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Sample records for alters colorectal transport

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Colorectal cancer (CRC) is the 3rd most common cancer globally, with 5year survival rates of ~50%. Response rates to standard treatments (irinotecan (SN38) or Oxaliplatin (Oxp)) are 31–56% and drug resistance is a major problem. Thus, we established in vitro CRC models to investigate SN38 and Oxp...... resistance in HCT-116, HT-29 and LoVo cells. Microarray analysis and qPCR validation showed that mRNA expression of glutamate transporters SLC1A1 and SLC1A3 were markedly altered in resistant cells. Remarkably, mRNA levels of SLC1A3 were increased by ~40-and ~2500-fold in SN38-and Oxp-resistant HT29 cells......, 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...

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

    NARCIS (Netherlands)

    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

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

    Science.gov (United States)

    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.

  4. 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

  5. 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 w...

  6. 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.

  7. 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...

  8. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer.

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    Nosho, Katsuhiko; Sukawa, Yasutaka; Adachi, Yasushi; Ito, Miki; Mitsuhashi, Kei; Kurihara, Hiroyoshi; Kanno, Shinichi; Yamamoto, Itaru; Ishigami, Keisuke; Igarashi, Hisayoshi; Maruyama, Reo; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

    2016-01-14

    The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6% (44/511), which was lower than that in United States cohort studies (13%). Similar to the United States studies, F. nucleatum positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain microRNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in

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

    DEFF Research Database (Denmark)

    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 tumour cells, and in tumour related angiogenesis. Additional activation by the surgical trauma and postoperative infections are discussed. Finally, anti-cancer modalities directed against regulation of the haemostatic system in CRC are considered....

  10. High-resolution analysis of HLA class I alterations in colorectal cancer

    OpenAIRE

    Dierssen, Jan Willem F; de Miranda, Noel FCC; Mulder, Arend; van Puijenbroek, Marjo; Verduyn, Willem; Claas, Frans HJ; van de Velde, Cornelis JH; Jan Fleuren, Gert; Cornelisse, Cees J; Corver, Willem E; Morreau, Hans

    2006-01-01

    Abstract Background Previous studies indicate that alterations in Human Leukocyte Antigen (HLA) class I expression are frequent in colorectal tumors. This would suggest serious limitations for immunotherapy-based strategies involving T-cell recognition. Distinct patterns of HLA surface expression might conceal different immune escape mechanisms employed by the tumors and are worth further study. Method We applied four-color multiparameter flow cytometry (FCM), using a large panel of alloantig...

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

    Science.gov (United States)

    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.

  12. 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.

  13. 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.

  14. 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.

  15. [Microsatellite alterations on chromosome 9p21-22 in sporadic colorectal cancer].

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    Zhang, Y; Lai, M

    1999-12-01

    To study whether alteration of p16 plays an important role in the development of colorectal carcinomas and the relationship between the molecular changes of 9p21-22 chromosome subregion in sporadic colorectal cancers. To detect microsatellite instability (MSI) and loss of heterozygosity (LOH) by PCR, denatured-polyacrylamide gel-electrophoresis and silver staining (microsatellite DNA-PCR-silver staining method) and to compare the results with the clinopathological parameters. Between MSI positive and negative cases and the clinopathological findings, some evidences found in the MSI positive group were as follows: (1) tendency towards younger patients (usually < 50 years in age, P < 0.05); (2) more frequently seen in mucoid carcinomas (P < 0.01). Microsatellite DNA-PCR-silver staining method is very sensitive in detecting even a tiny change of a single base. MSI occured in the selected microsatellite loci of different subregions and different chromosomes might be different in significance, therefore, a right choice of the suitable loci for studying the microsatellite changes is important. Since the frequency of loss of heterozygosity at 9p21-22 is low (merely 8.42%), it is considered that p16 is not closely associated with the development of sporadic colorectal cancer.

  16. 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.

  17. 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.

  18. High-resolution analysis of HLA class I alterations in colorectal cancer

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    Jan Fleuren Gert

    2006-10-01

    Full Text Available Abstract Background Previous studies indicate that alterations in Human Leukocyte Antigen (HLA class I expression are frequent in colorectal tumors. This would suggest serious limitations for immunotherapy-based strategies involving T-cell recognition. Distinct patterns of HLA surface expression might conceal different immune escape mechanisms employed by the tumors and are worth further study. Method We applied four-color multiparameter flow cytometry (FCM, using a large panel of alloantigen-specific anti-HLA-A and -B monoclonal antibodies, to study membranous expression of individual HLA alleles in freshly isolated colorectal cancer cell suspensions from 21 patients. Results Alterations in HLA class I phenotype were observed in 8 (38% of the 21 tumors and comprised loss of a single A or B alleles in 4 cases, and loss of all four A and B alleles in the other 4 cases. Seven of these 8 tumors were located on the right side of the colon, and those showing loss of both HLA-A and -B membranous expression were all of the MSI-H phenotype. Conclusion FCM allows the discrimination of complex phenotypes related to the expression of HLA class I. The different patterns of HLA class I expression might underlie different tumor behavior and influence the success rate of immunotherapy.

  19. Microsatellite alterations at selected tetranucleotide repeats are associated with morphologies of colorectal neoplasias

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    Lee, Sun-Young; Chung, Heekyung; Devaraj, Bikash; Iwaizumi, Moriya; Han, Hye Seung; Hwang, Dae-Yong; Seong, Moo Kyung; Jung, Barbara H.; Carethers, John M.

    2010-01-01

    Background & Aims Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) occurs during microsatellite instability (MSI) that is not associated with major defects in DNA mismatch repair (MMR) but rather the reduced (heterogenous) expression of the MMR protein hMSH3; it occurs in sporadic colorectal tumors. We examined the timing of development of EMAST during progression of colorectal neoplasias and looked for correlations between EMAST and clinical and pathology features of tumors. Methods We evaluated tumor samples from a cohort of patients that had 24 adenomas and 84 colorectal cancers. EMAST were analyzed after DNA microdissection of matched normal and tumor samples using the polymorphic tetranucleotide microsatellite markers MYCL1, D9S242, D20S85, D8S321, and D20S82; data were compared with clinical and pathology findings. Traditional MSI analysis was performed and hMSH3 expression was measured. Results Moderately-differentiated adenocarcinomas and poorly-differentiated adenocarcinomas had higher frequencies of EMAST (56.9% and 40.0%, respectively) than well-differentiated adenocarcinomas (12.5%) or adenomas (33.3%) (P=0.040). In endoscopic analysis, ulcerated tumors had a higher frequency of EMAST (52.3%) than flat (44.0%) or protruded tumors (20.0%) (P=0.049). In quantification, all tumors with >3 tetranucleotide defects lost MSH3 (>75% of cells); nuclear heterogeneity of hMSH3 occurred more frequently in EMAST-positive (40.0%) than in EMAST-negative tumors (13.2%) (P=0.010). Conclusions EMAST is acquired during progression of adenoma and well-differentiated carcinomas to moderately and poorly differentiated carcinomas; it correlates with nuclear heterogeneity for hMSH3. Loss of hMSH3 corresponds with multiple tetranucleotide frameshifts. The association between EMAST and ulcerated tumors might result from increased inflammation. PMID:20708618

  20. Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

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    Shafina-Nadiawati Abdul

    2017-07-01

    Full Text Available Despite global progress in research, improved screening and refined treatment strategies, colorectal cancer (CRC remains as the third most common malignancy. As each type of cancer is different and exhibits unique alteration patterns, identifying and characterizing gene alterations in CRC that may serve as biomarkers might help to improve diagnosis, prognosis and predict potential response to therapy. With the emergence of next generation sequencing technologies (NGS, it is now possible to extensively and rapidly identify the gene profile of individual tumors. In this study, we aimed to identify actionable somatic alterations in Dukes’ B and C in CRC via NGS. Targeted sequencing of 409 cancer-related genes using the Ion AmpliseqTM Comprehensive Cancer Panel was performed on genomic DNA obtained from paired fresh frozen tissues, cancer and normal, of Dukes’ B (n = 10 and Dukes’ C (n = 9 CRC. The sequencing results were analyzed using Torrent Suite, annotated using ANNOVAR and validated using Sanger sequencing. A total of 141 somatic non-synonymous sequence variations were identified in 86 genes. Among these, 64 variants (45% were predicted to be deleterious, 38 variants (27% possibly deleterious while the other 39 variants (28% have low or neutral protein impact. Seventeen genes have alterations with frequencies of ≥10% in the patient cohort and with 14 overlapped genes in both Dukes’ B and C. The adenomatous polyposis coli gene (APC was the most frequently altered gene in both groups (n = 6 in Dukes’ B and C. In addition, TP53 was more frequently altered in Dukes’ C (n = 7 compared to Dukes’ B (n = 4. Ten variants in APC, namely p.R283∗, p.N778fs, p.R805∗, p.Y935fs, p.E941fs, p.E1057∗, p.I1401fs, p.Q1378∗, p.E1379∗, and p.A1485fs were predicted to be driver variants. APC remains as the most frequently altered gene in the intermediate stages of CRC. Wnt signaling pathway is the major affected pathway followed by P53, RAS

  1. JK1 (FAM134B) gene and colorectal cancer: a pilot study on the gene copy number alterations and correlations with clinicopathological parameters.

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    Kasem, Kais; Gopalan, Vinod; Salajegheh, Ali; Lu, Cu-Tai; Smith, Robert A; Lam, Alfred K Y

    2014-08-01

    The aims of the study are to characterize changes in JK-1 (FAM134B) at the DNA level in colorectal adenocarcinoma and adenoma and exploring the possible correlations with clinical and pathological features. JK-1 gene DNA copy number changes were studied in 211 colorectal carcinomas, 32 colorectal adenoma and 20 colorectal non-cancer colorectal tissue samples by real-time quantitative polymerase chain reaction. The results were correlated with clinical and pathological parameters. Colorectal adenomas were more likely to be amplified than deleted with regard to JK-1 (FAM134B) DNA copy number change. The copy number level of JK-1 (FAM134B) DNA in colorectal adenocarcinomas was significantly lower in comparison to colorectal adenomas. Changes in JK-1 (FAM134B) DNA copy number were associated with histological subtypes, and cancer stage. Lower copy numbers were associated with higher tumor stage, lymph node stage and overall pathological stage of cancer. Conversely, higher DNA copy numbers were detected more often in the mucinous adenocarcinoma. This is the first study showing significant correlations of the JK-1 (FAM134B) gene copy number alterations with clinical and pathological features in a large cohort of pre-invasive and invasive colorectal malignancies. The changes in DNA copy number associated with progression of colorectal malignancies reflect that JK-1 (FAM134B) gene could play a role in controlling some steps in development of the invasive phenotypes. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

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

    DEFF Research Database (Denmark)

    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...

  4. 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...

  5. Continuous-time random walks that alter environmental transport properties.

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    Angstmann, C; Henry, B I

    2011-12-01

    We consider continuous-time random walks (CTRWs) in which the walkers have a finite probability to alter the waiting-time and/or step-length transport properties of their environment, resulting in possibly transient anomalous diffusion. We refer to these CTRWs as transmogrifying continuous-time random walks (TCTRWs) to emphasize that they change the form of the transport properties of their environment, and in a possibly strange way. The particular case in which the CTRW waiting-time density has a finite probability to be permanently altered at a given site, following a visitation by a walker, is considered in detail. Master equations for the probability density function of transmogrifying random walkers are derived, and results are compared with Monte Carlo simulations. An interesting finding is that TCTRWs can generate transient subdiffusion or transient superdiffusion without invoking truncated or tempered power law densities for either the waiting times or the step lengths. The transient subdiffusion or transient superdiffusion arises in TCTRWs with Gaussian step-length densities and exponential waiting-time densities when the altered average waiting time is greater than or less than, respectively, the original average waiting time.

  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. 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...... with metastatic colorectal cancer. Methods From a national cohort, we identified 163 patients treated every third week with irinotecan 350 mg/m2 as second-line therapy. Among these 108 were eligible for analyses and thus entered the study. Primary tumors samples were collected and tissue microarray (TMA) blocks...... of the markers TOP1 CN, TOP1/CEN-20-ratio or TOP1/CEN-2-ratio were associated with progression free survival, overall survival or baseline characteristics. Yet, we observed a borderline association for a stepwise increase of the TOP1 CN in relation to objective response as hazard ratio were 1.35 (95% CI 0...

  8. 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.

  9. 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

  10. 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 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.

  11. 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.)

  12. 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...

  13. 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.

  14. TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells.

    Science.gov (United States)

    Fricke, Fabia; Lee, Jennifer; Michalak, Malwina; Warnken, Uwe; Hausser, Ingrid; Suarez-Carmona, Meggy; Halama, Niels; Schnölzer, Martina; Kopitz, Jürgen; Gebert, Johannes

    2017-04-04

    Colorectal cancers (CRCs) that lack DNA mismatch repair function exhibit the microsatellite unstable (MSI) phenotype and are characterized by the accumulation of frameshift mutations at short repetitive DNA sequences (microsatellites). These tumors recurrently show inactivating frameshift mutations in the tumor suppressor Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) thereby abrogating downstream signaling. How altered TGFBR2 signaling affects exosome-mediated communication between MSI tumor cells and their environment has not been resolved. Here, we report on molecular alterations of exosomes shed by MSI cells and the biological response evoked in recipient cells. Exosomes were isolated and characterized by electron microscopy, nanoparticle tracking, and western blot analysis. TGFBR2-dependent effects on the cargo and functions of exosomes were studied in a MSI CRC model cell line enabling reconstituted and inducible TGFBR2 expression and signaling. Microsatellite frameshift mutations in exosomal and cellular DNA were examined by PCR-based DNA fragment analysis and exosomal protein profiles were identified by mass spectrometry. Uptake of fluorescent-labeled exosomes by hepatoma recipient cells was monitored by confocal microscopy. TGFBR2-dependent exosomal effects on secreted cytokine levels of recipient cells were analyzed by Luminex technology and ELISA. Frameshift mutation patterns in microsatellite stretches of TGFBR2 and other MSI target genes were found to be reflected in the cargo of MSI CRC-derived exosomes. At the proteome level, reconstituted TGFBR2 expression and signaling uncovered two protein subsets exclusively occurring in exosomes derived from TGFBR2-deficient (14 proteins) or TGFBR2-proficient (five proteins) MSI donor cells. Uptake of these exosomes by recipient cells caused increased secretion (2-6 fold) of specific cytokines (Interleukin-4, Stem Cell Factor, Platelet-derived Growth Factor-B), depending on the TGFBR2 expression status

  15. 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.

  16. Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations

    Directory of Open Access Journals (Sweden)

    Hussain Azhar R

    2010-07-01

    Full Text Available Abstract Background Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4 and TRAIL receptor 2 (DR5. Expression of TRAIL receptors is higher in colorectal carcinoma (CRC as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells. Methods We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival. Results CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251 and a histology subtype of adenocarcinomas (p = 0.0355. Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011. Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L phenotype (p = 0.0003 and with absence of KRAS mutations (p = 0.0481. Conclusion TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.

  17. 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.

  18. Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Anna-Maria Pehserl

    2016-12-01

    Full Text Available MicroRNAs (miRNAs are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC. Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18, and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720 and two small RNAs (SNORD 13 and hsa-miR-3182 were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720 were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle–arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies.

  19. 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.

  20. 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.)

  1. 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

  2. Comparison of genetic and epigenetic alterations of primary tumors and matched plasma samples in patients with colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Elisa Danese

    Full Text Available Although recent advances in circulating DNA analysis allow the prediction of tumor genomes by noninvasive means, some challenges remain, which limit the widespread introduction of cfDNA in cancer diagnostics. We analyzed the status of the two best characterized colorectal cancer (CRC genetic and epigenetic alterations in a cohort of CRC patients, and then compared the degree to which the two patterns move from tissue to plasma in order to improve our understanding of biology modulating the concordance between tissues and plasma methylation and mutation profiles.Plasma and tumor tissues were collected from 85 patients (69±14 years, 56 males. KRAS and SEPT9 status was assessed by allele refractory mutation system quantitative PCR and quantitative methylation-specific PCR, respectively. Six of the most common point mutations at codon 12 and 13 were investigated for KRAS analysis.KRAS mutations and SEPT9 promoter methylation were present in 34% (29/85 and in 82% (70/85 of primary tumor tissue samples. Both genetic and epigenetic analyses of cfDNA revealed a high overall concordance and specificity compared with tumor-tissue analyses. Patients presenting with both genetic and epigenetic alterations in tissue specimens (31.8%, 27/85 were considered for further analyses. The median methylation rates in tumour tissues and plasma samples were 64.5% (12.2-99.8% and 14.5% (0-45.5%, respectively. The median KRAS mutation load (for matched mutations was 33.6% (1.8-86.3% in tissues and 2.9% (0-17.3 in plasma samples. The plasma/tissue (p/t ratio of SEPT9 methylation rate was significantly higher than the p/t ratio of KRAS mutation load, especially in early stage cancers (p=0.0108.The results of this study show a discrepant rate of epigenetic vs. genetic alterations moving from tissue to plasma. Many factors could affect mutation cfDNA analysis, including both presence of tumor clonal heterogeneity and strict compartmentalization of KRAS mutation profile. The

  3. 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...

  4. 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

  5. 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

  6. Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia

    DEFF Research Database (Denmark)

    Mahmood, Badar; Damm, Morten Matthiesen Bach; Jensen, Thorbjørn Søren Rønn

    2016-01-01

    BACKGROUND: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic...... functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. RESULTS: In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis...... showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia...

  7. 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

  8. Salt-stress alters proton transport by the tonoplast ATPase

    International Nuclear Information System (INIS)

    DuPont, F.; Morrissey, P.

    1990-01-01

    A tonoplast-enriched membrane fraction was obtained from roots of barley (Hordeum vulgare cv CM72) seedlings grown in half-strength nutrient solution with or without 100 mM NaCl. Proton transport by the tonoplast ATPase was measured using acridine orange, quinacrine or uptake of [ 14 C]-methylamine. The Vmax for proton transport was 2 to 4-fold higher for the ATPase from salt-grown compared to control roots. However, the rate of ATP hydrolysis was not significantly different for the two treatments. The percent inhibition of ATP hydrolysis by DCCD, DIDS and KNO 3 was similar for the two treatments, as was the percent stimulation by Cl. The pH optimum for proton transport was more alkaline for the ATPase from salt-grown roots. No difference was observed between membranes from control and salt-grown roots when oxonol fluorescence was used to measure formation of a membrane potential by the ATPase. Immunoblots of SDS gels were reacted with the antibody to the 68-kD subunit from red beet to assess the relative amount of the 68-kD subunit of the tonoplast ATPase from control or salt-grown roots. The relative amount of the 16-kD DCCD-binding subunit was compared by binding of [ 14 C]-DCCD. The amounts of the two subunits were not significantly different in membranes from control or salt-grown roots. The increase in rate of formation of the pH gradient was not accounted for by an increase in the amount of the ATPase

  9. Relevance of copper transporter 1 and organic cation transporters 1-3 for oxaliplatin uptake and drug resistance in colorectal cancer cells.

    Science.gov (United States)

    Buß, I; Hamacher, A; Sarin, N; Kassack, M U; Kalayda, G V

    2018-03-01

    Oxaliplatin is a routinely used drug in the treatment of colorectal cancer. However, development of resistance is a major hurdle of the chemotherapy success. Defects in cellular accumulation represent a frequently reported feature of cells with acquired resistance to platinum drugs. Nevertheless, the mechanisms of oxaliplatin uptake and their role in oxaliplatin resistance remain poorly elucidated. The aim of this study was to investigate the relevance of copper transporter 1 (CTR1) and organic cation transporters 1-3 (OCT1-3) for oxaliplatin uptake and resistance to the drug in sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cells. Co-incubation with copper(ii) sulfate, a CTR1 substrate, significantly decreased oxaliplatin accumulation but not cytotoxicity in both cell lines. Pre- as well as co-incubation with the OCT1 inhibitor atropine led to a significant reduction in oxaliplatin accumulation in sensitive but not in resistant cells. However, oxaliplatin cytotoxicity was also decreased in the presence of atropine in both cell lines. Cimetidine, an inhibitor of OCT2, induced a significant reduction in the cellular accumulation and potency of oxaliplatin in sensitive and resistant cells. An inhibitor of OCT3, decynium-22, had no influence on oxaliplatin accumulation and cytotoxicity in either cell line. No differences in the transporter expressions were observed between the cell lines, drug-treated or not, either at the mRNA or protein levels. A fluorescent oxaliplatin derivative CFDA-oxPt co-localized with CTR1, OCT1 and OCT2 in sensitive cells, but only with CTR1 and OCT2 in the resistant cell line. Our results suggest that oxaliplatin is transported into the cell by CTR1 in both cell lines. However, contribution of CTR1-mediated uptake to resistance seems unlikely. Uptake of oxaliplatin via OCT1 appears to take place in the sensitive but not in the resistant cell line underscoring the transporter relevance for oxaliplatin resistance. OCT

  10. 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

    Study design: Clinical study. Objectives: To explore how supraconal spinal cord injury (SCI) affects colorectal emptying at defecation. Further, to relate findings to subject symptomatology expressed by bowel function scores and gastrointestinal transit time (GITT). Setting: Aarhus University...... 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...

  11. Metabolic Adaptation to Nutritional Stress in Human Colorectal Cancer.

    Science.gov (United States)

    Miyo, Masaaki; Konno, Masamitsu; Nishida, Naohiro; Sueda, Toshinori; Noguchi, Kozo; Matsui, Hidetoshi; Colvin, Hugh; Kawamoto, Koichi; Koseki, Jun; Haraguchi, Naotsugu; Nishimura, Junichi; Hata, Taishi; Gotoh, Noriko; Matsuda, Fumio; Satoh, Taroh; Mizushima, Tsunekazu; Shimizu, Hiroshi; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

    2016-12-07

    Tumor cells respond to their microenvironment, which can include hypoxia and malnutrition, and adapt their metabolism to survive and grow. Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters. However, the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear. We found that colorectal cancer cells survived under the condition of glucose depletion, and their resistance to such conditions depended on genomic alterations rather than on KRAS mutation alone. Metabolomic analysis demonstrated that those cells maintained tricarboxylic acid cycle activity and ATP production under such conditions. Furthermore, we identified pivotal roles of GLUD1 and SLC25A13 in nutritional stress. GLUD1 and SLC25A13 were associated with tumor aggressiveness and poorer prognosis of colorectal cancer. In conclusion, GLUD1 and SLC25A13 may serve as new targets in treating refractory colorectal cancer which survive in malnutritional microenvironments.

  12. 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

  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. [Utility of immunohistochemistry in detecting alterations of mismatch repair genes of DNA. A series of 48 cases of colorectal cancer].

    Science.gov (United States)

    Ziadi, Sonia; Gacem, Riath Ben; Haoues, Imen; Hachana, Mouhamed; Amara, Khaled; Trimeche, Mounir; Golli, Lamia; Mokni, Moncef; Korbi, Sadok

    2011-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is associated in more than 95% to a germline mutation in the genes of the mismatch repair (MMR) of DNA. The aim of this study was to assess the utility of immunohistochemistry, a simple and fast technique, in the triage of families where HNPCC is suspected. Tumor samples included in this study were from patients with resection for colorectal cancer, examined in our laboratory between 2004 and 2007. For each case, a formalin-fixed paraffin-embedded tissue block containing tumor tissue and normal adjacent mucosa was selected. Tumor specimens were examined with immunohistochemistry for the presence of hMLH1, hMSH2, and hMSH6 proteins. Scoring of the tumor staining was performed without any knowledge of patients' family history. The loss of protein expression was noted in four patients among 48 cases tested: two cases with isolated loss of hMSH2, a case with isolated loss of hMSH6 and one case with combined loss of MSH2/MSH6. No case has shown a suppression of hMLH1 protein. Comparing the immunohistochemical results for clinical has revealed a clear correlation between loss of protein expression demonstrated by immunohistochemistry and clinical data. Indeed, three cases among the four who showed no expression of MMR proteins showed at least one clinical criterion predictive of HNPCC. In conclusion, our study support the potential utility of immunohistochemistry to identify a significant portion of colorectal tumors derived from germline mutation of MMR genes and can be used as an adjunct measure in the identification of HNPCC.

  15. DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity.

    Science.gov (United States)

    Rumiato, Enrica; Boldrin, Elisa; Amadori, Alberto; Saggioro, Daniela

    2013-08-01

    5-fluorouracil (5-FU) has been widely used since the 1980s, and it remains the backbone of many chemotherapeutic combination regimens. However, its use is often limited by the occurrence of severe toxicity. Although several reports have shown the detrimental effect of some dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) gene polymorphisms in patients undergoing 5-FU-based treatment, they account for only a minority of toxicities. Looking for new candidate genetic variants associated with 5-FU-induced toxicity, we used the innovative genotyping microarray Affymetrix Drug-Metabolizing Enzymes and Transporters (DMET)™ Plus GeneChip that interrogates 1,936 genetic variants distributed in 231 genes involved in drug metabolism, excretion, and transport. To reduce variability, we analyzed samples from colorectal cancer patients who underwent fairly homogenous treatments (i.e., Machover or Folfox) and experienced G3 or G4 toxicity; control patients were matched for therapy and selected from those who did not disclose toxicity (G0-G1). Pharmacogenetic genotyping showed no significant difference in DPYD and TYMS genetic variants distribution between cases and controls. However, other polymorphisms could account for 5-FU-induced toxicity, with the CHST1 rs9787901 and GSTM3 rs1799735 having the strongest association. Although exploratory, this study suggests that genetic polymorphisms not directly related to 5-FU pharmacokinetics and pharmacodynamics are involved in 5-FU-induced toxicity. Our data also indicates DMET™ microarray as a valid approach to discover new genetic determinants influencing chemotherapy-induced toxicity.

  16. [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.

  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....../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...... translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters...

  18. A comprehensive investigation on common polymorphisms in the MDR1/ABCB1 transporter gene and susceptibility to colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Daniele Campa

    Full Text Available ATP Binding Cassette B1 (ABCB1 is a transporter with a broad substrate specificity involved in the elimination of several carcinogens from the gut. Several polymorphic variants within the ABCB1 gene have been reported as modulators of ABCB1-mediated transport. We investigated the impact of ABCB1 genetic variants on colorectal cancer (CRC risk. A hybrid tagging/functional approach was performed to select 28 single nucleotide polymorphisms (SNPs that were genotyped in 1,321 Czech subjects, 699 CRC cases and 622 controls. In addition, six potentially functional SNPs were genotyped in 3,662 German subjects, 1,809 cases and 1,853 controls from the DACHS study. We found that three functional SNPs (rs1202168, rs1045642 and rs868755 were associated with CRC risk in the German population. Carriers of the rs1202168_T and rs868755_T alleles had an increased risk for CRC (P(trend = 0.016 and 0.029, respectively, while individuals bearing the rs1045642_C allele showed a decreased risk of CRC (P(trend = 0.022. We sought to replicate the most significant results in an independent case-control study of 3,803 subjects, 2,169 cases and 1,634 controls carried out in the North of Germany. None of the SNPs tested were significantly associated with CRC risk in the replication study. In conclusion, in this study of about 8,800 individuals we show that ABCB1 gene polymorphisms play at best a minor role in the susceptibility to CRC.

  19. Altered magnesium transport in slices of kidney cortex from chemically-induced diabetic rats

    International Nuclear Information System (INIS)

    Hoskins, B.

    1981-01-01

    The uptake of magnesium-28 was measured in slices of kidney cortex from rats with alloxan-diabetes and from rats with streptozotocin-diabetes of increasing durations. In both forms of chemically-induced diabetes, magnesium-28 uptake by kidney cortex slices was significantly increased over uptake measured in kidney cortex slices from control rats. Immediate institution of daily insulin therapy to the diabetic rats prevented the diabetes-induced elevated uptake of magnesium without controlling blood glucose levels. Late institution of daily insulin therapy was ineffective in restoring the magnesium uptake to control values. These alterations in magnesium uptake occurred prior to any evidence of nephropathy (via the classic indices of proteinuria and increased BUN levels). The implications of these findings, together with our earlier demonstrations of altered calcium transport by kidney cortex slices from chemically-induced diabetic rats, are discussed in terms of disordered divalent cation transport being at least part of the basic pathogenesis underlying diabetic nephropathy

  20. Vitamin E Prevents Cold Wrap Restraint Stress-Induced Intestinal Fluid Transport Alterations in Rats

    Directory of Open Access Journals (Sweden)

    Scott Burdick

    1994-01-01

    Full Text Available Psychological stress may alter gastrointestinal absorptive function by increasing the quantity of intestinal free radicals or by lowering endogenous intestinal free radical scavenging capacity. Vitamin E has been shown to be a potent endogenous antioxidant and free radical scavenger under both physiological and pathological conditions. The purpose of this study was to determine whether cold wrap restraint stress altered in vivo intestinal fluid absorption in rats, and whether vitamin E administration prior to the induction of cold wrap restraint stress could prevent such changes in intestinal secretion. Jejunal, ileal and colonic fluid and electrolyte transport rates were measured in vivo using an isolated loop technique. Cold wrap restraint stress reduced in vivo fluid absorption in the ileum and colon, but not in the jejunum. Administration of vitamin E prior to the cold wrap restraint stress procedure completely prevented this alteration of ileal and colonic fluid absorption.

  1. 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

  2. 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.

  3. [Colorectal cancer and folate].

    Science.gov (United States)

    Bott, C; Lembcke, B; Stein, J

    2003-03-01

    Nutritional factors are important contributors to colorectal cancer prevention. There is some evidence to suggest that a high dietary folate intake is associated with a reduced risk of colorectal cancer. Folate, which is found in green leafy vegetables, is involved in C1 group transfer and contributes to purin and thymi-dilate synthesis as well as to DNA methylation. Alterations in gene expression and DNA damage are discussed to result from low folate levels and might be associated with an elevated risk of colorectal malignancies. This hypothesis can be supported by the finding that a common polymorphism in the methylentetrahydrofolate reductase gene enhances the risk of colorectal cancer when folate status is low. Both retrospective and prospective epidemiologic studies confirm the observation that a high intake of folate correlates with a lower risk of colorectal cancer. There is also evidence from epidemiological studies that diets which are low in methyl donors, such as low contents of folate and/or methionine combined with relatively high alcohol consumption, even enhance the risk of colorectal cancer. A small number of intervention trials provide first evidence that folate intakes far above recommended dietary allowances might influence possible biomarkers of colorectal tumours.

  4. 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.

  5. 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.

  6. A comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations.

    Directory of Open Access Journals (Sweden)

    Tao Xie

    Full Text Available To develop a comprehensive overview of copy number aberrations (CNAs in stage-II/III colorectal cancer (CRC, we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS samples (n = 269 had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%, 7 (41.8%, 8 q (33.1% and 13 q (51.0% and losses on 18 (58.6%, 4 q (26% and 21 q (21.6%. MSS tumors have significantly more CNAs than microsatellite-instable (MSI tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01. Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.

  7. 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.

  8. Effects of common haplotypes of the ileal sodium dependent bile acid transporter gene on the development of sporadic and familial colorectal cancer: A case control study

    Directory of Open Access Journals (Sweden)

    Friedrichs Nicolaus

    2008-07-01

    Full Text Available Abstract Background The genetics of sporadic and non-syndromic familial colorectal cancer (CRC is not well defined. However, genetic factors that promote the development of precursor lesions, i.e. adenomas, might also predispose to CRC. Recently, an association of colorectal adenoma with two variants (c.507C>T;p.L169L and c.511G>T;p.A171S of the ileal sodium dependent bile acid transporter gene (SLC10A2 has been reported. Here, we reconstructed haplotypes of the SLC10A2 gene locus and tested for association with non-syndromic familial and sporadic CRC compared to 'hyper-normal' controls who displayed no colorectal polyps on screening colonoscopy. Methods We included 150 patients with sporadic CRC, 93 patients with familial CRC but exclusion of familial adenomatous polyposis and Lynch's syndrome, and 204 'hyper-normal' controls. Haplotype-tagging SLC10A2 gene variants were identified in the Hapmap database and genotyped using PCR-based 5' exonuclease assays with fluorescent dye-labelled probes. Haplotypes were reconstructed using the PHASE algorithm. Association testing was performed with both SNPs and reconstructed haplotypes. Results Minor allele frequencies of all SLC10A2 polymorphisms are within previously reported ranges, and no deviations from Hardy-Weinberg equilibrium are observed. However, we found no association with any of the SLC10A2 haplotypes with sporadic or familial CRC in our samples (all P values > 0.05. Conclusion Common variants of the SLC10A2 gene are not associated with sporadic or familial CRC. Hence, albeit this gene might be associated with early stages of colorectal neoplasia, it appears not to represent a major risk factor for progression to CRC.

  9. 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 ...

  10. DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up.

    Science.gov (United States)

    Bigagli, Elisabetta; De Filippo, Carlotta; Castagnini, Cinzia; Toti, Simona; Acquadro, Francesco; Giudici, Francesco; Fazi, Marilena; Dolara, Piero; Messerini, Luca; Tonelli, Francesco; Luceri, Cristina

    2016-12-01

    DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study. Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes. Correlations between these genomic and transcriptomic changes and their associations with clinical and histopathological parameters were assessed with the aim to identify molecular signatures associated with disease-free survival of the CRC patients during a 10 year follow-up. DNA copy number gains were frequently detected in chromosomes 7, 8q, 13, 19, 20q and X, whereas DNA copy number losses were frequently detected in chromosomes 1p, 4, 8p, 15, 17p, 18, 19 and 22q. None of these alterations were observed in all samples. In addition, we found that 2,498 genes were up- and that 1,094 genes were down-regulated in the tumor samples compared to their corresponding normal mucosa (p number gains, whereas decreased expression levels of the MUC1, E2F2, HRAS and SIRT3 genes were associated with copy number losses. Pathways related to cell cycle progression, eicosanoid metabolism, and TGF-β and apoptosis signaling, were found to be most significantly affected. Our results suggest that CNAs in CRC tumor tissues are associated with concomitant changes in the expression of cancer-related genes. In other genes epigenetic mechanism may be at work. Up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, appear to be associated with a poor survival. These alterations may, in addition to Dukes' staging

  11. 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...... 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....... pathogen-free Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid...

  12. Genetic variation in serotonin transporter alters resting brain function in healthy individuals.

    Science.gov (United States)

    Rao, Hengyi; Gillihan, Seth J; Wang, Jiongjiong; Korczykowski, Marc; Sankoorikal, Geena Mary V; Kaercher, Kristin A; Brodkin, Edward S; Detre, John A; Farah, Martha J

    2007-09-15

    Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4) on resting brain function of healthy individuals. Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. Compared with the l/l group, the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood. The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.

  13. The Antiepileptic Ketogenic Diet Alters Hippocampal Transporter Levels and Reduces Adiposity in Aged Rats.

    Science.gov (United States)

    Hernandez, Abbi R; Hernandez, Caesar M; Campos, Keila T; Truckenbrod, Leah M; Sakarya, Yasemin; McQuail, Joseph A; Carter, Christy S; Bizon, Jennifer L; Maurer, Andrew P; Burke, Sara N

    2018-03-14

    Nutritional ketosis is induced by high fat/low carbohydrate dietary regimens, which produce high levels of circulating ketone bodies, shifting metabolism away from glucose utilization. While ketogenic diets (KD) were initially introduced to suppress seizures, they are garnering attention for their potential to treat a myriad of neurodegenerative and metabolic disorders that are associated with advanced age. The feasibility and physiological impact of implementing a long-term KD in old animals, however, has not been systematically examined. In this study, young and aged rats consumed a calorically- and nutritionally-matched KD or control diet for 12 weeks. All KD-fed rats maintained higher levels of BHB and lower levels of glucose relative to controls. However, it took the aged rats longer to reach asymptotic levels of BHB compared to young animals. Moreover, KD-fed rats had significantly less visceral white and brown adipose tissue than controls without a loss of lean mass. Interestingly, the KD led to significant alterations in protein levels of hippocampal transporters for monocarboxylates, glucose, and vesicular glutamate and gamma-aminobutyric acid. Most notably, the age-related decline in vesicular glutamate transporter expression was reversed by the KD. These data demonstrate the feasibility and potential benefits of KDs for treating age-associated neural dysfunction.

  14. The dimethylhydrazine induced colorectal tumours in rat - experimental colorectal carcinogenesis

    International Nuclear Information System (INIS)

    Perse, M.; Cerar, A.

    2005-01-01

    Animal models of colorectal carcinogenesis represent invaluable research tool for investigating colorectal cancer (CRC). Experimentally induced tumours in laboratory animals provide opportunity for studying certain aspects of tumours that cannot be effectively studied in humans. Significant information on human CRC aetiology or factors influencing it has derived from studies using dimethylhydrazine (DMH) model that is one of the experimental models appreciated for its morphological similarity to human CRC. Today, DMH model represents useful research tool for the studies of colon carcinogens and chemopreventive agents. The review offers insight into morphogenesis and genetic alterations of DMH induced colorectal epithelial tumours in rats. (author)

  15. Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

    Science.gov (United States)

    Satoh, Kiyotoshi; Yachida, Shinichi; Sugimoto, Masahiro; Oshima, Minoru; Nakagawa, Toshitaka; Akamoto, Shintaro; Tabata, Sho; Saitoh, Kaori; Kato, Keiko; Sato, Saya; Igarashi, Kaori; Aizawa, Yumi; Kajino-Sakamoto, Rie; Kojima, Yasushi; Fujishita, Teruaki; Enomoto, Ayame; Hirayama, Akiyoshi; Ishikawa, Takamasa; Taketo, Makoto Mark; Kushida, Yoshio; Haba, Reiji; Okano, Keiichi; Tomita, Masaru; Suzuki, Yasuyuki; Fukuda, Shinji; Aoki, Masahiro; Soga, Tomoyoshi

    2017-01-01

    Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy. PMID:28847964

  16. 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

  17. Linking Gut Microbiota to Colorectal Cancer

    DEFF Research Database (Denmark)

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

    2017-01-01

    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......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...

  18. 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.

  19. Cronobacter sakazakii infection alters serotonin transporter and improved fear memory retention in the rat

    Science.gov (United States)

    Sivamaruthi, Bhagavathi S.; Madhumita, Rajkumar; Balamurugan, Krishnaswamy; Rajan, Koilmani E.

    2015-01-01

    It is well established that Cronobacter sakazakii infection cause septicemia, necrotizing enterocolitis 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-15 (PND-15), wistar rat pups were administered with single dose of C. sakazakii culture (infected group; 107 CFU) or 100 μL of Luria-Bertani broth (medium control) or without any treatment (naïve control). 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 and heat-shock proteins-90 (Hsp-90). On the other hand, level of serotonin (5-hydroxytryptamine) and SERT protein was down-regulated. Furthermore, we show that C. sakazakii infection up-regulate microRNA-16 (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. sakazakii 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. PMID:26388777

  20. The alteration of serine transporter activity in a cell line model of amyotrophic lateral sclerosis (ALS).

    Science.gov (United States)

    Lee, Na-Young; Kim, Yunha; Ryu, Hoon; Kang, Young-Sook

    2017-01-29

    The alteration of d-serine levels is associated with the pathogenesis of sporadic ALS and mutant SOD1 (G93A) animal model of ALS. However, the exact mechanism of d-serine transport is not known in ALS. To better understand the distribution of d-serine in ALS, we determined the activity and the expression of serine transporter in a motor neuronal cell line model of ALS (NSC-34/hSOD1 G93A cells). The uptake of [ 3 H]d-serine was significantly lower in NSC-34/hSOD1 G93A cells than in control NSC-34 and NSC-34/hSOD1 wt cells. In contrast, the uptake of [ 3 H]l-serine, precursor of d-serine, was markedly increased in NSC-34/hSOD1 G93A cells compared to control NSC-34 and NSC-34/hSOD1 wt cells. Both [ 3 H]d-serine and [ 3 H]l-serine uptake were saturable in these cells. The estimated Michaelis-Menten constant, K m , for d-serine uptakes was higher in NSC-34/hSOD1 G93A cells than in NSC-34/hSOD1 wt cells while the K m for l-serine uptake was 2 fold lower in NSC-34/hSOD1 G93A cells than in control cells. [ 3 H]d-serine and [ 3 H]l-serine uptakes took place in a Na + -dependent manner, and both uptakes were significantly inhibited by system ASC (alanine-serine-cysteine) substrates. As a result of small interfering RNA experiments, we found that ASCT2 (SLC1A5) and ASCT1 (SLC1A4) are involved in [ 3 H]d-serine and [ 3 H]l-serine uptake in NSC-34/hSOD1 G93A cells, respectively. The level of SLC1A4 mRNA was significantly increased in NSC-34/hSOD1 G93A compared to NSC-34 and NSC-34/hSOD1 wt cells. In contrast, the level of SLC7A10 mRNA was relatively lower in NSC-34/hSOD1 G93A cells than the control cells. Together, these data suggest that the pathological alteration of d- and l-serine uptakes in ALS is driven by the affinity change of d-and l-serine uptake system. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Alteration of membrane complement regulators is associated with transporter status in patients on peritoneal dialysis

    Science.gov (United States)

    Biegger, Dagmar; Segerer, Stephan; Braun, Niko; Alscher, M. Dominik; Latus, Joerg

    2017-01-01

    Introduction A growing body of evidence from animal models and cell culture studies indicate an important role of a local regulatory complement system (CS) in peritoneal injury during peritoneal dialysis (PD). We investigated the expression of the local regulatory CS (reflected by CD46,CD55,CD59) in the peritoneal tissue of patients with different membrane function characteristics. Patients and methods Biopsies from the parietal peritoneum were taken from 24 patients on PD, 22 uremic patients prior to PD. PD patients were grouped according to the dialysate-to-plasma ratio of creatinine (D/P Cre) and ratio of dialysate glucose at 4 hours versus dialysate glucose at time zero (D/D0 glucose) into low or low-average peritoneal transport status (L/LA) and high-average or high-transport status (HA/H) groups. CD46, CD55, and CD59 RNA expression were analyzed by real-time polymerase chain reaction (RT-PCR). Further localization of membrane complement regulators (CRegs) and semiquantitatively analysis was done by immunohistochemistry (IHC). Results CD46 and CD59 expression were similar in all groups. CD55 expression was significantly decreased in the HA/H group compared to the L/LA group and to uremic controls (p peritonitis. There was no statistically significant correlation between PD duration and the expressions of CD46, CD55, and CD59. IHC revealed strong CD46, CD55, and CD59 expression in mesothelial cells. CD55 and CD59 were additionally detected in the vasculature. Using IHC, CD46 was lower in PD patients compared to uremic controls (p>0.05), but there was no difference between the L/LA compared to the H/HA group. Moreover IHC confirmed decreased expression of CD55 in the HA/H group compared to the L/LA group and uremic controls (pperitonitis and PD duration do not appear to alter CReg expression. PMID:28542228

  2. Calcium Intake and Ion Transporter Genetic Polymorphisms Interact in Human Colorectal Neoplasia Risk in a 2-Phase Study123

    Science.gov (United States)

    Zhu, Xiangzhu; Liang, Ji; Shrubsole, Martha J.; Ness, Reid M.; Cai, Qiuyin; Long, Jirong; Chen, Zhi; Li, Guoliang; Wiese, Dawn; Zhang, Bing; Smalley, Walter E.; Edwards, Todd L.; Giovannucci, Edward; Zheng, Wei; Dai, Qi

    2014-01-01

    Background: The kidney-specific sodium-potassium-chloride cotransporter (NKCC2) protein encoded by solute carrier family 12 member 1 (SLC12A1) is the direct downstream effector of the inward-rectifier potassium channel (ROMK) encoded by potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), both of which are critical for calcium reabsorption in the kidney. Objective: We hypothesized that polymorphisms in KCNJ1, SLC12A1, and 7 other genes may modify the association between calcium intake and colorectal neoplasia risk. Methods: We conducted a 2-phase study in 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. Results: In phase I, we identified 5 single-nucleotide polymorphisms (SNPs) that significantly interacted with calcium intake in adenoma risk. In phase II, rs2855798 in KCNJ1 was replicated. In combined analysis of phases I and II, the P values for interactions between calcium intake and rs2855798 were 1 × 10−4 for all adenoma and 5 × 10−3 for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with no variant allele but was significantly associated with a 41% reduced adenoma risk among those who carried at least 1 variant allele in KCNJ1. The corresponding reduction in risk of multiple or advanced adenomas was 52% among those with at least 1 variant allele. The P values for interactions between calcium intake and combined SNPs from the KCNJ1 and SLC12A1 genes were 7.5 × 10−5 for adenoma and 9.9 × 10−5 for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with nonvariant alleles in 2 genes but was significantly associated with a 34% reduced adenoma risk among those who carried a variant allele in 1 of the genes. The corresponding reduction in risk of multiple or advanced adenomas was 64% among those with variant alleles in both genes. Conclusion: These findings, if confirmed, will be critical for the development of personalized

  3. 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 ...

  4. 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.)

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

    Science.gov (United States)

    2014-10-01

    510. Duncan JE, Goldstein LS. 2006. The Genetics of Axonal Transport and Axonal Transport Disorders PLoS Genet . 2(9): e124. 25 Duysen EG, Li...Gitajn L, Rea W, Yang Y, Stein EA.2007. Cocaine -induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI

  6. Changes in apoptosis during the development of colorectal cancer : a systematic review of the literature

    NARCIS (Netherlands)

    Koornstra, JJ; de Jong, S; Hollema, H; de Vries, EGE; Kleibeuker, JH

    The development of colorectal cancer is characterised by an accumulation of molecular genetic alterations causing disorders in cell growth, differentiation and apoptosis. Although changes in apoptosis with colorectal cancer development have been studied extensively, a clear consensus of opinion has

  7. Solute carrier organic anion transporter family member 4A1 (SLCO4A1) as a prognosis marker of colorectal cancer.

    Science.gov (United States)

    Ban, Myung Jin; Ji, Sang Hee; Lee, Chi-Kyu; Bae, Sang Byung; Kim, Han Jo; Ahn, Tae Sung; Lee, Moon Soo; Baek, Moo-Jun; Jeong, Dongjun

    2017-08-01

    Solute carrier organic anion transporter family member 4A1 (SLCO4A1) is involved in the transport of various compounds, including sugars, bile salts, organic acids, metal ions, amine compounds, and estrogen. SLCO4A1 is highly expressed in several cancers and a gender bias has been observed in colorectal cancer (CRC). We investigated SLCO4A1 expression, its prognostic value in patients with CRC, and its role in CRC cell proliferation and metastasis. SLCO4A1 expression was assessed by immunohistochemistry (IHC) on specimens from 84 patients with CRC. The association of SLCO4A1 expression with clinicopathological features was examined. To confirm the biological role of SLCO4A1 in CRC, four CRC cell lines expressing SLCO4A1 were used and SLCO4A1 expression was knocked down by siRNA. Cell proliferation, MTT, migration, invasion, and semisolid agar colony formation assays were performed. SLCO4A1 was overexpressed in 32% of the CRC samples. SLCO4A1 overexpression and pathologic T stage were independent prognostic factors of decreased survival (P = 0.021). Kaplan-Meier analysis indicated a decreased cumulative survival for patients highly expressing SLCO4A1 compared to patients showing low SLCO4A1 expression (Log-rank test, P = 0.025). In cell lines, SLCO4A1 knockdown resulted in a significant decrease of viability, invasion, and migration when compared to control cells. Semisolid colony formation assay indicated that SLCO4A1-knocked down cells presented poor carcinogenic abilities compared to control cells. SLCO4A1 may be a valuable marker of poor prognostic for CRC. Furthermore, SLCO4A1 plays an important role in CRC cell proliferation, migration, invasion, and carcinogenesis.

  8. 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.

  9. 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.

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

    Science.gov (United States)

    Deschuyteneer, Aude; Boeckstaens, Mélanie; De Mees, Christelle; Van Vooren, Pascale; Wintjens, René; Marini, Anna Maria

    2013-01-01

    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.

  11. Induction of Drug Transporters Alters Disposition of Risperidone - A Study in Mice

    Directory of Open Access Journals (Sweden)

    David Holthoewer

    2010-06-01

    Full Text Available Pharmacokinetic interactions, e.g. modulation of drug transporters like P-glycoprotein at the blood-brain barrier, can be a reason for treatment non-response. This study focuses on the influence of induction of drug transporters on the disposition of the antipsychotic drugs risperidone and 9-hydroxyrisperidone. Brain and serum concentrations of risperidone and its active metabolite 9-hydroxyrisperidone, which are known P-glycoprotein substrates, were measured after drug transporter induction with rifampicin, dexamethasone or 5-pregnene-3beta-ol-20-on-16alpha-carbonitrile using high performance liquid chromatography. Disposition of risperidone and 9-hydroxyrisperidone was dramatically decreased in mouse brain and serum after drug transporter induction. The metabolism of risperidone was also affected.

  12. Alterations in adhesion, transport, and membrane characteristics in an adhesion-deficient pseudomonad

    Energy Technology Data Exchange (ETDEWEB)

    DeFlaun, M.F.; Streger, S.; Condee, C.W. [Envirogen, Inc., Lawrenceville, NJ (United States). Princeton Research Center; Oppenheimer, S.R.; Fletcher, M. [Univ. of Maryland Biotechnology Inst., Baltimore, MD (United States). Center of Marine Biotechnology

    1999-02-01

    A stable adhesion-deficient mutant of Burkholderia cepacia G4, a soil pseudomonad, was selected in a sand column assay. This mutant (ENV435) was compared to the wild-type strain by examining the adhesion of the organisms to silica sand and their transport through two aquifer sediments that differed in their sand, silt, and clay contents. The authors compared the longitudinal transport of the wild type and the adhesion mutant to the transport of a conservative chloride tracer in 25-cm-long glass columns. The transport of the wild-type strain was severely retarded compared to the transport of the conservative tracer in a variety of aquifer sediments, while the adhesion mutant and the conservative tracer traveled at similar rates. An intact sediment core study produced similar results; ENV435 was transported at a faster rate and in much greater numbers than G4. The results of hydrophobic interaction chromatography revealed that G4 was significantly more hydrophobic than ENV435, and polyacrylamide gel electrophoresis revealed significant differences in the lipopolysaccharide O-antigens of the adhesion mutant and the wild type. Differences in this cell surface polymer may explain the decreased adhesion of strain ENV435.

  13. Early alterations in soleus GLUT-4, glucose transport, and glycogen in voluntary running rats

    Science.gov (United States)

    Henriksen, Erik J.; Halseth, Amy E.

    1994-01-01

    Voluntary wheel running (WR) by juvenile female rats was used as a noninterventional model of soleus muscle functional overload to study the regulation of insulin-stimulated glucose transport activity by the glucose transporter (GLUT-4 isoform) protein level and glycogen concentration. Soleus total protein content was significantly greater (+18%;P greater than 0.05) than in age-matched controls after 1 wk of WR, and this hypertrophic response continued in weeks 2-4 (+24-32%). GLUT-4 protein was 39% greater than in controls in 1-wk WR soleus, and this adaptation was accompanied by a similar increase in in vitro insulin-stimulated glucose transport activity(+29%). After 2 and 4 wk of WR, however, insulin-stimulated glucose transport activity had returned to control levels, despite a continued elevation (+25-28%) of GLUT-4 protein. At these two time points, glycogen concentration was significantly enhanced in WR soleus (+21-42%), which coincided with significant reductions in glycogen synthase activity ratios (-23 to-41%). These results indicate that, in this model of soleus muscle functional overload, the GLUT-4 protein level may initially regulate insulin-stimulated glucose transport activity in the absence of changes in other modifying factors. However,this regulation of glucose transport activity by GLUT-4 protein may be subsequently overridden by elevated glycogen concentration.

  14. 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

  15. Presynaptic transporter-mediated release of glutamate evoked by the protonophore FCCP increases under altered gravity conditions

    Science.gov (United States)

    Borisova, T. A.; Krisanova, N. V.

    2008-12-01

    High-affinity Na +-dependent glutamate transporters of the plasma membrane mediate the glutamate uptake into neurons, and thus maintain low levels of extracellular glutamate in the synaptic cleft. The study focused on the release of glutamate by reversal of Na +-dependent glutamate transporters from rat brain nerve terminals (synaptosomes) under conditions of centrifuge-induced hypergravity. Flow cytometric analysis revealed similarity in the size and cytoplasmic granularity between synaptosomal preparations obtained from control and G-loaded animals (10 G, 1 h). The release of cytosolic L-[ 14C]glutamate from synaptosomes was evaluated using the protonophore FCCP, which dissipated synaptic vesicle proton gradient, thus synaptic vesicles were not able to keep glutamate inside and the latter enriched cytosol. FCCP per se induced the greater release of L-[ 14C]glutamate in hypergravity as compared to control (4.8 ± 1.0% and 8.0 ± 1.0% of total label). Exocytotic release of L-[ 14C]glutamate evoked by depolarization was reduced down to zero after FCCP application under both conditions studied. Depolarization stimulated release of cytosolic L-[ 14C]glutamate from synaptosomes preliminary treated with FCCP was considerably increased from 27.0 ± 2.2% of total label in control to 35.0 ± 2.3% in hypergravity. Non-transportable inhibitor of glutamate transporter DL-threo-β-benzyloxyaspartate was found to significantly inhibit high-KCl and FCCP-stimulated release of L-[ 14C]glutamate, confirming the release by reversal of glutamate transporters. The enhancement of transporter-mediated release of glutamate in hypergravity was found to result at least partially from the inhibition of the activity of Na/K-ATPase in the plasma membrane of synaptosomes. We suggested that hypergravity-induced alteration in transporter-mediated release of glutamate indicated hypoxic injury of neurons.

  16. 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...

  17. Colorectal Cancer

    African Journals Online (AJOL)

    Peter Donald

    15 years. Colorectal cancer occurs in hereditary, sporadic or familial forms. Hereditary forms have been extensively described and are characterized by family history, young age at onset and presence of other specific tumours and defects. Among these defects are familial adenomatous polyposis (FAP), hereditary non-.

  18. Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder.

    Science.gov (United States)

    Vermeire, Simon; Audenaert, Kurt; De Meester, Rudy; Vandermeulen, Eva; Waelbers, Tim; De Spiegeleer, Bart; Eersels, Jos; Dobbeleir, André; Peremans, Kathelijne

    2012-01-30

    Neuro-imaging studies have shown altered, yet often inconsistent, serotonergic and dopaminergic neurotransmission in patients with obsessive-compulsive disorder (OCD). We investigated both serotonergic and dopaminergic neurotransmission in 9 drug-naïve dogs with compulsive behaviour, as a potential model for human OCD. Single photon emission computed tomography was used with (123)I-R91150 and (123)I-FP-CIT, in combination with (99m)Tc-ECD brain perfusion co-registration, to measure the serotonin (5-HT) 2A receptor, dopamine transporter (DAT) and serotonin transporter (SERT) availability. Fifteen normally behaving dogs were used as reference group. Significantly lower 5-HT2A receptor radioligand availability in frontal and temporal cortices (bilateral) was observed. Further, in 78% of the compulsive dogs abnormal DAT ratios in left and right striatum were demonstrated. Interestingly, both increased and decreased DAT ratios were observed. Finally, significantly lower subcortical perfusion and (hypo)thalamic SERT availability were observed in the compulsive dogs. This study provides evidence for imbalanced serotonergic and dopaminergic pathways in the pathophysiology of compulsions in dogs. The similarities with the altered neurotransmission in human OCD provide construct validity for this non-induced, natural canine model, suggesting its usefulness for future investigations of the pathophysiology of human OCD as well as the effectiveness of psychopharmacological interventions. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. 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.

  20. 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 ...

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

    Science.gov (United States)

    2015-10-01

    standard 12-h light/dark cycle with free access to food (Teklad Global C.M. Hernandez et al. / NeuroToxicology 47 (2015) 17–26 19Rodent Diet 2918, Harlan...transport deficits in a triple transgenic mouse model of Alzheimer’s disease using manganese-enhanced MRI. Neuroimage 2011;56:1286–92. Lange G, Tiersky LA

  2. Cellular effects of fluorodeoxyglucose: Global changes in the lipidome and alteration in intracellular transport.

    Science.gov (United States)

    Kavaliauskiene, Simona; Torgersen, Maria Lyngaas; Lingelem, Anne Berit Dyve; Klokk, Tove Irene; Lintonen, Tuulia; Simolin, Helena; Ekroos, Kim; Skotland, Tore; Sandvig, Kirsten

    2016-11-29

    2-fluoro-2-deoxy-D-glucose (FDG), labeled with 18F radioisotope, is the most common imaging agent used for positron emission tomography (PET) in oncology. However, little is known about the cellular effects of FDG. Another glucose analogue, 2-deoxy-D-glucose (2DG), has been shown to affect many cellular functions, including intracellular transport and lipid metabolism, and has been found to improve the efficacy of cancer chemotherapeutic agents in vivo. Thus, in the present study, we have investigated cellular effects of FDG with the focus on changes in cellular lipids and intracellular transport. By quantifying more than 200 lipids from 17 different lipid classes in HEp-2 cells and by analyzing glycosphingolipids from MCF-7, HT-29 and HBMEC cells, we have discovered that FDG treatment inhibits glucosylceramide synthesis and thus reduces cellular levels of glycosphingolipids. In addition, in HEp-2 cells the levels and/or species composition of other lipid classes, namely diacylglycerols, phosphatidic acids and phosphatidylinositols, were found to change upon treatment with FDG. Furthermore, we show here that FDG inhibits retrograde Shiga toxin transport and is much more efficient in protecting cells against the toxin than 2DG. In summary, our data reveal novel effects of FDG on cellular transport and glycosphingolipid metabolism, which suggest a potential clinical application of FDG as an adjuvant for cancer chemotherapy.

  3. 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.

  4. 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.)

  5. Roux-en-Y gastric bypass alters small intestine glutamine transport in the obese Zucker rat

    OpenAIRE

    Wolff, Brynn S.; Meirelles, Katia; Meng, Qinghe; Pan, Ming; Cooney, Robert N.

    2009-01-01

    The metabolic effects of Roux-en-Y gastric bypass (RYGB) are caused by postsurgical changes in gastrointestinal anatomy affecting gut function. Glutamine is a critical gut nutrient implicated in regulating glucose metabolism as a substrate for intestinal gluconeogenesis. The present study examines the effects of obesity and RYGB on intestinal glutamine transport and metabolism. First, lean and obese Zucker rats (ZRs) were compared. Then the effects of RYGB and sham surgery with pair feeding (...

  6. 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

  7. Specific inhibition of bile acid transport alters plasma lipids and GLP-1

    DEFF Research Database (Denmark)

    Rudling, Mats; Camilleri, Michael; Graffner, Hans

    2015-01-01

    BACKGROUND: Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes....../L; p = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; p = 0.02). CONCLUSIONS: Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans. TRIAL REGISTRATIONS: ClinicalTrial.gov: NCT01069783...

  8. Tissue Plasminogen Activator Alters Intracellular Sequestration of Zinc through Interaction with the Transporter ZIP4

    Energy Technology Data Exchange (ETDEWEB)

    Emmetsberger, Jaime; Mirrione, Martine M.; Zhou, Chun; Fernandez-Monreal, Monica; Siddiq, Mustafa M.; Ji, Kyungmin; Tsirka, Stella E. (SBU)

    2010-09-17

    Glutamatergic neurons contain free zinc packaged into neurotransmitter-loaded synaptic vesicles. Upon neuronal activation, the vesicular contents are released into the synaptic space, whereby the zinc modulates activity of postsynaptic neurons though interactions with receptors, transporters and exchangers. However, high extracellular concentrations of zinc trigger seizures and are neurotoxic if substantial amounts of zinc reenter the cells via ion channels and accumulate in the cytoplasm. Tissue plasminogen activator (tPA), a secreted serine protease, is also proepileptic and excitotoxic. However, tPA counters zinc toxicity by promoting zinc import back into the neurons in a sequestered form that is nontoxic. Here, we identify the zinc influx transporter, ZIP4, as the pathway through which tPA mediates the zinc uptake. We show that ZIP4 is upregulated after excitotoxin stimulation of the mouse, male and female, hippocampus. ZIP4 physically interacts with tPA, correlating with an increased intracellular zinc influx and lysosomal sequestration. Changes in prosurvival signals support the idea that this sequestration results in neuroprotection. These experiments identify a mechanism via which neurons use tPA to efficiently neutralize the toxic effects of excessive concentrations of free zinc.

  9. 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.

  10. Effect of altered thyroid status on the transport of hepatobiliary radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Pahuja, D.N.; Noronha, O.P.

    1985-10-01

    The effect of induced hypothyroidism (by feeding an antithyroid drug-propylthiouracil) on the transport and clearance of the routinely used hepatobiliary radiopharmaceuticals--radioiodinated iodine- T (131I) rose bengal and technetium-99m-N-(4-n-butylphenylcarbamoylmethyl) iminodiacetate, was studied in the rats. Hypothyroidism was associated with depressed growth and retarded clearance of these radiotracers from the in vivo system. Treatment of the hypothyroid rats with thyroxine (2-5 micrograms/100 g b.w. day) for 6 wk, restored these parameters towards normal values. These data suggest that delayed clearance of these hepatobiliary tracers could be related to reduced metabolic rate accompanied with the hypotonia and hypomotility of intestine normally observed in the hypothyroid state.

  11. 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.

  12. Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer.

    Science.gov (United States)

    Disciglio, Vittoria; Devecchi, Andrea; Palumbo, Orazio; Carella, Massimo; Penso, Donata; Milione, Massimo; Valle, Giorgio; Pierotti, Marco Alessandro; Vitellaro, Marco; Bertario, Lucio; Canevari, Silvana; Signoroni, Stefano; De Cecco, Loris

    2016-06-07

    Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described. Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers. By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.

  13. 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...

  14. 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 ...

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria

    Science.gov (United States)

    Maria, Zahra; Campolo, Allison R.; Lacombe, Veronique A.

    2015-01-01

    Although diabetes has been identified as a major risk factor for atrial fibrillation, little is known about glucose metabolism in the healthy and diabetic atria. Glucose transport into the cell, the rate-limiting step of glucose utilization, is regulated by the Glucose Transporters (GLUTs). Although GLUT4 is the major isoform in the heart, GLUT8 has recently emerged as a novel cardiac isoform. We hypothesized that GLUT-4 and -8 translocation to the atrial cell surface will be regulated by insulin and impaired during insulin-dependent diabetes. GLUT protein content was measured by Western blotting in healthy cardiac myocytes and type 1 (streptozotocin-induced, T1Dx) diabetic rodents. Active cell surface GLUT content was measured using a biotinylated photolabeled assay in the perfused heart. In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, Pinsulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (Pinsulin signaling pathway. This was confirmed by the rescued translocation of GLUT-4 and -8 to the atrial cell surface upon insulin stimulation in the atria of type 1 diabetic subjects. In conclusion, our data suggest that: 1) both GLUT-4 and -8 are insulin-sensitive in the healthy atria through an Akt/AS160 dependent pathway; 2) GLUT-4 and -8 trafficking is impaired in the diabetic atria and rescued by insulin treatment. Alterations in atrial glucose transport may induce perturbations in energy production, which may provide a metabolic substrate for atrial fibrillation during diabetes. PMID:26720696

  20. 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

  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......' C, and clustered Dukes' D separately. Real-time PCR of 10 known genes and 5 ESTs demonstrated excellent reproducibility of the array-based findings. The most frequently altered genes belonged to functional categories of metabolism (22%), transcription and translation (11%), and cellular processes (9...

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

    Energy Technology Data Exchange (ETDEWEB)

    DH Bacon; MD White; BP McGrail

    2000-03-07

    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{sub 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.

  3. 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

  4. 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.

  5. 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

  6. Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer

    DEFF Research Database (Denmark)

    Isinger-Ekstrand, Anna; Therkildsen, Christina; Bernstein, Inge

    2011-01-01

    The Wnt signaling pathway is frequently deranged in colorectal cancer and is a key target for future preventive and therapeutic approaches. Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are characterized by wide-spread microsatellite instability......, but show few gross genomic alterations. We characterized expression of the Wnt signaling pathway markers β-catenin, E-cadherin, TCF-4, and PTEN using immunohistochemical staining in colorectal cancers from individuals with HNPCC. Reduced membranous staining for β-catenin was found in 64% and for E......% of the tumors. In summary, altered expression of target molecules in the Wnt signaling pathway was demonstrated in the vast majority of the HNPCC-associated tumors, which support deranged Wnt-signaling as a central tumorigenic mechanism also in MMR defective colorectal cancer....

  7. Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer

    DEFF Research Database (Denmark)

    Isinger-Ekstrand, Anna; Therkildsen, Christina; Bernstein, Inge

    2011-01-01

    The Wnt signaling pathway is frequently deranged in colorectal cancer and is a key target for future preventive and therapeutic approaches. Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are characterized by wide-spread microsatellite instability......, but show few gross genomic alterations. We characterized expression of the Wnt signaling pathway markers ß-catenin, E-cadherin, TCF-4, and PTEN using immunohistochemical staining in colorectal cancers from individuals with HNPCC. Reduced membranous staining for ß-catenin was found in 64% and for E......% of the tumors. In summary, altered expression of target molecules in the Wnt signaling pathway was demonstrated in the vast majority of the HNPCC-associated tumors, which support deranged Wnt-signaling as a central tumorigenic mechanism also in MMR defective colorectal cancer....

  8. 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.

  9. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals.

    Science.gov (United States)

    McKinlay, Colin J; Vargas, Jessica R; Blake, Timothy R; Hardy, Jonathan W; Kanada, Masamitsu; Contag, Christopher H; Wender, Paul A; Waymouth, Robert M

    2017-01-24

    Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here we report the step-economical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.

  10. 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

  11. 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

    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...... (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...

  12. [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.

  13. 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.

  14. 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 ...

  15. 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".

  16. Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder

    NARCIS (Netherlands)

    Vermeire, S.; Audenaert, K.; Meester, R.; Vandermeulen, E.; Waelbers, T.; De Spiegeleer, B.; Eersels, J.L.H.; Dobbeleir, A.; Peremans, K.

    2012-01-01

    Neuro-imaging studies have shown altered, yet often inconsistent, serotonergic and dopaminergic neurotransmission in patients with obsessive-compulsive disorder (OCD). We investigated both serotonergic and dopaminergic neurotransmission in 9 drug-naïve dogs with compulsive behaviour, as a potential

  17. Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet.

    Science.gov (United States)

    Rutkowsky, Jennifer M; Lee, Linda L; Puchowicz, Michelle; Golub, Mari S; Befroy, Douglas E; Wilson, Dennis W; Anderson, Steven; Cline, Gary; Bini, Jason; Borkowski, Kamil; Knotts, Trina A; Rutledge, John C

    2018-01-01

    Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways.

  18. 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...

  19. 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

  20. 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.)

  1. Metabolic Adaptation to Nutritional Stress in Human Colorectal Cancer

    OpenAIRE

    Miyo, Masaaki; Konno, Masamitsu; Nishida, Naohiro; Sueda, Toshinori; Noguchi, Kozo; Matsui, Hidetoshi; Colvin, Hugh; Kawamoto, Koichi; Koseki, Jun; Haraguchi, Naotsugu; Nishimura, Junichi; Hata, Taishi; Gotoh, Noriko; Matsuda, Fumio; Satoh, Taroh

    2016-01-01

    Tumor cells respond to their microenvironment, which can include hypoxia and malnutrition, and adapt their metabolism to survive and grow. Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters. However, the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear. We found that colorectal cancer cells survived under the condition of glucose depletion, and their resistance to such conditions dep...

  2. Diet-gene interactions in sporadic and hereditary colorectal carcinogenesis : epidemiological perspectives

    NARCIS (Netherlands)

    Voskuil, D.

    1999-01-01

    Colorectal cancer is known to develop by accumulation of alterations in regulatory genes. Both familial and environmental factors play a role in the etiology of colorectal cancer and its adenomatous precursor lesions. This thesis examines diet-gene interactions in sporadic and hereditary

  3. 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, Douglas; 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...

  4. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy.

    Science.gov (United States)

    Yu, TaChung; Guo, Fangfang; Yu, Yanan; Sun, Tiantian; Ma, Dan; Han, Jixuan; Qian, Yun; Kryczek, Ilona; Sun, Danfeng; Nagarsheth, Nisha; Chen, Yingxuan; Chen, Haoyan; Hong, Jie; Zou, Weiping; Fang, Jing-Yuan

    2017-07-27

    Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. 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.

  6. 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

  7. Transport current loss of BSCCO/Ag tape in different orientations of the external alteranting magnetic field

    NARCIS (Netherlands)

    Rabbers, J.J.; ten Haken, Bernard; ten Kate, Herman H.J.

    1999-01-01

    BSCCO/Ag tapes are being developed for electrical power applications at liquid nitrogen temperatures. In these applications, conductors are exposed to an alternating magnetic field and fed simultaneously with an alternating transport current. In this contribution the influence of an external

  8. 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...... 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....

  9. 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....

  10. Regulatory miRNAs in Colorectal Carcinogenesis and Metastasis.

    Science.gov (United States)

    Guo, Yongchen; Bao, Yonghua; Yang, Wancai

    2017-04-22

    Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in carcinogenesis and progression through regulating of oncogenic signaling pathways, stem cells, epithelial-mesenchymal transition, and metastasis. This review summarizes the roles of microRNAs in the regulating of Wnt, Ras, TGF-β, and inflammatory signaling pathways, stemness, and epithelial-mesenchymal transition, for carcinogenesis and metastasis in colorectal cancer. Improving our understanding of the mechanisms of regulatory interactions of microRNAs with signaling pathways in colorectal cancer formation and progression will aid in determining the genes responsible for colorectal cancer initiation, progression, metastasis, and recurrence and, finally, in developing personalized approaches for cancer prevention and therapy.

  11. Altered expression of polyamine transporters reveals a role for spermidine in the timing of flowering and other developmental response pathways.

    Science.gov (United States)

    Ahmed, Sheaza; Ariyaratne, Menaka; Patel, Jigar; Howard, Alexander E; Kalinoski, Andrea; Phuntumart, Vipaporn; Morris, Paul F

    2017-05-01

    Changes in the levels of polyamines are correlated with the activation or repression of developmental response pathways, but the role of polyamine transporters in the regulation of polyamine homeostasis and thus indirectly gene expression, has not been previously addressed. Here we show that the A. thaliana and rice transporters AtPUT5 and OsPUT1 were localized to the ER, while the AtPUT2, AtPUT3, and OsPUT3 were localized to the chloroplast by transient expression in N. benthamiana. A. thaliana plants that were transformed with OsPUT1 under the control the PUT5 promoter were delayed in flowering by 16days. In contrast, put5 mutants flowered four days earlier than WT plants. The delay of flowering was associated with significantly higher levels of spermidine and spermidine conjugates in the leaves prior to flowering. A similar delay in flowering was also noted in transgenic lines with constitutive expression of either OsPUT1 or OsPUT3. All three transgenic lines had larger rosette leaves, thicker flowering stems, and produced more siliques than wild type plants. In contrast, put5 plants had smaller leaves, thinner flowering stems, and produced fewer siliques. Constitutive expression of PUTs was also associated with an extreme delay in both plant senescence and maturation rate of siliques. These experiments provide the first genetic evidence of polyamine transport in the timing of flowering, and indicate the importance of polyamine transporters in the regulation of flowering and senescence pathways. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  12. 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.

  13. 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 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 in silico modeling requires experimental validation. When administered in combination, the disposition of the proposed triple-therapy antiretroviral drugs in the colorectal mucosa will depend on their distinctly

  14. 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.

  15. 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....

  16. Colorectal Cancer Screening

    Science.gov (United States)

    ... Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All Cancer Types A to ...

  17. 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...

  18. 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...

  19. 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.......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...... 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....

  20. 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.

  1. Colorectal polyps in childhood.

    Science.gov (United States)

    Thakkar, Kalpesh; Fishman, Douglas S; Gilger, Mark A

    2012-10-01

    Colorectal polyps are a common cause of gastrointestinal bleeding in children. This review updates the information on colorectal polyps and summarizes the recent advances in genetics, diagnosis, and treatment of polyps in the large intestine. A review of recent literature regarding colorectal polyps demonstrates an estimated detected prevalence of 6.1% overall and 12.0% among those with lower gastrointestinal bleeding during pediatric colonoscopy. Non-Caucasian races (e.g., black and Hispanic) are at higher risk for colorectal polyps in childhood. Recent data show juvenile polyps may recur in approximately 45% of children with multiple polyps and 17% of children with solitary polyps. A clinical trial showed that celecoxib, a cyclooxygenase (COX)-2 inhibitor, significantly reduced the number of colorectal polyps in children with familial adenomatous polyposis (FAP). Ethical challenges related to genetic tests for FAP have been newly examined. The utility of novel endoscopic techniques (e.g., enteroscopy) in Peutz-Jeghers Syndrome to prevent intussusception have been newly described. Although colorectal polyps in children are generally benign and easily removed, careful clinical evaluation and ongoing research are needed to identify the small proportion of children at risk for cancer. The current paradigm of using the polyp number at presentation as a primary determinant of subsequent surveillance may be inadequate for many patients.

  2. 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

    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. CONCLUSIONS: SLC1A1 expression...... 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. RESULTS: 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...

  3. Probenecid, an inhibitor of transmembrane organic anion transporters, alters tissue distribution of DNA adducts in 1-hydroxymethylpyrene-treated rats.

    Science.gov (United States)

    Monien, Bernhard H; Müller, Carolin; Bakhiya, Nadiya; Donath, Claudia; Frank, Heinz; Seidel, Albrecht; Glatt, Hansruedi

    2009-07-28

    1-Methylpyrene (1-MP), an abundant alkylated polycyclic aromatic hydrocarbon, is activated by side-chain hydroxylation to 1-hydroxymethylpyrene (1-HMP) and subsequent sulfo-conjugation to electrophilic 1-sulfooxymethylpyrene (1-SMP). In rats, this activation mainly occurs in liver. 1-SMP may react with hepatic DNA or be exported into the blood circulation to reach other tissues, in particular kidneys. Findings with recombinant cell lines suggest that renal 1-SMP uptake proceeds via organic anion transporters (OATs). Here, we tested the hypothesis that probenecid, a characteristic OAT inhibitor, interferes with kidney damage brought about by 1-SMP formed in rats. 1-HMP was administered intraperitoneally to 30 rats, half of which were co-treated with probenecid. The tissue distribution of DNA adducts was analyzed using (32)P-postlabeling and isotope dilution LC-MS/MS for the detection of the adducts N(2)-(1-methylpyrenyl)-2'-deoxyguanosine and N(6)-(1-methylpyrenyl)-2'-deoxyadenosine. In rats treated solely with 1-HMP, adduct levels in kidney tissue were about 3-fold and 8-fold higher than those in liver and lung, respectively. After co-treatment with probenecid, hepatic and pulmonary adduct levels were 12-fold and 4-fold elevated, respectively, whereas renal adduct levels were slightly lower compared to those of rats receiving 1-HMP alone. Moreover, serum levels of 1-SMP were increased 23-fold in animals pre-treated with probenecid. The differential effects on hepatic and pulmonary adduct levels suggest that not only renal OATs, but also additional anion transporters, e.g. those mediating the hepatic export of 1-SMP into the bile, were inhibited. Thus, transmembrane transport proteins play a crucial role in the distribution of reactive phase II metabolites, and thereby in tissue allocation of DNA adducts.

  4. 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.

  5. Transient Congenital Hypothyroidism Alters Gene Expression of Glucose Transporters and Impairs Glucose Sensing Apparatus in Young and Aged Offspring Rats

    Directory of Open Access Journals (Sweden)

    Hanieh Gholami

    2017-10-01

    Full Text Available Background/Aims: Transient congenital hypothyroidism (TCH could disturb carbohydrate metabolism in adulthood. Aging is associated with increased risk of type 2 diabetes. This study aims to address effects of TCH on mRNA expressions of glucose transporters (GLUTs and glucokinase (GcK in islets and insulin target tissues of aged offspring rats. Methods: The TCH group received water containing 0.025% 6-propyl-2-thiouracil during gestation. Offspring from control and TCH groups (n=6 in each group were followed until month 19. Gene expressions of GLUTs and GcK were measured at months 3 and 19. Results: Compared to controls, aged TCH rats had higher GLUT4 expression in heart (4.88 fold and soleus (6.91 fold, while expression was lower in epididymal fat (12%. In TCH rats, GLUT2 and GcK expressions in islets were lower in young (12% and 10%, respectively and higher in aged (10.85 and 8.42 fold, respectively rats. In addition, liver GLUT2 and GcK expressions were higher in young (13.11 and 21.15 fold, respectively and lower in aged rats (44% and 5%, respectively. Conclusion: Thyroid hormone deficiency during fetal period impaired glucose sensing apparatus and changed glucose transporter expression in insulin-sensitive tissues of aged offspring rats. These changes may contribute to impaired carbohydrate metabolism.

  6. Transient Congenital Hypothyroidism Alters Gene Expression of Glucose Transporters and Impairs Glucose Sensing Apparatus in Young and Aged Offspring Rats.

    Science.gov (United States)

    Gholami, Hanieh; Jeddi, Sajad; Zadeh-Vakili, Azita; Farrokhfall, Khadije; Rouhollah, Fatemeh; Zarkesh, Maryam; Ghanbari, Mahboubeh; Ghasemi, Asghar

    2017-01-01

    Transient congenital hypothyroidism (TCH) could disturb carbohydrate metabolism in adulthood. Aging is associated with increased risk of type 2 diabetes. This study aims to address effects of TCH on mRNA expressions of glucose transporters (GLUTs) and glucokinase (GcK) in islets and insulin target tissues of aged offspring rats. The TCH group received water containing 0.025% 6-propyl-2-thiouracil during gestation. Offspring from control and TCH groups (n=6 in each group) were followed until month 19. Gene expressions of GLUTs and GcK were measured at months 3 and 19. Compared to controls, aged TCH rats had higher GLUT4 expression in heart (4.88 fold) and soleus (6.91 fold), while expression was lower in epididymal fat (12%). In TCH rats, GLUT2 and GcK expressions in islets were lower in young (12% and 10%, respectively) and higher in aged (10.85 and 8.42 fold, respectively) rats. In addition, liver GLUT2 and GcK expressions were higher in young (13.11 and 21.15 fold, respectively) and lower in aged rats (44% and 5%, respectively). Thyroid hormone deficiency during fetal period impaired glucose sensing apparatus and changed glucose transporter expression in insulin-sensitive tissues of aged offspring rats. These changes may contribute to impaired carbohydrate metabolism. © 2017 The Author(s). Published by S. Karger AG, Basel.

  7. Older adults exhibit altered motor coordination during an upper limb object transport task requiring a lateral change in support.

    Science.gov (United States)

    Huntley, Andrew H; Zettel, John L; Vallis, Lori Ann

    2017-04-01

    Investigating an ecologically relevant upper limb task, such as manually transporting an object with a concurrent lateral change in support (sidestepping alongside a kitchen counter), may provide greater insight into potential deficits in postural stability, variability and motor coordination in older adults. Nine healthy young and eleven older, community dwelling adults executed an upper limb object transport task requiring a lateral change in support in two directions at two self-selected speeds, self-paced and fast-paced. Dynamic postural stability and movement variability was quantified via whole-body center of mass motion. The onset of lead lower limb movement in relation to object movement onset was quantified as a measure of motor coordination. Older adults demonstrated similar levels of stability and variability as their younger counterparts, but at slower peak movement velocity and increased task duration. Furthermore, older adults demonstrated asymmetrical motor coordination between left and right task directions, while younger adults remained consistent regardless of task direction. Thus, older adults significantly modulated movement speed and motor coordination to maintain similar levels of stability and variability compared to their younger counterparts. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Expression of AQP5 and AQP8 in human colorectal carcinoma and their clinical significance

    Directory of Open Access Journals (Sweden)

    Wang Wei

    2012-11-01

    Full Text Available Abstract Background The aquaporins (AQPs are a family of small membrane transport proteins whose overexpression has been implicated in tumorigenesis. However, the expression of AQP5 and AQP8 in colorectal cancer and the clinical significance remain unexplored. This study aimed to detect the expression of AQP5 and AQP8 in clinical samples of colorectal cancer and analyze the correlations of their expression with the clinicopathological features of colorectal cancer. Methods Forty pairs of colorectal cancer tissue and paraneoplastic normal tissue were obtained at the time of surgery from patients with colorectal cancer. The expression of AQP5 and AQP8 was detected by immunohistochemical staining and reverse transcriptase polymerase chain reaction. Results AQP5 was mainly expressed in colorectal carcinoma cells and barely expressed in paraneoplastic normal tissues. By contrast, AQP8 was mainly expressed in paraneoplastic normal tissues and barely expressed in colorectal carcinoma cells. AQP5 expression was not significantly associated with the sex or age of the patient with colorectal cancer (P>0.05, but was closely associated with the differentiation, tumor-nodes-metastasis stage and distant lymph node metastasis of colorectal carcinoma (P Conclusions AQP5 might be a novel prognostic biomarker for patients with colorectal cancer.

  9. 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

  10. 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 ...

  11. Single-quantum-dot tracking reveals altered membrane dynamics of an attention-deficit/hyperactivity-disorder-derived dopamine transporter coding variant.

    Science.gov (United States)

    Kovtun, Oleg; Sakrikar, Dhananjay; Tomlinson, Ian D; Chang, Jerry C; Arzeta-Ferrer, Xochitl; Blakely, Randy D; Rosenthal, Sandra J

    2015-04-15

    The presynaptic, cocaine- and amphetamine-sensitive dopamine (DA) transporter (DAT, SLC6A3) controls the intensity and duration of synaptic dopamine signals by rapid clearance of DA back into presynaptic nerve terminals. Abnormalities in DAT-mediated DA clearance have been linked to a variety of neuropsychiatric disorders, including addiction, autism, and attention deficit/hyperactivity disorder (ADHD). Membrane trafficking of DAT appears to be an important, albeit incompletely understood, post-translational regulatory mechanism; its dysregulation has been recently proposed as a potential risk determinant of these disorders. In this study, we demonstrate a link between an ADHD-associated DAT mutation (Arg615Cys, R615C) and variation on DAT transporter cell surface dynamics, a combination only previously studied with ensemble biochemical and optical approaches that featured limited spatiotemporal resolution. Here, we utilize high-affinity, DAT-specific antagonist-conjugated quantum dot (QD) probes to establish the dynamic mobility of wild-type and mutant DATs at the plasma membrane of living cells. Single DAT-QD complex trajectory analysis revealed that the DAT 615C variant exhibited increased membrane mobility relative to DAT 615R, with diffusion rates comparable to those observed after lipid raft disruption. This phenomenon was accompanied by a loss of transporter mobilization triggered by amphetamine, a common component of ADHD medications. Together, our data provides the first dynamic imaging of single DAT proteins, providing new insights into the relationship between surface dynamics and trafficking of both wild-type and disease-associated transporters. Our approach should be generalizable to future studies that explore the possibilities of perturbed surface DAT dynamics that may arise as a consequence of genetic alterations, regulatory changes, and drug use that contribute to the etiology or treatment of neuropsychiatric disorders.

  12. Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Theodoros I. Roumeliotis

    2017-08-01

    Full Text Available Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.

  13. 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

  14. 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.

  15. SLCO1B3 screening in colorectal cancer patients using High-Resolution Melting Analysis method and immunohistochemistry.

    Science.gov (United States)

    Evangeli, Lampri; Ioannis, Sainis; Valentinos, Kounnis; Antigony, Mitselou; Elli, Ioachim; Eleftheria, Hatzimichael; Vasiliki, Galani; Evangelos, Briasoulis

    2017-03-01

    Personalized medicine has made some major advances in colorectal cancer, but new biomarkers still remain a hot issue as an emerging tool with potential prognostic and therapeutic potential. We investigated for SLCO1B3 gene alterations and protein expression in colorectal cancer, using the novel high-resolution melting analysis technique and immunohistochemistry. Formalin-fixed paraffin-embedded tumor samples from 30 colorectal cancer patients were used. The screening for gene alterations was done by high-resolution melting analysis for all exons of SLCO1B3 gene. Organic anion-transporting polypeptide 1B3 protein expression was assessed by immunohistochemistry using the monoclonal mouse MDQ antibody. High level of polymorphism was observed in the SLCO1B3 gene. We identified three previously reported polymorphisms in exons 7, 12, and 14, 699G>A, 1557A>G, and 1833G>A, respectively. In the exon 5, one variant seems to correspond to an as yet unknown SLCO family member. The immunohistochemical study revealed that organic anion-transporting polypeptide 1B3 was expressed in 27/30 samples. Of great interest, the three samples, which were immunohistochemically negative, all appeared to accommodate mutations which lead to either early stop codons or other conformations of the tertiary protein structures affecting the antibody-epitope binding. The results of this study are of much interest as high-resolution melting analysis proved to be a reliable and rapid genotyping/scanning method for mutation detection of SLCO1B3 gene.

  16. 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

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

    Science.gov (United States)

    Gutiérrez-Torres, Daniela Sarahí; González-Horta, Carmen; Del Razo, Luz María; Infante-Ramírez, Rocío; Ramos-Martínez, Ernesto; Levario-Carrillo, Margarita; Sánchez-Ramírez, Blanca

    2015-01-01

    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. PMID:26339590

  18. 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.

  19. 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.

  20. 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.

  1. Drosophila ABC transporter mutants white, brown and scarlet have altered contents and distribution of biogenic amines in the brain.

    Science.gov (United States)

    Borycz, J; Borycz, J A; Kubów, A; Lloyd, V; Meinertzhagen, I A

    2008-11-01

    Monoamines such as dopamine, histamine and serotonin (5-HT) are widely distributed throughout the brain of the fruit fly Drosophila melanogaster, where many of their actions have been investigated. For example, histamine is released from photoreceptor synapses in the lamina neuropile of the visual system. Mutations of the genes white, an important eye pigmentation marker in fly genetics that encodes an ABC transporter, and its binding partner brown, cause neural phenotypes not readily reconciled solely with actions in eye pigmentation. We find that flies mutant for these genes, and another binding partner, scarlet, have about half the wild-type amount of histamine in the head, as well as reduced 5-HT and dopamine. These differences parallel reductions in immunoreactivity to the corresponding biogenic amines. They also correlate with the amine content of fractions after differential centrifugation of head homogenates. Thus, most of the amine is found in the vesicle-rich fraction of wild-type head homogenates, whereas it is found in the supernatant fractions from white, brown and scarlet flies. White co-expresses in lamina epithelial glia with Ebony, which conjugates histamine to beta-alanine. Histamine is then released when the conjugate is hydrolyzed in photoreceptors, by Tan. Mutant white ameliorates the effects of tan on head histamine whereas it exacerbates the effects of ebony. Our results are consistent with the proposal that histamine uptake by the epithelial glia may be white dependent. Behavioral abnormalities in white, brown and scarlet mutants could arise because aminergic neurons in the Drosophila brain have reduced amine for release.

  2. Colorectal adenomas produce lysozyme.

    Science.gov (United States)

    Rubio, C A

    2003-01-01

    Lysozyme is an innate non-immunologic antibacterial enzyme produced by the Paneth cells of the upper intestinal tract. Lysozyme is not normally secreted in the lower intestinal tract. Previous reports indicate, however, that lysozyme may be secreted by colorectal neoplasias. The aim was to audit lysozyme expression in colorectal diseases including neoplasias. For that purpose, sections were stained with lysozyme (Muramidase), Ki67 (MIB1) and CD 68. Intense lysozyme overexpression (+++) was compared among 177 colorectal tissues: 35 having normal mucosa, 20 regenerative mucosa in inflammatory bowel disease (IBD), 2 inflammatory polyps, 3 collagenous colitis, 2 melanosis coli, 21 hyperplastic polyps, 42 tubular adenomas, 9 serrated adenomas, 30 villous adenomas and 13 invasive carcinomas. Intense lysozyme overexpression (+++) was found in 9.5% of the hyperplastic polyps, in 97.6% of the tubular adenomas, in 88.9% of the serrated adenomas, in 93.3% of the villous adenomas, in 76.9% of the carcinomas, but in none of the other tissues investigated. Neoplastic colorectal cells may acquire the capacity to produce lysozyme. The presence of that enzyme may not be a haphazard, capricious event in mutated colorectal epithelial cells but part of a more elaborate molecular behavior, not necessarily antibacterial. Recently, it was demonstrated that patients having lysozyme-secreting breast carcinomas were associated with a favorable prognosis. Whether lysozyme expression has any bearing on the biological behavior of colorectal carcinomas remains to be elucidated. Lysozyme overexpression (+++) also occurred in 2 of the 21 hyperplastic polyps, suggesting that intense lysozyme production might herald a possible dysplastic evolution in some hyperplastic polyps.

  3. Colorectal Cancer Screening

    OpenAIRE

    Beck, David E.

    2007-01-01

    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...

  4. Acetylcholine-related proteins in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia

    DEFF Research Database (Denmark)

    Damm, Morten Matthiesen Bach; Jensen, Thorbjørn Søren Rønn; Mahmood, Badar

    2017-01-01

    The pathogenesis of colorectal neoplasia (CRN) has been associated with altered non-neuronal acetylcholine (ACh) metabolism. The aim of this study was to characterize expression, function, and cellular location of ACh-related proteins in biopsies obtained from endoscopic normal-appearing sigmoid...... colon in patients with and without CRN. Messenger-RNA (mRNA) levels of 17 ACh-related proteins were quantified by rt-qPCR. Functional responses to ACh, measured as electrogenic transepithelial short circuit current (SCC), were recorded using the Ussing chamber technique. Finally, cellular localization...... of choline transporter-like proteins (CTLs) and butyryl-cholinesterase enzyme (BChE) was determined by immunohistochemistry. mRNA expression of CTL1 and CTL4 was increased in patients with CRN (P = 0.002 and P = 0.04, respectively). In functional experiments, baseline SCC was increased in CRN patients. ACh...

  5. Prostaglandin E2-induced colonic secretion in patients with and without colorectal neoplasia

    DEFF Research Database (Denmark)

    Kaltoft, Nicolai; Tilotta, Maria C; Witte, Anne-Barbara

    2010-01-01

    cm(-2) (p = 0.027). Stimulation or inhibition with theophylline, ouabain, bumetanide, forskolin or the EP receptor agonists prostaglandin E2, butaprost, sulprostone and prostaglandin E1 (OH) did not differ significantly between the two groups. Histology was with normal findings in both groups......BACKGROUND: The pathogenesis for colorectal cancer remains unresolved. A growing body of evidence suggests a direct correlation between cyclooxygenase enzyme expression, prostaglandin E2 metabolism and neoplastic development. Thus further understanding of the regulation of epithelial functions...... by prostaglandin E2 is needed. We hypothesized that patients with colonic neoplasia have altered colonic epithelial ion transport and express functionally different prostanoid receptor levels in this respect. METHODS: Patients referred for colonoscopy were included and grouped into patients with and without...

  6. Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression.

    Science.gov (United States)

    Xu, Xinyuan; Li, Jianying; Sun, Xiang; Guo, Yan; Chu, Dake; Wei, Li; Li, Xia; Yang, Guodong; Liu, Xinping; Yao, Libo; Zhang, Jian; Shen, Lan

    2015-09-22

    Cancer cells use glucose and glutamine as the major sources of energy and precursor intermediates, and enhanced glycolysis and glutamimolysis are the major hallmarks of metabolic reprogramming in cancer. Oncogene activation and tumor suppressor gene inactivation alter multiple intracellular signaling pathways that affect glycolysis and glutaminolysis. N-Myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene inhibiting cancer growth, metastasis and invasion. However, the role and molecular mechanism of NDRG2 in cancer metabolism remains unclear. In this study, we discovered the role of the tumor suppressor gene NDRG2 in aerobic glycolysis and glutaminolysis of cancer cells. NDRG2 inhibited glucose consumption and lactate production, glutamine consumption and glutamate production in colorectal cancer cells. Analysis of glucose transporters and the catalytic enzymes involved in glycolysis revealed that glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase M2 isoform (PKM2) and lactate dehydrogenase A (LDHA) was significantly suppressed by NDRG2. Analysis of glutamine transporter and the catalytic enzymes involved in glutaminolysis revealed that glutamine transporter ASC amino-acid transporter 2 (ASCT2) and glutaminase 1 (GLS1) was also significantly suppressed by NDRG2. Transcription factor c-Myc mediated inhibition of glycolysis and glutaminolysis by NDRG2. More importantly, NDRG2 inhibited the expression of c-Myc by suppressing the expression of β-catenin, which can transcriptionally activate C-MYC gene in nucleus. In addition, the growth and proliferation of colorectal cancer cells were suppressed significantly by NDRG2 through inhibition of glycolysis and glutaminolysis. Taken together, these findings indicate that NDRG2 functions as an essential regulator in glycolysis and glutaminolysis via repression of c-Myc, and acts as a suppressor of carcinogenesis through coordinately targeting glucose and glutamine transporter, multiple catalytic

  7. 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

  8. Colorectal Cancer Prevention

    Science.gov (United States)

    ... Kidney problems. Bleeding in the stomach, intestines, or brain. Heart problems such as heart attack and congestive heart failure . Calcium It is not known if taking calcium supplements lowers the risk of colorectal cancer. Diet It is not known if a diet low ...

  9. [Nationwide colorectal cancer screening].

    NARCIS (Netherlands)

    Rossum, L.G.M. van; Laheij, R.J.F.; Jansen, J.B.M.J.

    2010-01-01

    Usually, colorectal cancer presents with complaints in a late stage, but can be detected in an earlier stage, with better prognosis, by colonoscopy. Using colonoscopy, also precancerous tumours, adenomas, can be detected and excised, but only in a national screening programme. However primary

  10. Complex I-associated hydrogen peroxide production is decreased and electron transport chain enzyme activities are altered in n-3 enriched fat-1 mice.

    Directory of Open Access Journals (Sweden)

    Kevork Hagopian

    Full Text Available The polyunsaturated nature of n-3 fatty acids makes them prone to oxidative damage. However, it is not clear if n-3 fatty acids are simply a passive site for oxidative attack or if they also modulate mitochondrial reactive oxygen species (ROS production. The present study used fat-1 transgenic mice, that are capable of synthesizing n-3 fatty acids, to investigate the influence of increases in n-3 fatty acids and resultant decreases in the n-6:n-3 ratio on liver mitochondrial H(2O(2 production and electron transport chain (ETC activity. There was an increase in n-3 fatty acids and a decrease in the n-6:n-3 ratio in liver mitochondria from the fat-1 compared to control mice. This change was largely due to alterations in the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine, with only a small percentage of fatty acids in cardiolipin being altered in the fat-1 animals. The lipid changes in the fat-1 mice were associated with a decrease (p<0.05 in the activity of ETC complex I and increases (p<0.05 in the activities of complexes III and IV. Mitochondrial H(2O(2 production with either succinate or succinate/glutamate/malate substrates was also decreased (p<0.05 in the fat-1 mice. This change in H(2O(2 production was due to a decrease in ROS production from ETC complex I in the fat-1 animals. These results indicate that the fatty acid changes in fat-1 liver mitochondria may at least partially oppose oxidative stress by limiting ROS production from ETC complex I.

  11. 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

  12. Loss of p27 expression and microsatellite instability in sporadic colorectal cancer.

    Science.gov (United States)

    Sarli, Leopoldo; Bottarelli, Lorena; Azzoni, Cinzia; Campanini, Nicoletta; Di Cola, Gabriella; Barilli, Angela Luciana; Marchesi, Federico; Mazzeo, Antonio; Salvemini, Carlo; Morari, Silvia; Di Mauro, Davide; Donadei, Enrico; Necchi, Fransesca; Roncoroni, Luigi; Bordi, Cesare

    2006-08-01

    The role of the loss of p27 protein expression in the oncogenesis of colorectal cancer is still in debate. In this study, we prospectively examined the immunohistochemical expression of p27 in 108 consecutive colorectal cancers, and we analysed the relationship with the results, the clinicopathological data, microsatellite instability (MSI) and other genetic alterations of tumours. Unselected patients (108) who underwent curative colorectal resection for sporadic colorectal cancer in a three-year period were evaluated for MSI using 6 microsatellite markers, and for the presence of p27, p53, Fhit, Mlh1 and Msh2 proteins by means of immunostaining. The relationships between these markers were analysed. p27 protein expression was examined for association with disease recurrences and survival. Lack of p27 expression was noted in 33 out of 108 (30.5%) colorectal cancer cases (Pcancers (Pcancers with MSI (Pcancers.

  13. 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...

  14. Underpinning the repurposing of anthracyclines towards colorectal cancer

    DEFF Research Database (Denmark)

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

    2013-01-01

    -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...... in breast cancer. No prognostic characteristic of TOP2A was identified. Conclusion. TOP2A gene gain is present in numbers relevant to identify a subgroup of patients who may benefit from anthracycline therapy. Based on the present findings, we will initiate a prospective clinical trial designed to evaluate......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...

  15. Culturing intestinal stem cells: applications for colorectal cancer research

    Directory of Open Access Journals (Sweden)

    Masayuki eFujii

    2014-06-01

    Full Text Available Recent advance of sequencing technology has revealed genetic alterations in colorectal cancer. The biological function of recurrently mutated genes has been intensively investigated through mouse genetic models and colorectal cancer cell lines. Although these experimental models may not fully reflect biological traits of human intestinal epithelium, they provided insights into the understanding of intestinal stem cell self-renewal, leading to the development of novel human intestinal organoid culture system. Intestinal organoid culture enabled to expand normal or tumor epithelial cells in vitro retaining their stem cell self-renewal and multiple differentiation. Gene manipulation of these cultured cells may provide an attractive tool for investigating genetic events involved in colorectal carcinogenesis.

  16. Enhancing the Ion Transport in LiMn1.5Ni0.5O4by Altering the Particle Wulff Shape via Anisotropic Surface Segregation.

    Science.gov (United States)

    Huang, Jiajia; Liu, Haodong; Zhou, Naixie; An, Ke; Meng, Ying Shirley; Luo, Jian

    2017-10-25

    Spontaneous and anisotropic surface segregation of W cations in LiMn 1.5 Ni 0.5 O 4 particles can alter the Wulff shape and improve surface stability, thereby significantly improving the electrochemical performance. An Auger electron nanoprobe was employed to identify the anisotropic surface segregation, whereby W cations prefer to segregate to {110} surface facets to decrease its relative surface energy according to Gibbs adsorption theory and subsequently increase its surface area according to Wulff theory. Consequently, the rate performance is improved (e.g., by ∼5-fold at a high rate of 25C) because the {110} facets have more open channels for fast lithium ion diffusion. Furthermore, X-ray photoelectron spectroscopy (XPS) depth profiling suggested that the surface segregation and partial reduction of W cation inhibit the formation of Mn 3+ on surfaces to improve cycling stability via enhancing the cathode electrolyte interphase (CEI) stability at high charging voltages. This is the first report of using anisotropic surface segregation to thermodynamically control the particle morphology as well as enhancing CEI stability as a facile, and potentially general, method to significantly improve the electrochemical performance of battery electrodes. Combining neutron diffraction, an Auger electron nanoprobe, XPS, and other characterizations, we depict the underlying mechanisms of improved ionic transport and CEI stability in high-voltage LiMn 1.5 Ni 0.5 O 4 spinel materials.

  17. Colorectal Cancer Complicating Crohn's Disease

    OpenAIRE

    Freeman, Hugh J

    2001-01-01

    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 w...

  18. Improving Quality in Colorectal Surgery

    OpenAIRE

    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 aspects through laparoscopy and enhanced recovery programs. However, postoperative complications painfully remain, despite efforts of amelioration of perioperative care. Research for molecular pathways ...

  19. 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....

  20. 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.

  1. 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.

  2. 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

  3. 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...

  4. Improving colorectal cancer referrals

    OpenAIRE

    Gregory, Claire

    2018-01-01

    The colorectal services at The Royal Bournemouth Hospital needed to adapt to meet the extra demand on fast-track patient referrals to the outpatient department, as a consequence of the changes in the National Institute for Health and Care Excellence (NICE) guidance on cancer referrals in June 2015. Learning from other units, a telephone assessment clinic (TAC) triaging patients straight to colonoscopy was trialled. A Plan–Do–Study–Act (PDSA) methodology was used. A baseline study showed that ...

  5. 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

  6. 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.

  7. 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(+).

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. Can land use changes alter carbon, nitrogen and major ion transport in subtropical brazilian streams? Modificações no uso da terra podem alterar o transporte fluvial de carbono, nitrogênio e íons maiores?

    Directory of Open Access Journals (Sweden)

    Daniela Mariano Lopes da Silva

    2007-08-01

    Full Text Available Several studies in tropical watersheds have evaluated the impact of urbanization and agricultural practices on water quality. In Brazil, savannas (known regionally as Cerrados represent 23% of the country's surface, representing an important share to the national primary growth product, especially due to intense agriculture. The purpose of this study is to present a comprehensive evaluation, on a yearly basis, of carbon, nitrogen and major ion fluxes in streams crossing areas under different land use (natural vegetation, sugar cane and eucalyptus in a savanna region of SE Brazil. Eucalyptus and sugar cane alter the transport of the investigated elements in small watersheds. The highest concentration of all parameters (abiotic parameters, ions, dissolved organic carbon DOC - and dissolved inorganic carbon - DIC were found in Sugar Cane Watersheds (SCW. The observed concentrations of major cations in Eucalyptus Watersheds (EW (Mg, Ca, K, Na, as well as DIN and DOC, were found frequently to be intermediate values between those of Savanna Watersheds (SW and SCW, suggesting a moderate impact of eucalyptus plantations on the streamwater. Same trends were found in relation to ion and nutrient fluxes, where the higher values corresponded to SCW. It is suggested that sugar cane plantations might be playing an important role in altering the chemistry of water bodies.Diversos estudos têm sido desenvolvidos em bacias de drenagem tropicais no intuito de avaliar o impacto da urbanização e das práticas agrícolas na qualidade dos corpos d'água. No Brasil, as savanas (conhecidas regionalmente como Cerrado representam 23% do território brasileiro, sendo uma região importante no crescimento nacional, especialmente devido às intensas atividades agrícolas. A finalidade deste trabalho é apresentar uma avaliação dos fluxos de carbono, nitrogênio e principais íons em córregos com diferentes usos do solo (vegetação, cana de açúcar e eucalipto em uma

  14. Genetic testing and counseling for hereditary forms of colorectal cancer.

    Science.gov (United States)

    Petersen, G M; Brensinger, J D; Johnson, K A; Giardiello, F M

    1999-12-01

    The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counseling. Germline mutations (nonsense, frameshift) of APC are associated with familial adenomatous polyposis, an autosomal dominant syndrome, clinically characterized by young onset, hundreds of adenomatous polyps in the colon, and increased risk for extracolonic tumors. Mutations in APC are also associated with forms of attenuated familial adenomatous polyposis. Germline mutations in five mismatch repair related genes (hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2) cause hereditary nonpolyposis colorectal cancer and are associated with increased risk of somatic genetic alterations and high DNA microsatellite instability. Hereditary nonpolyposis colorectal cancer is characterized by young onset colorectal cancer, proximal colon location, and increased risk of extracolonic cancers. A missense mutation in APC (I1307K) is associated with some familial colorectal cancer in Ashkenazic Jews. For persons at risk for hereditary forms of colorectal cancer, testing algorithms and gene test interpretations depend on identification of the pedigree germline gene mutation. Careful evaluation of the kindred for characteristic aggregation of tumor types among affected individuals and the availability of affected persons for testing are important issues in implementing genetic testing and follow-up management. Case reports illustrate the importance of genetic counseling as a component of cancer genetic risk assessment. The genetic counseling process includes exploration of patient risk perception, sources of anxiety related to cancer risk, patient education (specific cancer-related issues, prevention/intervention options), discussion of possible gene test options, test limitations, and consequences of various gene test outcomes.

  15. 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

  16. 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.

  17. Analysis of mitochondrial ND1 gene in human colorectal cancer

    Directory of Open Access Journals (Sweden)

    Mansoureh Akouchekian

    2011-01-01

    Conclusions: Results showed that a high frequency of somatic alterations of mtDNA occurs during the carcinogenesis and/or the progression of colorectal cancer. Based on the mtDNA mutation pattern observed in this study and other pre-viously studies it is believed that looking for somatic mutations in mtDNA would be one of the diagnostic values in early detection of cancer.

  18. 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.

  19. Suboptimal maternal diets alter mu opioid receptor and dopamine type 1 receptor binding but exert no effect on dopamine transporters in the offspring brain.

    Science.gov (United States)

    Thanos, Panayotis K; Zhuo, Jianmin; Robison, Lisa; Kim, Ronald; Ananth, Mala; Choai, Ilon; Grunseich, Adam; Grissom, Nicola M; George, Robert; Delis, Foteini; Reyes, Teresa M

    2018-02-01

    Birthweight is a marker for suboptimal fetal growth and development in utero. Offspring can be born large for gestational age (LGA), which is linked to maternal obesity or excessive gestational weight gain, as well as small for gestational age (SGA), arising from nutrient or calorie deficiency, placental dysfunction, or other maternal conditions (hypertension, infection). In humans, LGA and SGA babies are at an increased risk for certain neurodevelopmental disorders, including Attention Deficit/Hyperactivity Disorder, schizophrenia, and social and mood disorders. Using mouse models of LGA (maternal high fat (HF) diet) and SGA (maternal low protein (LP) diet) offspring, our lab has previously shown that these offspring display alterations in the expression of mesocorticolimbic genes that regulate dopamine and opioid function, thus indicating that these brain regions and neurotransmitter systems are vulnerable to gestational insults. Interestingly, these two maternal diets affected dopamine and opioid systems in somewhat opposing directions (e.g., LP offspring are generally hyperdopaminergic with reduced opioid expression, and the reverse is found for the HF offspring). These data largely involved evaluation at the transcriptional level, so the present experiment was designed to extend these analyses through an assessment of receptor binding. In this study, control, SGA and LGA offspring were generated from dams fed control, low protein or high fat diet, respectively, throughout pregnancy and lactation. At weaning, mice were placed on the control diet and sacrificed at 12 weeks of age. In vitro autoradiography was used to measure mu-opioid receptor (MOR), dopamine type 1 receptor (D1R), and dopamine transporter (DAT) binding level in mesolimbic brain regions. Results showed that the LP offspring (males and females) had significantly higher MOR and D1R binding than the control animals in the regions associated with reward. In HF offspring there were no differences in

  20. Mitochondrial DNA variants in colorectal carcinogenesis: Drivers or passengers?

    Science.gov (United States)

    Errichiello, Edoardo; Venesio, Tiziana

    2017-10-01

    Mitochondrial DNA alterations have widely been reported in many age-related degenerative diseases and tumors, including colorectal cancer. In the past few years, the discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. Mitochondrial DNA alterations include point mutations, deletions, inversions, and copy number variations, but numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, the biological impact of mitochondrial DNA variants may vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (heteroplasmy). In this review, we discuss the role of different type of mitochondrial DNA alterations in colorectal carcinogenesis and, in particular, we revisit the issue of whether they may be considered as causative driver or simply genuine passenger events. The advent of high-throughput techniques as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in colorectal cancer are also explored.

  1. 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.

  2. 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.

  3. [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.

  4. 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.

  5. 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.

  6. 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...

  7. 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

  8. 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

  9. 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....

  10. 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....

  11. 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...

  12. [Colorectal cancer prevention by flavonoids].

    Science.gov (United States)

    Hoensch, Harald; Richling, Elke; Kruis, Wolfgang; Kirch, Wilhelm

    2010-08-01

    Valid, sustained and safe clinical means of colorectal cancer prevention are still lacking, but they are urgently needed to lower the incidence of colorectal cancer. Dietary factors and phytochemicals such as flavonoids play an important role for prevention. A selective search of the literature using PubMed was performed with the following key words: flavonoids, cancer, therapy, colorectal cancer focused on clinical queries. Results of clinical studies including the authors' own were compared. In vivo and in vitro studies with animals, cell cultures and subcellular components provide ample evidence for antimutagenic and anticarcinogenic effects of flavonoids as shown for multiple biological and molecular endpoints. Isoflavonoids in vitro have been shown to induce proliferation of breast cancer cells. Epidemiologic trials (cohort, case-control and cross-sectional studies) yielded inconsistent results for flavonoid protection. Systematic reviews and meta-analyses support the protective role of tea flavonoids on adenoma incidence. An interventional pilot study with sustained flavonoid supplementation was shown to reduce the rate of neoplasia in patients with resected colorectal cancer. Selected flavonoids possess antimutagenic and anticarcinogenic properties and could reduce the incidence of colorectal neoplasias as shown in epidemiologic trials. Randomized controlled clinical studies with flavonoid intervention are necessary to provide evidence for their role in colorectal cancer prevention.

  13. 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

  14. 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.

  15. 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.

  16. 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...... in carcinogenesis suggesting that these ABC transporters are involved in the early steps of carcinogenesis as previously reported for ABCB1. These results suggest that dysfunctional transport across the epithelial barrier may contribute to colorectal carcinogenesis....

  17. (−-Epigallocatechin-3-Gallate Inhibits Colorectal Cancer Stem Cells by Suppressing Wnt/β-Catenin Pathway

    Directory of Open Access Journals (Sweden)

    Yue Chen

    2017-06-01

    Full Text Available The beneficial effects of tea consumption on cancer prevention have been generally reported, while (−-Epigallocatechin-3-gallate (EGCG is the major active component from green tea. Cancer stem cells (CSCs play a crucial role in the process of cancer development. Targeting CSCs may be an effective way for cancer intervention. However, the effects of EGCG on colorectal CSCs and the underlying mechanisms remain unclear. Spheroid formation assay was used to enrich colorectal CSCs from colorectal cancer cell lines. Immunoblotting analysis and quantitative real-time polymerase chain reaction were used to measure the alterations of critical molecules expression. Immunofluorescence staining analysis was also used to determine the expression of CD133. We revealed that EGCG inhibited the spheroid formation capability of colorectal cancer cells as well as the expression of colorectal CSC markers, along with suppression of cell proliferation and induction of apoptosis. Moreover, we illustrated that EGCG downregulated the activation of Wnt/β-catenin pathway, while upregulation of Wnt/β-catenin diminished the inhibitory effects of EGCG on colorectal CSCs. Taken together, this study suggested that EGCG could be an effective natural compound targeting colorectal CSCs through suppression of Wnt/β-catenin pathway, and thus may be a promising agent for colorectal cancer intervention.

  18. An Optimal Mean Based Block Robust Feature Extraction Method to Identify Colorectal Cancer Genes with Integrated Data.

    Science.gov (United States)

    Liu, Jian; Cheng, Yuhu; Wang, Xuesong; Zhang, Lin; Liu, Hui

    2017-08-17

    It is urgent to diagnose colorectal cancer in the early stage. Some feature genes which are important to colorectal cancer development have been identified. However, for the early stage of colorectal cancer, less is known about the identity of specific cancer genes that are associated with advanced clinical stage. In this paper, we conducted a feature extraction method named Optimal Mean based Block Robust Feature Extraction method (OMBRFE) to identify feature genes associated with advanced colorectal cancer in clinical stage by using the integrated colorectal cancer data. Firstly, based on the optimal mean and L 2,1 -norm, a novel feature extraction method called Optimal Mean based Robust Feature Extraction method (OMRFE) is proposed to identify feature genes. Then the OMBRFE method which introduces the block ideology into OMRFE method is put forward to process the colorectal cancer integrated data which includes multiple genomic data: copy number alterations, somatic mutations, methylation expression alteration, as well as gene expression changes. Experimental results demonstrate that the OMBRFE is more effective than previous methods in identifying the feature genes. Moreover, genes identified by OMBRFE are verified to be closely associated with advanced colorectal cancer in clinical stage.

  19. 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 ...

  20. 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...

  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. Outcome of colorectal cancer resection in octogenarians

    African Journals Online (AJOL)

    elderly, age was not an independent contributor, and medical. Outcome of colorectal ... Introduction. Octogenarians constitute a rapidly growing segment of patients undergoing colorectal cancer resection, but their outcomes .... Characteristics of patients aged >80 years and 60 - 70 years undergoing colorectal resection.

  3. Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome.

    Science.gov (United States)

    Naito, Yoshiro; Sawada, Hisashi; Oboshi, Makiko; Okuno, Keisuke; Yasumura, Seiki; Okuhara, Yoshitaka; Eguchi, Akiyo; Nishimura, Koichi; Soyama, Yuko; Asakura, Masanori; Ishihara, Masaharu; Tsujino, Takeshi; Masuyama, Tohru

    2017-11-01

    The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio-renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham-operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome.

  4. Unique insight into microenvironmental changes in colorectal cancer

    DEFF Research Database (Denmark)

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

    2017-01-01

    of the characterization, C3M was determined subsequent to the tumor tissue being cleaved with recombinant MMP-2/-9 and trypsin. C3M was generated by MMP-2/-9, but not by trypsin. In addition, the level of C3M was significantly elevated in the conditioned medium from tumor tissues (3.7 ng/ml) compared with that observed......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...... the dynamic processes of the MMP-mediated degradation of signature proteins from colorectal tissue. The aim of the present study was to profile and characterize the release of MMP-degraded type III collagen (C3M) and citrullinated and MMP-degraded vimentin (VICM) from tumor tissue and corresponding non...

  5. 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)

  6. A complex microsatellite at chromosome 7q33 as a new prognostic marker of colorectal cancer.

    Science.gov (United States)

    Ye, Xu; Deng, Hongyu; Su, Min; Liao, Qianjin; Huang, Dan; Liao, Duan-Fang; Xiao, Zhi-Qiang; Cao, Deliang

    2017-10-24

    Disease-specific markers are critical for early diagnosis, targeted therapy and prognostic prediction of diseases. Current study reports a complex microsatellite as a new prognostic marker of sporadic colorectal cancer. This microsatellite located at Chromosome 7q33 is composed of three tetranucleotide tandem repeats, (TTCC) 2 (TCCC) 5 (TCCT) 7 , flanked by a CT-rich sequence. We analyzed polymorphisms of this microsatellite in 158 sporadic colorectal cancer, 143 matched normal adjacent tissues (NAT) and 150 health donors. Our results showed that this complex microsatellite was instable with polymorphic frequency of 77.2% in colorectal cancer, 52.4% in NAT and 54.7% in health donors (pmicrosatellite, followed by (TTCC) 2 site for approximately 20%. Polymorphisms in (TCCC) 5 was rare. Polymorphisms at the (TCCT) 7 site were mainly insertions of 1 to 4 copies of TCCT (88.6%), and deletions occurred in about 6.4% of cases. The (TTCC) 2 site was featured with one copy TTCC insertions. Pair-wise analyses between colorectal tumors and NAT revealed that 88 of 121 (72.7%) tumors displayed expansion, contraction or both in these tetranucleotide tandem repeats when compared to NAT. A cross-analysis with clinicopathological data of 158 colorectal cancers revealed that polymorphic alterations of the microsatellite associated with less lymphatic metastasis (pmicrosatellite demonstrated better survival (n=112, p=0.0058). Together these data suggest that this complex microsatellite is a potential prognostic marker of sporadic colorectal cancer.

  7. Colorectal cancer desmoplastic reaction up-regulates collagen synthesis and restricts cancer cell invasion.

    Science.gov (United States)

    Coulson-Thomas, Vivien J; Coulson-Thomas, Yvette M; Gesteira, Tarsis F; de Paula, Cláudia A A; Mader, Ana M; Waisberg, Jaques; Pinhal, Maria A; Friedl, Andreas; Toma, Leny; Nader, Helena B

    2011-11-01

    During cancer cell growth many tumors exhibit various grades of desmoplasia, unorganized production of fibrous or connective tissue, composed mainly of collagen fibers and myofibroblasts. The accumulation of an extracellular matrix (ECM) surrounding tumors directly affects cancer cell proliferation, migration and spread; therefore the study of desmoplasia is of vital importance. Stromal fibroblasts surrounding tumors are activated to myofibroblasts and become the primary producers of ECM during desmoplasia. The composition, density and organization of this ECM accumulation play a major role on the influence desmoplasia has upon tumor cells. In this study, we analyzed desmoplasia in vivo in human colorectal carcinoma tissue, detecting an up-regulation of collagen I, collagen IV and collagen V in human colorectal cancer desmoplastic reaction. These components were then analyzed in vitro co-cultivating colorectal cancer cells (Caco-2 and HCT116) and fibroblasts utilizing various co-culture techniques. Our findings demonstrate that direct cell-cell contact between fibroblasts and colorectal cancer cells evokes an increase in ECM density, composed of unorganized collagens (I, III, IV and V) and proteoglycans (biglycan, fibromodulin, perlecan and versican). The desmoplastic collagen fibers were thick, with an altered orientation, as well as deposited as bundles. This increased ECM density inhibited the migration and invasion of the colorectal tumor cells in both 2D and 3D co-culture systems. Therefore this study sheds light on a possible restricting role desmoplasia could play in colorectal cancer invasion.

  8. 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

  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. 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

  11. 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

  12. A chemo-mechano-biological formulation for the effects of biochemical alterations on arterial mechanics: the role of molecular transport and multiscale tissue remodelling.

    Science.gov (United States)

    Marino, Michele; Pontrelli, Giuseppe; Vairo, Giuseppe; Wriggers, Peter

    2017-11-01

    This paper presents a chemo-mechano-biological framework for arterial physiopathology. The model accounts for the fine remodelling in the multiscale hierarchical arrangement of tissue constituents and for the diffusion of molecular species involved in cell-cell signalling pathways. Effects in terms of alterations in arterial compliance are obtained. A simple instructive example is introduced. Although oversimplified with respect to realistic case studies, the proposed application mimics the biochemical activity of matrix metalloproteinases, transforming growth factors beta and interleukins on tissue remodelling. Effects of macrophage infiltration, of intimal thickening and of a healing phase are investigated, highlighting the corresponding influence on arterial compliance. The obtained results show that the present approach is able to capture changes in arterial mechanics as a consequence of the alterations in tissue biochemical environment and cellular activity, as well as to incorporate the protective role of both autoimmune responses and pharmacological treatments. © 2017 The Author(s).

  13. 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)

  14. 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.

  15. Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor.

    Science.gov (United States)

    Wei, Tzu-Tang; Lin, Yi-Ting; Tseng, Ruo-Yu; Shun, Chia-Tung; Lin, Yu-Chin; Wu, Ming-Shiang; Fang, Jim-Min; Chen, Ching-Chow

    2016-08-15

    Colorectal cancer is a worldwide cancer with rising annual incidence. Inflammation is a well-known cause of colorectal cancer carcinogenesis. Metabolic inflammation (metaflammation) and altered gut microbiota (dysbiosis) have contributed to colorectal cancer. Chemoprevention is an important strategy to reduce cancer-related mortality. Recently, various polypharmacologic molecules that dually inhibit histone deacetylases (HDAC) and other therapeutic targets have been developed. Prevention for colitis was examined by dextran sodium sulfate (DSS) mouse models. Prevention for colorectal cancer was examined by azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models. Immunohistochemical staining was utilized to analyze the infiltration of macrophages and neutrophils and COX-II expression in mouse tissue specimens. The endotoxin activity was evaluated by Endotoxin Activity Assay Kit. We synthesized a statin hydroxamate that simultaneously inhibited HDAC and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Its preventive effect on colitis and colitis-associated colorectal cancer in mouse models was examined. Oral administration of this statin hydroxamate could prevent acute inflammation in the DSS-induced colitis and AOM/DSS-induced colorectal cancer with superior activity than the combination of lovastatin and SAHA. It also reduced proinflammatory cytokines, chemokines, expression of COX-II, and cyclin D1 in inflammation and tumor tissues, as well as decreasing the infiltration of macrophages and neutrophils in tumor-surrounding regions. Stemness of colorectal cancer and the release of endotoxin in AOM/DSS mouse models were also attenuated by this small molecule. This study demonstrates that the polypharmacological HDAC inhibitor has promising effect on the chemoprevention of colorectal cancer, and serum endotoxin level might serve as a potential biomarker for its chemoprevention. Clin Cancer Res; 22(16); 4158-69. ©2016 AACR. ©2016 American Association for

  16. Evaluation of frequency of kirsten rat sarcoma gene mutations in Iranian colorectal cancer

    Directory of Open Access Journals (Sweden)

    Fatemeh Roudbari

    2016-09-01

    Full Text Available Background: Kirsten rat sarcoma (KRAS gene is a target of genetic alterations which are diagnostic and prognostic biomarkers in patients with metastatic colorectal cancer who are treated with monoclonal anti-EGFR antibodies such as cetuximab and panitumumab. KRAS mutations are seen in 35-42% of patients with colorectal cancer. The high frequency of these mutations in colorectal cancer represents their high potential as a biomarker in early diagnosis of cancer. This study was done to evaluate the frequency of KRAS gene mutations in a small population of Iranian patients suffering from colorectal cancer.   Methods: 50 formalin-fixed paraffin-embedded tissue blocks with colorectal cancer (CRC, already confirmed by histopathology and immunohistochemistry testing, were received to Payvand Clinical and Specialty Laboratory, Tehran, from across the country in 2015. DNA was extracted from the tissue blocks and its quality was then evaluated. The reverse dot blotting method was used to evaluate KRAS gene mutations. Results: KRAS mutations were found in 42% of the study patients. 30% and 12% of the mutations were found in codon 12 and codon 13, respectively. Moreover, no mutation was found in codon 61. Results also showed that the most frequency of samples examined belonged to male with 68% (average age of 56 years old and then to female with 32% (median age of 54.8 years old. Conclusion: This study was performed to evaluate the frequency of KRAS gene mutations in Iranian colorectal cancer patients. According to the study results, the frequency of KRAS mutations was consistent with that of other countries, reported in previous studies. The high prevalence of these mutations in patients with colorectal cancer indicates the important role of these genes in this group of patients. Thus, the presence of these mutations can be used as a suitable biomarker for evaluation of response to targeted therapies in patients suffering from colorectal cancer.

  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. Nutrients, Foods, and Colorectal Cancer Prevention

    Science.gov (United States)

    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, folate, fruits and vegetables. Nutrients and foods may also 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 over-nutrition 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. PMID:25575572

  20. Use of confocal laser endomicroscopy with a fluorescently labeled fatty acid to diagnose colorectal neoplasms

    Science.gov (United States)

    Shen, Zhiyong; Gong, Wei; Liu, Tao; Wen, Jing; Zhang, Wanling; Zhu, Xianjun; Zhong, Hui; Wang, Tong; Zhi, Fachao; Nie, Biao

    2017-01-01

    Endoscopic treatment for early colorectal cancer closely correlates with patient prognosis. However, endoscopic differentiation between carcinomas and non-neoplastic lesions remains difficult. Here, we topically stained colorectal neoplasms with a fatty acid analogue (BODIPY-FA) and quantified the fluorescent signals using confocal laser endomicroscopy (CLE) and fluorescence microscopy. We also analyzed protein expression in colorectal cancer tissues. We found that expression of fatty acid synthase was elevated, while the expression of fatty acid transporters was reduced in colorectal cancer. In colorectal cancer mouse models and patients, the BODIPY-FA signals were higher in normal epithelia than in carcinomas or colonic intraepithelial neoplasias. BODIPY-FA staining revealed both the arrangement of intestinal glands and the intracellular structures under CLE screening. In a double-blind trial, CLE images stained with BODIPY-FA exhibited greater consistency (κ = 0.68) and overall validity (74.65%) than those stained using intravenous fluorescein sodium (κ = 0.43, 55.88%) when the results were compared with histological diagnoses. These findings suggest that topical use of BODIPY-FA with CLE is a promising imaging approach for early colorectal neoplasm screening. PMID:28938608

  1. Dietary α-linolenic acid supplementation alters skeletal muscle plasma membrane lipid composition, sarcolemmal FAT/CD36 abundance, and palmitate transport rates.

    Science.gov (United States)

    Chorner, Zane; Barbeau, Pierre-Andre; Castellani, Laura; Wright, David C; Chabowski, Adrian; Holloway, Graham P

    2016-12-01

    The cellular processes influenced by consuming polyunsaturated fatty acids remains poorly defined. Within skeletal muscle, a rate-limiting step in fatty acid oxidation is the movement of lipids across the sarcolemmal membrane, and therefore, we aimed to determine the effects of consuming flaxseed oil high in α-linolenic acid (ALA), on plasma membrane lipid composition and the capacity to transport palmitate. Rats fed a diet supplemented with ALA (10%) displayed marked increases in omega-3 polyunsaturated fatty acids (PUFAs) within whole muscle and sarcolemmal membranes (approximately five-fold), at the apparent expense of arachidonic acid (-50%). These changes coincided with increased sarcolemmal palmitate transport rates (+20%), plasma membrane fatty acid translocase (FAT/CD36; +20%) abundance, skeletal muscle triacylglycerol content (approximately twofold), and rates of whole body fat oxidation (~50%). The redistribution of FAT/CD36 to the plasma membrane could not be explained by increased phosphorylation of signaling pathways implicated in regulating FAT/CD36 trafficking events (i.e., phosphorylation of ERK1/2, CaMKII, AMPK, and Akt), suggesting the increased n-3 PUFA composition of the plasma membrane influenced FAT/CD36 accumulation. Altogether, the present data provide evidence that a diet supplemented with ALA increases the transport of lipids into resting skeletal muscle in conjunction with increased sarcolemmal n-3 PUFA and FAT/CD36 contents. Copyright © 2016 the American Physiological Society.

  2. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the mRNA expression of critical genes associated with cholesterol metabolism, bile acid biosynthesis, and bile transport in rat liver: A microarray study

    International Nuclear Information System (INIS)

    Fletcher, Nick; Wahlstroem, David; Lundberg, Rebecca; Nilsson, Charlotte B.; Nilsson, Kerstin C.; Stockling, Kenneth; Hellmold, Heike; Hakansson, Helen

    2005-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatotoxin that exerts its toxicity through binding to the aryl hydrocarbon receptor (AhR) and the subsequent induction or repression of gene transcription. In order to further identify novel genes and pathways that may be associated with TCDD-induced hepatotoxicity, we investigated gene changes in rat liver following exposure to single oral doses of TCDD. Male Sprague-Dawley rats were administered single doses of 0.4 μg/kg bw or 40 μg/kg bw TCDD and killed at 6 h, 24 h, or 7 days, for global analyses of gene expression. In general, low-dose TCDD exposure resulted in greater than 2-fold induction of genes coding for a battery of phase I and phase II metabolizing enzymes including CYP1A1, CYP1A2, NADPH quinone oxidoreductase, UGT1A6/7, and metallothionein 1. However, 0.4 μg/kg bw TCDD also altered the expression of Gadd45a and Cyclin D1, suggesting that even low-dose TCDD exposure can alter the expression of genes indicative of cellular stress or DNA damage and associated with cell cycle control. At the high-dose, widespread changes were observed for genes encoding cellular signaling proteins, cellular adhesion, cytoskeletal and membrane transport proteins as well as transcripts coding for lipid, carbohydrate and nitrogen metabolism. In addition, decreased expression of cytochrome P450 7A1, short heterodimer partner (SHP; gene designation nr0b2), farnesyl X receptor (FXR), Ntcp, and Slc21a5 (oatp2) were observed and confirmed by RT-PCR analyses in independent rat liver samples. Altered expression of these genes implies major deregulation of cholesterol metabolism and bile acid synthesis and transport. We suggest that these early and novel changes have the potential to contribute significantly to TCDD induced hepatotoxicity and hypercholesterolemia

  3. Colonoscopic evaluation of middle aged patients with altered bowel habits

    International Nuclear Information System (INIS)

    Bhatti, M.A.; Kashif, M.A.; Imran, M.

    2004-01-01

    Objective: To determine the frequency of colorectal carcinoma in-patients above 40 years of age presenting with altered bowel habits by colonoscopy. Patients and Methods: A group of 50 consecutive cases presenting with altered bowel habits meeting the inclusion and exclusion criteria were included in the study. History and physical examination were recorded on a specifically designed proforma. Colonoscopy was done in these patients and any abnormality found was reported and biopsy specimen taken and sent for histopathology. Results: A total number of 17 patients presenting with altered bowel habits were found to be suffering from colorectal carcinoma by colonoscopy. Among these in 30% the lesion was in the rectum , in 9% the lesion was in the sigmoid colon, 6% in the descending colon, 4% at the splenic flexure, 5% in the transverse colon, in 16% the lesion was found at the hepatic flexure and in 30% the lesion was in the ascending colon and caecum. Conclusion: Frequency of colorectal carcinoma is high in-patients above 40 years of age who presenting with altered bowel habits. They should be investigated preferably by means of colonoscopy which is the most complete method of investigation and diagnostic procedure of choice in patients with a clinical suspicion of colorectal carcinoma.(author)

  4. 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.

  5. 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.

  6. 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...

  7. Biological therapy of colorectal cancer

    NARCIS (Netherlands)

    de Kleijn, E. M. H. A.; Punt, C. J. A.

    2002-01-01

    In this review, the immunogenicity of colorectal cancer (CRC) and the results of clinical and recent preclinical studies are discussed. Evidence for immune reactivity has been found in several preclinical models and the prognostic value of some of these immune responses have been reported. The

  8. 6 Common Cancers - Colorectal Cancer

    Science.gov (United States)

    ... that may become cancerous. A family history of colon or rectal cancer puts you at higher risk, as does ulcerative ... in combination with chemotherapy for patients with advanced rectal ... chemotherapy for colorectal cancer usually consisted of treatment with just two drugs, ...

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 2,4-Dichlorophenoxyacetic acid alters intracellular pH and ion transport in the outer mantle epithelium of the bivalve Anodonta cygnea.

    Science.gov (United States)

    Alves, Marco G; Oliveira, Pedro F

    2014-09-01

    Bivalve molluscs, due to their sedentary mode of life and filter-feeding behavior, are very susceptible to pollutant bioaccumulation and used as sentinel organisms in the assessment of environment pollution. Herein we aimed to determine the in vivo, ex vivo and in vitro effects of 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide, in Anodonta cygnea shell growth mechanisms. For that, we evaluated the effect of 2,4-D (100 μM) exposure on the transepithelial short-circuit current (Isc), potential (Vt) and conductance (Gt), as well as on OME ion transport systems and intracellular pH (pHi). In vivo exposure to 2,4-D caused an increase of 50% on the Isc generated by OME and ex vivo addition of that compound to the apical side of OME also induced an Isc increase. Furthermore, 2,4-D was able to cause a pHi increase in isolated cells of OME. Noteworthy, when 2,4-D was added following the exposure to specific inhibitors of several membrane transporters identified as responsible for pHi maintenance in these cells, no significant effect was observed on pHi except when the V-type ATPase inhibitor was used, indicating an overlap with the effect of 2,4-D. Thus, we concluded that 2,4-D is able of enhancing the activity of the V-ATPases present on the OME of A. cygnea and that this effect seems to be due to a direct stimulation of those H(+) transporters present on the apical portion of the membrane of OME cells, which are vital for shell maintenance and growth. This study allows us to better understand the molecular mechanisms behind 2,4-D toxicity and its deleterious effect in aquatic ecosystems, with particular emphasis on those involved in shell formation of bivalves. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. The potential role of Alu Y in the development of resistance to SN38 (Irinotecan) or oxaliplatin in colorectal cancer

    DEFF Research Database (Denmark)

    Lin, Xue; Stenvang, Jan; Rasmussen, Mads Heilskov

    2015-01-01

    or oxaliplatin resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of 'DNA methylation entropy...... states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. Conclusion: Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated...... toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. Results: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38...

  20. Expression of genes involved in fatty acid transport and insulin signaling is altered by physical inactivity and exercise training in human skeletal muscle.

    Science.gov (United States)

    Lammers, Gerwen; Poelkens, Fleur; van Duijnhoven, Noortje T L; Pardoel, Elisabeth M; Hoenderop, Joost G; Thijssen, Dick H J; Hopman, Maria T E

    2012-11-15

    Physical deconditioning is associated with the development of chronic diseases, including type 2 diabetes and cardiovascular disease. Exercise training effectively counteracts these developments, but the underlying mechanisms are largely unknown. To gain more insight into these mechanisms, muscular gene expression levels were assessed after physical deconditioning and after exercise training of the lower limbs in humans by use of gene expression microarrays. To exclude systemic effects, we used human models for local physical inactivity (3 wk of unilateral limb suspension) and for local exercise training (6 wk of functional electrical stimulation exercise of the extremely deconditioned legs of individuals with a spinal cord injury). The most interesting subset of genes, those downregulated after deconditioning as well as upregulated after exercise training, contained 18 genes related to both the "insulin action" and "adipocytokine signaling" pathway. Of these genes, the three with strongest up/downregulation were the muscular fatty acid-binding protein-3 (FABP3), the fatty acid oxidizing enzyme hydroxyacyl-CoA dehydrogenase (HADH), and the mitochondrial fatty acid transporter solute carrier 25 family member A20 (SLC25A20). The expression levels of these genes were confirmed using RT-qPCR. The results of the present study indicate an important role for a decreased transport and metabolism of fatty acids, which provides a link between physical activity levels and insulin signaling.

  1. Microbiota regulation of inflammatory bowel disease and colorectal cancer.

    Science.gov (United States)

    Liu, Zhanju; Cao, Anthony T; Cong, Yingzi

    2013-12-01

    The host and microbiota have evolved mechanisms for coexistence over millions of years. Accumulating evidence indicates that a dynamic mutualism between the host and the commensal microbiota has important implications for health, and microbial colonization contributes to the maintenance of intestinal immune homeostasis. However, alterations in communication between the mucosal immune system and gut microbial communities have been implicated as the core defect that leads to chronic intestinal inflammation and cancer development. We will discuss the recent progress on how gut microbiota regulates intestinal homeostasis and the pathogenesis of inflammatory bowel disease and colorectal cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Inadequate preoperative colonic evaluation for synchronous colorectal cancer

    DEFF Research Database (Denmark)

    Achiam, M P; Burgdorf, S K; Wilhelmsen, M

    2009-01-01

    BACKGROUND AND AIMS: Synchronous cancers (SC) are well known (2-11%) in patients with colorectal carcinoma (CRC). One study has shown that intraoperative palpation can miss up to 69% of the SC while other studies have shown altered planned surgical procedure due to preoperatively diagnosed...... in our department were reviewed. Only patients with CRC were included. Information regarding pre-, per- and postoperative colonic evaluation were obtained and occurrences of SC were evaluated. RESULTS: Of the 534 patients included 124 (23%) patients had an impassable stenosis. Full preoperative colonic...

  3. 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

  4. 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

  5. GLUT-1 overexpression as an unfavorable prognostic biomarker in patients with colorectal cancer.

    Science.gov (United States)

    Yang, Jing; Wen, Jing; Tian, Tian; Lu, Zhongsheng; Wang, Yao; Wang, Zikai; Wang, Xiangdong; Yang, Yunsheng

    2017-02-14

    Glucose transporter-1 (GLUT-1) exhibits altered expression in colorectal cancer (CRC). The aim of this study was to explore the association between GLUT-1 and survival conditions, as well as clinical features in CRC by meta-analysis. Relevant studies were searched through predefined strategies, hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) were used as effective measures. A total of 14 studies with 2,077 patients were included in this meta-analysis. The results showed that GLUT-1 was not significantly associated with overall survival (OS) (HR=1.28, 95% CI=0.86-1.91, p=0.22) or disease-free survival (DFS) (HR=1.71, 95% CI=0.78-3.72, p=0.179). However, subgroup analysis indicated that GLUT-1 was a significant biomarker for poor DFS in rectal cancer (HR=2.47, 95% CI=1.21-5.05, p=0.013). GLUT-1 expression was also found to be significantly correlated with the presence of lymph node metastasis (n=8, OR=2.14, 95% CI=1.66-2.75, pGLUT-1 was associated with poor DFS in rectal cancer (RC). Furthermore, GLUT-1 was also an indicator of aggressive clinical features in CRC.

  6. 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...

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 18S rRNA degradation is not accompanied by altered rRNA transport at early times following irradiation of HeLa cells

    Energy Technology Data Exchange (ETDEWEB)

    Fuchs, P.; Krolak, J.M.; McClain, D.; Minton, K.W.

    1990-01-01

    In recent investigations on the effects of radiation on rRNA processing in HeLa S3 cells, the authors pulse-labeled the cells with uridine immediately prior to irradiation. The 45 S rRNA precursor, which undergoes nuclear processing to form one each of its major daughter species, 28S and 18S rRNA, was separated from the daughter species by gel electrophoresis and the radiolabel in each species determined at various times after irradiation. By pulse-labeling the cells prior to irradiation, superimposed effects caused by radiation-induced alterations of rRNA transcription and Refs. therein were minimized, permitting selective analysis of the processing of that fraction of 45S precursor that had been synthesized (radiolabeled) predominantly prior to irradiation. They now report more detailed studies on 45S rRNA processing within the first 2 h following irradiation in which they have found a maximum 28 S:18 S ratio of 2:1 that is observed about 1 h following irradiation of 5 or 10 Gy.

  12. Clinical and molecular characterization of colorectal cancer in young Moroccan patients.

    Science.gov (United States)

    Benmoussa, Amal; Badre, Wafaa; Pedroni, Monica; Zamiati, Soumia; Badre, Latifa; Digregorio, Carmela; De Leon, Maurizio Ponz; Nadifi, Selama

    2012-01-01

    Early-onset colorectal cancers are relatively rare. About 20% of colorectal cancers are familial or hereditary. Two autosomal dominantly inherited cancer syndromes are more studied: Lynch syndrome accounts for 2-5% of colorectal cancers and familial adenomatous polyposis represents 1% of total colorectal cancers. Unlike the familial adenomatous polyposis syndrome, there are no clinical features that help in easily recognizing Lynch syndrome. The young age of cancer occurrence could be a criterion that should raise a suspicion of Lynch syndrome. In Morocco, the average age at diagnosis of colorectal cancers according to the register of cancers of Casablanca is 56 years, which is 10 years earlier than in European countries. Our study aimed to assess the frequency and molecular characteristics of the Lynch syndrome in Moroccan early-onset colorectal cancers patients. The population analyzed included 70 patients. The criteria for inclusion of patients in this study were a colorectal cancers before age 50 and the exclusion of familial adenomatous polyposis. We started by searching for microsatellite instability, first by immunohistochemistry of 3 mismatch repair proteins (MLH1, MSH2 and MSH6) and with second confirmation using 4 monomorphic markers (BAT25, BAT26, NR21, and CAT25). We found instability in 10/70 (15%) of the cases. The loss of expression affects more often the MLH1 protein, with 8 cases, versus 2 cases of altered MSH2. None of the 70 patients of the series fulfilled the Amsterdam II criteria, indicative of Lynch syndrome. Further work needs to be done to discriminate hereditary cases from sporadic ones, but testing for microsatellite instability as a first step is important.

  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. 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...

  15. Optimizing Outcomes of Colorectal Cancer Screening

    OpenAIRE

    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 improvement of screening programs. The thesis includes studies on the effect of the test used for screening, long-term adherence with screening, the quality of colorectal examinations, time to diagno...

  16. Hydrothermal Alteration of Glass from Underground Nuclear Tests: Formation and Transport of Pu-clay Colloids at the Nevada National Security Site

    Energy Technology Data Exchange (ETDEWEB)

    Zavarin, M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Zhao, P. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Joseph, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Begg, J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Boggs, M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Dai, Z. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Kersting, A. B. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-05-27

    The testing of nuclear weapons at the Nevada National Security Site (NNSS), formerly the Nevada Test Site (NTS), has led to the deposition of substantial quantities of plutonium into the environment. Approximately 2.8 metric tons (3.1×104 TBq) of Pu were deposited in the NNSS subsurface as a result of underground nuclear testing. While 3H is the most abundant anthropogenic radionuclide deposited in the NNSS subsurface (4.7×106 TBq), plutonium is the most abundant from a molar standpoint. The only radioactive elements in greater molar abundance are the naturally occurring K, Th, and U isotopes. 239Pu and 240Pu represent the majority of alpha-emitting Pu isotopes. The extreme temperatures associated with underground nuclear tests and the refractory nature of Pu results in most of the Pu (98%) being sequestered in melted rock, referred to as nuclear melt glass (Iaea, 1998). As a result, Pu release to groundwater is controlled, in large part, by the leaching (or dissolution) of nuclear melt glass over time. The factors affecting glass dissolution rates have been studied extensively. The dissolution of Pu-containing borosilicate nuclear waste glasses at 90ºC has been shown to lead to the formation of dioctahedral smectite colloids. Colloid-facilitated transport of Pu at the NNSS has been observed. Recent groundwater samples collected from a number of contaminated wells have yielded a wide range of Pu concentrations from 0.00022 to 2.0 Bq/L. While Pu concentrations tend to fall below the Maximum Contaminant Level (MCL) established by the Environmental Protection Agency (EPA) for drinking water (0.56 Bq/L), we do not yet understand what factors limit the Pu concentration or its transport behavior. To quantify the upper limit of Pu concentrations produced as a result of melt glass dissolution and determine the nature of colloids and Pu associations, we performed a 3 year nuclear melt glass dissolution experiment

  17. 5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats.

    Science.gov (United States)

    Elangbam, Chandikumar S; Job, Lauren E; Zadrozny, Leah M; Barton, Joanna C; Yoon, Lawrence W; Gates, Lisa D; Slocum, Nikki

    2008-08-01

    Several drugs have been linked to valvulopathy in humans, including therapeutic agents for obesity, Parkinson's disease and migraine. There is increasing evidence that the 5-hydroxytryptamine 2B receptor (5HT2BR) activation and/or increased circulating 5HT (5-hydroxytryptamine) may play a significant role in the pathogenesis of drug-induced valvulopathy. In the present study, we investigated whether 7-day 5HT subcutaneous injections led to structural and compositional abnormalities in conjunction with transcriptomic modulation of 5HT2BR and 5HT transporter (5HTT) genes in the aortic and mitral valves of Sprague-Dawley (SD) rats. Subcutaneous injections of 5HT for 7 days resulted in thickening and compositional alteration of aortic and mitral valves in SD rats. More specifically, valve-leaflets from 5HT-treated rats had greater valve thickness, a higher amount of glycosaminoglycans (GAGs) and a lower amount of collagen. The compositional alteration was associated with up-regulation and down-regulation of 5HT2BR and 5HTT genes, respectively. The present study strongly suggests that the activation of 5HT2BR and inhibition of 5HTT played a significant role in the pathogenesis of 5HT-induced valvulopathy in SD rats. Thus, these findings further highlight the necessity and/or utilization of animal models to screen potential valvular effects of serotonergic compounds.

  18. A multidimensional integration analysis reveals potential bridging targets in the process of colorectal cancer liver metastasis.

    Directory of Open Access Journals (Sweden)

    Bo Gao

    Full Text Available Approximately 9% of cancer-related deaths are caused by colorectal cancer. Liver metastasis is a major factor for the high colorectal cancer mortality rate. However, the molecular mechanism underlying colorectal cancer liver metastasis remains unclear. Using a global and multidimensional integration approach, we studied sequencing data, protein-protein interactions, and regulation of transcription factor and non-coding RNAs in primary tumor samples and liver metastasis samples to unveil the potential bridging molecules and the regulators that functionally link different stages of colorectal cancer liver metastasis. Primary tumor samples and liver metastasis samples had modules with significant overlap and crosstalk from which we identified several bridging genes (e.g. KNG1 and COX5B, transcription factors (e.g. E2F4 and CDX2, microRNAs (e.g. miR-590-3p and miR-203 and lncRNAs (e.g. lincIRX5 and lincFOXF1 that may play an important role in the process of colorectal cancer liver metastasis. This study enhances our understanding of the genetic alterations and transcriptional regulation that drive the metastatic process, but also provides the methodology to guide the studies on other metastatic cancers.

  19. Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment.

    Science.gov (United States)

    Yu, Ya-Nan; Yu, Ta-Chung; Zhao, Hui-Jun; Sun, Tian-Tian; Chen, Hui-Min; Chen, Hao-Yan; An, Hui-Fang; Weng, Yu-Rong; Yu, Jun; Li, Min; Qin, Wen-Xin; Ma, Xiong; Shen, Nan; Hong, Jie; Fang, Jing-Yuan

    2015-10-13

    Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated. 454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting. The levels of opportunistic pathogens, such as Fusobacterium, Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) (P nucleatum-mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p-STAT3, p-STAT5 and p-ERK1/2 in mice, compared with mice fed with F. nucleatum alone. F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways.

  20. Chronic Vitamin C Deficiency Promotes Redox Imbalance in the Brain but Does Not Alter Sodium-Dependent Vitamin C Transporter 2 Expression

    Directory of Open Access Journals (Sweden)

    Maya D. Paidi

    2014-04-01

    Full Text Available 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 < 0.0001 compared to controls. VitC repleted animals were not significantly different from controls. No significant changes were detected in either gene or protein expression of SVCT2 between groups or brain regions. In conclusion, chronic pre-and postnatal VitC deficiency increased brain redox imbalance but did not increase SVCT2 expression. Our findings show potential implications for VitC deficiency induced negative effects of redox imbalance in the brain and provide novel insight to the regulation of VitC in the brain during deficiency.

  1. Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons

    Directory of Open Access Journals (Sweden)

    Katherina Beck

    2015-11-01

    Full Text Available Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2 acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling.

  2. 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...... of these tumors eligible for anti-EGFR directed therapy regimens.Modern Pathology advance online publication, 12 January 2018; doi:10.1038/modpathol.2017.184....

  3. 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...

  4. 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...

  5. 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....

  6. 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...

  7. 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

  8. Significant alteration of Critical Zone processes in urban watersheds: shifting from a transport-limited to a weathering-limited regime

    Science.gov (United States)

    Moore, J.; Bird, D. L.; Dobbis, S. K.; Woodward, G.

    2016-12-01

    Urban areas and associated impervious surface cover (ISC) are among the fastest growing land use types. Rapid growth of urban lands has significant implications for geochemical cycling and solute sources to streams, estuaries, and coastal waters. However, little work has been done to investigate the impacts of urbanization on Critical Processes, including on the export of solutes from urban watersheds. Despite observed elevated solute concentrations in urban streams in some previous studies, neither solute sources nor total solute fluxes have been quantified due to mixed bedrock geology, lack of a forested reference watershed, or the presence of point sources that confounded separation of anthropologic and natural sources. We investigated the geochemical signal of the urban built environment (e.g., roads, parking lots, buildings) in a set of five USGS-gaged watersheds across a rural (forested) to urban gradient in the Maryland Piedmont. These watersheds have ISC ranging from 0 to 25%, no point sources, and similar felsic bedrock chemistry. Weathering from the urban built environment and ISC produces dramatically higher solute concentrations in urban watersheds than in the forested watershed. Higher solute concentrations result in chemical weathering fluxes from urban watersheds that are 11-13 times higher than the forested watershed and are similar to fluxes from mountainous, weathering-limited watersheds rather than fluxes from transport-limited, dilute streams like the forested watershed. Weathering of concrete in urban watersheds produces geochemistry similar to weathering-limited watersheds with high concentrations of Ca2+, Mg2+, and DIC, which is similar to stream chemistry due to carbonate weathering. Road salt dissolution results in high Na+ and Cl- concentrations similar to evaporite weathering. Quantifying processes causing elevated solute fluxes from urban areas is essential to understanding cycling of Ca2+, Mg2+, and DIC in urban streams and in

  9. 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.

  10. Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons.

    Science.gov (United States)

    Beck, Katherina; Ehmann, Nadine; Andlauer, Till F M; Ljaschenko, Dmitrij; Strecker, Katrin; Fischer, Matthias; Kittel, Robert J; Raabe, Thomas

    2015-11-01

    Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling. © 2015. Published by The Company of Biologists Ltd.

  11. 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

  12. 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.

  13. [Antibiotic prophylaxis in colorectal surgery].

    Science.gov (United States)

    Hrivnák, R; Hanke, I; Hansliánová, M; Kala, Z; Sevcíková, A

    2009-06-01

    Antibiotic (ATB) prophylaxis is generaly recommended in surgery. There is an important role in colorectal surgery especially. Colorectal surgery is associated with a particularly high risk of post-operative infection because of contamination of the wound with faecal bacteria. ATB prophylaxis decreases surgical wound infection, morbidity and mortality as well. Morbidity and mortality are associated with longer hospital stays and increased costs of care. At surgical department of Faculty hospital Brno, during March-June 2008 an 88 patients were operated because of different diagnoses in colorectum. Both an emergent and schedule operations were made. Type of ATBs, time of application before operation, reapplication after operation and surgical site infection (SSI), in - hospital stay were followed up prospectively. SSI were divided into superficial, deep and intraabdominal. Data were analyse statistically. The most used combination of ATBs, almost in 91%, were Cefazoline and Metronidazole. In 50% were time of application till 20 minutes before incision. Only in 17% were time of application in interval 20-30 minutes before incision, which is recommended. We noticed 25 SSI. We prove that patients with SSI has almost two-times longer in-hospital stay. Enterococcus and enterobacterias were the most common etiological agents. ATB prophylaxis is indicated in colorectal surgery. It has to be applied in correct dose and right time before operation to decrease SSI.

  14. Colorectal cancer defeating? Challenge accepted!

    Science.gov (United States)

    Di Franco, S; Todaro, M; Dieli, F; Stassi, G

    2014-10-01

    Colorectal tumours are actually considered as aberrant organs, within it is possible to notice a different stage of cell growth and differentiation. Their origin is reported to arise from a subpopulation of tumour cells endowed with, just like the healthy stem cells, self-renewal and aberrant multi-lineage differentiation capacity likely to be called colorectal cancer stem cells (CCSCs). Cancer stem cells (CSCs) fate, since their origin, reflects the influences from their microenvironment (or niche) both in the maintenance of stemness, in promoting their differentiation, and in inducing epithelial-mesenchymal transition, responsible of CSCs dissemination and subsequent formation of metastatic lesions. The tumour cells heterogeneity and their immuno-response resistance nowadays probably responsible of the failure of the conventional therapies, make this research field an open issue. Even more importantly, our increasing understanding of the cellular and molecular mechanisms that regulate CSC quiescence and cell cycle regulation, self-renewal, chemotaxis and resistance to cytotoxic agents, is expected to eventually result in tailor-made therapies with a significant impact on the morbidity and overall survival of colorectal cancer patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. ADAMTS Expression in Colorectal Cancer

    Science.gov (United States)

    Filou, Serafula; Korpetinou, Aggeliki; Kyriakopoulou, Dora; Bounias, Dimitrios; Stavropoulos, Michael; Ravazoula, Panagiota; Papachristou, Dionysios J.; Theocharis, Achilleas D.; Vynios, Demitrios H.

    2015-01-01

    ADAMTSs are a family of secreted proteinases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). By acting on a large panel of extracellular substrates, they control several cell functions such as fusion, adhesion, proliferation and migration. Through their thrombospondin motifs they also possess anti-angiogenic properties. We investigated whether ADAMTSs participate in colorectal cancer progression and invasion. Their expression was investigated at both mRNA and protein levels. Using RT-PCR, the expression of ADAMTS-1, -4, -5 and ADAMTS-20 was estimated in colorectal tumors of different cancer stage and anatomic site and 3 cell lines of different aggressiveness. An overexpression of ADAMTS-4 and -5 was observed, especially in tissue samples, whereas ADAMTS-1 and -20 were found to be down-regulated. Western blot analysis further supported the RT-PCR findings, revealing in addition the degradation of ADAMTS-1 and -20 in cancer. In situ expression and localization of ADAMTS-1, -4, -5 and -20 was also investigated by immunohistochemical analysis. Our data suggest a positive correlation between ADAMTS-4 and -5 expression and cancer progression, in contrast with the anti-angiogenic members of the family, ADAMTS-1 and -20, which were found to be down-regulated. Our findings support the notion that overexpression of ADAMTS-4 and ADAMTS-5 in colorectal cancer might be a possible invasive mechanism of cancer cells in order to degrade proteoglycans of ECM. PMID:25786261

  16. ADAMTS expression in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Serafula Filou

    Full Text Available ADAMTSs are a family of secreted proteinases that share the metalloproteinase domain with matrix metalloproteinases (MMPs. By acting on a large panel of extracellular substrates, they control several cell functions such as fusion, adhesion, proliferation and migration. Through their thrombospondin motifs they also possess anti-angiogenic properties. We investigated whether ADAMTSs participate in colorectal cancer progression and invasion. Their expression was investigated at both mRNA and protein levels. Using RT-PCR, the expression of ADAMTS-1, -4, -5 and ADAMTS-20 was estimated in colorectal tumors of different cancer stage and anatomic site and 3 cell lines of different aggressiveness. An overexpression of ADAMTS-4 and -5 was observed, especially in tissue samples, whereas ADAMTS-1 and -20 were found to be down-regulated. Western blot analysis further supported the RT-PCR findings, revealing in addition the degradation of ADAMTS-1 and -20 in cancer. In situ expression and localization of ADAMTS-1, -4, -5 and -20 was also investigated by immunohistochemical analysis. Our data suggest a positive correlation between ADAMTS-4 and -5 expression and cancer progression, in contrast with the anti-angiogenic members of the family, ADAMTS-1 and -20, which were found to be down-regulated. Our findings support the notion that overexpression of ADAMTS-4 and ADAMTS-5 in colorectal cancer might be a possible invasive mechanism of cancer cells in order to degrade proteoglycans of ECM.

  17. 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.

  18. Ulcerative colitis-associated colorectal cancer

    Science.gov (United States)

    Yashiro, Masakazu

    2014-01-01

    The association between ulcerative colitis (UC) and colorectal cancer (CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC (UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, low-grade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC. PMID:25469007

  19. 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.

  20. 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.

  1. 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.

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

    Science.gov (United States)

    Mármol, Inés; Sánchez-de-Diego, Cristina; Pradilla Dieste, Alberto; Cerrada, Elena; Rodriguez Yoldi, María Jesús

    2017-01-19

    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 with

  3. 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

  4. 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....

  5. 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

  6. 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

  7. Colorectal cancer in Jordan: prevention and care.

    Science.gov (United States)

    Ahmad, Muayyad M; Dardas, Latefa; Dardas, Lubna; Ahmad, Huthaifa

    2015-12-01

    The aim of this study was to describe the knowledge, attitudes, and practices toward colorectal cancer prevention and care in Jordan. A survey was designed to produce reliable estimates for the population's knowledge, attitudes, and practices in all 12 governorates of Jordan by using stratified random sampling. A representative sample of the adult population in Jordan completed a comprehensive tool which explored participants' knowledge about the risk factors associated with colorectal cancer, cancer prevention through lifestyle changes, and early cancer diagnosis and screening. According to the participants (n = 3196), colorectal cancer had the second highest percentage of screening recommendation (12.6%) after breast cancer (57.3%). Only 340 individuals (11%) reported ever screening for cancer. About 20% of the participants had heard of one of the screening tests for colorectal cancer. In fact, only 290 (9.1%) participants had performed the colorectal cancer screening tests. This study provides data that will help colorectal cancer prevention and treatment programs and may enhance the efficiency of colorectal cancer-controlling programs. The findings confirm the necessity of starting colorectal screening intervention that targets the most vulnerable individuals. © The Author(s) 2014.

  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. Diet and colorectal cancer risk and survival

    NARCIS (Netherlands)

    Winkels, R.M.; Duijnhoven, van F.J.B.; Heine-Bröring, R.C.; Kampman, E.

    2013-01-01

    Unhealthy dietary and other lifestyle factors account for 20–45% of all colorectal cancer cases. Being overweight or obese, having a high intake of red and processed meat and alcohol increase the risk of colorectal cancer, while a high intake of dairy products, fruits and vegetables, foods

  10. Risk of colorectal cancer in juvenile polyposis

    NARCIS (Netherlands)

    Brosens, Lodewijk A. A.; van Hattem, Arnout; Hylind, Linda M.; Iacobuzio-Donahue, Christine; Romans, Katharine E.; Axilbund, Jennifer; Cruz-Correa, Marcia; Tersmette, Anne C.; Offerhaus, G. Johan A.; Giardiello, Francis M.

    2007-01-01

    BACKGROUND: Juvenile polyposis (JP) is an autosomal-dominant syndrome characterised by the development of hamartomatous gastrointestinal polyps and is associated with colorectal cancer. However, the relative and absolute risk of colorectal malignancy in these patients is not known. METHODS: The

  11. Modern management of colorectal liver metastases

    African Journals Online (AJOL)

    6. Modern management of colorectal liver metastases e liver is the most frequent site of metastases from colorectal cancer. ... and the assessment of associated medical co-morbidity, meticulous appraisal of the patient's liver ... information regarding the anatomical characteristics of the metastatic lesions and their relation to ...

  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. 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.

  14. Serum Trimethylamine N-oxide, Carnitine, Choline, and Betaine in Relation to Colorectal Cancer Risk in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study.

    Science.gov (United States)

    Guertin, Kristin A; Li, Xinmin S; Graubard, Barry I; Albanes, Demetrius; Weinstein, Stephanie J; Goedert, James J; Wang, Zeneng; Hazen, Stanley L; Sinha, Rashmi

    2017-06-01

    Background: Trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and its biomarker precursors have not been adequately evaluated in relation to colorectal cancer risk. Methods: We investigated the relationship between serum concentrations of TMAO and its biomarker precursors (choline, carnitine, and betaine) and incident colorectal cancer risk in a nested case-control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We measured biomarker concentrations in baseline fasting serum samples from 644 incident colorectal cancer cases and 644 controls using LC/MS-MS. Logistic regression models estimated the ORs and 95% confidence interval (CI) for colorectal cancer by quartile (Q) of serum TMAO, choline, carnitine, and betaine concentrations. Results: Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing (median ± IQR) 14 ± 10 years (in fully adjusted models, Q4 vs. Q1, OR, 3.22; 95% CI, 2.24-4.61; P trend colorectal cancer was similarly robust for proximal, distal, and rectal colon cancers (all P colorectal cancer risk was not statistically significant ( P = 0.25, 0.71, and 0.61, respectively). Conclusions: Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer. Impact: Serum choline levels showed strong prognostic value for prediction of incident colorectal cancer risk across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis. Cancer Epidemiol Biomarkers Prev; 26(6); 945-52. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. 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)

  16. Estrogen and colorectal cancer incidence and mortality.

    Science.gov (United States)

    Lavasani, Sayeh; Chlebowski, Rowan T; Prentice, Ross L; Kato, Ikuko; Wactawski-Wende, Jean; Johnson, Karen C; Young, Alicia; Rodabough, Rebecca; Hubbell, F Allan; Mahinbakht, Ali; Simon, Michael S

    2015-09-15

    The preponderance of observational studies describe an association between the use of estrogen alone and a lower incidence of colorectal cancer. In contrast, no difference in the incidence of colorectal cancer was seen in the Women's Health Initiative (WHI) randomized, placebo-controlled trial with estrogen alone after a mean intervention of 7.1 years and cumulative follow-up of 13.2 years. This study extends these findings by providing detailed analyses of the effects of estrogen alone on the histology, grade, and stage of colorectal cancer, relevant subgroups, and deaths from and after colorectal cancer. The WHI study was a randomized, double-blind, placebo-controlled trial involving 10,739 postmenopausal women with prior hysterectomy. Participants were assigned to conjugated equine estrogen at 0.625 mg/d (n = 5279) or a matching placebo (n = 5409). Rates of colorectal cancer diagnoses and deaths from and after colorectal cancer were assessed throughout the study. Colorectal cancer rates in the estrogen-alone and placebo groups were comparable: 0.14% and 0.12% per year, respectively (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.83-1.58; P = .43). Bowel screening examinations were comparable between the 2 groups throughout the study. The grade, stage, and location of colorectal cancer did not differ between the randomization groups. There were more colorectal cancer deaths in the estrogen-alone group (34 [0.05%] vs 24 [0.03%]; HR, 1.46, 95% CI, 0.86-2.46; P = .16), but the difference was not statistically significant. The colorectal cancer incidence was higher for participants with a history of colon polyp removal in the estrogen-alone group (0.23% vs 0.02%; HR, 13.47; nominal 95% CI, 1.76-103.0; P colorectal cancer or deaths from or after colorectal cancer. A possibly higher risk of colorectal cancer in women with prior colon polyp removal who use estrogen alone requires confirmation. © 2015 American Cancer Society.

  17. 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.

  18. Preoperative hypoxyradiotherapy of colorectal carcinoma

    International Nuclear Information System (INIS)

    Tacev, T.; Skricka, T.; Zaloudik, J.; Pacovsky, Z.

    2002-01-01

    Aim: The article focuses on the radioprotective effect of acute hypoxia on healthy tissues during preoperative accelerated hypoxyradiotherapy of colorectal carcinoma performed as locoregional irradiation including the common iliac lymph nodes. Analysis of early and late side effects and complications. Patients and Methods: In this prospective study, early and late complications were assessed in 50 patients as a function of hypoxyradiotherapeutic dose increase. The preliminary treatment results of this radiotherapeutic modification were evaluated after a median follow-up of 48 months using Kaplan-Meier analysis. Between April 1991 and February 1997, 50 patients (36 men and 14 women) with colorectal carcinoma were treated preoperatively with locoregional accelerated hypofractionated hypoxyradiotherapy. The extent of disease was classified according to Dukes' criteria (A: four patients, B: 28 patients, C: 18 patients). We used a 20-MeV linear accelerator with two parallel opposed fields. Hypoxyradiotherapy was performed extending from the perineum to the L4 region. Acute hypoxia was induced during irradiation by ventilation of a hypoxic gas mixture containing 7.8-8.0% oxygen. Total doses of 24 Gy/8 days, 28 Gy/9 days, and 32 Gy/10 days were applied in five, 20, and 25 patients, respectively. Low anterior resection or abdominoperineal amputation of the rectum was performed the day after completion of preoperative hypoxyradiotherapy. The early reactions after irradiation were evaluated according to the Common Toxicity Criteria of the National Cancer Institute (CTC-NCI). Results: Early postirradiation proctitis was documented in three and early radiation-induced cystitis in two patients only. Neither early nor late radiation-associated complications were observed in any of the three hypoxyradiotherapy schedules during the follow-uper period of 6-105 months. Based on Kaplan-Meier analysis (median 48 months), a 5-year overall survival rate of 61.5% and a local relapse

  19. Red meat and colorectal cancer

    Directory of Open Access Journals (Sweden)

    Nuri Faruk Aykan

    2015-12-01

    Full Text Available Colorectal cancer (CRC is the third most common cancer in men and the second in women worldwide. More than half of cases occur in more developed countries. The consumption of red meat (beef, pork, lamb, veal, mutton is high in developed countries and accumulated evidence until today demonstrated a convincing association between the intake of red meat and especially processed meat and CRC risk. In this review, meta-analyses of prospective epidemiological studies addressed to this association, observed link of some subtypes of red meat with CRC risk, potential carcinogenic compounds, their mechanisms and actual recommendations of international guidelines are presented.

  20. Chronic Inflammation in Colorectal Carcinogenesis: Role of Inflammatory Mediators, Intestinal Microbes, and Chemoprevention Potency

    OpenAIRE

    Tedja, Irwin; Abdullah, Murdani

    2013-01-01

    Colorectal carcinogenesis is a multi-factorial process which involves accumulation of genetic defect, protein modification, and cell interaction with matrix in colonic epithelial cells. Chronic inflammation is suspected to play role in carcinogenesis by inhibiting apoptosis, impairing DNA, and chronically stimulating mucosal proliferation. Alteration in intestinal microbes' population, either in one particular species or in overall composition, may also cause chronic inflammation which increa...

  1. 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...

  2. 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.

  3. Colorectal Cancer Metastasis to the Thymus Gland: Rare Presentation of Colorectal Cancer as Anterior Mediastinal Mass

    OpenAIRE

    Peters, H. Charles; Liu, Xiuli; Iqbal, Atif; Cunningham, Lisa A.; Tan, Sanda A.

    2017-01-01

    Despite improved screening modalities, 15–25% of newly diagnosed colorectal cancers are metastatic at the time of diagnosis. The vast majority of these cases present as hepatic metastasis; however, 22% present with concomitant extrahepatic disease. The thymus gland is an uncommon site of metastasis for any primary malignancy, particularly, colorectal cancer given its vascular and lymphatic drainage. This case report details our experience with a rare case of colorectal cancer metastasis to th...

  4. Colorectal Cancer Metastasis to the Thymus Gland: Rare Presentation of Colorectal Cancer as Anterior Mediastinal Mass.

    Science.gov (United States)

    Peters, H Charles; Liu, Xiuli; Iqbal, Atif; Cunningham, Lisa A; Tan, Sanda A

    2017-01-01

    Despite improved screening modalities, 15-25% of newly diagnosed colorectal cancers are metastatic at the time of diagnosis. The vast majority of these cases present as hepatic metastasis; however, 22% present with concomitant extrahepatic disease. The thymus gland is an uncommon site of metastasis for any primary malignancy, particularly, colorectal cancer given its vascular and lymphatic drainage. This case report details our experience with a rare case of colorectal cancer metastasis to the thymus gland presenting as a symptomatic mediastinal mass.

  5. [PREVENTION AND EARLY DETECTION OF COLORECTAL CANCER].

    Science.gov (United States)

    Marković, B Bergman

    2015-11-01

    Colorectal cancer is a global problem worldwide because of its very high prevalence and mortality. Therefore, prevention of colorectal cancer and its early diagnosis is of great importance. In Croatia, the National Program for Colorectal Cancer has been carried out since 2007; however, the rate of response was about 18 percent, depending on the region. Such a great public health and social and economic problem requires multidisciplinary approach in which family physicians have an important role. The well spread and developed network of primary health care and the availability of family physicians to each inhabitant have not been sufficiently exploited, especially for such preventive activities where family physicians could supervise program implementation.

  6. [Colorectal cancer in the elderly].

    Science.gov (United States)

    Hoch, J; Bláha, M; Malúšková, D

    2016-01-01

    High incidence of colorectal cancer in the Czech Republic is an actual and demographically significant health issue. Half of all of the patients is older than 70 years. Both surgical and non-surgical treatment options in this group of patients depend on factors that are difficult to measure only by current oncological and anesthesiological classifications (cTcNcM, ASA). The objective of this paper is to measure the impact of age on the use of various treatment modalities within the protocol and their results, and also to suggest alternative options for therapy tolerance assessment. Analysis of data over a five-year period from the NOR database prepared by the Institute of Biostatistics and Analyses, Masaryk University. In all parameters a difference was demonstrated between patients below the age of 70 and those above the age of 70 years. Older patients were disadvantaged. Only 11.2% of patients younger than 70 years were not treated, whereas 25.2% over the age of 70 years were not treated. A complex geriatric examination could improve the indication process in various treatment modalities, including surgery. colorectal cancer - elderly - treatment - geriatric assesment.

  7. 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.

  8. Immunohistochemistry expression of TCF4 protein on carcinoma, adenoma and non neoplastic colorectal mucosa

    OpenAIRE

    Tauil, Leonardo Huber; Mader, Ana Maria Amaral; Tauil, Thamires Huber; Pires, Andrea; Rezende, Lidia Maria Magalhães; Waisberg, Jaques

    2014-01-01

    PURPOSE: To detect and quantify the immunoreactivity of TCF4 protein in colorectal carcinoma, colorectal adenoma and non-neoplasic colorectal epithelium.METHODS: We studied 129 individuals: 40 with colorectal cancer, 52 with colorectal adenoma and 37 with non-neoplastic colorectal epithelium. The colorectal adenoma and carcinoma samples were obtained from patients who underwent surgical procedures, and colonoscopies and samples of non-neoplastic colorectal epithelium were taken from patients ...

  9. 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...

  10. 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...

  11. 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

    = 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......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...

  12. 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

  13. A comprehensive review of 5-fluorouracil and leucovorin in patients with metastatic colorectal carcinoma.

    Science.gov (United States)

    Machover, D

    1997-10-01

    Colorectal carcinoma is the third leading cause of cancer-related death. The primary treatment for patients with metastatic colorectal carcinoma is systemic chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV), a biomodulator of 5-FU that has been shown to enhance its activity. Optimal dosing and administration strategies remain to be determined. This article is a review of recent studies reporting on the use of high dose and low dose LV as a biomodulator of 5-FU in patients with advanced colorectal carcinoma. Studies of LV plus 5-FU demonstrated response rates of 7-58% in patients who had not received prior chemotherapy. A survival advantage was recorded in some trials. LV plus 5-FU produces mild and transient hematologic toxicity. The most common toxicities from LV plus 5-FU were gastrointestinal and schedule-dependent, but generally resolved within a few days. The combination of LV and 5-FU provides a favorable treatment regimen for patients with metastatic colorectal carcinoma. Growing evidence suggests that altering the dose and schedule of both LV and 5-FU can impact positively on the response rate. However, controversy remains regarding the optimal dosing regimen. Therefore, continued study of LV plus 5-FU is urged and a favorable impact on survival is requisite before definitive conclusions are drawn, particularly in relation to LV dosage.

  14. Treatment options for metastatic colorectal cancer in patients with liver dysfunction due to malignancy.

    Science.gov (United States)

    Faugeras, L; Dili, A; Druez, A; Krug, B; Decoster, C; D'Hondt, L

    2017-07-01

    The survival of colorectal cancer patients is frequently determined by the extent of metastatic invasion to the liver; in cases of major involvement, therapeutic strategies are limited because the liver is necessary for drug metabolism. We have reviewed articles about the pharmacokinetic profiles of each drug used in colorectal cancer patients with hepatic dysfunction to determine which of these treatments are most feasible. Some drugs appear to be feasible options for patients with hepatic insufficiency. Agents such as 5-fluorouracil and oxaliplatin, as well as monoclonal antibodies such as bevacizumab, cetuximab, and panitumumab, can potentially be used in these cases. On the other hand, irinotecan and regorafenib cannot be recommended because of the risk of increased toxicity. Treatment of patients with colorectal cancer and liver dysfunction represents a major challenge because the prognosis is usually very poor and alteration of liver function is normally an exclusion criterion in clinical trials. In this review, we present evidence regarding the use of each drug in patients with colorectal cancer and hepatic impairment. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  15. 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.

  16. Plant sterol intakes and colorectal cancer risk in the Netherlands Cohort Study on Diet and Cancer.

    Science.gov (United States)

    Normén, A L; Brants, H A; Voorrips, L E; Andersson, H A; van den Brandt, P A; Goldbohm, R A

    2001-07-01

    Plant sterols in vegetable foods might prevent colorectal cancer. The objective was to study plant sterol intakes in relation to colorectal cancer risk in an epidemiologic study. The study was performed within the framework of the Netherlands Cohort Study on Diet and Cancer in 120852 subjects who completed a baseline questionnaire in 1986. After 6.3 y of follow-up, 620 colon and 344 rectal cancer cases were detected. A case-cohort approach was used to calculate confounder-adjusted rate ratios (RRs) and their 95% CIs for quintiles of plant sterol intake. The total mean (+/-SD) intake of campesterol, stigmasterol, beta-sitosterol, campestanol, and beta-sitostanol was 285 +/- 97 mg/d. Major contributors to plant sterol intake were bread (38%), vegetable fats (26%), and fruit and vegetables (21%). For men, there was no clear association between intake of any of the plant sterols and colon cancer risk when age, smoking, alcohol use, family history of colorectal cancer, education level, and cholecystectomy were controlled for. Adjustment for energy did not alter the result. For rectal cancer, adjustment for energy resulted in positive associations between risk and campesterol and stigmasterol intakes. For women, there was no clear association between intake of any of the plant sterols and colorectal cancer risk. A high dietary intake of plant sterols was not associated with a lower risk of colon and rectal cancers in the Netherlands Cohort Study on Diet and Cancer.

  17. MicroRNAs in the etiology of colorectal cancer: pathways and clinical implications

    Directory of Open Access Journals (Sweden)

    Ashlee M. Strubberg

    2017-03-01

    Full Text Available MicroRNAs (miRNAs are small single-stranded RNAs that repress mRNA translation and trigger mRNA degradation. Of the ∼1900 miRNA-encoding genes present in the human genome, ∼250 miRNAs are reported to have changes in abundance or altered functions in colorectal cancer. Thousands of studies have documented aberrant miRNA levels in colorectal cancer, with some miRNAs reported to actively regulate tumorigenesis. A recurrent phenomenon with miRNAs is their frequent participation in feedback loops, which probably serve to reinforce or magnify biological outcomes to manifest a particular cellular phenotype. Here, we review the roles of oncogenic miRNAs (oncomiRs, tumor suppressive miRNAs (anti-oncomiRs and miRNA regulators in colorectal cancer. Given their stability in patient-derived samples and ease of detection with standard and novel techniques, we also discuss the potential use of miRNAs as biomarkers in the diagnosis of colorectal cancer and as prognostic indicators of this disease. MiRNAs also represent attractive candidates for targeted therapies because their function can be manipulated through the use of synthetic antagonists and miRNA mimics.

  18. 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

  19. 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.

  20. 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

  1. Cost Analysis for Therapy of Colorectal Cancer

    OpenAIRE

    Kocábková, Eliška

    2011-01-01

    The aim of thesis is to identify and quantify the cost for therapy of colorectal cancer. The aim is to quantify the cost of individual treatments normally used in different stages of the disease and the total cost of treatment.

  2. Genetic risk factors in colorectal cancer.

    Science.gov (United States)

    Bonaïti-Pellié, C

    1999-12-01

    Familial risk factors are known to play an important role in colorectal cancer (CRC) risk, particularly when the relatives are affected by early-onset cancer. Part of this familial aggregation can be accounted for by inherited forms of colorectal cancer, i.e. familial adenomatous polyposis (less than 1% of all CRC) and hereditary nonpolyposis colorectal cancer (about 3%). Other genetic factors may be involved in the development of adenoma or in the transformation of adenoma into carcinoma. That the existence of polymorphisms of the adenomatous polyposis coli gene increase susceptibility to both adenomas and cancer favours this hypothesis. Interactions between environmental factors, and most of all dietary factors, and polymorphisms of carcinogen-metabolizing enzymes may also be involved. Better knowledge of these mechanisms will substantially widen the scope of colorectal cancer prevention.

  3. Automated spectroscopic tissue classification in colorectal surgery

    NARCIS (Netherlands)

    Schols, R.M.; Alic, L.; Beets, G.L.; Breukink, S.O.; Wieringa, F.P.; Stassen, L.P.S.

    2015-01-01

    In colorectal surgery, detecting ureters and mesenteric arteries is of utmost importance to prevent iatrogenic injury and to facilitate intraoperative decision making. A tool enabling ureter- and artery-specific image enhancement within (and possibly through) surrounding adipose tissue would

  4. [Guidelines for enhanced recovery after elective colorectal surgery].

    Science.gov (United States)

    Alfonsi, P; Slim, K; Chauvin, M; Mariani, P; Faucheron, J-L; Fletcher, D

    2014-05-01

    Early recovery after surgery provides patients with all means to counteract or minimize the deleterious effects of surgery. This concept is suitable for a surgical procedure (e.g., colorectal surgery) and comes in the form of a clinical pathway that covers three periods (pre-, intra- and postoperative). The purpose of this Expert panel guideline is firstly to assess the impact of each parameter usually included in the rehabilitation programs on 6 foreseeable consequences of colorectal surgery: surgical stress, postoperative ileus, water and energy imbalance, postoperative immobility, sleep alterations and postoperative complications; secondly, to validate the usefulness of each as criteria of efficiency criteria for success of rehabilitation programs. Two main criteria were selected to evaluate the impact of each parameter: the length of stay and frequency of postoperative complications. Lack of information in the literature forced experts to assess some parameters with criteria (duration of postoperative ileus or quality of analgesia) that mainly surrogate a positive impact for the implementation of an early recovery program. After literature analysis, 19 parameters were identified as potentially interfering with at least one of the foreseeable consequences of colorectal surgery. GRADE® methodology was applied to determine a level of evidence and strength of recommendation. After synthesis of the work of experts using GRADE® method on 19 parameters, 35 recommendations were produced by the organizing committee. The recommendations were submitted and amended by a group of reviewers. After three rounds of Delphi quotes, strong agreement was obtained for 28 recommendations (80%) and weak agreement for seven recommendations. A consensus was reached among anesthesiologists and surgeons on a number of approaches that are likely not sufficiently applied for rehabilitation programs in colorectal surgery such as: preoperative intake of carbohydrates; intraoperative

  5. 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

  6. 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....

  7. 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...

  8. 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...

  9. Television watching and risk of colorectal adenoma

    OpenAIRE

    Cao, Y; Keum, N N; Chan, A T; Fuchs, C S; Wu, K; Giovannucci, E L

    2015-01-01

    Background: Prolonged TV watching, a major sedentary behaviour, is associated with increased risk of obesity and diabetes and may involve in colorectal carcinogenesis. Methods: We conducted a cross-sectional analysis among 31?065 men with ?1 endoscopy in the Health Professionals Follow-up Study (1988?2008) to evaluate sitting while watching TV and its joint influence with leisure-time physical activity on risk of colorectal adenoma. Logistic regression was used to calculate odds ratios (ORs) ...

  10. 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.

  11. 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.

  12. Association of mitochondrial copy number variation and T16189C polymorphism with colorectal cancer in North Indian population.

    Science.gov (United States)

    Kumar, Bhupender; Bhat, Zafar Iqbal; Bansal, Savita; Saini, Sunil; Naseem, Afreen; Wahabi, Khushnuma; Burman, Archana; Kumar, Geeta Trilok; Saluja, Sundeep Singh; Rizvi, M Moshahid Alam

    2017-11-01

    Globally, colorectal cancer is the third most common type of cancer. Genetic instability leading to cancer development is one of the major causes for development of cancer. Alterations in mitochondrial genome, that is, mutations, single-nucleotide polymorphisms, and copy number variations are known to contribute in cancer development. The aim of our study was to investigate association of mitochondrial T16189C polymorphism and copy number variation with colorectal cancer in North Indian population. DNA isolated from peripheral blood of 126 colorectal cancer patients and 114 healthy North Indian subjects was analyzed for T16189C polymorphism and half of them for mitochondrial copy number variation. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism, and copy number variation was estimated using real-time polymerase chain reaction, numbers of mitochondrial copies and found to be significantly higher in colorectal cancer patients than healthy controls (88 (58-154), p = 0.001). In the regression analysis, increased mitochondrial copy number variation was associated with risk of colorectal cancer (odds ratio = 2.885, 95% confidence interval = 1.3-6.358). However, T16189C polymorphism was found to be significantly associated with the risk of rectal cancer (odds ratio = 5.213, p = 0.001) and non-significantly with colon cancer (odds ratio = 0.867, p = 0.791). Also, false-positive report probability analysis was done to validate the significant findings. Our results here indicate that mitochondrial copy number variation may be playing an important role in the development of colorectal cancer, and detection of mitochondrial copy number variation can be used as a biomarker for predicting the risk of colorectal cancer in North Indian subjects.

  13. 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

  14. Clinical and molecular analysis of hereditary non-polyposis colorectal cancer in Chinese colorectal cancer patients

    OpenAIRE

    Wang, Jun; Luo, Mao-Hong; Zhang, Zuo-Xing; Zhang, Pei-Da; Jiang, Xi-Li; Ma, Dong-Wang; Suo, Rong-Zeng; Zhao, Li-Zhong; Qi, Qing-Hui

    2007-01-01

    AIM: To analyze the frequency of hereditary non-polyposis colorectal cancer (HNPCC) in Chinese colorectal cancer (CRC) patients, and to discuss the value of microsatellite instability (MSI) and/or immunohistochemistry (IHC) for MSH2/MLH1 protein analysis as pre-screening tests in China.

  15. Survival of MUTYH-associated polyposis patients with colorectal cancer and matched control colorectal cancer patients

    NARCIS (Netherlands)

    M. Nielsen (Maartje); L.N. van Steenbergen (Liza); N. Jones (Natalie); S. Vogt (Stefanie); H.F. Vasen (Hans); H. Morreau (Hans); S. Aretz (Stefan); J. Sampson (Julian); O.M. Dekkers (Olaf); M.L.G. Janssen-Heijnen (Maryska); F.J. Hes (Frederik)

    2010-01-01

    textabstractBackground MUTYH-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular genetic features of MUTYH-associated polyposis colorectal cancers might influence tumor behavior

  16. Seromic profiling of colorectal cancer patients with novel glycopeptide microarray

    DEFF Research Database (Denmark)

    Pedersen, Johannes W; Blixt, Ola; Bennett, Eric P

    2011-01-01

    array displaying a comprehensive library of glycopeptides and glycoproteins derived from a panel of human mucins (MUC1, MUC2, MUC4, MUC5AC, MUC6 and MUC7) known to have altered glycosylation and expression in cancer. Seromic profiling of patients with colorectal cancer identified cancer......Cancer-associated autoantibodies hold promise as sensitive biomarkers for early detection of cancer. Aberrant post-translational variants of proteins are likely to induce autoantibodies, and changes in O-linked glycosylation represent one of the most important cancer-associated post......-associated autoantibodies to a set of aberrant glycopeptides derived from MUC1 and MUC4. The cumulative sensitivity of the array analysis was 79% with a specificity of 92%. The most prevalent of the identified autoantibody targets were validated as authentic cancer immunogens by showing expression of the epitopes in cancer...

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. Colorectal (Colon) Cancer: Questions to Ask Your Doctor

    Science.gov (United States)

    ... The CDC Cancel Submit Search The CDC Colorectal (Colon) Cancer Note: Javascript is disabled or is not supported ... Cancer Home Questions to Ask Your Doctor About Colorectal Cancer Language: English Español (Spanish) Recommend on Facebook Tweet ...

  3. Cost considerations in the treatment of colorectal cancer

    NARCIS (Netherlands)

    Jansman, F.G.A.; Postma, M.J.; Brouwers, J.R.B.J.

    2007-01-01

    Colorectal cancer is among the most common malignancies in developed countries. Screening can reduce mortality significantly, although the most appropriate method is still under debate. Observational studies have revealed that lifestyle measures may also be beneficial for prevention of colorectal

  4. 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 ...

  5. Pathological and biological aspects of colorectal cancer treatment

    NARCIS (Netherlands)

    Gosens, Marleen Johanna Elisabeth Maria

    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

  6. 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

  7. Symptom appraisal and healthcare-seeking for symptoms suggestive of colorectal cancer: a qualitative study.

    Science.gov (United States)

    Hall, N; Birt, L; Banks, J; Emery, J; Mills, K; Johnson, M; Rubin, G P; Hamilton, W; Walter, F M

    2015-10-09

    Timely diagnosis of colorectal cancer is important to improve survival. This study explored symptom appraisal and help-seeking among patients referred to specialist services with symptoms of colorectal cancer. Qualitative in-depth interview study. Participants were recruited on referral to gastroenterology clinics (North East and East of England); interviews were conducted soon after referral. We purposively sampled participants to ensure a range of accounts in terms of age, sex, diagnosis and geographical location. Data collection and analysis were underpinned by the Model of Pathways to Treatment. Framework analysis was used to explore the data within and across cases, focusing on patient beliefs and experiences, disease factors and healthcare influences. 40 participants were interviewed (aged 43-87 years, 17 women, 18 diagnosed with colorectal cancer). Patients diagnosed with and without colorectal cancer had similar symptom pathways. We found a range of interacting and often competing biopsychosocial, contextual and cultural influences on the way in which people recognised, interpreted and acted on their symptoms. People attempted to 'maintain normality' through finding benign explanations for their symptoms. Bodily changes were appraised within the context of usual bowel patterns, comorbidities and life events, and decisions to seek help were made in relation to expectations about the course of symptoms. The 'private nature' of colorectal cancer symptoms could affect both their identification and discussions with others including healthcare professionals. Within the context of the National Health Service, people needed to legitimise appropriate use of healthcare services and avoid being thought of as wasting doctors' time. Findings provide guidance for awareness campaigns on reducing stigma around appraising and discussing bowel movements, and the importance of intermittent and non-specific symptoms. Altering perceptions about the appropriate use of health

  8. Reduced 30-Day Mortality After Laparoscopic Colorectal Cancer Surgery: A Population Based Study From the Dutch Surgical Colorectal Audit (DSCA)

    NARCIS (Netherlands)

    Gietelink, Lieke; Wouters, Michel W. J. M.; Bemelman, Willem A.; Dekker, Jan Willem; Tollenaar, Rob A. E. M.; Tanis, Pieter J.

    2016-01-01

    To evaluate the impact of a laparoscopic resection on postoperative mortality after colorectal cancer surgery. The question whether laparoscopic resection (LR) compared with open surgery [open resection (OR)] for colorectal cancer influences the risk of postoperative mortality remains unresolved.

  9. 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

  10. 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 ...

  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. Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency

    DEFF Research Database (Denmark)

    Jensen, Lars Henrik; Lindebjerg, J; Byriel, L

    2007-01-01

    nonpolyposis colon cancer or Lynch syndrome), but most are epigenetic changes of sporadic origin. The aim of this study was to define a robust and inexpensive strategy for such classification in clinical practice. Method Tumours and blood samples from 262 successive patients with colorectal adenocarcinomas......Objective Deficiency of DNA mismatch repair (MMR) causes microsatellite instability (MSI) in a subset of colorectal cancers. Patients with these tumours have a better prognosis and may have an altered response to chemotherapy. Some of the tumours are caused by hereditary mutations (hereditary...... of molecular characteristics we found 223 patients with intact MMR, 35 patients with sporadic MMR deficiency, and four patients who were likely to have hereditary MMR deficiency. Conclusion To obtain the maximal benefit for patients and clinicians, MMR testing should be supplemented with MLH1 methylation...

  13. 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.

  14. Calcium remodeling in colorectal cancer.

    Science.gov (United States)

    Villalobos, Carlos; Sobradillo, Diego; Hernández-Morales, Miriam; Núñez, Lucía

    2017-06-01

    Colorectal cancer (CRC) is the third most frequent form of cancer and the fourth leading cause of cancer-related death in the world. Basic and clinical data indicate that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may prevent colon cancer but mechanisms remain unknown. Aspirin metabolite salicylate and other NSAIDs may inhibit tumor cell growth acting on store-operated Ca 2+ entry (SOCE), suggesting an important role for this pathway in CRC. Consistently, SOCE is emerging as a novel player in different forms of cancer, including CRC. SOCE and store-operated currents (SOCs) are dramatically enhanced in CRC while Ca 2+ stores are partially empty in CRC cells. These features may contribute to CRC hallmarks including enhanced cell proliferation, migration, invasion and survival. At the molecular level, enhanced SOCE and depleted stores are mediated by overexpression of Orai1, Stromal interaction protein 1 (STIM1) and Transient receptor protein channel 1 (TRPC1) and downregulation of STIM2. In normal colonic cells, SOCE is mediated by Ca 2+ -release activated Ca 2+ channels made of STIM1, STIM2 and Orai1. In CRC cells, SOCE is mediated by different store-operated currents (SOCs) driven by STIM1, Orai1 and TRPC1. Loss of STIM2 contributes to depletion of Ca 2+ stores and enhanced resistance to cell death in CRC cells. Thus, SOCE is a novel key player in CRC and inhibition by salicylate and other NSAIDs may contribute to explain chemoprevention activity. Colorectal cancer (CRC) is the third most frequent form of cancer worldwide. Recent evidence suggests that intracellular Ca 2+ remodeling may contribute to cancer hallmarks. In addition, aspirin and other NSAIDs might prevent CRC acting on remodeled Ca 2+ entry pathways. In this review, we will briefly describe 1) the players involved in intracellular Ca 2+ homeostasis with a particular emphasis on the mechanisms involved in SOCE activation and inactivation, 2) the evidence that aspirin metabolite

  15. Prevalence of colorectal polyps in pediatric colonoscopy.

    Science.gov (United States)

    Thakkar, Kalpesh; Alsarraj, Abeer; Fong, Emily; Holub, Jennifer L; Gilger, Mark A; El Serag, Hashem B

    2012-04-01

    The available data regarding the prevalence, types, and clinical determinants of colonic polyps in children is limited. We aimed to estimate the prevalence of colorectal polyps in a large cohort of children. We conducted a cross-sectional study to determine the presence, number, and location of colorectal polyps reported in all children (0-20 years) who underwent colonoscopy at 14 pediatric facilities between January 2000 and December 2007 recorded in Pediatric Endoscopy Database System Clinical Outcomes Research Initiative (PEDS-CORI). We compared procedures with and without polyps with respect to procedure indication, age, sex, and race. We also reviewed a sample of histopathologic reports from one participating center. We analyzed 13,115 colonoscopy procedures performed in 11,637 patients. Colorectal polyps were reported in 810 procedures (6.1%; 95% CI: 5.7-6.5%) performed in 705 patients, and in 12% of patients with lower GI bleeding. Children with colorectal polyps were significantly younger (8.9 years vs. 11.9 years; p children without polyps. In a sample of 122 patients with polyps from a single center, the histological types were solitary juvenile in 91 (70.5%), multiple juvenile in 20 (15.5%), adenoma in 14 (10.9%) and hyperplastic polyps in four patients (3.1%). Colorectal polyps are detected in 6.1% overall and in 12.0% among those with lower gastrointestinal bleeding during pediatric colonoscopy. Approximately 26% are multiple juvenile or adenoma.

  16. [Screening and prevention of colorectal cancer].

    Science.gov (United States)

    Faivre, Jean; Manfredi, Sylvain

    2015-06-01

    Population-based studies have shown that guaiac faecal occult blood testing followed by colonoscopy in case of positivity can reduce colorectal cancer mortality. However attention has been given for alternative tests in particular to immunochemical faecal occult blood tests. It is now clear from available data that immunochemical tests outperform guaiac tests. They should be preferred for CRC screening. The one sample strategy has been adopted in most screening programmes. Given the superior performance characteristics of immunochemical, it is reasonable to assume that an organized programme using this type of test would lead to a greater reduction in colorectal cancer mortality and possibly of colorectal cancer incidence. Epidemiological studies allow us to define subjects at very high risk (genetic origin) and high risk for colorectal cancer. Colonoscopy screening is recommended in first degree relatives of patients with colorectal cancer or large adenoma diagnosed before 60 years or with two affected first-degree relatives, in subjects with an extended inflammatory bowel disease, or with a personal history of large bowel cancer or large adenoma.

  17. Genetic Variants Associated with Colorectal Adenoma Susceptibility.

    Directory of Open Access Journals (Sweden)

    Anna Abulí

    Full Text Available Common low-penetrance genetic variants have been consistently associated with colorectal cancer risk.To determine if these genetic variants are associated also with adenoma susceptibility and may improve selection of patients with increased risk for advanced adenomas and/or multiplicity (≥ 3 adenomas.We selected 1,326 patients with increased risk for advanced adenomas and/or multiplicity and 1,252 controls with normal colonoscopy from population-based colorectal cancer screening programs. We conducted a case-control association study analyzing 30 colorectal cancer susceptibility variants in order to investigate the contribution of these variants to the development of subsequent advanced neoplasia and/or multiplicity.We found that 14 of the analyzed genetic variants showed a statistically significant association with advanced adenomas and/or multiplicity: the probability of developing these lesions increased with the number of risk alleles reaching a 2.3-fold risk increment in individuals with ≥ 17 risk alleles.Nearly half of the genetic variants associated with colorectal cancer risk are also related to advanced adenoma and/or multiplicity predisposition. Assessing the number of risk alleles in individuals within colorectal cancer screening programs may help to identify better a subgroup with increased risk for advanced neoplasia and/or multiplicity in the general population.

  18. Worldwide burden of colorectal cancer: a review.

    Science.gov (United States)

    Favoriti, Pasqualino; Carbone, Gabriele; Greco, Marco; Pirozzi, Felice; Pirozzi, Raffaele Emmanuele Maria; Corcione, Francesco

    2016-03-01

    Colorectal cancer is a major public health problem, being the third most commonly diagnosed cancer and the fourth cause of cancer death worldwide. There is wide variation over time among the different geographic areas due to variable exposure to risk factors, introduction and uptake of screening as well as access to appropriate treatment services. Indeed, a large proportion of the disparities may be attributed to socioeconomic status. Although colorectal cancer continues to be a disease of the developed world, incidence rates have been rising in developing countries. Moreover, the global burden is expected to further increase due to the growth and aging of the population and because of the adoption of westernized behaviors and lifestyle. Colorectal cancer screening has been proven to greatly reduce mortality rates that have declined in many longstanding as well as newly economically developed countries. Statistics on colorectal cancer occurrence are essential to develop targeted strategies that could alleviate the burden of the disease. The aim of this paper is to provide a review of incidence, mortality and survival rates for colorectal cancer as well as their geographic variations and temporal trends.

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. Abnormal Fhit protein expression and high frequency of microsatellite instability in sporadic colorectal cancer.

    Science.gov (United States)

    Sarli, Leopoldo; Bottarelli, Lorena; Azzoni, Cinzia; Campanini, Nicoletta; Di Cola, Gabriella; Bader, Giovanni; Iusco, Domenico; Salvemini, Carlo; Caruso, Giuseppe; Donadei, Enrico; Pizzi, Silvia; D'Adda, Tiziana; Renato, Costi; Roncoroni, Luigi; Bordi, Cesare

    2004-07-01

    The role of Fhit protein in the oncogenesis of colorectal cancer is still in debate. Recent studies have revealed that reduced Fhit protein expression is associated with a deficiency of the mismatch repair protein. One hundred and twenty unselected patients who underwent curative resection for sporadic colorectal cancer in a three-year period were evaluated for microsatellite instability (MSI) using six microsatellite markers, and for the presence of Fhit and mismatch repair (MMR) proteins (Mlh1 and Msh2) by means of immunostaining. The relations between these markers were analysed. Reduced or absent Fhit expression was noted in 18 out of 118 patients. This altered expression was significantly higher in right-sided cancer (P = 0.005), mucinous tumours (P = 0.005) and in poorly differentiated histological types (P = 0.0001). MSI was found in 22 out of 109 patients, more so in right-sided cancer (P = 0.0001), poorly differentiated histology (P = 0.0001), and mucinous tumours (P = 0.0001). No association was found with TNM stage. MSI was present in 66.7% of tumours with altered Fhit expression and in only 10% of tumours with preserved or intermediate Fhit expression (P = 0.0001). Of the tumours with reduced or absent Fhit expression, 72.2% had loss of nuclear Mlh1 or Msh2 expression compared with only 14% of the preserved or intermediate Fhit expression tumours (P = 0.0001). These results support the hypothesis that deficiency in a MMR gene could be a cause of the high frequency of alterations in Fhit expression, and they permit the suggestion that FHIT gene alteration may be part of the genetic pathway involving MSI through which some colorectal cancers arise.

  4. Glucose transporter expression in the human colon.

    Science.gov (United States)

    Merigo, Flavia; Brandolese, Alessandro; Facchin, Sonia; Missaggia, Silvia; Bernardi, Paolo; Boschi, Federico; D'Incà, Renata; Savarino, Edoardo Vincenzo; Sbarbati, Andrea; Sturniolo, Giacomo Carlo

    2018-02-21

    To investigate by immunostaining glucose transporter expression in human colorectal mucosa in controls and patients with inflammatory bowel disease (IBD). Colorectal samples were obtained from patients undergoing lower endoscopic colonoscopy or recto-sigmoidoscopy. Patients diagnosed with ulcerative colitis ( n = 18) or Crohn's disease ( n = 10) and scheduled for diagnostic colonoscopy were enrolled. Patients who underwent colonoscopy for prevention screening of colorectal cancer or were followed-up after polypectomy or had a history of lower gastrointestinal symptoms were designated as the control group (CTRL, n = 16). Inflammatory status of the mucosa at the sampling site was evaluated histologically and/or endoscopically. A total of 147 biopsies of colorectal mucosa were collected and processed for immunohistochemistry analysis. The expression of GLUT2, SGLT1, and GLUT5 glucose transporters was investigated using immunoperoxidase labeling. To compare immunoreactivity of GLUT5 and LYVE-1, which is a marker for lymphatic vessel endothelium, double-labeled confocal microscopy was used. Immunohistochemical analysis revealed that GLUT2, SGLT1, and GLUT5 were expressed only in short epithelial portions of the large intestinal mucosa. No important differences were observed in glucose transporter expression between the samples obtained from the different portions of the colorectal tract and between the different patient groups. Unexpectedly, GLUT5 expression was also identified in vessels, mainly concentrated in specific areas where the vessels were clustered. Immunostaining with LYVE-1 and GLUT5 antibodies revealed that GLUT5-immunoreactive (-IR) clusters of vessels were concentrated in areas internal to those that were LYVE-1 positive. GLUT5 and LYVE-1 did not appear to be colocalized but rather showed a close topographical relationship on the endothelium. Based on their LYVE-1 expression, GLUT5-IR vessels were identified as lymphatic. Both inflamed and non

  5. Colorectal Cancer Metastasis to the Thymus Gland: Rare Presentation of Colorectal Cancer as Anterior Mediastinal Mass

    Directory of Open Access Journals (Sweden)

    H. Charles Peters

    2017-01-01

    Full Text Available Despite improved screening modalities, 15–25% of newly diagnosed colorectal cancers are metastatic at the time of diagnosis. The vast majority of these cases present as hepatic metastasis; however, 22% present with concomitant extrahepatic disease. The thymus gland is an uncommon site of metastasis for any primary malignancy, particularly, colorectal cancer given its vascular and lymphatic drainage. This case report details our experience with a rare case of colorectal cancer metastasis to the thymus gland presenting as a symptomatic mediastinal mass.

  6. Do NSAIDs Prevent Colorectal Cancer?

    Directory of Open Access Journals (Sweden)

    Nadir Arber

    2000-01-01

    Full Text Available There is increasing evidence to suggest that acetylsalicylic acid (ASA and other nonsteroidal anti-inflammatory drugs (NSAIDs reduce the risk of colorectal cancer. This observation is supported by animal studies that show fewer tumours per animal and fewer animals with tumours after administration of several different NSAIDs. Studies in humans consistently support this hypothesis. Intervention data from familial adenomatosis coli establish that the process of human colonic adenoma polyp formation is affected. Supportive evidence comes from 21 of 23 human studies -- both case-control and cohort. The reduced risk has been found in men and women, for cancers of the colon and the rectum and for the use of both ASA and the other NSAIDs. Earlier detection of lesions as a result of drug-induced bleeding does not seem to account for these findings. The molecular mechanisms responsible for the chemopreventive action of this class of drugs is not completely established. Protection may affect several pathways, including cell cycle arrest and induction of apoptosis.  Because of the consistency of epidemiological, clinical and experimental data, there is no need for further placebo trials. At the same time, there is a need to establish the dose, duration and frequency of use required for cancer-preventive activity.

  7. Colorectal cancer screening in Canada

    Energy Technology Data Exchange (ETDEWEB)

    Butler, G. [Hamilton Health Sciences Corp., Henderson Campus, Dept. of Diagnostic Imaging, Hamilton, Ontario (Canada)

    2001-02-01

    Colorectal carcinoma (CRC) is an important cause of morbidity and mortality in Canada, ranking third among all cancers. In 1998, there were 16,500 new cases and 6300 deaths from this disease. Predictions for 2000 were similar. There has been a gradual decrease in age-adjusted incidence and mortality from CRC over the last few years, but the actual number of cases is expected to increase significantly over the next decade because of changing age demographics. The regional incidence is lowest on the west coast and highest on the east coast, with Ontario and Quebec in between. In Canada, the lifetime risk of dying from CRC is 2.8%, compared with 8.1% for lung cancer in men, 4.5% for lung cancer in women, 3.6% for prostate cancer in men and 3.9% for breast cancer in women. CRC is a disease of developed, rather than developing countries, and the incidence in Canada is among the highest in the world, and higher in relative terms than in the United States. Primary prevention, including diet modification and other lifestyle influences, may have the most significant long-term effects on the problem, but earlier detection and treatment would seem to be the most advantageous medium-term objectives. An excellent review and guidelines article by Winawer and colleagues has formed the basis for an informed discussion on CRC and screening-related issues. (author)

  8. SNP rs16906252C>T Is an Expression and Methylation Quantitative Trait Locus Associated with an Increased Risk of Developing MGMT-Methylated Colorectal Cancer.

    Science.gov (United States)

    Kuroiwa-Trzmielina, Joice; Wang, Fan; Rapkins, Robert W; Ward, Robyn L; Buchanan, Daniel D; Win, Aung Ko; Clendenning, Mark; Rosty, Christophe; Southey, Melissa C; Winship, Ingrid M; Hopper, John L; Jenkins, Mark A; Olivier, Jake; Hawkins, Nicholas J; Hitchins, Megan P

    2016-12-15

    Methylation of the MGMT promoter is the major cause of O 6 -methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter enhancer SNP rs16906252C>T. We sought evidence for an association between the rs16906252C>T genotype and increased risk of developing a subtype of colorectal cancer featuring MGMT methylation, mediated by genotype-dependent epigenetic silencing within normal tissues. By applying a molecular pathologic epidemiology case-control study design, associations between rs16906252C>T and risk for colorectal cancer overall, and colorectal cancer stratified by MGMT methylation status, were estimated using multinomial logistic regression in two independent retrospective series of colorectal cancer cases and controls. The test sample comprised 1,054 colorectal cancer cases and 451 controls from Sydney, Australia. The validation sample comprised 612 colorectal cancer cases and 245 controls from the Australasian Colon Cancer Family Registry (ACCFR). To determine whether rs16906252C>T was linked to a constitutively altered epigenetic state, quantitative allelic expression and methylation analyses were performed in normal tissues. An association between rs16906252C>T and increased risk of developing MGMT-methylated colorectal cancer in the Sydney sample was observed [OR, 3.3; 95% confidence interval (CI), 2.0-5.3; P methylated in a minority of normal cells, indicating that rs16906252C>T represents an expression and methylation quantitative trait locus. We provide evidence that rs16906252C>T is associated with elevated risk for MGMT-methylated colorectal cancer, likely mediated by constitutive epigenetic repression of the T allele. Clin Cancer Res; 22(24); 6266-77. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. [The colorectal carcinoma; pathological remarks (author's transl)].

    Science.gov (United States)

    Simon, H

    1980-01-01

    A survey is presented on the incidence of colorectal carcinomas in the GDR, exogenous causes possibly being responsible for the increase in incidence, common screening methods, macro-anatomy and micro-anatomy of colorectal carcinoma, staging, prognosis, and pathways of metastases. The correlation between intestinal polypi and colorectal carcinoma as well as the frequency of their degeneration are also referred to. Adenomatous polypi (polypous adenoma), villous polypi (villous adenoma), and certain rare intestinal polypi, such as familial polyposis coli, multiple polyposis of the entire gastro-intestinal tract, as well as the Gardner- and Turcot-syndromes, are some of those polypi which depending on their size tend to malignant degeneration. Histological information provided by the pathologist is discussed in its value and importance for surgical practice.

  10. 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.

  11. 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

  12. The stability of colorectal cancer mathematical models

    Science.gov (United States)

    Khairudin, Nur Izzati; Abdullah, Farah Aini

    2013-04-01

    Colorectal cancer is one of the most common types of cancer. To better understand about the kinetics of cancer growth, mathematical models are used to provide insight into the progression of this natural process which enables physicians and oncologists to determine optimal radiation and chemotherapy schedules and develop a prognosis, both of which are indispensable for treating cancer. This thesis investigates the stability of colorectal cancer mathematical models. We found that continuous saturating feedback is the best available model of colorectal cancer growth. We also performed stability analysis. The result shows that cancer progress in sequence of genetic mutations or epigenetic which lead to a very large number of cells population until become unbounded. The cell population growth initiate and its saturating feedback is overcome when mutation changes causing the net per-capita growth rate of stem or transit cells exceed critical threshold.

  13. GYNECOLOGICAL STATUS OF PATIENTS WITH COLORECTAL CANCER

    Directory of Open Access Journals (Sweden)

    V. A. Solodky

    2015-01-01

    Full Text Available The purpose of the study was to identify risk factors for colorectal cancer on the basis of retrospective analysis of gynecological history and status of 183 patients with colon adenocarcinoma treated at the Russian X-Ray Radiology Research Center between 1996 and 2011. Evaluation of gynecological status was based on findings  of gynecological, transvaginal and ultrasound examinations of the genitals, as well as on cytological cervical screening and colposcopy. Hysteroscopy and separate diagnostic curettage were performed if necessary. Gynecological status of patients with colorectal cancer was characterized by ovarian hypofunction and high incidence of benign non-inflammatory (78.1 % and inflammatory (88.0 % disorders of genital tract. In most cases (63.9 % polyneoplasia in patients with colorectal cancer combined with breast, endometrial and ovarian cancers. Considering younger age of the onset of benign disease of the genital tract, this group of patients should be followed up carefully for the development of colon cancer.

  14. 49 CFR 195.205 - Repair, alteration and reconstruction of aboveground breakout tanks that have been in service.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 3 2010-10-01 2010-10-01 false Repair, alteration and reconstruction of... Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) PIPELINE SAFETY TRANSPORTATION OF HAZARDOUS LIQUIDS BY PIPELINE...

  15. Korean Guidelines for Colorectal Cancer Screening and Polyp Detection

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Bo In [The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of); Hong, Sung Pil [Yensei University College of Medicine, Seoul (Korea, Republic of); Kim, Seong Eun [Ewha Womans University School of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    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.

  16. How Many Diseases Are Colorectal Cancer?

    Directory of Open Access Journals (Sweden)

    A. Greystoke

    2012-01-01

    Full Text Available The development of personalised therapy and mechanism-targeted agents in oncology mandates the identification of the patient populations most likely to benefit from therapy. This paper discusses the increasing evidence as to the heterogeneity of the group of diseases called colorectal cancer. Differences in the aetiology and epidemiology of proximal and distal cancers are reflected in different clinical behaviour, histopathology, and molecular characteristics of these tumours. This may impact response both to standard cytotoxic therapies and mechanism-targeted agents. This disease heterogeneity leads to challenges in the design of clinical trials to assess novel therapies in the treatment of “colorectal cancer.”

  17. 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.

  18. An apple a day may hold colorectal cancer at bay: recent evidence from a case-control study.

    Science.gov (United States)

    Jedrychowski, Wieslaw; Maugeri, Umberto

    2009-01-01

    Environmental factors play an important role in the etiology of colorectal cancer, the second-most common malignancy in both genders in developed countries. Evidence has shown that potential cancer-inducing oxidative damage might be prevented or restricted largely by the presence of dietary antioxidants of plant origin, such as fruits or vegetables. The protective antioxidant effect of fruits and vegetables has been attributed to flavonoids, a major class of phytochemicals naturally occurring in fruits, vegetables, and various foods of plant origin. Yet, epidemiologic cohort studies relating flavonoid intake to risk of colorectal cancer have been sparse and inconclusive. Apples are a rich source of flavonoids and have the second highest level of antioxidant power among all fruits, with peels having a stronger antioxidant activity than apple flesh. A recent reanalysis of several case-control studies in Italy demonstrated a consistent inverse association between apple consumption and the risk of various cancers, and among them ofcolorectal cancer. Here we assessed the potential protective impact of apples on risk of colorectal cancer in the course of a recently performed hospital-based case-control study in a country with dietary habits very different from those of Mediterranean region. The results showed that highest risk of colorectal cancer was among older persons and those who were residents of villages or small towns. The risk of colorectal cancer was inversely correlated with daily number of apple servings, but the most significant reductions of OR estimates were observed for an intake one or more apple servings daily (OR = 0.37, 95% CI: 0.15-0.91). No other fruit was significantly associated with altering the risk of colorectal cancer.

  19. 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.

  20. 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.

  1. Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

    Science.gov (United States)

    Konda, Kenichi; Konishi, Kazuo; Yamochi, Toshiko; Ito, Yoichi M.; Nozawa, Hisako; Tojo, Masayuki; Shinmura, Kensuke; Kogo, Mari; Katagiri, Atsushi; Kubota, Yutaro; Muramoto, Takashi; Yano, Yuichiro; Kobayashi, Yoshiya; Kihara, Toshihiro; Tagawa, Teppei; Makino, Reiko; Takimoto, Masafumi; Imawari, Michio; Yoshida, Hitoshi

    2014-01-01

    Background 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). Methods 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. Results 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). Conclusion 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

  2. 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...

  3. Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus : role of lipolytic enzymes, lecithin : cholesterol acyltransferase and lipid transfer proteins

    NARCIS (Netherlands)

    Borggreve, SE; de Vries, R; Dullaart, RPF

    2003-01-01

    Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from

  4. The Epigenomics of Embryonic Pathway Signaling in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Curt Balch

    2017-05-01

    Full Text Available Colorectal cancer (CRC is the second-leading cause of cancer death in developed countries. While early detection (e.g., colonoscopy generally yields excellent outcomes, metastatic and drug-resistant disease is uniformly fatal, and non-compliance for screening remains over 25%. Familial CRCs (10% of total cases primarily include mutations in the gene APC. Somatic disease is linked to several environmental several risk factors, including mutations in WNT, KRAS, and TGFβ. To reflect the genesis/progression of CRC, a series of five discrete stages, from normal colon mucosa to fully invasive carcinoma, each regulated by specific “gatekeeper” genes, remains well-accepted after 20 years. However, many CRC tumors do not possess those particular mutations, suggesting alternative mechanisms. More recently, embryo-like “cancer stem cells” have been proposed to undergo self-renewal and drive tumorigenesis (and possibly, metastasis, as governed by specific “epigenomic” alterations. Here, we review recent literature describing possible mechanisms that underlie these phenotypes, including cancer “stemness,” believed by many to associate with the epithelial-to-mesenchymal transition (EMT. We further propose that the maintenance of undifferentiated phenotypes, by the activity of distinct transcription factors, facilitates chromatin remodeling and phenotypic plasticity. With that regard, we support recent assertions that EMT is not an “either/or” event, but rather a continuous spectrum of mesenchymal vs. epithelial phenotypes (in various degrees of aberrant differentiation/undifferentiation. Finally, we discuss possible methods of pharmacologically targeting such aberrant epigenomes, with regard to their possible relevance toward halting, or even reversing, colorectal cancer progression.

  5. ACR Appropriateness Criteria pretreatment staging of colorectal cancer.

    Science.gov (United States)

    Dewhurst, Catherine; Rosen, Max P; Blake, Michael A; Baker, Mark E; Cash, Brooks D; Fidler, Jeff L; Greene, Frederick L; Hindman, Nicole M; Jones, Bronwyn; Katz, Douglas S; Lalani, Tasneem; Miller, Frank H; Small, William C; Sudakoff, Gary S; Tulchinsky, Mark; Yaghmai, Vahid; Yee, Judy

    2012-11-01

    Because virtually all patients with colonic cancer will undergo some form of surgical therapy, the role of preoperative imaging is directed at determining the presence or absence of synchronous carcinomas or adenomas and local or distant metastases. In contrast, preoperative staging for rectal carcinoma has significant therapeutic implications and will direct the use of radiation therapy, surgical excision, or chemotherapy. CT of the chest, abdomen, and pelvis is recommended for the initial evaluation for the preoperative assessment of patients with colorectal carcinoma. Although the overall accuracy of CT varies directly with the stage of colorectal carcinoma, CT can accurately assess the presence of metastatic disease. MRI using endorectal coils can accurately assess the depth of bowel wall penetration of rectal carcinomas. Phased-array coils provide additional information about lymph node involvement. Adding diffusion-weighted imaging to conventional MRI yields better diagnostic accuracy than conventional MRI alone. Transrectal ultrasound can distinguish layers within the rectal wall and provides accurate assessment of the depth of tumor penetration and perirectal spread, and PET and PET/CT have been shown to alter therapy in almost one-third of patients with advanced primary rectal cancer. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Copyright © 2012 American College of Radiology. Published by Elsevier Inc. All rights reserved.

  6. Diet, microbiota, and colorectal cancer.

    Science.gov (United States)

    Akin, Hakan; Tözün, Nurdan

    2014-01-01

    Colorectal cancer (CRC) is the third most common cancer in the world causing nearly 500,000 deaths every year. In addition to genetic background, environmental factors including diet and lifestyle are accepted as major contributors to adenoma and CRC development. Lifestyle factors include high BMI, obesity, and reduced physical activity. Growing interest and accumulating data on human microbiota implicate that host-microbe interplay has an important role in the development of metabolic, neoplastic, and inflammatory diseases. Findings from recent studies suggest that colon cancer risk is determined by the interaction between diet and gut microbiota. Dietary changes affect gut microbiota and conversely microbiota mediates the generation of dietary factors triggering colon cancer. Identification of the microbial communities associated with carcinogenesis is of crucial importance. Nowadays, with the evolvement of culture-independent molecular techniques, it has become possible to identify main bacterial species in healthy individuals, inflammatory conditions, and CRC. Some recent studies have shown the differences in intestinal microbiota between colon cancer patients and healthy individuals. Animal studies have provided a better understanding of interaction between pathobionts and symbionts in the development of colon cancer. There is no single causative organism identified in CRC; however, there is strong evidence that reduction of protective bacteria, increase in some bacteria (ie, fusobacterium members; Bacteroides/Prevotella), and age-related changes in microbiota have an impact on adenoma or cancer development. Future studies will enable us to understand procarcinogenic and anticarcinogenic mechanisms and give insights to rational manipulation of the microbiota with prebiotics, probiotics, or dietary modifications.

  7. Assessment of clinically related outcomes and biomarker analysis for translational integration in colorectal cancer (ACROBATICC): study protocol for a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastasis.

    Science.gov (United States)

    Søreide, Kjetil; Watson, Martin M; Lea, Dordi; Nordgård, Oddmund; Søreide, Jon Arne; Hagland, Hanne R

    2016-06-29

    More accurate predictive and prognostic biomarkers for patients with colorectal cancer (CRC) primaries or colorectal liver metastasis (CLM) are needed. Outside clinical trials, the translational integration of emerging pathways and novel techniques should facilitate exploration of biomarkers for improved staging and prognosis. An observational study exploring predictive and prognostic biomarkers in a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastases. Long-term outcomes will be cancer-specific survival, recurrence-free survival and overall survival at 5 years from diagnosis. Beyond routine clinicopathological and anthropometric characteristics and laboratory and biochemistry results, the project allows for additional blood samples and fresh-frozen tumour and normal tissue for investigation of circulating tumour cells (CTCs) and novel biomarkers (e.g. immune cells, microRNAs etc.). Tumour specimens will be investigated by immunohistochemistry in full slides. Extracted DNA/RNA will be analysed for genomic markers using specific PCR techniques and next-generation sequencing (NGS) panels. Flow cytometry will be used to characterise biomarkers in blood. Collaboration is open and welcomed, with particular interest in mutual opportunities for validation studies. The project is ongoing and recruiting at an expected rate of 120-150 patients per year, since January 2013. A project on circulating tumour cells (CTCs) has commenced, with analysis being prepared. Investigating molecular classes beyond the TNM staging is under way, including characteristics of microsatellite instability (MSI) and elevated microsatellite alterations in selected tetranucleotides (EMAST). Hot spot panels for known mutations in CRC are being investigated using NGS. Immune-cell characteristics are being performed by IHC and flow cytometry in tumour and peripheral blood samples. The project has ethical approval (REK Helse Vest, #2012

  8. hereditary non-polyposis colorectal carcinoma (hnpcc)

    African Journals Online (AJOL)

    2011-08-08

    Aug 8, 2011 ... eight siblings had developed colorectal cancer, with incidence in three consecutive generations. This family satisfied Amsterdam criteria (I and II) for Lynch syndrome: three generations affected, six of them below age 50, with proximal colon tumours. Genetic testing showed loss of mismatched repair protein ...

  9. 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 ...

  10. 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 ...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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

  16. 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

  17. Blood transfusions and prognosis in colorectal cancer

    NARCIS (Netherlands)

    Busch, O. R.; Hop, W. C.; Hoynck van Papendrecht, M. A.; Marquet, R. L.; Jeekel, J.

    1993-01-01

    BACKGROUND: Blood transfusions may adversely affect the prognosis of patients treated surgically for cancer, although definite proof of this adverse effect has not been reported. METHODS: We carried out a randomized trial to investigate whether the prognosis in patients with colorectal cancer would

  18. 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.

  19. Tests to Detect Colorectal Cancer and Polyps

    Science.gov (United States)

    ... colorectal-cancer screening in an average-risk population. New England Journal of Medicine 2004; 351(26):2704-2714. [PubMed Abstract] Elmunzer ... cancer incidence and mortality with screening flexible sigmoidoscopy. New England Journal of Medicine 2012; 366(25):2345-2357. [PubMed Abstract] Atkin ...

  20. Loss of heterozygosity in colorectal cancer

    African Journals Online (AJOL)

    STORAGESEVER

    2009-12-29

    Dec 29, 2009 ... progression of CRC is a multistep process, which involves many dietary and environmental factors. A great number of oncogenes, ... Key words: Colorectal cancer, tumour suppressor gene, loss of heterozygosity (LOH). INTRODUCTION .... LOH, identified by comparing patterns of polymor- phisms in normal ...

  1. 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.

  2. 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 ...

  3. Molecular pathology of colorectal cancer predisposing syndromes

    NARCIS (Netherlands)

    Puijenbroek, Marjo van

    2008-01-01

    Each year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of great importance to identify individuals with an increased risk for CRC. In this thesis, we evaluate the

  4. 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

  5. Treatment of liver metastases from colorectal cancer

    NARCIS (Netherlands)

    Tol, J.; Punt, C. J. A.

    2006-01-01

    In recent years several new local as well as systemic treatment options have become available for patients with advanced colorectal cancer. A survey among Dutch hospitals revealed considerable differences in the use of diagnostic and therapeutic strategies. Radiofrequency ablation is a promising

  6. 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

  7. 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.

  8. Clinical Outcomes of Colorectal Cancer in Kenya

    African Journals Online (AJOL)

    42 January 2011 • Volume 7 • The ANNALS of AFRICAN SURGERY. Original article. Clinical Outcomes of Colorectal. Cancer in Kenya tients with sufficient information on CRC pathology, treatment and follow up were included. Patient profile, tumor sub-site, pathology details, recurrence and mor- tality data were collected.

  9. Gynecologic screening in hereditary nonpolyposis colorectal cancer

    NARCIS (Netherlands)

    Rijcken, FEM; Mourits, MJE; Kleibeuker, JH; Hollema, H; van der Zee, AGJ

    2003-01-01

    Objective. In hereditary nonpolyposis colorectal cancer (HNPCC), women with a mismatch repair (MMR) gene mutation have a cumulative lifetime risk of 25-50% for endometrial cancer and 8-12% for ovarian cancer. Therefore, female members of HNPCC families are offered an annual gynecologic and

  10. Hereditary Colorectal Cancer : Genetics and Screening

    NARCIS (Netherlands)

    Brosens, Lodewijk A A; Offerhaus, G. Johan A; Giardiello, Francis M.

    2015-01-01

    Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in men and women in the United States. About 30% of patients with CRC report a family history of CRC. However, only 5% of CRCs arise in the setting of a well-established mendelian inherited disorder.

  11. 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...

  12. [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.

  13. Does fixity affect prognosis in colorectal tumours?

    Science.gov (United States)

    Habib, N A; Peck, M A; Sawyer, C N; Blaxland, J W; Luck, R J

    1983-07-01

    In a retrospective series of 301 colorectal tumours, tumour fixity was assessed, and was found to be of prognostic significance in relation to 5-year survival. Fixity of the tumour was associated with low curative resection rate and advanced tumour state. Fixation did not correlate significantly with the site or differentiation of the tumour nor with operative mortality.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. Dietary supplement use is not associated with recurrence of colorectal adenomas: A prospective cohort study

    NARCIS (Netherlands)

    Heine-Broring, R.C.; Winkels, R.M.; Botma, A.; Wahab, PJ; Tan, A.C.I.T.; Nagengast, F.M.; Witteman, B.J.M.; Kampman, E.

    2013-01-01

    Diet and lifestyle influence colorectal adenoma recurrence. The role of dietary supplement use in colorectal adenoma recurrence remains controversial. In this prospective cohort study, we examined the association between dietary supplement use, total colorectal adenoma recurrence and advanced

  19. Concordant DNA Methylation in Synchronous Colorectal Carcinomas

    Science.gov (United States)

    Konishi, Kazuo; Shen, Lanlan; Jelinek, Jaroslav; Watanabe, Yoshiyuki; Ahmed, Saira; Kaneko, Kazuhiro; Kogo, Mari; Takano, Toshihumi; Imawari, Michio; Hamilton, Stanley R.; Issa, Jean-Pierre J.

    2012-01-01

    Epigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P < 0.05). We found significant (P < 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account. PMID:19737982

  20. 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.

  1. 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....

  2. Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-κB activation.

    Science.gov (United States)

    Wu, Xiao-Bing; Liu, Yang; Wang, Gui-Hua; Xu, Xiao; Cai, Yang; Wang, Hong-Yi; Li, Yan-Qi; Meng, Hong-Fang; Dai, Fu; Jin, Ji-De

    2016-02-19

    Mesenchymal stem cells (MSCs) exert a tumor-promoting effect in a variety of human cancers. This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer. In vitro analysis of colorectal cancer cell lines cultured in MSC conditioned media (MSC-CM) showed that MSC-CM significantly promoted the progression of the cancer cells by enhancing cell proliferation, migration and colony formation. The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis. Furthermore, MSC-CM induced high level expression of a number of pluripotency factors in the cancer cells. ELISAs revealed MSC-CM contained higher levels of IL-6 and IL-8, which are associated with the progression of cancer. Moreover, MSC-CM downregulated AMPK mRNA and protein phosphorylation, but upregulated mTOR mRNA and protein phosphorylation. The NF-κB pathway was activated after addition of MSC-CM. An in vivo model in Balb/C mice confirmed the ability of MSC-CM to promote the invasion and proliferation of colorectal cancer cells. This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.

  3. 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.

  4. 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.

  5. 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.

  6. Inositol Hexaphosphate and Inositol Inhibit Colorectal Cancer Metastasis to the Liver in BALB/c Mice.

    Science.gov (United States)

    Fu, Min; Song, Yang; Wen, Zhaoxia; Lu, Xingyi; Cui, Lianhua

    2016-05-12

    Inositol hexaphosphate (IP6) and inositol (Ins), naturally occurring carbohydrates present in most mammals and plants, inhibit the growth of numerous cancers both in vitro and in vivo. In this study, we first examined the anti-metastatic effects of IP6 and Ins using a liver metastasis model of colorectal cancer (CRC) in BALB/c mice. CT-26 cells were injected into the splenic capsule of 48 BALB/c mice. The mice were then randomly divided into four groups: IP6, Ins, IP6 + Ins and normal saline control (n = 12 per group). IP6 and/or Ins (80 mg/kg each, 0.2 mL/day) were injected into the gastrointestinal tracts of the mice on the second day after surgery. All mice were sacrificed after 20 days, and the tumor inhibition rates were determined. The results demonstrated that the tumor weights of liver metastases and the tumor inhibition rates were reduced in the experimental groups compared to the control group and that treatment with the combination of IP6 and Ins resulted in greater inhibition of tumor growth than treatment with either compound alone. These findings suggest that IP6 and Ins prevent the development and metastatic progression of colorectal cancer to the liver in mice by altering expression of the extracellular matrix proteins collagen IV, fibronectin and laminin; the adhesion factor receptor integrin-β1; the proteolytic enzyme matrix metalloproteinase 9; and the angiogenic factors vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor beta in the tumor metastasis microenvironment. In conclusion, IP6 and Ins inhibited the development and metastatic progression of colorectal cancer to the liver in BALB/c mice, and the effect of their combined application was significantly greater than the effect of either compound alone. This evidence supports further testing of the combined application of IP6 and Ins for the prevention of colorectal cancer metastasis to the liver in clinical studies.

  7. Relationship Between Dual Time Point FDG PET and Immunohistochemical Parameters in Preoperative Colorectal Cancer: Preliminary Study

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jai Hyuen; Lee, Won Ae; Park, Seok Gun; Park, Dong Kook; Namgung, Hwan [Dankook Univ. College of Medicine, Cheonan (Korea, Republic of)

    2012-03-15

    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{sup earlya}nd SUV{sup delayed,} respectively). The retention index (RI) was calculated as follows: (SUV{sup delayed-} SUV{sup early)} x 100/ SUV{sup 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 {beta} 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<0.05). Among the immunohistochemical analytic markers, GLUT 1 had the highest positive staining rate (93.6%) compared to other markers. Based on unvariable analysis, it was shown that the RI of high level GLUT 1 expression was significantly higher than low level GLUT 1 expression (p=0.01), and the RI of high level p53 expression (p=0.08). Multivariate analysis to investigate a link between RI and clinico pathologic parameters of colorectal carcinoma showed that GLUT 1, p53, and T staging were independently connected with increased RIs (p<0.05, total) using backward selection methods. There was no significant statistical relationship between SUV

  8. 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)

  9. Developing a molecular marker for metachronous colorectal cancer.

    Science.gov (United States)

    de Silva, W M

    1999-12-01

    To determine the prevalence of microsatellite instability in patients with metachronous colorectal cancer as a potential marker for identification of high risk individuals. Surgical research laboratory, Whittington Hospital, Highgate Hill, London. 37 colorectal tumours from 18 individuals with metachronous colorectal cancers were investigated at five microsatellite loci by single stranded conformational polymorphism (SSCP) analysis. A control group of 11 individuals who had developed one sporadic colorectal cancer each were also similarly analysed. Tumour microsatellite instability was defined as the appearance of new polymarase chain reaction (PCR) bands, either larger or smaller than those produced from the normal mucosa. 27 of the total of 37 metachronous cancer specimens PCR amplified successfully. Microsatellite instability was demonstrated in 59.3% (16/27) of individuals with metachronous tumours. None of the tumours in the control group showed microsatellite instability. These results suggest that individuals with colorectal cancer with replication errors are at a greater risk of developing metachronous colorectal cancer than those without replication errors.

  10. 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...

  11. Optimization of peri-operative care in colorectal surgery

    OpenAIRE

    Kornmann, V.N.N.

    2016-01-01

    Colorectal cancer is an important health issue, and colorectal surgery is increasingly being performed. During the last years, quality and safety of care, new surgical techniques and attention for peri-operative risks resulted in reduction of postoperative morbidity and mortality. Despite these improvements, complications still occur. The aim of this thesis was to gain more insight in optimization of peri-operative care in colorectal surgery. Four main subjects were discussed in the presented...

  12. Clinicopathologic and immunohistochemical profile of ovarian metastases from colorectal carcinoma

    OpenAIRE

    Kir, Gozde; Gurbuz, Ayse; Karateke, Ates; Kir, Mustafa

    2010-01-01

    Metastasis of colorectal adenocarcinoma of the ovary is not an uncommon occurrence and ovarian metastases from colorectal carcinoma frequently mimic endometrioid and mucinous primary ovarian carcinoma. The clinical and pathologic features of metastatic colorectal adenocarcinoma involving the ovary is reviewed with particular focus on the diagnostic challenge of distinguishing these secondary ovarian tumors from primary ovarian neoplasm. Immunohistochemical stains that may be useful in the dif...

  13. 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.

  14. Oestrogen receptor beta isoform expression in sporadic colorectal cancer, familial adenomatous polyposis and progressive stages of colorectal cancer

    DEFF Research Database (Denmark)

    Stevanato Filho, Paulo Roberto; Aguiar Júnior, Samuel; Begnami, Maria Dirlei

    2017-01-01

    BACKGROUND: Among the sex hormones, oestrogen may play a role in colorectal cancer, particularly in conjunction with oestrogen receptor-β (ERβ). The expression of ERβ isoform variants and their correlations with familial adenomatous polyposis (FAP) syndrome and sporadic colorectal carcinomas are ...... provide a better understanding of oestrogens and their potential preventive and therapeutic effects on sporadic colorectal cancer and cancers associated with FAP syndrome.......BACKGROUND: Among the sex hormones, oestrogen may play a role in colorectal cancer, particularly in conjunction with oestrogen receptor-β (ERβ). The expression of ERβ isoform variants and their correlations with familial adenomatous polyposis (FAP) syndrome and sporadic colorectal carcinomas...... was identified in sporadic polyps and in sporadic colorectal cancer as well as in polyps from FAP syndrome patients compared with normal tissues (p

  15. 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.

  16. Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis

    DEFF Research Database (Denmark)

    Selzer-Plon, J.; Bornholdt, J.; Friis, S.

    2009-01-01

    is inhibited by protease nexin-1 (PN-1) and the two isoforms encoded by the mRNA splice variants of hepatocyte growth factor activator inhibitor-1 (HAI-1), HAI-1A, and HAI-1B. Methods: Using quantitative RT-PCR, we have determined the mRNA levels for prostasin and PN-1 in colorectal cancer tissue (n = 116.......01) and in carcinomas (p colorectal cancer tissue as compared to healthy individuals (p colorectal cancer...... tissue (p Immunohistochemistry showed that prostasin is located mainly on the apical plasma membrane in normal colorectal tissue. A large variation was found...

  17. 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.

  18. 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.

  19. Targeted sequencing of cancer-related genes in colorectal cancer using next-generation sequencing.

    Directory of Open Access Journals (Sweden)

    Sae-Won Han

    Full Text Available Recent advance in sequencing technology has enabled comprehensive profiling of genetic alterations in cancer. We have established a targeted sequencing platform using next-generation sequencing (NGS technology for clinical use, which can provide mutation and copy number variation data. NGS was performed with paired-end library enriched with exons of 183 cancer-related genes. Normal and tumor tissue pairs of 60 colorectal adenocarcinomas were used to test feasibility. Somatic mutation and copy number alteration were analyzed. A total of 526 somatic non-synonymous sequence variations were found in 113 genes. Among these, 278 single nucleotide variations were 232 different somatic point mutations. 216 SNV were 79 known single nucleotide polymorphisms in the dbSNP. 32 indels were 28 different indel mutations. Median number of mutated gene per tumor was 4 (range 0-23. Copy number gain (>X2 fold was found in 65 genes in 40 patients, whereas copy number loss (altered genes (mutation and/or copy number alteration were APC in 35 patients (58%, TP53 in 34 (57%, and KRAS in 24 (40%. Altered gene list revealed ErbB signaling pathway as the most commonly involved pathway (25 patients, 42%. Targeted sequencing platform using NGS technology is feasible for clinical use and provides comprehensive genetic alteration data.

  20. 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...

  1. 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

  2. X-ray diagnosis of colorectal endometriosis

    International Nuclear Information System (INIS)

    Runte, F.; Majewski, A.; Reichert, B.

    1987-01-01

    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. (orig.) [de

  3. [Colorectal cancer: prevention and early detection].

    Science.gov (United States)

    Kolligs, Frank Thomas

    2015-09-01

    Colorectal cancer is one of the leading causes of cancer associated morbidity and mortality. Main risk factors include advanced age, affected family members, male sex and lifestyle factors. The development of early adenoma to invasive cancer requires 10 and more years. Therefore, prevention via colonoscopy with polypectomy and early detection of asymptomatic stages is possible. Colonoscopy is a diagnostic and therapeutic tool with the highest sensitivity for precancerous lesions and early cancers of the colon. New fecal immunological tests reveal a higher sensitivity for advanced adenoma and cancer than guaiac based hemoccult tests while maintaining a high specificity. Molecular stool and blood tests are promising new developments. However, similar to virtual colonoscopy and colon capsule endoscopy, they have so far not been established as routine instruments for prevention and early detection of colorectal cancer. © Georg Thieme Verlag KG Stuttgart · New York.

  4. 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.

  5. 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.

  6. Colorectal Cancer Stem Cells and Cell Death

    Energy Technology Data Exchange (ETDEWEB)

    Catalano, Veronica [Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, 90127 Palermo, PA (Italy); Gaggianesi, Miriam [Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, 90127 Palermo, PA (Italy); Department of Cellular and Molecular Oncology, IRCCS Fondazione Salvatore Maugeri, Via Salvatore Maugeri, 27100 Pavia, PV (Italy); Spina, Valentina; Iovino, Flora [Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, 90127 Palermo, PA (Italy); Dieli, Francesco [Departement of Biopathology and Medicine Biotechnologies, University of Palermo, Via Liborio Giuffrè 5, 90127 Palermo, PA (Italy); Stassi, Giorgio, E-mail: giorgio.stassi@unipa.it [Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, 90127 Palermo, PA (Italy); Department of Cellular and Molecular Oncology, IRCCS Fondazione Salvatore Maugeri, Via Salvatore Maugeri, 27100 Pavia, PV (Italy); Todaro, Matilde [Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, 90127 Palermo, PA (Italy)

    2011-04-11

    Nowadays it is reported that, similarly to other solid tumors, colorectal cancer is sustained by a rare subset of cancer stem–like cells (CSCs), which survive conventional anticancer treatments, thanks to efficient mechanisms allowing escape from apoptosis, triggering tumor recurrence. To improve patient outcomes, conventional anticancer therapies have to be replaced with specific approaches targeting CSCs. In this review we provide strong support that BMP4 is an innovative therapeutic approach to prevent colon cancer growth increasing differentiation markers expression and apoptosis. Recent data suggest that in colorectal CSCs, protection from apoptosis is achieved by interleukin-4 (IL-4) autocrine production through upregulation of antiapoptotic mediators, including survivin. Consequently, IL-4 neutralization could deregulate survivin expression and localization inducing chemosensitivity of the colon CSCs pool.

  7. Biomarkers for colitis-associated colorectal cancer

    Science.gov (United States)

    Chen, Ru; Lai, Lisa A; Brentnall, Teresa A; Pan, Sheng

    2016-01-01

    Patients with extensive ulcerative colitis (UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques - including cutting-edge OMICS technologies - recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer. PMID:27672285

  8. 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...... the rectal surgery to clean the rectum and facilitate the manipulation for the mechanical anastomosis is used for many surgeons. This is analysed separately...

  9. Hereditary Colorectal Cancer (CRC Program in Latvia

    Directory of Open Access Journals (Sweden)

    Irmejs Arvids

    2003-12-01

    Full Text Available Abstract Introduction The aim of the study is to evaluate the incidence and phenotype - genotype characteristics of hereditary colorectal cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by these syndromes. Materials and methods From 02/1999-09/2002 in several hospitals in Latvia cancer family histories were collected from 865 patients with CRC. In families suspected of having a history consistent with a hereditary colorectal cancer syndrome, DNA testing for MLH1, MSH2 and MSH6 genes was performed. In addition immunohistochemical (IH examination of the normal and cancer tissue from large bowel tumors for MSH2 and MSH6 protein expression was performed prior to DNA analysis. Results From the 865 CRC cases only 3 (0.35% pedigrees fulfilled the Amsterdam II criteria of Hereditary Nonpolyposis Colorectal Cancer (HNPCC and 15 cases (1.73% were suspected of HNPCC. In 69 cases (8% with a cancer family aggregation (CFA were identified. Thus far 27 IH analyses have been performed and in 3 cancers homogenous lack of MSH2 or MSH6 protein expression was found. In one of these cases a mutation in MSH6 was identified. In 18 patients suspected of HNPCC or of matching the Amsterdam II criteria, denaturing high performance liquid chromatography (DHPLC followed by DNA sequencing of any heteroduplexes of the 35 exons comprising both MLH1 and MSH2 was performed revealing 3 mutations. For all of kindreds diagnosed definitively or with a high probability of being an HNPCC family appropriate recommendations concerning prophylactic measures, surveillance and treatment were provided in written form. Conclusions Existing pedigree/clinical data suggest that in Latvia the frequency of HNPCC is around 2% of consecutive colorectal cancer patients. It is crucial that genetic counseling is an integral part of cancer family syndrome management.

  10. Television watching and risk of colorectal adenoma.

    Science.gov (United States)

    Cao, Y; Keum, N N; Chan, A T; Fuchs, C S; Wu, K; Giovannucci, E L

    2015-03-03

    Prolonged TV watching, a major sedentary behaviour, is associated with increased risk of obesity and diabetes and may involve in colorectal carcinogenesis. We conducted a cross-sectional analysis among 31 065 men with ⩾1 endoscopy in the Health Professionals Follow-up Study (1988-2008) to evaluate sitting while watching TV and its joint influence with leisure-time physical activity on risk of colorectal adenoma. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Prolonged sitting while watching TV was significantly associated with increased risk of colorectal adenoma (n=4280), and adjusting for physical activity or a potential mediator body mass index did not change the estimates. The ORs (95% CIs) across categories of TV watching (0-6, 7-13, 14-20, and 21+ h per week) were 1.00 (referent), 1.09 (1.01-1.17), 1.16 (1.06-1.27), and 1.10 (0.97-1.25) (OR per 14-h per week increment=1.11; 95% CI: 1.04-1.18; Ptrend=0.001). Compared with the least sedentary (0-6 h per week of TV) and most physically active (highest quintile) men, the most sedentary (14+ h per week) and least active (lowest quintile) men had a significant increased risk of adenoma (OR=1.25; 95% CI: 1.05-1.49), particularly for high-risk adenoma. Prolonged TV viewing is associated with modest increased risk of colorectal adenoma independent of leisure-time physical activity and minimally mediated by obesity.

  11. A transcriptome anatomy of human colorectal cancers

    International Nuclear Information System (INIS)

    Lü, Bingjian; Xu, Jing; Lai, Maode; Zhang, Hao; Chen, Jian

    2006-01-01

    Accumulating databases in human genome research have enabled integrated genome-wide study on complicated diseases such as cancers. A practical approach is to mine a global transcriptome profile of disease from public database. New concepts of these diseases might emerge by landscaping this profile. In this study, we clustered human colorectal normal mucosa (N), inflammatory bowel disease (IBD), adenoma (A) and cancer (T) related expression sequence tags (EST) into UniGenes via an in-house GetUni software package and analyzed the transcriptome overview of these libraries by GOTree Machine (GOTM). Additionally, we downloaded UniGene based cDNA libraries of colon and analyzed them by Xprofiler to cross validate the efficiency of GetUni. Semi-quantitative RT-PCR was used to validate the expression of β-catenin and. 7 novel genes in colorectal cancers. The efficiency of GetUni was successfully validated by Xprofiler and RT-PCR. Genes in library N, IBD and A were all found in library T. A total of 14,879 genes were identified with 2,355 of them having at least 2 transcripts. Differences in gene enrichment among these libraries were statistically significant in 50 signal transduction pathways and Pfam protein domains by GOTM analysis P < 0.01 Hypergeometric Test). Genes in two metabolic pathways, ribosome and glycolysis, were more enriched in the expression profiles of A and IBD than in N and T. Seven transmembrane receptor superfamily genes were typically abundant in cancers. Colorectal cancers are genetically heterogeneous. Transcription variants are common in them. Aberrations of ribosome and glycolysis pathway might be early indicators of precursor lesions in colon cancers. The electronic gene expression profile could be used to highlight the integral molecular events in colorectal cancers

  12. Crohn's disease: risk factor for colorectal cancer

    OpenAIRE

    Santos, Sandra Cristina Dias dos; Barbosa, Laura Elisabete Ribeiro

    2016-01-01

    ABSTRACT Background: Crohn's disease is an inflammatory disease that can reach any part of the gastrointestinal tract. This disease has been associated with an increased neoplastic risk, including colorectal carcinoma. Objective: The objective of this work is to describe the mechanisms present in two diseases, and that are responsible for the increased risk in Crohn's disease. Methods: A bibliographic research was conducted in PubMed database. In addition to the articles obtained with an i...

  13. DCLK1 immunoreactivity in colorectal neoplasia

    Directory of Open Access Journals (Sweden)

    Bellows CF

    2012-04-01

    Full Text Available Giuseppe Gagliardi1, Monica Goswami1, Roberto Passera2, Charles F Bellows11Department of Surgery and Pathology, Tulane University, New Orleans, LA, USA; 2Division of Nuclear Medicine Azienda Ospedaliero-Universitaria San Giovanni Battista, Turin, ItalyIntroduction: Microtubule-associated doublecortin and CaM kinase-like-1 (DCLK1 is a novel candidate marker for intestinal stem cells. The aim of our study was to assess DCLK1 immunoreactivity in colorectal carcinogenesis and its correlation with prognosis.Methods: DCLK1 immunostaining was performed in colorectal tissue from 71 patients, including 18 adenomatous polyps, 40 primary adenocarcinomas, and 14 metastatic lesions. Each case was evaluated by a combined scoring method based on the intensity of staining (score 0–3 and the percentage of tissue staining positive (score 0–3. Immunoexpression for DCLK1 was considered as positive when the combined score was 2–6 and negative with a score of 0–1.Results: Overall, 14/18 (78% of polyps, 30/40 (75% of primary adenocarcinomas, and 7/14 (50% of distant metastases were positive for DCLK1. In adenomatous polyps and primary cancer there was no association between DCLK1 staining score and tumor pathology. However, after curative colorectal cancer resection, patients whose tumor had a high (≥5 combined staining score had increased cancer-specific mortality compared to patients with low (0–4 staining score (hazard ratio 5.89; 95% confidence interval: 1.22–28.47; P = 0.027.Conclusion: We found that DCLK1 is frequently expressed in colorectal neoplasia and may be associated with poor prognosis. Further studies are necessary to validate the use of DCLK1 as a prognostic marker.Keywords: DCLK1, DCAMKL-1, gastrointestinal stem cell, cancer stem cell, adenomatous polyps, liver metastasis, immunohistochemistry

  14. Colorectal cancer among atomic bomb survivors

    International Nuclear Information System (INIS)

    Nakatsuka, Hirofumi; Ezaki, Haruo.

    1986-01-01

    Studies on autopsied and surgical cases of colorectal cancer in Hiroshima and Nagasaki atomic bomb (A-bomb) survivors have not shown a relationship to radiation. In a recent epidemiologic study made on a fixed population at the Radiation Effects Research Foundation (RERF), the risk of colon cancer was found to increase significantly with increasing radiation dose in both Hiroshima and Nagasaki, and also in both males and females. The dose effect for the cities and sexes combined was especially pronounced for cancer of the sigmoid colon. The effect of radiation was found to vary by age at the time of the bomb (ATB) and the effect was remarkable among those under age 20 ATB. The risk of rectal cancer was not found to increase significantly with radiation and the distribution of histological types for cancer of either the colon or rectum was unrelated to radiation dose. The effect of A-bomb exposure on the postoperative survival rate for colorectal cancer patients was studied. No difference by radiation dose could be demonstrated. In Japan, the incidence of colorectal cancer, and of colon cancer in particular, has been increasing. Therefore, close attention should be paid to changes occurring in A-bomb survivors. (author)

  15. Colorectal cancer among atomic bomb survivors

    International Nuclear Information System (INIS)

    Nakatsuka, H.; Ezaki, H.

    1986-01-01

    Studies on autopsied and surgical cases of colorectal cancer in Hiroshima and Nagasaki atomic bomb (A-bomb) survivors have not shown a relationship to radiation. In a recent epidemiologic study made on a fixed population at the Radiation Effects Research Foundation (RERF), the risk of colon cancer was found to increase significantly with increasing radiation dose in both Hiroshima and Nagasaki, and also in both males and females. The dose effect for the cities and sexes combined was especially pronounced for cancer of the sigmoid colon. The effect of radiation was found to vary by age at the time of the bomb (ATB) and the effect was remarkable among those under age 20 ATB. The risk of rectal cancer was not found to increase significantly with radiation and the distribution of histological types for cancer of either the colon or rectum was unrelated to radiation dose. The effect of A-bomb exposure on the postoperative survival rate for colorectal cancer patients was studied. No difference by radiation dose could be demonstrated. In Japan, the incidence of colorectal cancer, and of colon cancer in particular, has been increasing. Therefore, close attention should be paid to changes occuring in A-bomb survivors

  16. Prevention and intervention trials for colorectal cancer.

    Science.gov (United States)

    Komiya, Masami; Fujii, Gen; Takahashi, Mami; Iigo, Masaaki; Mutoh, Michihiro

    2013-07-01

    There have been a number of candidates for chemopreventive agents from synthetic drugs and natural compounds suggested to prevent colorectal cancer. However, they have shown modest efficacy in humans. The reason for this could be partly explained by the use of inappropriate models in vitro and in vivo, and the limitation of chemoprevention trials. In Japan, there are no cancer chemopreventive medicines, and few cancer chemoprevention trials to date. In contrast, an increase in the prevalence of colorectal cancer in Japan has forced us to develop more efficient chemopreventive strategies. It is now a good time to review in detail the current status and future prospects for chemoprevention of colorectal cancer with respect to the future development of chemopreventive medicines, particularly using synthetic drugs and natural compounds in Asian populations. The role and mode of action of available synthetic drugs, mainly aspirin and metformin, are reviewed. In addition, the possible impact of natural compounds with anti-inflammatory/immunosuppressive properties, such as ω3 polyunsaturated fatty acid and lactoferrin, are also reviewed.

  17. Surgery in hepatic and extrahepatic colorectal metastases.

    Science.gov (United States)

    Favero, A; Benzoni, E; Zompicchiatti, A; Rossit, L; Bresadola, F; De Anna, D; Uzzau, A

    2007-01-01

    Extrahepatic disease (EHD) has been considered a contraindication to hepatectomy. Over the last few years, some series reported interesting 5-year survival rates after resection with hepatic colorectal metastases and EHD free margins. Between August 1989 and October 2005, 116 patients underwent liver resection for colorectal metastases at Surgical Department of the University of Udine, Italy. Among these, we reviewed the data of 5 patients affected by EHD. In 3 patients there were also an anastomotic recurrence of the primary tumor, in 3 patients diaphragm was infiltrated by contiguous liver metastases. We performed in all the patients minor liver resections. We have associated the radiofrequence ablation of a lesion not surgically resectable with liver resection in one case. The surgical procedure was always considered as curative. We observed no case of operative mortality. The mean survival of the entire cohort is 23.2 months (range 4-42 months). Our study, even if based upon a limited number of patients, supports the thesis that extrahepatic disease in patients affected by colorectal cancer with hepatic metastases should not be considered as an absolute contraindication to liver resection especially for the cases in with local radical cure exeresis is achievable.

  18. Aberrant promoter methylation of beta-1,4 galactosyltransferase 1 as potential cancer-specific biomarker of colorectal tumors.

    Science.gov (United States)

    Poeta, Maria Luana; Massi, Emanuela; Parrella, Paola; Pellegrini, Pasquale; De Robertis, Mariangela; Copetti, Massimiliano; Rabitti, Carla; Perrone, Giuseppe; Muda, Andrea Onetti; Molinari, Francesca; Zanellato, Elena; Crippa, Stefano; Caputo, Damiano; Caricato, Marco; Frattini, Milo; Coppola, Roberto; Fazio, Vito Michele

    2012-12-01

    Epigenetic alterations, such as CpG islands methylation and histone modifications, are recognized key characteristics of cancer. Glycogenes are a group of genes which epigenetic status was found to be changed in several tumors. In this study, we determined promoter methylation status of the glycogene beta-1,4-galactosyltransferase 1 (B4GALT1) in colorectal cancer patients. Methylation status of B4GALT1 was assessed in 130 colorectal adenocarcinomas, 13 adenomas, and in paired normal tissue using quantitative methylation specific PCR (QMSP). B4GALT1 mRNA expression was evaluated in methylated/unmethylated tumor and normal specimens. We also investigated microsatellite stability and microsatellite instability status and KRAS/BRAF mutations. Discriminatory power of QMSP was assessed by receiving operating curve (ROC) analysis on a training set of 24 colorectal cancers and paired mucosa. The area under the ROC curve (AUC) was 0.737 (95% confidence interval [CI]:0.591-0.881, P = 0.005) with an optimal cutoff value of 2.07 yielding a 54% sensitivity (95% CI: 35.1%-72.1%) and a specificity of 91.7% (95% CI: 74.1%-97.7%). These results were confirmed in an independent validation set where B4GALT1 methylation was detected in 52/106 patients. An inverse correlation was observed between methylation and B4GALT1 mRNA expression levels (r = -0.482, P = 0.037). Significant differences in methylation levels and frequencies was demonstrated in invasive lesions as compared with normal mucosa (P = 0.0001) and in carcinoma samples as compared with adenoma (P = 0.009). B4GALT1 methylation is a frequent and specific event in colorectal cancer and correlates with downregulation of mRNA expression. These results suggest that the glycogene B4GALT1 represent a valuable candidate biomarker of invasive phenotype of colorectal cancer. Copyright © 2012 Wiley Periodicals, Inc.

  19. 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 ...

  20. 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 ...