tobacco alters morphogenesis and assimilate partitioning.

    Science.gov (United States)

    Leterrier, Marina; Atanassova, Rossitza; Laquitaine, Laurent; Gaillard, Cécile; Coutos-Thévenot, Pierre; Delrot, Serge

    2003-04-01

    Tobacco plants were transformed by leaf disc regeneration with the VvHT1 (Vitis vinifera hexose transporter 1) cDNA under the control of the constitutive CaMV 35S promoter in a sense or antisense orientation. Among the 20 sense plants and 10 antisense plants obtained, two sense plants showed a mutant phenotype when grown in vitro, with stunted growth and an increase in the (leaves+stem)/roots dry weight ratio. The rate of [(3)H]-glucose uptake in leaf discs from these plants was decreased to 25% of the value measured in control plants. The amount of VvHT1 transgene and of host monosaccharide transporter MST transcripts in the leaves were studied by RNA gel blot analysis. The VvHT1 transcripts were usually present, but the amount of MST transcripts was the lowest in the plants that exhibited the most marked phenotype. Although the phenotype was lost when the plants were transferred from in vitro to greenhouse conditions, it was found again in vitro in the progeny obtained by self-pollination or by back-cross. The data show that VvHT1 sense expression resulted in unidirectional post-transcriptional gene inactivation of MST in some of the transformants, with dramatic effects on growth. They provide the first example of plants modified for hexose transport by post-transcriptional gene silencing. Some of the antisense plants also showed reduced expression of MST, and decreased growth. These results indicate that, like the sucrose transporters, hexose transporters play an important role in assimilate transport and in morphogenesis.

  4. Coronary Heart Disease Alters Intercellular Communication by Modifying Microparticle-Mediated MicroRNA Transport

    Science.gov (United States)

    Finn, Nnenna A.; Eapen, Danny; Manocha, Pankaj; Kassem, Hatem Al; Lassegue, Bernard; Ghasemzadeh, Nima; Quyyumi, Arshed; Searles, Charles D.

    2013-01-01

    Coronary heart disease (CHD) is characterized by abnormal intercellular communication and circulating microRNAs (miRNAs) are likely involved in this process. Here, we show that CHD was associated with changes in the transport of circulating miRNA, particularly decreased miRNA enrichment in microparticles (MPs). Additionally, MPs from CHD patients were less efficient at transferring miRNA to cultured HUVECs, which correlated with their diminished capacity to bind developmental endothelial locus-1 (Del-1). In summary, CHD was associated with distinct changes in circulating miRNA transport and these changes may contribute to the abnormal intercellular communication that underlies CHD initiation and progression. PMID:24042051

  5. Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Rich, Tyvin; Innominato, Pasquale F; Boerner, Julie; Mormont, M Christine; Iacobelli, Stefano; Baron, Benoit; Jasmin, Claude; Lévi, Francis

    2005-03-01

    Incapacitating symptom burden in cancer patients contributes to poor quality of life (QOL) and can influence treatment outcomes because of poor tolerance to therapy. In this study, the role of circulating cytokines in the production symptoms in cancer patients is evaluated. Eighty patients with metastatic colorectal cancer with either normal (group I, n = 40) or dampened (group II, n = 40) 24-hour rest/activity patterns measured by actigraphy were identified. Actigraphy patterns were correlated with QOL indices, serum cortisol obtained at 8:00 a.m. and 4:00 p.m. and with serum levels of transforming growth factor-alpha, tumor necrosis factor-alpha, and interleukin 6 (IL-6) obtained at 8:00 a.m. and analyzed in duplicate by ELISA. Cytokine levels and survival were also correlated. Group II patients had significantly higher pre treatment levels of all three cytokines, displayed significantly poorer emotional and social functioning, had higher fatigue, more appetite loss, and poorer performance status compared with group I patients. Transforming growth factor-alpha (TGF-alpha) and IL-6 were significantly increased in the patients with WHO performance status >1 and in those with appetite loss. Fatigue was significantly associated with elevated TGF-alpha only. IL-6 was increased in those patients with extensive liver involvement and multiple organ replacement, and it was significantly correlated with dampened cortisol rhythm. In a multivariate analysis, IL-6 was correlated with poor treatment outcome. Significant correlations were found between serum levels of TGF-alpha and IL-6, circadian patterns in wrist activity and serum cortisol and tumor-related symptoms in patients with metastatic colorectal cancer. These data support the hypothesis that some cancer patient's symptoms of fatigue, poor QOL, and treatment outcome are related to tumor or host generated cytokines and could reflect cytokine effects on the circadian timing system. This interplay between cytokine

  6. Prenatal Transportation Stress Alters Temperament and Serum Cortisol Concentrations in Suckling Brahman Calves

    Science.gov (United States)

    This experiment examined the relationship between prenatal stress and subsequent calf temperament through weaning. The prenatal stressor utilized was repeated transportation of pregnant Brahman cows for 2 hours at 60, 80, 100, 120, and 140 days of gestation. Prenatally stressed calves (n = 41) were ...

  7. Altered Colonic Environment, a Possible Predisposition to Colorectal Cancer and Colonic Inflammatory Bowel Disease: Rationale of Dietary Manipulation with Emphasis on Disaccharides

    Directory of Open Access Journals (Sweden)

    A Szilagyi

    1998-01-01

    Full Text Available A recurrent theme in the schema of pathogenetic mechanisms attributed to colorectal cancer (CRC and inflammatory bowel disease (IBD is the interaction between genes and environment. Dietary and other environmental factors, and lower intestinal flora and their chemical interactions occur in the pathogenesis of both. Events at the mucosal surface may be influenced by factors in the luminal environment and by contributions of the host. In addition, both forms of IBD - Crohn's disease (CD and ulcerative colitis (UC - have distinctive associated host events. Even within CD and UC, different clinical patterns and prognoses may have different specific host mechanisms. Some of the current putative pathogenetic processes in CRC and IBD are reviewed. Particular attention is given to hypotheses relating to the role of dietetic substances, mainly fibre and dairy products, and how they may affect disease formation. It is argued that within the context of hypotheses proposed for possible beneficial effects of these two dietetic factors, CRC and IBD may be considered together. Further support is lent to arguments that similar and additional hypothetical features ascribed to beneficial effects of fibre may be attributed to disaccharides, lactose and its derivatives, lactulose and lactitol.

  8. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria

    Science.gov (United States)

    Chino, Yukihiro; Samukawa, Yoshishige; Sakai, Soichi; Nakai, Yasuhiro; Yamaguchi, Jun-ichi; Nakanishi, Takeo; Tamai, Ikumi

    2014-01-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UEUA) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UEUA, suggesting that SUA decreased as a result of the increase in the UEUA. The increase in UEUA was correlated with an increase in urinary d-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UEUA is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and d-glucose. It was observed that the efflux of [14C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm d-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [14C]UA by oocytes was cis-inhibited by 100 mm d-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UEUA could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. PMID:25044127

  9. Colorectal cancer

    International Nuclear Information System (INIS)

    Akiba, Suminori

    1992-01-01

    This paper describes colorectal cancer risk in relation to A-bomb radiation. The RERF Life Span Study has revealed the incidence of colorectal cancer to be significantly high in the group of A-bomb survivors than the control group. With regard to relative risk or excess relative risk, there is no definitive difference among sites in the colon. Risk for colon cancer is found to be linearly increased with increasing radiation doses, and in younger A-bomb survivors at the time of exposure. Risk associated with one Gy is estimated to be increased by double. There is no definitive variation between sex and between Hiroshima and Nagasaki. Excess relative risk would be increased rapidly with aging in the whole group of A-bomb survivors and with the cancer-prone age in younger A-bomb survivors at the time of exposure. (N.K.)

  10. Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET.

    Science.gov (United States)

    Vanicek, Thomas; Kutzelnigg, Alexandra; Philippe, Cecile; Sigurdardottir, Helen L; James, Gregory M; Hahn, Andreas; Kranz, Georg S; Höflich, Anna; Kautzky, Alexander; Traub-Weidinger, Tatjana; Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus; Kasper, Siegfried; Lanzenberger, Rupert

    2017-02-01

    Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP ND ) in patients with ADHD and to assess associations of SERT BP ND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [ 11 C]DASB. SERT BP ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP ND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R 2  = 0.284, R 2  = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley

  11. Polymorphisms in ATP-binding cassette transporter genes and interaction with diet and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study

    DEFF Research Database (Denmark)

    Kopp, Tine Iskov; Andersen, Vibeke; Tjonneland, Anne

    2015-01-01

    to assess whether polymorphisms in ABCB1, ABCC2 and ABCG2 were associated with risk of colorectal cancer (CRC) and to investigate gene-environment (dietary factors, smoking and use of non-steroidal anti-inflammatory drugs) and gene-gene interactions between previously studied polymorphisms in IL1B and IL10......The ATP-binding cassette (ABC) transporter family transports various molecules across the enterocytes in the gut protecting the intestine against potentially harmful substances. Moreover, ABC transporters are involved in mucosal immune defence through interaction with cytokines. The study aimed...... of the polymorphisms were associated with CRC, but ABCB1 and ABCG2 haplotypes were associated with risk of CRC. ABCB1/rs1045642 interacted with intake of cereals and fiber (p-Value for interaction (Pint) = 0.001 and 0.01, respectively). In a three-way analysis, both ABCB1/rs1045642 and ABCG2/rs2231137 in combination...

  12. Interacting effects of discharge and channel morphology on transport of semibuoyant fish eggs in large, altered river systems.

    Directory of Open Access Journals (Sweden)

    Thomas A Worthington

    Full Text Available Habitat fragmentation and flow regulation are significant factors related to the decline and extinction of freshwater biota. Pelagic-broadcast spawning cyprinids require moving water and some length of unfragmented stream to complete their life cycle. However, it is unknown how discharge and habitat features interact at multiple spatial scales to alter the transport of semi-buoyant fish eggs. Our objective was to assess the relationship between downstream drift of semi-buoyant egg surrogates (gellan beads and discharge and habitat complexity. We quantified transport time of a known quantity of beads using 2-3 sampling devices at each of seven locations on the North Canadian and Canadian rivers. Transport time was assessed based on median capture time (time at which 50% of beads were captured and sampling period (time period when 2.5% and 97.5% of beads were captured. Habitat complexity was assessed by calculating width∶depth ratios at each site, and several habitat metrics determined using analyses of aerial photographs. Median time of egg capture was negatively correlated to site discharge. The temporal extent of the sampling period at each site was negatively correlated to both site discharge and habitat-patch dispersion. Our results highlight the role of discharge in driving transport times, but also indicate that higher dispersion of habitat patches relates to increased retention of beads within the river. These results could be used to target restoration activities or prioritize water use to create and maintain habitat complexity within large, fragmented river systems.

  13. ESKIMO1 disruption in Arabidopsis alters vascular tissue and impairs water transport.

    Directory of Open Access Journals (Sweden)

    Valérie Lefebvre

    Full Text Available Water economy in agricultural practices is an issue that is being addressed through studies aimed at understanding both plant water-use efficiency (WUE, i.e. biomass produced per water consumed, and responses to water shortage. In the model species Arabidopsis thaliana, the ESKIMO1 (ESK1 gene has been described as involved in freezing, cold and salt tolerance as well as in water economy: esk1 mutants have very low evapo-transpiration rates and high water-use efficiency. In order to establish ESK1 function, detailed characterization of esk1 mutants has been carried out. The stress hormone ABA (abscisic acid was present at high levels in esk1 compared to wild type, nevertheless, the weak water loss of esk1 was independent of stomata closure through ABA biosynthesis, as combining mutant in this pathway with esk1 led to additive phenotypes. Measurement of root hydraulic conductivity suggests that the esk1 vegetative apparatus suffers water deficit due to a defect in water transport. ESK1 promoter-driven reporter gene expression was observed in xylem and fibers, the vascular tissue responsible for the transport of water and mineral nutrients from the soil to the shoots, via the roots. Moreover, in cross sections of hypocotyls, roots and stems, esk1 xylem vessels were collapsed. Finally, using Fourier-Transform Infrared (FTIR spectroscopy, severe chemical modifications of xylem cell wall composition were highlighted in the esk1 mutants. Taken together our findings show that ESK1 is necessary for the production of functional xylem vessels, through its implication in the laying down of secondary cell wall components.

  14. Cytogenetic analysis of colorectal adenomas: karyotypic comparisons of synchronous tumors

    DEFF Research Database (Denmark)

    Bomme, L; Bardi, G; Pandis, N

    1998-01-01

    The phenotypic progression of colorectal tumors is driven by their step-by-step acquisition of genomic alterations. These pathogenetically important mutations are at the same time markers of tumor clonality. The aim of this study was to describe the clonal relation among synchronous colorectal ad...

  15. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.

    Science.gov (United States)

    Nath, Aritro; Chan, Christina

    2016-01-04

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers.

  16. Alteration of natural (37)Ar activity concentration in the subsurface by gas transport and water infiltration.

    Science.gov (United States)

    Guillon, Sophie; Sun, Yunwei; Purtschert, Roland; Raghoo, Lauren; Pili, Eric; Carrigan, Charles R

    2016-05-01

    High (37)Ar activity concentration in soil gas is proposed as a key evidence for the detection of underground nuclear explosion by the Comprehensive Nuclear Test-Ban Treaty. However, such a detection is challenged by the natural background of (37)Ar in the subsurface, mainly due to Ca activation by cosmic rays. A better understanding and improved capability to predict (37)Ar activity concentration in the subsurface and its spatial and temporal variability is thus required. A numerical model integrating (37)Ar production and transport in the subsurface is developed, including variable soil water content and water infiltration at the surface. A parameterized equation for (37)Ar production in the first 15 m below the surface is studied, taking into account the major production reactions and the moderation effect of soil water content. Using sensitivity analysis and uncertainty quantification, a realistic and comprehensive probability distribution of natural (37)Ar activity concentrations in soil gas is proposed, including the effects of water infiltration. Site location and soil composition are identified as the parameters allowing for a most effective reduction of the possible range of (37)Ar activity concentrations. The influence of soil water content on (37)Ar production is shown to be negligible to first order, while (37)Ar activity concentration in soil gas and its temporal variability appear to be strongly influenced by transient water infiltration events. These results will be used as a basis for practical CTBTO concepts of operation during an OSI. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Disruption of the ammonium transporter AMT1.1 alters basal defences generating resistance against Pseudomonas syringae and Plectosphaerella cucumerina

    Directory of Open Access Journals (Sweden)

    Victoria ePastor

    2014-05-01

    Full Text Available Disruption of the high-affinity nitrate transporter NRT2.1 activates the priming defence against Pseudomonas syringae, resulting in enhanced resistance. In this study, it is demonstrated that the high-affinity ammonium transporter AMT1.1 is a negative regulator of Arabidopsis defence responses. The T-DNA knockout mutant amt1.1 displays enhanced resistance against Plectosphaerella cucumerina and reduced susceptibility to P. syringae. The impairment of AMT1.1 induces significant metabolic changes in the absence of challenge, suggesting that amt1.1 retains constitutive defence responses. Interestingly, amt1.1 combats pathogens differently depending on the lifestyle of the pathogen. In addition, N starvation enhances the susceptibility of wild type plants and the mutant amt1.1 to P. syringae whereas it has no effect on P. cucumerina resistance. The metabolic changes of amt1.1 against P. syringae are subtler and are restricted to the phenylpropanoid pathway, which correlates with its reduced susceptibility. By contrast, the amt1.1 mutant responds by activating higher levels of camalexin and callose against P. cucumerina. In addition, amt1.1 shows altered levels of aliphatic and indolic glucosinolates and other Trp-related compounds following infection by the necrotroph. These observations indicate that AMT1.1 may play additional roles that affect N uptake and plant immune responses.

  18. Colloid Genesis/Transport and Flow Pathway Alterations Resulting From Interactions of Reactive Waste Solutions and Hanford Vadose Zone Sediments

    International Nuclear Information System (INIS)

    Wan, Jiamin; Tokunaga, Tetsu K.

    2001-01-01

    Leakage of underground tanks containing high-level nuclear waste solutions has been identified at various DOE facilities. The Hanford Site is one the main facilities of concern, with about 2,300 to 3,400 m3 of leaked waste liquids. Radionuclides and other contaminants have been found in elevated concentrations in the vadose zone and groundwater underneath single shell tank farms. We do not currently know the mechanisms responsible for the unexpected deep migration of some contaminants through the vadose zone, and such understanding is urgently needed for planning remediation. Due to the extreme chemical conditions of the tank waste solutions (very high pH, aluminum concentration, and ionic strength), interactions between the highly reactive waste solutions and sediments underneath the tanks can result in dissolution of primary minerals of the sediments and precipitation of secondary phases including colloidal particles. Contaminants can sorb onto and/or co-precipitate with the secondary phases. Therefore transport of strongly associated contaminants on mobile colloids can be substantially greater than without colloids. The overall objective of this research is to improve our understanding on the effects of interactions between the tank waste solution and sediments on deep contaminant migration under Hanford Site conditions. This objective will be achieved through the following four tasks: (1) colloid generation and transport studies, (2) studies on sediment permeability and chemical composition alterations, (3) quantifying associations of contaminants with secondary colloids, and (4) studies on the combined effects of the aforementioned processes on deep contaminant migration

  19. Alterações gastrointestinais em pacientes com câncer colorretal em ensaio clínico com fungos Agaricus sylvaticus Gastrointestinal alterations in patients with colorectal cancer on clinical trial supplemented with Agaricus sylvaticus fungus

    Directory of Open Access Journals (Sweden)

    Renata Costa Fortes

    2010-03-01

    Full Text Available INTRODUÇÃO: Fungos medicinais podem normalizar a função intestinal, aumentar o apetite e reduzir os efeitos adversos do tratamento convencional do câncer. OBJETIVO: Avaliar as alterações gastrointestinais de pacientes com câncer colorretal em fase pós-operatória após suplementação dietética com fungos Agaricus sylvaticus. METODOLOGIA: Ensaio clínico randomizado, duplo-cego, placebo-controlado, realizado no Hospital de Base do Distrito Federal. Amostra constituída de 56 pacientes (24 homens e 32 mulheres, estádios I, II e III, seguindo determinados critérios de inclusão e exclusão, separados em grupos placebo e Agaricus sylvaticus (30mg/kg/dia e acompanhados por um período de seis meses. Para avaliar as alterações gastrointestinais foram utilizados um formulário-padrão e uma anamnese dirigida-padrão. O método de análise dos resultados foi qualitativo e descritivo, utilizando os programas Microsoft Excel 2003 e Epi Info 2004 para Windows, versão 3.3.2. RESULTADOS: Após seis meses de tratamento, observou-se, no grupo Agaricus sylvaticus, aumento do apetite e redução da constipação, diarréia, diarréia alternada com constipação, flatulência, retenção de flatos, pirose, plenitude pós-prandial, náuseas, distensão e dor abdominais, fatos não observados no grupo placebo. CONCLUSÃO: Os resultados sugerem que a suplementação dietética com fungos Agaricus sylvaticus é capaz de melhorar as alterações gastrointestinais de pacientes no pós-operatório de câncer colorretal, promovendo melhoria na qualidade de vida desses pacientes.INTRODUCTION: Medicinal fungus may normalize intestinal function, increase appetite and reduce adverse effects caused by conventional cancer treatment. OBJECTIVE: To evaluate the gastrointestinal alterations of patients with colorectal cancer in post-operative phase after dietary supplementation with Agaricus sylvaticus fungus. METHODOLOGY: Randomized, double-blind, placebo

  20. A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab.

    Science.gov (United States)

    Berger, Martin D; Stintzing, Sebastian; Heinemann, Volker; Cao, Shu; Yang, Dongyun; Sunakawa, Yu; Matsusaka, Satoshi; Ning, Yan; Okazaki, Satoshi; Miyamoto, Yuji; Suenaga, Mitsukuni; Schirripa, Marta; Hanna, Diana L; Soni, Shivani; Puccini, Alberto; Zhang, Wu; Cremolini, Chiara; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef

    2018-02-15

    Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab. Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes ( GC, CYP24A1, CYP27B1, VDR, DKK1, CST5 ) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D-binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable ( P = 0.001) and multivariable analyses ( P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable ( P = 0.033) and multivariable analyses ( P = 0.046). Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784-93. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. Get Tested for Colorectal Cancer

    Science.gov (United States)

    ... Print This Topic En español Get Tested for Colorectal Cancer Browse Sections The Basics Overview What to Expect ... section Overview 2 of 6 sections The Basics: Colorectal Cancer What is colorectal cancer? Colorectal cancer is a ...

  2. Surfactant-enhanced flushing enhances colloid transport and alters macroporosity in diesel-contaminated soil.

    Science.gov (United States)

    Guan, Zhuo; Tang, Xiang-Yu; Nishimura, Taku; Katou, Hidetaka; Liu, Hui-Yun; Qing, Jing

    2018-02-01

    Soil contamination by diesel has been often reported as a result of accidental spillage, leakage and inappropriate use. Surfactant-enhanced soil flushing is a common remediation technique for soils contaminated by hydrophobic organic chemicals. In this study, soil flushing with linear alkylbenzene sulfonates (LAS, an anionic surfactant) was conducted for intact columns (15cm in diameter and 12cm in length) of diesel-contaminated farmland purple soil aged for one year in the field. Dynamics of colloid concentration in column outflow during flushing, diesel removal rate and resulting soil macroporosity change by flushing were analyzed. Removal rate of n-alkanes (representing the diesel) varied with the depth of the topsoil in the range of 14%-96% while the n-alkanes present at low concentrations in the subsoil were completely removed by LAS-enhanced flushing. Much higher colloid concentrations and larger colloid sizes were observed during LAS flushing in column outflow compared to water flushing. The X-ray micro-computed tomography analysis of flushed and unflushed soil cores showed that the proportion of fine macropores (30-250μm in diameter) was reduced significantly by LAS flushing treatment. This phenomenon can be attributed to enhanced clogging of fine macropores by colloids which exhibited higher concentration due to better dispersion by LAS. It can be inferred from this study that the application of LAS-enhanced flushing technique in the purple soil region should be cautious regarding the possibility of rapid colloid-associated contaminant transport via preferential pathways in the subsurface and the clogging of water-conducting soil pores. Copyright © 2017. Published by Elsevier B.V.

  3. Cortical compression rapidly trimmed transcallosal projections and altered axonal anterograde transport machinery.

    Science.gov (United States)

    Chen, Li-Jin; Wang, Yueh-Jan; Tseng, Guo-Fang

    2017-10-24

    Trauma and tumor compressing the brain distort underlying cortical neurons. Compressed cortical neurons remodel their dendrites instantly. The effects on axons however remain unclear. Using a rat epidural bead implantation model, we studied the effects of unilateral somatosensory cortical compression on its transcallosal projection and the reversibility of the changes following decompression. Compression reduced the density, branching profuseness and boutons of the projection axons in the contralateral homotopic cortex 1week and 1month post-compression. Projection fiber density was higher 1-month than 1-week post-compression, suggesting adaptive temporal changes. Compression reduced contralateral cortical synaptophysin, vesicular glutamate transporter 1 (VGLUT1) and postsynaptic density protein-95 (PSD95) expressions in a week and the first two marker proteins further by 1month. βIII-tubulin and kinesin light chain (KLC) expressions in the corpus callosum (CC) where transcallosal axons traveled were also decreased. Kinesin heavy chain (KHC) level in CC was temporarily increased 1week after compression. Decompression increased transcallosal axon density and branching profuseness to higher than sham while bouton density returned to sham levels. This was accompanied by restoration of synaptophysin, VGLUT1 and PSD95 expressions in the contralateral cortex of the 1-week, but not the 1-month, compression rats. Decompression restored βIII-tubulin, but not KLC and KHC expressions in CC. However, KLC and KHC expressions in the cell bodies of the layer II/III pyramidal neurons partially recovered. Our results show cerebral compression compromised cortical axonal outputs and reduced transcallosal projection. Some of these changes did not recover in long-term decompression. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity.

    Science.gov (United States)

    Truong, Jannine G; Wilkins, Diana G; Baudys, Jakub; Crouch, Dennis J; Johnson-Davis, Kamisha L; Gibb, James W; Hanson, Glen R; Fleckenstein, Annette E

    2005-09-01

    Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.

  5. Alteration of CNS dopamine transporter and D2 receptor in aged and scopolamine induced amnestic rats

    International Nuclear Information System (INIS)

    Lin Yansong; Ding Shiyu; Chen Zhengping; Zhou Xiang; Fang Ping; Wang Bocheng; Zhang Manda

    2002-01-01

    Objective: To evaluate the effect of aging and scopolamine (Sco) induced amnesia on central dopamine transporter (DAT), D 2 receptor in rats. Methods: The 3 month old amnestic rat models were made by peritoneal injection of the muscarinic receptor antagonist Sco (5 mg/kg) for 10 d. Passive avoidance task was carried out to evaluate the recent learning and memory of rats. The biodistribution of 125 I-2-β-carbomethoxy-3-β(4-iodophenyl)-tropan ( 125 I-β-CIT) and 125 I-s-3-iodo-N-(1-ethyl-2-pyrolidinyl) methyl-2-hydroxy-6-methoxybenzamide (IBZM) in the brain was used to evaluate the DAT and D 2 receptor. Results: During 10 d passive avoidance task testing, no difference was found for the first day among 3 month control, 26 month old and Sco group rats, on the 10th day the entry number of aged and Sco group rats was (1.33 +- 0.82)/10 min, (3.00 +- 0.63)/10 min, respectively, higher than that of the control rats (t was 5.682 and 6.372, respectively, P 125 I-β-CIT binding were found in the striatum (ST), hippocampus (HIP) and frontal cortex (FC) of the aged and Sco group rats (t was 4.151, 5.416, 4.871, 6.922, 7.331 and 3.990, respectively, P 125 I-IBZM binding in ST was found in both Sco and old rats (t was 6.021 and 3.227, respectively, P 2 receptor, was found in ST, HIP and cortex of the aged and Sco group suggesting a gradual degeneration of dopaminergic neurons in aged rats. The decreased levels of 125 I-β-CIT and 125 I-IBZM binding in cortex area might be responsible for the amnesia in he Sco group through the dopaminergic pathway of midbrain-frontal cortex

  6. SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking.

    Science.gov (United States)

    Bowton, E; Saunders, C; Reddy, I A; Campbell, N G; Hamilton, P J; Henry, L K; Coon, H; Sakrikar, D; Veenstra-VanderWeele, J M; Blakely, R D; Sutcliffe, J; Matthies, H J G; Erreger, K; Galli, A

    2014-10-14

    Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or attention-deficit hyperactivity disorder (ADHD). We have demonstrated that this variant is hyper-phosphorylated at the amino (N)-terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Here, we report the novel identification of hDAT A559V in two unrelated ASD subjects and provide the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. Here, we show that hDAT A559V is resistant to AMPH-induced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C β (PKCβ) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCβ activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. Mechanistically, we link the inability of hDAT A559V to traffic in response to AMPH to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these N-terminal Ser to Ala restores AMPH-induced trafficking. Furthermore, hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCβ or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission

  7. Integrated proteomic and genomic analysis of colorectal cancer

    Science.gov (United States)

    Investigators who analyzed 95 human colorectal tumor samples have determined how gene alterations identified in previous analyses of the same samples are expressed at the protein level. The integration of proteomic and genomic data, or proteogenomics, pro

  8. Underpinning the repurposing of anthracyclines towards colorectal cancer

    DEFF Research Database (Denmark)

    Nygård, Sune Boris; Christensen, Ib Jarle; Smith, David Hersi

    2013-01-01

    Abstract Objective. We propose a repurposing strategy where anthracyclines are reintroduced to a subgroup of patients with metastatic colorectal cancer with the highest likelihood of response. In breast cancer, DNA topoisomerase II alpha gene (TOP2A) alterations predict incremental benefit...... of anthracyclines, but this association has not been investigated in colorectal cancer. Frequency analysis of TOP2A gene alterations in colorectal cancer and the association with prognosis are evaluated and the challenges of using a TOP2A/CEN-17 FISH probe combination are addressed. Material and methods. Formalin......-fixed, paraffin-embedded material from 154 stage III colorectal cancer patients included in the RANX05 clinical trial was retrospectively assessed for TOP2A gene alterations using FISH. The TOP2A/CEN-17 ratio as well as the TOP2A gene copy number alone was used to define gene alterations and associations between...

  9. Subsurface Transport Over Reactive Multiphases (STORM): A general, coupled, nonisothermal multiphase flow, reactive transport, and porous medium alteration simulator, Version 2 user's guide

    International Nuclear Information System (INIS)

    Bacon, D.H.; White, M.D.; McGrail, B.P.

    2000-01-01

    The Hanford Site, in southeastern Washington State, has been used extensively to produce nuclear materials for the US strategic defense arsenal by the Department of Energy (DOE) and its predecessors, the US Atomic Energy Commission and the US Energy Research and Development Administration. A large inventory of radioactive and mixed waste has accumulated in 177 buried single- and double shell tanks. Liquid waste recovered from the tanks will be pretreated to separate the low-activity fraction from the high-level and transuranic wastes. Vitrification is the leading option for immobilization of these wastes, expected to produce approximately 550,000 metric tons of Low Activity Waste (LAW) glass. This total tonnage, based on nominal Na 2 O oxide loading of 20% by weight, is destined for disposal in a near-surface facility. Before disposal of the immobilized waste can proceed, the DOE must approve a performance assessment, a document that described the impacts, if any, of the disposal facility on public health and environmental resources. Studies have shown that release rates of radionuclides from the glass waste form by reaction with water determine the impacts of the disposal action more than any other independent parameter. This report describes the latest accomplishments in the development of a computational tool, Subsurface Transport Over Reactive Multiphases (STORM), Version 2, a general, coupled non-isothermal multiphase flow and reactive transport simulator. The underlying mathematics in STORM describe the rate of change of the solute concentrations of pore water in a variably saturated, non-isothermal porous medium, and the alteration of waste forms, packaging materials, backfill, and host rocks

  10. Environmental Effects of Sediment Transport Alteration and Impacts on Protected Species: Edgartown Tidal Energy Project

    Energy Technology Data Exchange (ETDEWEB)

    Barrett, Stephen B; Schlezinger, David, Ph.D; Cowles, Geoff, Ph.D; Hughes, Patricia; Samimy,; Roland, I; and Terray, E, Ph.D.

    2012-12-29

    potential for biofouling and foundation scouring. Woods Hole Oceanographic Institution, cooperating with SMAST, developed an oceanographic model to predict changes in sediment transport as a result of the proposed tidal energy project. Provincetown Center for Coastal Studies prepared background material on protected species - including whales, seals, and sea turtles - in the project area and implemented an initial tagging program to record location specific information on seals and sea turtles. HMMH communicated research plans and findings with local stakeholder groups, state and federal resource agency staff, and the ocean power industry. The information is being used to prepare environmental permit applications and obtain approvals for project construction.

  11. Transport and Breakdown of Organic Matter in Urban and Forested Streams: The Effects of Altered Hydrology and Landscape Position

    Science.gov (United States)

    Belt, K. T.; Swan, C. M.; Pouyat, R. V.; Kaushal, S.; Groffman, P. M.; Stack, W. P.; Fisher, G. T.

    2006-05-01

    A better understanding of how urbanization and trees interact to alter organic matter transport and cycling is needed to assess retention in catchments and streams, as well as to estimate the magnitude of carbon fluxes to the atmosphere and to downstream aquatic ecosystems. The influx of particulate and dissolved organic matter (POM/DOC) to headwater streams normally originates within or near riparian areas, and is important to aquatic food webs in stream ecosystems. Urban catchments, however, have huge effective drainage densities (due to storm drainage infrastructure), which facilitate a POM/DOC "gutter subsidy" to streams that dwarfs riparian inputs and alters benthic litter quality (and represents a major short-circuit in the carbon vegetation-soil cycle.) We measured in-situ leaf litter breakdown rates, flows, DOC, BOD and nutrients in forested, suburban and urban streams of the BES LTER and Baltimore City DPW sampling networks, which encompassed a variety of urban and rural landscapes. Sycamore and Planetree leaf litter in-situ experiments revealed faster breakdown rates for suburban and urban landscape litter than for riparian litter, with rates being much faster than literature values for forested catchments. DOC, BOD and nutrient data (storm and dry weather) from BES/DPW stream sites showed much higher concentrations and loads in the more urbanized catchments and indicate the streams are likely heterotrophic and experience transient but high dissolved oxygen demands. High nutrient concentrations, faster litter breakdown rates, and substantially higher upland urban fluxes of organic matter (particulate and dissolved) in urban streams suggest that export rates are likely substantially higher than in forested systems and that carbon loads to both downstream aquatic systems and to the atmosphere (as CO2) are substantial.

  12. Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

    Science.gov (United States)

    Erickson, Susan L.; Gandhi, Anjalika R.; Asafu-Adjei, Josephine K.; Sampson, Allan R.; Miner, LeeAnn; Blakely, Randy D.; Sesack, Susan R.

    2011-01-01

    Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabeling for NET and colocalization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 days, 15 mg/kg/day), NET-immunoreactive (-ir) axons were significantly less likely to colocalize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI and vehicle treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labeling. Our findings encourage consideration of possible postranslational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance. PMID:21208501

  13. Downregulation of hepatic and intestinal ATP-binding-cassette transporters abcg5 and abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

    NARCIS (Netherlands)

    Bloks, VW; Bakker-van Waarde, WW; Verkade, HJ; Kema, IP; Havinga, R; Wolters, H; Schaap, FG; Sauer, PJJ; Vink, E; Groen, AK; Kuipers, F

    ABSTRACT: P234 Downregulation of Hepatic and Intestinal ATP-Binding-Cassette Transporters Abcg5 and Abcg8 Expression Associated with Altered Sterol Fluxes in Rats with Streptozotocin-Induced Diabetes Vincent W. Bloks, Willie W. Bakker-van Waarde, Henkjan J. Verkade, Ido P. Kema, Rick Havinga, Henk

  14. Altered ion transport in normal human bronchial epithelial cells following exposure to chemically distinct metal welding fume particles.

    Science.gov (United States)

    Fedan, Jeffrey S; Thompson, Janet A; Meighan, Terence G; Zeidler-Erdely, Patti C; Antonini, James M

    2017-07-01

    Welding fume inhalation causes pulmonary toxicity, including susceptibility to infection. We hypothesized that airway epithelial ion transport is a target of fume toxicity, and investigated the effects of fume particulates from manual metal arc-stainless steel (MMA-SS) and gas metal arc-mild steel (GMA-MS) on ion transport in normal human bronchial epithelium (NHBE) cultured in air-interface. MMA-SS particles, more soluble than GMA-MS particles, contain Cr, Ni, Fe and Mn; GMA-MS particles contain Fe and Mn. MMA-SS or GMA-MS particles (0.0167-166.7μg/cm 2 ) were applied apically to NHBEs. After 18h transepithelial potential difference (V t ), resistance (R t ), and short circuit current (I sc ) were measured. Particle effects on Na + and Cl¯ channels and the Na + ,K + ,2Cl¯-cotransporter were evaluated using amiloride (apical), 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB, apical), and bumetanide (basolateral), respectively. MMA-SS (0.0167-16.7μg/cm 2 ) increased basal V t . Only 16.7μg/cm 2 GMA-MS increased basal V t significantly. MMA-SS or GMA-MS exposure potentiated I sc responses (decreases) to amiloride and bumetanide, while not affecting those to NPPB, GMA-MS to a lesser degree than MMA-SS. Variable effects on R t were observed in response to amiloride, and bumetanide. Generally, MMA-SS was more potent in altering responses to amiloride and bumetanide than GMA-MS. Hyperpolarization occurred in the absence of LDH release, but decreases in V t , R t , and I sc at higher fume particulate doses accompanied LDH release, to a greater extent for MMA-SS. Thus, Na + transport and Na + ,K + ,2Cl¯-cotransport are affected by fume exposure; MMA-MS is more potent than GMA-MS. Enhanced Na + absorption and decreased airway surface liquid could compromise defenses against infection. Published by Elsevier Inc.

  15. Altered ion transport in normal human bronchial epithelial cells following exposure to chemically distinct metal welding fume particles

    Energy Technology Data Exchange (ETDEWEB)

    Fedan, Jeffrey S., E-mail: jsf2@cdc.gov; Thompson, Janet A.; Meighan, Terence G.; Zeidler-Erdely, Patti C.; Antonini, James M.

    2017-07-01

    Welding fume inhalation causes pulmonary toxicity, including susceptibility to infection. We hypothesized that airway epithelial ion transport is a target of fume toxicity, and investigated the effects of fume particulates from manual metal arc-stainless steel (MMA-SS) and gas metal arc-mild steel (GMA-MS) on ion transport in normal human bronchial epithelium (NHBE) cultured in air-interface. MMA-SS particles, more soluble than GMA-MS particles, contain Cr, Ni, Fe and Mn; GMA-MS particles contain Fe and Mn. MMA-SS or GMA-MS particles (0.0167–166.7 μg/cm{sup 2}) were applied apically to NHBEs. After 18 h transepithelial potential difference (V{sub t}), resistance (R{sub t}), and short circuit current (I{sub sc}) were measured. Particle effects on Na{sup +} and Cl¯ channels and the Na{sup +},K{sup +},2Cl¯-cotransporter were evaluated using amiloride (apical), 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB, apical), and bumetanide (basolateral), respectively. MMA-SS (0.0167–16.7 μg/cm{sup 2}) increased basal V{sub t}. Only 16.7 μg/cm{sup 2} GMA-MS increased basal V{sub t} significantly. MMA-SS or GMA-MS exposure potentiated I{sub sc} responses (decreases) to amiloride and bumetanide, while not affecting those to NPPB, GMA-MS to a lesser degree than MMA-SS. Variable effects on R{sub t} were observed in response to amiloride, and bumetanide. Generally, MMA-SS was more potent in altering responses to amiloride and bumetanide than GMA-MS. Hyperpolarization occurred in the absence of LDH release, but decreases in V{sub t}, R{sub t}, and I{sub sc} at higher fume particulate doses accompanied LDH release, to a greater extent for MMA-SS. Thus, Na{sup +} transport and Na{sup +},K{sup +},2Cl¯-cotransport are affected by fume exposure; MMA-MS is more potent than GMA-MS. Enhanced Na{sup +} absorption and decreased airway surface liquid could compromise defenses against infection. - Highlights: • Welding fume particle toxicity was investigated in human bronchial

  16. Dietary fatty acids regulate hepatic low density lipoprotein (LDL) transport by altering LDL receptor protein and mRNA levels.

    Science.gov (United States)

    Horton, J D; Cuthbert, J A; Spady, D K

    1993-01-01

    The concentration of LDL in plasma is strongly influenced by the amount and the type of lipid in the diet. Recent studies in the hamster have shown that dietary fatty acids differentially affect circulating LDL levels primarily by altering receptor-dependent LDL uptake in the liver. To investigate the mechanistic basis of this effect, rates of receptor-dependent LDL transport in the liver were correlated with LDL receptor protein and mRNA levels in hamsters fed safflower oil or coconut oil and varying amounts of cholesterol. Hepatic LDL receptor activity was significantly lower in animals fed coconut oil than in animals fed safflower oil at all levels of cholesterol intake (26, 53, and 61% lower at cholesterol intakes of 0, 0.06, and 0.12%, respectively). These fatty acid-induced changes in hepatic LDL receptor activity were accompanied by parallel changes in hepatic LDL receptor protein and mRNA levels, suggesting that dietary fatty acids regulate the LDL receptor pathway largely at the mRNA level. Images PMID:8349814

  17. Colorectal visceral perception in diverticular disease

    NARCIS (Netherlands)

    Clemens, C. H. M.; Samsom, M.; Roelofs, J.; van Berge Henegouwen, G. P.; Smout, A. J. P. M.

    2004-01-01

    BACKGROUND AND AIMS: The pathogenesis of asymptomatic diverticular disease (ADD) and symptomatic uncomplicated diverticular disease (SUDD) has not been elucidated. The aim of our study was to assess whether altered visceral perception or abnormal compliance of the colorectal wall play a role in

  18. Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Østergaard, Mette; Christensen, Jane

    2009-01-01

    (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study. Results Carriers of the variant......Background The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived...... prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness. The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors...

  19. [Aspirin and colorectal cancer].

    Science.gov (United States)

    Grancher, Adrien; Michel, Pierre; Di Fiore, Frédéric; Sefrioui, David

    2018-02-01

    Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  20. Pathophysiological mechanisms of death resistance in colorectal carcinoma.

    Science.gov (United States)

    Huang, Ching-Ying; Yu, Linda Chia-Hui

    2015-11-07

    Colon cancers develop adaptive mechanisms to survive under extreme conditions and display hallmarks of unlimited proliferation and resistance to cell death. The deregulation of cell death is a key factor that contributes to chemoresistance in tumors. In a physiological context, balance between cell proliferation and death, and protection against cell damage are fundamental processes for maintaining gut epithelial homeostasis. The mechanisms underlying anti-death cytoprotection and tumor resistance often bear common pathways, and although distinguishing them would be a challenge, it would also provide an opportunity to develop advanced anti-cancer therapeutics. This review will outline cell death pathways (i.e., apoptosis, necrosis, and necroptosis), and discuss cytoprotective strategies in normal intestinal epithelium and death resistance mechanisms of colon tumor. In colorectal cancers, the intracellular mechanisms of death resistance include the direct alteration of apoptotic and necroptotic machinery and the upstream events modulating death effectors such as tumor suppressor gene inactivation and pro-survival signaling pathways. The autocrine, paracrine and exogenous factors within a tumor microenvironment can also instigate resistance against apoptotic and necroptotic cell death in colon cancers through changes in receptor signaling or transporter uptake. The roles of cyclooxygenase-2/prostaglandin E2, growth factors, glucose, and bacterial lipopolysaccharides in colorectal cancer will be highlighted. Targeting anti-death pathways in the colon cancer tissue might be a promising approach outside of anti-proliferation and anti-angiogenesis strategies for developing novel drugs to treat refractory tumors.

  1. Colorectal Cancer: A Personal Journey

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Colorectal Cancer Colorectal Cancer: A Personal Journey Past Issues / Summer 2016 Table ... Carmen Marc Valvo is an outspoken voice for colorectal cancer screening. Photo Courtesy of: Phil Fisch Photography Designer ...

  2. Linking Gut Microbiota to Colorectal Cancer

    DEFF Research Database (Denmark)

    Raskov, Hans; Burcharth, Jakob; Pommergaard, Hans-Christian

    2017-01-01

    Pre-clinical and clinical data produce mounting evidence that the microbiota is strongly associated with colorectal carcinogenesis. Dysbiosis may change the course of carcinogenesis as microbial actions seem to impact genetic and epigenetic alterations leading to dysplasia, clonal expansion...... and malignant transformation. Initiation and promotion of colorectal cancer may result from direct bacterial actions, bacterial metabolites and inflammatory pathways. Newer aspects of microbiota and colorectal cancer include quorum sensing, biofilm formation, sidedness and effects/countereffects of microbiota...... and probiotics on chemotherapy. In the future, targeting the microbiota will probably be a powerful weapon in the battle against CRC as gut microbiology, genomics and metabolomics promise to uncover important linkages between microbiota and intestinal health....

  3. Metachronous colorectal carcinoma

    DEFF Research Database (Denmark)

    Bülow, Steffen; Svendsen, L B; Mellemgaard, A

    1990-01-01

    During the period 1943-67, 903 Danish patients aged less than 40 years had colorectal carcinoma. The patients were followed up for up to 41 years and during this period 44 of 501 (9 per cent) operated on for cure developed a metachronous colorectal carcinoma. The cumulative risk of a metachronous...... colorectal carcinoma was 30 per cent after up to 41 years of observation. The occurrence of a metachronous colorectal carcinoma was evenly distributed in the observation period. The cumulative survival rate after operation for a metachronous colorectal carcinoma was 41 per cent after 20 years of observation....... We propose a lifelong follow-up programme after resection of colorectal carcinoma for cure in this age group, including annual Hemoccult test and colonoscopy at 3-year intervals....

  4. Schisandra chinensis peptidoglycan-assisted transmembrane transport of lignans uniquely altered the pharmacokinetic and pharmacodynamic mechanisms in human HepG2 cell model.

    Directory of Open Access Journals (Sweden)

    Charng-Cherng Chyau

    Full Text Available Schisandra chinensis (Turz Baill (S. chinensis (SC fruit is a hepatoprotective herb containing many lignans and a large amount of polysaccharides. A novel polysaccharide (called SC-2 was isolated from SC of MW 841 kDa, which exhibited a protein-to-polysaccharide ratio of 0.4089, and showed a characteristic FTIR spectrum of a peptidoglycan. Powder X-ray diffraction revealed microcrystalline structures within SC-2. SC-2 contained 10 monosaccharides and 15 amino acids (essential amino acids of 78.12%w/w. In a HepG2 cell model, SC-2 was shown by MTT and TUNEL assay to be completely non-cytotoxic. A kinetic analysis and fluorescence-labeling technique revealed no intracellular disposition of SC-2. Combined treatment of lignans with SC-2 enhanced the intracellular transport of schisandrin B and deoxyschisandrin but decreased that of gomisin C, resulting in alteration of cell-killing bioactivity. The Second Law of Thermodynamics allows this type of unidirectional transport. Conclusively, SC-2 alters the transport and cell killing capability by a "Catcher-Pitcher Unidirectional Transport Mechanism".

  5. Point mutations in a nucleoside transporter gene from Leishmania donovani confer drug resistance and alter substrate selectivity

    OpenAIRE

    Vasudevan, Gayatri; Ullman, Buddy; Landfear, Scott M.

    2001-01-01

    Leishmania parasites lack a purine biosynthetic pathway and depend on surface nucleoside and nucleobase transporters to provide them with host purines. Leishmania donovani possess two closely related genes that encode high affinity adenosine-pyrimidine nucleoside transporters LdNT1.1 and LdNT1.2 and that transport the toxic adenosine analog tubercidin in addition to the natural substrates. In this study, we have characterized a drug-resistant clonal mutant of L. do...

  6. Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD: an in vitro study

    Directory of Open Access Journals (Sweden)

    Vumma Ravi

    2011-09-01

    Full Text Available Abstract Background The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD. The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport. Methods Fibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (Vmax and affinity constant (Km were determined. Any difference between the two groups was analyzed by Student's unpaired t-test or the Mann Whitney U test. Results The ADHD group had significantly decreased Vmax (p = 0.039 and Km (increased affinity (p = 0.010 of tryptophan transport in comparison to controls. They also had a significantly higher Vmaxof alanine transport (p = 0.031, but the Km of alanine transport did not differ significantly. There were no significant differences in any of the kinetic parameters regarding tyrosine transport in fibroblasts for the ADHD group. Conclusions Tryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB. Hence, a decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group. This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic

  7. Radioimmunoguided surgery using the monoclonal antibody B72.3 in colorectal tumors

    International Nuclear Information System (INIS)

    Sickle-Santanello, B.J.; O'Dwyer, P.J.; Mojzisik, C.

    1987-01-01

    The authors have developed a hand-held gamma-detecting probe (GDP) for intraoperative use that improves the sensitivity of external radioimmunodetection. Radiolabeled monoclonal antibody (MAb) B72.3 was injected in six patients with primary colorectal cancer and 31 patients with recurrent colorectal cancer an average of 16 days preoperatively. The GDP localized the MAb B72.3 in 83 percent of sites. The technique, known as a radioimmunoguided surgery (RIGS) system did not alter the surgical procedure in patients with primary colorectal cancer but did alter the approach in 26 percent (8/31) of patients with recurrent colorectal cancer. Two patients avoided unnecessary liver resections and two underwent extraabdominal approaches to document their disease. The RIGS system may influence the short-term morbidity and mortality of surgery for colorectal cancer. Larger series and longer follow-up are needed to determine whether the RIGS system confers a survival advantage to the patient with colorectal cancer

  8. Synchronous colorectal liver metastases

    NARCIS (Netherlands)

    A.E.M. van der Pool (Anne)

    2011-01-01

    textabstractColorectal cancer is one of the most common malignancies worldwide and ranks second in cancer-related deaths in many parts of the Western world. Once in the lymph or blood vessels, colorectal cancer can quickly spread and the liver is known to be a favourable site for metastases. The

  9. Reactive transport and mass balance modeling of the Stimson sedimentary formation and altered fracture zones constrain diagenetic conditions at Gale crater, Mars

    Science.gov (United States)

    Hausrath, E. M.; Ming, D. W.; Peretyazhko, T. S.; Rampe, E. B.

    2018-06-01

    On a planet as cold and dry as present-day Mars, evidence of multiple aqueous episodes offers an intriguing view into very different past environments. Fluvial, lacustrine, and eolian depositional environments are being investigated by the Mars Science Laboratory Curiosity in Gale crater, Mars. Geochemical and mineralogical observations of these sedimentary rocks suggest diagenetic processes affected the sediments. Here, we analyze diagenesis of the Stimson formation eolian parent material, which caused loss of olivine and formation of magnetite. Additional, later alteration in fracture zones resulted in preferential dissolution of pyroxene and precipitation of secondary amorphous silica and Ca sulfate. The ability to compare the unaltered parent material with the reacted material allows constraints to be placed on the characteristics of the altering solutions. In this work we use a combination of a mass balance approach calculating the fraction of a mobile element lost or gained, τ, with fundamental geochemical kinetics and thermodynamics in the reactive transport code CrunchFlow to examine the characteristics of multiple stages of aqueous alteration at Gale crater, Mars. Our model results indicate that early diagenesis of the Stimson sedimentary formation is consistent with leaching of an eolian deposit by a near-neutral solution, and that formation of the altered fracture zones is consistent with a very acidic, high sulfate solution containing Ca, P and Si. These results indicate a range of past aqueous conditions occurring at Gale crater, Mars, with important implications for past martian climate and environments.

  10. Temporal alteration of spreading depression by the glycine transporter type-1 inhibitors NFPS and Org-24461 in chicken retina.

    Science.gov (United States)

    Kertesz, Szabolcs; Szabo, Geza; Udvari, Szabolcs; Levay, Gyorgy; Matyus, Peter; Harsing, Laszlo G

    2013-01-25

    We used isolated chicken retina to induce spreading depression by the glutamate receptor agonist N-methyl-d-aspartate. The N-methyl-d-aspartate-induced latency time of spreading depression was extended by the glycine(B) binding site competitive antagonist 7-chlorokynurenic acid. Addition of the glycine transporter type-1 inhibitors NFPS and Org-24461 reversed the inhibitory effect of 7-chlorokynurenic acid on N-methyl-d-aspartate-evoked spreading depression. The glycine uptake inhibitory activity of Org-24461, NFPS, and some newly synthesized analogs of NFPS was determined in CHO cells stably expressing human glycine transporter type-1b isoform. Compounds, which failed to inhibit glycine transporter type-1, also did not have effect on retinal spreading depression. These experiments indicate that the spreading depression model in chicken retina is a useful in vitro test to determine activity of glycine transporter type-1 inhibitors. In addition, our data serve further evidence for the role of glycine transporter type-1 in retinal neurotransmission and light processing. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Genomics of Colorectal Cancer in African Americans

    OpenAIRE

    Brim, Hassan; Ashktorab, Hassan

    2016-01-01

    Genome-wide studies are increasingly becoming a must, especially for complex diseases such as cancer where multiple genes and diverse molecular mechanisms are known to be involved in genes’ function alteration. In this review, we report our latest genomic and epigenomic findings in African-American colorectal cancer patients. This population suffers a higher burden of the disease and most investigators in this field are looking for the underlying genetic and epigenetic targets that might be r...

  12. Transportation

    National Research Council Canada - National Science Library

    Adams, James; Carr, Ron; Chebl, Maroun; Coleman, Robert; Costantini, William; Cox, Robert; Dial, William; Jenkins, Robert; McGovern, James; Mueller, Peter

    2006-01-01

    ...., trains, ships, etc.) and maximizing intermodal efficiency. A healthy balance must be achieved between the flow of international commerce and security requirements regardless of transportation mode...

  13. Altered biodistribution of gallium-67 in a patient with multiple factors influencing iron-transport protein saturation

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jeon Young; Kim, Sang Eun; Lee, Kyung Han; Kim, Byung Tae [College of Medicine, Samsung Medical Center, Seoul (Korea, Republic of)

    1998-01-01

    We present a case of a young female patient with fulminant hepatitis who showed an altered biodistribution of Ga-67, after being scanned twice at 10 month intervals. On initial scan, uptake of Ga-67 was increased in the liver, kidneys, and skeletons. Increased hepatic Ga-67 uptake may be explained by increased transferrin unbound Ga-67 that was taken up by the inflamed liver. The saturation of iron-binding proteins due to multiple transfusions may lead to increased renal and skeletal Ga-67 uptake. On follow-up scan hepatic Ga-67 uptake was markedly increased. Also increased Ga-67 uptake in the axial skeleton and normalized renal uptake were shown. The findings were consistent with iron deficiency anemia. This case demonstrates altered Ga-67 biodistribution associated with multiple transfusions, fulminant hepatitis, and iron deficiency anemia.

  14. The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells

    DEFF Research Database (Denmark)

    Cuesta, Elena Pedraz; Christensen, Sandra; Jensen, Anders A.

    2015-01-01

    affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability...... was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-β-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [(3)H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration...... and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments CRC cell death induced by SN38, while attenuating that induced by oxaliplatin. These findings may point...

  15. Altered expression and modulation of activity-regulated cytoskeletal associated protein (Arc) in serotonin transporter knockout rats.

    NARCIS (Netherlands)

    Molteni, R.; Calabrese, F.; Maj, P.F.; Olivier, J.D.A.; Racagni, G.; Ellenbroek, A.A.; Riva, M.A.

    2009-01-01

    A gene variant in the human serotonin transporter (SERT) can increase the vulnerability to mood disorders. SERT knockout animals show similarities to the human condition and represent an important tool to investigate the mechanisms underlying the pathologic condition in humans. Along this line of

  16. Inactivation of the Ecs ABC Transporter of Staphylococcus aureus Attenuates Virulence by Altering Composition and Function of Bacterial Wall

    NARCIS (Netherlands)

    Jonsson, Ing-Marie; Juuti, Jarmo T.; Francois, Patrice; AlMajidi, Rana; Pietiainen, Milla; Girard, Myriam; Lindholm, Catharina; Saller, Manfred J.; Driessen, Arnold J. M.; Kuusela, Pentti; Bokarewa, Maria; Schrenzel, Jacques; Kontinen, Vesa P.

    2010-01-01

    Background: Ecs is an ATP-binding cassette (ABC) transporter present in aerobic and facultative anaerobic Gram-positive Firmicutes. Inactivation of Bacillus subtilis Ecs causes pleiotropic changes in the bacterial phenotype including inhibition of intramembrane proteolysis. The molecule(s)

  17. Transportation

    International Nuclear Information System (INIS)

    Anon.

    1998-01-01

    Here is the decree of the thirtieth of July 1998 relative to road transportation, to trade and brokerage of wastes. It requires to firms which carry out a road transportation as well as to traders and to brokers of wastes to declare their operations to the prefect. The declaration has to be renewed every five years. (O.M.)

  18. Subsurface Transport Over Reactive Multiphases (STORM): A Parallel, Coupled, Nonisothermal Multiphase Flow, Reactive Transport, and Porous Medium Alteration Simulator, Version 3.0

    International Nuclear Information System (INIS)

    Bacon, Diana H.; White, Mark D.; McGrail, B PETER

    2004-01-01

    The U.S. Department of Energy must approve a performance assessment (PA) to support the design, construction, approval, and closure of disposal facilities for immobilized low-activity waste (ILAW) currently stored in underground tanks at Hanford, Washington. A critical component of the PA is to provide quantitative estimates of radionuclide release rates from the engineered portion of the disposal facilities. Computer simulations are essential for this purpose because impacts on groundwater resources must be projected to periods of 10,000 years and longer. The computer code selected for simulating the radionuclide release rates is the Subsurface Transport Over Reactive Multiphases (STORM) simulator. The STORM simulator solves coupled conservation equations for component mass and energy that describe subsurface flow over aqueous and gas phases through variably saturated geologic media. The resulting flow fields are used to sequentially solve conservation equations for reactive aqueous phase transport through variably saturated geologic media. These conservation equations for component mass, energy, and solute mass are partial differential equations that mathematically describe flow and transport through porous media. The STORM simulator solves the governing-conservation equations and constitutive functions using numerical techniques for nonlinear systems. The partial differential equations governing thermal and fluid flow processes are solved by the integral volume finite difference method. These governing equations are solved simultaneously using Newton-Raphson iteration. The partial differential equations governing reactive solute transport are solved using either an operator split technique where geochemical reactions and solute transport are solved separately, or a fully coupled technique where these equations are solved simultaneously. The STORM simulator is written in the FORTRAN 77 language, following American National Standards Institute (ANSI) standards

  19. Detection of colorectal neoplasia

    DEFF Research Database (Denmark)

    Wilhelmsen, Michael; Christensen, Ib J; Rasmussen, Louise

    2017-01-01

    Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA...... value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC....

  20. Screening for colorectal cancer

    DEFF Research Database (Denmark)

    Nielsen, Hans J.; Jakobsen, Karen V.; Christensen, Ib J.

    2011-01-01

    Emerging results indicate that screening improves survival of patients with colorectal cancer. Therefore, screening programs are already implemented or are being considered for implementation in Asia, Europe and North America. At present, a great variety of screening methods are available including...... into improvements of screening for colorectal cancer includes blood-based biological markers, such as proteins, DNA and RNA in combination with various demographically and clinically parameters into a "risk assessment evaluation" (RAE) test. It is assumed that such a test may lead to higher acceptance among...... procedures for colorectal cancer. Therefore, results of present research, validating RAE tests, are awaited with interest....

  1. Acute exposure to space flight results in evidence of reduced lymph Transport, tissue fluid Shifts, and immune alterations in the rat gastrointestinal system

    Science.gov (United States)

    Cromer, W. E.; Zawieja, D. C.

    2018-05-01

    Space flight causes a number of alterations in physiological systems, changes in the immunological status of subjects, and altered interactions of the host to environmental stimuli. We studied the effect of space flight on the lymphatic system of the gastrointestinal tract which is responsible for lipid transport and immune surveillance which includes the host interaction with the gut microbiome. We found that there were signs of tissue damage present in the space flown animals that was lacking in ground controls (epithelial damage, crypt morphological changes, etc.). Additionally, morphology of the lymphatic vessels in the tissue suggested a collapsed state at time of harvest and there was a profound change in the retention of lipid in the villi of the ileum. Contrary to our assumptions there was a reduction in tissue fluid volume likely associated with other fluid shifts described. The reduction of tissue fluid volume in the colon and ileum is a likely contributing factor to the state of the lymphatic vessels and lipid transport issues observed. There were also associated changes in the number of MHC-II+ immune cells in the colon tissue, which along with reduced lymphatic competence would favor immune dysfunction in the tissue. These findings help expand our understanding of the effects of space flight on various organ systems. It also points out potential issues that have not been closely examined and have to potential for the need of countermeasure development.

  2. The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters

    Science.gov (United States)

    Li, Xiaofeng; Yu, Xiaozhou; Dai, Dong; Song, Xiuyu; Xu, Wengui

    2016-01-01

    Extracellular matrix metalloproteinase inducer, also knowns as cluster of differentiation 147 (CD147) or basigin, is a widely distributed cell surface glycoprotein that is involved in numerous physiological and pathological functions, especially in tumor invasion and metastasis. Monocarboxylate transporters (MCTs) catalyze the proton-linked transport of monocarboxylates such as L-lactate across the plasma membrane to preserve the intracellular pH and maintain cell homeostasis. As a chaperone to some MCT isoforms, CD147 overexpression significantly contributes to the metabolic transformation of tumor. This overexpression is characterized by accelerated aerobic glycolysis and lactate efflux, and it eventually provides the tumor cells with a metabolic advantage and an invasive phenotype in the acidic tumor microenvironment. This review highlights the roles of CD147 and MCTs in tumor cell metabolism and the associated molecular mechanisms. The regulation of CD147 and MCTs may prove to be with a therapeutic potential for tumors through the metabolic modification of the tumor microenvironment. PMID:27009812

  3. Oral peptide specific egg antibody to intestinal sodium-dependent phosphate co-transporter-2b is effective at altering phosphate transport in vitro and in vivo.

    Science.gov (United States)

    Bobeck, Elizabeth A; Hellestad, Erica M; Sand, Jordan M; Piccione, Michelle L; Bishop, Jeff W; Helvig, Christian; Petkovich, Martin; Cook, Mark E

    2015-06-01

    Hyperimmunized hens are an effective means of generating large quantities of antigen specific egg antibodies that have use as oral supplements. In this study, we attempted to create a peptide specific antibody that produced outcomes similar to those of the human pharmaceutical, sevelamer HCl, used in the treatment of hyperphosphatemia (a sequela of chronic renal disease). Egg antibodies were generated against 8 different human intestinal sodium-dependent phosphate cotransporter 2b (NaPi2b) peptides, and hNaPi2b peptide egg antibodies were screened for their ability to inhibit phosphate transport in human intestinal Caco-2 cell line. Antibody produced against human peptide sequence TSPSLCWT (anti-h16) was specific for its peptide sequence, and significantly reduced phosphate transport in human Caco-2 cells to 25.3±11.5% of control nonspecific antibody, when compared to nicotinamide, a known inhibitor of phosphate transport (P≤0.05). Antibody was then produced against the mouse-specific peptide h16 counterpart (mouse sequence TSPSYCWT, anti-m16) for further analysis in a murine model. When anti-m16 was fed to mice (1% of diet as dried egg yolk powder), egg yolk immunoglobulin (IgY) was detected using immunohistochemical staining in mouse ileum, and egg anti-m16 IgY colocalized with a commercial goat anti-NaPi2b antibody. The effectiveness of anti-m16 egg antibody in reducing serum phosphate, when compared to sevelamer HCl, was determined in a mouse feeding study. Serum phosphate was reduced 18% (Pegg yolk powder) and 30% (Pegg immunoglobulin. The methods described and the findings reported show that oral egg antibodies are useful and easy to prepare reagents for the study and possible treatment of select diseases. © 2015 Poultry Science Association Inc.

  4. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport

    International Nuclear Information System (INIS)

    Rebouche, C.J.; Engel, A.G.

    1984-01-01

    The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and ''other tissues'') was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract

  5. Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ying [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Department of Pathology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang 050200, Hebei (China); Zhao, Xin [Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei (China); Chang, Yanzhong [Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei (China); Zhang, Yuanyuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Xi [Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei (China); Zhang, Xuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Liu, Zhenyi; Guo, Hui [Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Wang, Na [Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Gao, Yonggang [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Zhang, Jianping, E-mail: zhangjianping14@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Li, E-mail: chuli0614@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei (China)

    2016-06-15

    Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n = 8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. - Highlights: • Calcium channel blockers (CCBs) reduced hepatic iron content. • CCBs decreased hepatic fibrotic areas and collagen expression levels. • CCBs resolve fibrosis by regulating iron transport and

  6. Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment.

    Directory of Open Access Journals (Sweden)

    Lucio A Ramos-Chávez

    2015-02-01

    Full Text Available Inorganic arsenic (iAs is an important natural pollutant. Millions of individuals worldwide drink water with high levels of iAs. Chronic exposure to iAs has been associated with lower IQ and learning disabilities as well as memory impairment. iAs is methylated in tissues such as the brain generating mono and dimethylated species. iAs methylation requires cellular glutathione (GSH, which is the main antioxidant in the central nervous system. In humans, As species cross the placenta and are found in cord blood. A CD1 mouse model was used to investigate effects of gestational iAs exposure which can lead to oxidative damage, disrupted cysteine/glutamate transport and its putative impact in learning and memory. On postnatal days (PNDs 1, 15 and 90, the expression of membrane transporters related to GSH synthesis and glutamate transport and toxicity, such as xCT, EAAC1, GLAST and GLT1, as well as LAT1, were analyzed. Also, the expression of the glutamate receptor N-methyl-D-aspartate (NMDAR subunits NR2A and B as well as the presence of As species in cortex and hippocampus were investigated. On PND 90, an object location task was performed to associate exposure with memory impairment. Gestational exposure to iAs affected the expression of cysteine/glutamate transporters in cortex and hippocampus and induced a negative modulation of NMDAR NR2B subunit in the hippocampus. Behavioral tasks showed significant spatial memory impairment in males while the effect was marginal in females.

  7. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport.

    OpenAIRE

    Rebouche, C J; Engel, A G

    1984-01-01

    The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine wa...

  8. Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans.

    Science.gov (United States)

    Heni, Martin; Schöpfer, Patricia; Peter, Andreas; Sartorius, Tina; Fritsche, Andreas; Synofzik, Matthis; Häring, Hans-Ulrich; Maetzler, Walter; Hennige, Anita M

    2014-08-01

    Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.

  9. Association between Fusobacterium nucleatum and colorectal cancer: Progress and future directions

    Science.gov (United States)

    Zhang, Sheng; Cai, Sanjun; Ma, Yanlei

    2018-01-01

    The initiation and progression of colorectal cancer (CRC) involves genetic and epigenetic alterations influenced by dietary and environmental factors. Increasing evidence has linked the intestinal microbiota and colorectal cancer. More recently, Fusobacterium nucleatum (Fn), an opportunistic commensal anaerobe in the oral cavity, has been associated with CRC. Several research teams have reported an overabundance of Fn in human CRC and have elucidated the possible mechanisms by which Fn is involved in colorectal carcinogenesis in vitro and in mouse models. However, the mechanisms by which Fn promotes colorectal carcinogenesis remain unclear. To provide new perspectives for early diagnosis, the identification of high risk populations and treatment for colorectal cancer, this review will summarize the relative research progresses regarding the relationship between Fn and colorectal cancer. PMID:29760804

  10. Altered Transport and Metabolism of Phenolic Compounds in Obesity and Diabetes: Implications for Functional Food Development and Assessment12

    Science.gov (United States)

    Redan, Benjamin W; Buhman, Kimberly K; Novotny, Janet A; Ferruzzi, Mario G

    2016-01-01

    Interest in the application of phenolic compounds from the diet or supplements for the prevention of chronic diseases has grown substantially, but the efficacy of such approaches in humans is largely dependent on the bioavailability and metabolism of these compounds. Although food and dietary factors have been the focus of intense investigation, the impact of disease states such as obesity or diabetes on their absorption, metabolism, and eventual efficacy is important to consider. These factors must be understood in order to develop effective strategies that leverage bioactive phenolic compounds for the prevention of chronic disease. The goal of this review is to discuss the inducible metabolic systems that may be influenced by disease states and how these effects impact the bioavailability and metabolism of dietary phenolic compounds. Because current studies generally report that obesity and/or diabetes alter the absorption and excretion of these compounds, this review includes a description of the absorption, conjugation, and excretion pathways for phenolic compounds and how they are potentially altered in disease states. A possible mechanism that will be discussed related to the modulation of phenolic bioavailability and metabolism may be linked to increased inflammatory status from increased amounts of adipose tissue or elevated plasma glucose concentrations. Although more studies are needed, the translation of benefits derived from dietary phenolic compounds to individuals with obesity or diabetes may require the consideration of dosing strategies or be accompanied by adjunct therapies to improve the bioavailability of these compounds. PMID:28140326

  11. Transportation

    National Research Council Canada - National Science Library

    Allshouse, Michael; Armstrong, Frederick Henry; Burns, Stephen; Courts, Michael; Denn, Douglas; Fortunato, Paul; Gettings, Daniel; Hansen, David; Hoffman, D. W; Jones, Robert

    2007-01-01

    .... The ability of the global transportation industry to rapidly move passengers and products from one corner of the globe to another continues to amaze even those wise to the dynamics of such operations...

  12. Hereditary colorectal cancer diagnostics

    DEFF Research Database (Denmark)

    Klarskov, Louise; Holck, Susanne; Bernstein, Inge

    2012-01-01

    BackgroundThe hereditary non-polyposis colorectal cancer (HNPCC) subset of tumours can broadly be divided into tumours caused by an underlying mismatch-repair gene mutation, referred to as Lynch syndrome, and those that develop in families with similar patterns of heredity but without disease......-predisposing germline mismatch repair mutations, referred to as familial colorectal cancer type X (FCCTX). Recognition of HNPCC-associated colorectal cancers is central since surveillance programmes effectively reduce morbidity and mortality. The characteristic morphological features linked to Lynch syndrome can aid...... in the identification of this subset, whereas the possibility to use morphological features as an indicator of FCCTX is uncertain.Objective and methodsTo perform a detailed morphological evaluation of HNPCC-associated colorectal cancers and demonstrate significant differences between tumours associated with FCCTX...

  13. Gallstones and colorectal cancer

    DEFF Research Database (Denmark)

    Jørgensen, Torben; Rafaelsen, Søren Rafael

    1992-01-01

    The prevalence of gallstone disease in 145 consecutive patients with colorectal cancer was compared with gallstone prevalence in 4,159 subjects randomly selected from a population. The group of patients had a significantly higher prevalence of gallstone disease than the population (odds ratio = 1...... substantial evidence for an association between gallstones and colorectal cancer, an association which is not due to cholecystectomy being a predisposing factor to colorectal cancer. Sporadic findings of an association between cholecystectomy and colorectal cancer can be explained by the above relationship........59; 95 percent confidence limits 1.04-2.45), whereas cholecystectomies occurred with equal frequency in the two groups. There was a nonsignificant trend toward more right-sided cancers in patients with gallstones than in patients without. These results, together with available literature, give...

  14. Prophylaxis against colorectal cancer

    DEFF Research Database (Denmark)

    Bülow, Steffen; Kronborg, O

    1996-01-01

    Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing...... with a well-established register of familial adenomatous polyposis and a recently founded register for hereditary nonpolyposis colorectal cancer, both with major international relationships. The Danish tradition of epidemiology and clinical trials has also been demonstrated in population screening trials...... for colorectal cancer in average-risk persons as well as high-risk groups with precursors of the disease. The present review places Danish contributions within the prophylaxis of colorectal cancer during the last decade in an international context....

  15. Colorectal cancer screening

    OpenAIRE

    Plumb, A. A.; Halligan, S.

    2015-01-01

    Colorectal cancer is a major public health burden worldwide. There is clear-cut evidence that screening will reduce colorectal cancer mortality and the only contentious issue is which screening tool to use. Most evidence points towards screening with fecal occult blood testing. The immunochemical fecal occult blood tests have a higher sensitivity than the guaiac-based tests. In addition, their automation and haemoglobin quantification allows a threshold for colonoscopy to be selected that can...

  16. Screening for colorectal cancer.

    Science.gov (United States)

    He, Jin; Efron, Jonathan E

    2011-01-01

    March is national colorectal cancer awareness month. It is estimated that as many as 60% of colorectal cancer deaths could be prevented if all men and women aged 50 years or older were screened routinely. In 2000, Katie Couric's televised colonoscopy led to a 20% increase in screening colonoscopies across America, a stunning rise called the "Katie Couric Effect". This event demonstrated how celebrity endorsement affects health behavior. Currently, discussion is ongoing about the optimal strategy for CRC screening, particularly the costs of screening colonoscopy. The current CRC screening guidelines are summarized in Table 2. Debates over the optimum CRC screening test continue in the face of evidence that 22 million Americans aged 50 to 75 years are not screened for CRC by any modality and 25,000 of those lives may have been saved if they had been screened for CRC. It is clear that improving screening rates and reducing disparities in underscreened communities and population subgroups could further reduce colorectal cancer morbidity and mortality. National Institutes of Health consensus identified the following priority areas to enhance the use and quality of colorectal cancer screening: Eliminate financial barriers to colorectal cancer screening and appropriate follow-up of positive results of colorectal cancer screening. Develop systems to ensure the high quality of colorectal cancer screening programs. Conduct studies to determine the comparative effectiveness of the various colorectal cancer screening methods in usual practice settings. Encouraging population adherence to screening tests and allowing patients to select the tests they prefer may do more good (as long as they choose something) than whatever procedure is chosen by the medical profession as the preferred test.

  17. The impact of ornithogenic inputs on phosphorous transport from altered wetland soils to waterways in East Mediterranean ecosystem.

    Science.gov (United States)

    Litaor, M Iggy; Reichmann, O; Dente, E; Naftaly, A; Shenker, M

    2014-03-01

    Large flocks of Eurasian crane (Grus grus, >35,000) have begun wintering in an altered wetland agro-ecosystem located in Northern Israel, a phenomenon that attracts more than 400,000 eco-tourists a year. A 100-ha plot has been used to feed the cranes in order to protect nearby fields. The objective of this study was to evaluate the influence of this bird's feeding practice on the P status of the altered wetland soils and waterways. We installed a series of wells at two depths (40 and 90 cm) between two major waterways in the feeding area and monitored the hydraulic heads and collected groundwater samples for elemental analyses. We collected six soil cores and four sediment samples from the waterways and conducted sequential P extraction. We found significant increase in groundwater soluble reactive P (SRP) (>0.5 mg l(-1)) compared with much lower concentrations (~0.06 mg l(-1)) collected in the period prior to the feeding. We found significant decrease in Fe((II)), Ca, and SO4 concentrations in the shallow groundwater (33, 208, and 213 mg l(-1), respectively) compared with the period prior to the feeding (47, 460, and 370 mg l(-1) respectively). An increase in the more labile P fraction was observed in soils and sediments compared with the period before the feeding. The P input by bird excrement to the feeding area was estimated around 700 kg P per season, while P removal by plant harvesting was estimated around 640 kg Pyr(-1). This finding supports the current eco-tourism practices in the middle of intensive farming area, suggesting little impact on waterways. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Perinatal Na+ Overload Programs Raised Renal Proximal Na+ Transport and Enalapril-Sensitive Alterations of Ang II Signaling Pathways during Adulthood

    Science.gov (United States)

    Cabral, Edjair V.; Vieira-Filho, Leucio D.; Silva, Paulo A.; Nascimento, Williams S.; Aires, Regina S.; Oliveira, Fabiana S. T.; Luzardo, Ricardo; Vieyra, Adalberto; Paixão, Ana D. O.

    2012-01-01

    Background High Na+ intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na+ overload-programmed alterations in Na+ transporters and the renin/angiotensin system (RAS) were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney. Methodology/Principal Findings Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control) or 0.17 M NaCl (saline group). Enalapril (100 mg/l), an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na++K+)ATPase expression and activity. Ouabain-insensitive Na+-ATPase activity remained unchanged but its response to angiotensin II (Ang II) was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS), macrophage infiltration and collagen deposition markedly increased, and AT2 receptor expression decreased while AT1 expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na++K+)ATPase, partially recovered the response of Na+-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na+ or not. In addition, treatment with enalapril per se reduced AT2 receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na+-overloaded offspring presented high numbers of Ang II-positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS. Conclusions/Significance Maternal Na+ overload programmed alterations in renal Na+ transporters and in its regulation, as well as severe structural lesions in adult offspring. Enalapril

  19. 6 Common Cancers - Colorectal Cancer

    Science.gov (United States)

    ... Home Current Issue Past Issues 6 Common Cancers - Colorectal Cancer Past Issues / Spring 2007 Table of Contents For ... of colon cancer. Photo: AP Photo/Ron Edmonds Colorectal Cancer Cancer of the colon (large intestine) or rectum ( ...

  20. Colorectal Cancer Risk Assessment Tool

    Science.gov (United States)

    ... 11/12/2014 Risk Calculator About the Tool Colorectal Cancer Risk Factors Download SAS and Gauss Code Page ... Rectal Cancer: Prevention, Genetics, Causes Tests to Detect Colorectal Cancer and Polyps Cancer Risk Prediction Resources Update November ...

  1. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells

    International Nuclear Information System (INIS)

    Kalayda, Ganna V; Wagner, Christina H; Buß, Irina; Reedijk, Jan; Jaehde, Ulrich

    2008-01-01

    Copper homeostasis proteins ATP7A and ATP7B are assumed to be involved in the intracellular transport of cisplatin. The aim of the present study was to assess the relevance of sub cellular localisation of these transporters for acquired cisplatin resistance in vitro. For this purpose, localisation of ATP7A and ATP7B in A2780 human ovarian carcinoma cells and their cisplatin-resistant variant, A2780cis, was investigated. Sub cellular localisation of ATP7A and ATP7B in sensitive and resistant cells was investigated using confocal fluorescence microscopy after immunohistochemical staining. Co-localisation experiments with a cisplatin analogue modified with a carboxyfluorescein-diacetate residue were performed. Cytotoxicity of the fluorescent cisplatin analogue in A2780 and A2780cis cells was determined using an MTT-based assay. The significance of differences was analysed using Student's t test or Mann-Whitney test as appropriate, p values of < 0.05 were considered significant. In the sensitive cells, both transporters are mainly localised in the trans-Golgi network, whereas they are sequestrated in more peripherally located vesicles in the resistant cells. Altered localisation of ATP7A and ATP7B in A2780cis cells is likely to be a consequence of major abnormalities in intracellular protein trafficking related to a reduced lysosomal compartment in this cell line. Changes in sub cellular localisation of ATP7A and ATP7B may facilitate sequestration of cisplatin in the vesicular structures of A2780cis cells, which may prevent drug binding to genomic DNA and thereby contribute to cisplatin resistance. Our results indicate that alterations in sub cellular localisation of transport proteins may contribute to cisplatin resistance in vitro. Investigation of intracellular protein localisation in primary tumour cell cultures and tumour tissues may help to develop markers of clinically relevant cisplatin resistance. Detection of resistant tumours in patients may in turn

  2. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells

    Directory of Open Access Journals (Sweden)

    Reedijk Jan

    2008-06-01

    Full Text Available Abstract Background Copper homeostasis proteins ATP7A and ATP7B are assumed to be involved in the intracellular transport of cisplatin. The aim of the present study was to assess the relevance of sub cellular localisation of these transporters for acquired cisplatin resistance in vitro. For this purpose, localisation of ATP7A and ATP7B in A2780 human ovarian carcinoma cells and their cisplatin-resistant variant, A2780cis, was investigated. Methods Sub cellular localisation of ATP7A and ATP7B in sensitive and resistant cells was investigated using confocal fluorescence microscopy after immunohistochemical staining. Co-localisation experiments with a cisplatin analogue modified with a carboxyfluorescein-diacetate residue were performed. Cytotoxicity of the fluorescent cisplatin analogue in A2780 and A2780cis cells was determined using an MTT-based assay. The significance of differences was analysed using Student's t test or Mann-Whitney test as appropriate, p values of Results In the sensitive cells, both transporters are mainly localised in the trans-Golgi network, whereas they are sequestrated in more peripherally located vesicles in the resistant cells. Altered localisation of ATP7A and ATP7B in A2780cis cells is likely to be a consequence of major abnormalities in intracellular protein trafficking related to a reduced lysosomal compartment in this cell line. Changes in sub cellular localisation of ATP7A and ATP7B may facilitate sequestration of cisplatin in the vesicular structures of A2780cis cells, which may prevent drug binding to genomic DNA and thereby contribute to cisplatin resistance. Conclusion Our results indicate that alterations in sub cellular localisation of transport proteins may contribute to cisplatin resistance in vitro. Investigation of intracellular protein localisation in primary tumour cell cultures and tumour tissues may help to develop markers of clinically relevant cisplatin resistance. Detection of resistant tumours

  3. Genetics, Cytogenetics, and Epigenetics of Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Lucia Migliore

    2011-01-01

    Full Text Available Most of the colorectal cancer (CRC cases are sporadic, only 25% of the patients have a family history of the disease, and major genes causing syndromes predisposing to CRC only account for 5-6% of the total cases. The following subtypes can be recognized: MIN (microsatellite instability, CIN (chromosomal instability, and CIMP (CpG island methylator phenotype. CIN occurs in 80–85% of CRC. Chromosomal instability proceeds through two major mechanisms, missegregation that results in aneuploidy through the gain or loss of whole chromosomes, and unbalanced structural rearrangements that lead to the loss and/or gain of chromosomal regions. The loss of heterozygosity that occur in the first phases of the CRC cancerogenesis (in particular for the genes on 18q as well as the alteration of methylation pattern of multiple key genes can drive the development of colorectal cancer by facilitating the acquisition of multiple tumor-associated mutations and the instability phenotype.

  4. Developments in Colorectal Cancer Screening

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Colorectal Cancer Developments in Colorectal Cancer Screening Past Issues / Summer 2016 Table of ... at the National Cancer Institute, shared developments in colorectal cancer screening methods with NIH MedlinePlus magazine. What ...

  5. Improving Quality in Colorectal Surgery

    NARCIS (Netherlands)

    J.C. Slieker (Juliette)

    2014-01-01

    markdownabstract__Abstract__ Colorectal surgery is an important aspect of our current health system, due to the high incidence of colorectal cancer combined with an ageing population, improved long-term outcomes after colorectal surgery, and the perfectioning of the operative and postoperative

  6. Alteration of natural "3"7Ar activity concentration in the subsurface by gas transport and water infiltration

    International Nuclear Information System (INIS)

    Guillon, Sophie; Sun, Yunwei; Purtschert, Roland; Raghoo, Lauren; Pili, Eric; Carrigan, Charles R.

    2016-01-01

    High "3"7Ar activity concentration in soil gas is proposed as a key evidence for the detection of underground nuclear explosion by the Comprehensive Nuclear Test-Ban Treaty. However, such a detection is challenged by the natural background of "3"7Ar in the subsurface, mainly due to Ca activation by cosmic rays. A better understanding and improved capability to predict "3"7Ar activity concentration in the subsurface and its spatial and temporal variability is thus required. A numerical model integrating "3"7Ar production and transport in the subsurface is developed, including variable soil water content and water infiltration at the surface. A parameterized equation for "3"7Ar production in the first 15 m below the surface is studied, taking into account the major production reactions and the moderation effect of soil water content. Using sensitivity analysis and uncertainty quantification, a realistic and comprehensive probability distribution of natural "3"7Ar activity concentrations in soil gas is proposed, including the effects of water infiltration. Site location and soil composition are identified as the parameters allowing for a most effective reduction of the possible range of "3"7Ar activity concentrations. The influence of soil water content on "3"7Ar production is shown to be negligible to first order, while "3"7Ar activity concentration in soil gas and its temporal variability appear to be strongly influenced by transient water infiltration events. These results will be used as a basis for practical CTBTO concepts of operation during an OSI. - Highlights: • "3"7Ar in the subsurface as a key evidence to detect underground nuclear explosions. • Numerical modeling of "3"7Ar production and transport in variably saturated soil. • Large uncertainty on predicting "3"7Ar activity concentration in soil gas. • Control of subsurface "3"7Ar temporal variability by water infiltration events. • Limited influence of soil water content on "3"7Ar production.

  7. Temporal variation of nitrate and phosphate transport in headwater catchments: the hydrological controls and land use alteration

    Directory of Open Access Journals (Sweden)

    T.-Y. Lee

    2013-04-01

    Full Text Available Oceania rivers are hotspots of DIN (dissolved inorganic nitrogen and DIP (dissolved inorganic phosphorus transport due to humid/warm climate, typhoon-induced episodic rainfall and high tectonic activity that create an environment favorable for high/rapid runoff and soil erosion. In spite of its uniqueness, effects of hydrologic controls and land use on the transport behaviors of DIN and DIP are rarely documented. A 2 yr monitoring study for DIN and DIP from three headwater catchments with different cultivation gradient (0 To 8.9% was implemented during a ~ 3 day interval with an additional monitoring campaign at a 3 h interval during typhoon periods. Results showed the DIN yields in the pristine, moderately cultivated (2.7%, and intensively cultivated (8.9% watersheds were 8.3, 26, and 37 kg N ha−1 yr−1, respectively. For the DIP yields, they were 0.36, 0.35, and 0.56 kg P ha−1 yr−1, respectively. Higher year-round DIN concentrations and five times larger in DIN yields in intensively cultivated watersheds indicate DIN is more sensitive to land use changes. The high background DIN yield from the relatively pristine watershed was likely due to high atmospheric nitrogen deposition and large subterranean N pool. The correlations between runoff and concentration reveals that typhoon floods purge out more DIN from the subterranean reservoir, i.e., soil, by contrast, runoff washes off surface soil resulting in higher suspended sediment with higher DIP. Collectively, typhoon runoff contributes 20–70% and 47–80%, respectively, to the annual DIN and DIP exports. The DIN yield to DIP yield ratio varied from 97 to 410, which is higher than the global mean of ~ 18. Such a high ratio indicates a P-limiting condition in stream and the downstream aquatic environment. Based on our field observation, we constructed a conceptual model illustrating different remobilization mechanisms for DIN and DIP from headwaters in a mountainous river, which is

  8. The somatic mutation landscape of premalignant colorectal adenoma.

    Science.gov (United States)

    Lin, Shu-Hong; Raju, Gottumukkala S; Huff, Chad; Ye, Yuanqing; Gu, Jian; Chen, Jiun-Sheng; Hildebrandt, Michelle A T; Liang, Han; Menter, David G; Morris, Jeffery; Hawk, Ernest; Stroehlein, John R; Futreal, Andrew; Kopetz, Scott; Mishra, Lopa; Wu, Xifeng

    2017-06-12

    There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma. Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC. Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941. The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. Prenatal Exposure to Sodium Arsenite Alters Placental Glucose 1, 3, and 4 Transporters in Balb/c Mice

    Directory of Open Access Journals (Sweden)

    Daniela Sarahí Gutiérrez-Torres

    2015-01-01

    Full Text Available Inorganic arsenic (iAs exposure induces a decrease in glucose type 4 transporter (GLUT4 expression on the adipocyte membrane, which may be related to premature births and low birth weight infants in women exposed to iAs at reproductive age. The aim of this study was to analyze the effect of sodium arsenite (NaAsO2 exposure on GLUT1, GLUT3, and GLUT4 protein expression and on placental morphology. Female Balb/c mice (n=15 were exposed to 0, 12, and 20 ppm of NaAsO2 in drinking water from 8th to 18th day of gestation. Morphological changes and GLUT1, GLUT3, and GLUT4 expression were evaluated in placentas by immunohistochemical and image analysis and correlated with iAs and arsenical species concentration, which were quantified by atomic absorption spectroscopy. NaAsO2 exposure induced a significant decrease in fetal and placental weight (P<0.01 and increases in infarctions and vascular congestion. Whereas GLUT1 expression was unchanged in placentas from exposed group, GLUT3 expression was found increased. In contrast, GLUT4 expression was significantly lower (P<0.05 in placentas from females exposed to 12 ppm. The decrease in placental GLUT4 expression might affect the provision of adequate fetal nutrition and explain the low fetal weight observed in the exposed groups.

  10. Unique insight into microenvironmental changes in colorectal cancer

    DEFF Research Database (Denmark)

    Willumsen, Nicholas; Bager, Cecilie L; Bay-Jensen, Anne-Christine

    2017-01-01

    Matrix metalloprotease (MMP)-mediated tissue remodeling is one of the malignant changes driving colorectal cancer. Measurement of altered MMP expression/activity is not sufficient to fully understand the effect of MMP-mediated tissue remodeling. Biomarkers are required that specifically reflect t...

  11. Prophylaxis against colorectal cancer

    DEFF Research Database (Denmark)

    Bülow, Steffen; Kronborg, O

    1996-01-01

    Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing with a w......Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing...... with a well-established register of familial adenomatous polyposis and a recently founded register for hereditary nonpolyposis colorectal cancer, both with major international relationships. The Danish tradition of epidemiology and clinical trials has also been demonstrated in population screening trials...... for colorectal cancer in average-risk persons as well as high-risk groups with precursors of the disease. The present review places Danish contributions within the prophylaxis of colorectal cancer during the last decade in an international context....

  12. Galectin-3 silencing inhibits epirubicin-induced ATP binding cassette transporters and activates the mitochondrial apoptosis pathway via β-catenin/GSK-3β modulation in colorectal carcinoma.

    Directory of Open Access Journals (Sweden)

    Yung-Kuo Lee

    Full Text Available Multidrug resistance (MDR, an unfavorable factor compromising the treatment efficacy of anticancer drugs, involves the upregulation of ATP binding cassette (ABC transporters and induction of galectin-3 signaling. Galectin-3 plays an anti-apoptotic role in many cancer cells and regulates various pathways to activate MDR. Thus, the inhibition of galectin-3 has the potential to enhance the efficacy of the anticancer drug epirubicin. In this study, we examined the effects and mechanisms of silencing galectin-3 via RNA interference (RNAi on the β-catenin/GSK-3β pathway in human colon adenocarcinoma Caco-2 cells. Galectin-3 knockdown increased the intracellular accumulation of epirubicin in Caco-2 cells; suppressed the mRNA expression of galectin-3, β-catenin, cyclin D1, c-myc, P-glycoprotein (P-gp, MDR-associated protein (MRP 1, and MRP2; and downregulated the protein expression of P-gp, cyclin D1, galectin-3, β-catenin, c-Myc, and Bcl-2. Moreover, galectin-3 RNAi treatment significantly increased the mRNA level of GSK-3β, Bax, caspase-3, and caspase-9; remarkably increased the Bax-to-Bcl-2 ratio; and upregulated the GSK-3β and Bax protein expressions. Apoptosis was induced by galectin-3 RNAi and/or epirubicin as demonstrated by chromatin condensation, a higher sub-G1 phase proportion, and increased caspase-3 and caspase-9 activity, indicating an intrinsic/mitochondrial apoptosis pathway. Epirubicin-mediated resistance was effectively inhibited via galectin-3 RNAi treatment. However, these phenomena could be rescued after galectin-3 overexpression. We show for the first time that the silencing of galectin-3 sensitizes MDR cells to epirubicin by inhibiting ABC transporters and activating the mitochondrial pathway of apoptosis through modulation of the β-catenin/GSK-3β pathway in human colon cancer cells.

  13. Zinc deficiency-induced iron accumulation, a consequence of alterations in iron regulatory protein-binding activity, iron transporters, and iron storage proteins.

    Science.gov (United States)

    Niles, Brad J; Clegg, Michael S; Hanna, Lynn A; Chou, Susan S; Momma, Tony Y; Hong, Heeok; Keen, Carl L

    2008-02-22

    One consequence of zinc deficiency is an elevation in cell and tissue iron concentrations. To examine the mechanism(s) underlying this phenomenon, Swiss 3T3 cells were cultured in zinc-deficient (D, 0.5 microM zinc), zinc-supplemented (S, 50 microM zinc), or control (C, 4 microM zinc) media. After 24 h of culture, cells in the D group were characterized by a 50% decrease in intracellular zinc and a 35% increase in intracellular iron relative to cells in the S and C groups. The increase in cellular iron was associated with increased transferrin receptor 1 protein and mRNA levels and increased ferritin light chain expression. The divalent metal transporter 1(+)iron-responsive element isoform mRNA was decreased during zinc deficiency-induced iron accumulation. Examination of zinc-deficient cells revealed increased binding of iron regulatory protein 2 (IRP2) and decreased binding of IRP1 to a consensus iron-responsive element. The increased IRP2-binding activity in zinc-deficient cells coincided with an increased level of IRP2 protein. The accumulation of IRP2 protein was independent of zinc deficiency-induced intracellular nitric oxide production but was attenuated by the addition of the antioxidant N-acetylcysteine or ascorbate to the D medium. These data support the concept that zinc deficiency can result in alterations in iron transporter, storage, and regulatory proteins, which facilitate iron accumulation.

  14. MzPIP2;1: An Aquaporin Involved in Radial Water Movement in Both Water Uptake and Transportation, Altered the Drought and Salt Tolerance of Transgenic Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Lin Wang

    Full Text Available Plants are unavoidably subjected to various abiotic stressors, including high salinity, drought and low temperature, which results in water deficit and even death. Water uptake and transportation play a critical role in response to these stresses. Many aquaporin proteins, localized at different tissues, function in various transmembrane water movements. We targeted at the key aquaporin in charge of both water uptake in roots and radial water transportation from vascular tissues through the whole plant.The MzPIP2;1 gene encoding a plasma membrane intrinsic protein was cloned from salt-tolerant apple rootstock Malus zumi Mats. The GUS gene was driven by MzPIP2;1 promoter in transgenic Arabidopsis. It indicated that MzPIP2;1 might function in the epidermal and vascular cells of roots, parenchyma cells around vessels through the stems and vascular tissues of leaves. The ectopically expressed MzPIP2;1 conferred the transgenic Arabidopsis plants enhanced tolerance to slight salt and drought stresses, but sensitive to moderate salt stress, which was indicated by root length, lateral root number, fresh weight and K+/Na+ ratio. In addition, the possible key cis-elements in response to salt, drought and cold stresses were isolated by the promoter deletion experiment.The MzPIP2;1 protein, as a PIP2 aquaporins subgroup member, involved in radial water movement, controls water absorption and usage efficiency and alters transgenic plants drought and salt tolerance.

  15. Transportation

    Science.gov (United States)

    2007-01-01

    Faculty ii INDUSTRY TRAVEL Domestic Assistant Deputy Under Secretary of Defense (Transportation Policy), Washington, DC Department of...developed between the railroad and trucking industries. Railroads: Today’s seven Class I freight railroad systems move 42% of the nation’s intercity ...has been successfully employed in London to reduce congestion and observed by this industry study during its travels . It is currently being

  16. Genetic Mechanisms of Immune Evasion in Colorectal Cancer.

    Science.gov (United States)

    Grasso, Catherine S; Giannakis, Marios; Wells, Daniel K; Hamada, Tsuyoshi; Mu, Xinmeng Jasmine; Quist, Michael; Nowak, Jonathan A; Nishihara, Reiko; Qian, Zhi Rong; Inamura, Kentaro; Morikawa, Teppei; Nosho, Katsuhiko; Abril-Rodriguez, Gabriel; Connolly, Charles; Escuin-Ordinas, Helena; Geybels, Milan S; Grady, William M; Hsu, Li; Hu-Lieskovan, Siwen; Huyghe, Jeroen R; Kim, Yeon Joo; Krystofinski, Paige; Leiserson, Mark D M; Montoya, Dennis J; Nadel, Brian B; Pellegrini, Matteo; Pritchard, Colin C; Puig-Saus, Cristina; Quist, Elleanor H; Raphael, Ben J; Salipante, Stephen J; Shin, Daniel Sanghoon; Shinbrot, Eve; Shirts, Brian; Shukla, Sachet; Stanford, Janet L; Sun, Wei; Tsoi, Jennifer; Upfill-Brown, Alexander; Wheeler, David A; Wu, Catherine J; Yu, Ming; Zaidi, Syed H; Zaretsky, Jesse M; Gabriel, Stacey B; Lander, Eric S; Garraway, Levi A; Hudson, Thomas J; Fuchs, Charles S; Ribas, Antoni; Ogino, Shuji; Peters, Ulrike

    2018-06-01

    To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730-49. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663 . ©2018 American Association for Cancer Research.

  17. Colorectal cancer screening

    OpenAIRE

    McLoughlin, Monica Ramona

    2008-01-01

    Colorectal cancer is a major public health burden and is the most common cause of mortality from cancer in Europe. Over the last two decades robust evidence from randomised clinical trials and case-control series have confirmed that the mortality from colorectal cancer can be reduced by screening. The challenge over the next decade is how to implement this in clinical practice. This is what we set out to answer with this thesis. Not all individuals are equal when it comes to screening and tho...

  18. Management of Colorectal Trauma

    Science.gov (United States)

    2011-01-01

    Although the treatment strategy for colorectal trauma has advanced during the last part of the twentieth century and the result has improved, compared to other injuries, problems, such as high septic complication rates and mortality rates, still exist, so standard management for colorectal trauma is still a controversial issue. For that reason, we designed this article to address current recommendations for management of colorectal injuries based on a review of literature. According to the reviewed data, although sufficient evidence exists for primary repair being the treatment of choice in most cases of nondestructive colon injuries, many surgeons are still concerned about anastomotic leakage or failure, and prefer to perform a diverting colostomy. Recently, some reports have shown that primary repair or resection and anastomosis, is better than a diverting colostomy even in cases of destructive colon injuries, but it has not fully established as the standard treatment. The same guideline as that for colonic injury is applied in cases of intraperitoneal rectal injuries, and, diversion, primary repair, and presacral drainage are regarded as the standards for the management of extraperitoneal rectal injuries. However, some reports state that primary repair without a diverting colostomy has benefit in the treatment of extraperitoneal rectal injury, and presacral drainage is still controversial. In conclusion, ideally an individual management strategy would be developed for each patient suffering from colorectal injury. To do this, an evidence-based treatment plan should be carefully developed. PMID:21980586

  19. Colorectal Cancer Rates by Race and Ethnicity

    Science.gov (United States)

    ... Associated Lung Ovarian Prostate Skin Uterine Cancer Home Colorectal Cancer Rates by Race and Ethnicity Language: English (US) ... Tweet Share Compartir The rate of people getting colorectal cancer or dying from colorectal cancer varies by race ...

  20. Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1 and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study

    Directory of Open Access Journals (Sweden)

    Overvad Kim

    2009-11-01

    Full Text Available Abstract Background The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1 and Breast Cancer Resistance Protein (BCRP/ABCG2 may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA and polycyclic aromatic hydrocarbons (PAH. Cyclooxygenase-2 (COX-2 derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness. The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC, and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use. Methods The following polymorphisms were analyzed; a synonymous MDR1 C3435T (rs1045642 in exon26, G-rs3789243-A in intron3, the functional BCRP C421A (rs2231142, the two COX-2 A-1195G (rs689466 and G-765C (rs20417 in the promoter region, and the COX-2 T8473C (rs5275 polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study. Results Carriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR = 1.52, 95% Confidence Interval (CI: 1.12-2.06. Carriers of the variant allele of MDR1 C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR = 0.71 (CI:0.50-1.00. There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous MDR1 C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16 whereas variant allele carriers were not at increased risk (p for interaction = 0.02. COX-2 and BCRP polymorphisms were not associated with CRC risk. There was interaction between NSAID use and MDR1 C3435T and COX-2 T

  1. Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study

    International Nuclear Information System (INIS)

    Andersen, Vibeke; Østergaard, Mette; Christensen, Jane; Overvad, Kim; Tjønneland, Anne; Vogel, Ulla

    2009-01-01

    The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness. The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use. The following polymorphisms were analyzed; a synonymous MDR1 C3435T (rs1045642) in exon26, G-rs3789243-A in intron3, the functional BCRP C421A (rs2231142), the two COX-2 A-1195G (rs689466) and G-765C (rs20417) in the promoter region, and the COX-2 T8473C (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study. Carriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR) = 1.52, 95% Confidence Interval (CI): 1.12-2.06). Carriers of the variant allele of MDR1 C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR = 0.71 (CI:0.50-1.00)). There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous MDR1 C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16) whereas variant allele carriers were not at increased risk (p for interaction = 0.02). COX-2 and BCRP polymorphisms were not associated with CRC risk. There was interaction between NSAID use and MDR1 C3435T and COX-2 T8473C (p-values for interaction 0

  2. Radioimmunodetection of colorectal cancer

    International Nuclear Information System (INIS)

    Kim, E.E.; Deland, F.H.; Casper, S.; Corgan, R.L.; Primus, F.J.; Goldenberg, D.M.

    1980-01-01

    This study examines the accuracy of colorectal cancer radioimmunodetection. Twenty-seven patients with a history of histologically-confirmed colonic or rectal carcinoma received a high-titer, purified goat anti-CEA IgG labelled with 131 I at a total dose of at least 1.0 μCi. Various body views were scanned at 24 and 48 hours after administration of the radioantibody. Three additional cases were evaluated; one had a villous adenoma in the rectum and received the 131 I-labeled anti-CEA IgG, while two colonic carcinoma patients received normal goat IgG labelled with 131 I. All of the 7 cases with primary colorectal cancer showed true-positive tumor localization, while 20 of 25 sites of metastatic colorectal cancer detected by immune scintigraphy were corroborated by other detection measures. The sensitivity of the radioimmunodetection of colorectal cancers (primary and metastatic) was found to be 90% (true-positive rate), the putative specificity (true-negative rate) was 94%, and the apparent overall accuracy of the technique was 93%. Neither the case of a villous adenoma receiving the anti-CEA IgG nor the two cases of colonic cancer receiving normal goat IgG showed tumor radiolocalization. Very high circulating CEA titers did not appear to hinder successful tumor radiolocalization. These findings suggest that in colorectal cancers the method of CEA radioimmunodetection may be of value in preoperatively determining the location and extent of disease, in assessing possible recurrence or spread postoperatively, and in localizing the source of CEA production in patients with rising or elevated CEA titers. An ancilliary benefit could be a more tumor-specific detection test for confirming the findings of other, more conventional diagnostic measures

  3. Microbiota, Inflammation and Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Cécily Lucas

    2017-06-01

    Full Text Available Colorectal cancer, the fourth leading cause of cancer-related death worldwide, is a multifactorial disease involving genetic, environmental and lifestyle risk factors. In addition, increased evidence has established a role for the intestinal microbiota in the development of colorectal cancer. Indeed, changes in the intestinal microbiota composition in colorectal cancer patients compared to control subjects have been reported. Several bacterial species have been shown to exhibit the pro-inflammatory and pro-carcinogenic properties, which could consequently have an impact on colorectal carcinogenesis. This review will summarize the current knowledge about the potential links between the intestinal microbiota and colorectal cancer, with a focus on the pro-carcinogenic properties of bacterial microbiota such as induction of inflammation, the biosynthesis of genotoxins that interfere with cell cycle regulation and the production of toxic metabolites. Finally, we will describe the potential therapeutic strategies based on intestinal microbiota manipulation for colorectal cancer treatment.

  4. Real-Time Monitoring of Results During First Year of Dutch Colorectal Cancer Screening Program and Optimization by Altering Fecal Immunochemical Test Cut-Off Levels.

    Science.gov (United States)

    Toes-Zoutendijk, Esther; van Leerdam, Monique E; Dekker, Evelien; van Hees, Frank; Penning, Corine; Nagtegaal, Iris; van der Meulen, Miriam P; van Vuuren, Anneke J; Kuipers, Ernst J; Bonfrer, Johannes M G; Biermann, Katharina; Thomeer, Maarten G J; van Veldhuizen, Harriët; Kroep, Sonja; van Ballegooijen, Marjolein; Meijer, Gerrit A; de Koning, Harry J; Spaander, Manon C W; Lansdorp-Vogelaar, Iris

    2017-03-01

    After careful pilot studies and planning, the national screening program for colorectal cancer (CRC), with biennial fecal immunochemical tests (FITs), was initiated in The Netherlands in 2014. A national information system for real-time monitoring was developed to allow for timely evaluation. Data were collected from the first year of this screening program to determine the importance of planning and monitoring for optimal screening program performance. The national information system of the CRC screening program kept track of the number of invitations sent in 2014, FIT kits returned, and colonoscopies performed. Age-adjusted rates of participation, the number of positive test results, and positive predictive values (PPVs) for advanced neoplasia were determined weekly, quarterly, and yearly. In 2014, there were 741,914 persons invited for FIT; of these, 529,056 (71.3%; 95% CI, 71.2%-71.4%) participated. A few months into the program, real-time monitoring showed that rates of participation and positive test results (10.6%; 95% CI, 10.5%-10.8%) were higher than predicted and the PPV was lower (42.1%; 95% CI, 41.3%-42.9%) than predicted based on pilot studies. To reduce the burden of unnecessary colonoscopies and alleviate colonoscopy capacity, the cut-off level for a positive FIT result was increased from 15 to 47 μg Hb/g feces halfway through 2014. This adjustment decreased the percentage of positive test results to 6.7% (95% CI, 6.6%-6.8%) and increased the PPV to 49.1% (95% CI, 48.3%-49.9%). In total, the first year of the Dutch screening program resulted in the detection of 2483 cancers and 12,030 advanced adenomas. Close monitoring of the implementation of the Dutch national CRC screening program allowed for instant adjustment of the FIT cut-off levels to optimize program performance. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  5. Intrabilary obstruction by colorectal metastases

    OpenAIRE

    Traeger, Luke; Kiroff, George

    2018-01-01

    Abstract Intrabiliary colorectal metastases are rare. We present a case of an 84-year-old man who developed obstructive jaundice secondary to intrabiliary growth of colorectal metastases. The patient presented with three weeks of jaundice and significant weight loss in the preceding months. The patient’s background included metastatic colorectal carcinoma, with a previous right hemicolectomy and left hepatectomy for liver metastases. A MRCP showed an obstruction of the biliary tract transitio...

  6. Colorectal cancer cells suppress CD4+ T cells immunity through canonical Wnt signaling.

    Science.gov (United States)

    Sun, Xuan; Liu, Suoning; Wang, Daguang; Zhang, Yang; Li, Wei; Guo, Yuchen; Zhang, Hua; Suo, Jian

    2017-02-28

    Understanding how colorectal cancer escapes from immunosurveillance and immune attack is important for developing novel immunotherapies for colorectal cancer. In this study we evaluated the role of canonical Wnt signaling in the regulation of T cell function in a mouse colorectal cancer model. We found that colorectal cancer cells expressed abundant Wnt ligands, and intratumoral T cells expressed various Frizzled proteins. Meanwhile, both active β-catenin and total β-catenin were elevated in intratumoral T cells. In vitro study indicated that colorectal cancer cells suppressed IFN-γ expression and increased IL-17a expression in activated CD4+ T cells. However, the cytotoxic activity of CD8+ T cells was not altered by colorectal cancer cells. To further evaluate the importance of Wnt signaling for CD4+ T cell-mediated cancer immunity, β-catenin expression was enforced in CD4+ T cells using lentiviral transduction. In an adoptive transfer model, enforced expression of β-catenin in intratumoral CD4+ T cells increased IL-17a expression, enhanced proliferation and inhibited apoptosis of colorectal cancer cells. Taken together, our study disclosed a new mechanism by which colorectal cancer impairs T cell immunity.

  7. RET is a potential tumor suppressor gene in colorectal cancer

    Science.gov (United States)

    Luo, Yanxin; Tsuchiya, Karen D.; Park, Dong Il; Fausel, Rebecca; Kanngurn, Samornmas; Welcsh, Piri; Dzieciatkowski, Slavomir; Wang, Jianping; Grady, William M.

    2012-01-01

    Cancer arises as the consequence of mutations and epigenetic alterations that activate oncogenes and inactivate tumor suppressor genes. Through a genome-wide screen for methylated genes in colon neoplasms, we identified aberrantly methylated RET in colorectal cancer. RET, a transmembrane receptor tyrosine kinase and a receptor for the GDNF-family ligands, was one of the first oncogenes to be identified and has been shown to be an oncogene in thyroid cancer and pheochromocytoma. However, unexpectedly, we found RET is methylated in 27% of colon adenomas and in 63% of colorectal cancers, and now provide evidence that RET has tumor suppressor activity in colon cancer. The aberrant methylation of RET correlates with decreased RET expression, whereas the restoration of RET in colorectal cancer cell lines results in apoptosis. Furthermore, in support of a tumor suppressor function of RET, mutant RET has also been found in primary colorectal cancer. We now show that these mutations inactivate RET, which is consistent with RET being a tumor suppressor gene in the colon. These findings suggest that the aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation and that RET can serve as a tumor suppressor gene in the colon. Moreover, the increased frequency of methylated RET in colon cancers compared to adenomas suggests RET inactivation is involved in the progression of colon adenomas to cancer. PMID:22751117

  8. Helicobacter pylori and colorectal neoplasia: Is there a causal link?

    Science.gov (United States)

    Papastergiou, Vasilios; Karatapanis, Stylianos; Georgopoulos, Sotirios D

    2016-01-01

    Ever since Helicobacter pylori (H. pylori) was recognized as an infectious cause of gastric cancer, there has been increasing interest in examining its potential role in colorectal carcinogenesis. Data from case-control and cross-sectional studies, mostly relying on hospital-based samples, and several meta-analyses have shown a positive statistical relationship between H. pylori infection and colorectal neoplasia. However, the possibility exists that the results have been influenced by bias, including the improper selection of patients and disparities with respect to potential confounders. While the evidence falls short of a definitive causal link, it appears that infection with H. pylori/H. pylori-related gastritis is associated with an increased, although modest, risk of colorectal adenoma and cancer. The pathogenic mechanisms responsible for this association remain uncertain. H. pylori has been detected in colorectal malignant tissues; however, the possibility that H. pylori is a direct activator of colonic carcinogenesis remains purely hypothetical. On the other hand, experimental data have indicated a series of potential oncogenic interactions between these bacteria and colorectal mucosa, including induction and perpetuation of inflammatory responses, alteration of gut microflora and release of toxins and/or hormonal mediators, such as gastrin, which may contribute to tumor formation. PMID:26811614

  9. Lysyl oxidase in colorectal cancer

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine T

    2013-01-01

    Colorectal cancer is the third most prevalent form of cancer worldwide and fourth-leading cause of cancer-related mortality, leading to ~600,000 deaths annually, predominantly affecting the developed world. Lysyl oxidase is a secreted, extracellular matrix-modifying enzyme previously suggested...... to act as a tumor suppressor in colorectal cancer. However, emerging evidence has rapidly implicated lysyl oxidase in promoting metastasis of solid tumors and in particular colorectal cancer at multiple stages, affecting tumor cell proliferation, invasion, and angiogenesis. This emerging research has...... advancements in the field of colorectal cancer....

  10. Endoscopic management of colorectal adenomas.

    Science.gov (United States)

    Meier, Benjamin; Caca, Karel; Fischer, Andreas; Schmidt, Arthur

    2017-01-01

    Colorectal adenomas are well known precursors of invasive adenocarcinoma. Colonoscopy is the gold standard for adenoma detection. Colonoscopy is far more than a diagnostic tool, as it allows effective treatment of colorectal adenomas. Endoscopic resection of colorectal adenomas has been shown to reduce the incidence and mortality of colorectal cancer. Difficult resection techniques are available, such as endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic full-thickness resection. This review aims to provide an overview of the different endoscopic resection techniques and their indications, and summarizes the current recommendations in the recently published guideline of the European Society of Gastrointestinal Endoscopy.

  11. Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation

    OpenAIRE

    JORDI SALAS; NURIA LASO; SERGI MAS; M. JOSE LAFUENTE; XAVIER CASTERAD; MANUEL TRIAS; ANTONIO BALLESTA; RAFAEL MOLINA; CARLOS ASCASO; SHICHUN ZHENG; JOHN K. WIENCKE; AMALIA LAFUENTE

    2004-01-01

    Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation BACKGROUND: The diversity of the Mediterranean diet and the heterogeneity of acquired genetic alterations in colorectal cancer (CRC) led us to examine the possible association between dietary factors and mutations, such as Ki-ras mutations, in genes implicated in the pathogenesis of these neoplasms. PATIENTS AND METHODS: The study was based on 246 cases and 296 controls. For th...

  12. Colorectal Cancer Screening

    OpenAIRE

    Quintero, Enrique; Saito, Yutaka; Hassan, Cessare; Senore, Carlo

    2012-01-01

    Colorectal cancer, which is the leading cancer in Singapore, can be prevented by increased use of screening and polypectomy. A range of screening strategies such as stool-based tests, flexible sigmoidoscopy, colonoscopy and computed tomography colonography are available, each with different strengths and limitations. Primary care physicians should discuss appropriate screening modalities with their patients, tailored to their individual needs. Physicians, patients and the government should wo...

  13. Intraoperative ultrasound in colorectal surgery.

    Science.gov (United States)

    Greif, Franklin; Aranovich, David; Hananel, Nissim; Knizhnik, Mikhail; Belenky, Alexander

    2009-09-01

    To assess the accuracy of intraoperative ultrasound (IOUS) as a localizing technique for colorectal resections, and its impact on surgical management. Twenty-five patients (15 men and 10 women; mean age, 74.4 years) with early cancers (p T1), or polyps, not amenable to endoscopic removal were selected. IOUS was used as a sole method of intraoperative localization. Its performance was evaluated through review of preoperative colonoscopy reports, intraoperative findings, histopathology reports, and clinical follow-up. The lesions were situated in the cecum (n = 5), ascending colon (n = 3), transverse colon (n = 4), descending colon (n = 7), and rectum (n = 6). IOUS technique allowed correct localization in 24 of 25 patients, visualization of the bowel wall, and its penetration by malignant tumors. In rectal lesions, IOUS showed clearly the tumor and its margin, which facilitated performance sphincter-sparing procedure. In patients with small polyps and early cancers of colon and rectum, IOUS may be effectively used as a sole method of intraoperative localization and provide additional information that may alter decision making with regard to surgical technique. (c) 2009 Wiley Periodicals, Inc.

  14. Epigenetics and Colorectal Cancer Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bardhan, Kankana; Liu, Kebin, E-mail: Kliu@gru.edu [Department of Biochemistry and Molecular Biology, Medical College of Georgia, and Cancer Center, Georgia Regents University, Augusta, GA 30912 (United States)

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  15. Epigenetics and colorectal cancer pathogenesis.

    Science.gov (United States)

    Bardhan, Kankana; Liu, Kebin

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  16. Epigenetics and Colorectal Cancer Pathogenesis

    International Nuclear Information System (INIS)

    Bardhan, Kankana; Liu, Kebin

    2013-01-01

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy

  17. Epigenetics and Colorectal Cancer Pathogenesis

    Directory of Open Access Journals (Sweden)

    Kebin Liu

    2013-06-01

    Full Text Available Colorectal cancer (CRC develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  18. Altered Na+ transport after an intracellular alpha-subunit deletion reveals strict external sequential release of Na+ from the Na/K pump.

    Science.gov (United States)

    Yaragatupalli, Siddhartha; Olivera, J Fernando; Gatto, Craig; Artigas, Pablo

    2009-09-08

    The Na/K pump actively exports 3 Na(+) in exchange for 2 K(+) across the plasmalemma of animal cells. As in other P-type ATPases, pump function is more effective when the relative affinity for transported ions is altered as the ion binding sites alternate between opposite sides of the membrane. Deletion of the five C-terminal residues from the alpha-subunit diminishes internal Na(+) (Na(i)(+)) affinity approximately 25-fold [Morth et al. (2007) Nature 450:1043-1049]. Because external Na(+) (Na(o)(+)) binding is voltage-dependent, we studied the reactions involving this process by using two-electrode and inside-out patch voltage clamp in normal and truncated (DeltaKESYY) Xenopus-alpha1 pumps expressed in oocytes. We observed that DeltaKESYY (i) decreased both Na(o)(+) and Na(i)(+) apparent affinities in the absence of K(o)(+), and (ii) did not affect apparent Na(o)(+) affinity at high K(o)(+). These results support a model of strict sequential external release of Na(+) ions, where the Na(+)-exclusive site releases Na(+) before the sites shared with K(+) and the DeltaKESYY deletion only reduces Na(o)(+) affinity at the shared sites. Moreover, at nonsaturating K(o)(+), DeltaKESYY induced an inward flow of Na(+) through Na/K pumps at negative potentials. Guanidinium(+) can also permeate truncated pumps, whereas N-methyl-D-glucamine cannot. Because guanidinium(o)(+) can also traverse normal Na/K pumps in the absence of both Na(o)(+) and K(o)(+) and can also inhibit Na/K pump currents in a Na(+)-like voltage-dependent manner, we conclude that the normal pathway transited by the first externally released Na(+) is large enough to accommodate guanidinium(+).

  19. An auxin transport independent pathway is involved in phosphate stress-induced root architectural alterations in Arabidopsis. Identification of BIG as a mediator of auxin in pericycle cell activation.

    Science.gov (United States)

    López-Bucio, José; Hernández-Abreu, Esmeralda; Sánchez-Calderón, Lenin; Pérez-Torres, Anahí; Rampey, Rebekah A; Bartel, Bonnie; Herrera-Estrella, Luis

    2005-02-01

    Arabidopsis (Arabidopsis thaliana) plants display a number of root developmental responses to low phosphate availability, including primary root growth inhibition, greater formation of lateral roots, and increased root hair elongation. To gain insight into the regulatory mechanisms by which phosphorus (P) availability alters postembryonic root development, we performed a mutant screen to identify genetic determinants involved in the response to P deprivation. Three low phosphate-resistant root lines (lpr1-1 to lpr1-3) were isolated because of their reduced lateral root formation in low P conditions. Genetic and molecular analyses revealed that all lpr1 mutants were allelic to BIG, which is required for normal auxin transport in Arabidopsis. Detailed characterization of lateral root primordia (LRP) development in wild-type and lpr1 mutants revealed that BIG is required for pericycle cell activation to form LRP in both high (1 mm) and low (1 microm) P conditions, but not for the low P-induced alterations in primary root growth, lateral root emergence, and root hair elongation. Exogenously supplied auxin restored normal lateral root formation in lpr1 mutants in the two P treatments. Treatment of wild-type Arabidopsis seedlings with brefeldin A, a fungal metabolite that blocks auxin transport, phenocopies the root developmental alterations observed in lpr1 mutants in both high and low P conditions, suggesting that BIG participates in vesicular targeting of auxin transporters. Taken together, our results show that auxin transport and BIG function have fundamental roles in pericycle cell activation to form LRP and promote root hair elongation. The mechanism that activates root system architectural alterations in response to P deprivation, however, seems to be independent of auxin transport and BIG.

  20. The dutch surgical colorectal audit

    NARCIS (Netherlands)

    Leersum, N.J. van; Snijders, H.S.; Henneman, D.; Kolfschoten, N.E.; Gooiker, G.A.; Berge, M.G. Ten; Eddes, E.H.; Wouters, M.W.; Tollenaar, R.A.E.M.; Bemelman, W.A.; Dam, R.M. van; Elferink, M.A.; Karsten, T.M.; Krieken, J.H. van; Lemmens, V.E.; Rutten, H.J.; Manusama, E.R.; Velde, C.J. van de; Meijerink, W.J.H.J.; Wiggers, T.; Harst, E. van der; Dekker, J.W.T.; Boerma, D.

    2013-01-01

    INTRODUCTION: In 2009, the nationwide Dutch Surgical Colorectal Audit (DSCA) was initiated by the Association of Surgeons of the Netherlands (ASN) to monitor, evaluate and improve colorectal cancer care. The DSCA is currently widely used as a blueprint for the initiation of other audits, coordinated

  1. Colorectal Cancer—Patient Version

    Science.gov (United States)

    Colorectal cancer often begins as a growth called a polyp inside the colon or rectum. Finding and removing polyps can prevent colorectal cancer. Start here to find information on colon and rectal cancer treatment, causes and prevention, screening, research, and statistics.

  2. The Dutch surgical colorectal audit

    NARCIS (Netherlands)

    van Leersum, N. J.; Snijders, H. S.; Henneman, D.; Kolfschoten, N. E.; Gooiker, G. A.; ten Berge, M. G.; Eddes, E. H.; Wouters, M. W. J. M.; Tollenaar, R. A. E. M.; Bemelman, W. A.; van Dam, R. M.; Elferink, M. A.; Karsten, Th M.; van Krieken, J. H. J. M.; Lemmens, V. E. P. P.; Rutten, H. J. T.; Manusama, E. R.; van de Velde, C. J. H.; Meijerink, W. J. H. J.; Wiggers, Th; van der Harst, E.; Dekker, J. W. T.; Boerma, D.

    2013-01-01

    In 2009, the nationwide Dutch Surgical Colorectal Audit (DSCA) was initiated by the Association of Surgeons of the Netherlands (ASN) to monitor, evaluate and improve colorectal cancer care. The DSCA is currently widely used as a blueprint for the initiation of other audits, coordinated by the Dutch

  3. Diets That Promote Colon Inflammation Associate With Risk of Colorectal Carcinomas That Contain Fusobacterium nucleatum.

    Science.gov (United States)

    Liu, Li; Tabung, Fred K; Zhang, Xuehong; Nowak, Jonathan A; Qian, Zhi Rong; Hamada, Tsuyoshi; Nevo, Daniel; Bullman, Susan; Mima, Kosuke; Kosumi, Keisuke; da Silva, Annacarolina; Song, Mingyang; Cao, Yin; Twombly, Tyler S; Shi, Yan; Liu, Hongli; Gu, Mancang; Koh, Hideo; Li, Wanwan; Du, Chunxia; Chen, Yang; Li, Chenxi; Li, Wenbin; Mehta, Raaj S; Wu, Kana; Wang, Molin; Kostic, Aleksander D; Giannakis, Marios; Garrett, Wendy S; Hutthenhower, Curtis; Chan, Andrew T; Fuchs, Charles S; Nishihara, Reiko; Ogino, Shuji; Giovannucci, Edward L

    2018-04-24

    Specific nutritional components are likely to induce intestinal inflammation, which is characterized by increased levels of interleukin 6 (IL6), C-reactive protein (CRP), and TNF receptor superfamily member 1B (TNFRSF1B) in the circulation and promotes colorectal carcinogenesis. The inflammatory effects of a diet can be estimated based on empirical dietary inflammatory pattern (EDIP) score, calculated based on intake of 18 foods associated with plasma levels of IL6, CRP, and TNFRSF1B. An inflammatory environment in the colon (based on increased levels of IL6, CRP, and TNFRSF1B in peripheral blood) contributes to impairment of the mucosal barrier and altered immune cell responses, affecting the composition of the intestinal microbiota. Colonization by Fusobacterium nucleatum has been associated with presence and features of colorectal adenocarcinoma. We investigated the association between diets that promote inflammation (based on EDIP score) and colorectal cancer subtypes classified by level of F nucleatum in the tumor microenvironment. We calculated EDIP scores based on answers to questionnaires collected from participants in the Nurses' Health Study (through June 1, 2012) and the Health Professionals Follow-up Study (through January 31, 2012). Participants in both cohorts reported diagnoses of rectal or colon cancer in biennial questionnaires; deaths from unreported colorectal cancer cases were identified through the National Death Index and next of kin. Colorectal tumor tissues were collected from hospitals where the patients underwent tumor resection and F nucleatum DNA was quantified by a PCR assay. We used multivariable duplication-method Cox proportional hazard regression to assess the associations of EDIP scores with risks of colorectal cancer subclassified by F nucleatum status. During 28 years of follow up of 124,433 participants, we documented 951 incident cases of colorectal carcinoma with tissue F nucleatum data. Higher EDIP scores associated with

  4. Exercise and Low-Dose Ibuprofen for Cognitive Impairment in Colorectal Cancer Patients Receiving Chemotherapy

    Science.gov (United States)

    2018-03-13

    Cognitive Impairment; Stage 0 Colorectal Cancer; Stage I Colorectal Cancer; Stage II Colorectal Cancer; Stage IIA Colorectal Cancer; Stage IIB Colorectal Cancer; Stage IIC Colorectal Cancer; Stage III Colorectal Cancer; Stage IIIA Colorectal Cancer; Stage IIIB Colorectal Cancer; Stage IIIC Colorectal Cancer

  5. Metastatic paediatric colorectal carcinoma.

    LENUS (Irish Health Repository)

    Woods, R

    2012-03-01

    A 16-year-old girl presented to our unit with crampy abdominal pain, change in bowel habit, a subjective impression of weight loss and a single episode of haematochezia. She was found to have a rectosigmoid adenocarcinoma and proceeded to laparoscopic anterior resection, whereupon peritoneal metastases were discovered. She received chemotherapy and is alive and well ten month later with no radiological evidence of disease. Colorectal carcinoma is rare in the paediatric population but is increasing in incidence. Early diagnosis is critical to enable optimal outcomes.

  6. Diagnosis of colorectal tumors

    International Nuclear Information System (INIS)

    Vogl, T.J.; Pegios, W.; Jacobi, V.; Schaefer, S.; Abolmaali, N.; Luboldt, W.

    2003-01-01

    With the introduction of multislice CT extensive volumetric data sets can be quickly acquired in high spatial resolution. The high spatial resolution reduces partial volume effects and enables multiplanar reconstructions. Regarding the colorectum this means that the colon can be assessed if the colon is sufficiently cleaned and distended, and that transmural infiltration of colorectal carcinoma and liver metastases can be better detected. T-staging of colon cancer is less important than T-staging of rectal cancer. Based on the higher contrast MRI is superior to CT in T-staging of rectal cancer and in the differentiation between scarring tissue and recurrence of carcinoma. (orig.) [de

  7. Colorectal cancer: genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells.

    Science.gov (United States)

    Testa, Ugo; Pelosi, Elvira; Castelli, Germana

    2018-04-13

    Colon cancer is the third most common cancer worldwide. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history; however, 20-30% of patients with colorectal cancer have a family history of colorectal cancer and 5% of these tumors arise in the setting of a Mendelian inheritance syndrome. In many patients, the development of a colorectal cancer is preceded by a benign neoplastic lesion: either an adenomatous polyp or a serrated polyp. Studies carried out in the last years have characterized the main molecular alterations occurring in colorectal cancers, showing that the tumor of each patient displays from two to eight driver mutations. The ensemble of molecular studies, including gene expression studies, has led to two proposed classifications of colorectal cancers, with the identification of four/five non-overlapping groups. The homeostasis of the rapidly renewing intestinal epithelium is ensured by few stem cells present at the level of the base of intestinal crypts. Various experimental evidence suggests that colorectal cancers may derive from the malignant transformation of intestinal stem cells or of intestinal cells that acquire stem cell properties following malignant transformation. Colon cancer stem cells seem to be involved in tumor chemoresistance, radioresistance and relapse.

  8. Primary prevention of colorectal cancer.

    Science.gov (United States)

    Chan, Andrew T; Giovannucci, Edward L

    2010-06-01

    Colorectal cancer has been strongly associated with a Western lifestyle. In the past several decades, much has been learned about the dietary, lifestyle, and medication risk factors for this malignancy. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. For example, several studies have shown that high intake of red and processed meats, highly refined grains and starches, and sugars is related to increased risk of colorectal cancer. Replacing these factors with poultry, fish, and plant sources as the primary source of protein; unsaturated fats as the primary source of fat; and unrefined grains, legumes and fruits as the primary source of carbohydrates is likely to lower risk of colorectal cancer. Although a role for supplements, including vitamin D, folate, and vitamin B6, remains uncertain, calcium supplementation is likely to be at least modestly beneficial. With respect to lifestyle, compelling evidence indicates that avoidance of smoking and heavy alcohol use, prevention of weight gain, and maintenance of a reasonable level of physical activity are associated with markedly lower risks of colorectal cancer. Medications such as aspirin and nonsteroidal anti-inflammatory drugs and postmenopausal hormones for women are associated with substantial reductions in colorectal cancer risk, though their utility is affected by associated risks. Taken together, modifications in diet and lifestyle should substantially reduce the risk of colorectal cancer and could complement screening in reducing colorectal cancer incidence.

  9. Gut flora profiling and fecal metabolite composition of colorectal cancer patients and healthy individuals.

    Science.gov (United States)

    Wang, Xiaoxue; Wang, Jianping; Rao, Benqiang; Deng, Li

    2017-06-01

    Colorectal cancer is one of the most common types of cancer in the world and its morbidity and mortality rates are increasing due to alterations to human lifestyle and dietary habits. The relationship between human gut flora and colorectal cancer has attracted increasing attention. In the present study, a metabolic fingerprinting technique that combined pyrosequencing with gas chromatography-mass spectrometry was utilized to compare the differences in gut flora profiling and fecal metabolites between healthy individuals and patients with colorectal cancer. The results demonstrated that there were no significant differences in the abundance and diversity of gut flora between healthy individuals and patients with colorectal cancer (P>0.05) and the dominant bacterial phyla present in the gut of both groups included Firmicutes , Bacteroidetes and Verrucomicrobia . At the bacterial strain/genus level, significant differences were observed in the relative abundance of 18 species of bacteria (Pflora profiling and metabolite composition. These findings suggest that gut flora disorder results in the alteration of bacterial metabolism, which may be associated with the pathogenesis of colorectal cancer. The results of the present study are useful as a foundation for further studies to elucidate a potential colorectal cancer diagnostic index and therapeutic targets.

  10. Social media in colorectal surgery.

    Science.gov (United States)

    Wexner, S D; Petrucci, A M; Brady, R R; Ennis-O'Connor, M; Fitzgerald, J E; Mayol, J

    2017-02-01

    The engagement of social media in healthcare continues to expand. For members of the colorectal community, social media has already made a significant impact on practice, education and patient care. The applications are unique such that they provide a platform for instant communication and information sharing with other users worldwide. The purpose of this article is to provide an overview of how social media has the potential to change clinical practice, training, research and patient care in colorectal surgery. Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.

  11. Reporting colorectal cancer.

    Science.gov (United States)

    Quirke, P; Morris, E

    2007-01-01

    The management of colorectal cancer is a team process. High-quality reporting of colorectal cancer is very important as the whole team relies upon the skill of the pathologist. Failure to report key features can lead to undertreatment of this disease. The use of a proforma has been demonstrated to be beneficial and we recommend staying with TNM5 due to scientific and reproducibility issues with TNM6. Important features in stage II/Dukes' B cases are extramural vascular invasion, peritoneal involvement, extent of extramural spread, incomplete resection and perforation. All of these may lead to adjuvant therapy being administered. The surgically created circumferential resection margin (CRM) and the mode of its creation are important features and the CRM retains its value after preoperative therapy. Regression grading should be applied only to fully resected tumours and the dissection and sampling must be standardized to allow comparison of results between trials and centres. When reporting local resections of early-stage cancers we need to look for features that predict spread to local lymph nodes to allow a full resection to be considered.

  12. Identification of normal and cancerous human colorectal muscularis propria by multiphoton microscopy in different sections

    International Nuclear Information System (INIS)

    Zhou, Yi; Li, Lianhuang; Zhuo, Shuangmu; Zhu, Xiaoqin; Chen, Jianxin; Chen, Zhifen; Guan, Guoxian; Kang, Deyong

    2016-01-01

    Multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) as a potential diagnostic tool is attractive. MPM can effectively provide information about morphological and biochemical changes in biological tissues at the molecular level. In this paper, we attempt to identify normal and cancerous human colorectal muscularis propria by multiphoton microscopy in different sections (both in transverse and longitudinal sections). The results show that MPM can display different microstructure changes in the transverse and longitudinal sections of colorectal muscularis propria. MPM also can quantitatively describe the alteration of collagen content between normal and cancerous muscle layers. These are important pathological findings that MPM images can bring more detailed complementary information about tissue architecture and cell morphology through observing the transverse and longitudinal sections of colorectal muscularis propria. This work demonstrates that MPM can be better for identifying the microstructural characteristics of normal and cancerous human colorectal muscularis propria in different sections. (paper)

  13. [Use of micro RNAs in the diagnosis and prognosis of colorectal cancer (CCR)].

    Science.gov (United States)

    Arredondo-Valdez, Abril Reneé; Wence-Chavez, Laura; Rosales-Reynoso, Mónica Alejandra

    2016-01-01

    The aim of this review is to present a general overview about the importance of micro RNAs (miRNAs) in colorectal carcinoma. First, we focused on the mechanisms whereby the miRNAs regulate the expression of target genes, and how an altered regulation of them is associated with several types of cancer, including colorectal carcinoma. Later, examples of some miRNAs that have been associated with cancer development and how the expression patterns of specific miRNAs can be used as potential biomarkers for prognosis, diagnosis and therapeutic outcome in colorectal carcinoma are addressed. Finally, several polymorphisms presents in the miRNAs that have been associated to risk and prognosis in colorectal carcinoma are described.

  14. Identification of normal and cancerous human colorectal muscularis propria by multiphoton microscopy in different sections

    Science.gov (United States)

    Zhou, Yi; Chen, Zhifen; Kang, Deyong; li, Lianhuang; Zhuo, Shuangmu; Zhu, Xiaoqin; Guan, Guoxian; Chen, Jianxin

    2016-01-01

    Multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) as a potential diagnostic tool is attractive. MPM can effectively provide information about morphological and biochemical changes in biological tissues at the molecular level. In this paper, we attempt to identify normal and cancerous human colorectal muscularis propria by multiphoton microscopy in different sections (both in transverse and longitudinal sections). The results show that MPM can display different microstructure changes in the transverse and longitudinal sections of colorectal muscularis propria. MPM also can quantitatively describe the alteration of collagen content between normal and cancerous muscle layers. These are important pathological findings that MPM images can bring more detailed complementary information about tissue architecture and cell morphology through observing the transverse and longitudinal sections of colorectal muscularis propria. This work demonstrates that MPM can be better for identifying the microstructural characteristics of normal and cancerous human colorectal muscularis propria in different sections.

  15. Fecal Molecular Markers for Colorectal Cancer Screening

    Directory of Open Access Journals (Sweden)

    Rani Kanthan

    2012-01-01

    Full Text Available Despite multiple screening techniques, including colonoscopy, flexible sigmoidoscopy, radiological imaging, and fecal occult blood testing, colorectal cancer remains a leading cause of death. As these techniques improve, their sensitivity to detect malignant lesions is increasing; however, detection of precursor lesions remains problematic and has generated a lack of general acceptance for their widespread usage. Early detection by an accurate, noninvasive, cost-effective, simple-to-use screening technique is central to decreasing the incidence and mortality of this disease. Recent advances in the development of molecular markers in faecal specimens are encouraging for its use as a screening tool. Genetic mutations and epigenetic alterations that result from the carcinogenetic process can be detected by coprocytobiology in the colonocytes exfoliated from the lesion into the fecal matter. These markers have shown promising sensitivity and specificity in the detection of both malignant and premalignant lesions and are gaining popularity as a noninvasive technique that is representative of the entire colon. In this paper, we summarize the genetic and epigenetic fecal molecular markers that have been identified as potential targets in the screening of colorectal cancer.

  16. Potential role of probiotics on colorectal cancer prevention

    Directory of Open Access Journals (Sweden)

    Uccello Mario

    2012-11-01

    Full Text Available Abstract Background Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. Discussion Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer prevention. Summary Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset. They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host’s immune response; anti-proliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase signaling pathways.

  17. In Silico and in Vitro Screening for P-Glycoprotein Interaction with Tenofovir, Darunavir, and Dapivirine: An Antiretroviral Drug Combination for Topical Prevention of Colorectal HIV Transmission.

    Science.gov (United States)

    Swedrowska, Magda; Jamshidi, Shirin; Kumar, Abhinav; Kelly, Charles; Rahman, Khondaker Miraz; Forbes, Ben

    2017-08-07

    The aim of the study was to use in silico and in vitro techniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir, and dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyze the identified drug-transporter interaction more mechanistically. The transport of tenofovir, darunavir, and dapivirine was investigated in the Caco-2 cell models and colorectal tissue, and their apparent permeability coefficient (P app ), efflux ratio (ER), and the effect of transporter inhibitors were evaluated. In silico, dapivirine and darunavir showed strong affinity for P-gp with similar free energy of binding; dapivirine exhibiting a ΔG PB value -38.24 kcal/mol, darunavir a ΔG PB value -36.84 kcal/mol. The rank order of permeability of the compounds in vitro was tenofovir dapivirine. The P app for tenofovir in Caco-2 cell monolayers was 0.10 ± 0.02 × 10 -6 cm/s, ER = 1. For dapivirine, P app was 32.2 ± 3.7 × 10 -6 cm/s, but the ER = 1.3 was lower than anticipated based on the in silico findings. Neither tenofovir nor dapivirine transport was influenced by P-gp inhibitors. The absorptive permeability of darunavir (P app = 6.4 ± 0.9 × 10 -6 cm/s) was concentration dependent with ER = 6.3, which was reduced by verapamil to 1.2. Administration of the drugs in combination did not alter their permeability compared to administration as single agents. In conclusion, in silico modeling, cell culture, and tissue-based assays showed that tenofovir does not interact with P-gp and is poorly permeable, consistent with a paracellular transport mechanism. In silico modeling predicted that darunavir and dapivirine were P-gp substrates, but only darunavir showed P-gp-dependent permeability in the biological models, illustrating that

  18. Diagnostic Ultrasound in Colorectal Cancer

    DEFF Research Database (Denmark)

    Rafaelsen, Søren Rafael

    2014-01-01

    SUMMARYBackground and purpose Colorectal cancer is a common disease in Denmark with considerable morbidity and mortality. Although survival in recent years has improved, Denmark still has the lowest 5-year survival compared to the other Nordic countries. The treatment of patients depends on local...... the potential to contribute to the staging of colorectal cancer. The purpose of these studies was to determine the usefulness of ultrasound diagnostics in patients with colorectal cancer.The purpose of the TRUS studies was to compare staging of rectal carcinomas using digital rectal exploration...... of 295 patients with primary colorectal cancer we found a sensitivity of preoperative ultrasound, surgical exploration, and intraoperative ultrasound of 70%, 84%, and 97%, respectively, based on a patient-by-patient comparison (p

  19. Danish Colorectal Cancer Group Database

    DEFF Research Database (Denmark)

    Ingeholm, Peter; Gögenur, Ismail; Iversen, Lene H

    2016-01-01

    AIM OF DATABASE: The aim of the database, which has existed for registration of all patients with colorectal cancer in Denmark since 2001, is to improve the prognosis for this patient group. STUDY POPULATION: All Danish patients with newly diagnosed colorectal cancer who are either diagnosed......, and other pathological risk factors. DESCRIPTIVE DATA: The database has had >95% completeness in including patients with colorectal adenocarcinoma with >54,000 patients registered so far with approximately one-third rectal cancers and two-third colon cancers and an overrepresentation of men among rectal...... diagnosis, surgical interventions, and short-term outcomes. The database does not have high-resolution oncological data and does not register recurrences after primary surgery. The Danish Colorectal Cancer Group provides high-quality data and has been documenting an increase in short- and long...

  20. Colorectal Anastomotic Leakage: New perspectives

    NARCIS (Netherlands)

    F. Daams (Freek)

    2014-01-01

    markdownabstract__Abstract__ This thesis provides new perspectives on colorectal anastomotic leakages. In both experimental and clinical studies, aspects of prevention, early identification, treatment and consequences of anastomotic leakage are discussed.

  1. Obesity and colorectal cancer risk

    International Nuclear Information System (INIS)

    Hano Garcia, Olga Marina; Wood Rodriguez, Lisette; Villa Jimenez, Oscar Manuel

    2011-01-01

    Obesity is a chronic and multifactor disease characterized by presence of excess body fat harmful for health. Several studies have been conducted to assess the possible risk character of different factors for colorectal cancer including the following modifying factors: a diet rich in saturated fats, a diet low in vegetables, physical inactivity, alcohol consumption and obesity. A case-control study was conducted to include 276 adult patients (93 cases and 184 controls) consecutively seen from May, 2008 to May, 2009 in the Institute of Gastroenterology determining a possible association between obesity as risk factor and colorectal cancer. Variables measures included: sex, age, skin color, body mass index, hip-waist circumference and endoscopic location of cancer. We conclude that the colorectal cancer with predominance in female sex and in white people in both groups. Obesity according to a great relation hip-waist had an strong relation with colorectal cancer, which had predominance towards distal colon in both sexes

  2. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    International Nuclear Information System (INIS)

    Trubicka, Joanna; Byrski, Tomasz; Gronwald, Jacek; Złowocka, Elżbieta; Kładny, Józef; Banaszkiewicz, Zbigniew; Wiśniowski, Rafał; Kowalska, Elżbieta; Lubinski, Jan; Scott, Rodney J; Grabowska-Kłujszo, Ewa; Suchy, Janina; Masojć, Bartłomiej; Serrano-Fernandez, Pablo; Kurzawski, Grzegorz; Cybulski, Cezary; Górski, Bohdan; Huzarski, Tomasz

    2010-01-01

    CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations

  3. Brain metastases from colorectal cancer

    DEFF Research Database (Denmark)

    Vagn-Hansen, Chris Aksel; Rafaelsen, Søren Rafael

    2001-01-01

    Brain metastases from colorectal cancer are rare. The prognosis for patients with even a single resectable brain metastasis is poor. A case of surgically treated cerebral metastasis from a rectal carcinoma is reported. The brain tumour was radically resected. However, cerebral, as well...... as extracerebral, disease recurred 12 months after diagnosis. Surgical removal of colorectal metastatic brain lesions in selected cases results in a longer survival time....

  4. Familial colorectal cancer type X

    DEFF Research Database (Denmark)

    Dominguez-Valentin, Mev; Therkildsen, Christina; Da Silva, Sabrina

    2015-01-01

    Heredity is a major cause of colorectal cancer, but although several rare high-risk syndromes have been linked to disease-predisposing mutations, the genetic mechanisms are undetermined in the majority of families suspected of hereditary cancer. We review the clinical presentation, histopathologic...... features, and the genetic and epigenetic profiles of the familial colorectal cancer type X (FCCTX) syndrome with the aim to delineate tumor characteristics that may contribute to refined diagnostics and optimized tumor prevention....

  5. EPIDEMIOLOGICAL EVALUATION OF COLORECTAL CANCER

    OpenAIRE

    B. Shafayan M. Keyhani

    2003-01-01

    This study was carried out to analyze certain epidemiological variations in Iranian patients with colorectal cancer. (CRC): From March 1981 up to March 1993, 103 patients were analyzed retrospectively for age, gender, marital state, job, nutritional habits, presenting symptoms and histopathological features. Most of the patients with colorectal cancer were male, age range 20-75 (mean 56), 25.4 percent were long-term smokers and bleeding was the most common symptom. The rectum was the most com...

  6. Robotics in Colorectal Surgery

    Science.gov (United States)

    Weaver, Allison; Steele, Scott

    2016-01-01

    Over the past few decades, robotic surgery has developed from a futuristic dream to a real, widely used technology. Today, robotic platforms are used for a range of procedures and have added a new facet to the development and implementation of minimally invasive surgeries. The potential advantages are enormous, but the current progress is impeded by high costs and limited technology. However, recent advances in haptic feedback systems and single-port surgical techniques demonstrate a clear role for robotics and are likely to improve surgical outcomes. Although robotic surgeries have become the gold standard for a number of procedures, the research in colorectal surgery is not definitive and more work needs to be done to prove its safety and efficacy to both surgeons and patients. PMID:27746895

  7. Colorectal Cancer: Prognostic Values

    Directory of Open Access Journals (Sweden)

    Suzana Manxhuka-Kerliu

    2009-02-01

    Full Text Available After lung cancer colorectal cancer (Cc is ranked the second, as a cause of cancer-related death. The purpose of this study was to analyze the Cc cases in our material with respect to all prognostic values including histological type and grade, vascular invasion, perineural invasion, and tumor border features. There were investigated 149 cases of resection specimen with colorectal cancer, which were fixed in buffered neutral formalin and embedded in paraffin. Tissue sections (4(µm thick were cut and stained with H&E. Adenocarcinoma was the most frequent histological type found in 85,90% of cases, in 60,94% of males and 39,06% of females; squamous cell carcinoma in 7,38%, in 63,63% of males and 36,36% of females; mucinous carcinoma in 4,68%, in 57,15% of males and 42,85% of females; while adenosquamous carcinoma, undifferentiated carcinoma and carcinoma in situ in 0,71% of cases each. Dukes' classification was used in order to define the depth of invasion. Dukes B was found in 68,45% of cases, whereas in 31,54% of cases Dukes C was found. As far as histological grading is concerned, Cc was mostly with moderate differentiation (75,16% with neither vascular nor perineural invasion. Resection margins were in all cases free of tumor. Our data indicate that the pathologic features of the resection specimen constitute the most powerful predictors of postoperative outcome in Cc. Dukes' stage and degree of differentiation provide independent prognostic information in Cc. However, differentiation should be assessed by the worst pattern.

  8. Colorectal Cancer: The Importance of Early Detection

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Colorectal Cancer The Importance of Early Detection Past Issues / Summer ... Cancer of the colon or rectum is called colorectal cancer. The colon and the rectum are part of ...

  9. Genetic Testing for Hereditary Colorectal Cancer

    Science.gov (United States)

    ... before 50). Dave has Lynch syndrome and had colorectal cancer at 28. Amy found out she has Lynch syndrome when she was diagnosed with colorectal cancer days after turning 47. Why is it Important ...

  10. Colorectal Cancer—Health Professional Version

    Science.gov (United States)

    Colorectal cancer studies often consider colon and rectal cancer together. Worldwide, colorectal cancer is the third most common form of cancer. Find evidence-based information on colon and rectal cancer treatment, causes and prevention, screening, research, genetics, and statistics.

  11. Colorectal Cancer: What You Should Know

    Science.gov (United States)

    ... Products For Consumers Home For Consumers Consumer Updates Colorectal Cancer: What You Should Know Share Tweet Linkedin Pin ... with—and more than 50,000 died from—colorectal cancer, according to the National Cancer Institute. It is ...

  12. Predictive cytogenetic biomarkers for colorectal neoplasia in medium risk patients.

    Science.gov (United States)

    Ionescu, E M; Nicolaie, T; Ionescu, M A; Becheanu, G; Andrei, F; Diculescu, M; Ciocirlan, M

    2015-01-01

    DNA damage and chromosomal alterations in peripheral lymphocytes parallels DNA mutations in tumor tissues. The aim of our study was to predict the presence of neoplastic colorectal lesions by specific biomarkers in "medium risk" individuals (age 50 to 75, with no personal or family of any colorectal neoplasia). We designed a prospective cohort observational study including patients undergoing diagnostic or opportunistic screening colonoscopy. Specific biomarkers were analyzed for each patient in peripheral lymphocytes - presence of micronuclei (MN), nucleoplasmic bridges (NPB) and the Nuclear Division Index (NDI) by the cytokinesis-blocked micronucleus assay (CBMN). Of 98 patients included, 57 were "medium risk" individuals. MN frequency and NPB presence were not significantly different in patients with neoplastic lesions compared to controls. In "medium risk" individuals, mean NDI was significantly lower for patients with any neoplastic lesions (adenomas and adenocarcinomas, AUROC 0.668, p 00.5), for patients with advanced neoplasia (advanced adenoma and adenocarcinoma, AUROC 0.636 p 0.029) as well as for patients with adenocarcinoma (AUROC 0.650, p 0.048), for each comparison with the rest of the population. For a cut-off of 1.8, in "medium risk" individuals, an NDI inferior to that value may predict any neoplastic lesion with a sensitivity of 97.7%, an advanced neoplastic lesion with a sensitivity of 97% and adenocarcinoma with a sensitivity of 94.4%. NDI score may have a role as a colorectal cancer-screening test in "medium risk" individuals. DNA = deoxyribonucleic acid; CRC = colorectal cancer; EU = European Union; WHO = World Health Organization; FOBT = fecal occult blood test; CBMN = cytokinesis-blocked micronucleus assay; MN = micronuclei; NPB = nucleoplasmic bridges; NDI = Nuclear Division Index; FAP = familial adenomatous polyposis; HNPCC = hereditary non-polypoid colorectal cancer; IBD = inflammatory bowel diseases; ROC = receiver operating

  13. RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers.

    Science.gov (United States)

    Fennell, Lochlan J; Clendenning, Mark; McKeone, Diane M; Jamieson, Saara H; Balachandran, Samanthy; Borowsky, Jennifer; Liu, John; Kawamata, Futoshi; Bond, Catherine E; Rosty, Christophe; Burge, Matthew E; Buchanan, Daniel D; Leggett, Barbara A; Whitehall, Vicki L J

    2018-01-01

    The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers

  14. The Association Between Molecular Markers in Colorectal Sessile Serrated Polyps and Colorectal Cancer Risk

    Science.gov (United States)

    2017-08-01

    AWARD NUMBER: W81XWH-15-1-0273 TITLE: The Association between Molecular Markers in Colorectal Sessile Serrated Polyps and Colorectal Cancer ... Colorectal Cancer Risk 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0273 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Andrea Burnett-Hartman 5d... cancer in patients with sessile serrated colorectal polyps (SSPs). The project’s specific aims are as follows: 1) Estimate the risk of colorectal

  15. Colorectal cancer with venous tumor thrombosis

    OpenAIRE

    Kensuke Otani; Soichiro Ishihara; Keisuke Hata; Koji Murono; Kazuhito Sasaki; Koji Yasuda; Takeshi Nishikawa; Toshiaki Tanaka; Tomomichi Kiyomatsu; Kazushige Kawai; Hiroaki Nozawa; Hironori Yamaguchi; Toshiaki Watanabe

    2018-01-01

    Summary: Colorectal cancer is seldom accompanied by venous tumor thrombosis, and little is known about the features of venous tumor thrombosis in colorectal cancer. However, some reports show that colorectal cancer patients can develop venous tumor thrombosis and warn clinicians not to overlook this complication. In this report, we perform a review of 43 previously reported cases and investigate the characteristics of colorectal cancer accompanied by venous tumor thrombosis. The histological ...

  16. Colorectal cancer complicating Crohn's disease.

    Science.gov (United States)

    Freeman, H J

    2001-04-01

    Some earlier studies have indicated that patients with inflammatory bowel disease, especially those with long-standing and extensive ulcerative colitis, have an increased risk of colorectal cancer. Moreover, others in tertiary care centres have suggested that patients with Crohn's disease also have a higher risk of colorectal cancer. Canadian data on colorectal cancer in Crohn's disease appear to be limited. For this investigation, a single clinician database of 877 patients with Crohn's disease was used. Altogether, there were six patients with colorectal cancer (ie, overall rate of 0.7%). All of these patients were men with an initial diagnosis of Crohn's disease established at a mean age of approximately 28 years, with either ileocolonic disease or colonic disease alone, but not with ileal disease alone. Although there was a predominance of women in the overall study population (ie, 56.1%), no women developed colorectal cancer. The clinical behaviour of Crohn's disease was classified as nonstricturing in all six patients with colorectal cancer, but in two patients, Crohn's disease was complicated by a perirectal abscess or a fistula. All cancers were located in the rectum and were diagnosed 30 years, 22 years, seven years, 18 years, 20 years and 40 years after Crohn's disease was initially diagnosed. In three patients, the cancer was detected in a residual rectal stump after a partial colon resection at least 10 years earlier. In five patients, localized extension of disease through the serosa, nodal or distant metastases (ie, liver, lung) was found at the time of cancer diagnosis; two patients have since died. The present study confirms that Crohn's disease involving the colon may be a possible risk factor for the development of colorectal cancer, at least in younger men, but, in this study, not in women. However, part of this increased risk in men may have been related to the presence of a rectal stump, rather than to Crohn's disease per se.

  17. Colorectal Cancer Complicating Crohn's Disease

    Directory of Open Access Journals (Sweden)

    Hugh J Freeman

    2001-01-01

    Full Text Available Some earlier studies have indicated that patients with inflammatory bowel disease, especially those with long-standing and extensive ulcerative colitis, have an increased risk of colorectal cancer. Moreover, others in tertiary care centres have suggested that patients with Crohn's disease also have a higher risk of colorectal cancer. Canadian data on colorectal cancer in Crohn's disease appear to be limited. For this investigation, a single clinician database of 877 patients with Crohn's disease was used. Altogether, there were six patients with colorectal cancer (ie, overall rate of 0.7%. All of these patients were men with an initial diagnosis of Crohn's disease established at a mean age of approximately 28 years, with either ileocolonic disease or colonic disease alone, but not with ileal disease alone. Although there was a predominance of women in the overall study population (ie, 56.1%, no women developed colorectal cancer. The clinical behaviour of Crohn's disease was classified as nonstricturing in all six patients with colorectal cancer, but in two patients, Crohn's disease was complicated by a perirectal abscess or a fistula. All cancers were located in the rectum and were diagnosed 30 years, 22 years, seven years, 18 years, 20 years and 40 years after Crohn's disease was initially diagnosed. In three patients, the cancer was detected in a residual rectal stump after a partial colon resection at least 10 years earlier. In five patients, localized extension of disease through the serosa, nodal or distant metastases (ie, liver, lung was found at the time of cancer diagnosis; two patients have since died. The present study confirms that Crohn's disease involving the colon may be a possible risk factor for the development of colorectal cancer, at least in younger men, but, in this study, not in women. However, part of this increased risk in men may have been related to the presence of a rectal stump, rather than to Crohn's disease per se.

  18. Molecular Events in Primary and Metastatic Colorectal Carcinoma: A Review

    Directory of Open Access Journals (Sweden)

    Rani Kanthan

    2012-01-01

    Full Text Available Colorectal cancer (CRC is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a genomic instability, including chromosomal instability (CIN, microsatellite instability (MSI, and CpG island methylator phenotype (CIMP, (b genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c microRNA, and (d epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT, with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript.

  19. Molecular Classification and Correlates in Colorectal Cancer

    OpenAIRE

    Ogino, Shuji; Goel, Ajay

    2008-01-01

    Molecular classification of colorectal cancer is evolving. As our understanding of colorectal carcinogenesis improves, we are incorporating new knowledge into the classification system. In particular, global genomic status [microsatellite instability (MSI) status and chromosomal instability (CIN) status] and epigenomic status [CpG island methylator phenotype (CIMP) status] play a significant role in determining clinical, pathological and biological characteristics of colorectal cancer. In thi...

  20. Cost-effectiveness of colorectal cancer screening

    NARCIS (Netherlands)

    I. Lansdorp-Vogelaar (Iris); A.B. Knudsen (Amy); H. Brenner (Hermann)

    2011-01-01

    textabstractColorectal cancer is an important public health problem. Several screening methods have been shown to be effective in reducing colorectal cancer mortality. The objective of this review was to assess the cost-effectiveness of the different colorectal cancer screening methods and to

  1. Bone morphogenetic protein signalling in colorectal cancer

    NARCIS (Netherlands)

    Hardwick, James C.; Kodach, Liudmila L.; Offerhaus, G. Johan; van den Brink, Gijs R.

    2008-01-01

    Much of the current understanding of colorectal cancer stems from the study of rare, inherited colorectal cancer syndromes. Mutations in the bone morphogenetic protein (BMP) pathway have been found in juvenile polyposis, an inherited polyposis syndrome that predisposes to colorectal cancer. The

  2. Oxidative alteration of uraninite at the Nopal I deposit, Mexico: Possible contaminant transport and source term constraints for the proposed repository at Yucca Mountain

    International Nuclear Information System (INIS)

    Leslie, B.W.; Pearcy, E.C.; Prikryl, J.D.

    1993-01-01

    The Nopal I uranium deposit at Pena Blanca, Mexico is being studied as a natural analog of the proposed high-level nuclear waste repository at Yucca Mountain. Identification of secondary uranium phases at Nopal I, and the sequence of their formation after uraninite oxidation, provides insight into the source term for uranium, and suggests that uranophane may control uranium release and transport in a silici, tuffaceous, chemically oxidizing, and hydrologically unsaturated environment. Possible constraints on contaminant transport at Nopal I are derived from the spatial distribution of uranium and from measurements of 238 U decay-series isotopes. The analyses indicate that flow of U-bearing fluids was influenced strongly by fracture density, but that the flow of these fluids was not restricted to fractures. Gamma spectroscopic measurements of 238 U decay-series isotopes indicates secular equilibrium, which suggests undetectable U transport under present conditions

  3. Inflammatory Dietary Pattern, IL-17F Genetic Variant, and the Risk of Colorectal Cancer.

    Science.gov (United States)

    Cho, Young Ae; Lee, Jeonghee; Oh, Jae Hwan; Chang, Hee Jin; Sohn, Dae Kyung; Shin, Aesun; Kim, Jeongseon

    2018-06-05

    A proinflammatory diet may increase the risk of colorectal cancer, but its role may differ according to individuals' genetic variants. We aimed to examine whether a specific dietary pattern reflecting inflammation was associated with a risk of colorectal cancer and whether IL-17F genetic variant altered this association. In a study of 695 colorectal cancer cases and 1846 controls, we derived a reduced rank regression dietary pattern using 32 food groups as predictors and the plasma C-reactive protein (CRP) concentration as the response. High CRP levels were associated with a high risk of colorectal cancer (OR (95% CI) = 3.58 (2.65⁻4.82) for the highest quartile vs. lowest quartile). After adjusting for potential confounding factors, high pattern scores were associated with a high risk of colorectal cancer (OR (95% CI) = 9.98 (6.81⁻14.62) for the highest quartile vs. lowest quartile). When stratified by the IL-17F rs763780 genotype, this association was stronger for individuals carrying the C allele ( p for interaction = 0.034), particularly for individuals with rectal cancer ( p for interaction = 0.011). In conclusion, a dietary pattern reflecting inflammation was significantly associated with colorectal cancer risk. Moreover, this association could be modified according to the IL-17F rs763780 genotype and anatomic site.

  4. Concordance of genotype for polymorphisms in DNA isolated from peripheral blood and colorectal cancer tumor samples

    NARCIS (Netherlands)

    van Huis-Tanja, Lieke; Kweekel, Dinemarie; Gelderblom, Hans; Koopman, Miriam; Punt, Kees; Guchelaar, Henk-Jan; van der Straaten, Tahar

    2013-01-01

    Background & aim: Results from different pharmacogenetic association studies in colorectal cancer are often conflicting. Both peripheral blood and formalin-fixed, paraffin-embedded (FFPE) tissue are routinely used as DNA source. This could cause bias due to somatic alterations in tumor tissue, such

  5. An evaluation of nuclear factor kappa B expression in colorectal carcinoma: An analysis of 50 cases

    Directory of Open Access Journals (Sweden)

    Nikhil Moorchung

    2014-01-01

    Conclusions: It is likely that NFkB is an important factor in the pathogenesis of CRC. Further studies including therapeutic intervention using strategies which prevent activation of NFkB in colorectal carcinoma patients will tell if we could alter the course of the disease favorably.

  6. Mononucleotide precedes dinucleotide repeat instability during colorectal tumour development in Lynch syndrome patients

    NARCIS (Netherlands)

    Ferreira, Ana M.; Westers, Helga; Sousa, Sonia; Wu, Ying; Niessen, Renee C.; Olderode-Berends, Maran; van der Sluis, Tineke; Reuvekamp, Peter T. W.; Seruca, Raquel; Kleibeuker, Jan H.; Hollema, Harry; Sijmons, Rolf H.; Hofstra, Robert M. W.

    A progressive accumulation of genetic alterations underlies the adenoma-carcinoma sequence of colorectal cancer. This accumulation of mutations is driven by genetic instability, of which there are different types. Microsatellite instability (MSI) is the predominant type present in the tumours of

  7. Synthesis, in vitro and in vivo small-animal SPECT evaluation of novel technetium labeled bile acid analogues to study (altered) hepatic transporter function

    International Nuclear Information System (INIS)

    Neyt, Sara; Vliegen, Maarten; Verreet, Bjorn; De Lombaerde, Stef; Braeckman, Kim; Vanhove, Christian; Huisman, Maarten Thomas; Dumolyn, Caroline; Kersemans, Ken; Hulpia, Fabian; Van Calenbergh, Serge; Mannens, Geert; De Vos, Filip

    2016-01-01

    Introduction: Hepatobiliary transport mechanisms are crucial for the excretion of substrate toxic compounds. Drugs can inhibit these transporters, which can lead to drug–drug interactions causing toxicity. Therefore, it is important to assess this early during the development of new drug candidates. The aim of the current study is the (radio)synthesis, in vitro and in vivo evaluation of a technetium labeled chenodeoxycholic and cholic acid analogue: [ 99m Tc]-DTPA-CDCA and [ 99m ]Tc-DTPA-CA, respectively, as biomarker for disturbed transporter functionality. Methods: [99mTc]-DTPA-CDCA([ 99m Tc]-3a) and [99mTc]-DTPA-CA ([ 99m Tc]-3b) were synthesized and evaluated in vitro and in vivo. Uptake of both tracers was investigated in NTCP, OCT1, OATP1B1, OATP1B3 transfected cell lines. K m and V max values were determined and compared to [ 99m Tc]-mebrofenin ([ 99m Tc]-MEB). Efflux was investigated by means of CTRL, MRP2 and BSEP transfected inside-out vesicles. Metabolite analysis was performed using pooled human liver S9. Wild type (n = 3) and rifampicin treated (n = 3) mice were intravenously injected with 37 MBq of tracer. After dynamic small-animal SPECT and short CT acquisitions, time–activity curves of heart, liver, gallbladder and intestines were obtained. Results: We demonstrated that OATP1B1 and OATP1B3 are the involved uptake transporters of both compounds. Both tracers show a higher affinity compared to [ 99m Tc]-MEB, but are in a similar range as endogenous bile acids for OATP1B1 and OATP1B3. [ 99m Tc]-3a shows higher affinities compared to [ 99m Tc]-3b. V max values were lower compared to [ 99m Tc]-MEB, but in the same range as endogenous bile acids. MRP2 was identified as efflux transporter. Less than 7% of both radiotracers was metabolized in the liver. In vitro results were confirmed by in vivo results. Uptake in the liver and efflux to gallbladder + intestines and urinary bladder of both tracers was observed. Transport was inhibited by rifampicin

  8. Brain metastasis from colorectal cancer

    International Nuclear Information System (INIS)

    Bamba, Yoshiko; Itabashi, Michio; Hirosawa, Tomoichiro; Ogawa, Shinpei; Noguchi, Eiichiro; Takemoto, Kaori; Shirotani, Noriyasu; Kameoka, Shingo

    2007-01-01

    The present study was performed to clarify the clinical characteristics of brain metastasis from colorectal cancer. Five patients with brain metastasis from colorectal cancer treated at our institute between 2001 and 2005 were included in the study. Clinical findings and survival time were determined and an appropriate system for follow-up in such cases was considered. Brain metastasis was found after surgery for colorectal cancer in 4 cases. In addition, colorectal cancer was found after diagnosis of brain metastasis in 1 case. At the time of diagnosis of brain metastasis, all patients had lung metastasis and 3 had liver metastasis. The mean periods between surgery for colorectal cancer and lung and brain metastases were 19.5 and 38.2 months, respectively. In all cases, brain metastasis was diagnosed by imaging after the appearance of neurological symptoms. Brain metastases were multiple in 1 case and focal in 4 cases. We performed gamma knife radiation therapy, and the symptoms disappeared or decreased in all cases. Mean survival time after brain metastasis was 3.0 months. Prognosis after brain metastasis is poor, but gamma knife radiation therapy contributed to patients' quality of life. (author)

  9. Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency.

    Science.gov (United States)

    Vahedi, Shahrooz; Chufan, Eduardo E; Ambudkar, Suresh V

    2017-11-01

    P-glycoprotein (P-gp), an ATP-dependent efflux pump, is linked to the development of multidrug resistance in cancer cells. However, the drug-binding sites and translocation pathways of this transporter are not yet well-characterized. We recently demonstrated the important role of tyrosine residues in regulating P-gp ATP hydrolysis via hydrogen bond formations with high affinity modulators. Since tyrosine is both a hydrogen bond donor and acceptor, and non-covalent interactions are key in drug transport, in this study we investigated the global effect of enrichment of tyrosine residues in the drug-binding pocket on the drug binding and transport function of P-gp. By employing computational analysis, 15 conserved residues in the drug-binding pocket of human P-gp that interact with substrates were identified and then substituted with tyrosine, including 11 phenylalanine (F72, F303, F314, F336, F732, F759, F770, F938, F942, F983, F994), two leucine (L339, L975), one isoleucine (I306), and one methionine (M949). Characterization of the tyrosine-rich P-gp mutant in HeLa cells demonstrated that this major alteration in the drug-binding pocket by introducing fifteen additional tyrosine residues is well tolerated and has no measurable effect on total or cell surface expression of this mutant. Although the tyrosine-enriched mutant P-gp could transport small to moderate size (transport large (>1000 Daltons) substrates such as NBD-cyclosporine A, Bodipy-paclitaxel and Bodipy-vinblastine was significantly decreased. This was further supported by the physico-chemical characterization of seventeen tested substrates, which revealed a negative correlation between drug transport and molecular size for the tyrosine-enriched P-gp mutant. Published by Elsevier Inc.

  10. Alterações lipídicas em pacientes com câncer colorretal em fase pós-operatória: ensaio clínico randomizado e duplo-cego com fungos Agaricus sylvaticus Lipidic alterations in patients with colorectal cancer in post-surgery phase: a randomized and double-blind clinical trial with Agaricus sylvaticus fungus

    Directory of Open Access Journals (Sweden)

    Renata Costa Fortes

    2008-09-01

    Full Text Available INTRODUÇÃO: Alterações no metabolismo lipídico são comuns em pacientes com câncer. Fungos medicinais podem exibir atividade hipolipidêmica. OBJETIVO: Avaliar os efeitos da suplementação dietética com fungos Agaricus sylvaticus no perfil lipídico de pacientes com câncer colorretal em fase pós-operatória. MÉTODOS: Ensaio clínico randomizado, duplo-cego, placebo-controlado, realizado no Hospital de Base do Distrito Federal por seis meses. Amostra constituída por 56 pacientes, estádios I, II e III, separados em dois grupos: placebo e suplementado com Agaricus sylvaticus (30mg/kg/dia. Resultados analisados pelos programas Microsoft Excel 2003 e SPSS 14.0 com p = 0.05. RESULTADOS: O grupo Agaricus sylvaticus apresentou níveis séricos iniciais de colesterol total de 207.36±52.67mg/dL, lipoproteína de baixa densidade de 120.79±44.02mg/dL e triglicérides de 181.64±187.52mg/dL. Após seis meses de suplementação, observou-se redução para 191.11±39.72mg/dL (p = 0.01, 103.08±39.20mg/dL (p = 0.0001 e 168.04±146.91mg/dL (p = 0.18, respectivamente. No grupo placebo, observou-se aumento não-significativo de colesterol total (p = 0.08 e aumento significativo de lipoproteína de baixa densidade (p = 0.01 e triglicérides (p = 0.0001. Não foram observadas, em ambos os grupos, alterações significantes nos níveis de lipoproteína de alta densidade e lipoproteína de muito baixa densidade. CONCLUSÃO: Os resultados sugerem que a suplementação dietética com Agaricus sylvaticus pode melhorar significativamente o perfil lipídico de pacientes com câncer colorretal em fase pós-operatória.INTRODUCTION: Alterations in the lipidic metabolism are common in patients with cancer. Medicinal fungus may show hypolipidemic activity. OBJECTIVE: To evaluate the effects of dietary supplementation with Agaricus sylvaticus fungus in lipidic profile of patients with colorectal cancer in post-surgery phase. MEHTODS: Randomized, double

  11. The understanding of the R7T7 glass blocks long term behavior: chemical and transport coupling in fractured media; Comprehension de l'alteration a long terme des colis de verre R7T7: etude du couplage chimie transport dans un milieu fissure

    Energy Technology Data Exchange (ETDEWEB)

    Chomat, L

    2008-04-15

    The long term behavior of nuclear waste glass blocks depends highly on chemical reactions which occur at the surface in contact with water. Studies carried out on inactive fractured glass blocks show that fracture networks play a significant part in reactive surface area. Nevertheless, the complexity of results interpretation, due to a weak knowledge of fracture networks and local lixiviation conditions, does not allow us to comprehend the physical and chemical mechanisms involved. Model cracks are a key step to study chemical and transport coupling in fractured media. Crack lixiviation in aggressive conditions (pH{>=}11) show that the crack's position (horizontal or vertical) determines the dominant transport mechanism (respectively diffusion or convection induced by gravity). This gravity driven flow seems to be negligible in lower pH conditions. The convective velocity is estimated by a 1D model of reactive transport. Two other parameters are studied: the influence of thermal gradient and the influence of interconnected cracks on alteration. A strong retroactive effect of convection, due to thermal gradient, on the alteration kinetic is observed inside the crack. These works lead to a complete alteration experiment of a 163 crack network subject to a thermal gradient. The use of the geochemical software, HYTEC, within the framework of this study shows the potential of the software which is however limited by the kinetics law used. (author)

  12. The understanding of the R7T7 glass blocks long term behavior: chemical and transport coupling in fractured media; Comprehension de l'alteration a long terme des colis de verre R7T7: etude du couplage chimie transport dans un milieu fissure

    Energy Technology Data Exchange (ETDEWEB)

    Chomat, L

    2008-04-15

    The long term behavior of nuclear waste glass blocks depends highly on chemical reactions which occur at the surface in contact with water. Studies carried out on inactive fractured glass blocks show that fracture networks play a significant part in reactive surface area. Nevertheless, the complexity of results interpretation, due to a weak knowledge of fracture networks and local lixiviation conditions, does not allow us to comprehend the physical and chemical mechanisms involved. Model cracks are a key step to study chemical and transport coupling in fractured media. Crack lixiviation in aggressive conditions (pH{>=}11) show that the crack's position (horizontal or vertical) determines the dominant transport mechanism (respectively diffusion or convection induced by gravity). This gravity driven flow seems to be negligible in lower pH conditions. The convective velocity is estimated by a 1D model of reactive transport. Two other parameters are studied: the influence of thermal gradient and the influence of interconnected cracks on alteration. A strong retroactive effect of convection, due to thermal gradient, on the alteration kinetic is observed inside the crack. These works lead to a complete alteration experiment of a 163 crack network subject to a thermal gradient. The use of the geochemical software, HYTEC, within the framework of this study shows the potential of the software which is however limited by the kinetics law used. (author)

  13. N-linked glycans do not affect plasma membrane localization of multidrug resistance protein 4 (MRP4) but selectively alter its prostaglandin E2 transport activity.

    Science.gov (United States)

    Miah, M Fahad; Conseil, Gwenaëlle; Cole, Susan P C

    2016-01-22

    Multidrug resistance protein 4 (MRP4) is a member of subfamily C of the ATP-binding cassette superfamily of membrane transport proteins. MRP4 mediates the ATP-dependent efflux of many endogenous and exogenous solutes across the plasma membrane, and in polarized cells, it localizes to the apical or basolateral plasma membrane depending on the tissue type. MRP4 is a 170 kDa glycoprotein and here we show that MRP4 is simultaneously N-glycosylated at Asn746 and Asn754. Furthermore, confocal immunofluorescence studies showed that N-glycans do not affect MRP4's apical membrane localization in polarized LLC-PK1 cells or basolateral membrane localization in polarized MDCKI cells. However, vesicular transport assays showed that N-glycans differentially affect MRP4's ability to transport prostaglandin E2, but not estradiol glucuronide. Together these data indicate that N-glycosylation at Asn746 and Asn754 is not essential for plasma membrane localization of MRP4 but cause substrate-selective effects on its transport activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Salinity does not alter the effectiveness of menthol as an anesthetic and sedative during the handling and transport of juvenile fat snook (Centropomus parallelus

    Directory of Open Access Journals (Sweden)

    L. C. O.’R. Sepulchro

    Full Text Available Abstract The effectiveness of menthol as anesthetic and sedative for fat snook (Centropomus parallelus was tested at different salinities. In the first experiment, the fish were exposed to different concentrations of menthol (25, 37 and 50 mg L–1 in water at different salinities (0, 17 and 36 ppt. In the second experiment, the fish were transported for 10 hours in water with menthol at concentrations of 0, 3.7 and 7.4 mg L–1 under different salinities. Na+ and K+ ions from fish body and water were analyzed after transport. The optimal concentrations of menthol for a short handling period and surgical induction was 37 and 50 mg L–1, respectively, and these values were independent of salinity. After transport, neither mortality nor significant changes in ammonia or dissolved oxygen were observed between treatments at the different salinities. The nitrite levels were lower in freshwater than in brackish and saltwater, but did not change with mentol. The total body levels of Na+ increased with the salinity increase. Menthol is an effective anesthetic for handling of juvenile fat snook at different salinities. Menthol did not influence the measured water parameters and body ions, and it is not necessary for the transport of fat snook.

  15. Salinity does not alter the effectiveness of menthol as an anesthetic and sedative during the handling and transport of juvenile fat snook (Centropomus parallelus).

    Science.gov (United States)

    Sepulchro, L C O 'r; Carvalho, M A G; Gomes, L C

    2016-04-19

    The effectiveness of menthol as anesthetic and sedative for fat snook (Centropomus parallelus) was tested at different salinities. In the first experiment, the fish were exposed to different concentrations of menthol (25, 37 and 50 mg L-1) in water at different salinities (0, 17 and 36 ppt). In the second experiment, the fish were transported for 10 hours in water with menthol at concentrations of 0, 3.7 and 7.4 mg L-1 under different salinities. Na+ and K+ ions from fish body and water were analyzed after transport. The optimal concentrations of menthol for a short handling period and surgical induction was 37 and 50 mg L-1, respectively, and these values were independent of salinity. After transport, neither mortality nor significant changes in ammonia or dissolved oxygen were observed between treatments at the different salinities. The nitrite levels were lower in freshwater than in brackish and saltwater, but did not change with mentol. The total body levels of Na+ increased with the salinity increase. Menthol is an effective anesthetic for handling of juvenile fat snook at different salinities. Menthol did not influence the measured water parameters and body ions, and it is not necessary for the transport of fat snook.

  16. Undefined familial colorectal cancer.

    Science.gov (United States)

    Zambirinis, Constantinos Pantelis; Theodoropoulos, George; Gazouli, Maria

    2009-10-15

    Colorectal cancer (CRC), one of the most common cancers of the world, is actually a spectrum of several subtypes, with different molecular profiles, clinico-pathological characteristics and possibly separate pathways of progression. It is estimated that in approximately 25%-35% of cases, a familial component exists, so they are classified as familial CRC (fCRC). However the known hereditary CRC syndromes justify only up to 5%. The rest are attributed to some inherited genetic predisposition passed to offspring through low-penetrance genes, which in the proper environmental setting can bring on tumorigenesis. Furthermore, part of the familial clustering may be attributed to chance. Because of the complexity regarding the etiology of CRC, the clinician is sometimes faced with obscure patient data, and cannot be sure if they are dealing with fCRC or sporadic CRC. The elucidation of what is going on with the as yet "undefined" portion of CRC will aid not only in the diagnosis, classification and treatment of CRC, but more importantly in the proper adjustment of the screening guidelines and in genetic counselling of patients.

  17. Subnuclear proteomics in colorectal cancer

    DEFF Research Database (Denmark)

    Albrethsen, Jakob; Knol, Jaco C; Piersma, Sander R

    2010-01-01

    for early cancer detection. Here we evaluate a proteomics work flow for profiling protein constituents in subnuclear domains in colorectal cancer tissues and apply this work flow to a comparative analysis of the nuclear matrix fraction in colorectal adenoma and carcinoma tissue samples. First, we......Abnormalities in nuclear phenotype and chromosome structure are key features of cancer cells. Investigation of the protein determinants of nuclear subfractions in cancer may yield molecular insights into aberrant chromosome function and chromatin organization and in addition may yield biomarkers...... with statistics, we identified proteins that are significantly enriched in the nuclear matrix fraction relative to two earlier fractions (the chromatin-binding and intermediate filament fractions) isolated from six colorectal tissue samples. The total data set contained 2,059 non-redundant proteins. Gene ontology...

  18. EPIDEMIOLOGICAL EVALUATION OF COLORECTAL CANCER

    Directory of Open Access Journals (Sweden)

    B. Shafayan M. Keyhani

    2003-07-01

    Full Text Available This study was carried out to analyze certain epidemiological variations in Iranian patients with colorectal cancer. (CRC: From March 1981 up to March 1993, 103 patients were analyzed retrospectively for age, gender, marital state, job, nutritional habits, presenting symptoms and histopathological features. Most of the patients with colorectal cancer were male, age range 20-75 (mean 56, 25.4 percent were long-term smokers and bleeding was the most common symptom. The rectum was the most common site and moderately differentiated carcinoma was considered as the main common histopathological variety. In conclusion, increasing incidence of colorectal cancer in younger Iranian population, below 30 and late admission and diagnosis were the main findings in the present study necessitating screening programs with annual fecal occult blood tests in high risk families.

  19. [Oligometastasized colorectal cancer-modern treatment strategies].

    Science.gov (United States)

    Binnebösel, M; Lambertz, A; Dejong, K; Neumann, U P

    2018-06-05

    The prognosis of colorectal cancer in UICC stage IV has been improved in the last decades by improvements in interdisciplinary treatment. Treatment strategies for oligometastasized colorectal cancer are developing more and more into an individualized treatment. An overview of the current literature of modern treatment concepts in oligometastasized colorectal cancer UICC stage IV is given. Surgery still has the supreme mandate in resectable colorectal liver metastases, as neoadjuvant and adjuvant treatment strategies to not provide any benefits for these patients. In marginal or non-resectable stages systemic treatment is superior in these patients depending on the prognostic parameters. Also in curative settings local treatment options should be considered as a reasonable additive tool. An interesting treatment approach for isolated liver metastases and non-resectable colorectal cancer is liver transplantation. Irrespective of new developments in treatment strategies for metastasized colorectal cancer, resection of colorectal liver metastases remains the gold standard whenever possible.

  20. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

    Energy Technology Data Exchange (ETDEWEB)

    Bajenova, Olga, E-mail: o.bazhenova@spbu.ru [Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034 (Russian Federation); Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034 (Russian Federation); Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); Chaika, Nina [Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); Tolkunova, Elena; Davydov-Sinitsyn, Alexander [Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064 (Russian Federation); Gapon, Svetlana [Boston Children' s Hospital, Boston, MA 02115 (United States); Thomas, Peter [Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); O’Brien, Stephen [Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034 (Russian Federation)

    2014-06-10

    Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein.

  1. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

    International Nuclear Information System (INIS)

    Bajenova, Olga; Chaika, Nina; Tolkunova, Elena; Davydov-Sinitsyn, Alexander; Gapon, Svetlana; Thomas, Peter; O’Brien, Stephen

    2014-01-01

    Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein

  2. Increased free Zn2+ correlates induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn2+ -transporters in heart failure.

    Science.gov (United States)

    Olgar, Yusuf; Durak, Aysegul; Tuncay, Erkan; Bitirim, Ceylan Verda; Ozcinar, Evren; Inan, Mustafa Bahadir; Tokcaer-Keskin, Zeynep; Akcali, Kamil Can; Akar, Ahmet Ruchan; Turan, Belma

    2018-03-01

    Zn 2+ -homoeostasis including free Zn 2+ ([Zn 2+ ] i ) is regulated through Zn 2+ -transporters and their comprehensive understanding may be important due to their contributions to cardiac dysfunction. Herein, we aimed to examine a possible role of Zn 2+ -transporters in the development of heart failure (HF) via induction of ER stress. We first showed localizations of ZIP8, ZIP14 and ZnT8 to both sarcolemma and S(E)R in ventricular cardiomyocytes (H9c2 cells) using confocal together with calculated Pearson's coefficients. The expressions of ZIP14 and ZnT8 were significantly increased with decreased ZIP8 level in HF. Moreover, [Zn 2+ ] i was significantly high in doxorubicin-treated H9c2 cells compared to their controls. We found elevated levels of ER stress markers, GRP78 and CHOP/Gadd153, confirming the existence of ER stress. Furthermore, we measured markedly increased total PKC and PKCα expression and PKCα-phosphorylation in HF. A PKC inhibition induced significant decrease in expressions of these ER stress markers compared to controls. Interestingly, direct increase in [Zn 2+ ] i using zinc-ionophore induced significant increase in these markers. On the other hand, when we induced ER stress directly with tunicamycin, we could not observe any effect on expression levels of these Zn 2+ transporters. Additionally, increased [Zn 2+ ] i could induce marked activation of PKCα. Moreover, we observed marked decrease in [Zn 2+ ] i under PKC inhibition in H9c2 cells. Overall, our present data suggest possible role of Zn 2+ transporters on an intersection pathway with increased [Zn 2+ ] i and PKCα activation and induction of HF, most probably via development of ER stress. Therefore, our present data provide novel information how a well-controlled [Zn 2+ ] i via Zn 2+ transporters and PKCα can be important therapeutic approach in prevention/treatment of HF. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and

  3. What is needed to understand feedback mechanisms from agricultural and climate changes that can alter the hydrological system and the transport of sediments and agricultural chemicals?

    Science.gov (United States)

    Coupe, Richard; Payraudeau, Sylvain; Babcsányi, Izabella; Imfeld, Gwenaël

    2015-04-01

    Modern agriculture activities are constantly changing as producers try to produce a crop, keep their soils fertile, control pests, and prevent contamination of air and water resources. Because most of the world's arable land is already in production we must become more efficient if we are to feed and clothe the world's growing population as well as do this in a sustainable manner; leaving a legacy of fertile soil and clean water resources for our descendants. The objective of this paper is to demonstrate the importance of historical datasets and of developing new strategies to understand the effects of changing agricultural systems on the environment. Scientists who study agriculture and its effects on water must constantly adapt their strategies and evaluate how changing agricultural activities impact the environment. As well as understand from historical datasets on hydrology and agriculture how a changing climate or agricultural activity such as a change in tillage method might impact the processes that determine the movement of agricultural chemicals off of the target site. The 42.7 ha Hohrain (Rouffach, Alsace, France) vineyard experimental catchment offers several examples of how scientists have used historical data from this catchment to understand how the transport of agricultural chemicals may change due to a changing climate as well as how new strategies are developed for understanding the transport of agricultural chemicals. Runoff is a major process of pesticide transport from agricultural land to downstream aquatic ecosystems. The impact of rainfall characteristics on the transport of runoff-related pesticides is crucial to understanding how to prevent or minimize their movement now, but also in understanding how climate change might affect runoff. If we understand how rainfall characteristics affect the transport of pesticides, we can use climate change models to predict how those characteristics might change in the future and be better prepared for

  4. Robotic colorectal surgery: previous laparoscopic colorectal experience is not essential.

    Science.gov (United States)

    Sian, Tanvir Singh; Tierney, G M; Park, H; Lund, J N; Speake, W J; Hurst, N G; Al Chalabi, H; Smith, K J; Tou, S

    2018-06-01

    A background in minimally invasive colorectal surgery (MICS) has been thought to be essential prior to robotic-assisted colorectal surgery (RACS). Our aim was to determine whether MICS is essential prior to starting RACS training based on results from our initial experience with RACS. Two surgeons from our centre received robotic training through the European Academy of Robotic Colorectal Surgery (EARCS). One surgeon had no prior formal MICS training. We reviewed the first 30 consecutive robotic colorectal procedures from a prospectively maintained database between November 2014 and January 2016 at our institution. Fourteen patients were male. Median age was 64.5 years (range 36-82) and BMI was 27.5 (range 20-32.5). Twelve procedures (40%) were performed by the non-MICS-trained surgeon: ten high anterior resections (one conversion), one low anterior resection and one abdomino-perineal resection of rectum (APER). The MICS-trained surgeon performed nine high and four low anterior resections, one APER and in addition three right hemicolectomies and one abdominal suture rectopexy. There were no intra-operative complications and two patients required re-operation. Median post-operative stay was five days (range 1-26). There were two 30-day re-admissions. All oncological resections had clear margins and median node harvest was 18 (range 9-39). Our case series demonstrates that a background in MICS is not essential prior to starting RACS training. Not having prior MICS training should not discourage surgeons from considering applying for a robotic training programme. Safe and successful robotic colorectal services can be established after completing a formal structured robotic training programme.

  5. High ABCC2 and Low ABCG2 Gene Expression Are Early Events in the Colorectal Adenoma-Carcinoma Sequence

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Vogel, Lotte K.; Kopp, Tine Iskov

    2015-01-01

    Development of colorectal cancer (CRC) may result from a dysfunctional interplay between diet, gut microbes and the immune system. The ABC transport proteins ABCB1 (P-glycoprotein, Multidrug resistance protein 1, MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) are involved in transport of various compounds...

  6. Altered Function and Expression of ABC Transporters at the Blood–Brain Barrier and Increased Brain Distribution of Phenobarbital in Acute Liver Failure Mice

    Directory of Open Access Journals (Sweden)

    Li Liu

    2018-03-01

    Full Text Available This study investigated alterations in the function and expression of P-glycoprotein (P-GP, breast cancer resistance protein (BCRP, and multidrug resistance-associated protein 2 (MRP2 at the blood–brain barrier (BBB of acute liver failure (ALF mice and its clinical significance. ALF mice were developed using intraperitoneal injection of thioacetamide. P-GP, BCRP, and MRP2 functions were determined by measuring the ratios of brain-to-plasma concentration of rhodamine 123, prazosin, and dinitrophenyl-S-glutathione, respectively. The mRNA and proteins expression levels of P-GP, BCRP, and MRP2 were evaluated with quantitative real-time PCR and western blot, respectively. MDCK-MDR1 and HCMEC/D3 cells were used to document the effects of the abnormally altered components in serum of ALF mice on the function and expression of P-GP. The clinical significance of alteration in P-GP function and expression was investigated by determining the distribution of the P-GP substrate phenobarbital (60 mg/kg, intravenous administration in the brain and loss of righting reflex (LORR induced by the drug (100 mg/kg. The results showed that ALF significantly downregulated the function and expression of both P-GP and BCRP, but increased the function and expression of MRP2 in the brain of mice. Cell study showed that increased chenodeoxycholic acid may be a reason behind the downregulated P-GP function and expression. Compared with control mice, ALF mice showed a significantly higher brain concentration of phenobarbital and higher brain-to-plasma concentration ratios. In accordance, ALF mice showed a significantly larger duration of LORR and shorter latency time of LORR by phenobarbital, inferring the enhanced pharmacological effect of phenobarbital on the central nervous system (CNS. In conclusion, the function and expression of P-GP and BCRP decreased, while the function and expression of MRP2 increased in the brain of ALF mice. The attenuated function and expression

  7. EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis

    International Nuclear Information System (INIS)

    Kokko, Antti; Tomlinson, Ian PM; Vahteristo, Pia; Aaltonen, Lauri A; Laiho, Päivi; Lehtonen, Rainer; Korja, Sanna; Carvajal-Carmona, Luis G; Järvinen, Heikki; Mecklin, Jukka-Pekka; Eng, Charis; Schleutker, Johanna

    2006-01-01

    Ephrin receptor B2 (EPHB2) has recently been proposed as a novel tumor suppressor gene in colorectal cancer (CRC). Inactivation of the gene has been shown to correlate with progression of colorectal tumorigenesis, and somatic mutations have been reported in both colorectal and prostate tumors. Here we have analyzed the EPHB2 gene for germline alterations in 101 individuals either with 1) CRC and a personal or family history of prostate cancer (PC), or 2) intestinal hyperplastic polyposis (HPP), a condition associated with malignant degeneration such as serrated adenoma and CRC. Four previously unknown missense alterations were observed, which may be associated with the disease phenotype. Two of the changes, I361V and R568W, were identified in Finnish CRC patients, but not in over 300 Finnish familial CRC or PC patients or more than 200 population-matched healthy controls. The third change, D861N, was observed in a UK HPP patient, but not in additional 40 UK HPP patients or in 200 UK healthy controls. The fourth change R80H, originally identified in a Finnish CRC patient, was also found in 1/106 familial CRC patients and in 9/281 healthy controls and is likely to be a neutral polymorphism. We detected novel germline EPHB2 alterations in patients with colorectal tumors. The results suggest a limited role for these EPHB2 variants in colon tumor predisposition. Further studies including functional analyses are needed to confirm this

  8. Mammary-Specific Ablation of the Calcium-Sensing Receptor During Lactation Alters Maternal Calcium Metabolism, Milk Calcium Transport, and Neonatal Calcium Accrual

    Science.gov (United States)

    Mamillapalli, Ramanaiah; VanHouten, Joshua; Dann, Pamela; Bikle, Daniel; Chang, Wenhan; Brown, Edward

    2013-01-01

    To meet the demands for milk calcium, the lactating mother adjusts systemic calcium and bone metabolism by increasing dietary calcium intake, increasing bone resorption, and reducing renal calcium excretion. As part of this adaptation, the lactating mammary gland secretes PTHrP into the maternal circulation to increase bone turnover and mobilize skeletal calcium stores. Previous data have suggested that, during lactation, the breast relies on the calcium-sensing receptor (CaSR) to coordinate PTHrP secretion and milk calcium transport with calcium availability. To test this idea genetically, we bred BLG-Cre mice with CaSR-floxed mice to ablate the CaSR specifically from mammary epithelial cells only at the onset of lactation (CaSR-cKO mice). Loss of the CaSR in the lactating mammary gland did not disrupt alveolar differentiation or milk production. However, it did increase the secretion of PTHrP into milk and decreased the transport of calcium from the circulation into milk. CaSR-cKO mice did not show accelerated bone resorption, but they did have a decrease in bone formation. Loss of the mammary gland CaSR resulted in hypercalcemia, decreased PTH secretion, and increased renal calcium excretion in lactating mothers. Finally, loss of the mammary gland CaSR resulted in decreased calcium accrual by suckling neonates, likely due to the combination of increased milk PTHrP and decreased milk calcium. These results demonstrate that the mammary gland CaSR coordinates maternal bone and calcium metabolism, calcium transport into milk, and neonatal calcium accrual during lactation. PMID:23782944

  9. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation.

    Directory of Open Access Journals (Sweden)

    Amy V Pointon

    2010-09-01

    Full Text Available Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.Mice were treated with an acute dose of either doxorubicin (DOX (15 mg/kg or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ (25 mg/kg. DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO. Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted.These data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these

  10. Alterations in mitochondrial electron transport system activity in response to warm acclimation, hypoxia-reoxygenation and copper in rainbow trout, Oncorhynchus mykiss

    International Nuclear Information System (INIS)

    Sappal, Ravinder; MacDougald, Michelle; Fast, Mark; Stevens, Don; Kibenge, Fred; Siah, Ahmed; Kamunde, Collins

    2015-01-01

    Highlights: • Sequential inhibition and activation allows assessment of multiple segments of the electron transport system. • Warm acclimation and hypoxia-reoxygenation have global effects on the electron transport system. • Warm acclimation and hypoxia-reoxygenation sensitize the electron transport system to copper. • Thermal stress, hypoxia-reoxygenation and copper act additively to impair mitochondrial function. - Abstract: Fish expend significant amounts of energy to handle the numerous potentially stressful biotic and abiotic factors that they commonly encounter in aquatic environments. This universal requirement for energy singularizes mitochondria, the primary cellular energy transformers, as fundamental drivers of responses to environmental change. Our study probed the interacting effects of thermal stress, hypoxia-reoxygenation (HRO) and copper (Cu) exposure in rainbow trout to test the prediction that they act jointly to impair mitochondrial function. Rainbow trout were acclimated to 11 (controls) or 20 °C for 2 months. Liver mitochondria were then isolated and their responses in vitro to Cu (0–20 μM) without and with HRO were assessed. Sequential inhibition and activation of mitochondrial electron transport system (ETS) enzyme complexes permitted the measurement of respiratory activities supported by complex I–IV (CI–IV) in one run. The results showed that warm acclimation reduced fish and liver weights but increased mitochondrial protein indicating impairment of energy metabolism, increased synthesis of defense proteins and/or reduced liver water content. Whereas acute rise (11 → 20 °C) in temperature increased mitochondrial oxidation rates supported by CI–IV, warm acclimation reduced the maximal (state 3) and increased the basal (state 4) respiration leading to global uncoupling of oxidative phosphorylation (OXPHOS). HRO profoundly inhibited both maximal and basal respiration rates supported by CI–IV, reduced RCR for all except

  11. Alterations in mitochondrial electron transport system activity in response to warm acclimation, hypoxia-reoxygenation and copper in rainbow trout, Oncorhynchus mykiss

    Energy Technology Data Exchange (ETDEWEB)

    Sappal, Ravinder [Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, C1A 4P3 (Canada); Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, C1A 4P3 (Canada); MacDougald, Michelle [Faculty of Medicine, Memorial University of Newfoundland, Health Sciences Centre, Prince Philip Drive, St. John’s, NL, A1B 3V6 (Canada); Fast, Mark [Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, C1A 4P3 (Canada); Stevens, Don [Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, C1A 4P3 (Canada); Kibenge, Fred [Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, C1A 4P3 (Canada); Siah, Ahmed [British Columbia Centre for Aquatic Health Sciences, 871A Island Highway, Campbell River, BC, V9W 2C2 (Canada); Kamunde, Collins, E-mail: ckamunde@upei.ca [Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, C1A 4P3 (Canada)

    2015-08-15

    Highlights: • Sequential inhibition and activation allows assessment of multiple segments of the electron transport system. • Warm acclimation and hypoxia-reoxygenation have global effects on the electron transport system. • Warm acclimation and hypoxia-reoxygenation sensitize the electron transport system to copper. • Thermal stress, hypoxia-reoxygenation and copper act additively to impair mitochondrial function. - Abstract: Fish expend significant amounts of energy to handle the numerous potentially stressful biotic and abiotic factors that they commonly encounter in aquatic environments. This universal requirement for energy singularizes mitochondria, the primary cellular energy transformers, as fundamental drivers of responses to environmental change. Our study probed the interacting effects of thermal stress, hypoxia-reoxygenation (HRO) and copper (Cu) exposure in rainbow trout to test the prediction that they act jointly to impair mitochondrial function. Rainbow trout were acclimated to 11 (controls) or 20 °C for 2 months. Liver mitochondria were then isolated and their responses in vitro to Cu (0–20 μM) without and with HRO were assessed. Sequential inhibition and activation of mitochondrial electron transport system (ETS) enzyme complexes permitted the measurement of respiratory activities supported by complex I–IV (CI–IV) in one run. The results showed that warm acclimation reduced fish and liver weights but increased mitochondrial protein indicating impairment of energy metabolism, increased synthesis of defense proteins and/or reduced liver water content. Whereas acute rise (11 → 20 °C) in temperature increased mitochondrial oxidation rates supported by CI–IV, warm acclimation reduced the maximal (state 3) and increased the basal (state 4) respiration leading to global uncoupling of oxidative phosphorylation (OXPHOS). HRO profoundly inhibited both maximal and basal respiration rates supported by CI–IV, reduced RCR for all except

  12. Minilaparoscopic Colorectal Resections: Technical Note

    Directory of Open Access Journals (Sweden)

    S. Bona

    2012-01-01

    Full Text Available Laparoscopic colorectal resections have been shown to provide short-term advantages in terms of postoperative pain, general morbidity, recovery, and quality of life. To date, long-term results have been proved to be comparable to open surgery irrefutably only for colon cancer. Recently, new trends keep arising in the direction of minimal invasiveness to reduce surgical trauma after colorectal surgery in order to improve morbidity and cosmetic results. The few reports available in the literature on single-port technique show promising results. Natural orifices endoscopic techniques still have very limited application. We focused our efforts in standardising a minilaparoscopic technique (using 3 to 5 mm instruments for colorectal resections since it can provide excellent cosmetic results without changing the laparoscopic approach significantly. Thus, there is no need for a new learning curve as minilaparoscopy maintains the principle of instrument triangulation. This determines an undoubted advantage in terms of feasibility and reproducibility of the procedure without increasing operative time. Some preliminary experiences confirm that minilaparoscopic colorectal surgery provides acceptable results, comparable to those reported for laparoscopic surgery with regard to operative time, morbidity, and hospital stay. Randomized controlled studies should be conducted to confirm these early encouraging results.

  13. Targeted nanoparticles for colorectal cancer

    DEFF Research Database (Denmark)

    Cisterna, Bruno A.; Kamaly, Nazila; Choi, Won Il

    2016-01-01

    Colorectal cancer (CRC) is highly prevalent worldwide, and despite notable progress in treatment still leads to significant morbidity and mortality. The use of nanoparticles as a drug delivery system has become one of the most promising strategies for cancer therapy. Targeted nanoparticles could...

  14. Colorectal Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing colorectal cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  15. Colorectal Cancer Awareness and Screening

    Centers for Disease Control (CDC) Podcasts

    2017-04-06

    An oncologist (cancer doctor) shares her medical and personal advice for people between the ages of 50 and 75 about getting screened for colorectal cancer.  Created: 4/6/2017 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 4/6/2017.

  16. Costs of Colorectal Cancer Screening

    Centers for Disease Control (CDC) Podcasts

    2017-04-04

    A health economist talks about studies on figuring out the costs of running a colorectal cancer screening program, and how this can lead to better screening.  Created: 4/4/2017 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 4/4/2017.

  17. Optimisation of colorectal cancer treatment

    NARCIS (Netherlands)

    Broek, Colette Bernadine Maria-Theresia van den

    2014-01-01

    Colorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain. For example among certain subgroups of patients, such as elderly patients and patients with

  18. Wound Disruption Following Colorectal Operations.

    Science.gov (United States)

    Moghadamyeghaneh, Zhobin; Hanna, Mark H; Carmichael, Joseph C; Mills, Steven; Pigazzi, Alessio; Nguyen, Ninh T; Stamos, Michael J

    2015-12-01

    Postoperative wound disruption is associated with high morbidity and mortality. We sought to identify the risk factors and outcomes of wound disruption following colorectal resection. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was used to examine the clinical data of patients who underwent colorectal resection from 2005 to 2013. Multivariate regression analysis was performed to identify risk factors of wound disruption. We sampled a total of 164,297 patients who underwent colorectal resection. Of these, 2073 (1.3 %) had wound disruption. Patients with wound disruption had significantly higher mortality (5.1 vs. 1.9 %, AOR: 1.46, P = 0.01). The highest risk of wound disruption was seen in patients with wound infection (4.8 vs. 0.9 %, AOR: 4.11, P disruption such as chronic steroid use (AOR: 1.71, P disruption compared to open surgery (AOR: 0.61, P disruption occurs in 1.3 % of colorectal resections, and it correlates with mortality of patients. Wound infection is the strongest predictor of wound disruption. Chronic steroid use, obesity, severe COPD, prolonged operation, non-elective admission, and serum albumin level are strongly associated with wound disruption. Utilization of the laparoscopic approach may decrease the risk of wound disruption when possible.

  19. Appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid are genetically distinct from primary colorectal-type adenocarcinoma of the appendix

    DEFF Research Database (Denmark)

    Jesinghaus, Moritz; Konukiewitz, Björn; Foersch, Sebastian

    2018-01-01

    The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis...... a morphomolecular entity, histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some....../adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes (eg, TP53, KRAS, APC) were rare to absent in both, goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid, but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large...

  20. Activating mutation in MET oncogene in familial colorectal cancer

    Directory of Open Access Journals (Sweden)

    Schildkraut Joellen M

    2011-10-01

    Full Text Available Abstract Background In developed countries, the lifetime risk of developing colorectal cancer (CRC is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. Methods MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies. Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. Results Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in Conclusions Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will

  1. Cell-Free DNA in Metastatic Colorectal Cancer

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise G.; Boysen, Anders K.; Pallisgard, Niels

    2017-01-01

    -analysis of the prognostic value of total cfDNA in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy. In addition, we report on the overall performance of cfDNA as source for KRAS mutation detection. MATERIALS AND METHODS: A systematic literature search of PubMed and Embase was performed by two......BACKGROUND: Circulating DNA can be detected and quantified in the blood of cancer patients and used for detection of tumor-specific genetic alterations. The clinical utility has been intensively investigated for the past 10 years. The majority of reports focus on analyzing the clinical potential...

  2. HISTOMORPHOLOGICAL STUDY OF COLORECTAL MALIGNANCIES

    Directory of Open Access Journals (Sweden)

    Sarvesh

    2015-07-01

    Full Text Available BACKGROUND: Colorectal cancer is the most common cancer in men and in women worldwide. Incidence rates of colorectal cancer vary 10 - fold in both sexes worldwide, Within Asia, the incidence rates vary widely and are uniformly low in all south Asian countries and high i n all developed Asian countries. Fortunately, the age adjusted incidence rates of colorectal cancer in all the Indian cancer registries are very close to the lowest rates in the world. The present study is under taken to study the prevalence and types of c olorectal cancer among the patients in the rural population in and around Chidambaram. OBJECTIVES: To study the prevalence of malignant colorectal neoplasms among the speci mens received in the Department of Pathology and the gross and histomorphological pa ttern of the lesions and finally to correlate the findings with clinical data. METHOD: The materials consisted of 68 specimens who were submitted to the Department of Pathology, during the period of Jan 2008 - Dec 2012. Data collected and entered in MS - Excel and were analyzed using SPSS - 16. RESULTS : Out of 8454 colonoscopic specimens, 68(0.8% showed colorectal malignancy. A higher frequency of colorectal was seen in 6 th decade. Out of 68 specimens of malignant neoplasms majority were Carcinoma of the Rectum (79.41% followed in decreasing order of frequency by malignant lesions of descending colon(8.82%, ascending and Sigmoid colon (4.41% each, recto - sigmoid (2.94% and cecum (2.63%, and transverse colon (2.63%. Youngest patient was 19 years old and the o ldest patient was 80 years old with a mean age of 49.5 years and median age of 50 years. CONCLUSION: Colorectal cancer is a common and lethal disease. The adenoma carcinoma. S equence offers a window of opportunity in which the precursor lesion or early car cinoma can be removed endoscopically to prevent systematic disease. The result of a careful and systematic examination of surgical specimens from patients with

  3. Persistence of blood changes associated with alteration of the dietary electrolyte balance in commercial pigs after feed withdrawal, transportation, and lairage, and the effects on performance and carcass quality.

    Science.gov (United States)

    Edwards, L N; Engle, T E; Paradis, M A; Correa, J A; Anderson, D B

    2010-12-01

    Increasing dietary electrolyte balance (dEB) has previously been shown to reduce the incidence of nonambulatory and noninjured swine, improve meat quality, and reduce the incidence of gastric ulcers. The objective of this study was to evaluate the effect of dEB under commercial conditions. Due to the variability in feed withdrawal, transport, and lairage conditions in the swine industry, it was necessary to determine first the persistence of blood changes during the marketing process after alteration of dEB. Sixteen pens of 8 crossbred barrows were assigned to a low (121 mEq/kg) or high (375 mEq/kg) dEB diet, calculated as Na(+) + K(+) - Cl(-), to determine the persistence of blood changes associated with the alteration of dEB. Diets were formulated to meet or exceed NRC (1998) requirements for energy, protein, vitamins, and minerals. Dietary treatments were provided for ad libitum intake for 3 d before slaughter. Before transport, animals were fasted in the barn for approximately 10 h. After fasting, animals were shipped to the packing plant, rested for 8 h, and subsequently slaughtered. Initial and final BW of the animals were obtained. Blood was sampled at baseline (2 d before administration of diets), before feed withdrawal (0 h), after feed withdrawal (10 h), and at exsanguination (20 h). Consumption of the high dEB diet for 3 d resulted in an increase in blood TCO(2) (P = 0.001), HCO(3)(-) (P = 0.001), and base excess (P = 0.0003) and a decrease in Cl(-) (P = 0.0002) and anion gap (P = 0.01). These differences, however, were not maintained for any of the blood components after the 10-h feed withdrawal (P > 0.22). Increasing dEB had no adverse effects (P > 0.18) on growth performance, meat quality, or carcass yield and did not decrease pars esophageal ulcer scores. This study demonstrated that the effect of dEB on blood components was not maintained after a 10-h feed withdrawal. Therefore, it is likely that the ability of the animal to withstand any increased

  4. Modifiable risk factors and colorectal adenomas among those at high risk of colorectal cancer

    NARCIS (Netherlands)

    Botma, A.

    2011-01-01

    Epidemiological studies have identified several modifiable risk factors for colorectal neoplasms in the general population. However, associations between modifiable risk factors, including body mass index (BMI), smoking, alcohol consumption and dietary patterns, and colorectal neoplasms in two

  5. Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression

    DEFF Research Database (Denmark)

    Paidi, Maya Devi; Schjoldager, Janne Gram; Lykkesfeldt, Jens

    2014-01-01

    Vitamin C (VitC) has several roles in the brain acting both as a specific and non-specific antioxidant. The brain upholds a very high VitC concentration and is able to preferentially retain VitC even during deficiency. The accumulation of brain VitC levels much higher than in blood is primarily...... achieved by the sodium dependent VitC transporter (SVCT2). This study investigated the effects of chronic pre-and postnatal VitC deficiency as well as the effects of postnatal VitC repletion, on brain SVCT2 expression and markers of oxidative stress in young guinea pigs. Biochemical analyses demonstrated...... significantly decreased total VitC and an increased percentage of dehydroascorbic acid, as well as increased lipid oxidation (malondialdehyde), in the brains of VitC deficient animals (p C repleted animals were not significantly different from controls. No significant changes...

  6. Shengjiang Xiexin Decoction Alters Pharmacokinetics of Irinotecan by Regulating Metabolic Enzymes and Transporters: A Multi-Target Therapy for Alleviating the Gastrointestinal Toxicity.

    Science.gov (United States)

    Guan, Huan-Yu; Li, Peng-Fei; Wang, Xiao-Ming; Yue, Jia-Jing; He, Yang; Luo, Xiao-Mei; Su, Mei-Feng; Liao, Shang-Gao; Shi, Yue

    2017-01-01

    Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medical formula chronicled in Shang Han Lun , is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT-11). In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G), and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC) and the initial plasma concentration (C 0 ) of CPT-11 but decreased the plasma clearance (CL). The AUC and the maximum plasma concentration (C max ) of SN-38 decreased, whereas the C max of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2), P-glycoprotein (P-gp), and carboxylesterase 2 (CES2) was significantly down-regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P

  7. Shengjiang Xiexin Decoction Alters Pharmacokinetics of Irinotecan by Regulating Metabolic Enzymes and Transporters: A Multi-Target Therapy for Alleviating the Gastrointestinal Toxicity

    Directory of Open Access Journals (Sweden)

    Huan-yu Guan

    2017-10-01

    Full Text Available Shengjiang Xiexin decoction (SXD, a classic traditional Chinese medical formula chronicled in Shang Han Lun, is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT-11. In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G, and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC and the initial plasma concentration (C0 of CPT-11 but decreased the plasma clearance (CL. The AUC and the maximum plasma concentration (Cmax of SN-38 decreased, whereas the Cmax of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2, P-glycoprotein (P-gp, and carboxylesterase 2 (CES2 was significantly down-regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP-glucuronosyltransferase 1A1 (UGT1A1 expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P

  8. Placentome Nutrient Transporters and Mammalian Target of Rapamycin Signaling Proteins Are Altered by the Methionine Supply during Late Gestation in Dairy Cows and Are Associated with Newborn Birth Weight.

    Science.gov (United States)

    Batistel, Fernanda; Alharthi, Abdulrahman Sm; Wang, Ling; Parys, Claudia; Pan, Yuan-Xiang; Cardoso, Felipe C; Loor, Juan J

    2017-09-01

    Background: To our knowledge, most research demonstrating a link between maternal nutrition and both fetal growth and offspring development after birth has been performed with nonruminants. Whether such relationships exist in large ruminants is largely unknown. Objective: We aimed to investigate whether increasing the methionine supply during late pregnancy would alter uteroplacental tissue nutrient transporters and mammalian target of rapamycin (mTOR) and their relation with newborn body weight. Methods: Multiparous Holstein cows were used in a randomized complete block design experiment. During the last 28 d of pregnancy, cows were fed a control diet or the control diet plus ethylcellulose rumen-protected methionine (0.9 g/kg dry matter intake) (Mepron; Evonik Nutrition & Care GmbH) to achieve a 2.8:1 ratio of lysine to methionine in the metabolizable protein reaching the small intestine. We collected placentome samples at parturition and used them to assess mRNA and protein expression and the phosphorylation status of mTOR pathway proteins. Results: Newborn body weight was greater in the methionine group than in the control group (44.1 kg and 41.8 kg, respectively; P ≤ 0.05). Increasing the methionine supply also resulted in greater feed intake (15.8 kg/d and 14.6 kg/d), plasma methionine (11.9 μM and 15.3 μM), and plasma insulin (1.16 μg/L and 0.81 μg/L) in cows during late pregnancy. As a result, mRNA expression of genes involved in neutral amino acid transport [solute carrier (SLC) family members SLC3A2 , SLC7A5 , SLC38A1 , and SLC38A10 ], glucose transport [ SLC2A1 , SLC2A3 , and SLC2A4 ], and the mTOR pathway [mechanistic target of rapamycin and ribosomal protein S6 kinase B1] were upregulated ( P ≤ 0.07) in methionine-supplemented cows. Among 6 proteins in the mTOR pathway, increasing the methionine supply led to greater ( P ≤ 0.09) protein expression of α serine-threonine kinase (AKT), phosphorylated (p)-AKT, p-eukaryotic elongation factor 2

  9. Altered sensitivity of system A amino acid transport to ouabain in normal and transformed C3H-10T1/2 cells during the cell cycle

    International Nuclear Information System (INIS)

    Leister, K.J.; Schenerman, M.A.; Racker, E.

    1989-01-01

    Quiescent C3H-10T1/2 mouse fibroblasts that have not undergone any type of stress have a relatively low rate of 2-aminoisobutyrate (Aib) uptake by means of system A, which is primarily energized by the transmembrane Na + chemical gradient potential. System A activity in these cells is not sensitive to ouabain or proton ionophores. In contrast, methylcholanthrene-transformed and cofluent C3H-10T1/2 cells treated with ouabain utilize the membrane potential generated by the Na + , K + -ATPase pump to drive Aib transport by means of system A as shown by the sensitivity of transport activity to ouabain and proton ionophores. Since glucose is present during the assay, the proton ionophores do not affect the availability of ATP, as indicated by the undiminished uptake of 86 Rb + by the Na + , K + -ATPase pump. As cells progress through the G 1 phase of the cell cycle, they show an increased system A activity prior to entry into the S phase, which is also dependent on the electrogenicity of the Na + , K + -ATPase pump. There appears to be in all these cases a qualitative shift in the bioenergetic mechanism for the uptake of Aib as well as a marked quantitative increase in Aib uptake. The high activity after ouabain treatment was sustained in the transformed cells after removal of the ouabain, whereas in the confluent 10T1/2 cells the rate of uptake decayed rapidly, suggesting a difference in the mode of regulation. The authors conclude that transformed cells and normal cells in late G 1 or under stress make use of the membrane potential generated by the Na + , K + -ATPase pump to drive amino acid uptake by means of system A

  10. Effects of altered groundwater chemistry upon the pH-dependency and magnitude of bacterial attachment during transport within an organically contaminated sandy aquifer

    Science.gov (United States)

    Harvey, Ronald W.; Metge, David W.; Barber, Larry B.; Aiken, George R.

    2010-01-01

    The effects of a dilute (ionic strength = 5 ?? 10-3 M) plume of treated sewage, with elevated levels (3.9 mg/L) of dissolved organic carbon (DOC), upon the pH-dependency and magnitude of bacterial transport through an iron-laden, quartz sand aquifer (Cape Cod, MA) were evaluated using sets of replicate, static minicolumns. Compared with uncontaminated groundwater, the plume chemistry diminished bacterial attachment under mildly acidic (pH 5.0-6.5) in-situ conditions, in spite of the 5-fold increase in ionic strength and substantively enhanced attachment under more alkaline conditions. The effects of the hydrophobic neutral and total fractions of the plume DOC; modest concentrations of fulvic and humic acids (1.5 mg/L); linear alkyl benzene sulfonate (LAS) (25 mg/L); Imbentin (200 ??g/L), a model nonionic surfactant; sulfate (28 mg/L); and calcium (20 mg/L) varied sharply in response to relatively small changes in pH, although the plume constituents collectively decreased the pH-dependency of bacterial attachment. LAS and other hydrophobic neutrals (collectively representing only ???3% of the plume DOC) had a disproportionately large effect upon bacterial attachment, as did the elevated concentrations of sulfate within the plume. The findings further suggest that the roles of organic plume constituents in transport or bacteria through acidic aquifer sediments can be very different than would be predicted from column studies performed at circumneutral pH and that the inorganic constituents within the plume cannot be ignored.

  11. Microbial and viral pathogens in colorectal cancer.

    LENUS (Irish Health Repository)

    Collins, Danielle

    2011-05-01

    The heterogenetic and sporadic nature of colorectal cancer has led to many epidemiological associations with causes of this disease. As our understanding of the underlying molecular processes in colorectal-cancer develops, the concept of microbial-epithelial interactions as an oncogenic trigger might provide a plausible hypothesis for the pathogenesis of colorectal cancer. By contrast with other cancers of the gastrointestinal tract (gastric carcinoma, mucosa-associated lymphoid-tissue lymphoma), a direct causal link between microbial infection (bacteria and viruses) and colorectal carcinoma has not been established. Studies support the involvement of these organisms in oncogenesis, however, in colorectal cancer, clinical data are lacking. Here, we discuss current evidence (both in vitro and clinical studies), and focus on a putative role for bacterial and viral pathogens as a cause of colorectal cancer.

  12. Microbial and viral pathogens in colorectal cancer.

    LENUS (Irish Health Repository)

    Collins, Danielle

    2012-02-01

    The heterogenetic and sporadic nature of colorectal cancer has led to many epidemiological associations with causes of this disease. As our understanding of the underlying molecular processes in colorectal-cancer develops, the concept of microbial-epithelial interactions as an oncogenic trigger might provide a plausible hypothesis for the pathogenesis of colorectal cancer. By contrast with other cancers of the gastrointestinal tract (gastric carcinoma, mucosa-associated lymphoid-tissue lymphoma), a direct causal link between microbial infection (bacteria and viruses) and colorectal carcinoma has not been established. Studies support the involvement of these organisms in oncogenesis, however, in colorectal cancer, clinical data are lacking. Here, we discuss current evidence (both in vitro and clinical studies), and focus on a putative role for bacterial and viral pathogens as a cause of colorectal cancer.

  13. Nutrients, Foods, and Colorectal Cancer Prevention

    OpenAIRE

    Song, Mingyang; Garrett, Wendy S.; Chan, Andrew T.

    2015-01-01

    Diet has an important role in the development of colorectal cancer. In the past few decades, findings from extensive epidemiologic and experimental investigation have linked consumption of several foods and nutrients to the risk of colorectal neoplasia. Calcium, fiber, milk, and whole grain have been associated with a lower risk of colorectal cancer, and red meat and processed meat with an increased risk. There is substantial evidence for the potential chemopreventive effects of vitamin D, fo...

  14. Attributable causes of colorectal cancer in China

    OpenAIRE

    Gu, Meng-Jia; Huang, Qiu-Chi; Bao, Cheng-Zhen; Li, Ying-Jun; Li, Xiao-Qin; Ye, Ding; Ye, Zhen-Hua; Chen, Kun; Wang, Jian-Bing

    2018-01-01

    Background Colorectal cancer is the 4th common cancer in China. Most colorectal cancers are due to modifiable lifestyle factors, but few studies have provided a systematic evidence-based assessment of the burden of colorectal cancer incidence and mortality attributable to the known risk factors in China. Methods We estimated the population attributable faction (PAF) for each selected risk factor in China, based on the prevalence of exposure around 2000 and relative risks from cohort studies a...

  15. Nutritional status assessment in colorectal cancer patients

    OpenAIRE

    Joana Pedro Lopes; Paula Manuela de Castro Cardoso Pereira; Ana Filipa dos Reis Baltazar Vicente; Alexandra Bernardo; María Fernanda de Mesquita

    2013-01-01

    The present study intended to evaluate the nutritional status of Portuguese colorectal patients and associated it with surgery type as well as quality of life outcomes. Malnutrition can affect up to 85% of cancer patients and specifically 30-60% in colorectal cancer and can significantly influence health outcomes. A sample of 50 colorectal cancer patients was evaluated in what refers to several anthropometric measures, food intake, clinical history, complications rate before and after surgery...

  16. Management of colorectal cancer and diabetes

    OpenAIRE

    Yao, Caroline; Nash, Guy F; Hickish, Tamas

    2014-01-01

    Colorectal cancer is associated with diabetes mellitus and both of these common conditions are often managed together by a surgeon. The surgical focus is usually upon cancer treatment rather than diabetes management. The relationship between colorectal cancer and diabetes is a complex one and can raise problems in both diagnosis and the management of patients with both conditions. This literature review explores the relationship between diabetes, diabetic treatment and colorectal cancer and a...

  17. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

    Science.gov (United States)

    Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

    2017-04-01

    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Altered glucose transport to utero-embryonic unit in relation to delayed embryonic development in the Indian short-nosed fruit bat, Cynopterus sphinx.

    Science.gov (United States)

    Arnab, Banerjee; Amitabh, Krishna

    2011-02-10

    The aim of this study was to compare the changes in concentration of glucose and glucose transporters (GLUTs) in the utero-embryonic unit, consisting of decidua, trophoblast and embryo, during delayed and non-delayed periods to understand the possible cause of delayed embryonic development in Cynopterus sphinx. The results showed a significantly decreased concentration of glucose in the utero-embryonic unit due to decline in the expression of insulin receptor (IR) and GLUT 3, 4 and 8 proteins in the utero-embryonic unit during delayed period. The in vitro study showed suppressive effect of insulin on expression of GLUTs 4 and 8 in the utero-embryonic unit and a significant positive correlation between the decreased amount of glucose consumed by the utero-embryonic unit and decreased expression of GLUTs 4 (r=0.99; psphinx. Increased supply of fatty acid to the delayed embryo may be responsible for its survival under low glucose condition but unable to promote embryonic development in C. sphinx. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  19. Dark matter sterile neutrinos in stellar collapse: Alteration of energy/lepton number transport, and a mechanism for supernova explosion enhancement

    Science.gov (United States)

    Hidaka, Jun; Fuller, George M.

    2006-12-01

    We investigate matter-enhanced Mikheyev-Smirnov-Wolfenstein (MSW) active-sterile neutrino conversion in the νe⇌νs channel in the collapse of the iron core of a presupernova star. For values of sterile neutrino rest mass ms and vacuum mixing angle θ (specifically, 0.5keV5×10-12) which include those required for viable sterile neutrino dark matter, our one-zone in-fall phase collapse calculations show a significant reduction in core lepton fraction. This would result in a smaller homologous core and therefore a smaller initial shock energy, disfavoring successful shock reheating and the prospects for an explosion. However, these calculations also suggest that the MSW resonance energy can exhibit a minimum located between the center and surface of the core. In turn, this suggests a post-core-bounce mechanism to enhance neutrino transport and neutrino luminosities at the core surface and thereby augment shock reheating: (1) scattering-induced or coherent MSW νe→νs conversion occurs deep in the core, at the first MSW resonance, where νe energies are large (˜150MeV); (2) the high energy νs stream outward at near light speed; (3) they deposit their energy when they encounter the second MSW resonance νs→νe just below the proto-neutron star surface.

  20. Predictors of advanced colorectal neoplasia for colorectal cancer screening.

    Science.gov (United States)

    Wong, Martin C S; Lam, Thomas Y T; Tsoi, Kelvin K F; Chan, Victor C W; Hirai, Hoyee W; Ching, Jessica Y L; Sung, Joseph J Y

    2014-05-01

    The Asia-Pacific Colorectal Screening (APCS) score based on age, gender, family history, and smoking is useful to predict advanced colorectal neoplasia (ACN) in asymptomatic Asian subjects. To evaluate the factors in addition to those of APCS associated with ACN colonoscopic findings. Data from 5,220 asymptomatic subjects aged between 50 and 70 years who underwent screening colonoscopy in a community center between 2008 and 2012 were analyzed. One binary logistic regression analysis was conducted in 2013 with the presence of ACN or cancer as the outcome, controlling for APCS score, alcohol consumption, BMI, hypertension, and other chronic diseases as independent variables. The average participant age was 57.7 years (SD=4.9) and 47.5% were men. Advanced neoplasms or cancers were identified at colonoscopy in 5.6% of all screening participants. From multivariate regression analysis, APCS score≥4 (adjusted OR [AOR]=1.74, 95% CI=1.34, 2.25, pstatistic of APCS score alone was 0.560 (95% CI=0.524, 0.595, p=0.001) and that of APCS score plus BMI, hypertension, and alcohol consumption was 0.613 (95% CI=0.578, 0.648, p<0.001). Alcohol consumption, hypertension, and BMI are independent predictors of ACN, which could be incorporated into the APCS for prioritizing Asian asymptomatic subjects for colorectal cancer screening. Copyright © 2014. Published by Elsevier Inc.

  1. Partial Loss of the Glutamate Transporter GLT-1 Alters Brain Akt and Insulin Signaling in a Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Meeker, Kole D; Meabon, James S; Cook, David G

    2015-01-01

    The glutamate transporter GLT-1 (also called EAAT2 in humans) plays a critical role in regulating extracellular glutamate levels in the central nervous system (CNS). In Alzheimer's disease (AD), EAAT2 loss is associated with neuropathology and cognitive impairment. In keeping with this, we have reported that partial GLT-1 loss (GLT-1+/-) causes early-occurring cognitive deficits in mice harboring familial AD AβPPswe/PS1ΔE9 mutations. GLT-1 plays important roles in several molecular pathways that regulate brain metabolism, including Akt and insulin signaling in astrocytes. Significantly, AD pathogenesis also involves chronic Akt activation and reduced insulin signaling in the CNS. In this report we tested the hypothesis that GLT-1 heterozygosity (which reduces GLT-1 to levels that are comparable to losses in AD patients) in AβPPswe/PS1ΔE9 mice would induce sustained activation of Akt and disturb components of the CNS insulin signaling cascade. We found that partial GLT-1 loss chronically increased Akt activation (reflected by increased phosphorylation at serine 473), impaired insulin signaling (reflected by decreased IRβ phosphorylation of tyrosines 1150/1151 and increased IRS-1 phosphorylation at serines 632/635 - denoted as 636/639 in humans), and reduced insulin degrading enzyme (IDE) activity in brains of mice expressing familial AβPPswe/PS1ΔE9 AD mutations. GLT-1 loss also caused an apparent compensatory increase in IDE activity in the liver, an organ that has been shown to regulate peripheral amyloid-β levels and expresses GLT-1. Taken together, these findings demonstrate that partial GLT-1 loss can cause insulin/Akt signaling abnormalities that are in keeping with those observed in AD.

  2. Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone.

    Science.gov (United States)

    Nagy, Katalin; Marko, Bernadett; Zsilla, Gabriella; Matyus, Peter; Pallagi, Katalin; Szabo, Geza; Juranyi, Zsolt; Barkoczy, Jozsef; Levay, Gyorgy; Harsing, Laszlo G

    2010-12-01

    The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced

  3. Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer

    Science.gov (United States)

    2018-03-22

    Colon Adenocarcinoma; Rectal Adenocarcinoma; Stage III Colorectal Cancer AJCC v7; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IV Colorectal Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7

  4. Pneumatic tube system transport does not alter platelet function in optical and whole blood aggregometry, prothrombin time, activated partial thromboplastin time, platelet count and fibrinogen in patients on anti-platelet drug therapy

    Science.gov (United States)

    Enko, Dietmar; Mangge, Harald; Münch, Andreas; Niedrist, Tobias; Mahla, Elisabeth; Metzler, Helfried; Prüller, Florian

    2017-01-01

    Introduction The aim of this study was to assess pneumatic tube system (PTS) alteration on platelet function by the light transmission aggregometry (LTA) and whole blood aggregometry (WBA) method, and on the results of platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen. Materials and methods Venous blood was collected into six 4.5 mL VACUETTE® 9NC coagulation sodium citrate 3.8% tubes (Greiner Bio-One International GmbH, Kremsmünster, Austria) from 49 intensive care unit (ICU) patients on dual anti-platelet therapy and immediately hand carried to the central laboratory. Blood samples were divided into 2 Groups: Group 1 samples (N = 49) underwent PTS (4 m/s) transport from the central laboratory to the distant laboratory and back to the central laboratory, whereas Group 2 samples (N = 49) were excluded from PTS forces. In both groups, LTA and WBA stimulated with collagen, adenosine-5’-diphosphate (ADP), arachidonic acid (AA) and thrombin-receptor-activated-peptide 6 (TRAP-6) as well as platelet count, PT, APTT, and fibrinogen were performed. Results No statistically significant differences were observed between blood samples with (Group 1) and without (Group 2) PTS transport (P values from 0.064 – 0.968). The AA-induced LTA (bias: 68.57%) exceeded the bias acceptance limit of ≤ 25%. Conclusions Blood sample transportation with computer controlled PTS in our hospital had no statistically significant effects on platelet aggregation determined in patients with anti-platelet therapy. Although AA induced LTA showed a significant bias, the diagnostic accuracy was not influenced. PMID:28392742

  5. Dietary patterns and colorectal cancer

    OpenAIRE

    Tayyem, Reema F.; Bawadi, Hiba A.; Shehadah, Ihab; Agraib, Lana M.; AbuMweis, Suhad S.; Al-Jaberi, Tareq; Al-Nusairr, Majed; Bani-Hani, Kamal E.; Heath, Dennis D.

    2016-01-01

    Summary Background & aimsDietary pattern and lifestyle have been reported to be important risk factors in the development of colorectal cancer (CRC). However, the mechanism of action of dietary factors in CRC disease is unclear. The aim of this study is the examination of several dietary choices and their potential association with the risk of developing CRC. MethodsDietary data was collected from 220 subjects who were previously diagnosed with CRC, and 281 control subjects (matched by age, g...

  6. Tumor markers in colorectal cancer

    OpenAIRE

    Fernandes, Luís César [UNIFESP; Matos, Delcio [UNIFESP

    2002-01-01

    Colorectal cancer is a clinical entity of a persistent relevance in clinical practice and its early diagnosis is a determinant factor to obtain better therapeutic results. Tumor markers are helpful means for a better approach to individuals with such neoplasm. In the present review, the authors analyze the phases in which surgical-clinical treatment markers must be used: diagnosis, determination of tumor stage, establishment of prognosis and detection of recurrence. Current and future markers...

  7. Syncytin immunoreactivity in colorectal cancer

    DEFF Research Database (Denmark)

    Larsen, Julie Mou; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    2009-01-01

    monoclonal syncytin antibody we have assessed syncytin expression in a retrospective series of 140 colorectal cancer patients. Variable degrees of syncytin expression were detected in both colonic and rectal tumors and the prognostic impact of such expression was analysed with the Kaplan-Meier method...... and the Cox proportional hazard model. Interestingly, increased syncytin expression was associated with decreased overall survival in rectal but not in colonic cancer patients. Thus, the prognostic impact of syncytin expression appears to vary with the tumor type....

  8. Immunotherapy for metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Ellebaek, Eva; Andersen, Mads Hald; Svane, Inge Marie

    2012-01-01

    Although no immunotherapeutic treatment is approved for colorectal cancer (CRC) patients, promising results from clinical trials suggest that several immunotherapeutic strategies may prove efficacious and applicable to this group of patients. This review describes the immunogenicity of CRC...... and presents the most interesting strategies investigated so far: cancer vaccination including antigen-defined vaccination and dendritic cell vaccination, chemo-immunotherapy, and adoptive cell transfer. Future treatment options as well as the possibility of combining existing therapies will be discussed along...

  9. Radiologic evaluation of colorectal cancer

    International Nuclear Information System (INIS)

    Lee, Young Joong; Kang, Hee Tae; Kim, Jong Deok; Rhee, Hak Song

    1984-01-01

    The incidence of colorectal cancer of Korea is much lower than that of Western countries, but has shown a tendency to a slight increase recently. Barium enema is the most valuable, noninvasive and inexpensive method available to evaluate the size, shape and site of colorectal cancer. The authors reviewed and radiologically classified barium enema studies of 232 cases of colorectal cancer from Aug. 1967 to July 1982 at Presbyterian Medical Center, Jeonju, Confirmed clinically, operatively and pathologically. The results were as follows; 1. The ratio of male and female was 1.3:1, and youngest was 13 year-old and the oldest 86 year-old. 2. The peak incidence occurred from 5th to 7th decades, accounting for 78% of all cases (181/232), and there was a relatively high incidence of the disease in patients below 30 years of age at 7.8% (18/232). 3. Rectum and rectosigmoid region are the most frequently involved regions (127/232:54.8%). 4. The positivity of barium enema examination was 4.0% (232/5807), and its accuracy was 96.5% (224/232). 5. The radiologic findings were classified into 4 groups, and they were annular encircling 62.9% (146/232). polypoid fungating 26.8% (62/232), infiltrating 8.6% (20/232), and primary ulcerating 1.7% (4/232) in order of frequency. 6. The linear length of the cancer ranged from 1.5 Cm to 15 Cm, and the average length was 5.5 Cm. 7. There was no statistical correlation between the length of lesion, the site, and the radiologic findings, and stages of the lesion (P:0.750-0.250). 8. The majority of colorectal cancers was adenocarcinoma (217/232:93.6%)

  10. Danish Colorectal Cancer Group Database.

    Science.gov (United States)

    Ingeholm, Peter; Gögenur, Ismail; Iversen, Lene H

    2016-01-01

    The aim of the database, which has existed for registration of all patients with colorectal cancer in Denmark since 2001, is to improve the prognosis for this patient group. All Danish patients with newly diagnosed colorectal cancer who are either diagnosed or treated in a surgical department of a public Danish hospital. The database comprises an array of surgical, radiological, oncological, and pathological variables. The surgeons record data such as diagnostics performed, including type and results of radiological examinations, lifestyle factors, comorbidity and performance, treatment including the surgical procedure, urgency of surgery, and intra- and postoperative complications within 30 days after surgery. The pathologists record data such as tumor type, number of lymph nodes and metastatic lymph nodes, surgical margin status, and other pathological risk factors. The database has had >95% completeness in including patients with colorectal adenocarcinoma with >54,000 patients registered so far with approximately one-third rectal cancers and two-third colon cancers and an overrepresentation of men among rectal cancer patients. The stage distribution has been more or less constant until 2014 with a tendency toward a lower rate of stage IV and higher rate of stage I after introduction of the national screening program in 2014. The 30-day mortality rate after elective surgery has been reduced from >7% in 2001-2003 to database is a national population-based clinical database with high patient and data completeness for the perioperative period. The resolution of data is high for description of the patient at the time of diagnosis, including comorbidities, and for characterizing diagnosis, surgical interventions, and short-term outcomes. The database does not have high-resolution oncological data and does not register recurrences after primary surgery. The Danish Colorectal Cancer Group provides high-quality data and has been documenting an increase in short- and long

  11. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Trubicka Joanna

    2010-08-01

    Full Text Available Abstract Background CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs, it represents an attractive candidate gene for studies into colorectal cancer susceptibility. Methods We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. Results The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Conclusion Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.

  12. MALIGNANCY IN LARGE COLORECTAL LESIONS

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Oliveira dos SANTOS

    2014-09-01

    Full Text Available Context The size of colorectal lesions, besides a risk factor for malignancy, is a predictor for deeper invasion Objectives To evaluate the malignancy of colorectal lesions ≥20 mm. Methods Between 2007 and 2011, 76 neoplasms ≥20 mm in 70 patients were analyzed Results The mean age of the patients was 67.4 years, and 41 were women. Mean lesion size was 24.7 mm ± 6.2 mm (range: 20 to 50 mm. Half of the neoplasms were polypoid and the other half were non-polypoid. Forty-two (55.3% lesions were located in the left colon, and 34 in the right colon. There was a high prevalence of III L (39.5% and IV (53.9% pit patterns. There were 72 adenomas and 4 adenocarcinomas. Malignancy was observed in 5.3% of the lesions. Thirty-three lesions presented advanced histology (adenomas with high-grade dysplasia or early adenocarcinoma, with no difference in morphology and site. Only one lesion (1.3% invaded the submucosa. Lesions larger than 30 mm had advanced histology (P = 0.001. The primary treatment was endoscopic resection, and invasive carcinoma was referred to surgery. Recurrence rate was 10.6%. Conclusions Large colorectal neoplasms showed a low rate of malignancy. Endoscopic treatment is an effective therapy for these lesions.

  13. Treatment of colorectal liver metastases

    Directory of Open Access Journals (Sweden)

    Ismaili Nabil

    2011-11-01

    Full Text Available Abstract Colorectal cancer (CRC is the third most common cancer in the word. Liver metastasis is the most common site of colorectal metastases. The prognosis of resectable colorectal liver metastases (CRLM was improved in the recent years with the consideration of chemotherapy and surgical resection as part of the multidisciplinary management of the disease; the current 5-year survival rates after resection of liver metastases are 25% to 40%. Resectable synchronous or metachronous liver metastases should be treated with perioperative chemotherapy based on three months of FOLFOX4 (5-fluorouracil [5FU], folinic acid [LV], and oxaliplatin chemotherapy before surgery and three months after surgery. In the case of primary surgery, pseudo-adjuvant chemotherapy for 6 months, based on 5FU/LV, FOLFOX4, XELOX (capecitabine and oxaliplatin or FOLFIRI (5FU/LV and irinotecan, should be indicated. In potentially resectable disease, primary chemotherapy based on more intensive regimens such as FOLFIRINOX (5FU/LV, irinotecan and oxaliplatin should be considered to enhance the chance of cure. The palliative chemotherapy based on FOLFIRI, or FOLFOX4/XELOX with or without targeted therapies, is the mainstay treatment of unresectable disease. This review would provide additional insight into the problem of optimal integration of chemotherapy and surgery in the management of CRLM.

  14. FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro.

    Science.gov (United States)

    Cha, Yongjun; Kim, Hwang-Phill; Lim, Yoojoo; Han, Sae-Won; Song, Sang-Hyun; Kim, Tae-You

    2018-03-24

    Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of FGFR2 was the only genetic alteration associated with in vitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in a dose-dependent manner and selectively in FGFR2 amplified cells. Regorafenib induced G1 arrest (SNU-16, KATO-III) and apoptosis (NCI-H716), however, no significant changes were seen in cell lines without FGFR2 amplification. In SNU-16 mice xenografts, regorafenib significantly inhibited tumor growth, proliferation, and FGFR signaling compared to treatment with control vehicle. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2 amplified gastric and colorectal cancer and therefore, might be considered for integration into treatment in patients with FGFR2 amplified gastric and colorectal cancers. This article is protected by copyright. All rights reserved. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  15. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer.

    Science.gov (United States)

    Akino, Kimishige; Toyota, Minoru; Suzuki, Hiromu; Mita, Hiroaki; Sasaki, Yasushi; Ohe-Toyota, Mutsumi; Issa, Jean-Pierre J; Hinoda, Yuji; Imai, Kohzoh; Tokino, Takashi

    2005-07-01

    Activation of Ras signaling is a hallmark of colorectal cancer (CRC), but the roles of negative regulators of Ras are not fully understood. Our aim was to address that question by surveying genetic and epigenetic alterations of Ras-Ras effector genes in CRC cells. The expression and methylation status of 6 RASSF family genes were examined using RT-PCR and bisulfite PCR in CRC cell lines and in primary CRCs and colorectal adenomas. Colony formation assays and flow cytometry were used to assess the tumor suppressor activities of RASSF1 and RASSF2. Immunofluorescence microscopy was used to determine the effect of altered RASSF2 expression on cell morphology. Mutations of K- ras , BRAF, and p53 were identified using single-strand conformation analysis and direct sequencing. Aberrant methylation and histone deacetylation of RASSF2 was associated with the gene's silencing in CRC. The activities of RASSF2, which were distinct from those of RASSF1, included induction of morphologic changes and apoptosis; moreover, its ability to prevent cell transformation suggests that RASSF2 acts as a tumor suppressor in CRC. Primary CRCs that showed K- ras /BRAF mutations also frequently showed RASSF2 methylation, and inactivation of RASSF2 enhanced K- ras -induced oncogenic transformation. RASSF2 methylation was also frequently identified in colorectal adenomas. RASSF2 is a novel tumor suppressor gene that regulates Ras signaling and plays a pivotal role in the early stages of colorectal tumorigenesis.

  16. Frequent occurrence of uniparental disomy in colorectal cancer

    DEFF Research Database (Denmark)

    Andersen, Claus Lindbjerg; Wiuf, Carsten; Kruhøffer, Mogens

    2007-01-01

      We used SNP arrays to identify and characterize genomic alterations associated with colorectal cancer (CRC). Laser microdissected cancer cells from 15 adenocarinomas were investigated by Affymetrix Mapping 10K SNP arrays. Analysis of the data extracted from the SNP arrays revealed multiple......, consisting of 17 normal mucosa and 66 adenocarcinoma samples. The transcriptional analysis revealed an unchanged expression level in areas with intact copy number, including regions with uniparental disomy, and a reduced expression level in the LOH regions representing factual losses (including 5q, 8p and 17......p). The analysis also showed that genes in regions with increased copy number (including 7p and 20q) were predominantly upregulated. Further analyses of the SNP data revealed a subset of the identified alterations to be specifically associated with TP53 inactivation (including 8q gain and 17p loss...

  17. A Big Bang model of human colorectal tumor growth.

    Science.gov (United States)

    Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A; Salomon, Matthew P; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F; Shibata, Darryl; Curtis, Christina

    2015-03-01

    What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

  18. Systems Support Mapping in Guiding Self-Management in Stage I-III Colorectal Cancer Survivors

    Science.gov (United States)

    2018-04-26

    Cancer Survivor; Stage I Colorectal Cancer AJCC v8; Stage II Colorectal Cancer AJCC v8; Stage IIA Colorectal Cancer AJCC v8; Stage IIB Colorectal Cancer AJCC v8; Stage IIC Colorectal Cancer AJCC v8; Stage III Colorectal Cancer AJCC v8; Stage IIIA Colorectal Cancer AJCC v8; Stage IIIB Colorectal Cancer AJCC v8; Stage IIIC Colorectal Cancer AJCC v8

  19. Impact of a Multidisciplinary Team Approach for Managing Advanced and Recurrent Colorectal Cancer.

    Science.gov (United States)

    Jung, Sung Min; Hong, Yong Sang; Kim, Tae Won; Park, Jin-Hong; Kim, Jong Hoon; Park, Seong Ho; Kim, Ah Young; Lim, Seok-Byung; Lee, Young-Joo; Yu, Chang Sik

    2017-12-27

    The wide variety of treatment strategies makes clinical decision-making difficult in advanced and recurrent colorectal cancer cases. Many hospitals have started multidisciplinary team (MDT) meetings comprising a team of dedicated specialists for discussing cases. MDTs for selected cases that are difficult to diagnose and treat are alternatives to regular MDTs. This study's aim was to determine the impact of a MDT for colorectal cancer on clinical decision-making. Cases were discussed when clinical specialists had difficulty making decisions alone. All processes done by the MDT were then recorded in prospectively designed medical case forms. From Jan 2011 to Dec 2014, 1383 cases were discussed. A total of 549 (39.8%) case forms were completed for patients with newly diagnosed colorectal cancer, whereas 833 (60.2%) were completed for those with recurrent diseases. The MDT altered the proposed treatment of the referring physician in 179 (13%) cases. In 85 of the 179 (47.5%) altered cases, the radiologist's review of clinical information affected the diagnosis and decision. Furthermore, 152 of the 1383 MDT decisions were not implemented. Treatment intent, therapeutic plan, and alteration of decision were important reasons for not following the MDT's recommendation. Case discussions in MDT meetings resulted in altered clinical decisions in >10% cases. Implementation rates after MDT discussions might be affected by the treatment decision-making process. Imperfect decisions made by individual physicians can be decreased by the multidisciplinary decision-making process.

  20. Association of Calcium-Sensing Receptor (CASR rs 1801725 with Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Fateme Rostami

    2012-07-01

    Full Text Available Background: Calcium induces apoptosis in intestinal epithelial cells and subsequently prevents colorectal cancer through ion calcium receptor. Calcium-sensing receptor mutation reduces the expression of this receptor, and subsequently in reduces calcium transportation. Many studies have shown that Calcium-sensing receptor gene polymorphism may increase the risk of colorectal cancer. The purpose of this study is to assess the prevalence of calcium-sensing receptor polymorphisms (rs 1801725 in Iran society and to examine the role of this polymorphism in the increased risk of colorectal cancer (CRC.Materials and Methods: The research was a case-control study. 105 patients with colorectal cancer and 105 controls were randomly studied using polymerase chain reaction and restriction fragment length polymorphism. χ2 test and software 16- SPSS were used for statistical analysis.Results: In patient samples, the frequency of the genotypes TT, GT, GG in gene CASR rs 1801725 was respectively 64.8, 32.4, and 2.9 and the frequency of this polymorphism in control samples was respectively 51.2, 45.7, and 2.9. Frequency of allele G in patient samples was 0/48 and frequency of allele T was 0.25. In addition, Frequency of allele G in control samples was 0.74 and Frequency of allele T was calculated 0.19.Conclusion: The results show that calcium-sensing receptor variant (1801725 rs is not associated with increased risk of colorectal cancer.

  1. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Inés Mármol

    2017-01-01

    Full Text Available Colorectal cancer (CRC is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%; inherited (5% and familial (25%. The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN, microsatellite instability (MSI and CpG island methylator phenotype (CIMP. Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53, and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined

  2. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

    International Nuclear Information System (INIS)

    Velho, Sérgia; Moutinho, Cátia; Cirnes, Luís; Albuquerque, Cristina; Hamelin, Richard; Schmitt, Fernando; Carneiro, Fátima; Oliveira, Carla; Seruca, Raquel

    2008-01-01

    BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC). In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP), MLH1 methylation and microsatellite instability (MSI). We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied. Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1 methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies. KRAS, PIK3CA or BRAF occur in 71% of polyps and were mutually exclusive. KRAS mutations occur in 35% of polyps. PIK3CA was found in one of the polyps. V600E BRAF mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for BRAF. MLH1 methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS) lead us to demonstrate that KRAS and PIK3CA are likely to precede both types of CRC. BRAF mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P = 0.9112), but statistically different from what is found in microsatellite stable (MSS) tumours (P = 0.0191). Our results show that BRAF, KRAS and PIK3CA mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF mutations occur in association with CIMP phenotype in colorectal serrated polyps and verified that colorectal serrated

  3. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

    Directory of Open Access Journals (Sweden)

    Schmitt Fernando

    2008-09-01

    Full Text Available Abstract Background BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC. In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP, MLH1 methylation and microsatellite instability (MSI. We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied. Methods Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1 methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies. Results KRAS, PIK3CA or BRAF occur in 71% of polyps and were mutually exclusive. KRAS mutations occur in 35% of polyps. PIK3CA was found in one of the polyps. V600E BRAF mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for BRAF. MLH1 methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS lead us to demonstrate that KRAS and PIK3CA are likely to precede both types of CRC. BRAF mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P = 0.9112, but statistically different from what is found in microsatellite stable (MSS tumours (P = 0.0191. Conclusion Our results show that BRAF, KRAS and PIK3CA mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF mutations occur in association with CIMP phenotype in colorectal

  4. Smectite alteration

    International Nuclear Information System (INIS)

    Anderson, D.M.

    1984-11-01

    This report contains the proceedings of a second workshop in Washington DC December 8-9, 1983 on the alteration of smectites intended for use as buffer materials in the long-term containment of nuclear wastes. It includes extended summaries of all presentations and a transcript of the detailed scientific discussion. The discussions centered on three main questions: What is the prerequisite for and what is the precise mechanism by which smectite clays may be altered to illite. What are likly sources of potassium with respect to the KBS project. Is it likely that the conversion of smectite to illite will be of importance in the 10 5 to the 10 6 year time frame. The workshop was convened to review considerations and conclusions in connection to these questions and also to broaden the discussion to consider the use of smectite clays as buffer materials for similar applications in different geographical and geological settings. SKBF/KBS technical report 83-03 contains the proceedings from the first workshop on these matters that was held at the State University of New York, Buffalo May 26-27, 1982. (Author)

  5. Expression of Lewisa, Sialyl Lewisa, Lewisx, Sialyl Lewisx, Antigens as Prognostic Factors in Patients with Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Tohru Nakagoe

    2000-01-01

    Full Text Available BACKGROUND: Altered expression of blood group-related carbohydrate antigens such as sialyl Lewis (Lex antigen in tumours is associated with tumour progression behaviour and subsequent prognosis. However, the prognostic value of the expression of Le-related antigens in colorectal tumours remains unclear.

  6. Indeterminate Pulmonary Nodules at Colorectal Cancer Staging

    DEFF Research Database (Denmark)

    Nordholm-Carstensen, Andreas; Wille-Jørgensen, Peer A; Jorgensen, Lars N

    2013-01-01

    This study aimed to estimate the prevalence of indeterminate pulmonary nodules and specific radiological and clinical characteristics that predict malignancy of these at initial staging chest computed tomography (CT) in patients with colorectal cancer. A considerable number of indeterminate...... pulmonary nodules, which cannot readily be classified as either benign or malignant, are detected at initial staging chest CT in colorectal cancer patients....

  7. Clinical Outcomes of Colorectal Cancer in Kenya

    African Journals Online (AJOL)

    treatment and follow up were included. Patient ... and recurrence and the associated patient and disease ... The incidence of colorectal cancer (CRC) in the devel- ... therapy, disease stage and curative intent (table 3). ... through genetic and family analyses (4,6). ... Polite BN, Dignam JJ: A colorectal cancer model of health.

  8. Iatrogenic colorectal Kaposi sarcoma complicating a refractory ...

    African Journals Online (AJOL)

    Kaposi sarcoma is a mesenchymal tumor associated to a human herpes virus-8. It often occurs in human immunodeficiency virus-positive subjects. Colorectal localization is rare. We report the case of a colorectal Kaposi sarcoma complicating a refractory ulcerative colitis treated with surgery after the failure of ...

  9. Vitamin D, inflammation, and colorectal cancer progression

    NARCIS (Netherlands)

    Harten-Gerritsen, van Suzanne; Balvers, Michiel G.J.; Witkamp, Renger F.; Kampman, Ellen; Duijnhoven, van F.J.B.

    2015-01-01

    Survival from colorectal cancer is positively associated with vitamin D status. However, whether this association is causal remains unclear. Inflammatory processes may link vitamin D to colorectal cancer survival, and therefore investigating inflammatory markers as potential mediators may be a

  10. Optimizing Outcomes of Colorectal Cancer Screening

    NARCIS (Netherlands)

    R.G.S. Meester (Reinier)

    2017-01-01

    markdownabstractColorectal cancer is a leading cause of cancer deaths. Screening for colorectal cancer is implemented in an increasing number of settings, but performance of programs is often suboptimal. In this thesis, advanced modeling, informed by empirical data, was used to identify areas for

  11. Pitfalls and Opportunities in Colorectal Cancer Screening

    NARCIS (Netherlands)

    P.G. van Putten (Paul)

    2013-01-01

    textabstractColorectal cancer (CRC) is the third most common cancer and the second leading cause of death from cancer in the Western world. Screening has been shown to reduce CRC incidence and mortality. The first evidence that colorectal cancer screening could effectively reduce mortality dates

  12. Colorectal Cancer Awareness for Women via Facebook: A Pilot Study.

    Science.gov (United States)

    Brittain, Kelly; Pennings Kamp, Kendra J; Salaysay, Zachary

    Colorectal cancer is the third leading cause of cancer death among U.S. women. Women report being screened for colorectal cancer less often than men, and if colorectal cancer screening guidelines were routinely followed, approximately 60% of colorectal cancer deaths could be prevented. Many colorectal cancer screening interventions have not used Facebook, which is the most popular social media site among women. Little is known about engaging women in colorectal cancer screening and risk reduction information using Facebook. The "Colorectal Cancer Screening Awareness for Women" Facebook page was created to promote colorectal cancer screening and risk reduction awareness among women. Facebook posts targeted women aged 45-64 years and highlighted colorectal cancer screening methods, guidelines, and colorectal cancer risk reduction strategies. Demographics and data about the women's interactions with the page were collected using Facebook analytics and analyzed. The majority of the 391 users of the Colorectal Cancer Screening Awareness for Women Facebook page were women aged 45-54 years (56.5%). The most "liked" posts were related to colorectal cancer risk reduction behaviors. In an effort to increase routine colorectal cancer screening and colorectal cancer risk reduction behaviors, gastroenterology nurses and practices should consider Facebook as a good method to regularly engage women in colorectal cancer screening and colorectal cancer risk reduction information.

  13. Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

    OpenAIRE

    Deschoolmeester, Vanessa; Baay, Marc; Lardon, Filip; Pauwels, Patrick; Peeters, Marc

    2011-01-01

    There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular anti-tumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. Howe...

  14. Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis

    OpenAIRE

    Hisataka Moriwaki; Masaya Kubota; Masahito Shimizu; Takuji Tanaka

    2012-01-01

    Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess a...

  15. Dietary patterns and colorectal cancer.

    Science.gov (United States)

    Tayyem, Reema F; Bawadi, Hiba A; Shehadah, Ihab; Agraib, Lana M; AbuMweis, Suhad S; Al-Jaberi, Tareq; Al-Nusairr, Majed; Bani-Hani, Kamal E; Heath, Dennis D

    2017-06-01

    Dietary pattern and lifestyle have been reported to be important risk factors in the development of colorectal cancer (CRC). However, the mechanism of action of dietary factors in CRC disease is unclear. The aim of this study is the examination of several dietary choices and their potential association with the risk of developing CRC. Dietary data was collected from 220 subjects who were previously diagnosed with CRC, and 281 control subjects (matched by age, gender, occupation and marital status). The data was collected between January 2010 and December 2012, using interview-based questionnaires. Multivariate logistic regression was used to estimate the relationship between dietary choices and risk of developing colorectal cancer. Factor analysis revealed three major dietary patterns. The first pattern we identified as the "Healthy Pattern", the second was identified as "High Sugar/High Tea Pattern" and the third as "Western Pattern". In the Healthy Pattern group we found a 10.54% variation in food intake, while the intake variation was 11.64% in the Western Pattern. After adjusting for confounding factors, the Western Pattern food choice was found to be significantly associated with an increased risk of developing CRC (OR = 1.88; 95% CI = 1.12-3.16). The results for the Healthy and High-Sugar/High Tea Patterns showed a decrease, but the statistic was not significant for the risk of CRC development. The Western Pattern of dietary choice was directly associated with CRC. The association between the dietary food choice in the Healthy and High-Sugar/High Tea Patterns and colorectal cancer needs further study in our Jordanian population. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  16. Nutrients, foods, and colorectal cancer prevention.

    Science.gov (United States)

    Song, Mingyang; Garrett, Wendy S; Chan, Andrew T

    2015-05-01

    Diet has an important role in the development of colorectal cancer. In the past few decades, findings from extensive epidemiologic and experimental investigations have linked consumption of several foods and nutrients to the risk of colorectal neoplasia. Calcium, fiber, milk, and whole grains have been associated with a lower risk of colorectal cancer, and red meat and processed meat have been associated with an increased risk. There is substantial evidence for the potential chemopreventive effects of vitamin D, folate, fruits, and vegetables. Nutrients and foods also may interact, as a dietary pattern, to influence colorectal cancer risk. Diet likely influences colorectal carcinogenesis through several interacting mechanisms. These include the direct effects on immune responsiveness and inflammation, and the indirect effects of overnutrition and obesity-risk factors for colorectal cancer. Emerging evidence also implicates the gut microbiota as an important effector in the relationship between diet and cancer. Dietary modification therefore has the promise of reducing colorectal cancer incidence. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  17. Update on Sporadic Colorectal Cancer Genetics.

    Science.gov (United States)

    Hardiman, Karin M

    2018-05-01

    Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/β-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future.

  18. Perceived religiousness is protective for colorectal cancer: data from the Melbourne Colorectal Cancer Study.

    OpenAIRE

    Kune, G A; Kune, S; Watson, L F

    1993-01-01

    The perceived or self-reported degree of 'religiousness' was obtained by interview from 715 colorectal cancer patients and 727 age/sex matched community controls, as part of a large, comprehensive population-based study of colorectal cancer incidence, aetiology and survival (The Melbourne Colorectal Cancer Study) conducted in Melbourne, Australia. Self-reported or perceived 'religiousness', as defined in the study, was a statistically significant protective factor [relative risk (RR) = 0.70, ...

  19. Xc- inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism.

    Science.gov (United States)

    Ma, Ming-zhe; Chen, Gang; Wang, Peng; Lu, Wen-hua; Zhu, Chao-feng; Song, Ming; Yang, Jing; Wen, Shijun; Xu, Rui-hua; Hu, Yumin; Huang, Peng

    2015-11-01

    Sulfasalazine (SSZ) is an anti-inflammatory drug that has been demonstrated to induce apoptosis and tumor regression through inhibition of plasma membrane cystine transporter xc(-). Cysteine is a rate-limiting precursor for intracellular glutathione (GSH) synthesis, which is vital for compound detoxification and maintaining redox balance. Platinum-based chemotherapy is an important regimen used in clinics for various cancers including colorectal cancer (CRC). We hypothesized that targeting xc(-) transporter by SSZ may annihilate cellular detoxification through interruption of GSH synthesis and may enhance the anti-cancer activity of cisplatin (CDDP) by increasing drug transport. In the present study, we revealed that xCT, the active subunit of xc(-), is highly expressed in CRC cell lines and human colorectal carcinoma tissues compared with their normal counterparts. SSZ effectively depleted cellular GSH, leading to significant accumulation of reactive oxygen species and growth inhibition in CRC cells. In contrast, the normal epithelial cells of colon origin were less sensitive to SSZ, showing a moderate ROS elevation. Importantly, SSZ effectively enhanced the intracellular platinum level and cytotoxicity of CDDP in CRC cells. The synergistic effect of SSZ and CDDP was reversed by antioxidant N-acetyl-L-cysteine (NAC). Together, these results suggest that SSZ, a relatively non-toxic drug that targets cystine transporter, may, in combination with CDDP, have effective therapy for colorectal cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Management of colorectal cancer and diabetes.

    Science.gov (United States)

    Yao, Caroline; Nash, Guy F; Hickish, Tamas

    2014-03-01

    Colorectal cancer is associated with diabetes mellitus and both of these common conditions are often managed together by a surgeon. The surgical focus is usually upon cancer treatment rather than diabetes management. The relationship between colorectal cancer and diabetes is a complex one and can raise problems in both diagnosis and the management of patients with both conditions. This literature review explores the relationship between diabetes, diabetic treatment and colorectal cancer and addresses the issues that arise in diagnosing and treating this patient group. By highlighting these difficulties, this review aims to improve understanding and to provide clearer insight into both surgical and non-surgical management.

  1. Confocal Endomicroscopy of Colorectal Polyps

    Directory of Open Access Journals (Sweden)

    Vivian M. Ussui

    2012-01-01

    Full Text Available Confocal laser endomicroscopy (CLE is one of several novel methods that provide real-time, high-resolution imaging at a micron scale via endoscopes. CLE has the potential to be a disruptive technology in that it can change the current algorithms that depend on biopsy to perform surveillance of high-risk conditions. Furthermore, it allows on-table decision making that has the potential to guide therapy in real time and reduce the need for repeated procedures. CLE and related technologies are often termed “virtual biopsy” as they simulate the images seen in traditional histology. However, the imaging of living tissue allows more than just pragmatic convenience; it also allows imaging of living tissue such as active capillary circulation, cellular death, and vascular and endothelial translocation, thus extending beyond what is capable in traditional biopsy. Immediate potential applications of CLE are to guide biopsy sampling in Barrett's esophagus and inflammatory bowel disease surveillance, evaluation of colorectal polyps, and intraductal imaging of the pancreas and bile duct. Data on these applications is rapidly emerging, and more is needed to clearly demonstrate the optimal applications of CLE. In this paper, we will focus on the role of CLE as applied to colorectal polyps detected during colonoscopy.

  2. Effects of the combination of blood transfusion and postoperative infectious complications on prognosis after surgery for colorectal cancer. Danish RANX05 Colorectal Cancer Study Group

    DEFF Research Database (Denmark)

    Mynster, T; Christensen, Ib Jarle; Moesgaard, F

    2000-01-01

    affects the prognosis. METHODS: Patient risk variables, variables related to operation technique, blood transfusion and the development of infectious complications were recorded prospectively in 740 patients undergoing elective resection for primary colorectal cancer. Endpoints were overall survival (n......BACKGROUND: The frequency of postoperative infectious complications is significantly increased in patients with colorectal cancer receiving perioperative blood transfusion. It is still debated, however, whether perioperative blood transfusion alters the incidence of disease recurrence or otherwise...... = 740) and time to diagnosis of recurrent disease in the subgroup of patients operated on with curative intention (n = 532). The patients were analysed in four groups divided with respect to administration or not of perioperative blood transfusion and development or non-development of postoperative...

  3. Effects of the combination of blood transfusion and postoperative infectious complications on prognosis after surgery for colorectal cancer. Danish RANX05 Colorectal Cancer Study Group

    DEFF Research Database (Denmark)

    Mynster, T; Christensen, Ib Jarle; Moesgaard, F

    2000-01-01

    BACKGROUND: The frequency of postoperative infectious complications is significantly increased in patients with colorectal cancer receiving perioperative blood transfusion. It is still debated, however, whether perioperative blood transfusion alters the incidence of disease recurrence or otherwise...... affects the prognosis. METHODS: Patient risk variables, variables related to operation technique, blood transfusion and the development of infectious complications were recorded prospectively in 740 patients undergoing elective resection for primary colorectal cancer. Endpoints were overall survival (n...... = 740) and time to diagnosis of recurrent disease in the subgroup of patients operated on with curative intention (n = 532). The patients were analysed in four groups divided with respect to administration or not of perioperative blood transfusion and development or non-development of postoperative...

  4. Increased expression of protease-activated receptor 4 and Trefoil factor 2 in human colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Guoyu Yu

    Full Text Available Protease-activated receptor 4 (PAR4, a member of G-protein coupled receptors family, was recently reported to exhibit decreased expression in gastric cancer and esophageal squamous cancer, yet increased expression during the progression of prostate cancer. Trefoil factor 2 (TFF2, a small peptide constitutively expressed in the gastric mucosa, plays a protective role in restitution of gastric mucosa. Altered TFF2 expression was also related to the development of gastrointestinal cancer. TFF2 has been verified to promote cell migration via PAR4, but the roles of PAR4 and TFF2 in the progress of colorectal cancer are still unknown. In this study, the expression level of PAR4 and TFF2 in colorectal cancer tissues was measured using real-time PCR (n = 38, western blotting (n=38 and tissue microarrays (n = 66. The mRNA and protein expression levels of PAR4 and TFF2 were remarkably increased in colorectal cancer compared with matched noncancerous tissues, especially in positive lymph node and poorly differentiated cancers. The colorectal carcinoma cell LoVo showed an increased response to TFF2 as assessed by cell invasion upon PAR4 expression. However, after intervention of PAR4 expression, PAR4 positive colorectal carcinoma cell HT-29 was less responsive to TFF2 in cell invasion. Genomic bisulfite sequencing showed the hypomethylation of PAR4 promoter in colorectal cancer tissues and the hypermethylation in the normal mucosa that suggested the low methylation of promoter was correlated to the increased PAR4 expression. Taken together, the results demonstrated that the up-regulated expression of PAR4 and TFF2 frequently occurs in colorectal cancer tissues, and that overexpression of PAR4 may be resulted from promoter hypomethylation. While TFF2 promotes invasion activity of LoVo cells overexpressing PAR4, and this effect was significantly decreased when PAR4 was knockdowned in HT-29 cells. Our findings will be helpful in further investigations into the

  5. Transport Statistics - Transport - UNECE

    Science.gov (United States)

    Sustainable Energy Statistics Trade Transport Themes UNECE and the SDGs Climate Change Gender Ideas 4 Change UNECE Weekly Videos UNECE Transport Areas of Work Transport Statistics Transport Transport Statistics About us Terms of Reference Meetings and Events Meetings Working Party on Transport Statistics (WP.6

  6. Complex pattern of immune evasion in MSI colorectal cancer.

    Science.gov (United States)

    Ozcan, Mine; Janikovits, Jonas; von Knebel Doeberitz, Magnus; Kloor, Matthias

    2018-01-01

    Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation, and 54% of these mutations were predicted to abrogate function. Mutations affecting the HLA class I transactivator NLRC5 were observed as a potential new immune evasion mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in MMR-deficient cancers were associated with decreased levels of HLA class I antigen expression. In summary, the majority of MMR-deficient cancers display mutations interfering with HLA class I antigen presentation that reflect active immune surveillance and immunoselection during tumor development. Clinical studies focusing on immune checkpoint blockade in MSI cancer should account for the broad variety of immune evasion mechanisms as potential biomarkers of therapy success.

  7. EGFR signaling in colorectal cancer: a clinical perspective

    Directory of Open Access Journals (Sweden)

    Saletti P

    2015-01-01

    Full Text Available Piercarlo Saletti,1 Francesca Molinari,2 Sara De Dosso,1 Milo Frattini2 1Oncology Institute of Southern Switzerland, Bellinzona, 2Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland Abstract: Colorectal cancer (CRC remains a formidable health burden worldwide, with up to 50% of patients developing metastases during the course of their disease. This group of CRC patients, characterized by the worst prognosis, has been extensively investigated to improve their life expectancy. Main efforts, focused on the epidermal growth-factor receptor (EGFR, which plays a pivotal role in CRC pathogenesis, have led to the development and introduction in clinical practice of specific targeted therapies (ie, monoclonal antibodies. Subsequently, the scientific community has tried to identify molecular predictors of the efficacy of such therapies. However, it has become clear that EGFR alterations occurring in CRC are difficult to investigate, and therefore their predictive role is unclear. In contrast, the clinical role of two downstream members (KRAS and NRAS has been clearly demonstrated. Currently, EGFR-targeted therapies can be administered only to patients with wild-type KRAS and NRAS genes. Our review addresses the medical management of metastatic CRC. Specifically, we describe in detail the molecular biology of metastatic CRC, focusing on the EGFR signaling pathway, and we discuss the role of current and emerging related biomarkers and therapies in this field. We also summarize the clinical evidence regarding anti-EGFR monoclonal antibodies and examine potential future perspectives. Keywords: colorectal cancer, EGFR, gene mutations, cetuximab, panitumumab

  8. Serrated Polyposis: An Enigmatic Model of Colorectal Cancer Predisposition

    Directory of Open Access Journals (Sweden)

    Christophe Rosty

    2011-01-01

    Full Text Available Serrated polyposis has only recently been accepted as a condition which carries an increased personal and familial risk of colorectal cancer. Described over four decades ago, it remains one of the most underrecognized and poorly understood of all the intestinal polyposes. With a variety of phenotypic presentations, it is likely that serrated polyposis represents a group of diseases rather than a single entity. Further, neoplastic progression in serrated polyposis may be associated with premature aging in the normal mucosa, typified by widespread gene promoter hypermethylation. From this epigenetically altered field, arise diverse polyps and cancers which show a range of molecular features. Despite a high serrated polyp count, only one-third of colorectal cancers demonstrate a BRAF V600E mutation, the molecular hallmark of the canonical serrated pathway, suggesting that though multiple serrated polyps act as a marker of an abnormal mucosa, the majority of CRC in these patients arise within lesions other than BRAF-mutated serrated polyps.

  9. A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Castanos-Velez Esmeralda

    2006-09-01

    Full Text Available Abstract Background Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. Results We investigated genome-wide gene expression in colorectal carcinoma (CRC and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. Conclusion An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin also have a substantial impact on the formation of co-expression islands in colorectal carcinoma.

  10. Butyrate decreases its own oxidation in colorectal cancer cells through inhibition of histone deacetylases.

    Science.gov (United States)

    Han, Anna; Bennett, Natalie; Ahmed, Bettaieb; Whelan, Jay; Donohoe, Dallas R

    2018-06-05

    Colorectal cancer is characterized by an increase in the utilization of glucose and a diminishment in the oxidation of butyrate, which is a short chain fatty acid. In colorectal cancer cells, butyrate inhibits histone deacetylases to increase the expression of genes that slow the cell cycle and induce apoptosis. Understanding the mechanisms that contribute to the metabolic shift away from butyrate oxidation in cancer cells is important in in understanding the beneficial effects of the molecule toward colorectal cancer. Here, we demonstrate that butyrate decreased its own oxidation in cancerous colonocytes. Butyrate lowered the expression of short chain acyl-CoA dehydrogenase, an enzyme that mediates the oxidation of short-chain fatty acids. Butyrate does not alter short chain acyl-CoA dehydrogenase levels in non-cancerous colonocytes. Trichostatin A, a structurally unrelated inhibitor of histone deacetylases, and propionate also decreased the level of short chain acyl-CoA dehydrogenase, which alluded to inhibition of histone deacetylases as a part of the mechanism. Knockdown of histone deacetylase isoform 1, but not isoform 2 or 3, inhibited the ability of butyrate to decrease short chain acyl-CoA dehydrogenase expression. This work identifies a mechanism by which butyrate selective targets colorectal cancer cells to reduce its own metabolism.

  11. Colorectal adenomatous polyposis syndromes: Genetic determinism, clinical presentation and recommendations for care.

    Science.gov (United States)

    Buecher, Bruno

    2016-02-01

    Colorectal adenomatous polyposis constitutes a diverse group of disorders with different modes of inheritance. Molecular diagnosis of this condition has become more complex. In fact, somatic mosaicism for APC mutations now appears to be more frequent than previously thought and rare germline alterations of this gene may be implicated in patients tested negative for "classical" APC mutations (point mutations and large genomic rearrangements). Moreover, the knowledge concerning several aspects of the MUTYH-associated polyposis has improved since its first description in 2002 and germline mutations in new genes have recently been implicated in some cases of unexplained adenomatous polyposis. Genetic testing in probands and their relatives should be conducted in the context of pre- and post-test genetic counseling. The recent advent of New Generation Sequencing (NGS) techniques affords the opportunity to rapidly screen patients for a comprehensive panel of colorectal cancer susceptibility genes in a cost-effective fashion. This type of approach will probably replace the classical sequential approach based on clinical presumptive diagnoses in the near future. The risk of colorectal cancer is very high in affected patients in the absence of appropriate care. Clinical management is complex and should be provided in centers with special expertise in these diseases. This review focuses on the various colorectal adenomatous polyposis syndromes with special attention to more innovative and important aspects. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  12. Internal hernia following laparoscopic colorectal surgery

    DEFF Research Database (Denmark)

    Svraka, Melina; Wilhelmsen, Michał; Bulut, Orhan

    2017-01-01

    Although internal hernias are rare complications of laparoscopic colorectal surgery, they can lead to serious outcomes and are associated with a high mortality of up 20 %. AIM OF THE STUDY: The aim of this study was to describe our experience regarding internal herniation following laparoscopic...... colorectal surgery. MATERIALS AND METHODS: From 2009 to 2015, more than 1,093 laparoscopic colorectal procedures were performed, and 6 patients developed internal herniation. Data were obtained from patients' charts and reviewed retrospectively. Perioperative course and outcomes were analyzed. RESULTS: All...... patients were previously operated due to colorectal cancer. Two patients presented with ischemia at laparotomy, and 2 had endoscopic examinations before surgery. One patient was diagnosed with cancer on screening colonoscopy. One patient died after laparotomy. CONCLUSION: Internal herniation that develops...

  13. Colorectal cancer, diabetes and survival : Epidemiological insights

    NARCIS (Netherlands)

    Zanders, M. M. J.; Vissers, P. A. J.; Haak, H. R.; van de Poll-Franse, L.

    Colorectal cancer (CRC) patients with pre-existing diabetes have significantly lower rates of overall survival compared with patients without diabetes. Against this backdrop, the American Diabetes Association and American Cancer Society in 2010 reviewed the scientific literature concerning diabetes

  14. Growth and progression of colorectal cancer

    International Nuclear Information System (INIS)

    Yamada, T.; Ushio, K.; Hirota, T.

    1988-01-01

    There is an increasing interest in the natural history of colorectal carcinoma, now that small polypoid lesions of the large intestine can be detected effectively by radiology and endoscopy. The problems of this histo- and morphogenesis of colorectal cancer have, however, remained unsettled because the observation of the sequential change of a lesion with time by follow-up radiology and/or endoscopy is impossible once its malignancy is proved. Clinically the retrospective review of radiographic findings in overlooked cases is the only means to evaluate the natural history of colorectal cancer. This paper attempts to estimate the growth rate of colorectal cancer, based on a retrospective review of radiographic findings of overlooked cases, and analyses of the radiographic features of small polypoid lesions which may develop into advanced cancers

  15. Meat and colo-rectal cancer.

    Science.gov (United States)

    Hill, M J

    1999-05-01

    In early epidemiological studies of diet and cancer the stress was on the search for causal factors. Population (ecological) studies tended to show a strong correlation between meat intake, particularly red meat, and the risk of colo-rectal cancer. They also tended to show meat to be strongly inversely correlated with cancers of the stomach and oesophagus and liver. Early case-control studies tended to support the postulated role for red meat in colo-rectal carcinogenesis, although more recent case-control studies, particularly those from Europe, have tended to show no relationship. The cohort studies in general failed to detect any relationship between meat intake and colo-rectal cancer risk. The available evidence points to the intake of protective factors such as vegetables and whole-grain cereals being the main determinants of colo-rectal cancer risk, with meat intake only coincidentally related.

  16. Colorectal cancer presenting as bone metastasis

    Directory of Open Access Journals (Sweden)

    M C Suresh Babu

    2017-01-01

    Conclusions: In this study, the patients of colorectal cancer presenting with bone metastasis were of male sex and younger age. The factors that were associated with reduced survival were extraosseous and liver involvement.

  17. Screening of colorectal early cancer by radiology

    International Nuclear Information System (INIS)

    Matsukawa, M.; Usui, Y.; Kobayashi, S.

    1988-01-01

    The incidence of colorectal cancer has been gradually increasing in Japan, and if the present rate of increase is maintained it has been estimated that it will become the most common of all malignant neoplasms by the year 2000. It has been proved that colorectal cancer can be completely cured, if it is treated in its early phase. Early cancer of the large bowel is defined as a cancer which is limited to the mucosal membrane or submucosal layer, regardless of lymph node and distant metastases. Detection of early cancer improves the overall curability of colorectal cancer. The greatest number of early cancers of the large bowel are polypoid lesions in their macroscopic form, and depressed lesions are rarely encountered. Accordingly, the first step in the detection of early cancer starts with the screening of polypoid lesion by radiology and endoscopy. This paper is concerned with diagnostic accuracy of radiology in the screening of colorectal cancer with endoscopic correlation

  18. Cancer immunology and colorectal cancer recurrence

    Czech Academy of Sciences Publication Activity Database

    Vannucci, Luca

    -, č. 3 (2011), s. 1421-1431 ISSN 1945-0524 R&D Projects: GA AV ČR IAA500200917 Institutional research plan: CEZ:AV0Z50200510 Keywords : colorectal cancer * inflammation * tumor Subject RIV: EC - Immunology

  19. Differential CARM1 expression in prostate and colorectal cancers

    International Nuclear Information System (INIS)

    Kim, Young-Rang; Lee, Byung Kook; Park, Ra-Young; Nguyen, Nguyen Thi Xuan; Bae, Jeong A; Kwon, Dong Deuk; Jung, Chaeyong

    2010-01-01

    , CARM1 functions as a transcriptional modulator by altering the activity of many transcriptional factors, especially with regard to androgen independent PCa and colorectal cancers

  20. Genetic prognostic markers in colorectal cancer.

    OpenAIRE

    Houlston, R S; Tomlinson, I P

    1997-01-01

    The contribution of molecular genetics to colorectal cancer has been restricted largely to relatively rare inherited tumours and to the detection of germline mutations predisposing to these cancers. However, much is now also known about somatic events leading to colorectal cancer. A number of studies has been undertaken examining possible relations between genetic features and prognostic indices. While many of these studies are small and inconclusive, it is clear that a number of different pa...

  1. Mitotic and apoptotic activity in colorectal neoplasia.

    Science.gov (United States)

    Kohoutova, Darina; Pejchal, Jaroslav; Bures, Jan

    2018-05-18

    Colorectal cancer (CRC) is third most commonly diagnosed cancer worldwide. The aim of the prospective study was to evaluate mitosis and apoptosis of epithelial cells at each stage of colorectal neoplasia. A total of 61 persons were enrolled into the study: 18 patients with non-advanced colorectal adenoma (non-a-A), 13 patients with advanced colorectal adenoma (a-A), 13 patients with CRC and 17 controls: individuals with normal findings on colonoscopy. Biopsy samples were taken from pathology (patients) and healthy mucosa (patients and healthy controls). Samples were formalin-fixed paraffin-embedded and stained with haematoxylin-eosin. Mitotic and apoptotic activity were evaluated in lower and upper part of the crypts and in the superficial compartment. Apoptotic activity was also assessed using detection of activated caspase-3. In controls, mitotic activity was present in lower part of crypts, accompanied with low apoptotic activity. Mitotic and apoptotic activity decreased (to almost zero) in upper part of crypts. In superficial compartment, increase in apoptotic activity was observed. Transformation of healthy mucosa into non-a-A was associated with significant increase of mitotic activity in lower and upper part of the crypts and with significant increase of apoptotic activity in all three compartments; p colorectal neoplasia were observed. Detection of activated caspase-3 confirmed the above findings in apoptotic activity. Significant dysregulation of mitosis and apoptosis during the progression of colorectal neoplasia, corresponding with histology, was confirmed. In patients with sporadic colorectal neoplasia, healthy mucosa does not display different mitotic and apoptotic activity compared to mucosa in healthy controls and therefore adequate endoscopic/surgical removal of colorectal neoplasia is sufficient.

  2. Ranitidine as adjuvant treatment in colorectal cancer

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Christensen, Ib Jarle; Moesgaard, F

    2002-01-01

    BACKGROUND: Results from short-term studies of histamine type 2 (H2) receptor antagonists on survival of patients with solid tumours are debatable. In this study the efficacy of the H2-receptor antagonist ranitidine on long-term survival of patients with colorectal cancer was evaluated. METHODS...... curative resection of colorectal cancer and who do not receive perioperative blood transfusion and do not develop postoperative infectious complications....

  3. Cytogenetic findings in metastases from colorectal cancer

    DEFF Research Database (Denmark)

    Bardi, G; Parada, L A; Bomme, L

    1997-01-01

    Eighteen tumor samples from 11 patients with metastatic colorectal cancer were cytogenetically analyzed after short-term culturing. Of the 13 metastases examined, 11 were from lymph nodes, 1 from the peritoneum and 1 from the lung. In 5 of the 11 patients, matched samples from the primary tumor...... colorectal carcinomas, and del(10)(q22) and add(16)(p13), which so far have not been associated with primary tumors and which may play a particular pathogenetic role in the metastatic process....

  4. Colorectal Cancer - What You Need to Know

    Centers for Disease Control (CDC) Podcasts

    This podcast is based on the July, 2011 CDC Vital Signs report. Colorectal cancer kills about 50,000 men and women every year. Screening can save lives! Screening can find abnormal growths so they can be removed before turning into cancer, and can find the cancer early, when it's easiest to treat. If you're over 50, talk to your doctor about getting screened for colorectal cancer.

  5. Implications of preoperative hypoalbuminemia in colorectal surgery.

    OpenAIRE

    Truong, A; Hanna, MH; Moghadamyeghaneh, Z; Stamos, MJ

    2016-01-01

    Serum albumin has traditionally been used as a quantitative measure of a patient’s nutritional status because of its availability and low cost. While malnutrition has a clear definition within both the American and European Societies for Parenteral and Enteral Nutrition clinical guidelines, individual surgeons often determine nutritional status anecdotally. Preoperative albumin level has been shown to be the best predictor of mortality after colorectal cancer surgery. Specifically in colorect...

  6. Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution

    Science.gov (United States)

    Niida, Atsushi; Shimamura, Teppei; Hirata, Hidenari; Sugimachi, Keishi; Sawada, Genta; Iwaya, Takeshi; Kurashige, Junji; Shinden, Yoshiaki; Iguchi, Tomohiro; Eguchi, Hidetoshi; Chiba, Kenichi; Shiraishi, Yuichi; Nagae, Genta; Yoshida, Kenichi; Nagata, Yasunobu; Haeno, Hiroshi; Yamamoto, Hirofumi; Ishii, Hideshi; Doki, Yuichiro; Iinuma, Hisae; Sasaki, Shin; Nagayama, Satoshi; Yamada, Kazutaka; Yachida, Shinichi; Kato, Mamoru; Shibata, Tatsuhiro; Oki, Eiji; Saeki, Hiroshi; Shirabe, Ken; Oda, Yoshinao; Maehara, Yoshihiko; Komune, Shizuo; Mori, Masaki; Suzuki, Yutaka; Yamamoto, Ken; Aburatani, Hiroyuki; Ogawa, Seishi; Miyano, Satoru; Mimori, Koshi

    2016-01-01

    Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients’ ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease. PMID:26890883

  7. Profile of colorectal cancer in Eastern India.

    Science.gov (United States)

    Sarkar, Snigdha; Mukherjee, Ramanuj; Paira, Susil Kumar; Roy, Bipradas; Banerjee, Shubhabrata; Mukherjee, Saibal Kumar

    2012-12-01

    Although colorectal cancer is a major cause of concern in the western population, recent studies are showing the incidence and mortality of colorectal cancer to be rapidly rising in Asia. The present study is an insight into the epidemiological profile of colorectal cancer of a representative Eastern Indian population. Over a period of three years, all histologically proved patients with colorectal cancer were assessed for age, sex, body mass index, dietary habits, socioeconomic status and stage of disease. Of a total of 168 patients male to female ratio was 1.7:1.The mean age of presentation was 47.01 years. Although colorectal cancer has been known as a disease of sedentary obese men, 41.66% of the patients were from a low socioeconomic rural set-up and 40.47% were involved in heavy physical labour with only 15% of being obese; 62% patients were harbouring a locally advanced disease at the time of presentation. The epidemiological pattern of colorectal cancer in India is different from that of the west as regards to earlier age of presentation, prevalence in low socio economic class with low fat diet and scanty meat intake.

  8. Industrial risk factors for colorectal cancer

    International Nuclear Information System (INIS)

    Lashner, B.A.; Epstein, S.S.

    1990-01-01

    Colorectal cancer is the second most common malignancy in the United States, and its incidence rates have sharply increased recently, especially in males. Industrial exposures, both occupational and environmental, are important colorectal cancer risk factors that are generally unrecognized by clinicians. Migration studies have documented that colorectal cancer is strongly associated with environmental risk factors. The causal role of occupational exposures is evidenced by a substantial literature associating specific work practices with increased colorectal cancer risks. Industrially related environmental exposures, including polluted drinking water and ionizing radiation, have also been associated with excess risks. Currently, there is a tendency to attribute colorectal cancer, largely or exclusively, to dietary and other lifestyle factors, thus neglecting these industrially related effects. Concerted efforts are needed to recognize the causal role of industrial risk factors and to encourage government and industry to reduce carcinogenic exposures. Furthermore, cost-effective screening programs for high-risk population groups are critically needed to further reduce deaths from colorectal cancer. 143 references

  9. Atrial fibrillation and survival in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Justin Timothy A

    2004-11-01

    Full Text Available Abstract Background Survival in colorectal cancer may correlate with the degree of systemic inflammatory response to the tumour. Atrial fibrillation may be regarded as an inflammatory complication. We aimed to determine if atrial fibrillation is a prognostic factor in colorectal cancer. Patients and methods A prospective colorectal cancer patient database was cross-referenced with the hospital clinical-coding database to identify patients who had underwent colorectal cancer surgery and were in atrial fibrillation pre- or postoperatively. Results A total of 175 patients underwent surgery for colorectal cancer over a two-year period. Of these, 13 patients had atrial fibrillation pre- or postoperatively. Atrial fibrillation correlated with worse two-year survival (p = 0.04; log-rank test. However, in a Cox regression analysis, atrial fibrillation was not significantly associated with survival. Conclusion The presence or development of atrial fibrillation in patients undergoing surgery for colorectal cancer is associated with worse overall survival, however it was not found to be an independent factor in multivariate analysis.

  10. Mass Spectrometry-Based N-Glycomics of Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Manveen K. Sethi

    2015-12-01

    Full Text Available Colorectal cancer (CRC is one of the most prevalent cancers worldwide. An increased molecular understanding of the CRC pathology is warranted to gain insights into the underlying molecular and cellular mechanisms of the disease. Altered protein glycosylation patterns are associated with most diseases including malignant transformation. Recent advances in mass spectrometry and bioinformatics have accelerated glycomics research and present a new paradigm for cancer biomarker discovery. Mass spectrometry (MS-based glycoproteomics and glycomics, therefore, hold considerable promise to improve the discovery of novel biomarkers with utility in disease diagnosis and therapy. This review focuses on the emerging field of glycomics to present a comprehensive review of advances in technologies and their application in studies aimed at discovering novel glycan-based biomarkers. We will also discuss some of the challenges associated with using glycans as biomarkers.

  11. Novel biotechnology approaches in colorectal cancer diagnosis and therapy.

    Science.gov (United States)

    Kavousipour, Soudabeh; Khademi, Fathemeh; Zamani, Mozhdeh; Vakili, Bahareh; Mokarram, Pooneh

    2017-06-01

    With ever-increasing molecular information about colorectal cancer (CRC), there is an expectation to detect more sensitive and specific molecular markers for new advanced diagnostic methods that can surpass the limitations of current screening tests. Moreover, enhanced molecular pathology knowledge about cancer has led to the development of targeted therapies, designed to interfere with specific aberrant biological pathways in cancer. Furthermore, biotechnology has opened a new window in CRC diagnosis and treatment by introducing different application of antibodies, antibody fragments, non-Ig scaffold proteins, and aptamers in targeted therapy and drug delivery. This review summarizes the molecular diagnostic and therapeutic approaches in CRC with a focus on genetic and epigenetic alterations, protein and metabolite markers as well as targeted therapy and drug delivery by Ig-scaffold proteins, non-Ig scaffold proteins, nanobodies, and aptamers.

  12. Colorectal Cancer Chemoprevention by Mesalazine and Its Derivatives

    Directory of Open Access Journals (Sweden)

    Carmine Stolfi

    2012-01-01

    Full Text Available Patients with inflammatory bowel disease (IBD face an increased lifetime risk of developing colorectal cancer (CRC. Independent factors associated with increased risk include long disease duration, extensive colonic involvement, young age at onset of IBD, severity of inflammation, primary sclerosing cholangitis, backwash ileitis, and a family history of CRC, thus emphasising the role of intestinal inflammation as an underlying mechanism. This notion is also supported by the demonstration that the use of certain drugs used to attenuate the ongoing mucosal inflammation, such as mesalazine, seems to associate with a reduced incidence of colitis-associated CRC. In the last decade, work from many laboratories has contributed to delineate the mechanisms by which mesalazine alters CRC cell behaviour. In this paper, we review the available experimental data supporting the ability of mesalazine and its derivatives to interfere with intracellular signals involved in CRC cell growth.

  13. Pneumatosis Coli Mimicking Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Teresa Jacob

    2014-01-01

    Full Text Available Pneumatosis coli (PC is a rare condition of the gastrointestinal tract involving extraluminal gas confined within the bowel wall. We report the case of a 40-year-old gentleman presenting clinically and endoscopically with suspected colorectal cancer. In light of the patient’s red flag symptoms, and carpet of polyps seen endoscopically, surgical management by an anterior resection was performed with the patient making a successful recovery. Histological analysis of the resected specimen confirmed pneumatosis coli with no evidence of colonic neoplasia. Although PC can be an incidental finding in asymptomatic patients and considered a benign condition, it can also present as a life-threatening emergency with bowel necrosis and obstruction requiring emergency surgical intervention. Also, when PC mimics malignancy, surgical management is the most appropriate step to ensure that the diagnosis of cancer is not missed.

  14. Personalizing therapy for colorectal cancer.

    Science.gov (United States)

    Wong, Ashley; Ma, Brigette B Y

    2014-01-01

    Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Several important scientific discoveries in the molecular biology of CRC have changed clinical practice in oncology. These included the comprehensive genome-wide profiling of CRC by the Cancer Genome Atlas Network, the discovery of mutations along the RAS-RAF signaling pathway as major determinants of response to antibodies against the epidermal growth factor receptor, the elucidation of new molecular subsets of CRC or gene signatures that may predict clinical outcome after adjuvant chemotherapy, and the innovative targeting of the family of vascular endothelial growth factor and receptors. These new data have allowed oncologists to individualize drug therapy on the basis of a patient's tumor's unique molecular profile, especially in the management of metastatic CRC. This review article will discuss the progress of personalized medicine in the contemporary management of CRC. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  15. Environmental Factors and Colorectal Tumor Risk in Individuals With Hereditary Nonpolyposis Colorectal Cancer

    NARCIS (Netherlands)

    Diergaarde, B.; Braam, H.; Vasen, H.F.; Nagengast, F.M.; Muijen, van G.N.P.; Kok, F.J.; Kampman, E.

    2007-01-01

    Background & Aims: Individuals with hereditary nonpolyposis colorectal cancer (HNPCC) are at increased risk for colorectal cancer. Environmental factors might play a role in HNPCC-associated carcinogenesis. The aim of this study was to gain insight into the effects of environmental factors on

  16. Diet, Gut Microbiota, and Colorectal Cancer Prevention: A Review of Potential Mechanisms and Promising Targets for Future Research.

    Science.gov (United States)

    Song, Mingyang; Chan, Andrew T

    2017-12-01

    Diet plays an important role in the development of colorectal cancer. Emerging data have implicated the gut microbiota in colorectal cancer. Diet is a major determinant for the gut microbial structure and function. Therefore, it has been hypothesized that alterations in gut microbes and their metabolites may contribute to the influence of diet on the development of colorectal cancer. We review several major dietary factors that have been linked to gut microbiota and colorectal cancer, including major dietary patterns, fiber, red meat and sulfur, and obesity. Most of the epidemiologic evidence derives from cross-sectional or short-term, highly controlled feeding studies that are limited in size. Therefore, high-quality large-scale prospective studies with dietary data collected over the life course and comprehensive gut microbial composition and function assessed well prior to neoplastic occurrence are critically needed to identify microbiome-based interventions that may complement or optimize current diet-based strategies for colorectal cancer prevention and management.

  17. Regulation of organic anion transport in the liver

    NARCIS (Netherlands)

    Roelofsen, H; Jansen, PLM

    1997-01-01

    In several liver diseases the biliary transport is disturbed, resulting in, for example, jaundice and cholestasis. Many of these symptoms can be attributed to altered regulation of hepatic transporters. Organic anion transport, mediated by the canalicular multispecific organic anion transporter

  18. Identification of α(1,6)fucosylated proteins differentially expressed in human colorectal cancer

    International Nuclear Information System (INIS)

    Muinelo-Romay, Laura; Villar-Portela, Susana; Cuevas, Elisa; Gil-Martín, Emilio; Fernández-Briera, Almudena

    2011-01-01

    A universal hallmark of cancer cells is the change in their glycosylation phenotype. One of the most frequent alterations in the normal glycosylation pattern observed during carcinogenesis is the enhancement of α(1,6)linked fucose residues of glycoproteins, due to the up-regulation of the α(1,6)fucosyltransferase activity. Our previous results demonstrated the specific alteration of this enzyme activity and expression in colorectal cancer, suggesting its implication in tumour development and progression. In the current work we combined a LCA-affinity chromatography with SDS-PAGE and mass spectrometry in order to identify α(1,6)fucosylated proteins differentially expressed in colorectal cancer. This strategy allowed the identification of a group of α(1,6)fucosylated proteins candidates to be involved in CRC malignancy. The majority of the identified proteins take part in cell signaling and interaction processes as well as in modulation of the immunological response. Likewise, we confirmed the increased expression of GRP94 in colorectal cancer tissue and the significant down-regulation of the IgGFcBP expression in tumour cells. All these results validate the importance of core-fucosylated proteins profile analysis to understand the mechanisms which promote cancer onset and progression and to discover new tumour markers or therapeutic targets

  19. Japanese Society of Medical Oncology Clinical Guidelines: Molecular Testing for Colorectal Cancer Treatment, Third Edition.

    Science.gov (United States)

    Yamazaki, Kentaro; Taniguchi, Hiroya; Yoshino, Takayuki; Akagi, Kiwamu; Ishida, Hideyuki; Ebi, Hiromichi; Nakatani, Kaname; Muro, Kei; Yatabe, Yasushi; Yamaguchi, Kensei; Tsuchihara, Katsuya

    2018-06-01

    The Japanese Society of Medical Oncology (JSMO) previously published 2 editions of the clinical guidelines: "Japanese guidelines for testing of KRAS gene mutation in colorectal cancer" in 2008 and "Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients" in 2014. These guidelines have contributed to the proper use of KRAS and RAS mutation testing, respectively. Recently, clinical utility, particularly for colorectal cancer (CRC) patients with BRAF V600E mutation or DNA mismatch-repair (MMR) deficiency, has been established. Therefore, the guideline members decided these genetic alterations should also be involved. The aim of this revision is to properly carry out testing for BRAF V600E mutation and MMR deficiency in addition to RAS mutation. The revised guidelines include the basic requirements for testing for these genetic alterations based on recent scientific evidence. Furthermore, because clinical utility of comprehensive genetic testing using next-generation sequencing and somatic gene testing of analyzing circulating tumor DNA has increasingly evolved with recent advancements in testing technology, we noted the current situation and prospects for these testing technologies and their clinical implementation in the revised guidelines. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  20. Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Fiorella Guadagni

    2012-01-01

    Full Text Available The K-ras gene is frequently mutated in colorectal cancer and has been associated with tumor initiation and progression; approximately 90% of the activating mutations are found in codons 12 and 13 of exon 1 and just under 5% in codon 61 located in exon 2. These mutations determine single aminoacidic substitutions in the GTPase pocket leading to a block of the GTP hydrolytic activity of the K-ras p21 protein, and therefore to its constitutive activation. Point mutations in sites of the K-ras gene, other than codons 12, 13 and 61, and other types of genetic alterations, may occur in a minority of cases, such as in the less frequent cases of double mutations in the K-ras gene. However, all mutations in this gene, even those which occur in non-canonical sites or double mutations, are relevant oncogenic alterations in colorectal cancer and may underlie K-ras pathway hyperactivation. In the present study, we report the case of a patient with colorectal cancer presenting a concurrent point mutation in exons 1 and 2 of the K-ras gene, a GGT to TGT substitution (Glycine to Cysteine at codon 12, and a GAC to AAC substitution (Aspartic Acid to Asparagine at codon 57. In addition, we found in the same patient’s sample a silent polymorphism at codon 11 (Ala11Ala of exon 1. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 729–733

  1. Genetic and epigenetic markers in colorectal cancer screening: recent advances.

    Science.gov (United States)

    Singh, Manish Pratap; Rai, Sandhya; Suyal, Shradha; Singh, Sunil Kumar; Singh, Nand Kumar; Agarwal, Akash; Srivastava, Sameer

    2017-07-01

    Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.

  2. Colorectal Cancer Screening: A Circle of Health for Alaskans

    Science.gov (United States)

    ... in the colon and rectum is often called colorectal cancer. But in this brochure we use the term ... tests can be used to find polyps or colorectal cancer. Each can be used alone. Sometimes they are ...

  3. Colorectal Cancer Prevention (PDQ®)—Patient Version

    Science.gov (United States)

    Colorectal cancer prevention strategies can include avoiding known risk factors, having a healthy lifestyle, taking aspirin, and removing polyps. Learn more about preventing colorectal cancer in this expert-reviewed summary.

  4. Pathological and Biological Aspects of Colorectal Cancer Treatment.

    NARCIS (Netherlands)

    Gosens, M.J.E.M.

    2008-01-01

    Pathological and biological aspects of colorectal cancer treatment. This thesis describes several pathological and biological aspects of colorectal cancer treatment. Different patient populations were investigated including patients with mobile rectal cancer enrolled in the Dutch TME trial, patients

  5. Advances in endoscopic ultrasound imaging of colorectal diseases

    DEFF Research Database (Denmark)

    Cârțână, Elena Tatiana; Gheonea, Dan Ionuț; Săftoiu, Adrian

    2016-01-01

    in colorectal cancer, the monitoring of disease activity in inflammatory bowel disease based on quantification of bowel wall vascularization, and differentiating between benign and malignant subepithelial tumours. Recent reports suggest that EUS elastography enables highly accurate discrimination of colorectal...

  6. Laser photocoagulation in the palliation of colorectal malignancies

    NARCIS (Netherlands)

    Mathus-Vliegen, E. M.; Tytgat, G. N.

    1986-01-01

    Besides surgical intervention, there are virtually no palliative treatment modalities available for bleeding and/or obstructing colorectal malignancy. The usefulness and safety of laser photocoagulation was prospectively investigated in 63 patients with colorectal cancer. The merits were evaluated

  7. Dipeptidyl-peptidase IV activity is correlated with colorectal cancer prognosis.

    Directory of Open Access Journals (Sweden)

    Gorka Larrinaga

    Full Text Available Dipeptidyl-peptidase IV (EC 3.4.14.5 (DPPIV is a serine peptidase involved in cell differentiation, adhesion, immune modulation and apoptosis, functions that control neoplastic transformation. Previous studies have demonstrated altered expression and activity of tissue and circulating DPPIV in several cancers and proposed its potential usefulness for early diagnosis in colorectal cancer (CRC.The activity and mRNA and protein expression of DPPIV was prospectively analyzed in adenocarcinomas, adenomas, uninvolved colorectal mucosa and plasma from 116 CRC patients by fluorimetric, quantitative RT-PCR and immunohistochemical methods. Results were correlated with the most important classic pathological data related to aggressiveness and with 5-year survival rates. Results showed that: 1 mRNA levels and activity of DPPIV increased in colorectal neoplasms (Kruskal-Wallis test, p<0.01; 2 Both adenomas and CRCs displayed positive cytoplasmic immunostaining with luminal membrane reinforcement; 3 Plasmatic DPPIV activity was lower in CRC patients than in healthy subjects (Mann-U test, p<0.01; 4 Plasmatic DPPIV activity was associated with worse overall and disease-free survivals (log-rank p<0.01, Cox analysis p<0.01.1 Up-regulation of DPPIV in colorectal tumors suggests a role for this enzyme in the neoplastic transformation of colorectal tissues. This finding opens the possibility for new therapeutic targets in these patients. 2 Plasmatic DPPIV is an independent prognostic factor in survival of CRC patients. The determination of DPPIV activity levels in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice.

  8. Self-renewal molecular mechanisms of colorectal cancer stem cells

    OpenAIRE

    Pan, Tianhui; Xu, Jinghong; Zhu, Yongliang

    2016-01-01

    Colorectal cancer stem cells (CCSCs) represent a small fraction of the colorectal cancer cell population that possess self-renewal and multi-lineage differentiation potential and drive tumorigenicity. Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood, the aberrant activation of signaling pathways, such as Wnt, Notch, transforming growth facto...

  9. Screening for colorectal cancer in defunctioned colons.

    Science.gov (United States)

    Akbar, Fayyaz; Quyn, Aaron; Steele, Robert

    2018-01-01

    Objectives Population-based colorectal (bowel) cancer screening using faecal occult blood tests leads to a reduction in cause-specific mortality. However, in people where the colon is defunctioned, the use of standard faecal occult blood test is not appropriate. The aim of this study was to examine the current trends of clinical practice for colorectal cancer screening in people with defunctioned colons. Methods An online survey was performed using SurveyMonkey. All members of the Association of Coloproctology of Great Britain and Ireland were invited by email to participate. Reminders were sent to non-responders and partial responders till six weeks. All responses were included in our analysis. Results Of the 206 (34.59%) questionnaires completed, all questions were answered in 110 (55.8%). Among responders, 94 (85.4%) were colorectal consultant surgeons, 72% had worked in their current capacity for more than five years, and 105 (50.9%) had encountered colorectal cancer in defunctioned colons during their career. Some 72.2% of responders stated that a screening test for colorectal cancer in patients with defunctioned colons was currently not offered, or that they did not know whether or not it was offered in their area. Conclusions Bowel screening in the United Kingdom is currently not offered to 72.2% of the age appropriate population with defunctioned colons. Among responding colorectal surgeons, 50% had encountered colorectal cancer in such patients. There is considerable variability in clinical practice regarding the optimal age for onset of screening, time interval, and the optimal modality to offer for screening in such cases.

  10. Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Kornel E Schuebel

    2007-09-01

    Full Text Available We have developed a transcriptome-wide approach to identify genes affected by promoter CpG island DNA hypermethylation and transcriptional silencing in colorectal cancer. By screening cell lines and validating tumor-specific hypermethylation in a panel of primary human colorectal cancer samples, we estimate that nearly 5% or more of all known genes may be promoter methylated in an individual tumor. When directly compared to gene mutations, we find larger numbers of genes hypermethylated in individual tumors, and a higher frequency of hypermethylation within individual genes harboring either genetic or epigenetic changes. Thus, to enumerate the full spectrum of alterations in the human cancer genome, and to facilitate the most efficacious grouping of tumors to identify cancer biomarkers and tailor therapeutic approaches, both genetic and epigenetic screens should be undertaken.

  11. Colorectal Anastomoses : Surgical outcome and prevention of anastomotic leakage

    NARCIS (Netherlands)

    Bakker, Ilsalien

    2016-01-01

    Colorectal surgery is a frequently performed procedure with more than 10.000 annual resections in the Netherlands. The majority of resections are performed for colorectal cancer. The first part of this thesis focused on outcome of colorectal cancer surgery in the Netherlands based on the nationwide

  12. An audit of colorectal cancer histopathology reports in a Tertiary ...

    African Journals Online (AJOL)

    Objective: To audit the completeness of histopathologic reports of Colorectal Cancer for prognostic information in a tertiary care hospital in the light of the minimum reporting standards for colorectal cancer resections recently proposed for use in Nigeria. Material and Methods: Twenty–five histopathology reports of colorectal ...

  13. Colorectal liver metastases: factors affecting outcome after surgery

    NARCIS (Netherlands)

    Snoeren, N.

    2013-01-01

    Colorectal cancer is the second leading cause of cancer related death in Europe. The overall survival rate of patients with colorectal cancer is greatly affected by the presence of liver metastases, which occurs in about 50% of patients. Radical resection of colorectal liver metastases means a

  14. Surgical outcome and clinical profile of emergency versus elective cases of colorectal cancer in College of Medical Sciences, Nepal

    Directory of Open Access Journals (Sweden)

    Sujit Kumar

    2014-01-01

    Full Text Available Background: Patients who undergo emergency colorectal cancer surgery has poor outcome compared to elective surgery, both in terms of morbidity and mortality. Approximately 15 to 30% of colorectal cancers present as an emergency, most often as obstruction or perforation. Objective: To compare surgical outcome and clinical profiles of emergency and elective cases for colorectal cancer. Methods: Retrospective analysis of 34 cases who underwent surgery for colorectal cancer between December 2011 to January 2013was carried out and their surgical outcomes, clinical presentation, demographic profile were analyzed. Results: The total numbers of patients included in this study were 34. Out of which 52.94 %( n=18 were emergency cases and 47.05 %( n=16 were elective. Male female ratio was 3:1 in emergency cases and 2.6:1 in elective cases. Per rectal bleeding (56% and altered bowel habit (31.25% was predominant clinical presentation in elective cases whereas intestinal obstruction (55.55% and peritonitis (22.22% were predominant clinical presentation in emergency cases. In emergency cases most of the tumors were located in left side (77.77% and in elective cases rectum was common site (37.5%. Left hemicolectomy was the commonest surgery performed (72.22% in emergency set up. In elective cases, right hemicolectomy, left hemicolectomy, APR and LAR was done in 31.25%, 31.25%, 25% and 25% cases respectively. In the emergency group 11.11% (n=2 developed enterocutaneous fistula and early mortality within 30 days was observed in 5% (n=1 of emergency cases only. Conclusion: In emergency conditions, colorectal cancer presented with intestinal obstruction where as elective cases presented with per rectal bleeding and altered bowel habits. Compared with the elective patients, the emergency patients had higher rate of morbidity and mortality. Because of higher incidence of colorectal cancer in our institution, in all emergency cases who presents with features of

  15. Toward standardizing and reporting colorectal cancer screening indicators on an international level: The International Colorectal Cancer Screening Network

    NARCIS (Netherlands)

    Benson, Victoria S.; Atkin, Wendy S.; Green, Jane; Nadel, Marion R.; Patnick, Julietta; Smith, Robert A.; Villain, Patricia; Patnick, J.; Atkin, W. S.; Altenhofen, L.; Ancelle-Park, R.; Benson, V. S.; Green, J.; Levin, T. R.; Moss, S. M.; Nadel, M.; Ransohoff, D.; Segnan, N.; Smith, R. A.; Villain, P.; Weller, D.; Koukari, A.; Young, G.; López-Kostner, F.; Antoljak, N.; Suchánek, S.; Zavoral, M.; Holten, I.; Malila, N.; Salines, E.; Brenner, G.; Herszényi, L.; Tulassay, Z.; Rennert, G.; Senore, C.; Zappa, M.; Zorzi, M.; Saito, H.; Leja, M.; Dekker, E.; Jansen, J.; Hol, L.; Kuipers, E.; Kaminski, M. F.; Regula, J.; Sfarti, C.; Trifan, A.; Tang, C.-L.; Hrcka, R.; Binefa, G.; Espinàs, J. A.; Peris, M.; Chen, T. H.; Steele, R.; Pou, G.; Bisges, D.; Dwyer, D.; Groves, C.; Courteau, S.; Kramer, R.; Siegenthaler, K.; Lane, D.; Herrera, C.; Rogers, J.; Rojewski, M.; Wolf, Holly; Sung, J. J.; Ling, K.; Bryant, H.; Rabeneck, L.; Dale, J.; Sware, L.; Yang, H.; Viguier, J.; Von Karsa, L.; Kupcinskas, L.; Deutekom, M.; Törnberg, S.; Austoker, J.; Beral, V.; Monk, C.; Valori, R.; Watson, J.; Kobrin, S.; Pignone, M.; Taplin, S.

    2012-01-01

    The International Colorectal Cancer Screening Network was established in 2003 to promote best practice in the delivery of organized colorectal cancer screening programs. To facilitate evaluation of such programs, we defined a set of universally applicable colorectal cancer screening measures and

  16. Relationship Between Dual Time Point FDG PET and Immunohistochemical Parameters in Preoperative Colorectal Cancer: Preliminary Study

    International Nuclear Information System (INIS)

    Lee, Jai Hyuen; Lee, Won Ae; Park, Seok Gun; Park, Dong Kook; Namgung, Hwan

    2012-01-01

    The clinical availability of 2 deoxy 2 [18F] fluoro D glucose (FDG) dual time point positron emission tomography/computerized tomography (DTPP) has been investigated in diverse oncologic fields. The aim of this preliminary study was to evaluate the relationship between various immunohistopathologic markers reflecting disease progression of colorectal cancer and parameters extracted from FDG DTPP in colorectal cancer patients. Forty seven patients with histologically confirmed colorectal cancer were analyzed in this preliminary study. FDG DTPP consisted of an early scan 1 h after FDG injection and a delayed scan 1.5 h after the early scan. Based on an analysis of FDG DTPP, we estimated the maximum standardized uptake value (SUV) of tumors on the early and delayed scans (SUV earlya nd SUV delayed, respectively). The retention index (RI) was calculated as follows: (SUV delayed- SUV early) x 100/ SUV early. The clinicopathological findings (size and T and N stages) and immunohistochemical factors [glucose transporter 1 (GLUT 1), hexokinase 2 (HK 2), p53, P504S, and β catenin] were analyzed by visual analysis. The RIs calculated from the SUVs ranged from -1.8 to 73.4 (31.8±15.5). The RIs were significantly higher in patients with high T stages (T3 and T4) than with low T stages (T1 and T2; P earlya nd SUV delayeda nd clinicopathologic parameters in this study. The RIs obtained from preoperative colorectal cancers had a significant relationship to tumor size, T staging, GLUT 1, and p53, in contrast to SUV earlyo r SUV delayed. Compared with previous reports, our results showed that RI can better predict GLUT 1 expression than HK 2 and other immunohistochemical markers. This study demonstrated that the RI might have the potential to be applied as a prognostic marked in preoperative colorectal cancer

  17. Sugars, sucrose and colorectal cancer risk: the Fukuoka colorectal cancer study.

    Science.gov (United States)

    Wang, Zhenjie; Uchida, Kazuhiro; Ohnaka, Keizo; Morita, Makiko; Toyomura, Kengo; Kono, Suminori; Ueki, Takashi; Tanaka, Masao; Kakeji, Yoshihiro; Maehara, Yoshihiko; Okamura, Takeshi; Ikejiri, Koji; Futami, Kitaroh; Maekawa, Takafumi; Yasunami, Yohichi; Takenaka, Kenji; Ichimiya, Hitoshi; Terasaka, Reiji

    2014-05-01

    A diet high in sugars may promote colorectal carcinogenesis, but it remains uncertain whether high intake of sugars or sucrose confers increased risk of colorectal cancer. The authors investigated the associations of sugars and sucrose intake with colorectal cancer risk in a community-based case-control study in Japan. The study subjects comprised 816 incident cases of colorectal cancer and 815 community controls. Consumption frequencies and portion sizes of 148 food and beverage items were ascertained by a computer-assisted interview. The authors used the consumption of 29 food items to estimate sugars and sucrose intake. The odds ratios of colorectal cancer risk according to intake categories were obtained using a logistic regression model with adjustment for potential confounding variables. Overall, intakes of sugars and sucrose were not related to colorectal cancer risk either in men or women. The association between sugars intake and colorectal cancer risk differed by smoking status and alcohol use in men, but not in women. In men, sugars intake tended to be associated with colorectal cancer risk inversely among never-smokers and positively among male ever-smokers (interaction p=0.01). Sugars intake was associated with an increased risk among men with no alcohol consumption, but was unrelated to the risk among male alcohol drinkers (interaction p=0.02). Body mass index did not modify the association with sugars intake in either men or women. Sugars intake was associated with increased risk of colorectal cancer among smokers and non-alcohol drinkers in men selectively.

  18. Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma

    Directory of Open Access Journals (Sweden)

    Mei-Ying Zhang

    2014-08-01

    Full Text Available Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05. According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM than adenoma and carcinoma (p < 0.05. Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05. Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05, but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM staging, differentiation or serum carcinoembryonic antigen (CEA concentration (p > 0.05. Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05. Cox’s model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05. It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma.

  19. Colorectal Cancer Screening: A Guide to the Guidelines

    Directory of Open Access Journals (Sweden)

    Douglas K Rex

    1999-01-01

    Full Text Available The two most recent guidelines for colorectal cancer screening are those of the Agency for Healthcare Policy and Research, and the American Cancer Society. The guidelines are similar in many regards and reflect current literature, consensus opinion and compromise between members of multidisciplinary panels. The emphasis of both guidelines is to increase the options available for colorectal cancer screening. Increasing choice should expand the attractiveness of colorectal cancer screening to more patients and physicians, and the development of guidelines should help compel payers to provide reimbursement for colorectal cancer screening. These guidelines are summarized and evaluated as they pertain to colorectal cancer screening.

  20. Precancerous Lesions in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Fayez Sandouk

    2013-01-01

    Full Text Available Colorectal cancer (CRC is the third most common cause of cancer death in the world. The incidence rate (ASR and age distribution of this disease differ between most of African-Middle-Eastern (AMAGE and North America and Europe for many reasons. However, in all areas, “CRC” is considered as one of the most preventable cancers, because it might develop from variant processes like polyps and IBD in addition to the genetic pathogenesis which became very well known in this disease. We tried in this paper to review all the possible reasons of the differences in incidence and age between the west and AMAGE. Also we reviewed all the mutations that lead to the hereditary and familiar clustering of this disease with the correlations with the surrounding food and environment of different areas. Then, we focused on the precancerous pathology of this disease with special focusing on early detection depending on new endoscopy technology and most important genetic studies. We lastly reviewed the evidence of some of the surveillance and put suggestions about future surveillance programs and how important those programs are on the psychological aspect of the patients and their families.

  1. Tissue Specific Promoters in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    A. R. Rama

    2015-01-01

    Full Text Available Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment.

  2. Ziv-aflibercept in metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Patel A

    2013-12-01

    Full Text Available Anuj Patel, Weijing Sun Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Abstract: The combination of cytotoxic chemotherapy and antiangiogenic agents has become a conventional treatment option for patients with metastatic colorectal cancer. Ziv-aflibercept is a fusion protein which acts as a decoy receptor for vascular endothelial growth factor (VEGF-A, VEGF-B, and placental growth factor (PlGF; it was approved in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen. Herein we review the role of tumor angiogenesis as the rationale for antiangiogenic therapy, the clinical data associated with ziv-aflibercept, and its current role as a treatment option compared to other antiangiogenic agents, such as bevacizumab and regorafenib. Keywords: aflibercept, angiogenesis, colorectal cancer

  3. Management of colorectal trauma: a review.

    Science.gov (United States)

    Cheong, Ju Yong; Keshava, Anil

    2017-07-01

    Traumatic colorectal injuries are common during times of military conflict, and major improvements in their care have arisen in such periods. Since World War II, many classification systems for colorectal trauma have been proposed, including (i) Flint Grading System; (ii) Penetrating Abdominal Trauma Index; (iii) Colonic/Rectal Injury Scale; and (iv) destructive/non-destructive colonic injuries. The primary goal of these classifications was to aid surgical management and, more particularly, to determine whether a primary repair or faecal diversion should be performed. Primary repair is now the preferred surgical option. Patients who have been identified as having destructive injuries have been found to have higher anastomotic leak rates after a primary repair. Damage control principles need to be adhered to in surgical decision-making. In this review, we discuss the mechanisms of injury, classifications, clinical presentation and current recommendations for the management of colorectal trauma. © 2017 Royal Australasian College of Surgeons.

  4. Clinicopathologic and Molecular Features of Colorectal Adenocarcinoma with Signet-Ring Cell Component.

    Directory of Open Access Journals (Sweden)

    Qing Wei

    Full Text Available We performed a retrospective study to assess the clinicopathological characters, molecular alterations and multigene mutation profiles in colorectal cancer patients with signet-ring cell component.Between November 2008 and January 2015, 61 consecutive primary colorectal carcinomas with signet-ring cell component were available for pathological confirmation. RAS/BRAF status was performed by direct sequencing. 14 genes associated with hereditary cancer syndromes were analyzed by targeted gene sequencing.A slight male predominance was detected in these patients (59.0%. Colorectal carcinomas with signet-ring cell component were well distributed along the large intestine. A frequently higher TNM stage at the time of diagnosis was observed, compared with the conventional adenocarcinoma. Family history of malignant tumor was remarkable with 49.2% in 61 cases. The median OS time of stage IV patients in our study was 14 months. RAS mutations were detected in 22.2% (12/54 cases with KRAS mutations in 16.7% (9/54 cases and Nras mutations in 5.4%(3/54 cases. BRAF V600E mutation was detected in 3.7% (2/54 cases. As an exploration, we analyzed 14 genes by targeted gene sequencing. These genes were selected based on their biological role in association with hereditary cancer syndromes. 79.6% cases carried at least one pathogenic mutation. Finally, the patients were classified by the percentage of signet-ring cell. 39 (63.9% cases were composed of ≥50% signet-ring cells; 22 (36.1% cases were composed of <50% signet-ring cells. We compared clinical parameters, molecular and genetic alterations between the two groups and found no significant differences.Colorectal adenocarcinoma with signet-ring cell component is characterized by advanced stage at diagnosis with remarkable family history of malignant tumor. It is likely a negative prognostic factor and tends to affect male patients with low rates of RAS /BRAF mutation. Colorectal patients with any component of

  5. Korean Guidelines for Colorectal Cancer Screening and Polyp Detection

    International Nuclear Information System (INIS)

    Lee, Bo In; Hong, Sung Pil; Kim, Seong Eun

    2012-01-01

    Colorectal cancer is currently the second most common cancer among Korean males and the fourth most common among females. Since the majority of colorectal cancer case present following the prolonged transformation of adenomas into carcinomas, early detection and removal of colorectal adenomas are vital methods in its prevention. Considering the increasing incidence of colorectal cancer and polyps in Korea, it is very important to establish national guidelines for colorectal cancer screening and polyp detection. The proposed guidelines have been developed by the Korean Multi-Society Task Force using evidence-based methods. Systematic reviews and meta-analyses have been used to form the statements contained in the guidelines. This paper discusses the epidemiology of colorectal cancers and adenomas in Korea as well as optimal methods for screening of colorectal cancer and detection of adenomas including fecal occult blood tests, radiologic tests, and endoscopic examinations.

  6. Effect of DNA methylation profile on OATP3A1 and OATP4A1 transcript levels in colorectal cancer.

    Science.gov (United States)

    Rawłuszko-Wieczorek, Agnieszka Anna; Horst, Nikodem; Horbacka, Karolina; Bandura, Artur Szymon; Świderska, Monika; Krokowicz, Piotr; Jagodziński, Paweł Piotr

    2015-08-01

    Epidemiological studies indicate that 17β-estradiol (E2) prevents colorectal cancer (CRC). Organic anion transporting polypeptides (OATPs) are involved in the cellular uptake of various endogenous and exogenous substrates, including hormone conjugates. Because transfer of estrone sulfate (E1-S) can contribute to intra-tissue conversion of estrone to the biologically active form -E2, it is evident that the expression patterns of OATPs may be relevant to the analysis of CRC incidence and therapy. We therefore evaluated DNA methylation and transcript levels of two members of the OATP family, OATP3A1 and OATP4A1, that may be involved in E1-S transport in colorectal cancer patients. We detected a significant reduction in OATP3A1 and a significant increase in OATP4A1 mRNA levels in cancerous tissue, compared with histopathologically unchanged tissue (n=103). Moreover, we observed DNA hypermethylation in the OATP3A1 promoter region in a small subset of CRC patients and in HCT116 and Caco-2 colorectal cancer cell lines. We also observed increased OATP3A1 transcript following treatment with 5-aza-2-deoxycytidine and sodium butyrate. The OATP4A1 promoter region was hypomethylated in analyzed tissues and CRC cell lines and was not affected by these treatments. Our results suggest a potential mechanism for OATP3A1 downregulation that involves DNA methylation during colorectal carcinogenesis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  7. Colorectal carcinogenesis-update and perspectives

    DEFF Research Database (Denmark)

    Raskov, Hans; Pommergaard, Hans-Christian; Burcharth, Jakob

    2014-01-01

    Colorectal cancer (CRC) is a very common malignancy in the Western World and despite advances in surgery, chemotherapy and screening, it is still the second leading cause of cancer deaths in this part of the world. Numerous factors are found important in the development of CRC including colonocyte....... To identify early cancers, screening programs have been initiated, and the leading strategy has been the use of faecal occult blood testing followed by colonoscopy in positive cases. Regarding the treatment of colorectal cancer, significant advances have been made in the recent decade. The molecular targets...

  8. Colorectal Cancer - What You Need to Know

    Centers for Disease Control (CDC) Podcasts

    2011-07-05

    This podcast is based on the July, 2011 CDC Vital Signs report. Colorectal cancer kills about 50,000 men and women every year. Screening can save lives! Screening can find abnormal growths so they can be removed before turning into cancer, and can find the cancer early, when it's easiest to treat. If you're over 50, talk to your doctor about getting screened for colorectal cancer.  Created: 7/5/2011 by Centers for Disease Control and Prevention (CDC).   Date Released: 7/5/2011.

  9. Microsatellite Status of Primary Colorectal Cancer Predicts the Incidence of Postoperative Colorectal Neoplasms.

    Science.gov (United States)

    Takiyama, Aki; Tanaka, Toshiaki; Yamamoto, Yoko; Hata, Keisuke; Ishihara, Soichiro; Nozawa, Hiroaki; Kawai, Kazushige; Kiyomatsu, Tomomichi; Nishikawa, Takeshi; Otani, Kensuke; Sasaki, Kazuhito; Watanabe, Toshiaki

    2017-10-01

    Few studies have evaluated the risk of postoperative colorectal neoplasms stratified by the nature of primary colorectal cancer (CRC). In this study, we revealed it on the basis of the microsatellite (MS) status of primary CRC. We retrospectively reviewed 338 patients with CRC and calculated the risk of neoplasms during postoperative surveillance colonoscopy in association with the MS status of primary CRC. A propensity score method was applied. We identified a higher incidence of metachronous rectal neoplasms after the resection of MS stable CRC than MS instable CRC (adjusted HR 5.74, p=0.04). We also observed a higher incidence of colorectal tubular adenoma in patients with MSS CRC (adjusted hazard ratio 7.09, pcolorectal cancer influenced the risk of postoperative colorectal neoplasms. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  10. Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

    Directory of Open Access Journals (Sweden)

    Kenichi Konda

    Full Text Available Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs.We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI] and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers alterations in 158 CRNs including 56 polypoid neoplasms (PNs, 25 granular type laterally spreading tumors (LST-Gs, 48 non-granular type LSTs (LST-NGs, 19 depressed neoplasms (DNs and 10 small flat-elevated neoplasms (S-FNs on the basis of macroscopic appearance.S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs (P<0.001. By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively (P<0.007. We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively (P<0.005. Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05. PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41.We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.

  11. Is prevalence of colorectal polyps higher in patients with family history of colorectal cancer?

    OpenAIRE

    Murad-Regadas, Sthela Maria; Bezerra, Carla Camila Rocha; Peixoto, Ana Ligia Rocha; Regadas, Francisco Sérgio Pinheiro; Rodrigues, Lusmar Veras; Siebra, José Airton Gonçalves; da Silva Fernandes, Graziela Olivia; Vasconcelos, Rafael Aragão

    2015-01-01

    ABSTRACTObjectives:To assess the prevalence of polyps in patients with a family history of colorectal cancer, in comparison to asymptomatic individuals with indication for screening.Methods:A prospective study in a group of patients who underwent colonoscopy between 2012 and 2014. Patients were divided into two groups: Group I: no family history of colorectal cancer, and Group II: with a family history in first-degree relatives. Demographic characteristics, findings on colonoscopy...

  12. Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study.

    Science.gov (United States)

    Momen-Heravi, Fatemeh; Babic, Ana; Tworoger, Shelley S; Zhang, Libin; Wu, Kana; Smith-Warner, Stephanie A; Ogino, Shuji; Chan, Andrew T; Meyerhardt, Jeffrey; Giovannucci, Edward; Fuchs, Charles; Cho, Eunyoung; Michaud, Dominique S; Stampfer, Meir J; Yu, Yau-Hua; Kim, David; Zhang, Xuehong

    2017-02-01

    Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. © 2016 UICC.

  13. Epigenetic-Mediated Downregulation of μ-Protocadherin in Colorectal Tumours

    Science.gov (United States)

    Mateusz, Bujko; Paulina, Kober; Małgorzata, Statkiewicz; Michal, Mikula; Marcin, Ligaj; Lech, Zwierzchowski; Jerzy, Ostrowski; Aleksander, Siedlecki Janusz

    2015-01-01

    Carcinogenesis involves altered cellular interaction and tissue morphology that partly arise from aberrant expression of cadherins. Mucin-like protocadherin is implicated in intercellular adhesion and its expression was found decreased in colorectal cancer (CRC). This study has compared MUPCDH (CDHR5) expression in three key types of colorectal tissue samples, for normal mucosa, adenoma, and carcinoma. A gradual decrease of mRNA levels and protein expression was observed in progressive stages of colorectal carcinogenesis which are consistent with reports of increasing MUPCDH 5′ promoter region DNA methylation. High MUPCDH methylation was also observed in HCT116 and SW480 CRC cell lines that revealed low gene expression levels compared to COLO205 and HT29 cell lines which lack DNA methylation at the MUPCDH locus. Furthermore, HCT116 and SW480 showed lower levels of RNA polymerase II and histone H3 lysine 4 trimethylation (H3K4me3) as well as higher levels of H3K27 trimethylation at the MUPCDH promoter. MUPCDH expression was however restored in HCT116 and SW480 cells in the presence of 5-Aza-2′-deoxycytidine (DNA methyltransferase inhibitor). Results indicate that μ-protocadherin downregulation occurs during early stages of tumourigenesis and progression into the adenoma-carcinoma sequence. Epigenetic mechanisms are involved in this silencing. PMID:25972897

  14. Hereditary & familial colorectal cancer : Identification, characteristics, surveillance

    NARCIS (Netherlands)

    Kallenberg, F.G.J.

    2017-01-01

    Of all colorectal cancer (CRC) cases, 15-20% is related to familial or hereditary factors. Diagnosing familial and hereditary CRC syndromes is important for several reasons. One of these is that surveillance colonoscopies can reduce CRC incidence and mortality importantly. A complete family history

  15. Parameters of biological activity in colorectal cancer

    Czech Academy of Sciences Publication Activity Database

    Svobodová, Š.; Topolčan, O.; Holubec jr., L.; Levý, M.; Pecen, Ladislav; Svačina, Š.

    2011-01-01

    Roč. 31, č. 1 (2011), s. 373-378 ISSN 0250-7005 Institutional research plan: CEZ:AV0Z10300504 Keywords : colorectal cancer * biological activity * prognosis * tumor markers * angiogenetic factors * metalloproteinases * adhesion molecules Subject RIV: FD - Oncology ; Hematology Impact factor: 1.725, year: 2011

  16. Nutritional status assessment in colorectal cancer patients.

    Science.gov (United States)

    Lopes, Joana Pedro; de Castro Cardoso Pereira, Paula Manuela; dos Reis Baltazar Vicente, Ana Filipa; Bernardo, Alexandra; de Mesquita, María Fernanda

    2013-01-01

    The present study intended to evaluate the nutritional status of Portuguese colorectal patients and associated it with surgery type as well as quality of life outcomes. Malnutrition can affect up to 85% of cancer patients and specifically 30-60% in colorectal cancer and can significantly influence health outcomes. A sample of 50 colorectal cancer patients was evaluated in what refers to several anthropometric measures, food intake, clinical history, complications rate before and after surgery procedure. The sample was divided between convention and fast-track procedures. Most of the individuals were overweight or obese but had lost weight on the past six months. Despite mild, there were signs of malnutrition in this sample with high losses of fat free mass, weight and also fat mass during the hospitalization period. These results reinforce the importance of malnutrition assessment in colorectal patients as well as consider weight loss on the past months and body composition in order to complement nutritional status evaluation. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

  17. Coffee consumption and risk of colorectal cancer.

    Science.gov (United States)

    Bidel, S; Hu, G; Jousilahti, P; Antikainen, R; Pukkala, E; Hakulinen, T; Tuomilehto, J

    2010-09-01

    The possible association between coffee consumption and risk of colorectal cancer has been extensively studied in the many populations. The aim of this study is to examine this relationship among Finns, who are the heaviest coffee consumers in the world. A total of 60 041 Finnish men and women who were 26-74 years of age and without history of any cancer at baseline were included in the present analyses. Their coffee consumption and other study characteristics were determined at baseline, and they were prospectively followed up for onset of colon and rectal cancer, emigration, death or until 30 June 2006. During a mean follow-up period of 18 years, 538 cases of colorectal cancer (304 cases of colon cancer and 234 cases of rectal cancer) were diagnosed. The multivariate-adjusted hazard ratio of colorectal cancer incidence for > or =10 cups of coffee per day compared with non-drinkers was 0.98 (95% CI, 0.47-2.03) for men (P for trend=0.86), 1.24 (95% CI, 0.49-3.14) for women (p for trend=0.83) and 1.03 (95% CI, 0.58-1.83) for men and women combined (P for trend=0.61). In this study, we found no association between coffee consumption and the risk of colorectal, colon and rectal cancer.

  18. App Improves Colorectal Cancer Screening Rates

    Science.gov (United States)

    Colorectal cancer screening reduces deaths from the disease, yet about one-third of Americans aren’t up to date with screening. In this Cancer Currents blog post, learn what happened when people waiting for routine checkups could order their own screening test using a computer app.

  19. Safe laparoscopic colorectal surgery performed by trainees

    DEFF Research Database (Denmark)

    Langhoff, Peter Koch; Schultz, Martin; Harvald, Thomas

    2013-01-01

    Laparoscopic surgery for colorectal cancer is safe, but there have been hesitations to implement the technique in all departments. One of the reasons for this may be suboptimal learning possibilities since supervised trainees have not been allowed to do the operations to an adequate extent...

  20. Serum YKL-40 and colorectal cancer

    DEFF Research Database (Denmark)

    Cintin, C; Johansen, J S; Christensen, Ib Jarle

    1999-01-01

    related to short survival. In the present study we analysed YKL-40 in preoperative sera from patients with colorectal cancer and evaluated its relation to survival. Serum YKL-40 was determined by RIA in 603 patients. Survival after operation was registered, and median follow-up time was 61 months. Three...

  1. Pulmonary nodules and metastases in colorectal cancer

    DEFF Research Database (Denmark)

    Nordholm-Carstensen, Andreas

    2016-01-01

    Patients with newly diagnosed colorectal cancer (CRC) are subjected to a preoperative thoraco-abdominal CT scan to determine the cancer stage. This staging is of relevance with regard to treatment and prognosis. About 20% of the patients have distant metastatic spread at the time of diagnosis, i...

  2. Systemic therapy for patients with colorectal cancer

    DEFF Research Database (Denmark)

    Pfeiffer, Per; Qvortrup, Camilla; Tabernero, Josep

    2015-01-01

    Recent modalities and strategies have increased the complexity of treatment choice in patients with colorectal cancer (CRC), and therefore all cases should be assessed at a multidisciplinary conference. Adjuvant chemotherapy for 6 months increases the chance of cure by absolutely 5 % in stage II...

  3. Diagnostic interval and mortality in colorectal cancer

    DEFF Research Database (Denmark)

    Tørring, Marie Louise; Frydenberg, Morten; Hamilton, William

    2012-01-01

    Objective To test the theory of a U-shaped association between time from the first presentation of symptoms in primary care to the diagnosis (the diagnostic interval) and mortality after diagnosis of colorectal cancer (CRC). Study Design and Setting Three population-based studies in Denmark...

  4. Radiological and clinical evaluation of colorectal cancer

    International Nuclear Information System (INIS)

    Shin, O. J.; Chin, S. Y.; Lee, K. S.; Park, S. S.

    1982-01-01

    One hundred thirty two cases of the pathologically proven colorectal cancer at Korea Atomic Energy Research Institute Hospital in the period from January 1973 to June 1980 were analyzed radiologically and clinically. The results were as follows: 1. The colorectal cancer was prevalent in rectosigmoid area and in the fourth to seventh decade of life. 2. The clinical pictures were classified into two groups. The one was rectosigmoid cancer with bowel habit changes. The other was one with no specific symptoms or signs. The clinical pictures of the right colon cancer were rather indirected, chronic and systemic than those of the left one. 3. The roentgenological findings were classified into two groups. The one was rectum and left colon cancer with symmetrical annular narrowing and the other showed trumpet-like proximal dilatation. 4. The most frequent complication was intestinal obstruction. 5. The majority of colorectal cancer was adenocarcinoma. The squamous cell carcinoma and atypical cell carcinoma were most prevalent in rectum, but malignantly lymphoma often occurred in right colon. The rarest colorectal cancer was atypical cell carcinoma in rectum

  5. Oxaliplatin-induced neuropathy in colorectal cancer

    DEFF Research Database (Denmark)

    Zedan, Ahmed; Hansen, Torben Frøstrup; Fex Svenningsen, Åsa

    2014-01-01

    Oxaliplatin is a chemotherapeutic agent effective against advanced colorectal cancer. Unlike with other platinum-based agents, the main side effect of oxaliplatin is polyneuropathy. Oxaliplatin-induced polyneuropathy (OIPN) has a unique profile, which can be divided into acute and chronic...

  6. Cetuximab in treatment of metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Guren, Tormod Kyrre; Thomsen, Maria Morandi; Kure, Elin H

    2017-01-01

    BACKGROUND: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival...

  7. Focus on periodontal disease and colorectal carcinoma.

    Science.gov (United States)

    Lauritano, D; Sbordone, L; Nardone, M; Iapichino, A; Scapoli, L; Carinci, F

    2017-01-01

    Diagnosis of focal disease, the theory that the human oral microbial (HOM) could affect the onset and development of systemic diseases, was very popular in the past, but the lack of scientific evidence has led to the abandonment of this idea. Interestingly, increasing evidence over the past 3 or so decades suggests that HOM can indeed serve as a reservoir for systemic dissemination of pathogenic bacteria and their toxins in distant body sites, favouring the developments of malignant tumours. Malignant tumours are complex communities of oncogenically transformed cells with aberrant genomes, associated non-neoplastic cells including immune and stromal cells, and sometimes HOM, including bacteria and viruses. Recent data suggest that HOM and periodontal disease play an active role in the pathogenesis of colorectal cancer, in fact HOM has been found within the colorectal cancer microenvironment, and the composition of the HOM was different from that of adjacent non-neoplastic tissue. An association of fusobacterium nucleatum with the colonic mucosa of colorectal cancer has been proven. Several questions thus arise. Is periodontal disease a risk factor for colorectal carcinoma? Given the connectivity of the digestive tract, could fusubacterium nucleatum or other HOM be involved in additional gastrointestinal disorders? Furthermore, based on the "mobility" of Fusubacterium nucleatum and the omnipresence of cadherins, could this organism be involved in cancers beyond the gastrointestinal tract? Answers to these questions will shed new lights on the role of the HOM in onset of diseases.

  8. Immunotherapy and immunoescape in colorectal cancer

    Science.gov (United States)

    Mazzolini, Guillermo; Murillo, Oihana; Atorrasagasti, Catalina; Dubrot, Juan; Tirapu, Iñigo; Rizzo, Miguel; Arina, Ainhoa; Alfaro, Carlos; Azpilicueta, Arantza; Berasain, Carmen; Perez-Gracia, José L; Gonzalez, Alvaro; Melero, Ignacio

    2007-01-01

    Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma. PMID:17990348

  9. Why I Got Tested for Colorectal Cancer

    Centers for Disease Control (CDC) Podcasts

    2016-02-29

    CDC’s Dr. Lisa Richardson explains why she got tested for colorectal cancer when she turned 50 years old. .  Created: 2/29/2016 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 2/29/2016.

  10. Cetuximab: clinical results in colorectal cancer.

    Science.gov (United States)

    Maiello, E; Giuliani, F; Gebbia, V; Piano, A; Agueli, R; Colucci, G

    2007-06-01

    In recent years, the introduction of targeted therapies into clinical practice seems to offer incremental benefits in the treatment of metastatic colorectal cancer (mCRC), mainly when they are employed in combination with optimal chemotherapy and/or radiotherapy. In this paper, we focus on Cetuximab and its role in the treatment of mCRC.

  11. Metalloproteinases and their regulators in colorectal cancer.

    NARCIS (Netherlands)

    Jagt, M.F.P. van der; Wobbes, T.; Strobbe, L.J.; Sweep, F.C.; Span, P.N.

    2010-01-01

    Metalloproteinases (MPs) such as the matrix metalloproteinases (MMPs) and adamalysins (ADAMs and ADAMTS) are expressed in various stages of colorectal cancer (CRC), and some correlate with survival and prognosis. The MPs are regulated by various factors including EMMPRIN, TIMPs, and RECK. In

  12. Manual Colostomy Reversals Following Wide Colorectal Resections ...

    African Journals Online (AJOL)

    Causes of WCRR were: sigmoid colon volvulus (58%); colorectal cancer: (17%); perforated sigmoid diverticulitis (11%), amoebic perforations (18%) and rectal cancer (6%). All 36 patients (100%) got discharged after successful management of the following complications: a faecal fistula in two patients, a surgical abdominal ...

  13. Epigenetic prognostic biomarkers in colorectal cancer

    NARCIS (Netherlands)

    Benard, Anne

    2015-01-01

    Colorectal cancer is one of the most common diagnosed cancers worldwide, and is the second most important cause of cancer mortality in Europe. The current TNM staging system used at the time of diagnosis is insufficient, as patients with the same tumor stage show wide variations in survival and

  14. Outcome of colorectal cancer resection in octogenarians

    African Journals Online (AJOL)

    Colorectal cancer is predominantly a disease of the elderly. It is the second most common cancer in the UK and the third most common cause of cancer-related death.[1] Surgical resection, either for cure or palliation, remains the mainstay of treatment.[1,2]. Long-term survival is related to the extent of disease at diagnosis.

  15. Colorectal cancer screening | Schneider | Continuing Medical ...

    African Journals Online (AJOL)

    Colorectal cancer (CRC) is one of the most common cancers in the Western world, with an estimated incidence of 148 810 cases in the USA in 2008, and about 50 000 deaths from this disease. If detected early, patients with disease localised to the colonic wall have a 5-year survival of 90%. The 5-year survival for patients ...

  16. Inflammatory bowel disease and colorectal cancer

    Directory of Open Access Journals (Sweden)

    Andreja Ocepek

    2006-12-01

    Full Text Available Background: Colorectal cancer is one of the most frequent cancers in developed countries and Slovenia, and the incidence is still rising. Groups of people with higher risk for colorectal cancer are well defined. Among them are patients with inflammatory bowel disease. The risk is highest in patients in whom whole large bowel is affected by inflammation, it rises after 8 to 10 years and increases with the duration of the disease. Precancerous lesion is a displastic, chronically inflammed mucosa and not an adenoma as in cases of sporadic colorectal carcinoma.Conclusions: Many studies suggest that the influence of genetic factors differs between sporadic and inflammatory bowel disease related colorectal cancer. Symptomatic patients at the time of diagnosis have a much worse prognosis. The goal of prevention programes is therefore discovering early precancerous lesions. Established screening protocols are based on relatively frequent colonoscopies which are inconvinient for the patient as well as the endoscopist. Use of specific genetic markers, mutations of candidate genes, as a screening method and a prognostic predictor could greatly lighten therapeutic decisions.

  17. Reverse transcriptase inhibitors as potential colorectal microbicides.

    Science.gov (United States)

    Herrera, Carolina; Cranage, Martin; McGowan, Ian; Anton, Peter; Shattock, Robin J

    2009-05-01

    We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.

  18. Mechanical bowel preparation for elective colorectal surgery

    DEFF Research Database (Denmark)

    Güenaga, Katia F; Matos, Delcio; Wille-Jørgensen, Peer

    2011-01-01

    The presence of bowel contents during colorectal surgery has been related to anastomotic leakage, but the belief that mechanical bowel preparation (MBP) is an efficient agent against leakage and infectious complications is based on observational data and expert opinions only.An enema before...

  19. Colorectal cancer screening: World Gastroenterology Organisation ...

    African Journals Online (AJOL)

    Colorectal cancer screening: World Gastroenterology Organisation/International Digestive Cancer Alliance Practice Guidelines. S Winawer, M Classen, R Lambert, M Fried, P Dite, K L Goh, F Guarner, D Lieberman, R Eliakim, B Levin, R Saenz, A G Khan, I Khalif, A Lanas, G Lindberg, M J O'Brien, G Young, J Krabshuis ...

  20. Colorectal cancer in younger population: our experience

    International Nuclear Information System (INIS)

    Amini, A.Q.; Samo, K.A.; Memon, A.S.

    2013-01-01

    Objective: To promote awareness regarding increased occurrence of colorectal cancer in younger population and its clinicopathological features compared to older patients. Methods: The cross-sectional study was conducted from February 2010 to January 2011 on patients with diagnosis of colorectal carcinoma admitted through emergency or outpatient departments to Surgical Unit 5, Civil Hospital, Karachi. Data regarding age, gender, presentation, site of tumour, surgery performed and Dukes staging was collected and analysed. Results: A total of 23 patients were operated during the study period: 13 (56.52%) males and 10 (43.47%) females. Of them 12 (52.17%) were below the age of 40 years, while 3 (13.04%) patients were in the 11-20 age group. In 7 (30.4%) patients, tumour was irresectable at the time of presentation so a palliative procedure (diversion colostomy or ileostomy) was performed. There was a higher proportion of younger patients with metastatic disease at the time of presentation (n=9; 75%) while 10 out of 12 patients in the younger age group (83.3%) had a tumour of left colon, particularly rectum. Conclusion: Although colorectal cancer is usually a disease of older patients, it is increasingly becoming more common in younger population. Data suggests a leftward distribution for colorectal carcinoma and that younger patients present with more advanced disease and poorer prognosis. (author)

  1. Status of colorectal cancer devices: present scenario.

    Science.gov (United States)

    Chandel, Shammy; Akhtar, Reyhan; Sarotra, Pooja; Medhi, Bikash

    2015-06-01

    The purpose of this study was the colonoscopic detection and removal of neoplasia from the colorectum to prevent the development of colorectal cancer. Various online medical databases were searched such as PubMed, ACS, NCI, NIH, WHO, etc. for relevant publications and clinical trials for new developments in colonoscopic devices that are intended for diagnostic visualization and therapeutic interventions of the digestive tract. HD colon and I-Scan both has shown to increase the detection of sporadic adenomas with high quality. Third Eye Retroscope confers the backward view of colon, but aeroscope screens the entire colon in 30-60 min. Narrow-band imaging enhances mucosal and vascular details through the color differentiation of precancerous or cancerous polyp, compared to white light colonoscopy. The PillCam Colon Capsule is another new technique which is easily inserted and painless. In case of chemotherapy, Therasphere with Yttrium-90 has good results in the treatment of colorectal adenocarcinoma metastasis. Radiofrequency ablation is a good technique for tumors ablation and Staple Line Reinforcement prevents the leak during and post-surgery of colon. FOBT is much more sensitive and cheaper test for colorectal cancer screening. Registered clinical trials have shown promising results for neoplasia detection by I-Scan, TER, and NBI imaging techniques will change current colonoscopic practice in colorectal cancer screening. However, more studies and inventions are required for improving the patient safety and efficacy.

  2. [Multiple primary colorectal cancer: Clinical aspects].

    Science.gov (United States)

    Soldatkina, N V; Kit, O I; Gevorkyan, Yu A; Milakin, A G

    to define some clinical characteristics of synchronous and metachronous colorectal cancer (CRC). The investigation was concerned with the data of 150 patients with T1-4N0-2M0-1 multiple primary CRC. The clinical, biological, and morphological characteristics of synchronous and metachronous tumors were analyzed. Multiple primary tumors were 6.01% of all the cases of CRC. There was a preponderance of synchronous CRC (63.75%) with the tumor localized in the sigmoid colon and rectum. In women, synchronous colorectal tumors were more often concurrent with breast tumors; metachronous ones were detected after treatment for genital tumors. In men, synchronous colorectal tumors were more frequently concurrent with kidney cancer; metachronous ones were identified after treatment for gastric cancer. The found characteristics of multiple primary colorectal tumors may be taken in account in programs for both primary diagnosis and follow-up after treatment for malignant tumors, which will be able to improve the early detection of cancer patients and their treatment results.

  3. Could polymorphisms in ATP-binding cassette C3/multidrug resistance associated protein 3 (ABCC3/MRP3) modify colorectal cancer risk?

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Vodička, Pavel; Pardini, Barbara; Novotný, J.; Försti, A.; Hemminki, K.; Barale, R.; Canzian, F.

    2008-01-01

    Roč. 44, č. 6 (2008), s. 854-857 ISSN 0959-8049 R&D Projects: GA ČR GA310/05/2626 Institutional research plan: CEZ:AV0Z50390512 Keywords : ABCC3 * Transporter * Colorectal Cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.475, year: 2008

  4. Colorectal carcinoma in a ten-year-old girl: A case report

    Directory of Open Access Journals (Sweden)

    Sarbani Chattopadhyay

    2012-01-01

    Full Text Available Colorectal carcinoma is very rare in childhood. In this case report, we depict a ten-year-old girl who presented with features of intestinal obstruction which turned out to be due to poorly differentiated mucin secreting adenocarcinoma of descending colon. Only increased awareness of this malignancy in this age-group and a high index of suspicion can help when a child complains of persistent pain of abdomen, altered bowel habits or rectal bleeding, and may provide diagnosis at an earlier stage, thereby improving the prognosis.

  5. Re-laparoscopy in the diagnosis and treatment of postoperative complications following laparoscopic colorectal surgery.

    LENUS (Irish Health Repository)

    O'Riordan, J M

    2013-08-01

    Laparoscopic colorectal surgery has increasingly become the standard of care in the management of both benign and malignant colorectal disease. We herein describe our experience with laparoscopy in the management of complications following laparoscopic colorectal surgery.

  6. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis

    NARCIS (Netherlands)

    Vasen, H. F.; Wijnen, J. T.; Menko, F. H.; Kleibeuker, J. H.; Taal, B. G.; Griffioen, G.; Nagengast, F. M.; Meijers-Heijboer, E. H.; Bertario, L.; Varesco, L.; Bisgaard, M. L.; Mohr, J.; Fodde, R.; Khan, P. M.

    1996-01-01

    Hereditary nonpolyposis colorectal cancer is characterized by early-onset colorectal cancer and the occurrence of various other cancers. The recent isolation of four mismatch repair genes responsible for hereditary nonpolyposis colorectal cancer allows for the identification of carriers within

  7. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis

    NARCIS (Netherlands)

    Vasen, HFA; Wijnen, JT; Menko, FH; Kleibeuker, JH; Taal, BG; Griffioen, G; Nagengast, FM; MeijersHeijboer, EH; Bertario, L; Varesco, L; Bisgaard, ML; Mohr, J; Fodde, R; Khan, PM

    Background & Aims: Hereditary nonpolyposis colorectal cancer is characterized by early-onset colorectal cancer and the occurrence of various other cancers, The recent isolation of four mismatch repair genes responsible for hereditary nonpolyposis colorectal cancer allows for the identification of

  8. The inflammatory microenvironment in colorectal neoplasia.

    Science.gov (United States)

    McLean, Mairi H; Murray, Graeme I; Stewart, Keith N; Norrie, Gillian; Mayer, Claus; Hold, Georgina L; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N Ashley G; Drew, Janice E; El-Omar, Emad M

    2011-01-07

    Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

  9. Sporadic colorectal polyps and mismatch repair proteins

    Directory of Open Access Journals (Sweden)

    Mahsa Molaei

    2011-01-01

    Full Text Available Background: Colorectal cancers often arise from benign polyps. Adenomatous polyps and serrated polyps progress step by step to adenocarcinoma and change into malignant cancers. Genetic and epigenetic changes have correlation with specific stages of polyp-adenocarcinoma progression and colorectal cancer histopathological changes. Aims: In this study we used immunohistochemistry (IHC staining in sporadic colorectal polyps to assay functional status of MLH1, MSH2, MSH6, and PMS2 proteins, to track genetic/epigenetic roles of this issue in our patients. Materials and Methods: In this cross-sectional study we assessed all patients who were admitted with sporadic colorectal polyps and underwent polypectomy in endoscopy department during 2004-2008. Result: IHC results were abnormal in 6.8% cases for MLH1, in 4.5% cases for MSH2, in 3% for MSH6, and in 4.8% for PMS2. In all cases with abnormal PMS2, MLH1 was also reported as abnormal. Same results were reported for abnormal MSH2, which is accompanied with abnormal MSH6 in all cases (P values < 0.001. There is no significant difference between IHC staining results, gender, dysplasia grade, adenomatous type, and invasion. On the other hand, there was significant difference between IHC staining results, polyp location, and mean age of patients. The same significant difference was between adenomatous polyps and serrated adenoma polyps by MLH1 and PMS2 (P values < 0.05. Conclusion: According to our findings, maybe MMR dysfunction is the cause of sporadic colorectal polyps in younger age and its increasing risk of dysplasia progression and malignancy progression is only in serrated adenoma. Sporadic polyps in left colon had a higher risk to progress to malignancies, and abnormal IHC staining for MLH1 and PMS2 in serrated polyps is much more than in other adenomatous polyps.

  10. The Inflammatory Microenvironment in Colorectal Neoplasia

    Science.gov (United States)

    McLean, Mairi H.; Murray, Graeme I.; Stewart, Keith N.; Norrie, Gillian; Mayer, Claus; Hold, Georgina L.; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N. Ashley G.; Drew, Janice E.; El-Omar, Emad M.

    2011-01-01

    Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified. PMID:21249124

  11. The inflammatory microenvironment in colorectal neoplasia.

    Directory of Open Access Journals (Sweden)

    Mairi H McLean

    Full Text Available Colorectal cancer (CRC is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5 are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

  12. Absence of diurnal variation in visceromotor response to colorectal distention in normal Long Evans rats [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sara Botschuijver

    2016-01-01

    Full Text Available Background: Enhanced colorectal sensitivity (i.e. visceral hypersensitivity is thought to be a pathophysiological mechanism in irritable bowel syndrome (IBS. In healthy men a circadian variation in rectal perception to colonic distention was described. Disturbed day and night rhythms, which occur in shift work and trans meridian flights, are associated with the prevalence of IBS. This raises the question whether disruptions of circadian control are responsible for the observed pathology in IBS. Prior to investigating altered rhythmicity in relation to visceral hypersensitivity in a rat model for IBS, it is relevant to establish whether normal rats display circadian variation similar to healthy men.  Methodology and findings: In rodents colorectal distension leads to reproducible contractions of abdominal musculature. We used quantification of this so called visceromotor response (VMR by electromyography (EMG to assess visceral sensitivity in rats. We assessed the VMR in normal male Long Evans rats at different time points of the light/dark cycle. Although a control experiment with male maternal separated rats confirmed that intentionally inflicted (i.e. stress induced changes in VMR can be detected, normal male Long Evans rats showed no variation in VMR along the light/dark cycle in response to colorectal distension. Conclusions: In the absence of a daily rhythm of colorectal sensitivity in normal control rats it is not possible to investigate possible aberrancies in our rat model for IBS.

  13. Distinct Gene Expression Signatures in Lynch Syndrome and Familial Colorectal Cancer Type X

    DEFF Research Database (Denmark)

    Valentin, Mev; Therkildsen, Christina; Veerla, Srinivas

    2013-01-01

    Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects.......Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects....

  14. Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis.

    Science.gov (United States)

    Sekine, Shigeki; Mori, Taisuke; Ogawa, Reiko; Tanaka, Masahiro; Yoshida, Hiroshi; Taniguchi, Hirokazu; Nakajima, Takeshi; Sugano, Kokichi; Yoshida, Teruhiko; Kato, Mamoru; Furukawa, Eisaku; Ochiai, Atsushi; Hiraoka, Nobuyoshi

    2017-08-01

    Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.

  15. Colorectal cancer stages transcriptome analysis.

    Directory of Open Access Journals (Sweden)

    Tianyao Huo

    Full Text Available Colorectal cancer (CRC is the third most common cancer and the second leading cause of cancer-related deaths in the United States. The purpose of this study was to evaluate the gene expression differences in different stages of CRC. Gene expression data on 433 CRC patient samples were obtained from The Cancer Genome Atlas (TCGA. Gene expression differences were evaluated across CRC stages using linear regression. Genes with p≤0.001 in expression differences were evaluated further in principal component analysis and genes with p≤0.0001 were evaluated further in gene set enrichment analysis. A total of 377 patients with gene expression data in 20,532 genes were included in the final analysis. The numbers of patients in stage I through IV were 59, 147, 116 and 55, respectively. NEK4 gene, which encodes for NIMA related kinase 4, was differentially expressed across the four stages of CRC. The stage I patients had the highest expression of NEK4 genes, while the stage IV patients had the lowest expressions (p = 9*10-6. Ten other genes (RNF34, HIST3H2BB, NUDT6, LRCh4, GLB1L, HIST2H4A, TMEM79, AMIGO2, C20orf135 and SPSB3 had p value of 0.0001 in the differential expression analysis. Principal component analysis indicated that the patients from the 4 clinical stages do not appear to have distinct gene expression pattern. Network-based and pathway-based gene set enrichment analyses showed that these 11 genes map to multiple pathways such as meiotic synapsis and packaging of telomere ends, etc. Ten of these 11 genes were linked to Gene Ontology terms such as nucleosome, DNA packaging complex and protein-DNA interactions. The protein complex-based gene set analysis showed that four genes were involved in H2AX complex II. This study identified a small number of genes that might be associated with clinical stages of CRC. Our analysis was not able to find a molecular basis for the current clinical staging for CRC based on the gene expression patterns.

  16. Family history of prostate and colorectal cancer and risk of colorectal cancer in the Women's health initiative.

    Science.gov (United States)

    Beebe-Dimmer, Jennifer L; Yee, Cecilia; Paskett, Electra; Schwartz, Ann G; Lane, Dorothy; Palmer, Nynikka R A; Bock, Cathryn H; Nassir, Rami; Simon, Michael S

    2017-12-13

    Evidence suggests that risk of colorectal and prostate cancer is increased among those with a family history of the same disease, particularly among first-degree relatives. However, the aggregation of colorectal and prostate cancer within families has not been well investigated. Analyses were conducted among participants of the Women's Health Initiative (WHI) observational cohort, free of cancer at the baseline examination. Subjects were followed for colorectal cancer through August 31st, 2009. A Cox-proportional hazards regression modeling approach was used to estimate risk of colorectal cancer associated with a family history of prostate cancer, colorectal cancer and both cancers among first-degree relatives of all participants and stratified by race (African American vs. White). Of 75,999 eligible participants, there were 1122 colorectal cancer cases diagnosed over the study period. A family history of prostate cancer alone was not associated with an increase in colorectal cancer risk after adjustment for confounders (aHR =0.94; 95% CI =0.76, 1.15). Separate analysis examining the joint impact, a family history of both colorectal and prostate cancer was associated with an almost 50% increase in colorectal cancer risk (aHR = 1.48; 95% CI = 1.04, 2.10), but similar to those with a family history of colorectal cancer only (95% CI = 1.31; 95% CI = 1.11, 1.54). Our findings suggest risk of colorectal cancer is increased similarly among women with colorectal cancer only and among those with both colorectal and prostate cancer diagnosed among first-degree family members. Future studies are needed to determine the relative contribution of genes and shared environment to the risk of both cancers.

  17. The effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma.

    Science.gov (United States)

    Han, Min Seok; Lee, Hyun Jung; Park, Soo Jung; Hong, Sung Pil; Cheon, Jae Hee; Kim, Won Ho; Kim, Tae Il

    2017-08-01

    Existing studies suggest that metformin lowers the risk and mortality of colorectal cancer. However, the effect of metformin on the suppression and prevention of colorectal adenomas is not clear. The aim of this study was to evaluate the effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma. Among 423 diabetic patients who underwent surveillance colonoscopy after resection of colorectal adenoma between 2005 and 2011, 257 patients were retrospectively reviewed. The patients were divided into two groups: one group comprising 106 patients who took metformin and another group comprising 151 patients who did not take metformin. The clinical characteristics, colorectal adenoma recurrence, and valuable factors for adenoma recurrence were analyzed. At surveillance colonoscopy after colonoscopic polypectomy for adenoma, 38 patients (35.8%) exhibited colorectal adenoma among 106 patients who took metformin, compared with 85 patients (56.3%) with colorectal adenoma among 151 patients who did not take metformin (odds ratio 0.434, 95% confidence interval 0.260-0.723, P = 0.001). Multivariate Cox analysis showed that metformin was associated with decreased recurrence of colorectal adenoma (hazard ratio 0.572, 95% confidence interval 0.385-0.852, P = 0.006) in diabetic patients with previous colorectal adenoma. The cumulative probability of colorectal adenoma recurrence was significantly lower in the metformin group than in the non-metformin group (P = 0.001). Metformin use in diabetic patients with previous colorectal adenoma is associated with a lower risk of colorectal adenoma recurrence.

  18. Reduced miR-433 expression is associated with advanced stages and early relapse of colorectal cancer and restored miR-433 expression suppresses the migration, invasion and proliferation of tumor cells in vitro and in nude mice.

    Science.gov (United States)

    Zhang, Jian; Zhang, Lei; Zhang, Tong; Dong, Xin-Min; Zhu, Yu; Chen, Long-Hua

    2018-05-01

    The expression of microRNA (miR-433) is altered in various types of human cancer. The present study analyzed the prognostic and biological value of miR-433 expression in colorectal cancer using reverse transcription-quantitative polymerase chain reaction in 125 colorectal tissue specimens (including a test cohort of 40 cases of paired colorectal cancer and adjacent normal mucosae and a confirmation cohort of 85 cases of stage I-III colorectal cancer). In vitro and nude mouse xenograft experiments were subsequently used to assess the effects of miR-433 expression on the regulation of colorectal cancer cell proliferation, adhesion, migration, and invasion. The data indicated that miR-433 expression was significantly downregulated in colorectal cancer tissues in the test and confirmation patient cohorts and that low miR-433 expression was associated with advanced tumor stage and early relapse. Furthermore, the restoration of miR-433 expression was able to significantly inhibit the proliferation of tumor cells by inducing G1-S cell cycle arrest, suppressing cyclinD1 and CDK4 expression, and markedly inhibited the migratory and invasive capacities of tumor cells in vitro . The restoration of miR-433 expression or liposome-based delivery of miR-433 mimics suppressed the growth of colorectal cancer cell xenografts in nude mice. In conclusion, miR-433 may be a putative tumor suppressor in colorectal cancer, and the detection of low miR-433 expression will be investigated in further studies as a putative biomarker for the detection of early relapse in patients with colorectal cancer.

  19. Dietary patterns and colorectal cancer in a Japanese population: the Fukuoka Colorectal Cancer Study.

    Science.gov (United States)

    Kurotani, Kayo; Budhathoki, Sanjeev; Joshi, Amit Man; Yin, Guang; Toyomura, Kengo; Kono, Suminori; Mibu, Ryuichi; Tanaka, Masao; Kakeji, Yoshihiro; Maehara, Yoshihiko; Okamura, Takeshi; Ikejiri, Koji; Futami, Kitaroh; Maekawa, Takafumi; Yasunami, Yohichi; Takenaka, Kenji; Ichimiya, Hitoshi; Terasaka, Reiji

    2010-12-01

    Few studies have addressed the relation between dietary patterns and colorectal cancer in Japan. We investigated dietary patterns in relation to colorectal cancer risk in a community-based case-control study. The association with dietary patterns was also examined for different sites of colorectal cancer. Data were derived from the Fukuoka Colorectal Cancer Study, including 800 cases and 775 controls interviewed from September 2000 to December 2003. The cases were admitted to one of the participating hospitals for the first surgical treatment during this period. We identified dietary patterns using principal component analysis of intakes of twenty-nine items of food groups and specific foods. Quartile categories of each dietary pattern were used, and non-dietary lifestyle factors and total energy intake were adjusted for in the analysis. We identified three dietary patterns: prudent, high-fat and light-meal patterns. The prudent dietary pattern characterised by high intakes of vegetables, fruits, seafoods and soya foods showed a nearly significant protective association with the overall risk of colorectal cancer (trend P = 0.054), and it was statistically significantly related to a decreased risk of distal colon cancer (trend P = 0.002), but not to that of either proximal colon or rectal cancer. The high-fat and light-meal dietary patterns were not materially related to the overall or site-specific risk of colorectal cancer. In summary, a prudent dietary pattern was associated with a decreased risk of colorectal cancer, especially with that of distal colon cancer, in a fairly large case-control study in Japan.

  20. Outreach training model for accredited colorectal specialists in laparoscopic colorectal surgery: feasibility and evaluation of challenges.

    Science.gov (United States)

    Hamdan, M F; Day, A; Millar, J; Carter, F J C; Coleman, M G; Francis, N K

    2015-07-01

    The aim of this study was to explore the feasibility and safety of an outreach model of laparoscopic colorectal training of accredited specialists in advanced laparoscopic techniques and to explore the challenges of this model from the perspective of a National Training Programme (NTP) trainer. Prospective data were collected for unselected laparoscopic colorectal training procedures performed by five laparoscopic colorectal NTP trainees supervised by a single NTP trainer with an outreach model between 2009 and 2012. The operative and postoperative outcomes were compared with standard laparoscopic colorectal training procedures performed by six senior colorectal trainees under the supervision of the same NTP trainer within the same study period. The primary outcome was 30-day mortality. The Mann-Whitney test was used to compare continuous variables and the Chi squared or Fisher's exact tests were applied for the analysis of categorical variables. The level of statistical significance was set at P groups. Seventy-eight per cent of the patients operated on by the NTP trainees had had no previous abdominal surgery, compared with 50% in the supervised trainees' group (P = 0.0005). There were no significant differences in 30-day mortality or the operative and postoperative outcome between both groups. There were, however, difficulties in training an already established consultant in his or her own hospital and these were overcome by certain adjustments to the programme. Outreach laparoscopic training of colorectal surgeons is a feasible and safe model of training accredited specialists and does not compromise patient care. The challenges encountered can be overcome with optimum training and preparation. Colorectal Disease © 2015 The Association of Coloproctology of Great Britain and Ireland.

  1. Investigations on aberrant glycosylation of glycosphingolipids in colorectal cancer tissues using liquid chromatography and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS).

    Science.gov (United States)

    Holst, Stephanie; Stavenhagen, Kathrin; Balog, Crina I A; Koeleman, Carolien A M; McDonnell, Liam M; Mayboroda, Oleg A; Verhoeven, Aswin; Mesker, Wilma E; Tollenaar, Rob A E M; Deelder, André M; Wuhrer, Manfred

    2013-11-01

    Cancer is a leading cause of death and alterations of glycosylation are characteristic features of malignant cells. Colorectal cancer is one of the most common cancers and its exact causes and biology are not yet well understood. Here, we compared glycosylation profiles of colorectal tumor tissues and corresponding control tissues of 13 colorectal cancer patients to contribute to the understanding of this cancer. Using MALDI-TOF(/TOF)-MS and 2-dimensional LC-MS/MS we characterized enzymatically released and 2-aminobenzoic acid labeled glycans from glycosphingolipids. Multivariate data analysis revealed significant differences between tumor and corresponding control tissues. Main discriminators were obtained, which represent the overall alteration in glycosylation of glycosphingolipids during colorectal cancer progression, and these were found to be characterized by (1) increased fucosylation, (2) decreased acetylation, (3) decreased sulfation, (4) reduced expression of globo-type glycans, as well as (5) disialyl gangliosides. The findings of our current research confirm former reports, and in addition expand the knowledge of glycosphingolipid glycosylation in colorectal cancer by revealing new glycans with discriminative power and characteristic, cancer-associated glycosylation alterations. The obtained discriminating glycans can contribute to progress the discovery of biomarkers to improve diagnostics and patient treatment.

  2. Investigations on Aberrant Glycosylation of Glycosphingolipids in Colorectal Cancer Tissues Using Liquid Chromatography and Matrix-Assisted Laser Desorption Time-of-Flight Mass Spectrometry (MALDI-TOF-MS)*

    Science.gov (United States)

    Holst, Stephanie; Stavenhagen, Kathrin; Balog, Crina I. A.; Koeleman, Carolien A. M.; McDonnell, Liam M.; Mayboroda, Oleg A.; Verhoeven, Aswin; Mesker, Wilma E.; Tollenaar, Rob A. E. M.; Deelder, André M.; Wuhrer, Manfred

    2013-01-01

    Cancer is a leading cause of death and alterations of glycosylation are characteristic features of malignant cells. Colorectal cancer is one of the most common cancers and its exact causes and biology are not yet well understood. Here, we compared glycosylation profiles of colorectal tumor tissues and corresponding control tissues of 13 colorectal cancer patients to contribute to the understanding of this cancer. Using MALDI-TOF(/TOF)-MS and 2-dimensional LC-MS/MS we characterized enzymatically released and 2-aminobenzoic acid labeled glycans from glycosphingolipids. Multivariate data analysis revealed significant differences between tumor and corresponding control tissues. Main discriminators were obtained, which represent the overall alteration in glycosylation of glycosphingolipids during colorectal cancer progression, and these were found to be characterized by (1) increased fucosylation, (2) decreased acetylation, (3) decreased sulfation, (4) reduced expression of globo-type glycans, as well as (5) disialyl gangliosides. The findings of our current research confirm former reports, and in addition expand the knowledge of glycosphingolipid glycosylation in colorectal cancer by revealing new glycans with discriminative power and characteristic, cancer-associated glycosylation alterations. The obtained discriminating glycans can contribute to progress the discovery of biomarkers to improve diagnostics and patient treatment. PMID:23878401

  3. Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment - A pilot study.

    LENUS (Irish Health Repository)

    Tsang, J S

    2014-07-28

    In rectal cancer, not all tumours display a response to neoadjuvant treatment. An accurate predictor of response does not exist to guide patient-specific treatment. DNA methylation is a distinctive molecular pathway in colorectal carcinogenesis. Whether DNA methylation is altered by neoadjuvant treatment and a potential response predictor is unknown. We aimed to determine whether DNA methylation is altered by neoadjuvant chemoradiotherapy (CRT) and to determine its role in predicting response to treatment.

  4. Clinical application and research of tumor markers in colorectal cancer

    International Nuclear Information System (INIS)

    Chen Yumei

    2005-01-01

    Colorectal cancer is one of the most common malignant tumors. There are many tumor markers for detecting colorectal cancer, some of which have been widely used in clinical area. However, still lack an ideal tumor marker of colorectal cancer. In this review, we simply characterized some common tumor markers including carcinoembryonic antigen, CA19-9, CA50, CA242 etc and their dignostic value. And here we discussed some combined detecting procedures which improve diagnostic accuracy of colorectal cancer. In addition, with the development of the biomoleculer technique, some newly discovered tumor markers and genetic marekers have gained great progress in the research of colorectal cancer, and will become a promissing technique in the diagnosis of colorectal cancer. (authors)

  5. Transportation Emissions: some basics

    DEFF Research Database (Denmark)

    Kontovas, Christos A.; Psaraftis, Harilaos N.

    2016-01-01

    transportation and especially carbon dioxide emissions are at the center stage of discussion by the world community through various international treaties, such as the Kyoto Protocol. The transportation sector also emits non-CO2 pollutants that have important effects on air quality, climate, and public health......Transportation is the backbone of international trade and a key engine driving globalization. However, there is growing concern that the Earth’s atmospheric composition is being altered by human activities, including transportation, which can lead to climate change. Air pollution from....... The main purpose of this chapter is to introduce some basic concepts that are relevant in the quest of green transportation logistics. First, we present the basics of estimating emissions from transportation activities, the current statistics and future trends, as well as the total impact of air emissions...

  6. The Role of Akt Isoforms in Colorectal Cancer

    Science.gov (United States)

    2015-09-01

    AD_________________ Award Number: W81XWH-13-1-0198 TITLE: The Role of Akt Isoforms in Colorectal Cancer PRINCIPAL INVESTIGATOR: Jatin Roper...CONTRACT NUMBER The Role of Akt Isoforms in Colorectal Cancer 5b. GRANT NUMBER W81XWH-13-1-0198 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER...substantially reduces colorectal tumorigenesis in our genetically engineered mouse model. We also successfully ablated novel downstream targets of Akt in our

  7. Quality of life and its determinants among colorectal cancer survivors

    OpenAIRE

    Hossein Ali Nikbakht; Nayyereh Amini Sani; Mohamad Asghari Jafarabadi; Seyed Reza Hosseini

    2015-01-01

    Background: Colorectal cancer has a significant impact on physical, mental and social discomfort of patients. The aim of this study was to assess different aspects of health-related quality of life and its association with demographic characteristics and some clinical features in colorectal cancer survivors in the city of Babol. Methods: This cross-sectional study was conducted in 2013 among 120 colorectal cancer survivors identified in the cancer registry from 2007 to 2012. A questionnair...

  8. Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype.

    Science.gov (United States)

    Whitehall, V L J; Dumenil, T D; McKeone, D M; Bond, C E; Bettington, M L; Buttenshaw, R L; Bowdler, L; Montgomery, G W; Wockner, L F; Leggett, B A

    2014-11-01

    The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.

  9. Robotic colorectal surgery: hype or new hope? A systematic review of robotics in colorectal surgery.

    Science.gov (United States)

    Mirnezami, A H; Mirnezami, R; Venkatasubramaniam, A K; Chandrakumaran, K; Cecil, T D; Moran, B J

    2010-11-01

    Robotic colorectal surgery is an emerging field and may offer a solution to some of the difficulties inherent to conventional laparoscopic surgery. The aim of this review is to provide a comprehensive and critical analysis of the available literature on the use of robotic technology in colorectal surgery. Studies reporting outcomes of robotic colorectal surgery were identified by systematic searches of electronic databases. Outcomes examined included operating time, length of stay, blood loss, complications, cost, oncological outcome, and conversion rates. Seventeen Studies (nine case series, seven comparative studies, one randomized controlled trial) describing 288 procedures were identified and reviewed. Study heterogeneity precluded a meta-analysis of the data. Robotic procedures tend to take longer and cost more, but may reduce the length of stay, blood loss, and conversion rates. Complication profiles and short-term oncological outcomes are similar to laparoscopic surgery. Robotic colorectal surgery is a promising field and may provide a powerful additional tool for optimal management of more challenging pathology, including rectal cancer. Further studies are required to better define its role. © 2010 The Authors. Colorectal Disease © 2010 The Association of Coloproctology of Great Britain and Ireland.

  10. [Chinese Protocol of Diagnosis and Treatment of Colorectal Cancer].

    Science.gov (United States)

    2018-04-01

    Colorectal cancer is one of the most common malignant tumors in China. In 2012 one million thirty six thousand cases of colorectal cancer were diagnosed all over the world, two hundred fifty three thousand cases were diagnosed in China (accounted for 18.6%). China has the largest number of new cases of colorectal cancer in the world. Colorectal cancer has becoming a serious threat of Chinese residents' health. In 2010, the National Ministry of Health organized colorectal cancer expertise of the Chinese Medical Association to write the "Chinese Protocol of Diagnosis and Treatment of Colorectal Cancer" (2010edition), and publish it publicly. In recent years, the National Health and Family Planning Commission has organized experts to revised the protocol 2 times: the first time in 2015, the second time in 2017. The revised part of "Chinese Protocol of Diagnosis and Treatment of Colorectal Cancer" (2017 edition) involves new progress in the field of imaging examination, pathological evaluation, surgery, chemotherpy and radiotherapy. The 2017 edition of the protocol not only referred to the contents of the international guidelines, but also combined with the specific national conditions and clinical practice in China, and also included many evidence-based clinical data in China recently. The 2017 edition of the protocol would further promote the standardization of diagnosis and treatment of colorectal cancer in China, improve the survival and prognosis of patients, and benefit millions of patients with colorectal cancer and their families.

  11. Prospective study of blood metabolites associated with colorectal cancer risk.

    Science.gov (United States)

    Shu, Xiang; Xiang, Yong-Bing; Rothman, Nathaniel; Yu, Danxia; Li, Hong-Lan; Yang, Gong; Cai, Hui; Ma, Xiao; Lan, Qing; Gao, Yu-Tang; Jia, Wei; Shu, Xiao-Ou; Zheng, Wei

    2018-02-26

    Few prospective studies, and none in Asians, have systematically evaluated the relationship between blood metabolites and colorectal cancer risk. We conducted a nested case-control study to search for risk-associated metabolite biomarkers for colorectal cancer in an Asian population using blood samples collected prior to cancer diagnosis. Conditional logistic regression was performed to assess associations of metabolites with cancer risk. In this study, we included 250 incident cases with colorectal cancer and individually matched controls nested within two prospective Shanghai cohorts. We found 35 metabolites associated with risk of colorectal cancer after adjusting for multiple comparisons. Among them, 12 metabolites were glycerophospholipids including nine associated with reduced risk of colorectal cancer and three with increased risk [odds ratios per standard deviation increase of transformed metabolites: 0.31-1.98; p values: 0.002-1.25 × 10 -10 ]. The other 23 metabolites associated with colorectal cancer risk included nine lipids other than glycerophospholipid, seven aromatic compounds, five organic acids and four other organic compounds. After mutual adjustment, nine metabolites remained statistically significant for colorectal cancer. Together, these independently associated metabolites can separate cancer cases from controls with an area under the curve of 0.76 for colorectal cancer. We have identified that dysregulation of glycerophospholipids may contribute to risk of colorectal cancer. © 2018 UICC.

  12. Stromal Expression of Hypoxia Regulated Proteins Is an Adverse Prognostic Factor in Colorectal Carcinomas

    Directory of Open Access Journals (Sweden)

    Arjen H. G. Cleven

    2007-01-01

    Full Text Available Background: Hypoxia modifies the phenotype of tumors in a way that promotes tumor aggressiveness and resistance towards chemotherapy and radiotherapy. However, the expression and influence of hypoxia-regulated proteins on tumor biology are not well characterized in colorectal tumors. We studied the role of protein expression of hypoxia-inducible factor (HIF-1α, HIF-2α, carbonic anhydrase 9 (CA9 and glucose transporter 1 (GLUT1 in patients with colorectal adenocarcinomas. Methods: Expression of HIF-1α, HIF-2α, CA9 and GLUT1 was quantified by immunohistochemistry in 133 colorectal adenocarcinomas. The expression of hypoxia markers was correlated with clinicopathological variables and overall patient survival. Results: Expression of these hypoxia markers was detected in the epithelial compartment of the tumor cells as well as in tumor-associated stromal cells. Although tumor cells frequently showed expression of one or more of the investigated hypoxia markers, no correlation among these markers or with clinical response was found. However, within the tumor stroma, positive correlations between the hypoxia markers HIF-2α, CA9 and GLUT1 were observed. Furthermore expression of HIF-2α and CA9 in tumor-associated stroma were both associated with a significantly reduced overall survival. In the Cox proportional hazard model, stromal HIF-2α expression was an independent prognostic factor for survival. Conclusion: These observations show, that expression of hypoxia regulated proteins in tumor-associated stromal cells, as opposed to their expression in epithelial tumor cells, is associated with poor outcome in colorectal cancer. This study suggests that tumor hypoxia may influence tumor-associated stromal cells in a way that ultimately contributes to patient prognosis.

  13. Altered membrane permeability in multidrug resistant Escherichia ...

    African Journals Online (AJOL)

    The study was conducted with the objective of examining the outer membrane proteins and their involvement during the transport of β - lactams in multidrug resistant Escherichia coli isolated from extra-intestinal infections. Also, the response of gram negative bacterial biomembrane alteration was studied using extended ...

  14. rights reserved Geophysical Identification of Hydrothermally Altered ...

    African Journals Online (AJOL)

    ADOWIE PERE

    the pole to the magnetic data aided in mapping of various hydrothermally altered structures that may favour gold mineralisation. The interpretation of the aero data set has enhanced a lot of ... water serves as a concentrating, transporting and depositing agent through faults (structures) to the earth's surface. Hydrothermal ...

  15. Indeterminate Pulmonary Nodules in Colorectal-Cancer

    DEFF Research Database (Denmark)

    Nordholm-Carstensen, Andreas; Jorgensen, Lars N; Wille-Jørgensen, Peer A

    2015-01-01

    BACKGROUND: The clinical significance of indeterminate pulmonary nodules (IPN) at staging computed tomography (CT) for colorectal cancer (CRC), and the optimal diagnostic approach, are debated. This study aimed to analyse variability in radiologists' detection of IPN at staging CT for CRC. METHODS......: All patients with CRC referred to our center between 2006 and 2011 were included. Primary staging CT scans were re-evaluated by an experienced thoracic radiologist whose findings were entered into a dedicated database and merged with data from the Danish Colorectal Cancer Group database, the National...... investigated radiological characteristics or clinicopathological factors were significantly associated with malignancy of IPN. CONCLUSION: The characterization of pulmonary findings on staging CT for CRC varied greatly between the radiologists, and double-reading of scans with IPN is recommended prior...

  16. Early colorectal Cancer: focuses and handling

    International Nuclear Information System (INIS)

    Rojas, Oscar A; Martinez, Carlos E; Escobar, Jaime; Sanchez, William; Serrano, Juan M

    2001-01-01

    Currently, early colorectal cancer (ECC) constitutes only 10% of the total of diagnosed colorectal malignancy. This proportion is expected to show an important increase with the different screening protocols that are on the way, together with recent advances in diagnostic and therapeutic colonoscopy. We compare the histopathologic spectrum of ECC from the western and Japanese viewpoint, defining the anatomopathologic characteristics of this lesions, together with the natural history and new classification and staging systems; variables which are all oriented to establish the grade of local invasion and risk of nodal spread. The knowledge and integral analysis of the different biologic, clinical, histological and endoscopic characteristics of ECC, will determine the most rational individual therapeutic pathway from the prognostic point of view

  17. Ranitidine as adjuvant treatment in colorectal cancer

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Christensen, Ib Jarle; Moesgaard, F

    2002-01-01

    BACKGROUND: Results from short-term studies of histamine type 2 (H2) receptor antagonists on survival of patients with solid tumours are debatable. In this study the efficacy of the H2-receptor antagonist ranitidine on long-term survival of patients with colorectal cancer was evaluated. METHODS...... infectious complications (n = 170; HR 0.6 (95 per cent c.i. 0.4 to 0.9), P = 0.01). In multivariate analysis of patients who had a curative resection, including Dukes' stage, age, gender, tumour location, blood transfusion, postoperative infectious complications and treatment, ranitidine still had...... curative resection of colorectal cancer and who do not receive perioperative blood transfusion and do not develop postoperative infectious complications....

  18. Potential targets for colorectal cancer prevention.

    Science.gov (United States)

    Temraz, Sally; Mukherji, Deborah; Shamseddine, Ali

    2013-08-22

    The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2), nuclear factor kappa B (NF-κB), survivin and insulin-like growth factor-I (IGF-I). Clinical trials of COX-2 inhibitors have provided the "proof of principle" that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research.

  19. Potential Targets for Colorectal Cancer Prevention

    Directory of Open Access Journals (Sweden)

    Ali Shamseddine

    2013-08-01

    Full Text Available The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2, nuclear factor kappa B (NF-κB, survivin and insulin-like growth factor-I (IGF-I. Clinical trials of COX-2 inhibitors have provided the “proof of principle” that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research.

  20. X-ray diagnosis of colorectal endometriosis

    Energy Technology Data Exchange (ETDEWEB)

    Runte, F.; Majewski, A.; Reichert, B.

    1987-05-01

    Preoperative diagnosis of symptomatic colorectal endometriosis is often difficult. Hence, the X-ray findings of eight woman patients with confirmed affection of the colon with endometriosis foci were evaluated together with the clinical, surgical and histological findings. In 50 % of the cases rectal haemorrhages were the most frequently occurring sign. In three-quarters of the cases the colon sigmoideum was involved. Radiologically it was possible to prove in 37,5 % each of the cases that there was a polypoid lesion and an irregular concentric stenosis of the intestinal lumen. In 25 % of the cases we found a complete stenosis of the intestinal lumen combined with ileus. X-ray sign pattern of colorectal endometriosis, however, is not pathognomonic.